US20030232869A1 - N3 alkylated benzimidazole derivatives as MEK inhibitors - Google Patents

N3 alkylated benzimidazole derivatives as MEK inhibitors Download PDF

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Publication number
US20030232869A1
US20030232869A1 US10/387,879 US38787903A US2003232869A1 US 20030232869 A1 US20030232869 A1 US 20030232869A1 US 38787903 A US38787903 A US 38787903A US 2003232869 A1 US2003232869 A1 US 2003232869A1
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aryl
heteroaryl
heterocyclyl
alkyl
arylalkyl
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US10/387,879
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Eli Wallace
Joseph Lyssikatos
Allison Marlow
T. Hurley
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AstraZeneca AB
Array Biopharma Inc
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Individual
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=28041856&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20030232869(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to US10/387,879 priority Critical patent/US20030232869A1/en
Application filed by Individual filed Critical Individual
Assigned to ARRAY BIOPHARMA, INC. reassignment ARRAY BIOPHARMA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HURLEY, T. BRIAN, LYSSIKATOS, JOSEPH P., MARLOW, ALLISON L., WALLACE, ELI M.
Priority to US10/652,733 priority patent/US7235537B2/en
Priority to BR122018007328A priority patent/BR122018007328B8/pt
Priority to BRPI0306026A priority patent/BRPI0306026B8/pt
Publication of US20030232869A1 publication Critical patent/US20030232869A1/en
Priority to US11/061,336 priority patent/US7425637B2/en
Priority to US11/762,897 priority patent/US7842816B2/en
Priority to US12/050,847 priority patent/US7576114B2/en
Priority to US12/050,827 priority patent/US7777050B2/en
Priority to US12/824,477 priority patent/US8003805B2/en
Priority to US12/824,547 priority patent/US8193230B2/en
Priority to US12/824,497 priority patent/US7973170B2/en
Priority to US12/824,559 priority patent/US8178693B2/en
Priority to US12/824,521 priority patent/US8193229B2/en
Priority to US12/826,158 priority patent/US8193231B2/en
Priority to US13/463,487 priority patent/US8513293B2/en
Assigned to ASTRAZENECA AB reassignment ASTRAZENECA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ARRAY BIOPHARMA, INC.
Assigned to ASTRAZENECA AB, ARRAY BIOPHARMA, INC. reassignment ASTRAZENECA AB CORRECTIVE ASSIGNMENT TO CORRECT THE RECEIVING PARTY DATA PREVIOUSLY RECORDED ON REEL 037387 FRAME 0824. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: ARRAY BIOPHARMA, INC.
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Definitions

  • This invention relates to a series of alkylated (1H-Benzoimidazol-5-yl)-(4-substituted-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 MEB1 and 2 on two serine residues (S218 and S222 for MEK1 and S222 and 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).
  • ERK 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).
  • 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.
  • 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 Apr. 6-10, 2002, Poster #5426; Tecle, H. IBC 2 nd International Conference of Protein Kinases, Sep. 9-10, 2002), block static allodynia in animals (WO 01/05390 published Jan. 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 (1H-benzoimidazol-5-yl)-(4-substituted 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.
  • a method for treatment of cancer Also provided are formulations containing compounds of formula I and methods of using the compounds to treat a patient in need thereof.
  • 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 , —C(O)OR 3 , NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 SO 2 R 6 , —SO 2 NR 3 R 4 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 , and
  • 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′′, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR′′′′, —NR′C(O)R′′, —C(O)NR′R′′, —SO 2 R′′′′, —NR′R′′, —NR′C(O)NR′′R′′′, —NR′C(NCN)NR′′R′′′, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,
  • R 4 and R 5 independently represent hydrogen or C 1 -C 6 alkyl
  • R 4 and R 5 together with the atom to which they are attached 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′′, —C(O)R′′′′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR′′′′, —NR′C(O)R′′, —C(O)NR′R′′, —SO 2 R′′′′, —NR′R′′, —NR′C(O)NR′′R′′′, —NR′C(NCN)NR′′R′′′, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocycl
  • R 6 is selected from trifluoromethyl
  • R 7 is selected from hydrogen
  • W is selected from heteroaryl, heterocyclyl, —C(O)OR 3 , —C(O)NR 3 R 4 , —C(O)NR 4 OR 3 , —C(O)R 4 OR 3 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 1 -C 10 alkyl), —C(O)(aryl), —C(O)(heteroaryl) and —C(O)(heterocyclyl), each of which is optionally substituted with 1-5 groups independently selected from
  • R 8 is selected from hydrogen, —SCF 3 , —Cl, —Br, —F, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —OR 3 , —C(O)R 3 , —C(O)OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 SO 2 R 6 , —SO 2 NR 3 R 4 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 3 R 4 , and
  • m is 0, 1, 2, 3, 4 or 5;
  • 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 C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylalkyl, C 3 -C 7 heterocycloalkyl or C 3 -C 7 heterocycloalkylalkyl 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
  • the present invention also provides compounds of formula I wherein R 8 is —OCF 3 , —Br or —Cl, R 2 is hydrogen, and R 1 is lower alkyl or halogen.
  • 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 .
  • R 7 is C 1 -C 10 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 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,
  • the present invention also provides compounds of formula II wherein R 8 is —OCF 3 , —Br or —Cl, and R 1 is lower alkyl or halogen.
  • 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 .
  • R 1 , R 2 , R 7 , R 8 and R 9 are as defined above for formula I, and A is —OR 3 or —NR 4 OR 3 , wherein R 3 and R 4 are as defined above for formula I.
  • R 7 is C 1 -C 10 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 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,
  • the present invention also provides compounds of formula III wherein R 8 is —OCF 3 , —Br or —Cl, R 2 is hydrogen, and R 1 is lower alkyl or halogen.
  • 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 OR 3 .
  • R 1 , R 2 , R 7 , R 8 and R 9 are as defined above for formula I, and A is —OR 3 or —NR 4 OR 3 , wherein R 3 and R 4 are as defined above for formula I.
  • R 7 is C 1 -C 10 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 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
  • the present invention also provides compounds of formula IIIa wherein R 8 is —OCF 3 , —Br or —Cl, R 2 is hydrogen, and R 1 is lower alkyl or halogen.
  • the present invention also provides compounds of formula IIIa wherein R 9 is hydrogen or halogen.
  • the present invention also provides compounds of formula IIIa wherein R 3 is hydrogen or lower alkyl when A is —OR 3 ; and R 4 is hydrogen when A is —NR 4 OR 3 .
  • R 7 , R 7 , R 8 and R 9 are as defined above for formula I
  • A is —OR 3 or —NR 4 OR 3 , wherein R 3 and R 4 are as defined above for formula I.
  • R 7 is C 1 -C 10 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 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
  • the present invention also provides compounds of formula IIIb wherein R 8 is —OCF 3 , —Br or —Cl, and R 1 is lower alkyl or halogen.
  • the present invention also provides compounds of formula IIIb wherein R 9 is fluoro or chloro.
  • the present invention also provides compounds of formula IIIb wherein R 3 is hydrogen or lower alkyl when A is —OR 3 ; and R 4 is hydrogen when A is —NR 4 OR 3 .
  • C 1 -C 10 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 1-6 alkyl. More preferred alkyl radicals are C 1-3 alkyl.
  • C 2 -C 10 alkenyl means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and at least one double bond and includes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like. More preferred are lower alkenyl having 3-5 carbon atoms.
  • C 2 -C 10 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 10 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 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl or di(C 1 -C 6 )alkylamino(C 1 -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).
  • An example of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo ( ⁇ O) moieties is 1,1-dioxo-thiomorpholinyl.
  • heterocycle groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • such heterocycle groups may be optionally substituted with, for example, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl or di(C 1 -C 6 )alkylamino(C 1 -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 1-3 -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 1-3 -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 1-3 -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 1-3 -alkyls. Examples include cyclopropylmethyl.
  • Me means methyl
  • Et means ethyl
  • Bu means butyl
  • Ac means acetyl
  • phrases “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.
  • 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, dibenzylammonium, 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 3 )C(CH 2 CH 3 )(CH 2 CH 2 CH 3 )— 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 Cl, 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 a compound of formulas I-IIIb 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, ganuna-aminobutyric acid, cirtulline, homocysteine, homoserine, omithine 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, esophageal, 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 the treatment of 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, 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 arthritis, atherosclerosis, inflammatory bowel disease, 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, esophageal, testicular, gynecological or thyroid cancer.
  • 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)).
  • 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 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 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 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.
  • 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 arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma,
  • 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
  • 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 hyperproliferative 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 hyperproliferative 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 metalloprotienase inhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European Patent Application No.
  • 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).
  • MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13 matrix-metalloproteinases
  • MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, and RS 13-0830.
  • abnormal cell growth and “hyperproliferative 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 organic solvent like xylenes.
  • step 5 the preferred method is stirring the ester with 10 equivalents aniline in xylenes at reflux until complete reaction.
  • the nitro arene is reduced to produce the diamine by standard reduction conditions, including by not limited to H 2 , and Pd/C or Pd(OH) 2 /C or Raney Nickel in organic solvent like EtOH or THF, Fe in AcOH, Zn in AcOH or Zn, NH 4 Cl (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.
  • a halide can be incorporated by standard methods, including but not limited to NBS or NCS and pTsOH in organic cosolvents like THF and MeOH.
  • the benzimidazole is alkylated to give a near equal mixture of N1 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.
  • 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.
  • Scheme 2 illustrates an example in which the R 8 substituent is on the aniline prior to the coupling procedure with the nitro ester.
