WO2003077855A2 - N3 alkylated benzimidazole derivatives as mek inhibitors - Google Patents

N3 alkylated benzimidazole derivatives as mek inhibitors Download PDF

Info

Publication number
WO2003077855A2
WO2003077855A2 PCT/US2003/007565 US0307565W WO03077855A2 WO 2003077855 A2 WO2003077855 A2 WO 2003077855A2 US 0307565 W US0307565 W US 0307565W WO 03077855 A2 WO03077855 A2 WO 03077855A2
Authority
WO
WIPO (PCT)
Prior art keywords
heteroaryl
aryl
heterocyclyl
arylalkyl
heterocyclylalkyl
Prior art date
Application number
PCT/US2003/007565
Other languages
French (fr)
Other versions
WO2003077855A3 (en
Inventor
Eli M. Wallace
Joseph P. Lyssikatos
Brian T. Hurley
Allison L. Marlow
Original Assignee
Array Biopharma, Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Array Biopharma, Inc filed Critical Array Biopharma, Inc
Priority to CA002478534A priority Critical patent/CA2478534A1/en
Priority to UA20040907721A priority patent/UA76837C2/en
Priority to MXPA04008894A priority patent/MXPA04008894A/en
Priority to IL16399603A priority patent/IL163996A0/en
Priority to EP03716498A priority patent/EP1482944A4/en
Priority to JP2003575909A priority patent/JP2005526076A/en
Priority to AU2003220202A priority patent/AU2003220202A1/en
Priority to KR10-2004-7014206A priority patent/KR20040098013A/en
Publication of WO2003077855A2 publication Critical patent/WO2003077855A2/en
Publication of WO2003077855A3 publication Critical patent/WO2003077855A3/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08Radicals containing only hydrogen and carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to a series of alkylated (lH-Benzoimidazol-5-yl)-(4-iodo- phenyl)-amine derivatives that are useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals.
  • This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
  • MAP kinase pathways are important regulator of cell growth, proliferation and differentiation.
  • growth factors through receptor activation (i.e. PDGF or EGF and others), activate MAP kinase pathways.
  • PDGF receptor activation
  • MAP kinase pathways One of the most important and most well understood MAP kinase pathways involved in normal and uncontrolled cell growth is the Ras/ Raf kinase pathway.
  • Active GTP -bound Ras results in the activation and indirect phosphorylation of Raf kinase. Raf then phosphorylates MEK1 and 2 on two serine residues (S218 and S222 for MEK1 and S222and S226 for MEK2) (Ahn et al, Methods in Enzymology 2001, 332, 417-431).
  • ERK phosphorylation by MEK occurs on Y204 and T202 for ERK1 and Y185 and T183 for ERK2 (Ahn et al, Methods in Enzymology 2001, 332, 417-431). Phosphorylated ERK dimerizes and then translocates to the nucleus where it accumulates (Khokhlatchev et al, Cell 1998, 93, 605-615).
  • ERK is involved in several important cellular functions, including but not limited to nuclear transport, signal transduction, DNA repair, nucleosome assembly and translocation, and mRNA processing and translation (Ahn et al, Molecular Cell 2000, 6, 1343-1354). Overall, treatment of cells with growth factors leads to the activation of ERK1 and 2 which results in proliferation and, in some cases, differentiation (Lewis et al, Adv. Cancer Res. 1998, 74, 49-139). hi proliferative diseases, genetic mutations and/or overexpression of the growth factor receptors, downstream signaling proteins, or protein kinases involved in the ERK kinase pathway lead to uncontrolled cell proliferation and, eventually, tumor formation.
  • some cancers contain mutations which result in the continuous activation of this pathway due to continuous production of growth factors. Other mutations can lead to defects in the deactivation of the activated GTP-bound Ras complex, again resulting in activation of the MAP kinase pathway. Mutated, oncogenic forms of Ras are found in 50% of colon and >90% pancreatic cancers as well as many others types of cancers (Kohl et al, Science 1993, 260, 1834-1837). Recently, bRaf mutations have been identified in more than 60% of malignant melanoma (Davies, H. et al, Nature 2002, 417, 949-954).
  • MEK is a key player in this pathway as it is downstream of Ras and Raf. Additionally, it is an attractive therapeutic target because the only known substrates for MEK phosphorylation are the MAP kinases, ERK1 and 2. Inhibition of MEK has been shown to have potential therapeutic benefit in several studies.
  • small molecule MEK inhibitors have been shown to inhibit human tumor growth in nude mouse xenografts, (Sebolt-Leopold et al, Nature-Medicine 1999, 5 (7), 810-816; Trachet et al., AACR April 6-10, 2002, Poster #5426; Tecle, H. IBC 2 nd International Conference of Protein Kinases, September 9-10, 2002), block static allodynia in animals (WO 01/05390 published January 25, 2001) and inhibit growth of acute myeloid leukemia cells (Milella et al J Clin Invest 2001, 108 (6), 851-859).
  • This invention provides for alkylated (lH-Benzoimidazol-5-yl)-(4-iodo-phenyl)- amine compounds of formula I, and pharmaceutically acceptable salts and prodrugs thereof, that are useful in the treatment of hyperproliferative diseases.
  • the present invention relates to compounds of formula I that act as MEK inhibitors.
  • formulations containing compounds of formula I and methods of using the compounds to treat a patient in need thereof are described processes for preparing the inhibitory compounds of formula I.
  • R 1 , R 2 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR 3 , -C(O)R 3 ,
  • R 3 is selected from hydrogen, trifluoromethyl, and
  • R', R" and R'" independently are selected from hydrogen, lower alkyl, lower alkenyl, aryl and arylalkyl;
  • R" is selected from lower alkyl, lower alkenyl, aryl and arylalkyl; or
  • R', R", R'" or R" can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R 3 and R 4 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR ' SO 2 R "" , -SO 2 NR
  • R 4 and R 5 independently represent hydrogen or C ⁇ -C 6 alkyl
  • R 4 and R 5 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR ' S0 2 R “” , -SO 2 NR ' R “ , -C(0)R “” , -C(O)OR , -OC(O)R , -NR ' C(0)0R “ , - NR C(O)R “ , -C(O)NRR “ , -SO 2 R “” 5 - R ' R “ , -NR C(O)NR “ R '” , - NR ' C( CN NR “ R “ , -OR , aryl, heteroaryl, arylalkyl, heteroaryl
  • R 6 is selected from trifluoromethyl
  • n 0, 1, 2, 3, 4 or 5; and j is 1 or 2.
  • novel compounds encompassed by the instant invention are those described by the general formula I set forth above, and the pharmaceutically acceptable salts and prodrugs thereof.
  • R 7 is Ci-Cio alkyl, C 3 -C 7 cycloalkyl or C -C 7 cycloalkylalkyl, each of which can be optionally substituted with 1 - 3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR 4 SO 2 R 6 , -SO 2 NR 3 R 4 , -C(O)R 3 , -C(O)OR 3 , -OC(O)R 3 , -SO 2 R 3 , -NR 4 C(O)OR 6 , -NR 4 C(O)R 3 , -C(O)NR 3 R 4 , - NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(NCN)NR 3 R 4 , -OR 3 , aryl, heteroaryl
  • the present invention also provides compounds of formula I wherein R 9 is hydrogen or halogen, and R 10 is hydrogen.
  • the present invention also provides compounds of formula I wherein W is -C(O)OR 3 or -C(O)NR 4 OR 3 .
  • the present invention also provides compounds of formula IT.
  • R 7 is - Cio alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkylalkyl, each of which can be optionally substituted with 1 - 3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR 4 SO R 6 , -SO 2 NR 3 R 4 , -C(O)R 3 , -C(O)OR 3 , -OC(O)R 3 , -SO 2 R 3 , -NR 4 C(O)OR 6 , -NR 4 C(O)R 3 , -C(O)NR 3 R 4 , - NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(NCN)NR 3 R 4 , -OR 3 , aryl, heteroaryl,
  • the present invention also provides compounds of formula II wherein R 9 is hydrogen or halogen, and R 10 is hydrogen.
  • the present invention also provides compounds of formula II wherein W is -C(O)OR 3 or -C(O)NR 4 OR 3 .
  • the present invention also provides compounds of formula III:
  • R 1 , R 2 , R 7 and R 9 are as defined above for formula I
  • A is -OR 3 or - NR 4 C(O)R 3 , wherein R 3 and R 4 are as defined above for formula I.
  • R is C ⁇ - Cio alkyl, C -C 7 cycloalkyl or C 3 -C 7 cycloalkylalkyl, each of which can be optionally substituted with 1 - 3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR 4 SO 2 R 6 , -SO NR 3 R 4 , -C(O)R 3 , -C(O)OR 3 , -OC(O)R 3 , -SO 2 R 3 , -NR 4 C(O)OR 6 , -NR 4 C(O)R 3 , -C(O)NR 3 R 4 , - NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(NCN)NR 3 R 4 , -OR 3 , aryl, heteroaryl
  • the present invention also provides compounds of formula III wherein R 9 is hydrogen or halogen.
  • the present invention also provides compounds of formula III wherein R 3 is hydrogen or lower alkyl when A is -OR 3 ; and R 4 is hydrogen when A is -NR 4 C(O)R 3 .
  • the present invention also provides compounds of formula Ilia:
  • R 1 , R 2 , R 7 and R 9 are as defined above for formula I
  • A is -OR 3 or -NR 4 C(O)R 3 , wherein R 3 and R 4 are as defined above for formula I.
  • R 7 is Ci- Cio alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkylalkyl, each of which can be optionally substituted with 1 - 3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR 4 SO 2 R 6 , -SO NR 3 R 4 , -C(O)R 3 , -C(O)OR 3 , -OC(O)R 3 , -SO 2 R 3 , -NR 4 C(O)OR 6 , -NR 4 C(O)R 3 , -C(O)NR 3 R 4 , - NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(NCN)NR 3 R 4 , -OR 3 , aryl, heteroary
  • the present invention also provides compounds of formula Ilia wherein R 9 is hydrogen or halogen.
  • the present invention also provides compounds of formula Ilia wherein R 3 is hydrogen or lower alkyl when A is -OR 3 ; and R 4 is hydrogen when A is -NR 4 C(O)R 3 .
  • Ci-Cio alkyl straight or branched chain alkyl groups having 1-10 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, heptyl, octyl, and the like.
  • Preferred alkyl radicals are C ⁇ _ 6 alkyl. More preferred alkyl radicals are C ⁇ _ 3 alkyl.
  • C 2 -C ⁇ o alkenyl means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and at least one double bond and includes ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the like. More preferred are lower alkenyl having 3-5 carbon atoms.
  • C 2 -C ⁇ o alkynyl means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like. More preferred are alkynyl having 3-5 carbon atoms.
  • halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
  • aryl is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl, and hydroxy.
  • heteroaryl is meant one or more aromatic ring systems of 5-, 6-, or 7- membered rings which includes fused ring systems (at least one of which is aromatic) of 5-10 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur.
  • heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,
  • Heteroaryl groups are optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.
  • the term "carbocycle”, “carbocyclyl”, “cycloalkyl” or “C 3 -C ⁇ o cycloalkyl” refers to saturated carbocyclic radicals having three to ten carbon atoms.
  • the cycloalkyl can be monocyclic, or a polycyclic fused system, and can be fused to an aromatic ring. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the cycloalkyl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • such cycloalkyl groups may be optionally substituted with, for example, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C ⁇ -C 6 )alkylamino, di(Cr C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 haloalkyl, C ⁇ -C 6 haloalkoxy, amino(C ⁇ -C 6 )alkyl, mono(C ⁇ -C 6 )alkylamino(C ⁇ -C 6 )alkyl or di(C ⁇ -C 6 )alkylamino(C ⁇ - C 6 )alkyl.
  • heterocycle or “heterocyclyl” is meant one or more carbocyclic ring systems of 5-, 6-, or 7-membered rings which includes fused ring systems of 4-10 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur, and with the proviso that the ring of the group does not contain two adjacent O or S atoms.
  • a fused system can be a heterocycle fused to an aromatic group.
  • Preferred heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3- pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,
  • Spiro moieties are also included within the scope of this definition.
  • the foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible.
  • a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
  • the heterocycle groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • heterocycle groups may be optionally substituted with, for example, C ⁇ -C 6 alkyl, C ⁇ -C alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C ⁇ -C 6 )alkylamino, di(C ⁇ -C 6 )alkylamino, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 haloalkyl, C ⁇ -C 6 haloalkoxy, amino(C ⁇ -C 6 )alkyl, mono(C ⁇ -C 6 )alkylamino(C ⁇ -C 6 )alkyl or di(C ⁇ -C 6 )alkylamino(C ⁇ -C 6 )alkyl.
  • arylalkyl means an alkyl moiety (as defined above) substituted with one or more aryl moiety (also as defined above). More preferred arylalkyl radicals are aryl-C ⁇ - 3 -alkyls. Examples include benzyl, phenylethyl, and the like.
  • heteroarylalkyl means an alkyl moiety (as defined above) substituted with a heteroaryl moiety (also as defined above). More preferred heteroarylalkyl radicals are 5- or 6-membered heteroaryl-C ⁇ - 3 -alkyls. Examples include, oxazolylmethyl, pyridylethyl and the like.
  • heterocyclylalkyl means an alkyl moiety (as defined above) substituted with a heterocyclyl moiety (also defined above). More preferred heterocyclylalkyl radicals are 5- or 6-membered heterocyclyl-C ⁇ - 3 -alkyls. Examples include tetrahydropyranylmethyl.
  • cycloalkylalkyl means an alkyl moiety (as defined above) substituted with a cycloalkyl moiety (also defined above). More preferred heterocyclyl radicals are 5- or 6-membered cycloalkyl-C ⁇ - 3 -alkyls. Examples include cyclopropylmethyl.
  • acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of the present invention are those that form non- toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate,
  • a salt may be formed by treatment of a compound of The present invention with a basic compound, particularly an inorganic base.
  • Preferred inorganic salts are those formed with alkali and alkaline earth metals such as lithium, sodium, potassium, barium and calcium.
  • Preferred organic base salts include, for example, ammonium, dibenzylatnmonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzyl-ethylenediamine, and the like salts.
  • salts of acidic moieties may include, for example, those salts formed with procaine, quinine and N-methylglusoamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine.
  • An especially preferred salt is a sodium or potassium salt of a compound of The present invention.
  • a salt is formed by the treatment of a compound of The present invention with an acidic compound, particularly an inorganic acid.
  • Preferred inorganic salts of this type may include, for example, the hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric or the like salts.
  • Preferred organic salts of this type may include, for example, salts formed with formic, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, D-camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, paratoluenesulfonic, sorbic, puric, benzoic, cinnamic and the like organic acids.
  • An especially preferred salt of this type is a hydrochloride or sulfate salt of a compound of The present invention.
  • R 4 and R 5 may vary with each iteration of m or t above 1.
  • R 4 and R 5 may equal -CH 2 CH 2 - or - CH(CH )C(CH 2 CH )(CH 2 CH 2 CH )- or any number of similar moieties falling within the scope of the definitions of R 4 and R 5 .
  • Certain compounds of the present invention may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of the present invention, the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds of the present invention may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
  • the subject invention also includes isotopically-labeled compounds, which are identical to those recited in the present invention, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • Isotopically labeled compound of the present invention and prodrugs thereof can generally be prepared by carrying out procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • This invention also encompasses pharmaceutical compositions containing and methods of treating proliferative disorders, or abnormal cell growth, by administering prodrugs of compounds of the the present invention.
  • Compounds of the present invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • radical arylalkyl is attached to the structure in question by the alkyl group.
  • the invention also relates to a pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier.
  • said pharmaceutical composition is for the treatment of cancer such as brain, lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, oesohageal, testicular, gynecological or thyroid cancer.
  • said pharmaceutical composition is for the treatment of a non- cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g.,benign prostatic hypertrophy (BPH)).
  • a non- cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g.,benign prostatic hypertrophy (BPH)).
  • the invention also relates to a pharmaceutical composition for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes- induced renal disease) or pain in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier.
  • the invention also relates to a pharmaceutical composition for the prevention of blastocyte implantation in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier.
  • the invention also relates to a pharmaceutical composition for treating a disease related to vasculogenesis or angiogenesis in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier.
  • said pharmaceutical composition is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
  • a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, excema, and scleroderma