  • the reaction description is exactly like that for Scheme 1 except that there is no need to incorporated R 8 as it is present in the aniline from the beginning.
  • step 3 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 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 amination 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.
  • a suitable solvent such as methylene chloride, acetonitrile or THF.
  • the preferable reduction amination is to treat the aldehyde with amine, Me 4 NBH(OAc) 3 and acetic acid in MeCN at room temperature.
  • Scheme 4 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 23 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 24 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 25 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.
  • step 1 the methyl ester is converted to the benzyl alcohol by standard reductive methods, preferably LAH in THF at 0° C. or NaBH 4 in EtOH:THF at room temperature. Oxidation to the aldehyde can be accomplished in step 2 using MnO 2 in acetone:THF at 50° C.
  • step 3 organometallic reageants, such as organolithium reagents and Grignard reagents, can be added to the aldehyde in THF at low temperature (e.g., ⁇ 78° C.) to give the substituted benzyl alcohol.
  • the keto derivatives can be prepared in step 4 by oxidation of the benyzl alcohol under standard conditions such as Swem or Dess-Martin oxidation.
  • 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 MEK1 is assessed by measuring the incorporation of ⁇ - 33 P-phosphate from ⁇ - 33 P-ATP onto N-terminal His tagged ERK2, which is expressed in E. coli and is purified by conventional methods, in the presence of MEK1. The assay is carried out in 96-well polypropylene plate.
  • the incubation mixture (100 ⁇ L) comprises of 25 mM Hepes, pH 7.4, 10 mM MgCl 2 , 5 mM ⁇ -glycerolphosphate, 100 ⁇ M Na-orthovanadate, 5 mM DTT, 5 nM MEK1, and 1 ⁇ M 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 ⁇ M ATP (with 0.5 gCi ⁇ - 33 P-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 filterplates, and excess labeled ATP washed off using a Tomtec MACH III harvester. Plates are allowed to air-dry prior to adding 30 ⁇ L/well of Packard Microscint 20, and plates are counted using a Packard TopCount. In this assay, compounds of the invention exhibited an IC 50 of less than 50 micromolar.
  • 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.
  • the pharmaceutical 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 purposes.
  • 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 3
  • Step C 4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4
  • Step D 4-Amino-3-fluoro-5-nitro-2-o-tolylamino-benzoic acid methyl ester 5a
  • Step E 7-Fluoro-6-o-tolylamino-1H-benzoimidazole-5-carboxylic acid methyl ester 7a
  • Step F 7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester 8a
  • Step G 7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid 10a
  • Step H 7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11a
  • Step A 4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid methyl ester 26a
  • Step B 7-Fluoro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 27a
  • Step A 6-(4-Bromo-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 28a
  • Step B 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b
  • reaction mixture is quenched by the addition of aqueous saturated sodium bisulfite solution and diluted with ethyl acetate and water and the layers separated.
  • the aqueous layer is extracted with ethyl acetate.
  • the combined organic extracts are washed with brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • the resulting solid residue is triturated with methylene chloride to yield a white solid which is collected by filtration to yield 1.05 g (85%) of the pure desired product.
  • Step A 4-Amino-3-fluoro-2-(2-fluoro-phenylamino)-5-nitro-benzoic acid methyl ester 5b
  • Step B 6-(4-Bromo-2-fluoro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8d
  • Step A 4-Amino-3-fluoro-2-(2-methyl-4-trifluoromethoxy-phenylamino)-5-nitro-benzoic acid methyl ester 12a
  • Step B 7-Fluoro-6-(2-methyl-4-trifluoromethoxy-phenylamino)-3H-benzoimidazole-5-carboxylic acid methyl ester 8f
  • Hydroxylamines useful for synthesizing compounds of the present invention may be prepared as follows
  • Step A 2-(2-Methoxy-ethoxy)-isoindole-1,3-dione
  • Step B O-(2-Methoxy-ethyl)-hydroxylamine
  • O-(2-Piperidin-1-yl-ethyl)-hydroxylamine is purified by Kugelrohr distillation (chamber temperature 140° C., 1 torr).
  • O-(2-Methylsulfanyl-ethyl)-hydroxylamine is purified by vacuum distillation (76-78° C., 20 torr).
  • O-(2-Phenylsulfanyl-ethyl)-hydroxylamine is used directly without purification.
  • O-(2-Benzenesulfonyl-ethyl)-hydroxylamine is purified by flash chromatography (1% MeOH in CH 2 Cl 2 ).
  • O-(3-Phenylsulfanyl-propyl)-hydroxylamine is prepared from PhSCH 2 CH 2 CH 2 Br and N-hydroxyphthalimide by the patent procedure WO 0018790 and then is deprotected by the procedure described above and used directly without purification.
  • O-(3-Benzenesulfonyl-propyl)-hydroxylamine is prepared from the above isoindole-1,3-dione through its oxidation with oxone followed by deprotection as described above and is purified by flash chromatography (100% CH 2 Cl 2 to 2% MeOH in CH 2 Cl 2 ).
  • Step A O-(2-Bromo-ethyl)-hydroxylamine hydrobromide
  • 2-(2-Bromo-ethoxy)-isoindole-1,3-dione is prepared from 1,2-dibromoethane and N-hydroxyphthalimide as described in WO 0018790, and is then subjected to the procedure in J. Org. Chem. 1963, 28, 1604 to yield the desired product.
  • Step B (2-Bromo-ethoxy)-carbamic acid tert-butyl ester
  • Step C (2-Morpholin-4-yl-ethoxy)-carbamic acid tert-butyl ester
  • Step D O-(2-Morpholin-4-yl-ethyl)-hydroxylamine dihydrochloride
  • the isoindole-1,3-dione intermediates of the following hydroxylamines are prepared from the appropriate alkyl halide and N-hydroxyphthalimide by the procedure described within J. Heterocyclic Chem. 2000, 37, 827-830.
  • the isoindole-1,3-diones are deprotected by the procedure described above: O-but-3-enyl-hydroxylamine; O-(tetrahydro-furan-2-ylmethyl)-hydroxylamine; O-(3-methoxy-propyl)-hydroxylamine; and O-(3-benzyloxy-propyl)-hydroxylamine.
  • Step A 4-Amino-2-(2-chloro-phenylamino)-3-fluoro-5-nitro-benzoic acid methyl ester 5b
  • Step B 4,5-Diamino-2-(2-chloro-phenylamino)-3-fluoro-benzoic acid methyl ester 6a
  • Step C 6-(2-Chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 7b
  • Step D 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b
  • Step E 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid 10b
  • Step F 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (11b)
  • Step A 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester 9a and 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-1-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester
  • Step B 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid 10c
  • aqueous solution is acidified to pH 2 by the addition of 1.0 M aqueous HCl and extracted with 1:1 tetrahydrofuran/ethyl acetate (3 ⁇ ), dried (Na 2 SO 4 ) and concentrated under reduced pressure to provide 43 mg (79%) pure carboxylic acid as an off white solid.
  • Step C 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide 29a
  • reaction mixture is diluted with ethyl acetate, washed with water (3 ⁇ ), saturated potassium carbonate (2 ⁇ ), saturated ammonium chloride (2 ⁇ ), brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure to an off-white solid. Trituration of the solid with diethyl ether provides 2.18 g (90%) desired product as an off-white solid. MS ESI (+) m/z 483, 485 (M+ Br pattern) detected.
  • Step D 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide 29c
  • Step A 6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylic acid methyl ester 9b
  • the organic layer is washed with water and brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • the N3 and N1 alkylated products are separated by flash column chromatography, eluted with 20:1 methylene chloride:ethyl acetate. Complete separation of the isomers is obtained by performing two chromatographic separations.
  • the higher R f product is the N3 product 9b, while the lower R f product is the N1 product.
  • the recovery of the N3 product 9b is 0.415 g (38%): LC/MS ESI (+) m/z 448, 446 (M+1 Br pattern) detected.
  • the recovery of the N1 product was 0.486 g (45%): LC/MS ESI (+) m/z 448, 446 (M+1 Br pattern) detected.
  • Step B 6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylic acid 10d
  • Step C 6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11f
  • Step D 6-(4-Bromo-2-methyl-phenylamino)-3-(4,5-dihydroxy-pentyl)-7-fluoro-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11m
  • reaction mixture is filtered through Celite rinsing with ethyl acetate and methylene chloride.
  • the filtrate is diluted with ethyl acetate and washed with 0.01 N HCl, and brine.
  • the organic layer is dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • the crude product is purified by FCC eluted with 9:1 ethyl acetate:MeOH to give 0.244 g (74%) pure desired product.
  • Step E 6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-(4-oxo-butyl)-3H benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11n
  • Step F 6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-[4-(4-methyl-piperazin-1-yl)-butyl]-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11o
  • step F The following compounds are prepared by methods similar to those described in Example 19 by using the appropriate alkenyl substituted benzimidazole and the appropriate amine in the reductive amination (step F): 18a 18b 18c 18d 18e 18f 18g 18h 18i 18j 18k 18l 18m 18n 18o 18p 18q 18r 18s 18t 18u 18v 18w 18x 18y 18z 18aa 18bb
  • Step A 6-(4-Bromo-2-chloro-phenylamino)-3-(2-tert-butoxycarbonyl-ethyl)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester
  • Step B 6-(4-Bromo-2-chloro-phenylamino)-3-(2-carboxy-ethyl)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester TFA salt
  • Step C 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylic acid methyl ester
  • Step D 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylic acid
  • Step E 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 18hhh
  • Step A 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid methyl ester 11q
  • Step B 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid 11r
  • reaction mixture is poured into a separatory funnel and diluted with ethyl acetate/tetrahydrofuran and water and the layers separated.
  • the aqueous layer is extracted with ethyl acetate.
  • the combined organic layers are washed with brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure to yield 0.11 g (100%) of the pure desired product as a white solid.
  • Step C 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide 11s
  • O-(2-vinyloxy-ethyl)-hydroxylamine (0.028 g, 0.27 mmol) and EDCI (0.056 g, 0.29 mmol) are added and the reaction mixture is stirred at room temperature under N 2 until HPLC shows the reaction is complete (2-3 days).
  • the reaction mixture is poured into a separatory funnel, diluted with ethyl acetate and water and the layers separated. The ethyl acetate layer is washed successively with aqueous saturated NH 4 Cl (2 ⁇ ), brine (1 ⁇ ), aqueous saturated sodium bicarbonate (2 ⁇ ), water (1 ⁇ ), and brine (1 ⁇ ), dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • Step D 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide 11p
  • Step A 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylic acid methyl ester 11cc
  • Step B 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11bb
  • 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylic acid methyl ester 11cc is subjected to methods previously described to give 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide: MS APCI (+) m/z 561, 559 (M+ Br pattern) and MS APCI ( ⁇ ) m/z 559, 557 (M ⁇ Br pattern) detected; 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 11.75 (s, 1H), 8.47 (s, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 7.62 (d, 1H),
  • Step A 6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20a
  • Step B [6-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-fluoro-1H-benzoimidazol-5-yl]-(4-bromo-2-methyl-phenyl)-amine 24a
  • [0312] [6-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-fluoro-1H-benzoimidazol-5-yl]-(4-chloro-2-methyl-phenyl)-amine 24b is prepared as described in example 31 starting with 6-(4-chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8e.
  • [0315] [6-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-fluoro-1H-benzoimidazol-5-yl]-(4-bromo-2-chloro-phenyl)-amine 24c is prepared as described in example 31 starting with 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b.
  • 6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20b is prepared as described in example 31, step A from 6-(4-chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8e.
  • the reaction mixture is poured into a separatory funnel and diluted with ethyl acetate and water and the layers separated.
  • the ethyl acetate layer is washed successively with aqueous saturated NH 4 Cl (2 ⁇ ), brine (1 ⁇ ), aqueous saturated sodium bicarbonate (2 ⁇ ), water (1 ⁇ ), and brine (1 ⁇ ), dried (MgSO 4 ) and concentrated under reduced pressure.
  • the resulting solid is purified by FCC (cluting with 19:1 methylene chloride:methanol) to yield 0.013 g (42%) of the pure desired product.
  • the filtrate is concentrated under reduced pressure to a small volume and then filtered through an Acrodisc syringe filter to remove small amounts of MnO 2 that passed through the silica gel.
  • the filtrate is concentrated under reduced pressure and the residue is purified by flash column chromatography (eluting with 20:1 methylene chloride:methanol) to yield 0.81 g (85%) of the pure desired product as a bright yellow solid.
  • Step A 1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanol 10i
  • Step B 1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanone 10j
  • Step C 1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-2-hydroxy-ethanone 10g
  • Step A 1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanol 101
  • Step B 1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanone 10m
  • reaction mixture is slowly warmed to room temperature, stirred for 5 min at room temperature, and diluted with water and CH 2 Cl 2 .
  • the organic layer is separated, dried over MgSO 4 , filtered, and concentrated to give the crude product which is directly used without further purification.
  • Step C 1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-hydroxy-ethanone 10k
  • Step A 1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-ethoxy-ethanol 10o
  • Step B 1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-ethoxy-ethanone 10n
  • the title compound is prepared from 1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-ethoxy-ethanol 10o according to the procedure described in Example 42, Step B except that the reaction mixture is not treated with saturated aqueous NaHCO 3 containing sodium thiosulfate pentahydrate.
  • Step A 2-Benzyloxy-1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-ethanol 10r
  • Step B 2-Benzyloxy-1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-ethanone 10q
  • Step A 1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methanesulfonyl-ethanol 10t
  • Step B 1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methanesulfonyl-ethanone 10s
  • Step A 1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-(isopropoxy-dimethyl-silanyl)-ethanol 10v
  • Step B 1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-ethane-1,2-diol 10u
  • Step A [6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazol-5-yl]-methanol 10y
  • Step B 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carbaldehyde 10z
  • reaction mixture is concentrated to dryness and the residue dissolved in 10:1 methylene chloride:MeOH.
  • the solution is filtered through a silica gel plug eluted with 10:1 methylene chloride:MeOH.
  • the resulting filtrate is concentrated under reduced pressure to give 41 mg (82%) desired product as a bright yellow solid.
  • Step C (4-Bromo-2-chloro-phenyl)-(4-fluoro-6-oxazol-5-yl-1H-benzoimidazol-5-yl)-amine 10x
  • Step A (4-Bromo-2-chloro-phenyl)- ⁇ 4fluoro-1-(2-methanesulfonyl-ethyl)-6-[4-(toluene-4-sulfonyl)-4,5-dihydro-oxazol-5-yl]-1H-benzoimidazol-5-yl ⁇ -amine 10bb
  • Step B (4-Bromo-2-chloro-phenyl)-[4-fluoro-6-(3H-imidazol-4-yl)-1H-benzoimidazol-5-yl]-amine 10aa
  • Step A 3-Chloro-2,4-difluoro-5-nitro-benzoic acid 2a
  • Step B 4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid 3a
  • Step C 4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester 4a
  • Step D 4-Amino-3-chloro-5-nitro-2-phenylamino-benzoic acid methyl ester 5c
  • Step E 4,5-Diamino-3-chloro-2-phenylamino-benzoic acid methyl ester 6b
  • Step F 7-Chloro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 7c
  • Step G 6-(4-Bromo-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester 8g
  • Step H 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester 10dd
  • Step I 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester 10ee
  • N3 and N1 alkylated regioisomers are separated by flash chromatography (EtOAc).
  • EtOAc flash chromatography
  • Step J 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylic acid 10ff
  • Step K 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide 10gg
  • Step L 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide 10cc
  • Step A 4,5-Diamino-3-fluoro-2-phenylamino-benzoic acid methyl ester 6c
  • Step B 7-Fluoro-2-methyl-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 31a
  • Step C 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-2-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide 10ii
  • Step A 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester 10jj
  • reaction mixture is quenched by the addition of 10% Na 2 S 2 O 4 solution.
  • the reaction mixture is then 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: MS ESI (+) m/z 426 (M+1) detected; MS ESI ( ⁇ ) m/z 424 (M ⁇ 1) detected.
  • Step B 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylic acid methyl ester 10kk
  • reaction mixture is quenched by the addition of water and brine.
  • the reaction mixture is extracted with ethyl acetate.
  • the combined organic extracts are washed with water and brine, and dried (MgSO 4 ) and concentrated under reduced pressure. Purification by flash column chromatography eluted with 1:1 hexanes:ethyl acetate gives 0.182 g (70%) of desired product as a 1:1 mixture of N1 and N3 isomers as a white foam.
  • Step C 6-(4-Cyano-2-methyl-phenylamino)-7-fluoro-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylic acid methyl ester 10ll
  • Step D 6-(4-Cyano-2-methyl-phenylamino)-7-fluoro-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylic acid 10mm
  • Step E 6-(4-Cyano-2-methyl-phenylamino)-7-fluoro-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylic acid cyclopropylmethyoxy-amide 11zz
  • Step F 6-(4-Cyano-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid cyclopropylmethyoxy-amide 11yy
  • Step A 7-Fluoro-6-(2-methyl-4-trimethylsilanylethynyl-phenylamino)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11bbb
  • Step B 6-(4-Ethynyl-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11aaa
  • reaction mixture is stirred at 50° C. for 2 hours under N 2 .
  • the reaction mixture is cooled to room temperature, a few drops of H 2 O are added and then it is concentrated under reduced pressure.
  • the residue is purified by FCC (eluting with 20:1 methylene chloride:methanol) to yield 0.011 g (65%) of the pure desired product.