  • diabetes diabetic retinopathy, retinopathy of prematurity
  • age-related macular degeneration hemangioma,
  • the invention also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • said method relates to the treatment of cancer such as brain, lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, oesohageal, testicular, gynecological or thyroid cancer, h another embodiment, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g.,benign prostatic hypertrophy (BPH)).
  • cancer such as brain, lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, oesohageal, testicular, gynecological or thyroid cancer
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., ps
  • the invention also relates to a method for the treatment of a hype ⁇ roliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti- metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, anti- hormones, angiogenesis inhibitors, and anti-androgens.
  • an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti- metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, anti- hormones, angiogenesis inhibitors, and anti-androgens.
  • the invention also relates to a method of treating pancreatitis or kidney disease or pain in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • the invention also relates to a method of preventing blastocyte implantation in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • the invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, hi one embodiment, said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
  • a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid
  • Patients that can be treated with compounds of the present invention, or pharmaceutically acceptable salts, prodrugs and hydrates of said compounds, according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis, restenosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands
  • This invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with an amount of a chemotherapeutic, wherein the amounts of the compound, salt, solvate, or prodrug, and of the chemotherapeutic are together effective in inhibiting abnormal cell growth.
  • chemotherapeutics are presently known in the art.
  • the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
  • This invention further relates to a method for inhibiting abnormal cell growth in a mammal or treating a hype ⁇ roliferative disorder which method comprises administering to the mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with radiation therapy, wherein the amounts of the compound, salt, solvate, or prodrug, is in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating the hype ⁇ roliferative disorder in the mammal.
  • Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.
  • the administration of the compound of the invention in this combination therapy can be determined as described herein.
  • this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention or pharmaceutically acceptable salt or solvate or prodrug thereof, which amount is effective is sensitizing abnormal cells to treatment with radiation.
  • the amount of the compound, salt, or solvate in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
  • the invention also relates to a method of and to a pharmaceutical composition of inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, a prodrug thereof, or an isotopically-labeled derivative thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents.
  • Anti-angiogenesis agents such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with a compound of the present invention and pharmaceutical compositions described herein.
  • MMP-2 matrix-metalloprotienase 2
  • MMP-9 matrix-metalloprotienase 9 inhibitors
  • COX-II cyclooxygenase II
  • Examples of useful COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib.
  • Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No.
  • PCT/IB98/01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), Great Britain Patent Application No. 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60/148,464 (filed August 12, 1999), United States Patent 5,863,949 (issued January 26, 1999), United States Patent 5,861,510 (issued January 19, 1999), and European Patent Publication 780,386 (published June 25, 1997), all of which are inco ⁇ orated herein in their entireties by reference.
  • Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1.
  • MMP-2 and/or MMP-9 are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
  • MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13 are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
  • MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, andRS 13-0830.
  • abnormal cell growth and “hype ⁇ roliferative disorder” are used interchangeably in this application.
  • abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes, for example, the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (3) any tumors that proliferate by receptor tyrosine kinases; (4) any tumors that proliferate by aberrant serine/threonine kinase activation; and (5) benign and malignant cells of other proliferative diseases in which aberrant serine/theroine kinase activation occurs.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • Representative compounds of the present invention include, but are not limited to the compounds of the examples and their pharmaceutically acceptable acid or base addition salts or prodrugs thereof.
  • Scheme 1 illustrates the synthesis of compounds of the present invention.
  • the acid is nitrated using standard conditions preferable fuming nitric acid in H 2 SO 4 .
  • the aniline is prepared by fluoride displacement with NH 4 OH at room temperature in water followed by careful acidification with concentrated mineral acid to pH near 0.
  • the ester is prepared by standard methods including by not limited to Fisher Esterification (MeOH, H 2 SO 4 ), and reaction with TMSCHN 2 in suitable organic solvents like PhMe/MeOH or THF/MeOH.
  • the dianilino derivative is prepared by heating (60 to 200 °C) the ester with an excess of the appropriate aniline neat or in an
  • step 5 organic solvent like xylenes.
  • the preferred method is stirring the ester with 10 equivalents aniline in xylenes at reflux until complete reaction.
  • step 5 the nitro arene is reduced to produce the diamine by standard reduction conditions, including by not limited to H , and Pd/C or Pd(OH) /C or Raney Nickel in organic solvent like EtOH or THF, Fe in AcOH, Zn in AcOH or Zn, NH 4 C1 (aq) in MeOH.
  • step 6 the diamine is cyclization by heating with formic acid neat or formamidine acetate in an appropriate solvent like EtOH.
  • the nitro arene can be converted directly to the benzimidazole in step 7 by heating in formic acid with Pd(OH) 2 /C or other palladium source like Pd/C.
  • the iodide is inco ⁇ orated by standard methods, including but not limited to NIS and pTsOH in organic cosolvents like THF and MeOH or benzyltrimethylammonium dichloroiodinate and ZnCl 2 in AcOH.
  • the benzimidazole is alkylated to give a near equal mixture of Nl and N3 products which are separable by standard techniques, including, for example, chromatography and trituration.
  • the alkylation is accomplished by use of an alkylating agent like an alkyl halide and base like NaH, or K 2 CO 3 in suitable organic solvent like DMF or THF at temperatures ranging from 0 to 80 °C.
  • R 7 can be further modified by various synthetic methods known in the art, as exemplified below, hi step 10, the ester is hydrolysized by standard saponification methods.
  • the acid is then converted to the desired hydroxamate in step 11 by standard coupling procedures including but not limited to EDCI, HOBt or PyBOP and the appropriate hydroxylamine in suitable organic solvents like DMF, THF or methylene chloride.
  • step 1 the terminal alkene of the N3 alkylated benzimidazole hydroxamate is dihydroxylated using a suitable oxidant like OsO 4 in suitable solvent or KMnO 4 or I 2 , AgOAc, AcOH, water.
  • a suitable oxidant like OsO 4 in suitable solvent or KMnO 4 or I 2 , AgOAc, AcOH, water.
  • the diol is then further oxidized in step 2 by NaIO 4 or Pb(OAc) 4 in suitable biphasic mixture to give the aldehyde.
  • step 3 the alkene can be directly converted to the aldehyde by standard methods including but not limited to ozone/Me 2 S, NaIO 4 /OsO 4 or KMnO 4 .
  • the amine is prepared by reductive animation using standard methods such as Na(CN)BH 3 , Na(OAc) 3 BH, NMe 4 BH(OAc) 3 with or without AcOH in a suitable solvent such as methylene chloride, acetonitrile or THF.
  • the preferable reduction animation is to treat the aldehyde with amine, Me4NBH(OAc) 3 and acetic acid in MeCN at room temperature.
  • Scheme 3 illustrates the preparation of compounds of the present invention where W is heterocyclic.
  • the methyl ester is converted to the hydrazide by stirring with hydrazine in a suitable solvent like EtOH at temperatures from 50 to 100 °C.
  • the desired heterocyclic derivative is then prepared by cyclization with the appropriate reagent.
  • the hydrazide is treated with an orthoformate like triethyl orthoformate, and an acid catalyst like pTsOH in a suitable organic solvent like EtOH at elevated temperatures (50 - 100 °C).
  • the hydrazide can be cyclized with phosgene or a phosgene equivalent like triphosgene or carbonyl diimidazole in a suitable organic solvent like toluene at temperatures ranging from 50 to 120 °C.
  • the mercapto oxadizaole 20 can be prepared by reaction with carbon disulfide, and base like KOH in suitable organic solvent like EtOH at elevated temperatures (50 - 100 °C).
  • the amino oxadiazole 21 can be made by reaction with BrCN and base like NaHCO 3 , in a suitable biphasic solvent system like dioxane and water at room temperature.
  • the substituted amino oxadiazole 22 can be prepared by first reacting the hydrazide with an appropriate isothiocyanate in a suitable organic solvent like DMF or THF at temperatures ranging from 25 to 100 °C.
  • the intermediate can be isolated or can be cyclized directly with the treatment of EDCI or other carbodiimide in suitable organic solvent like THF or DMF at temperatures ranging from room temperature to 80 °C.
  • the compounds of the present invention may have asymmetric carbon atoms.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomer mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
  • the activity of the compounds of the present invention may be determined by the following procedure. N-terminal 6 His-tagged, constitutively active MEK1 (2-393) is expressed in E. coli and protein is purified by conventional methods (Ahn et al. Science 1994, 265, 966-970). The activity of MEKl is assessed by measuring the inco ⁇ oration
  • the assay is carried out in 96-well polypropylene plate.
  • the incubation mixture (100 ⁇ L) comprises
  • Administration of the compounds of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.
  • an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • the active compound may be applied as a sole therapy or may involve one or more other anti-tumor substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosine arabinside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No.
  • mitotic inhibitors for example vinblastine
  • alkylating agents for example cis-platin, carboplatin and cyclophosphamide
  • anti-metabolites for example 5-fluorouracil, cytosine arabinside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No.
  • 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4- oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid; growth factor inhibitors; cell cycle inhibitors; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example, interferon; and anti-hormones, for example anti- estrogens such as NolvadexTM (tamoxifen) or, for example anti-androgens such as CasodexTM (4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-
  • the phannaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as citric acid
  • disintegrants such as starch, alginic acid and certain complex silicates
  • binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting pu ⁇ oses.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols.
  • active compound may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • the starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.
  • Step B 4-Amino-2,3-difluoro-5-nitro-benzoic acid
  • Ammonium hydroxide solution ( ⁇ 30% in water) (35 ml, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid (15 g, 67.8 mmol) in 30 ml water at 0 °C with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 h, the reaction mixture is cooled to 0 °C and concentrated HCI is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 ml) and extracted with diethyl ether (3 x 50 ml). The combined organic extracts are dried (MgSO 4 ) and concentrated under reduced pressure to give 14 g (95%) of pure desired product.
  • Step C 4-An ⁇ ino-2,3-difluoro-5-nitro-benzoic acid methyl ester
  • Step D 4-Amino-3-fluoro-5-nitro-2-o-tolylamino-benzoic acid methyl ester
  • the residue is dissolved in methylene chloride and filtered through silica gel in a fritted funnel, rinsing with methylene chloride. Three fractions are recovered. The first (2 liter) is nearly clean. The second (1 liter) and third (1 liter) fractions are only partially pure. The first fraction is concentrated under reduced pressure and triturated with diethyl ether to give 11.2 g (68%) of clean desired product as a bright yellow solid.
  • Step E 7-Fluoro-6-o-tolylamino-lH-benzoimidazole-5-carboxylic acid methyl ester
  • Step F 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-lH-benzoimidazole-5-carboxylic acid methyl ester
  • reaction mixture is quenched by the addition of 10% Na 2 S 2 O 4 solution.
  • the reaction mixture is diluted with water and ethyl acetate and the layers separated.
  • the aqueous layer is extracted with ethyl acetate.
  • the combined organic extracts are dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • the recovered solid is triturated with MeOH to give 1.45 g (69%) pure desired product.
  • Step G 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5- carboxylic acid methyl ester
  • Step H 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5- carboxylic acid
  • Step I 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide
  • methyl hydroxylamine hydrochloride (10 mg, 0.085 mmol) (WO 0042022) is added followed by EDCI (18 mg, 0.092 mmol). After 16 h, the reaction mixture is diluted with ethyl acetate and water and the layers separated. The organic layer is washed with saturated N ⁇ 4 C1, brine, saturated NaHCO 3 , water and brine. The organic layer is dried (MgSO 4 ) and concentrated under reduced pressure.
  • Step A 4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid methyl ester 4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester (23.48 g, 101.1 mmol) is suspended in xylenes (125 mL) and aniline (92 mL, 1011 mmol) is added. The reaction
  • Step B 7 -Fluoro-6-phenylamino-3H-benzoimidazole-5 -carboxylic acid methyl ester 4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid methyl ester (16.70 g, 54.71 mmol), formic acid (250 mL, 6.63 mol) and 20% Pd(OH) 2 /C (9.00 g, 16.91 mmol) in
  • Step C 7-Fluoro-6-(4-iodo-phenylamino)-3H-benzoimidazole-5-carboxylic acid methyl ester
  • Step E 6-(2-Chloro-4-iodo-phenylamino)- 7-fluoro-3-methyl-3H-benzoimidazole-5- carboxylic acid methyl ester
  • Step F 6-(2-Chloro-4-iodo-phenylamino)- 7-fluoro-3-methyl-3H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide
  • 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-methoxy-ethyl)-3H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (lie) is prepared from 6- (2-chloro-4-iodo-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester and l-bromo-2-methoxy-ethane and carried forward as previously described: 1H
  • 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-[4-(3-hydroxy-azetidin-l-yl)-butyl]-3H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (llf) is prepared as described above using azetidin-3-ol tosylate and potassium carbonate: MS APCI (-) m/z
  • Step A 3-(4-Chloro-butyl)-6-(2-chloro-4-iodo-phenylamino)-7-fluoro-3H- benzoimidazole-5 -carboxylic acid (2-vinyloxy-ethoxy)-amide
  • Step B 6-(2-Chloro-4-iodo-phenylamino) ⁇ 7-fluoro-3-(4-morpholin-4-yl-butyl)-3H- benzoimidazole-5 -carboxylic acid (2-vinyloxy-ethoxy)-amide 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(4-mo ⁇ holin-4-yl-butyl)-3H- benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide is prepared from 3-(4- chloro-butyl)-6-(2-chloro-4-iodo-phenylamino)-7-fluoro-3H-benzoimidazole-5- carboxylic acid (2-vinyloxy-ethoxy)-amide as described previously: MS APCI (-) m/z 656, 658 (M-, Cl pattern).
  • Step C 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(4-morpholin-4-yl-butyl)-3H- benzoimidazole-5-carboxylic acid (2-hydroxy-eihoxy)-amide 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(4-mo ⁇ holin-4-yl-butyl)-3H- benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide (24 mg, 0.036 mmols) is suspended in T ⁇ F (1 ml) and 1.0 N ⁇ C1 solution (0.18 ml, 0.182 mmols) is added.
  • reaction mixture is diluted with ethyl acetate and neutralized with saturated Na ⁇ CO 3 solution.
  • the orgamc layer is washed with brine, dried over MgSO 4 and concentrated under reduced pressure.
  • the crude reaction mixture is purified by FCC eluted with 10% MeOH:DCM to give 12 mg (52%) pure desired product (ll ) as a white solid: MS APCI (-) m/z 630, 632 (M-, Cl pattern) detected; 1H NMR (400 MHz, MeOH-
  • Step A 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H- benzoimidazole-5 -carboxylic acid methyl ester
  • Step B 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H- benzoimidazole-5 -carboxylic acid cyclopropylmethoxy-amide

Abstract

Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts and prodrugs thereof, wherein W, t, R1, R2, R7, R9, R10, R11 and R12 are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals. Also disclosed is a method of using such compounds in the treatment of hyperproliferative diseases in mammals, and pharmaceutical compositions containing such compounds.

Description

N3 Alkylated Benzimidazole Derivatives as MEK Inhibitors
BACKGROUND OF THE INVENTION Field of the Invention
This invention relates to a series of alkylated (lH-Benzoimidazol-5-yl)-(4-iodo- phenyl)-amine derivatives that are useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds. Summary of the Related Art
Cell signaling through growth factor receptors and protein kinases is an important regulator of cell growth, proliferation and differentiation. In normal cell growth, growth factors, through receptor activation (i.e. PDGF or EGF and others), activate MAP kinase pathways. One of the most important and most well understood MAP kinase pathways involved in normal and uncontrolled cell growth is the Ras/ Raf kinase pathway. Active GTP -bound Ras results in the activation and indirect phosphorylation of Raf kinase. Raf then phosphorylates MEK1 and 2 on two serine residues (S218 and S222 for MEK1 and S222and S226 for MEK2) (Ahn et al, Methods in Enzymology 2001, 332, 417-431). Activated MEK then phosphorylates its only known substrates, the MAP kinases, ERK1 and 2. ERK phosphorylation by MEK occurs on Y204 and T202 for ERK1 and Y185 and T183 for ERK2 (Ahn et al, Methods in Enzymology 2001, 332, 417-431). Phosphorylated ERK dimerizes and then translocates to the nucleus where it accumulates (Khokhlatchev et al, Cell 1998, 93, 605-615). In the nucleus, ERK is involved in several important cellular functions, including but not limited to nuclear transport, signal transduction, DNA repair, nucleosome assembly and translocation, and mRNA processing and translation (Ahn et al, Molecular Cell 2000, 6, 1343-1354). Overall, treatment of cells with growth factors leads to the activation of ERK1 and 2 which results in proliferation and, in some cases, differentiation (Lewis et al, Adv. Cancer Res. 1998, 74, 49-139). hi proliferative diseases, genetic mutations and/or overexpression of the growth factor receptors, downstream signaling proteins, or protein kinases involved in the ERK kinase pathway lead to uncontrolled cell proliferation and, eventually, tumor formation. For example, some cancers contain mutations which result in the continuous activation of this pathway due to continuous production of growth factors. Other mutations can lead to defects in the deactivation of the activated GTP-bound Ras complex, again resulting in activation of the MAP kinase pathway. Mutated, oncogenic forms of Ras are found in 50% of colon and >90% pancreatic cancers as well as many others types of cancers (Kohl et al, Science 1993, 260, 1834-1837). Recently, bRaf mutations have been identified in more than 60% of malignant melanoma (Davies, H. et al, Nature 2002, 417, 949-954). These mutations in bRaf result in a constitutively active MAP kinase cascade. Studies of primary tumor samples and cell lines have also shown constitutive or overactivation of the MAP kinase pathway in cancers of pancreas, colon, lung, ovary and kidney (Hoshino, R. et al, Oncogene 1999, 18, 813-822). Hence, there is a strong correlation between cancers and an overactive MAP kinase pathway resulting from genetic mutations.
As constitutive or overactivation of MAP kinase cascade plays a pivotal role in cell proliferation and differentiation, inhibition of this pathway is believed to be beneficial in hypeφroliferative diseases. MEK is a key player in this pathway as it is downstream of Ras and Raf. Additionally, it is an attractive therapeutic target because the only known substrates for MEK phosphorylation are the MAP kinases, ERK1 and 2. Inhibition of MEK has been shown to have potential therapeutic benefit in several studies. For example, small molecule MEK inhibitors have been shown to inhibit human tumor growth in nude mouse xenografts, (Sebolt-Leopold et al, Nature-Medicine 1999, 5 (7), 810-816; Trachet et al., AACR April 6-10, 2002, Poster #5426; Tecle, H. IBC 2nd International Conference of Protein Kinases, September 9-10, 2002), block static allodynia in animals (WO 01/05390 published January 25, 2001) and inhibit growth of acute myeloid leukemia cells (Milella et al J Clin Invest 2001, 108 (6), 851-859).
Small molecule inhibitors of MEK have been disclosed. At least thirteen patent applications have appeared in the last several years: US 5,525,625 filed January 24, 1995; WO 98/43960 published October 8, 1998; WO 99/01421 published January 14, 1999; WO 99/01426 published January 14, 1999; WO 00/41505 published July 20, 2000; WO 00/42002 published July 20, 2000; WO 00/42003 published July 20, 2000; WO 00/41994 published July 20, 2000; WO 00/42022 published July 20, 2000; WO 00/42029 published July 20, 2000; WO 00/68201 published November 16, 2000; WO 01/68619 published September 20, 2001; and WO 02/06213 published January 24, 2002.
SUMMARY OF THE INVENTION
This invention provides for alkylated (lH-Benzoimidazol-5-yl)-(4-iodo-phenyl)- amine compounds of formula I, and pharmaceutically acceptable salts and prodrugs thereof, that are useful in the treatment of hyperproliferative diseases. Specifically, the present invention relates to compounds of formula I that act as MEK inhibitors. Also provided are formulations containing compounds of formula I and methods of using the compounds to treat a patient in need thereof. In addition, there are described processes for preparing the inhibitory compounds of formula I.
Accordingly, the present invention refers to compounds of the formula I:
Figure imgf000005_0001
I and pharmaceutically accepted salts, prodrugs and solvates thereof, wherein:
R1, R2, R9 and R10 are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR3, -C(O)R3,
-C(O)OR3, NR4C(O)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR4C(O)R3,
-C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, and <
Ci-Cio alkyl, C2-Cιo alkenyl, C2-Cιo alkynyl, C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, -S(O)j(Cι-C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m- aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m- heteroaryl, -O(CR4R5)m-heterocyclyl and -NR4(CR4R5)m-heterocyclyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R3 is selected from hydrogen, trifluoromethyl, and
Ci-Cio alkyl, C2-Cιo alkenyl, C2-Cιo alkynyl, C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -N SO2R , -SO2NRR", -C(0)R", -C(O)OR , -OC(O)R , -NR'C(0)0R"", -NR'C(0)R",
-C(O)NR'R", -SR"", -S(O)R"", -SO2R , -NR'R", -NR'C(0)NR" ", - 1S[R'C(NCN)NR"R'", -OR , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R', R" and R'" independently are selected from hydrogen, lower alkyl, lower alkenyl, aryl and arylalkyl;
R"" is selected from lower alkyl, lower alkenyl, aryl and arylalkyl; or
Any two of R', R", R'" or R"" can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R3 and R4 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR'SO2R"", -SO2NR'R", -C(O)R , -C(O)OR', -OC(O)R", -NR'C(0)0R"", -
NR C(O)R", -C(O)NR'R", -SO2R"", -NR'R", -NR C(O)NR"R'", -
NR C(NCN)NR "R ", -OR , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or
R4 and R5 independently represent hydrogen or Cι-C6 alkyl; or
R4 and R5 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR'S02R"", -SO2NR'R", -C(0)R"", -C(O)OR , -OC(O)R , -NR'C(0)0R", - NR C(O)R", -C(O)NRR", -SO2R"" 5 - R'R", -NR C(O)NR"R'", - NR'C( CN NR"R ", -OR , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R6 is selected from trifluoromethyl; and
Ci-Cio alkyl, C -Cιo cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -N SO2R , -SO2NR'R", -C(O)R , -C(O)OR , -OC(O)R , -NR'C(O)OR"", -NR'C(0)R",
-C(O)NR'R", -SO2R"", -NR'R , -NR'C(O)NR"R ", -NR'C(NCN)NR"R ", - OR , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R7 is selected from hydrogen; and
Ci-Cio alkyl, C2-Cιo alkenyl, C2-Cιo alkynyl, C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO R6, -SO2NR3R4, -C(O)R3, -C(O)OR3 5 -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -SO2R6, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, - OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; W is selected from heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -
C(O)R4OR3, -C(O)(C3-Cιo cycloalkyl), -C(O)(Cι-C10 alkyl), -C(O)(aryl), -
C(O)(heteroaryl) and -C(O)(heterocyclyl), each of which is optionally substituted with 1-5 groups independently selected from -NR3R4 5 -OR3, -R2, and Ci-Cio alkyl, C2-Cιo alkenyl, and C2-Cιo alkynyl, each of which is optionally substituted with 1 or 2 groups independently selected
Figure imgf000009_0001
m is 0, 1, 2, 3, 4 or 5; and j is 1 or 2.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds encompassed by the instant invention are those described by the general formula I set forth above, and the pharmaceutically acceptable salts and prodrugs thereof.
The present invention also provides compounds of formula I in which R7 is Ci-Cio alkyl, C3-C7 cycloalkyl or C -C7 cycloalkylalkyl, each of which can be optionally substituted with 1 - 3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, - NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.
The present invention also provides compounds of formula I wherein R9 is hydrogen or halogen, and R10 is hydrogen.
The present invention also provides compounds of formula I wherein W is -C(O)OR3 or -C(O)NR4OR3.
The present invention also provides compounds of formula IT.
Figure imgf000010_0001
II wherein W, R1, R7, R9 and R10 are as defined above for formula I.
The present invention also provides compounds of formula II in which R7 is - Cio alkyl, C3-C7 cycloalkyl or C3-C7 cycloalkylalkyl, each of which can be optionally substituted with 1 - 3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, - NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.
The present invention also provides compounds of formula II wherein R9 is hydrogen or halogen, and R10 is hydrogen.
The present invention also provides compounds of formula II wherein W is -C(O)OR3 or -C(O)NR4OR3.
The present invention also provides compounds of formula III:
Figure imgf000010_0002
III wherein R1, R2, R7 and R9 are as defined above for formula I, and A is -OR3 or - NR4C(O)R3, wherein R3 and R4 are as defined above for formula I.
The present invention also provides compounds of formula III in which R is C\- Cio alkyl, C -C7 cycloalkyl or C3-C7 cycloalkylalkyl, each of which can be optionally substituted with 1 - 3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, - NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.
The present invention also provides compounds of formula III wherein R9 is hydrogen or halogen.
The present invention also provides compounds of formula III wherein R3 is hydrogen or lower alkyl when A is -OR3; and R4 is hydrogen when A is -NR4C(O)R3.
The present invention also provides compounds of formula Ilia:
Figure imgf000011_0001
IHa wherein R1, R2, R7 and R9 are as defined above for formula I, and A is -OR3 or -NR4C(O)R3, wherein R3 and R4 are as defined above for formula I.
The present invention also provides compounds of formula Ilia in which R7 is Ci- Cio alkyl, C3-C7 cycloalkyl or C3-C7 cycloalkylalkyl, each of which can be optionally substituted with 1 - 3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, - NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.
The present invention also provides compounds of formula Ilia wherein R9 is hydrogen or halogen.
The present invention also provides compounds of formula Ilia wherein R3 is hydrogen or lower alkyl when A is -OR3; and R4 is hydrogen when A is -NR4C(O)R3.
Except as expressly defined otherwise, the following definition of terms is employed throughout this specification.
By "Ci-Cio alkyl", "alkyl" and "lower alkyl" in the present invention is meant straight or branched chain alkyl groups having 1-10 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, heptyl, octyl, and the like. Preferred alkyl radicals are Cι_6 alkyl. More preferred alkyl radicals are Cι_3 alkyl.
By "C2-Cιo alkenyl", "lower alkenyl" and "alkenyl" means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and at least one double bond and includes ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the like. More preferred are lower alkenyl having 3-5 carbon atoms.
By "C2-Cιo alkynyl", "lower alkynyl" and "alkynyl" means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like. More preferred are alkynyl having 3-5 carbon atoms. By the term "halogen" in the present invention is meant fluorine, bromine, chlorine, and iodine.
By "aryl" is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl, and hydroxy.
By "heteroaryl" is meant one or more aromatic ring systems of 5-, 6-, or 7- membered rings which includes fused ring systems (at least one of which is aromatic) of 5-10 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiro moieties are also included within the scope of this definition. Heteroaryl groups are optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.
As used herein, the term "carbocycle", "carbocyclyl", "cycloalkyl" or "C3-Cιo cycloalkyl" refers to saturated carbocyclic radicals having three to ten carbon atoms. The cycloalkyl can be monocyclic, or a polycyclic fused system, and can be fused to an aromatic ring. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such cycloalkyl groups may be optionally substituted with, for example, Cι-C6 alkyl, Cι-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(Cι-C6)alkylamino, di(Cr C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, Cι-C6 haloalkyl, Cι-C6 haloalkoxy, amino(Cι-C6)alkyl, mono(Cι-C6)alkylamino(Cι-C6)alkyl or di(Cι-C6)alkylamino(Cι- C6)alkyl.
By "heterocycle" or "heterocyclyl" is meant one or more carbocyclic ring systems of 5-, 6-, or 7-membered rings which includes fused ring systems of 4-10 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur, and with the proviso that the ring of the group does not contain two adjacent O or S atoms. A fused system can be a heterocycle fused to an aromatic group. Preferred heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3- pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3 -azabicyco [3.1. OJhexanyl, 3 - azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl and quinolizinyl. Spiro moieties are also included within the scope of this definition. The foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). An example of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo (=O) moieties is 1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such heterocycle groups may be optionally substituted with, for example, Cι-C6 alkyl, Cι-C alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(Cι-C6)alkylamino, di(Cι-C6)alkylamino, C2- C6alkenyl, C2-C6alkynyl, Cι-C6 haloalkyl, Cι-C6 haloalkoxy, amino(Cι-C6)alkyl, mono(Cι-C6)alkylamino(Cι-C6)alkyl or di(Cι-C6)alkylamino(Cι-C6)alkyl.
The term "arylalkyl" means an alkyl moiety (as defined above) substituted with one or more aryl moiety (also as defined above). More preferred arylalkyl radicals are aryl-Cι-3-alkyls. Examples include benzyl, phenylethyl, and the like.
The term "heteroarylalkyl" means an alkyl moiety (as defined above) substituted with a heteroaryl moiety (also as defined above). More preferred heteroarylalkyl radicals are 5- or 6-membered heteroaryl-Cι-3-alkyls. Examples include, oxazolylmethyl, pyridylethyl and the like.
The term "heterocyclylalkyl" means an alkyl moiety (as defined above) substituted with a heterocyclyl moiety (also defined above). More preferred heterocyclylalkyl radicals are 5- or 6-membered heterocyclyl-Cι-3-alkyls. Examples include tetrahydropyranylmethyl.
The term "cycloalkylalkyl" means an alkyl moiety (as defined above) substituted with a cycloalkyl moiety (also defined above). More preferred heterocyclyl radicals are 5- or 6-membered cycloalkyl-Cι-3-alkyls. Examples include cyclopropylmethyl.
The term "Me" means methyl, "Et" means ethyl, "Bu" means butyl and "Ac" means acetyl. The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic and basic groups which may be present in the compounds of the present invention. The compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of the present invention are those that form non- toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palimitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts. Since a single compound of the present invention may include more than one acidic or basic moieties, the compounds of the present invention may include mono, di or tri-salts in a single compound.
In the case of an acidic moiety in a compound of the present invention, a salt may be formed by treatment of a compound of The present invention with a basic compound, particularly an inorganic base. Preferred inorganic salts are those formed with alkali and alkaline earth metals such as lithium, sodium, potassium, barium and calcium. Preferred organic base salts include, for example, ammonium, dibenzylatnmonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzyl-ethylenediamine, and the like salts. Other salts of acidic moieties may include, for example, those salts formed with procaine, quinine and N-methylglusoamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. An especially preferred salt is a sodium or potassium salt of a compound of The present invention.
With respect to basic moieties, a salt is formed by the treatment of a compound of The present invention with an acidic compound, particularly an inorganic acid. Preferred inorganic salts of this type may include, for example, the hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric or the like salts. Preferred organic salts of this type, may include, for example, salts formed with formic, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, D-camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, paratoluenesulfonic, sorbic, puric, benzoic, cinnamic and the like organic acids. An especially preferred salt of this type is a hydrochloride or sulfate salt of a compound of The present invention.