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US10/387,879 US20030232869A1 (en) 2002-03-13 2003-03-13 N3 alkylated benzimidazole derivatives as MEK inhibitors
US10/652,733 US7235537B2 (en) 2002-03-13 2003-08-29 N3 alkylated benzimidazole derivatives as MEK inhibitors
BR122018007328A BR122018007328B8 (pt) 2002-03-13 2003-12-12 composto, composição farmaceutica e uso do dito composto
BRPI0306026A BRPI0306026B8 (pt) 2003-03-13 2003-12-12 composto, composição farmaceutica e uso de um composto
US11/061,336 US7425637B2 (en) 2002-03-13 2005-02-18 N3 alkylated benzimidazole derivatives as MEK inhibitors
US11/762,897 US7842816B2 (en) 2002-03-13 2007-06-14 N3 alkylated benzimidazole derivatives as MEK inhibitors
US12/050,847 US7576114B2 (en) 2002-03-13 2008-03-18 N3 alkylated benzimidazole derivatives as MEK inhibitors
US12/050,827 US7777050B2 (en) 2002-03-13 2008-03-18 N3 alkylated benzimidazole derivatives as MEK inhibitors
US12/824,521 US8193229B2 (en) 2002-03-13 2010-06-28 Method of treatment using N3 alkylated benzimidazole derivatives as MEK inhibitors
US12/824,477 US8003805B2 (en) 2002-03-13 2010-06-28 N3 alkylated benzimidazole derivatives as MEK inhibitors
US12/824,559 US8178693B2 (en) 2002-03-13 2010-06-28 N3 alkylated benzimidazole derivatives as MEK inhibitors
US12/824,497 US7973170B2 (en) 2002-03-13 2010-06-28 N3 alkylated benzimidazole derivatives as MEK inhibitors
US12/824,547 US8193230B2 (en) 2002-03-13 2010-06-28 Compositions comprising N3 alkylated benzimidazole derivatives as MEK inhibitors and methods of use thereof
US12/826,158 US8193231B2 (en) 2002-03-13 2010-06-29 Compositions comprising N3 alkylated benzimidazole derivatives as MEK inhibitors and methods of use thereof
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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050054701A1 (en) * 2003-09-03 2005-03-10 Eli Wallace Heterocyclic inhibitors of MEK and methods of use thereof
WO2005051300A2 (en) 2003-11-19 2005-06-09 Array Biopharma Inc. Bicyclic inhibitors of mek and methods of use thereof
US20050130954A1 (en) * 2003-11-21 2005-06-16 Mitchell Ian S. AKT protein kinase inhibitors
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
US20050256123A1 (en) * 2003-11-19 2005-11-17 Marlow Allison L Heterocyclic inhibitors of MEK and methods of use thereof
US20060030610A1 (en) * 2003-09-03 2006-02-09 Kevin Koch Method of treating inflammatory diseases
US20070112038A1 (en) * 2003-11-19 2007-05-17 Marlow Allison L Heterocyclic inhibitors of MEK and methods of use thereof
WO2007002157A3 (en) * 2005-06-23 2007-11-01 Array Biopharma Inc Process for preparing benzimidazole compounds
US20080051399A1 (en) * 2006-07-06 2008-02-28 Mitchell Ian S Hydroxylated and methoxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors
US20080058327A1 (en) * 2006-07-06 2008-03-06 Mitchell Ian S Pyrimidyl cyclopentanes as akt protein kinase inhibitors
US20080280957A1 (en) * 2005-05-18 2008-11-13 Array Biopharma, Inc. Heterocyclic Inhibitors of Mek and Methods of Use Thereof
US20090030058A1 (en) * 2005-12-21 2009-01-29 Mohammed Pervez 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
US20100016393A1 (en) * 2005-12-21 2010-01-21 Demattei John Novel hydrogen sulfate salt
US20100069381A1 (en) * 2006-08-03 2010-03-18 Fumio Itoh Gsk-3betainhibitor
WO2010051933A2 (en) 2008-11-10 2010-05-14 Bayer Schering Pharma Aktiengesellschaft Substituted sulphonamido phenoxybenzamides
US20100130748A1 (en) * 2005-06-23 2010-05-27 Array Biopharma Inc. Snar process for preparing benzimidazole compounds
US20100292244A1 (en) * 2008-01-09 2010-11-18 Array Biopharma Inc. Hydroxylated pyrimidyl cyclopentane as akt protein kinase inhibitor
US20110065716A1 (en) * 2008-01-09 2011-03-17 Array Biopharma Inc. Hydroxylated pyrimidyl cyclopentanes as akt protein kinase 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
US20110160221A1 (en) * 2007-07-05 2011-06-30 Array Biopharma Inc. Pyrimidyl cyclopentanes as akt protein kinase inhibitors
WO2012055953A1 (en) 2010-10-29 2012-05-03 Bayer Pharma Aktiengesellschaft Substituted phenoxypyridines
WO2012085244A1 (fr) 2010-12-23 2012-06-28 Sanofi Derives de pyrimidinone, leur preparation et leur utilisation pharmaceutique
US8329701B2 (en) 2006-07-06 2012-12-11 Array Biopharma Inc. Dihydrofuro pyrimidines as AKT protein kinase inhibitors
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US8846683B2 (en) 2007-07-05 2014-09-30 Array Biopharma, Inc. Pyrimidyl cyclopentanes as Akt protein kinase inhibitors
US9150548B2 (en) 2011-04-01 2015-10-06 Genentech, Inc. Combinations of AKT inhibitor compounds and vemurafenib, and methods of use
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
US9682082B2 (en) 2011-04-01 2017-06-20 Genentech, Inc. Combinations of AKT and MEK inhibitor compounds, and methods of use

Families Citing this family (225)

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Publication number Priority date Publication date Assignee Title
US7235537B2 (en) * 2002-03-13 2007-06-26 Array Biopharma, Inc. N3 alkylated benzimidazole derivatives as MEK inhibitors
WO2004054515A2 (en) * 2002-12-13 2004-07-01 Smithkline Beecham Corporation Thrombopoietin mimetics
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CA2532067C (en) 2003-07-24 2010-12-21 Stephen Douglas Barrett N-methyle-substituted benzamidazoles
WO2005028447A1 (en) 2003-09-22 2005-03-31 S*Bio Pte Ltd Benzimidazole derivates: preparation and pharmaceutical applications
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US7429667B2 (en) 2005-01-20 2008-09-30 Ardea Biosciences, Inc. Phenylamino isothiazole carboxamidines as MEK inhibitors
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EA025871B9 (ru) 2005-10-07 2017-08-31 Экселиксис, Инк. Ингибиторы mek и способы их применения
AU2012261703B2 (en) * 2005-10-07 2015-08-13 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
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US7968108B2 (en) * 2005-10-25 2011-06-28 Metbro Distributing L.P. Hydrogen cyanamide pesticide formulations
US7572460B2 (en) * 2005-10-25 2009-08-11 Rodrigo Rodriguez-Kabana Hydrogen cyanamide pesticide formulations
RU2418790C3 (ru) * 2005-12-21 2022-03-14 Астразенека Аб Новая гидросульфатная соль
CA2534243A1 (fr) 2006-01-25 2007-07-25 Hydro Quebec Particules d'oxyde metallique enrobees a faible taux de dissolution, procedes de preparation et utilisation dans les systemes electrochimiques
GB0601962D0 (en) 2006-01-31 2006-03-15 Ucb Sa Therapeutic agents
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DE602007009663D1 (de) * 2006-04-18 2010-11-18 Ardea Biosciences Inc Pyridonsulfonamide und pyridonsulfamide als mek-hemmer
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JO2985B1 (ar) 2006-12-20 2016-09-05 Takeda Pharmaceuticals Co مثبطات كينازmapk/erk
CN101678001A (zh) * 2007-04-13 2010-03-24 阿斯利康(瑞典)有限公司 包含azd2171和azd6244或mek-抑制剂ⅱ的组合治疗
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AU2008340247B2 (en) 2007-12-21 2012-11-15 Genentech, Inc. Azaindolizines and methods of use
EP2240494B1 (en) 2008-01-21 2016-03-30 UCB Biopharma SPRL Thieno-pyridine derivatives as mek inhibitors
SA109300195B1 (ar) 2008-03-28 2013-04-20 Astrazeneca Ab تركيبة صيدلانية جديدة مضادة للسرطان
GB0811304D0 (en) 2008-06-19 2008-07-30 Ucb Pharma Sa Therapeutic agents
JP5404622B2 (ja) 2008-06-23 2014-02-05 パナソニック株式会社 無線通信基地局装置および参照信号割当方法