In the compounds of the present invention, where terms such as (CR4R5)m or (CR4R5)t are used, R4 and R5 may vary with each iteration of m or t above 1. For instance, where m or t is 2, the terms (CR4R5)m or (CR4R5)t may equal -CH2CH2- or - CH(CH )C(CH2CH )(CH2CH2CH )- or any number of similar moieties falling within the scope of the definitions of R4 and R5.
Certain compounds of the present invention may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of the present invention, the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds of the present invention may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
The subject invention also includes isotopically-labeled compounds, which are identical to those recited in the present invention, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36C1, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Futher, substitution with heavier isotopes such as deuterium, i.e., H, can 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 compound of the present invention and prodrugs thereof can generally be prepared by carrying out procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
This invention also encompasses pharmaceutical compositions containing and methods of treating proliferative disorders, or abnormal cell growth, by administering prodrugs of compounds of the the present invention. Compounds of the present invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
It is to be understood that in instances where two or more radicals are used in succession to define a substituent attached to a structure, the first named radical is considered to be terminal and the last named radical is considered to be attached to the structure in question. Thus, for example, the radical arylalkyl is attached to the structure in question by the alkyl group.
The invention also relates to a pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier. In one embodiment, said pharmaceutical composition is for the treatment of cancer such as brain, lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, oesohageal, testicular, gynecological or thyroid cancer. In another embodiment, said pharmaceutical composition is for the treatment of a non- cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g.,benign prostatic hypertrophy (BPH)).
The invention also relates to a pharmaceutical composition for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes- induced renal disease) or pain in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for the prevention of blastocyte implantation in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for treating a disease related to vasculogenesis or angiogenesis in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier. In one embodiment, said pharmaceutical composition is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
The invention also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof. In one embodiment, said method relates to the treatment of cancer such as brain, lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, oesohageal, testicular, gynecological or thyroid cancer, h another embodiment, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g.,benign prostatic hypertrophy (BPH)).
The invention also relates to a method for the treatment of a hypeφroliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti- metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, anti- hormones, angiogenesis inhibitors, and anti-androgens.
The invention also relates to a method of treating pancreatitis or kidney disease or pain in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
The invention also relates to a method of preventing blastocyte implantation in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
The invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, hi one embodiment, said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer. Patients that can be treated with compounds of the present invention, or pharmaceutically acceptable salts, prodrugs and hydrates of said compounds, according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis, restenosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), or neoplasms of the central nervous system (e.g., primary CNS lymphona, spinal axis tumors, brain stem gliomas or pituitary adenomas).
This invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with an amount of a chemotherapeutic, wherein the amounts of the compound, salt, solvate, or prodrug, and of the chemotherapeutic are together effective in inhibiting abnormal cell growth. Many chemotherapeutics are presently known in the art. In one embodiment, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
This invention further relates to a method for inhibiting abnormal cell growth in a mammal or treating a hypeφroliferative disorder which method comprises administering to the mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with radiation therapy, wherein the amounts of the compound, salt, solvate, or prodrug, is in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating the hypeφroliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein.
It is believed that the compounds of the present invention can render abnormal cells more sensitive to treatment with radiation for puφoses of killing and/or inhibiting the growth of such cells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention or pharmaceutically acceptable salt or solvate or prodrug thereof, which amount is effective is sensitizing abnormal cells to treatment with radiation. The amount of the compound, salt, or solvate in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
The invention also relates to a method of and to a pharmaceutical composition of inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, a prodrug thereof, or an isotopically-labeled derivative thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents.
Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with a compound of the present invention and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931,788 (published July 28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published June 17, 1999), PCT International Application No. PCT/IB98/01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), Great Britain Patent Application No. 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60/148,464 (filed August 12, 1999), United States Patent 5,863,949 (issued January 26, 1999), United States Patent 5,861,510 (issued January 19, 1999), and European Patent Publication 780,386 (published June 25, 1997), all of which are incoφorated herein in their entireties by reference. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, andRS 13-0830.
The terms "abnormal cell growth" and "hypeφroliferative disorder" are used interchangeably in this application.
"Abnormal cell growth", as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes, for example, the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (3) any tumors that proliferate by receptor tyrosine kinases; (4) any tumors that proliferate by aberrant serine/threonine kinase activation; and (5) benign and malignant cells of other proliferative diseases in which aberrant serine/theroine kinase activation occurs.
The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above.
Representative compounds of the present invention, which are encompassed by the present invention include, but are not limited to the compounds of the examples and their pharmaceutically acceptable acid or base addition salts or prodrugs thereof.
The examples presented below are intended to illustrate particular embodiments of the invention, and are not intended to limit the scope of the specification or the claims in any way.
An illustration of the preparation of compounds of the present invention is shown in Schemes 1-3.
Scheme 1 - N alkyl iodo
Figure imgf000028_0001
Figure imgf000028_0002
10 Scheme 2 - N amino alkyl iodo
Figure imgf000029_0001
14 15
Scheme 3 - heterocyclic - oxadiazole example
Figure imgf000030_0001
General synthetic methods which may be referred to for preparing some of the compounds of the present invention are provided in PCT published application number WO 00/42022 (published July 20, 2000). The foregoing patent application is incoφorated herein by reference in its entirety.
The examples presented below are intended to illustrate particular embodiments of the invention, and are not intended to limit the scope of the specification or the claims in any way. An illustration of the preparation of compounds of the present invention is shown in Schemes 1-3.
Scheme 1 illustrates the synthesis of compounds of the present invention. In step 1, the acid is nitrated using standard conditions preferable fuming nitric acid in H2SO4. In step 2, the aniline is prepared by fluoride displacement with NH4OH at room temperature in water followed by careful acidification with concentrated mineral acid to pH near 0. step 3, the ester is prepared by standard methods including by not limited to Fisher Esterification (MeOH, H2SO4), and reaction with TMSCHN2 in suitable organic solvents like PhMe/MeOH or THF/MeOH. In step 4, the dianilino derivative is prepared by heating (60 to 200 °C) the ester with an excess of the appropriate aniline neat or in an
1 9 organic solvent like xylenes. For example, when R = Me and R = H the preferred method is stirring the ester with 10 equivalents aniline in xylenes at reflux until complete reaction. In step 5, the nitro arene is reduced to produce the diamine by standard reduction conditions, including by not limited to H , and Pd/C or Pd(OH) /C or Raney Nickel in organic solvent like EtOH or THF, Fe in AcOH, Zn in AcOH or Zn, NH4C1 (aq) in MeOH. In step 6, the diamine is cyclization by heating with formic acid neat or formamidine acetate in an appropriate solvent like EtOH. Alternatively, when R1 or R2 does not equal halo the nitro arene can be converted directly to the benzimidazole in step 7 by heating in formic acid with Pd(OH)2/C or other palladium source like Pd/C. In step 8, the iodide is incoφorated by standard methods, including but not limited to NIS and pTsOH in organic cosolvents like THF and MeOH or benzyltrimethylammonium dichloroiodinate and ZnCl2 in AcOH. In step 9, the benzimidazole is alkylated to give a near equal mixture of Nl and N3 products which are separable by standard techniques, including, for example, chromatography and trituration. The alkylation is accomplished by use of an alkylating agent like an alkyl halide and base like NaH, or K2CO3 in suitable organic solvent like DMF or THF at temperatures ranging from 0 to 80 °C. R7 can be further modified by various synthetic methods known in the art, as exemplified below, hi step 10, the ester is hydrolysized by standard saponification methods. The acid is then converted to the desired hydroxamate in step 11 by standard coupling procedures including but not limited to EDCI, HOBt or PyBOP and the appropriate hydroxylamine in suitable organic solvents like DMF, THF or methylene chloride.
In Scheme 2, the preparation of N3 alkyl amino benzimidazole derivatives is illustrated, step 1, the terminal alkene of the N3 alkylated benzimidazole hydroxamate is dihydroxylated using a suitable oxidant like OsO4 in suitable solvent or KMnO4 or I2, AgOAc, AcOH, water. The diol is then further oxidized in step 2 by NaIO4 or Pb(OAc)4 in suitable biphasic mixture to give the aldehyde. Alternatively (step 3), the alkene can be directly converted to the aldehyde by standard methods including but not limited to ozone/Me2S, NaIO4/OsO4 or KMnO4. In step 4, the amine is prepared by reductive animation using standard methods such as Na(CN)BH3, Na(OAc)3BH, NMe4BH(OAc)3 with or without AcOH in a suitable solvent such as methylene chloride, acetonitrile or THF. The preferable reduction animation is to treat the aldehyde with amine, Me4NBH(OAc)3 and acetic acid in MeCN at room temperature.
Scheme 3 illustrates the preparation of compounds of the present invention where W is heterocyclic. In step 1, the methyl ester is converted to the hydrazide by stirring with hydrazine in a suitable solvent like EtOH at temperatures from 50 to 100 °C. The desired heterocyclic derivative is then prepared by cyclization with the appropriate reagent. For oxadiazole 18 the hydrazide is treated with an orthoformate like triethyl orthoformate, and an acid catalyst like pTsOH in a suitable organic solvent like EtOH at elevated temperatures (50 - 100 °C). For hydroxy oxadiazole 19 the hydrazide can be cyclized with phosgene or a phosgene equivalent like triphosgene or carbonyl diimidazole in a suitable organic solvent like toluene at temperatures ranging from 50 to 120 °C. The mercapto oxadizaole 20 can be prepared by reaction with carbon disulfide, and base like KOH in suitable organic solvent like EtOH at elevated temperatures (50 - 100 °C). The amino oxadiazole 21 can be made by reaction with BrCN and base like NaHCO3, in a suitable biphasic solvent system like dioxane and water at room temperature. Finally, the substituted amino oxadiazole 22 can be prepared by first reacting the hydrazide with an appropriate isothiocyanate in a suitable organic solvent like DMF or THF at temperatures ranging from 25 to 100 °C. The intermediate can be isolated or can be cyclized directly with the treatment of EDCI or other carbodiimide in suitable organic solvent like THF or DMF at temperatures ranging from room temperature to 80 °C.
The compounds of the present invention may have asymmetric carbon atoms. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
The activity of the compounds of the present invention may be determined by the following procedure. N-terminal 6 His-tagged, constitutively active MEK1 (2-393) is expressed in E. coli and protein is purified by conventional methods (Ahn et al. Science 1994, 265, 966-970). The activity of MEKl is assessed by measuring the incoφoration
of γ-33P-phosphate from γ-33P-ATP onto N-terminal His tagged ERK2, which is expressed
in E. coli and is purified by conventional methods, in the presence of MEKl. The assay is carried out in 96-well polypropylene plate. The incubation mixture (100 μL) comprises
of 25 mM Hepes, pH 7.4, 10 mM MgCl2, 5 mM β-glycerolphosphate, 100 μM Na-
orthovanadate, 5 mM DTT, 5 nM MEKl, and 1 μM ERK2. Inhibitors are suspended in DMSO, and all reactions, including controls are performed at a final concentration of 1% '
DMSO. Reactions are initiated by the addition of 10 μM ATP (with 0.5 μCi γ-33P-
ATP/well) and incubated at ambient temperature for 45 minutes. Equal volume of 25% TCA is added to stop the reaction and precipitate the proteins. Precipitated proteins are trapped onto glass fiber B filteφlates, and excess labeled ATP washed off using a Tomtec MACH III harvestor. Plates are allowed to air-dry prior to adding 30 μL/well of Packard Microscint 20, and plates are counted using a Packard TopCount. In this assay, compounds of the invention exhibited an IC50 of less than 50 micromolar. The following compounds exemplify such activity.
Compound #
11a lib lie lid lie
llf
Hg llh
Figure imgf000035_0001
Administration of the compounds of the present invention (hereinafter the "active compound(s)") can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.
The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
The active compound may be applied as a sole therapy or may involve one or more other anti-tumor substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosine arabinside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4- oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid; growth factor inhibitors; cell cycle inhibitors; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example, interferon; and anti-hormones, for example anti- estrogens such as NolvadexTM (tamoxifen) or, for example anti-androgens such as CasodexTM (4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-
(trifluoromethyl)propionanilide). Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of treatment.
The phannaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting puφoses. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Ester, Pa., 15th Edition (1975).
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
The disclosures in this application of all articles and references, including patents, are incoφorated herein by reference.
The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them.
The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.
Representative examples of methods for preparing intermediates of the invention are set forth below.
Examples Example 1
Figure imgf000038_0001
7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (11a)
Step A: 2,3 ,4-Trifluoro-5-nitro-benzoic acid
A 3 liter three neck round bottom flask is charged with 125 ml H2SO4. Fuming nitric acid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4- Trifluorobenzoic acid (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 min at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3 x 600 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 min after which time it is filtered to give 29 g (92%) of clean desired product as an off-yellow solid.
Step B: 4-Amino-2,3-difluoro-5-nitro-benzoic acid
Ammonium hydroxide solution (~30% in water) (35 ml, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid (15 g, 67.8 mmol) in 30 ml water at 0 °C with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 h, the reaction mixture is cooled to 0 °C and concentrated HCI is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 ml) and extracted with diethyl ether (3 x 50 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product.
Step C: 4-Anιino-2,3-difluoro-5-nitro-benzoic acid methyl ester
A 2 M solution of TMS diazomethane in hexanes (6.88 ml, 13.75 mmol) is added to a suspension of 4-amino-2,3-difluoro-5-nitro-benzoic acid (2.00 g, 9.17 mmol) in 25 ml of 4:1 THF:MeOH at 0 °C under nitrogen atmosphere. Upon completion of addition, reaction mixture is warmed to room temperature. After 0.5 h, excess TMS diazomethane is destroyed by the careful addition of acetic acid. The reaction is then concentrated under reduced pressure and dried in vacuo to give 1.95 g (92%) of pure desired product.
Step D: 4-Amino-3-fluoro-5-nitro-2-o-tolylamino-benzoic acid methyl ester
4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester (12.0 g, 51.7 mmol) is suspended in xylenes (60 ml) and ortbo-toluidine is added (55.2 ml, 517 mmol). The reaction mixture is heated to reflux with stirring under a nitrogen atmosphere. After 36 h, the reaction mixture is cooled to room temperature, diluted with diethyl ether and washed with 10% aqueous HCI solution. The aqueous washings are extracted with diethyl ether. The combined organic extracts are concentrated under reduced pressure. The residue is dissolved in methylene chloride and filtered through silica gel in a fritted funnel, rinsing with methylene chloride. Three fractions are recovered. The first (2 liter) is nearly clean. The second (1 liter) and third (1 liter) fractions are only partially pure. The first fraction is concentrated under reduced pressure and triturated with diethyl ether to give 11.2 g (68%) of clean desired product as a bright yellow solid.
Step E: 7-Fluoro-6-o-tolylamino-lH-benzoimidazole-5-carboxylic acid methyl ester
4-Amino-3-fluoro-5-nitro-2-o-tolylamino-benzoic acid methyl ester (1.57 g, 4.92 mmol), formic acid (25 ml, 26.5 mmol) and 20% Pd(OH)2/C (1.57 g, 2.95 mmol) in 25 ml EtOH are heating with stirring to 95 °C. After 16 h, the reaction mixture is cooled to room temperature and 0.5 g 20% Pd(OH) /C and 10 ml formic acid added. The reaction mixture is heated to 95 °C with stirring. After 16 h, the reaction mixture is cooled to room temperature and filtered through Celite rinsing with EtOH. The filtrate is concentrated under reduced pressure until the desired product precipitates. The desired product is collected by filtration. The filtrate is concentrated again until more desired product precipitates. The product is collected by filtration. Repeated EtOH concentration, product filtration several times. Recovered 1.09 g (74%) pure desired product.
Step F: 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-lH-benzoimidazole-5-carboxylic acid methyl ester
7-Fluoro-6-o-tolylamino-lH-benzoimidazole-5-carboxylic acid methyl ester (1.47 g, 4.92 mmol) is suspended in 1:1 TΗF:MeOΗ mixture (44 ml) and cooled to -78 °C under a nitrogen atmosphere. A solution of NIS (1.66 g, 7.39 mmol) in THF (2 ml) is added followed by a MeOH (2 ml) solution of TsOH-H2O (1.87 g, 9.84 mmol). After 30 min, reaction mixture is warmed to 0 °C and 1 ml methylene chloride is added. The reaction is slowly allowed to warm to room temperature with stirring over 16 h. The reaction mixture is quenched by the addition of 10% Na2S2O4 solution. The reaction mixture is diluted with water and ethyl acetate and the layers separated. The aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. The recovered solid is triturated with MeOH to give 1.45 g (69%) pure desired product.
Step G: 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5- carboxylic acid methyl ester
7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-lH-benzoimidazole-5-carboxylic acid methyl ester (100 mg, 0.235 mmol) is suspended in DMF (2.5 ml) and cooled to 0 °C under an atmosphere of nitrogen. NaΗ (95%) (6 mg, 0.238 mmol) is added. After 10
min, Mel (15 μl, 0.238 mmol) is added. After 45 min, the reaction mixture is warmed to
rt. After 1.5 h, the reaction mixture is quenched with water and diluted with ethyl acetate and brine. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. The crude product mixture is purified by FCC (10:1 methylene chloride: ethyl acetate) to give 36 mg (36%) of the desired methyl N3 product and 43 mg (43%) of methyl Nl product.
Step H: 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5- carboxylic acid
7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5- carboxylic acid methyl ester (34 mg, 0.077 mmol) is suspended in 1:1 TΗF:MeOΗ (2 ml)
and 20% NaOH (500 μl) is added. After 16 h, the reaction mixture is cooled to 0 °C and
1 M HCI solution is added dropwise until pH is 1 to 2. The reaction is diluted with ethyl acetate and water and the layers separated. The organic layer is washed with brine, dried (MgSO4) and concentrated under reduced pressure to give 33 mg (100%) of desired product as a white solid.
Step I: 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide
7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5- carboxylic acid (30 mg, 0.071 mmol) is suspended in DMF (1 ml) and ΗOBt (11 mg,
0.085 mmol) followed by triethyl amine (22 μl, 0.162 mmol) is added. Cyclopropyl
methyl hydroxylamine hydrochloride (10 mg, 0.085 mmol) (WO 0042022) is added followed by EDCI (18 mg, 0.092 mmol). After 16 h, the reaction mixture is diluted with ethyl acetate and water and the layers separated. The organic layer is washed with saturated NΗ4C1, brine, saturated NaHCO3, water and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure. The crude reaction mixture is purified by FCC eluted with 20:1 methylene chloride:MeOH to give 21 mg (61%) pure desired product (11a) as a beige solid: MS APCI (+) m/z 495 (M+l) detected; MS APCI (-) m/z 493 (M-l) detected; 1H NMR (400MHz, DMSO-d6) δ 11.62 (s, 1H), 8.38 (s, 1H),
7.69 (s, 1H), 7.57 (s, 1H), 7.43 (d, 1H), 7.25 (dd, 1H), 6.12 (dd, 1H), 3.89 (s, 3H), 3.58 (d, 2H), 2.23 (s, 3H), 1.01 (m, 1H), 0.47 (m, 2H), 0.19 (m, 2H); 19F NMR (376MHz,
DMSO-d6) δ -133.71 (s).
Example 2
Figure imgf000043_0001
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (lib)
Step A: 4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid methyl ester 4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester (23.48 g, 101.1 mmol) is suspended in xylenes (125 mL) and aniline (92 mL, 1011 mmol) is added. The reaction
mixture is stirred at 125 °C for 16 hours under N2. The reaction mixture is cooled to
room temperature and solids precipitate out of solution. The solids are collected by filtration and are washed with xylenes and then diethyl ether. Recovered 22.22 g (72.78 mmol) of yellow solid which is pure desired product. The filtrate is concentrated under reduced pressure, redissolved in methylene chloride and flushed through a plug of silica gel eluting with methylene chloride. The desired fractions are concentrated under reduced pressure to give a brown solid which is triturated with diethyl ether to give 5.47 g (17.91 mmol) of yellow solid which is pure desired product. Combined product yield is 27.69 g (90%): MS APCI (-) m/z 304 (M-l) detected.
Step B: 7 -Fluoro-6-phenylamino-3H-benzoimidazole-5 -carboxylic acid methyl ester 4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid methyl ester (16.70 g, 54.71 mmol), formic acid (250 mL, 6.63 mol) and 20% Pd(OH)2/C (9.00 g, 16.91 mmol) in
ethanol (250 L) are stirred at 40 °C for two hours under N2 and then at 95 °C for 16
hours. The reaction mixture is cooled to room temperature and filtered through Celite rinsing with ethyl acetate. The filtrate is concentrated under reduced pressure to give a yellow solid. The solid is triturated with diethyl ether to give 13.47 g (86%) of the desired product as a tan solid: MS APCI (+) m/z 286 (M+l) detected; MS APCI (-) m/z 284 (M-l) detected.
Step C: 7-Fluoro-6-(4-iodo-phenylamino)-3H-benzoimidazole-5-carboxylic acid methyl ester
7-Fluoro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester (1.47 g, 4.91 mmol) is suspended in 1:1 THF:MeOH (40 ml) and cooled to -78 °C. Solid pTsOH monohydrate (1.5 g, 7.4 mmol) is added followed 5 min later by NIS (1.2 g, 5.2 mmol). After 15 min, the reaction mixture is warmed to 0 °C and then slowly warmed to rt over 16 h. The reaction mixture is quenched by the addition of 10% NaHSO . After 30 min, the reaction mixture is poured into a separatory funnel and the layers separated. The aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried (Na2SO ) and concentrated under reduced pressure. The residue is trituated with methylene chloride to give 1.47 g (69%) pure desired product as a reddish solid: LC/MS ESI (+) m/z 412 (M+l) detected. Step D: 6-(2-Chloro-4-iodo-phenylamino)- 7-fluoro-3H-benzoiιnidazole-5-carboxylic acid methyl ester
7-Fluoro-6-(4-iodo-phenylamino)-3H-benzoimidazole-5-carboxylic acid methyl ester (1.4 g, 3.5 mmol) is dissolved in DMF (60 ml) and NCS (470 mg, 3.51 mmol) is added. The reaction mixture is stirred 144 h at rt, and then heated to 60 °C. After 40 h at 60 °C, the reaction mixture is cooled to rt and quenched with 10% NaHSO3 and diluted with diethyl ether. The layers are separated and the organic layer is washed with water, dried (Na2SO4) and concentrated under reduced pressure to give 1.24 g (80%) of desired
product as a brown solid: 1H NMR (400MHz, DMSO-d6) δ 8.50 (s, 1H), 7.97 (s, 1H), 7.78 (d, 1H), 7.42 (dd, 1H), 6.1 (bs, 1H), 3.82 (s, 3H).
Step E: 6-(2-Chloro-4-iodo-phenylamino)- 7-fluoro-3-methyl-3H-benzoimidazole-5- carboxylic acid methyl ester
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester (205 mg, 0.46 mmol) is dissolved in DMF (3 ml) and K2CO3 is added (76 mg, 0.55
mmol) followed by Mel (36 μl, 0.58 mmol). After 2 h, the reaction mixture is
concentrated under reduced pressure to near dryness. The residue is dissolved in ethyl acetate and washed with saturated NaHCO3 and brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by FCC eluted with 9:1 methylene chloride:MeCN
gives 35 mg (17%) desired product: 1H NMR (400MHz, MeOH-d-j) δ 8.38 (s, 1H), 8.17
(s, 1H), 7.67 (d, 1H), 7.39 (dd, 1H), 6.40 (dd, 1H), 3.98 (s, 3H), 3.93 (s, 3H); 19F NMR
(376MHz, MeOH-d4) δ -133.8 (s). Step F: 6-(2-Chloro-4-iodo-phenylamino)- 7-fluoro-3-methyl-3H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester is carried forward as described in Example 1 to give 6-(2-chloro-4-iodo- phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid
cyclopropylmethoxy-amide (lib): 1H NMR (400 MHz, acetone-d6) δ 8.24 (s, IH), 7.79
(s, IH), 7.68 (d, IH), 7.45 (dd, IH), 6.41 (dd, IH), 4.01 (s, 3H), 3.75 (m, 2H), 1.09 (m, IH), 0.51 (m, 2H), 0.23 (m, 2H).
Example 3
Figure imgf000046_0001
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-methoxy-ethyl)-3H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (lie)
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-methoxy-ethyl)-3H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (lie) is prepared from 6- (2-chloro-4-iodo-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester and l-bromo-2-methoxy-ethane and carried forward as previously described: 1H
NMR (400 MHz, MeOH-d4) δ 8.32 (s, IH), 7.72 (s, IH), 7.63 (m, IH), 7.33 (dd, IH),
6.27 (m, IH), 4.50 (t, 2H), 3.77 (t, 2H), 3.61 (dd, 2H), 3.37 (s, 3H), 1.06 (m, IH), 0.51
(m, 2H), 0.22 (m, 2H); 19F NMR (376 MHz, MeOH- κ ) δ -134.91 (s). Example 4
Figure imgf000047_0001
3-(4-Chloro-butyl)-6-(2-chloro-4-iodo-phenylamino)-7-fluoro-3H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide (lid)
3-(4-Chloro-butyl)-6-(2-chloro-4-iodo-phenylamino)-7-fluoro-3H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide (lid) is prepared from 6-(2-chloro-4-iodo- phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester and 1-bromo- 4-chloro-butane and carried forward as previously described: MS APCI (-) m/z 589, 591, 593 (M-, Cl pattern) detected.
Example 5
Figure imgf000047_0002
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(4-morpholin-4-yl-butyl)-3H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (lie)
3-(4-Chloro-butyl)-6-(2-chloro-4-iodo-phenylamino)-7-fluoro-3H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide (lid) (45 mg, 0.076 mmol) is dissolved in DMF (0.5 ml) in a pressure tube reactor and Nal (19 mg, 0.12 mmol) is added followed by moφholine (22 μl, 0.25 mmol). The reaction mixture is purged with nitrogen, sealed
and heated to 65 °C with stirring for 16 h. The reaction mixture is concentrated under reduced pressure and the residue diluted with ethyl acetate. The organics are washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by FCC eluted with 95:5 CH3CN:MeOH gives 36 mg (66%) desired product (lie) as a solid:
MS APCI (-) m/z 640, 642 (M-, Cl pattern) detected; 1H NMR (400 MHz, MeOH-d4) δ
8.37 (s, IH), 7.71 (s, IH), 7.63 (m, IH), 7.33 (dd, IH), 6.27 (m, IH), 4.38 (t, 2H), 3.65 (m, 6H), 2.41 (m, 6H), 1.96 (m, 2H), 1.56 (m, 2H), 1.05 (m, IH), 0.50 (m, 2H), 0.22 (m, 2H).
Example 6
Figure imgf000048_0001
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-[4-(3-hydroxy-azetidin-l-yl)-butyl]-3H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (llf)
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-[4-(3-hydroxy-azetidin-l-yl)-butyl]-3H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (llf) is prepared as described above using azetidin-3-ol tosylate and potassium carbonate: MS APCI (-) m/z
626, 628 (M-, Cl pattern) detected; 1H NMR (400 MHz, MeOH-d4) δ 8.34 (s, IH), 7.72
(s, IH), 7.63 (m, IH), 7.34 (dd, IH), 6.27 (m, IH), 4.34 (m, 3H), 3.61 (m, 3H), 3.38 (m, 2H), 2.86 (m, 2H), 2.54 (m, 2H), 1.95 (m, 2H), 1.41 (m, IH), 1.06 (m, IH), 0.51 (m, 2H), 0.22 (m, 2H); 19F NMR (376 MHz, MeOH- d^ δ -133.38 (s).
Example 7
Figure imgf000049_0001
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(4-morpholin-4-yl-butyl)-3H- benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide (llg)
Step A: 3-(4-Chloro-butyl)-6-(2-chloro-4-iodo-phenylamino)-7-fluoro-3H- benzoimidazole-5 -carboxylic acid (2-vinyloxy-ethoxy)-amide
3-(4-Chloro-butyl)-6-(2-chloro-4-iodo-phenylamino)-7-fluoro-3H-benzoimidazole-5- carboxylic acid (70 mg, 0.134 mmol) is suspended in DMF (1 ml) under nitrogen and
triethyl amine (44 μl, 0.32 mmol) is added followed by HOBT (25 mg, 0.16 mmol).
After 5 min, O-(2-vinyloxy-ethyl)-hydroxylamine (WO 0206213) (17 mg, 0.16 mmol) is added followed by EDCI (31 mg, 0.16 mmol). After 16 h, the reaction mixture is diluted with 1:1 ethyl acetate:THF. The organics are washed with saturated NaHCO3, saturated NH4C1, and brine, and dried (Na2SO4) and concentrated under reduced pressure. Purification by trituation with methylene chloride gives 80 mg (98%) desired product: MS APCI (-) m/z 605, 607, 609 (M-, Cl pattern) detected.
Step B: 6-(2-Chloro-4-iodo-phenylamino)~ 7-fluoro-3-(4-morpholin-4-yl-butyl)-3H- benzoimidazole-5 -carboxylic acid (2-vinyloxy-ethoxy)-amide 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(4-moφholin-4-yl-butyl)-3H- benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide is prepared from 3-(4- chloro-butyl)-6-(2-chloro-4-iodo-phenylamino)-7-fluoro-3H-benzoimidazole-5- carboxylic acid (2-vinyloxy-ethoxy)-amide as described previously: MS APCI (-) m/z 656, 658 (M-, Cl pattern).
Step C: 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(4-morpholin-4-yl-butyl)-3H- benzoimidazole-5-carboxylic acid (2-hydroxy-eihoxy)-amide 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(4-moφholin-4-yl-butyl)-3H- benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide (24 mg, 0.036 mmols) is suspended in TΗF (1 ml) and 1.0 N ΗC1 solution (0.18 ml, 0.182 mmols) is added. After 16 h, the reaction mixture is diluted with ethyl acetate and neutralized with saturated NaΗCO3 solution. The orgamc layer is washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude reaction mixture is purified by FCC eluted with 10% MeOH:DCM to give 12 mg (52%) pure desired product (ll ) as a white solid: MS APCI (-) m/z 630, 632 (M-, Cl pattern) detected; 1H NMR (400 MHz, MeOH-
d4) δ 8.39 (s, IH), 7.74 (s, IH), 7.63 (m, IH), 7.33 (dd, IH), 6.26 (m, IH), 4.38 (t, 2H),
3.92 (t, 2H), 3.66 (m, 6H), 2.41 (m, 6H), 1.97 (m, 2H), 1.56 (m, 2H); 19F NMR (376
MHz, MeOH- d4) δ -135.94 (s).
Example 8
Figure imgf000051_0001
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (llh)
Step A: 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H- benzoimidazole-5 -carboxylic acid methyl ester
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester (220 mg, 0.494 mmol) is dissolved in 1:1 THF:DMF (2 ml) under nitrogen and
K2CO3 (69 mg, 0.499 mmol) is added followed by methyl vinyl sulfone (51 μl, 0.592
mmol). After 16 h, the reaction mixture is concentrated under reduced pressure and the residue is dissolved in ethyl acetate. The organics are washed with saturated NaHCO3, and brine, and dried (Na2SO4) and concentrated under reduced pressure. Purification by FCC eluted with 1:1 methylene chloride:MeCN gives 122 mg (45%) desired product as an off-white solid.
Step B: 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H- benzoimidazole-5 -carboxylic acid cyclopropylmethoxy-amide
Hydroylsis and coupling as previously described gives desired product (llh): MS APCI
(-) m/z 605, 607 (M-, Cl pattern) detected; 1H NMR (400 MHz, acetone-d6) δ 10.95 (bs, IH), 8.37 (s, IH), 8.21 (bs, IH), 7.92 (s, IH), 7.70 (d, IH), 7.46 (dd, IH), 6.44 (m, IH), 4.93 (t, 2H), 3.85 (t, 2H), 3.75 (dd, 2H), 2.98 (s, 3H) 1.09 (m, IH), 0.44 (m, 2H), 0.24
(m, 2H); 19F NMR (376 MHz, acetone- dg) δ -132.31 (s).
Example 9
The following compounds are prepared similarly using the appropriate Michael acceptor and hydroxylamine.
Figure imgf000052_0001
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H- benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide (Hi)'. MS APCI (-) m/z
595, 597 (M-, Cl pattern) detected; 1H NMR (400 MHz, MeOH-d4) δ 8.39 (s, IH), 7.78
(s, IH), 7.64 (d, IH), 7.34 (dd, IH), 6.28 (m, IH), 4.87 (t, 2H), 3.93 (m, 2H), 3.79 (t, 2H),
3.67 (m, 2H) 2.98 (s, 3H); 19F NMR (376 MHz, MeOH- d4) δ -134.00 (s).
Figure imgf000052_0002
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-pyridin-2-yl-ethyl)-3H-benzoimidazole- 5-carboxylic acid cyclopropylmethoxy-amide (llj): MS APCI (+) m/z 606, 608 (M+, Cl pattern) detected; MS APCI (-) m/z 604, 606 (M-, Cl pattern) detected; 1H NMR (400
MHz, MeOH-d4) δ 8.47 (d, IH), 8.13 (s, IH), 7.65 (dt, IH), 7.62 (rn, 2H), 7.35 (dd, IH),
7.26 (dd, 2H), 7.20 (d, IH), 6.25 (dd, IH), 4.75 (t, 2H), 3.62 (d, 2H), 3.39 (t, 2H), 1.09
(m, IH), 0.51 (m, 2H), 0.25 (m, 2H); 19F NMR (376 MHz, MeOH- d4) δ -134.62 (s).
The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Claims