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ES2426096T3 (es) * 2008-07-01 2013-10-21 Genentech, Inc. Derivados de isoindolona como inhibidores de la quinasa MEK y métodos de utilización
EA018539B1 (ru) 2008-08-04 2013-08-30 Мерк Патент Гмбх Фениламино-изоникотинамидные соединения
CN101653607B (zh) * 2008-08-19 2013-02-13 鼎泓国际投资（香港）有限公司 含有肝细胞生长因子受体抑制剂和丝裂原细胞外激酶抑制剂的药物组合物及其用途
WO2010051245A1 (en) * 2008-11-03 2010-05-06 Merck Sharp & Dohme Corp. Benzimidazole and aza-benzimidazole carboxamides
JO3002B1 (ar) 2009-08-28 2016-09-05 Irm Llc مركبات و تركيبات كمثبطات كيناز بروتين
US8242260B2 (en) 2009-08-28 2012-08-14 Novartis Ag Compounds and compositions as protein kinase inhibitors
WO2011095807A1 (en) 2010-02-07 2011-08-11 Astrazeneca Ab Combinations of mek and hh inhibitors
US9205086B2 (en) 2010-04-19 2015-12-08 Synta Pharmaceuticals Corp. Cancer therapy using a combination of a Hsp90 inhibitory compounds and a EGFR inhibitor
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
AU2011268906A1 (en) 2010-06-25 2013-01-31 Novartis Ag Heteroaryl compounds and compositions as protein kinase inhibitors
CN103221043B (zh) 2010-08-05 2016-04-06 卡斯西部储备大学 用于治疗神经元连接发育障碍的erk抑制剂
CN103124496B (zh) 2010-10-06 2016-03-30 葛兰素史密丝克莱恩有限责任公司 作为pi3激酶抑制剂的苯并咪唑衍生物
CN102020651B (zh) 2010-11-02 2012-07-18 北京赛林泰医药技术有限公司 6-芳基氨基吡啶酮甲酰胺mek抑制剂
EP2655601A4 (en) 2010-12-22 2014-09-10 Fate Therapeutics Inc CELL CULTURAL PLATFORM FOR INDIVIDUAL CELL SIZING AND IMPROVED RESOLUTION OF IPSCS
WO2012145503A1 (en) 2011-04-21 2012-10-26 Novartis Ag Pharmaceutical combinations
WO2012162293A1 (en) * 2011-05-23 2012-11-29 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitory compounds with mek inhibitors
CA2836364C (en) 2011-05-25 2021-01-26 Universite Paris Descartes Erk inhibitors for use in treating spinal muscular atrophy
JP6105578B2 (ja) 2011-07-21 2017-03-29 トレロ ファーマシューティカルズ， インコーポレイテッド 複素環式プロテインキナーゼ阻害剤
PL2739358T3 (pl) 2011-08-01 2019-04-30 Hoffmann La Roche Sposoby leczenia nowotworu z użyciem związków antagonistycznych wiązania osi pd-1 i inhibitorów mek
US10307167B2 (en) 2012-12-14 2019-06-04 Corquest Medical, Inc. Assembly and method for left atrial appendage occlusion
US10314594B2 (en) 2012-12-14 2019-06-11 Corquest Medical, Inc. Assembly and method for left atrial appendage occlusion
US10813630B2 (en) 2011-08-09 2020-10-27 Corquest Medical, Inc. Closure system for atrial wall
RU2607944C2 (ru) * 2011-08-31 2017-01-11 Новартис Аг Синергические композиции ингибиторов pi3k и мек
JP2014528928A (ja) * 2011-09-01 2014-10-30 ノバルティス アーゲー ヌーナン症候群の治療のための有機化合物の使用
EP2570127A1 (en) 2011-09-16 2013-03-20 Sanofi Compositions and methods for treating cancer using PI3KB beta inhibitor and MAPK pathway inhibitor, including MEK and RAF inhibitors
RU2629116C2 (ru) 2011-10-14 2017-08-24 Эррэй Биофарма Инк. Полиморфы arry-380, селективного ингибитора erbb2, и фармацевтические составы, содержащие их
AU2012332421A1 (en) 2011-11-02 2014-06-05 Synta Pharmaceuticals Corp. Cancer therapy using a combination of Hsp90 inhibitors with topoisomerase I inhibitors
JP2014534228A (ja) 2011-11-02 2014-12-18 シンタ ファーマシューティカルズ コーポレーション 白金含有剤とｈｓｐ９０阻害剤の組合せ療法
JP2014533299A (ja) 2011-11-14 2014-12-11 シンタ ファーマシューティカルズ コーポレーション Ｂｒａｆ阻害剤とｈｓｐ９０阻害剤の組合せ療法
JP6180425B2 (ja) 2011-11-23 2017-08-23 メディミューン，エルエルシー Ｈｅｒ３に特異的な結合分子及びそれらの使用
WO2013082511A1 (en) 2011-12-02 2013-06-06 Genentech, Inc. Methods for overcoming tumor resistance to vegf antagonists
AU2013208720A1 (en) 2012-01-09 2014-07-24 Arrowhead Research Corporation RNAi agents to treat Beta-Catenin related diseases
WO2013109142A1 (en) 2012-01-16 2013-07-25 Stichting Het Nederlands Kanker Instituut Combined pdk and mapk/erk pathway inhibition in neoplasia
CN103204822B (zh) 2012-01-17 2014-12-03 上海科州药物研发有限公司 作为蛋白激酶抑制剂的苯并噁唑化合物及其制备方法和用途
GB201201332D0 (en) 2012-01-26 2012-03-14 Imp Innovations Ltd Method
MX359770B (es) * 2012-03-20 2018-10-10 Novartis Ag Star Terapia de combinacion de un inhibidor de mek e inhibidor de igf1r.
EP2836873B1 (en) 2012-04-09 2020-03-11 Switch Materials, Inc. Switching materials, and compositions and methods for making same
CN104508520B (zh) 2012-05-29 2018-03-27 思维奇材料公司 包含可变透射率层的滤光片
BR112014029338A2 (pt) 2012-05-31 2017-06-27 Bayer Pharma AG biomarcadores para determinação da resposta eficaz dos tratamentos de pacientes com carcinoma hepatocelular (hcc)
AR091876A1 (es) * 2012-07-26 2015-03-04 Novartis Ag Combinaciones farmaceuticas para el tratamiento de enfermedades proliferativas
MX367970B (es) 2012-08-17 2019-09-11 Hoffmann La Roche Tratamientos de combinación para melanoma que comprenden la administración de cobimetinib y vemurafinib.
CN107434803B (zh) 2012-10-02 2020-05-05 吉利德科学公司 组蛋白去甲基化酶抑制剂
NZ706723A (en) 2012-10-12 2018-07-27 Exelixis Inc Novel process for making compounds for use in the treatment of cancer
ES2644758T3 (es) 2012-10-16 2017-11-30 Tolero Pharmaceuticals, Inc. Moduladores de PKM2 y métodos para su uso
HRP20240033T1 (hr) 2012-10-19 2024-03-29 Array Biopharma, Inc. Formulacija koja sadrži inhibitor mek
US20140142689A1 (en) 2012-11-21 2014-05-22 Didier De Canniere Device and method of treating heart valve malfunction
RU2674995C2 (ru) * 2012-11-29 2018-12-14 Новартис Аг Фармацевтические комбинации
EP2934515B1 (en) 2012-12-20 2018-04-04 Novartis AG A pharmaceutical combination comprising binimetinib
EP2752191A1 (en) 2013-01-07 2014-07-09 Sanofi Compositions and methods using hdm2 antagonist and mek inhibitor
CN105229144A (zh) 2013-02-22 2016-01-06 细胞动力学国际有限公司 通过组合的遗传工程和化学工程经由正向编程产生肝细胞
ES2703208T3 (es) 2013-02-27 2019-03-07 Daiichi Sankyo Co Ltd Método de predicción de la sensibilidad a un compuesto que inhibe la vía de transducción de señales de MAPK
WO2014131777A1 (en) 2013-02-27 2014-09-04 Epitherapeutics Aps Inhibitors of histone demethylases
PL2970205T3 (pl) 2013-03-14 2019-10-31 Tolero Pharmaceuticals Inc Inhibitory jak2 i alk2 oraz sposoby ich zastosowania
NZ712184A (en) 2013-03-21 2020-01-31 Array Biopharma Inc Combination therapy comprising a b-raf inhibitor and a second inhibitor
AR097617A1 (es) 2013-09-13 2016-04-06 Actelion Pharmaceuticals Ltd Derivados antibacterianos del 2h-indazol
WO2015041534A1 (en) 2013-09-20 2015-03-26 Stichting Het Nederlands Kanker Instituut P90rsk in combination with raf/erk/mek
EP3046557A1 (en) 2013-09-20 2016-07-27 Stichting Het Nederlands Kanker Instituut Rock in combination with mapk-pathway
WO2015048312A1 (en) 2013-09-26 2015-04-02 Costim Pharmaceuticals Inc. Methods for treating hematologic cancers
US9566443B2 (en) 2013-11-26 2017-02-14 Corquest Medical, Inc. System for treating heart valve malfunction including mitral regurgitation
EP3083567B1 (en) 2013-12-19 2018-03-07 Idorsia Pharmaceuticals Ltd Antibacterial 1h-indazole and 1h-indole derivatives
CA2935804A1 (en) 2014-01-14 2015-07-23 Dana-Farber Cancer Institute, Inc. Compositions and methods for identification, assessment, prevention, and treatment of melanoma using pd-l1 isoforms
CN104788365B (zh) * 2014-01-16 2018-08-10 上海艾力斯医药科技有限公司 异烟酰胺衍生物、其制备方法及应用
JOP20200094A1 (ar) 2014-01-24 2017-06-16 Dana Farber Cancer Inst Inc جزيئات جسم مضاد لـ pd-1 واستخداماتها
JOP20200096A1 (ar) 2014-01-31 2017-06-16 Children’S Medical Center Corp جزيئات جسم مضاد لـ tim-3 واستخداماتها
AR099612A1 (es) 2014-03-04 2016-08-03 Actelion Pharmaceuticals Ltd Derivados antibacterianos de 1,2-dihidro-3h-pirrolo[1,2-c]imidazol-3-ona
WO2015134652A1 (en) 2014-03-04 2015-09-11 Bahram Valamehr Improved reprogramming methods and cell culture platforms
WO2015138920A1 (en) 2014-03-14 2015-09-17 Novartis Ag Antibody molecules to lag-3 and uses thereof
CA2943824A1 (en) 2014-03-31 2015-10-08 Gilead Sciences, Inc. Inhibitors of histone demethylases
WO2015164228A1 (en) 2014-04-21 2015-10-29 Cellular Dynamics International, Inc. Hepatocyte production via forward programming by combined genetic and chemical engineering
EA201692305A1 (ru) 2014-05-16 2017-05-31 Актелион Фармасьютиклз Лтд. Антибактериальные хиназолин-4(3н)-оновые производные
US10023879B2 (en) 2014-06-04 2018-07-17 Fate Therapeutics, Inc. Minimal volume reprogramming of mononuclear cells
KR20170026630A (ko) 2014-07-15 2017-03-08 제넨테크, 인크. Pd-1 축 결합 길항제 및 mek 저해제를 사용하는 암의 치료용 조성물
CA2957947A1 (en) 2014-08-27 2016-03-03 Gilead Sciences, Inc. Compounds and methods for inhibiting histone demethylases
WO2016040880A1 (en) 2014-09-13 2016-03-17 Novartis Ag Combination therapies of alk inhibitors
ES2774448T3 (es) 2014-10-03 2020-07-21 Novartis Ag Terapias de combinación
EP3204516B1 (en) 2014-10-06 2023-04-26 Dana-Farber Cancer Institute, Inc. Angiopoietin-2 biomarkers predictive of anti-immune checkpoint response
MA41044A (fr) 2014-10-08 2017-08-15 Novartis Ag Compositions et procédés d'utilisation pour une réponse immunitaire accrue et traitement contre le cancer
AU2015333687B2 (en) 2014-10-14 2021-03-18 Dana-Farber Cancer Institute, Inc. Antibody molecules to PD-L1 and uses thereof
US10842626B2 (en) 2014-12-09 2020-11-24 Didier De Canniere Intracardiac device to correct mitral regurgitation
WO2016100882A1 (en) 2014-12-19 2016-06-23 Novartis Ag Combination therapies
DK3237418T3 (da) 2014-12-23 2019-05-13 Novartis Ag Triazolopyrimidinforbindelser og anvendelser deraf
EP3250680A4 (en) 2015-01-26 2018-12-05 Fate Therapeutics, Inc. Methods and compositions for inducing hematopoietic cell differentiation
CN105566225A (zh) * 2015-02-16 2016-05-11 苏州晶云药物科技有限公司 一种口服丝裂原活化蛋白激酶抑制剂的晶型及其制备方法
JP2016155776A (ja) * 2015-02-24 2016-09-01 学校法人兵庫医科大学 抗腫瘍効果増強剤および抗腫瘍剤
MY190404A (en) 2015-03-10 2022-04-21 Aduro Biotech Inc Compositions and methods for activating "stimulator of interferon gene"-dependent signalling
JP6695353B2 (ja) 2015-03-25 2020-05-20 ノバルティス アーゲー Ｆｇｆｒ４阻害剤としてのホルミル化ｎ−複素環式誘導体
MA41866A (fr) 2015-03-31 2018-02-06 Massachusetts Gen Hospital Molécules à auto-assemblage pour l'administration ciblée de médicaments
EP3878465A1 (en) 2015-07-29 2021-09-15 Novartis AG Combination therapies comprising antibody molecules to tim-3
EP3328418A1 (en) 2015-07-29 2018-06-06 Novartis AG Combination therapies comprising antibody molecules to pd-1
PT3317301T (pt) 2015-07-29 2021-07-09 Novartis Ag Terapias de associação compreendendo moléculas de anticorpo contra lag-3
AR105646A1 (es) 2015-08-11 2017-10-25 Actelion Pharmaceuticals Ltd Agentes antibacterianos de 1,2-dihidro-3h-pirrolo[1,2-c]imidazol-3-ona sustituida
US20190008859A1 (en) 2015-08-21 2019-01-10 Acerta Pharma B.V. Therapeutic Combinations of a MEK Inhibitor and a BTK Inhibitor
RU2020142739A (ru) 2015-08-28 2021-01-15 Новартис Аг Ингибиторы mdm2 и их комбинации
AR105889A1 (es) 2015-09-03 2017-11-22 Actelion Pharmaceuticals Ltd Compuestos antibacterianos 1,2-dihidro-3h-pirrolo[1,2-c]imidazol-3-ona sustituidos
KR102746585B1 (ko) 2015-10-16 2024-12-24 페이트 세러퓨틱스, 인코포레이티드 기저 상태 다능성의 유도 및 유지를 위한 플랫폼
JP2019500892A (ja) 2015-11-03 2019-01-17 ヤンセン バイオテツク，インコーポレーテツド Ｔｉｍ−３に特異的に結合する抗体及びその使用
CN108473961B (zh) 2015-11-04 2022-11-29 菲特治疗公司 用于诱导造血细胞分化的方法和组合物
PT3371314T (pt) 2015-11-04 2023-08-31 Fate Therapeutics Inc Modificação genómica de células pluripotentes
JP2019503349A (ja) 2015-12-17 2019-02-07 ノバルティス アーゲー Ｐｄ−１に対する抗体分子およびその使用
WO2017127755A1 (en) 2016-01-20 2017-07-27 Fate Therapeutics, Inc. Compositions and methods for immune cell modulation in adoptive immunotherapies
KR20180096707A (ko) 2016-01-20 2018-08-29 페이트 세러퓨틱스, 인코포레이티드 입양 면역요법에서 면역 세포 조절을 위한 조성물 및 방법
WO2017150725A1 (ja) 2016-03-04 2017-09-08 大鵬薬品工業株式会社 悪性腫瘍治療用製剤及び組成物
US11883404B2 (en) 2016-03-04 2024-01-30 Taiho Pharmaceuticals Co., Ltd. Preparation and composition for treatment of malignant tumors
AR108257A1 (es) 2016-05-02 2018-08-01 Mei Pharma Inc Formas polimórficas de 3-[2-butil-1-(2-dietilamino-etil)-1h-bencimidazol-5-il]-n-hidroxi-acrilamida y usos de las mismas
FI3463345T3 (fi) 2016-06-03 2023-01-31 Farmaseuttisia yhdistelmiä
US10676479B2 (en) 2016-06-20 2020-06-09 Novartis Ag Imidazolepyridine compounds and uses thereof
CN109563100B (zh) 2016-06-20 2021-08-27 诺华股份有限公司 三唑并嘧啶化合物的晶体形式
ES2798424T3 (es) 2016-06-20 2020-12-11 Novartis Ag Compuestos de triazolopiridina y usos de estos
US11098077B2 (en) 2016-07-05 2021-08-24 Chinook Therapeutics, Inc. Locked nucleic acid cyclic dinucleotide compounds and uses thereof
WO2018065924A1 (en) * 2016-10-04 2018-04-12 Sun Pharmaceutical Industries Limited Intermediates of mitogen-activated protein kinase kinase (map2k or mek) inhibitors and process for their preparation
WO2018092064A1 (en) 2016-11-18 2018-05-24 Novartis Ag Combinations of mdm2 inhibitors and bcl-xl inhibitors
CN108084078B (zh) * 2016-11-24 2021-07-30 中山大学 一种治疗银屑病性关节炎疾病的药物阿普斯特的合成方法
JP7098615B2 (ja) 2016-12-05 2022-07-11 フェイト セラピューティクス，インコーポレイテッド 養子免疫療法における免疫細胞調節のための組成物および方法
EP3372624A1 (en) 2017-03-06 2018-09-12 Henkel AG & Co. KGaA One component composition based on compounds with at least two exo-vinylene cyclic carbonate units
UY37695A (es) 2017-04-28 2018-11-30 Novartis Ag Compuesto dinucleótido cíclico bis 2’-5’-rr-(3’f-a)(3’f-a) y usos del mismo
US12116348B2 (en) 2017-11-14 2024-10-15 Shenzhen Targetrx, Inc. Substituted benzimidazole compound and composition comprising same
AU2018368731A1 (en) 2017-11-16 2020-05-14 Novartis Ag Combination therapies
TW201938165A (zh) 2017-12-18 2019-10-01 美商輝瑞股份有限公司 治療癌症的方法及組合療法
US12398209B2 (en) 2018-01-22 2025-08-26 Janssen Biotech, Inc. Methods of treating cancers with antagonistic anti-PD-1 antibodies
EP3769765B1 (en) 2018-03-19 2024-04-17 Taiho Pharmaceutical Co., Ltd. Pharmaceutical composition including sodium alkyl sulfate
AU2019247498A1 (en) 2018-04-05 2020-11-26 Sumitomo Pharma Oncology, Inc. AXL kinase inhibitors and use of the same
AU2019274657A1 (en) 2018-05-24 2020-12-10 Janssen Biotech, Inc. PSMA binding agents and uses thereof
AR116109A1 (es) 2018-07-10 2021-03-31 Novartis Ag Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos
EP4541380A3 (en) 2018-07-25 2025-07-23 Advanced Accelerator Applications S.A. Stable, concentrated radionuclide complex solutions
WO2020021465A1 (en) 2018-07-25 2020-01-30 Advanced Accelerator Applications (Italy) S.R.L. Method of treatment of neuroendocrine tumors
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same
JP7328323B2 (ja) 2018-08-17 2023-08-16 ノバルティス アーゲー ＳＭＡＲＣＡ２／ＢＲＭ ＡＴＰａｓｅ阻害剤としての尿素化合物及び組成物
WO2020064693A1 (en) 2018-09-25 2020-04-02 Advanced Accelerator Applications (Italy) Srl Combination therapy
EP3883552B1 (en) 2018-11-20 2025-04-09 NFlection Therapeutics, Inc. Cyanoaryl-aniline compounds for treatment of dermal disorders
WO2020106308A1 (en) 2018-11-20 2020-05-28 Nflection Therapeutics, Inc. Naphthyridinone-aniline compounds for treatment of dermal disorders
MX2021007392A (es) 2018-12-20 2021-08-24 Novartis Ag Regimen de dosificacion y combinacion farmaceutica que comprende derivados de 3-(1-oxoisoindolin-2-il)piperidina-2,6-diona.