WHAT IS CLAIMED IS:
1. A compound of the fomiula
Figure imgf000054_0001
I and pharmaceutically accepted salts, prodrugs and solvates thereof, wherein:
R1, R2, R9 and R10 are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR , -C(O)R ,
-C(O)OR3, NR4C(O)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR4C(O)R3,
-C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, and
Ci-Cio alkyl, C2-Cιo alkenyl, C2-Cιo alkynyl, C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, -S(O)j(Cι-C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m- aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m- heteroaryl, -O(CR4R5)m-heterocyclyl and -NR4(CR4R5)m-heterocyclyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4,
-C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3,
-C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R3 is selected from hydrogen, trifluoromethyl, and
Ci-Cio alkyl, C2-Cι0 alkenyl, C2-Cιo alkynyl, C3-Cι0 cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR SO2R , -SO2NR'R", -C(O)R , -C(O)OR , -OC(O) , -NR'C(O)OR"", -NR'C(0)R",
-C(O)NR'R", -SR"", -S(O)R"", -SO2R , -NR'R", -NR'C(0)NR"R ", - NR C(NCN)NR "R ", -OR , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R', R" and R'" independently are selected from hydrogen, lower alkyl, lower alkenyl, aryl and arylalkyl; R"" is selected from lower alkyl, lower alkenyl, aryl and arylalkyl; or Any two of R', R", R'" or R"" can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R3 and R4 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR'SOZR"", -SO2NRR", -C(O)R , -C(O)OR', -OC(O)R , -NR'C(0)0R"", - NR'C(0)R", -C(O)NR'R", -SO2R"", -NR'R", -NR C(O)NR"R'", - NR'C(NCN)NR"R'", -OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R4 and R5 independently represent hydrogen or Cι-C6 alkyl; or
R4 and R5 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR'SO2R"", -SO2NR'R", -C(O)R"", -C(O)OR , -OC(O)R, -NR'C(0)0R", - NR'C(0)R", -C(O)NR'R", -SO2R"", -NR'R", -NR C(O)NR"R'", - NR'C(NCN)NR"R'", -OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R6 is selected from trifluoromethyl; and
Ci-Cio alkyl, C -Cιo cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR SO2R , -SO2NR'R", -C(O)R , -C(O)OR , -OC(O)R , -NR'C(0)0R"", -NR'C(O)R", -C(O)NR'R", -SO2R"", - R'R', -NR'C(O)NR"R'", -NR'C(NCN)NR"R'", - OR , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R7 is selected from hydrogen; and
Ci-Cio alkyl, C2-Cιo alkenyl, C2-Cιo alkynyl, C3-Cιo cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6,
-SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3,
-C(O)NR3R4, -SO2R6, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -
OR , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
W is selected from heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -
C(O)R4OR3, -C(O)(C3-Cιo cycloalkyl), -C(O)(Cι-Cιo alkyl), -C(O)(aryl), -
C(O)(heteroaryl) and -C(O)(heterocyclyl), each of which is optionally substituted with 1-5 groups independently selected from
-NR3R4, -OR3, -R2, and
Ci-Cio alkyl, C2-Cιo alkenyl, and C2-Cιo alkynyl, each of which is optionally substituted with 1 or 2 groups independently selected
Figure imgf000057_0001
m is 0, 1, 2, 3, 4 or 5; and j is 1 or 2.
2. A compound of the formula
Figure imgf000058_0001
and pharmaceutically accepted salts, prodrugs and solvates thereof, wherein:
R1, R9 and R10 are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR3, -C(O)R3,
-C(O)OR3, NR4C(O)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR4C(O)R3,
-C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, and
Ci-Cio alkyl, C2-Cι0 alkenyl, C2-C10 alkynyl, C3-Cιo cycloalkyl, C3-Cι0 cycloalkylalkyl, -S(O)j(Cι-C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m- aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m- heteroaryl, -O(CR4R5)m-heterocyclyl and -NR4(CR4R5)m-heterocyclyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R3 is selected from hydrogen, trifluoromethyl, and
Ci-Cio alkyl, C2-Cι0 alkenyl, C2-Cιo alkynyl, C -Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -N SO2R , -SO2NR'R", -C(O)R , -C(O)OR , -OC(O)R , -NR'C(0)0R"", -NR'C(0)R",
-C(O)NR'R", -SR"", -S(O)R"", -SO2R , -NR'R", -NR'C(0)NR"R"', - NR C(NCN)NR "R "', -OR , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R', R" and R'" independently are selected from hydrogen, lower alkyl, lower alkenyl, aryl and arylalkyl; R" " is selected from lower alkyl, lower alkenyl, aryl and arylalkyl; or Any two of R', R", R'" or R"" can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R3 and R4 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR'S02R"", -SO2NR'R", -C(O)R , -C(O)OR', -OC(O)R , -NR'C(O)OR"", - NR'C(0)R", -C(O)NRR", -SO2R"", -NR'R", -NR'C(O)NR"R'", - NR'C(NCN)NR"R'", -OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R4 and R5 independently represent hydrogen or Cι-C6 alkyl; or
R4 and R5 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR'S02R"", -SO2NR'R", -C(O)R , -C(O)OR , -OC(O)R , -NR'C(0)0R"", - NR'C(O)R", -C(O)NR'R", -SO2R"", - R'R", -NR'C(O)NR"R'", - NR'C(NCN)NR"R'", -OR , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; Rδ is selected from trifluoromethyl; and
C1-C10 alkyl, C -Cιo cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR SO2R "", -SO2NR'R", -C(O)R , -C(O)OR , -OC(O)R , -NR'C(0)0R"", -NR'C(0)R",
-C(O)NR'R", -SO2R'"', -NR'R , -NR'C(O)NR"R'", -NR'C(NCN)NR"R'", -OR , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R7 is selected from hydrogen; and
Ci-Cio alkyl, C2- o alkenyl, C2-Cι0 alkynyl, C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3,
-C(O)NR >3JτR>4*, -SO2R°, -NR >3'nR4'*, -NR:,C(O)NR >3JrR4't, -NR5C(NCN)NR3R4, - OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; W is selected from heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, - C(O)R4OR3, -C(O)(C3-Ci0 cycloalkyl), -C(O)(Cι-Cιo alkyl), -C(O)(aryl), - C(O)(heteroaryl) and -C(O)(heterocyclyl), each of which is optionally substituted with 1-5 groups independently selected from -NR3R4, -OR3, -R2, and
Ci-Cio alkyl, C2-Cιo alkenyl, and C2-Cιo alkynyl, each of which is optionally substituted with 1 or 2 groups independently selected from -NR3R4 and -OR3; m is 0, 1, 2, 3, 4 or 5; and j is 1 or 2.
A compound of the formula
Figure imgf000061_0001
and pharmaceutically accepted salts, prodrugs and solvates thereof, wherein: R1, R2, and R9 are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR , -C(O)R , -C(O)OR3, NR4C(O)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, and Ci-Cio alkyl, C2-Cιo alkenyl, C2-Cιo alkynyl, C3-Cιo cycloalkyl, C o cycloalkylalkyl, -S(O)j(Cι-C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m- aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m- heteroaryl, -O(CR4R5)m-heterocyclyl and -NR4(CR4R5)m-heterocyclyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R3 is selected from hydrogen, trifluoromethyl; and
Ci-Cio alkyl, C2-Cχo alkenyl, C2-Cιo alkynyl, C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR SO2R , -SO2NRR", -C(O)R , -C(O)OR , -OC(O)R , -NR'C(0)0R"", -NR'C(0)R",
-C(O)NR'R", -SR', -S(O)R"", -SO2R"", -NR'R", -NR'C(0)NR"R'", - NR'C(NCN)NR"R'", -OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R', R" and R'" independently are selected from hydrogen, lower alkyl, lower alkenyl, aryl and arylalkyl;
R"" is selected from lower alkyl, lower alkenyl, aryl and arylalkyl; or
Any two of R', R", R'" or R"" can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or
R3 and R4 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR'S02R"", -SO2NR'R", -C(O)R , -C(O)OR , -OC(O)R , -NR'C(0)0R"", - NR'C(O)R", -C(O)NR'R", -SO2R"", -NR'R", -NR'C(O)NR"R'", - NR'C(NCN)NR"R'", -OR , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or
R and R5 independently represent hydrogen or Cι-C6 alkyl, or
R4 and R5 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR'S02R"", -SO2NRR", -C(O)R , -C(O)OR , -OC(O)R , -NR'C(0)0R"", - NR'C(0)R", -C(O)NR'R", -SO2R"", -NR'R", -NR'C(O)NR"R'", - NR'C(NCN)NR"R'", -OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R is selected from trifluoromethyl; and
Ci-Cio alkyl, C3-Cιo cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR SO2R , -SO2NR'R", -C(O)R , -C(O)OR , -OC(O)R , -NR'C(0)0R"", -NR'C(0)R",
-C(O)NR'R", -SO2R"", -NR'R', -NR'C(O)NR"R'", -NR'C(NCN)NR"R'", - OR , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R7 is selected from hydrogen; and
Ci-Cio alkyl, C2-Cιo alkenyl, C2-Cιo alkynyl, C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -SO2R6, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, - OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
A is selected from -C(O)OR3 or -C(O)NR4OR3; m is 0, 1, 2,
3,
4 or 5; and j is 1 or 2.
A compound according to claim 3 having the formula
Figure imgf000065_0001
5. A compound according to claim 4 wherein
R7 is Ci-Cio alkyl, C3-C7 cycloalkyl, C3-C cycloalkylalkyl, C -C7 heterocycloalkyl or C3- C7 heterocycloalkylalkyl, each of which can be optionally substituted with 1 - 3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, - C(O)OR3, -OC(O)R3, -SO2R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, - NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R9 is hydrogen or halogen; and
R1 is lower alkyl or halogen.
6. A compound according to claim 5 wherein R9 is fluoro.
A compound according to claim 6 wherein R1 is methyl or chloro.
A compound according to claim 5 wherein A is -C(O)NR OR
9. A compound according to claim 1 wherein
R7 is Ci-Cio alkyl, C3-C cycloalkyl, C3-C cycloalkylalkyl, C3-C7 heterocycloalkyl or C3- C7 heterocycloalkylalkyl, each of which can be optionally substituted with 1 - 3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, - C(O)OR3, -OC(O)R3, -SO2R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, - NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R9 is hydrogen or halogen;
R10 is hydrogen; and
W is -C(O)OR3 or -C(O)NR4OR3.
10. A compound according to claim 9 wherein W is -C(O)NR4OR3.
11. A compound according to claim 2 wherein
R7 is Ci-Cio alkyl, C3-C cycloalkyl, C3-C7 cycloalkylalkyl, C3-C7 heterocycloalkyl or C3- C7 heterocycloalkylalkyl, each of which can be optionally substituted with 1 - 3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, - C(O)OR3, -OC(O)R3, -SO2R6, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, - NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R9 is hydrogen or halogen;
R10 is hydrogen; and
W is -C(O)OR3 or -C(O)NR4OR3.
12. A compound according to claim 11 wherein W is -C(O)NR4OR3.
13. A compound according to claim 1 which is selected from 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide; 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide; 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-methoxy-ethyl)-3H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide; 3-(4-Chloro-butyl)-6-(2-chloro-4-iodo-phenylamino)-7-fluoro-3H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide; 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(4-moφholin-4-yl-butyl)-3H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide; 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-[4-(3-hydroxy-azetidin-l-yl)-butyl]-3H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide; 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(4-moφholin-4-yl-butyl)-3H- benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide; 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide; 6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H- benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide; and
6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-3-(2-pyridin-2-yl-ethyl)-3H-benzoimidazole-
5-carboxylic acid cyclopropylmethoxy-amide.
14. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
15. A composition comprising a compound of claim 13 and a pharmaceutically acceptable carrier.
16. A method of inhibiting MEK activity in a mammal comprising administrating an effective amount of a compound of claim 1 to the mammal.
17. A method for treatment of cancer in a mammal comprising administrating an effective amount of a compound of claim 1 to the mammal.
PCT/US2003/007565 2002-03-13 2003-03-13 N3 alkylated benzimidazole derivatives as mek inhibitors WO2003077855A2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
CA002478534A CA2478534A1 (en) 2002-03-13 2003-03-13 N3 alkylated benzimidazole derivatives as mek inhibitors
UA20040907721A UA76837C2 (en) 2002-03-13 2003-03-13 N3 alkylated derivatives of benzimidazole as mek inhibitors
MXPA04008894A MXPA04008894A (en) 2002-03-13 2003-03-13 N3 alkylated benzimidazole derivatives as mek inhibitors.
IL16399603A IL163996A0 (en) 2002-03-13 2003-03-13 N3 alkylated benzimidazole derivatives as mek inhibitors
EP03716498A EP1482944A4 (en) 2002-03-13 2003-03-13 N3 alkylated benzimidazole derivatives as mek inhibitors
JP2003575909A JP2005526076A (en) 2002-03-13 2003-03-13 N3 alkylated benzimidazole derivatives as MEK inhibitors
AU2003220202A AU2003220202A1 (en) 2002-03-13 2003-03-13 N3 alkylated benzimidazole derivatives as mek inhibitors
KR10-2004-7014206A KR20040098013A (en) 2002-03-13 2003-03-13 N3 Alkylated Benzimidazole Derivatives as MEK Inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36416402P 2002-03-13 2002-03-13
US60/364,164 2002-03-13

Publications (2)

Publication Number Publication Date
WO2003077855A2 true WO2003077855A2 (en) 2003-09-25
WO2003077855A3 WO2003077855A3 (en) 2004-03-04

Family

ID=28041882

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/007565 WO2003077855A2 (en) 2002-03-13 2003-03-13 N3 alkylated benzimidazole derivatives as mek inhibitors

Country Status (18)

Country Link
US (2) US20030216460A1 (en)
EP (1) EP1482944A4 (en)
JP (1) JP2005526076A (en)
KR (1) KR20040098013A (en)
CN (1) CN1652792A (en)
AR (1) AR038972A1 (en)
AU (1) AU2003220202A1 (en)
CA (1) CA2478534A1 (en)
CO (1) CO5611145A2 (en)
DO (1) DOP2003000614A (en)
IL (1) IL163996A0 (en)
MX (1) MXPA04008894A (en)
PA (1) PA8569201A1 (en)
PL (1) PL378635A1 (en)
RU (1) RU2300528C2 (en)
TW (1) TW200406203A (en)
UA (1) UA76837C2 (en)
WO (1) WO2003077855A2 (en)

Cited By (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005009975A2 (en) 2003-07-24 2005-02-03 Warner-Lambert Company Llc Benzimidazole derivatives as mek inhibitors
WO2005028447A1 (en) * 2003-09-22 2005-03-31 S*Bio Pte Ltd Benzimidazole derivates: preparation and pharmaceutical applications
WO2006045514A1 (en) 2004-10-20 2006-05-04 Applied Research Systems Ars Holding N.V. 3-arylamino pyridine derivatives
EP1663210A1 (en) * 2003-08-29 2006-06-07 Array Biopharma, Inc. N3 alkylated benzimidazole derivatives as mek inhibitors
WO2006058752A1 (en) * 2004-12-01 2006-06-08 Laboratoires Serono S.A. [1,2,4]triazolo[4,3-a]pyridine derivatives for the treatment of hyperproliferative diseases
JP2007512362A (en) * 2003-11-19 2007-05-17 アレイ バイオファーマ、インコーポレイテッド MEK heterocyclic inhibitors and methods of use thereof
US7230099B2 (en) 2003-09-03 2007-06-12 Array Biopharma, Inc. Heterocyclic inhibitors of MEK and methods of use thereof
JP2008019277A (en) * 2002-03-13 2008-01-31 Array Biopharma Inc N3 alkylated benzimidazole as mek inhibitor
WO2008024724A1 (en) * 2006-08-21 2008-02-28 Genentech, Inc. Aza-benzothiophenyl compounds and methods of use
JP2009511490A (en) * 2005-10-07 2009-03-19 エグゼリクシス, インコーポレイテッド MEK inhibitor and method of use thereof
US7517994B2 (en) 2003-11-19 2009-04-14 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US7538120B2 (en) 2003-09-03 2009-05-26 Array Biopharma Inc. Method of treating inflammatory diseases
WO2009082687A1 (en) 2007-12-21 2009-07-02 Genentech, Inc. Azaindolizines and methods of use
WO2009085983A1 (en) * 2007-12-19 2009-07-09 Genentech, Inc. 5-anilinoimidazopyridines and methods of use
WO2010003022A1 (en) 2008-07-01 2010-01-07 Genentech, Inc. Isoindolone derivatives as mek kinase inhibitors and methods of use
WO2010051933A2 (en) 2008-11-10 2010-05-14 Bayer Schering Pharma Aktiengesellschaft Substituted sulphonamido phenoxybenzamides
US7732616B2 (en) 2003-11-19 2010-06-08 Array Biopharma Inc. Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof
WO2010068738A1 (en) 2008-12-10 2010-06-17 Dana-Farber Cancer Institute, Inc. Mek mutations conferring resistance to mek inhibitors
US7759518B2 (en) 2005-07-21 2010-07-20 Ardea Biosciences Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK
WO2011047795A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
WO2011047796A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted halophenoxybenzamide derivatives
WO2011047788A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
US7999006B2 (en) 2006-12-14 2011-08-16 Exelixis, Inc. Methods of using MEK inhibitors
US8003651B2 (en) 2006-07-06 2011-08-23 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
EP2361905A1 (en) 2005-05-18 2011-08-31 Array Biopharma Inc. Heterocyclic Inhibitors of MEK and methods of use thereof
WO2011106298A1 (en) 2010-02-25 2011-09-01 Dana-Farber Cancer Institute, Inc. Braf mutations conferring resistance to braf inhibitors
US8022057B2 (en) 2007-11-12 2011-09-20 Takeda Pharmaceutical Company Limited MAPK/ERK kinase inhibitors
US8030317B2 (en) 2006-12-20 2011-10-04 Takeda Pharmaceutical Company Limited MAPK/ERK kinase inhibitors
US8063050B2 (en) 2006-07-06 2011-11-22 Array Biopharma Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors
WO2012055953A1 (en) 2010-10-29 2012-05-03 Bayer Pharma Aktiengesellschaft Substituted phenoxypyridines
US8258152B2 (en) 2007-06-12 2012-09-04 Genentech, Inc. N-substituted azaindoles and methods of use
US8283359B2 (en) 2006-01-31 2012-10-09 Ucb Pharma S.A. Thieno-pyridine derivatives as MEK inhibitors
US8293763B2 (en) 2007-12-19 2012-10-23 Genentech, Inc. 8-anilinoimidazopyridines and their use as anti-cancer and/or anti-inflammatory agents
WO2012160130A1 (en) 2011-05-25 2012-11-29 Universite Paris Descartes Erk inhibitors for use in treating spinal muscular atrophy
US8329701B2 (en) 2006-07-06 2012-12-11 Array Biopharma Inc. Dihydrofuro pyrimidines as AKT protein kinase inhibitors
US8350037B2 (en) 2007-07-23 2013-01-08 Ucb Pharma, S.A. Thieno-pyridine derivatives as MEK inhibitors
US8377937B2 (en) 2007-07-05 2013-02-19 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8383832B2 (en) 2005-06-23 2013-02-26 Array Biopharma Inc. Process for preparing benzimidazole compounds
US8404725B2 (en) 2008-08-04 2013-03-26 Merck Patent Gmbh Phenylamino isonicotinamide compounds
US8435988B2 (en) 2010-10-06 2013-05-07 Glaxosmithkline Llc Benzimidazole derivatives as P13 kinase inhibitors
WO2013082511A1 (en) 2011-12-02 2013-06-06 Genentech, Inc. Methods for overcoming tumor resistance to vegf antagonists
US8487101B2 (en) 2008-01-21 2013-07-16 Ucb Pharma S.A. Thieno-pyridine derivatives as MEK inhibitors
WO2013107283A1 (en) 2012-01-17 2013-07-25 Tianjin Binjiang Pharma, Inc. Benzoheterocyclic compounds and use thereof
WO2013169858A1 (en) 2012-05-08 2013-11-14 The Broad Institute, Inc. Diagnostic and treatment methods in patients having or at risk of developing resistance to cancer therapy
WO2013178581A1 (en) 2012-05-31 2013-12-05 Bayer Pharma Aktiengesellschaft Biomarkers for determining effective response of treatments of hepatocellular carcinoma (hcc) patients
US8618097B2 (en) 2007-07-05 2013-12-31 Array Biopharma, Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8637491B2 (en) 2008-06-19 2014-01-28 Ucb Pharma S.A. Thieno-pyridine derivatives as MEK inhibitors
US8680114B2 (en) 2003-11-21 2014-03-25 Array Biopharma, Inc. AKT protein kinase inhibitors
US8835434B2 (en) 2008-01-09 2014-09-16 Array Biopharma, Inc. Hydroxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors
US8841462B2 (en) 2008-07-01 2014-09-23 Robert A. Heald Bicyclic heterocycles as MEK kinase inhibitors
WO2014147573A2 (en) 2013-03-21 2014-09-25 Novartis Ag Combination therapy
US8846683B2 (en) 2007-07-05 2014-09-30 Array Biopharma, Inc. Pyrimidyl cyclopentanes as Akt protein kinase inhibitors
US8853216B2 (en) 2008-01-09 2014-10-07 Array Biopharma, Inc. Hydroxylated pyrimidyl cyclopentane as AKT protein kinase inhibitor
WO2015038704A1 (en) 2013-09-11 2015-03-19 The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone Compositions for preparing cardiomyocytes
US9303040B2 (en) 2006-07-06 2016-04-05 Array Biopharma Inc. Substituted piperazines as AKT inhibitors
US9409886B2 (en) 2007-07-05 2016-08-09 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US9610289B2 (en) 2011-04-01 2017-04-04 Genentech, Inc. Combinations of AKT inhibitor compounds and erlotinib, and methods of use
US9682082B2 (en) 2011-04-01 2017-06-20 Genentech, Inc. Combinations of AKT and MEK inhibitor compounds, and methods of use
US10626092B2 (en) 2016-05-02 2020-04-21 Mei Pharma, Inc. Polymorphic forms of 3-[(2-butyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide and uses thereof
WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
US11078540B2 (en) 2010-03-09 2021-08-03 Dana-Farber Cancer Institute, Inc. Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy
US11414396B2 (en) 2012-10-12 2022-08-16 Exelixis, Inc. Process for making compounds for use in the treatment of cancer
WO2023168203A1 (en) 2022-03-04 2023-09-07 Kinnate Biopharma Inc. Inhibitors of mek kinase

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050171182A1 (en) * 2003-12-11 2005-08-04 Roger Briesewitz Methods and compositions for use in the treatment of mutant receptor tyrosine kinase driven cellular proliferative diseases
WO2007071951A1 (en) * 2005-12-21 2007-06-28 Astrazeneca Ab Tosylate salt of 6- (4-br0m0-2-chl0r0phenylamin0) -7-fluoro-n- (2-hydroxyethoxy) -3-methyl-3h-benzimi dazole- 5 - carboxamide , mek inhibitor useful in the treatment of cancer
ZA200901009B (en) * 2006-08-21 2010-05-26 Genentech Inc Aza-benzothiophenyl compounds and methods of use
ES2376771T3 (en) * 2006-08-21 2012-03-16 Genentech, Inc. Aza-benzofuranyl compounds and methods of use
CN105384754B (en) * 2014-09-02 2018-04-20 上海科州药物研发有限公司 Heterocycle compound as kinases inhibitor and its preparation method and application
WO2017033113A1 (en) 2015-08-21 2017-03-02 Acerta Pharma B.V. Therapeutic combinations of a mek inhibitor and a btk inhibitor
WO2019096112A1 (en) * 2017-11-14 2019-05-23 深圳市塔吉瑞生物医药有限公司 Substituted benzimidazole compound and composition comprising same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5502187A (en) * 1992-04-03 1996-03-26 The Upjohn Company Pharmaceutically active bicyclic-heterocyclic amines
WO2000042022A1 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company Benzoheterocycles and their use as mek inhibitors

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5525625A (en) * 1995-01-24 1996-06-11 Warner-Lambert Company 2-(2-Amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran for treating proliferative disorders
US6469009B1 (en) * 1996-04-08 2002-10-22 Ucb, S.A. Pharmaceutical compositions for the treatment of rhinitis
US6821963B2 (en) * 1997-07-01 2004-11-23 Warner-Lambert Company 4-Bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as MEK inhibitors
US6506798B1 (en) * 1997-07-01 2003-01-14 Warner-Lambert Company 4-Arylamino, 4-aryloxy, and 4-arylthio diarylamines and derivatives thereof as selective MEK inhibitors
DE69928286T2 (en) * 1999-01-13 2006-07-13 Warner-Lambert Co. Llc BENZENESULFONAMIDE DERIVATIVES AND THEIR USE AS MEK INHIBITORS
CA2377092A1 (en) * 1999-07-16 2001-01-25 Warner-Lambert Company Method for treating chronic pain using mek inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5502187A (en) * 1992-04-03 1996-03-26 The Upjohn Company Pharmaceutically active bicyclic-heterocyclic amines
WO2000042022A1 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company Benzoheterocycles and their use as mek inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1482944A2 *