BR112021011894A2 (pt) 2018-12-21 2021-09-08 Daiichi Sankyo Company, Limited Composição farmacêutica
EP3924351B1 (en) 2019-02-12 2025-05-21 Sumitomo Pharma America, Inc. Crystalline form of the hydrochloride salt of 2-((1r,4r)-4-((3-(3-(trifluoromethyl)phenyl) imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol
US20220144798A1 (en) 2019-02-15 2022-05-12 Novartis Ag Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
EP3924054B1 (en) 2019-02-15 2025-04-02 Novartis AG 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US20220143049A1 (en) 2019-03-21 2022-05-12 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
JP7547360B2 (ja) 2019-03-22 2024-09-09 スミトモ ファーマ オンコロジー， インコーポレイテッド Ｐｋｍ２モジュレーターを含む組成物およびそれを使用する処置の方法
WO2020212832A1 (en) * 2019-04-16 2020-10-22 Alembic Pharmaceuticals Limited Process of preparation of benzimidazole compounds
BR112021020532A2 (pt) 2019-04-19 2022-03-15 Janssen Biotech Inc Métodos para tratamento de câncer de próstata com um anticorpo anti-psma/cd3
TWI817018B (zh) 2019-06-28 2023-10-01 美商艾瑞生藥股份有限公司 用於治療ｂｒａｆ相關的疾病和失調症之化合物
WO2021003417A1 (en) 2019-07-03 2021-01-07 Sumitomo Dainippon Pharma Oncology, Inc. Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof
CN114746414B (zh) 2019-09-26 2024-10-18 诺华公司 氮杂-喹啉化合物及其用途
AU2020378630A1 (en) 2019-11-08 2022-05-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021116901A1 (en) * 2019-12-09 2021-06-17 Biocon Limited Forms of binimetinib and process for preparation thereof
WO2021123996A1 (en) 2019-12-20 2021-06-24 Novartis Ag Uses of anti-tgf-beta antibodies and checkpoint inhibitors for the treatment of proliferative diseases
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
JP2023517393A (ja) * 2020-03-17 2023-04-25 メッドシャイン ディスカバリー インコーポレイテッド タンパク質分解調整剤およびその使用方法
WO2021206167A1 (ja) 2020-04-10 2021-10-14 大鵬薬品工業株式会社 ３，５－二置換ベンゼンアルキニル化合物とｍｅｋ阻害剤とを用いた癌治療法
AU2021289163B2 (en) 2020-06-09 2024-05-02 Array Biopharma Inc. 4-oxo-3,4-dihydroquinazolinon compounds for the treatment of BRAF-associated diseases and disorders
KR20230027056A (ko) 2020-06-23 2023-02-27 노파르티스 아게 3-(1-옥소이소인돌린-2-일)피페리딘-2,6-디온 유도체를 포함하는 투약 요법
AR123185A1 (es) 2020-08-10 2022-11-09 Novartis Ag Compuestos y composiciones para inhibir ezh2
WO2022043557A1 (en) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
WO2022043556A1 (en) 2020-08-31 2022-03-03 Novartis Ag Stable radiopharmaceutical composition
US20230338587A1 (en) 2020-08-31 2023-10-26 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
EP4225307A1 (en) 2020-10-05 2023-08-16 Pierre Fabre Medicament Combination of encorafenib and binimetinib as adjuvant treatment for resected stage ii melanoma
TW202237119A (zh) 2020-12-10 2022-10-01 美商住友製藥腫瘤公司 Ａｌｋ﹘５抑制劑和彼之用途
CN112759552A (zh) * 2020-12-31 2021-05-07 武汉九州钰民医药科技有限公司 司美替尼的合成方法
CN112679438A (zh) * 2020-12-31 2021-04-20 武汉九州钰民医药科技有限公司 制备司美替尼的方法
US12141240B2 (en) 2021-01-20 2024-11-12 Rutgers, The State University Of New Jersey Method of calibration using master calibration function
EP4281069A1 (en) * 2021-01-21 2023-11-29 NFlection Therapeutics, Inc. Processes for preparing pyrrolopyridine-aniline compounds
PE20240761A1 (es) 2021-01-28 2024-04-17 Janssen Biotech Inc Proteinas de union a psma y usos de estas
CN117794929A (zh) 2021-02-02 2024-03-29 法国施维雅药厂 选择性bcl-xl protac化合物及使用方法
WO2022195551A1 (en) 2021-03-18 2022-09-22 Novartis Ag Biomarkers for cancer and methods of use thereof
TW202304979A (zh) 2021-04-07 2023-02-01 瑞士商諾華公司 抗ＴＧＦβ抗體及其他治療劑用於治療增殖性疾病之用途
AU2022257621A1 (en) 2021-04-13 2023-11-23 Nuvalent, Inc. Amino-substituted heterocycles for treating cancers with egfr mutations
EP4322953A4 (en) * 2021-04-15 2025-01-22 Ideaya Biosciences, Inc. COMBINATION THERAPY WITH A PKC INHIBITOR AND A MEK INHIBITOR
AR125874A1 (es) 2021-05-18 2023-08-23 Novartis Ag Terapias de combinación
CN117642166A (zh) 2021-06-09 2024-03-01 中外制药株式会社 用于癌症治疗的组合疗法
WO2022262699A1 (zh) * 2021-06-17 2022-12-22 深圳市塔吉瑞生物医药有限公司 取代的苯并咪唑类化合物及包含该化合物的组合物及其用途
EP4367112A1 (en) 2021-07-09 2024-05-15 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate ikzf2
MX2024005107A (es) 2021-11-04 2024-05-14 Hoffmann La Roche Nuevo uso de compuesto de quinazolinona para el tratamiento de cancer.
WO2023084489A1 (en) 2021-11-15 2023-05-19 Pfizer Inc. Methods of treating coronavirus disease 2019
TW202342018A (zh) 2022-03-04 2023-11-01 美商奇奈特生物製藥公司 Mek激酶抑制劑
AU2023271885A1 (en) 2022-05-20 2024-12-12 Les Laboratoires Servier Epha2 bcl-xl inhibitor antibody-drug conjugates and methods of use thereof
TW202404645A (zh) 2022-05-20 2024-02-01 瑞士商諾華公司 Met bcl-xl抑制劑抗體-藥物結合物及其使用方法
WO2023238000A1 (en) * 2022-06-06 2023-12-14 Glenmark Life Sciences Limited Process for preparation of selumetinib and salts thereof
CN120265291A (zh) 2022-11-18 2025-07-04 豪夫迈·罗氏有限公司 喹唑啉酮化合物的新用途和制剂
AU2024234194A1 (en) 2023-03-10 2025-08-07 Novartis Ag Panras inhibitor antibody-drug conjugates and methods of use thereof
WO2025073765A1 (en) 2023-10-03 2025-04-10 Institut National de la Santé et de la Recherche Médicale Methods of prognosis and treatment of patients suffering from melanoma
WO2025111450A1 (en) 2023-11-22 2025-05-30 Les Laboratoires Servier Anti-cd74 antibody-drug conjugates and methods of use thereof
PL451049A1 (pl) * 2025-01-27 2025-08-04 Politechnika Lubelska Kompozytowa konstrukcja przekładkowa
PL451045A1 (pl) * 2025-01-27 2025-06-09 Politechnika Lubelska Kompozytowa konstrukcja przekładkowa
PL451050A1 (pl) * 2025-01-27 2025-08-04 Politechnika Lubelska Kompozytowa konstrukcja przekładkowa
PL451048A1 (pl) * 2025-01-27 2025-08-04 Politechnika Lubelska Kompozytowa konstrukcja przekładkowa
PL451046A1 (pl) * 2025-01-27 2025-06-09 Politechnika Lubelska Kompozytowa konstrukcja przekładkowa
PL451047A1 (pl) * 2025-01-27 2025-08-18 Politechnika Lubelska Kompozytowa konstrukcja przekładkowa

Citations (5)

* 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
US6469004B1 (en) * 1999-01-13 2002-10-22 Warner-Lambert Company Benzoheterocycles and their uses 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
US20030078428A1 (en) * 1997-07-01 2003-04-24 Barrett Stephen Douglas 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as MEK inhibitors
US20030092748A1 (en) * 1999-01-13 2003-05-15 Barrett Stephen Douglas Benzenesulfonamide derivatives and their use as MEK inhibitors

Family Cites Families (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1980001113A1 (en) 1978-11-20 1980-05-29 Braun Ag Time-keeper in particular quartz controlled clock
GB8607683D0 (en) 1986-03-27 1986-04-30 Ici Plc Anti-tumor agents
GB8827305D0 (en) 1988-11-23 1988-12-29 British Bio Technology Compounds
IL95975A (en) 1989-10-24 1997-06-10 Takeda Chemical Industries Ltd N-benzyl- 2-alkylbenzimidazole derivatives, their production and pharmaceutical compositions containing them
US5250554A (en) 1989-10-24 1993-10-05 Takeda Chemical Industries, Ltd. Benzimidazole derivatives useful as angiotensin II inhibitors
US5218356A (en) * 1991-05-31 1993-06-08 Guenther Knapp Wireless indoor data relay system
US5216003A (en) 1992-01-02 1993-06-01 G. D. Searle & Co. Diacid-containing benzimidazole compounds for treatment of neurotoxic injury
US5455258A (en) 1993-01-06 1995-10-03 Ciba-Geigy Corporation Arylsulfonamido-substituted hydroxamic acids
WO1995003286A1 (fr) 1993-07-23 1995-02-02 The Green Cross Corporation Derive de triazole et son utilisation pharmaceutique
EP0639573A1 (de) 1993-08-03 1995-02-22 Hoechst Aktiengesellschaft Benzokondensierte 5-Ringheterocyclen, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, ihre Verwendung als Diagnostikum, sowie sie enthaltendes Medikament
IL113472A0 (en) 1994-04-29 1995-07-31 Lilly Co Eli Non-peptidyl tachykinin receptor antogonists
US5520187A (en) 1994-11-25 1996-05-28 General Electric Company Ultrasonic probe with programmable multiplexer for imaging systems with different channel counts
US5863949A (en) 1995-03-08 1999-01-26 Pfizer Inc Arylsulfonylamino hydroxamic acid derivatives
WO1996033172A1 (en) 1995-04-20 1996-10-24 Pfizer Inc. Arylsulfonyl hydroxamic acid derivatives as mmp and tnf inhibitors
US5972980A (en) 1995-10-05 1999-10-26 Warner-Lambert Company Method for treating and preventing inflammation and atherosclerosis
DK0780386T3 (da) 1995-12-20 2003-02-03 Hoffmann La Roche Matrixmetalloproteaseinhibitorer
GB9600344D0 (en) 1996-01-09 1996-03-13 Lilly Co Eli Benzimidzolyl neuropeptide y receptor antagonists
JP3299975B2 (ja) 1996-07-18 2002-07-08 ファイザー・インク マトリックスメタロプロテアーゼのホスフィン酸塩ベース阻害薬
SK21499A3 (en) 1996-08-23 2000-05-16 Pfizer Arylsulfonylamino hydroxamic acid derivatives
ES2224277T3 (es) 1997-01-06 2005-03-01 Pfizer Inc. Derivados de sulfonas ciclicas.