Cited By (139)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008163034A (en) * 2002-03-13 2008-07-17 Array Biopharma Inc N3 alkylated benzimidazole derivative as mek inhibitor
US8513293B2 (en) 2002-03-13 2013-08-20 Array Biopharma Inc. Methods of treating a hyperproliferative disorder or inhibiting cell growth in a mammal
JP2008019277A (en) * 2002-03-13 2008-01-31 Array Biopharma Inc N3 alkylated benzimidazole as mek inhibitor
JP4896717B2 (en) * 2003-07-24 2012-03-14 ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー N-methyl-substituted benzamidazole
WO2005009975A3 (en) * 2003-07-24 2005-04-07 Warner Lambert Co Benzimidazole derivatives as mek inhibitors
WO2005009975A2 (en) 2003-07-24 2005-02-03 Warner-Lambert Company Llc Benzimidazole derivatives as mek inhibitors
JP2006528621A (en) * 2003-07-24 2006-12-21 ワーナー−ランバート カンパニー リミティド ライアビリティー カンパニー N-methyl-substituted benzamidazole
US7160915B2 (en) 2003-07-24 2007-01-09 Warner-Lambert Company, Llc N-methyl-substituted benzamidazoles
EP1663210A1 (en) * 2003-08-29 2006-06-07 Array Biopharma, Inc. N3 alkylated benzimidazole derivatives as mek inhibitors
EP1663210A4 (en) * 2003-08-29 2009-04-22 Array Biopharma Inc N3 alkylated benzimidazole derivatives as mek inhibitors
US7538120B2 (en) 2003-09-03 2009-05-26 Array Biopharma Inc. Method of treating inflammatory diseases
US7230099B2 (en) 2003-09-03 2007-06-12 Array Biopharma, Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US8551988B2 (en) 2003-09-22 2013-10-08 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US7781595B2 (en) 2003-09-22 2010-08-24 S*Bio Pte Ltd. Benzimidazole derivatives: preparation and pharmaceutical applications
WO2005028447A1 (en) * 2003-09-22 2005-03-31 S*Bio Pte Ltd Benzimidazole derivates: preparation and pharmaceutical applications
US10201527B2 (en) 2003-09-22 2019-02-12 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9024029B2 (en) 2003-09-22 2015-05-05 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US10736881B2 (en) 2003-09-22 2020-08-11 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9717713B2 (en) 2003-09-22 2017-08-01 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9402829B2 (en) 2003-09-22 2016-08-02 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US7598383B2 (en) 2003-11-19 2009-10-06 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US7772234B2 (en) 2003-11-19 2010-08-10 Array Biopharma Inc. Bicyclic inhibitors of MEK and methods of use thereof
JP4842137B2 (en) * 2003-11-19 2011-12-21 アレイ バイオファーマ、インコーポレイテッド MEK heterocyclic inhibitors and methods of use thereof
US8101611B2 (en) 2003-11-19 2012-01-24 Array Biopharma Inc. Substituted pyridazines inhibitors of MEK
US7732616B2 (en) 2003-11-19 2010-06-08 Array Biopharma Inc. Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof
US7517994B2 (en) 2003-11-19 2009-04-14 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
JP2007512362A (en) * 2003-11-19 2007-05-17 アレイ バイオファーマ、インコーポレイテッド MEK heterocyclic inhibitors and methods of use thereof
US8268852B2 (en) 2003-11-19 2012-09-18 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US7576072B2 (en) 2003-11-19 2009-08-18 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US7485643B2 (en) 2003-11-19 2009-02-03 Array Biopharma Inc. Bicyclic inhibitors of MEK and methods of use thereof
EP2251327A2 (en) 2003-11-19 2010-11-17 Array Biopharma, Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US8211920B2 (en) 2003-11-19 2012-07-03 Array Biopharma Inc. 6-oxo-1,6-dihydropyridine derivatives as inhibitors of MEK and methods of use thereof
US8431574B2 (en) 2003-11-19 2013-04-30 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US8680114B2 (en) 2003-11-21 2014-03-25 Array Biopharma, Inc. AKT protein kinase inhibitors
US8198457B2 (en) 2004-10-20 2012-06-12 Merck Serono S.A. 3-arylamino pyridine derivatives
WO2006045514A1 (en) 2004-10-20 2006-05-04 Applied Research Systems Ars Holding N.V. 3-arylamino pyridine derivatives
US7956191B2 (en) 2004-10-20 2011-06-07 Merck Serono Sa 3-arylamino pyridine derivatives
US8841459B2 (en) 2004-10-20 2014-09-23 Merck Serono Sa 3-arylamino pyridine derivatives
US8524911B2 (en) 2004-10-20 2013-09-03 Merck Serono Sa 3-arylamino pyridine derivatives
WO2006058752A1 (en) * 2004-12-01 2006-06-08 Laboratoires Serono S.A. [1,2,4]triazolo[4,3-a]pyridine derivatives for the treatment of hyperproliferative diseases
US8299076B2 (en) 2005-05-18 2012-10-30 Array Biopharma Inc. Crystalline forms of 2-(2-flouro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide
EP2361905A1 (en) 2005-05-18 2011-08-31 Array Biopharma Inc. Heterocyclic Inhibitors of MEK and methods of use thereof
EP2364973A1 (en) 2005-05-18 2011-09-14 Array Biopharma, Inc. Heterocyclic inhibitors of MEK and Methods of use thereof
US8383832B2 (en) 2005-06-23 2013-02-26 Array Biopharma Inc. Process for preparing benzimidazole compounds
US9024040B2 (en) 2005-06-23 2015-05-05 Array Biopharma Inc. Processes for preparing benzimidazole compounds
US8501956B2 (en) 2005-06-23 2013-08-06 Array Biopharma Inc. Benzimidazole compounds
US7759518B2 (en) 2005-07-21 2010-07-20 Ardea Biosciences Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK
US8101799B2 (en) 2005-07-21 2012-01-24 Ardea Biosciences Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK
US8829052B2 (en) 2005-07-21 2014-09-09 Ardea Biosciences, Inc. Derivatives of N-(arylamino)sulfonamides as inhibitors of MEK
US8362002B2 (en) 2005-10-07 2013-01-29 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
US7915250B2 (en) 2005-10-07 2011-03-29 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
JP2014111659A (en) * 2005-10-07 2014-06-19 Exelixis Inc Mek inhibitor and use method thereof
JP2013014601A (en) * 2005-10-07 2013-01-24 Exelixis Inc Mek inhibitor and method of using the same
CN109053523B (en) * 2005-10-07 2022-03-25 埃克塞利希斯股份有限公司 Azetidines as MEK inhibitors for the treatment of proliferative diseases
JP2009511490A (en) * 2005-10-07 2009-03-19 エグゼリクシス, インコーポレイテッド MEK inhibitor and method of use thereof
US7803839B2 (en) 2005-10-07 2010-09-28 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
US11597699B2 (en) 2005-10-07 2023-03-07 Exelixis, Inc. MEK inhibitors and methods of their use
CN109053523A (en) * 2005-10-07 2018-12-21 埃克塞利希斯股份有限公司 Azetidine as the mek inhibitor for treating proliferative disease
US8604051B2 (en) 2006-01-31 2013-12-10 Ucb Pharma S.A. Thieno-pyridine derivatives as MEK inhibitors
US8394822B2 (en) 2006-01-31 2013-03-12 Ucb Pharma, S.A. Thieno-pyridine derivatives as MEK inhibitors
US8283359B2 (en) 2006-01-31 2012-10-09 Ucb Pharma S.A. Thieno-pyridine derivatives as MEK inhibitors
US8003651B2 (en) 2006-07-06 2011-08-23 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8846681B2 (en) 2006-07-06 2014-09-30 Array Biopharma, Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8329701B2 (en) 2006-07-06 2012-12-11 Array Biopharma Inc. Dihydrofuro pyrimidines as AKT protein kinase inhibitors
US9359340B2 (en) 2006-07-06 2016-06-07 Array Biopharma Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as Akt protein kinase inhibitors
US8853199B2 (en) 2006-07-06 2014-10-07 Array Biopharma, Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US9303040B2 (en) 2006-07-06 2016-04-05 Array Biopharma Inc. Substituted piperazines as AKT inhibitors
US8063050B2 (en) 2006-07-06 2011-11-22 Array Biopharma Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors
WO2008024724A1 (en) * 2006-08-21 2008-02-28 Genentech, Inc. Aza-benzothiophenyl compounds and methods of use
US7893085B2 (en) 2006-08-21 2011-02-22 Genentech, Inc Aza-benzothiophenyl compounds and methods of use
US7999006B2 (en) 2006-12-14 2011-08-16 Exelixis, Inc. Methods of using MEK inhibitors
US8470837B2 (en) 2006-12-20 2013-06-25 Takeda Pharmaceutical Company Limted MAPK/ERK kinase inhibitors
US8030317B2 (en) 2006-12-20 2011-10-04 Takeda Pharmaceutical Company Limited MAPK/ERK kinase inhibitors
US8258152B2 (en) 2007-06-12 2012-09-04 Genentech, Inc. N-substituted azaindoles and methods of use
US9409886B2 (en) 2007-07-05 2016-08-09 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8846683B2 (en) 2007-07-05 2014-09-30 Array Biopharma, Inc. Pyrimidyl cyclopentanes as Akt protein kinase inhibitors
US8377937B2 (en) 2007-07-05 2013-02-19 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8618097B2 (en) 2007-07-05 2013-12-31 Array Biopharma, Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8350037B2 (en) 2007-07-23 2013-01-08 Ucb Pharma, S.A. Thieno-pyridine derivatives as MEK inhibitors
US8022057B2 (en) 2007-11-12 2011-09-20 Takeda Pharmaceutical Company Limited MAPK/ERK kinase inhibitors
US8288408B2 (en) 2007-12-19 2012-10-16 Genentech, Inc. 5-anilinoimidazopyridines and methods of use
US7923456B2 (en) 2007-12-19 2011-04-12 Genentech, Inc. 5-anilinoimidazo[1,5-a]-pyridines inhibitors of MEK kinase
AU2008343065B2 (en) * 2007-12-19 2012-04-05 Genentech, Inc. 5-anilinoimidazopyridines and methods of use
US9206174B2 (en) 2007-12-19 2015-12-08 Genentech, Inc. 5-anilinoimidazopyridines and methods of use
EP2690101A1 (en) 2007-12-19 2014-01-29 Genentech, Inc. 5-Anilinoimidazopyridines and Methods of Use
US8293763B2 (en) 2007-12-19 2012-10-23 Genentech, Inc. 8-anilinoimidazopyridines and their use as anti-cancer and/or anti-inflammatory agents
WO2009085983A1 (en) * 2007-12-19 2009-07-09 Genentech, Inc. 5-anilinoimidazopyridines and methods of use
US8486963B2 (en) 2007-12-21 2013-07-16 Genentech, Inc. Azaindolizines and methods of use
WO2009082687A1 (en) 2007-12-21 2009-07-02 Genentech, Inc. Azaindolizines and methods of use
US8835434B2 (en) 2008-01-09 2014-09-16 Array Biopharma, Inc. Hydroxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors
US8853216B2 (en) 2008-01-09 2014-10-07 Array Biopharma, Inc. Hydroxylated pyrimidyl cyclopentane as AKT protein kinase inhibitor
US8487101B2 (en) 2008-01-21 2013-07-16 Ucb Pharma S.A. Thieno-pyridine derivatives as MEK inhibitors
US8637491B2 (en) 2008-06-19 2014-01-28 Ucb Pharma S.A. Thieno-pyridine derivatives as MEK inhibitors
WO2010003022A1 (en) 2008-07-01 2010-01-07 Genentech, Inc. Isoindolone derivatives as mek kinase inhibitors and methods of use
US8841462B2 (en) 2008-07-01 2014-09-23 Robert A. Heald Bicyclic heterocycles as MEK kinase inhibitors
US8492427B2 (en) 2008-07-01 2013-07-23 Genentech, Inc. Isoindolones derivatives as MEK kinase inhibitors and methods of use
US8404725B2 (en) 2008-08-04 2013-03-26 Merck Patent Gmbh Phenylamino isonicotinamide compounds
WO2010051933A2 (en) 2008-11-10 2010-05-14 Bayer Schering Pharma Aktiengesellschaft Substituted sulphonamido phenoxybenzamides
US9084781B2 (en) 2008-12-10 2015-07-21 Novartis Ag MEK mutations conferring resistance to MEK inhibitors
WO2010068738A1 (en) 2008-12-10 2010-06-17 Dana-Farber Cancer Institute, Inc. Mek mutations conferring resistance to mek inhibitors
WO2011047795A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
WO2011047796A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted halophenoxybenzamide derivatives
WO2011047788A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
US9279144B2 (en) 2010-02-25 2016-03-08 Dana-Farber Cancer Institute, Inc. Screening method for BRAF inhibitors
WO2011106298A1 (en) 2010-02-25 2011-09-01 Dana-Farber Cancer Institute, Inc. Braf mutations conferring resistance to braf inhibitors
US8637246B2 (en) 2010-02-25 2014-01-28 Dana-Farber Cancer Institute, Inc. BRAF mutations conferring resistance to BRAF inhibitors
EP3028699A1 (en) 2010-02-25 2016-06-08 Dana-Farber Cancer Institute, Inc. Braf mutations conferring resistance to braf inhibitors
US11078540B2 (en) 2010-03-09 2021-08-03 Dana-Farber Cancer Institute, Inc. Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy
US10660898B2 (en) 2010-10-06 2020-05-26 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8435988B2 (en) 2010-10-06 2013-05-07 Glaxosmithkline Llc Benzimidazole derivatives as P13 kinase inhibitors
US8674090B2 (en) 2010-10-06 2014-03-18 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9062003B2 (en) 2010-10-06 2015-06-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8541411B2 (en) 2010-10-06 2013-09-24 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9156797B2 (en) 2010-10-06 2015-10-13 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8865912B2 (en) 2010-10-06 2014-10-21 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US10314845B2 (en) 2010-10-06 2019-06-11 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9872860B2 (en) 2010-10-06 2018-01-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
WO2012055953A1 (en) 2010-10-29 2012-05-03 Bayer Pharma Aktiengesellschaft Substituted phenoxypyridines
US10092567B2 (en) 2011-04-01 2018-10-09 Genentech, Inc. Combinations of AKT inhibitor compounds and chemotherapeutic agents, and methods of use
US9682082B2 (en) 2011-04-01 2017-06-20 Genentech, Inc. Combinations of AKT and MEK inhibitor compounds, and methods of use
US9610289B2 (en) 2011-04-01 2017-04-04 Genentech, Inc. Combinations of AKT inhibitor compounds and erlotinib, and methods of use
US9717730B2 (en) 2011-04-01 2017-08-01 Genentech, Inc. Combinations of AKT inhibitor compounds and chemotherapeutic agents, and methods of use
US9833439B2 (en) 2011-05-25 2017-12-05 Universite Paris Descartes ERK inhibitors for use in treating spinal muscular atrophy
WO2012160130A1 (en) 2011-05-25 2012-11-29 Universite Paris Descartes Erk inhibitors for use in treating spinal muscular atrophy
WO2013082511A1 (en) 2011-12-02 2013-06-06 Genentech, Inc. Methods for overcoming tumor resistance to vegf antagonists
WO2013107283A1 (en) 2012-01-17 2013-07-25 Tianjin Binjiang Pharma, Inc. Benzoheterocyclic compounds and use thereof
US9937158B2 (en) 2012-01-17 2018-04-10 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof
US9290468B2 (en) 2012-01-17 2016-03-22 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof
WO2013169858A1 (en) 2012-05-08 2013-11-14 The Broad Institute, Inc. Diagnostic and treatment methods in patients having or at risk of developing resistance to cancer therapy
WO2013178581A1 (en) 2012-05-31 2013-12-05 Bayer Pharma Aktiengesellschaft Biomarkers for determining effective response of treatments of hepatocellular carcinoma (hcc) patients
US11414396B2 (en) 2012-10-12 2022-08-16 Exelixis, Inc. Process for making compounds for use in the treatment of cancer
WO2014147573A2 (en) 2013-03-21 2014-09-25 Novartis Ag Combination therapy
WO2015038704A1 (en) 2013-09-11 2015-03-19 The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone Compositions for preparing cardiomyocytes
US10626092B2 (en) 2016-05-02 2020-04-21 Mei Pharma, Inc. Polymorphic forms of 3-[(2-butyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide and uses thereof
WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
WO2023168203A1 (en) 2022-03-04 2023-09-07 Kinnate Biopharma Inc. Inhibitors of mek kinase
US11780862B2 (en) 2022-03-04 2023-10-10 Kinnate Biopharma Inc. Inhibitors of MEK kinase

Also Published As

Publication number Publication date
KR20040098013A (en) 2004-11-18
AR038972A1 (en) 2005-02-02
US20030216460A1 (en) 2003-11-20
MXPA04008894A (en) 2005-06-20
PA8569201A1 (en) 2004-05-21
CN1652792A (en) 2005-08-10
CO5611145A2 (en) 2006-02-28
EP1482944A4 (en) 2006-04-19
IL163996A0 (en) 2005-12-18
US20060106225A1 (en) 2006-05-18
RU2004127925A (en) 2005-05-27
TW200406203A (en) 2004-05-01
WO2003077855A3 (en) 2004-03-04
JP2005526076A (en) 2005-09-02
RU2300528C2 (en) 2007-06-10
EP1482944A2 (en) 2004-12-08
DOP2003000614A (en) 2009-09-30
PL378635A1 (en) 2006-05-15
UA76837C2 (en) 2006-09-15
AU2003220202A1 (en) 2003-09-29
CA2478534A1 (en) 2003-09-25

Similar Documents

Publication Publication Date Title
US20030216460A1 (en) N3 alkylated benzimidazole derivatives as MEK inhibitors
DK2275102T3 (en) N3-ALKYLED BENZIMIDAZOLD DERIVATIVES AS MEK INHIBITORS
EP1663210B1 (en) Benzimidazole derivatives as mek inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2478534

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 535159

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 163996

Country of ref document: IL

Ref document number: 200407221

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 378635

Country of ref document: PL

Ref document number: PA/a/2004/008894

Country of ref document: MX

Ref document number: 1020047014206

Country of ref document: KR

Ref document number: 2003575909

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 1-2004-501420

Country of ref document: PH

Ref document number: 2003220202

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2003716498

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 3047/DELNP/2004

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 2004127925

Country of ref document: RU

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 20038107678

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 1020047014206

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2003716498

Country of ref document: EP