IL131042A0 (en) 1997-02-03 2001-01-28 Pfizer Prod Inc Arylsulfonylamino hydroxamic acid derivatives
WO1998034915A1 (en) 1997-02-07 1998-08-13 Pfizer Inc. N-hydroxy-beta-sulfonyl-propionamide derivatives and their use as inhibitors of matrix metalloproteinases
PL334997A1 (en) 1997-02-11 2000-03-27 Pfizer Derivatives or arylosulphonyl-hydroxamic acid
UA73073C2 (uk) 1997-04-03 2005-06-15 Уайт Холдінгз Корпорейшн Заміщені 3-ціанохіноліни, спосіб їх одержання та фармацевтична композиція
AU756586C (en) 1997-07-01 2004-01-29 Warner-Lambert Company 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as MEK inhibitors
BR9810366A (pt) 1997-07-01 2000-08-29 Warner Lambert Co Derivados de ácido 4-bromo ou 4-iodo fenilamino benzidroxîmico e seu uso como inibidores de mek
US6310060B1 (en) 1998-06-24 2001-10-30 Warner-Lambert Company 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as MEK inhibitors
GB9725782D0 (en) 1997-12-05 1998-02-04 Pfizer Ltd Therapeutic agents
GB9801690D0 (en) 1998-01-27 1998-03-25 Pfizer Ltd Therapeutic agents
PA8469501A1 (es) 1998-04-10 2000-09-29 Pfizer Prod Inc Hidroxamidas del acido (4-arilsulfonilamino)-tetrahidropiran-4-carboxilico
PA8469401A1 (es) 1998-04-10 2000-05-24 Pfizer Prod Inc Derivados biciclicos del acido hidroxamico
US6534503B1 (en) 1998-04-28 2003-03-18 Lion Bioscience Ag Melanocortin receptor-3 ligands to treat sexual dysfunction
AUPP616498A0 (en) 1998-09-25 1998-10-15 University Of Queensland, The Synthesis of cyclic peptides
JP2002534381A (ja) 1999-01-07 2002-10-15 ワーナー−ランバート・カンパニー Ｍｅｋ阻害剤を用いた抗ウィルス法
ATE292462T1 (de) 1999-01-07 2005-04-15 Warner Lambert Co Behandlung von asthma anhand von mek-inhibitoren
JP2000204077A (ja) 1999-01-13 2000-07-25 Warner Lambert Co ジアリ―ルアミン
CA2348236A1 (en) 1999-01-13 2000-07-20 Stephen Douglas Barrett 4-arylamino, 4-aryloxy, and 4-arylthio diarylamines and derivatives thereof as selective mek inhibitors
ATE311363T1 (de) 1999-01-13 2005-12-15 Warner Lambert Co Sulfohydroxamsäure and sulfohydroxamate und ihre verwendung als mek-inhibitoren
AU2483400A (en) 1999-01-13 2000-08-01 Warner-Lambert Company 4'heteroaryl diarylamines
US6545030B1 (en) 1999-01-13 2003-04-08 Warner-Lambert Company 1-heterocycle substituted diarylamines
GB9910577D0 (en) 1999-05-08 1999-07-07 Zeneca Ltd Chemical compounds
GB9912961D0 (en) 1999-06-03 1999-08-04 Pfizer Ltd Metalloprotease inhibitors
WO2001005390A2 (en) 1999-07-16 2001-01-25 Warner-Lambert Company Method for treating chronic pain using mek inhibitors
CN1365277A (zh) 1999-07-16 2002-08-21 沃尼尔·朗伯公司 使用mek抑制剂治疗慢性疼痛的方法
CN1358095A (zh) 1999-07-16 2002-07-10 沃尼尔·朗伯公司 使用mek抑制剂治疗慢性疼痛的方法
US7030119B1 (en) * 1999-07-16 2006-04-18 Warner-Lambert Company Method for treating chronic pain using MEK inhibitors
PL352684A1 (pl) 1999-07-16 2003-09-08 Warner-Lambert Company Sposób leczenia chronicznego bólu z użyciem inhibitorów MEK
EP1214330A1 (en) 1999-09-21 2002-06-19 LION Bioscience AG Benzimidazole derivatives and combinatorial libraries thereof
BR0109188A (pt) 2000-03-15 2003-03-18 Warner Lambert Co Diarilaminas 5-amida substituìdas como inibidores de mex
EP1339702A1 (en) 2000-03-15 2003-09-03 Warner-Lambert Company 5-amide substituted diarylamines as mek inhibitors
DZ3401A1 (fr) 2000-07-19 2002-01-24 Warner Lambert Co Esters oxygenes d'acides 4-iodophenylamino benzhydroxamiques
BR0113520A (pt) 2000-08-25 2003-06-24 Warner Lambert Co Processo de preparação de ácidos n-aril-antranìlicos e seus derivados
WO2002044166A1 (en) 2000-11-02 2002-06-06 Astrazeneca Ab Substituted quinolines as antitumor agents
US20070004713A1 (en) 2000-12-07 2007-01-04 Bernard Barlaam Therapeutic benimidazole compounds
US7102009B2 (en) 2001-01-12 2006-09-05 Amgen Inc. Substituted amine derivatives and methods of use
MXPA03008143A (es) 2001-03-09 2005-08-16 Johnson & Johnson Compuestos heterociclicos.
US20040039208A1 (en) 2001-07-20 2004-02-26 Chen Michael Huai Gu Process for making n-aryl-anthranilic acids and their derivatives
WO2003024899A2 (en) 2001-09-17 2003-03-27 Bristol-Myers Squibb Company CYCLIC HYDROXAMIC ACIDS AS INHIBITORS OF MATRIX METALLOPROTEINASES AND/OR TNF-α CONVERTING ENZYME (TACE)
WO2003054180A1 (en) 2001-12-21 2003-07-03 Warner-Lambert Company Llc Modified mek1 and mek2, crystal of a peptide: ligand: cofactor complex containing such modified mek1 or mek2, and methods of use thereof
BR0307060A (pt) 2002-01-23 2004-10-26 Warner Lambert Co ésteres hidroxamato do ácido n-(fenil 4-substituìdo)-antranìlico
US7235537B2 (en) * 2002-03-13 2007-06-26 Array Biopharma, Inc. N3 alkylated benzimidazole derivatives as MEK inhibitors
PL378635A1 (pl) * 2002-03-13 2006-05-15 Array Biopharma, Inc. N3 alkilowane pochodne benzoimidazolu jako inhibitory MEK
CN101486682B (zh) 2002-03-13 2013-08-14 阵列生物制药公司 作为mek抑制剂的n3烷基化苯并咪唑衍生物
DE10238002A1 (de) 2002-08-20 2004-03-04 Merck Patent Gmbh Benzimidazolderivate
BR0314059A (pt) 2002-09-06 2005-07-05 Janssen Pharmaceutica Nv Compostos heterocìclicos
US20040127395A1 (en) 2002-09-06 2004-07-01 Desai Pragnya J. Use of histamine H4 receptor modulators for the treatment of allergy and asthma
US7582635B2 (en) 2002-12-24 2009-09-01 Purdue Pharma, L.P. Therapeutic agents useful for treating pain
CA2532067C (en) 2003-07-24 2010-12-21 Stephen Douglas Barrett N-methyle-substituted benzamidazoles
DE102005032379A1 (de) 2005-07-08 2007-01-11 Conti Temic Microelectronic Gmbh Zugangskontrollsystem für ein Kraftfahrzeug
TWI405756B (zh) 2005-12-21 2013-08-21 Array Biopharma Inc 新穎硫酸氫鹽
EP2934515B1 (en) 2012-12-20 2018-04-04 Novartis AG A pharmaceutical combination comprising binimetinib

Patent Citations (5)

* 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
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
US20030078428A1 (en) * 1997-07-01 2003-04-24 Barrett Stephen Douglas 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as MEK inhibitors
US6469004B1 (en) * 1999-01-13 2002-10-22 Warner-Lambert Company Benzoheterocycles and their uses as MEK inhibitors
US20030092748A1 (en) * 1999-01-13 2003-05-15 Barrett Stephen Douglas Benzenesulfonamide derivatives and their use as MEK inhibitors

Cited By (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8513293B2 (en) 2002-03-13 2013-08-20 Array Biopharma Inc. Methods of treating a hyperproliferative disorder or inhibiting cell growth in a mammal
US20060030610A1 (en) * 2003-09-03 2006-02-09 Kevin Koch Method of treating inflammatory diseases
US20050054701A1 (en) * 2003-09-03 2005-03-10 Eli Wallace 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
US7230099B2 (en) 2003-09-03 2007-06-12 Array Biopharma, Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US20110183981A1 (en) * 2003-11-19 2011-07-28 Array Biopharma Inc. Heterocyclic inhibitors of mek and methods of use thereof
US20090143579A1 (en) * 2003-11-19 2009-06-04 Array Biopharma Inc. Heterocyclic Inhibitors of MEK and Methods of Use Thereof
US20050250782A1 (en) * 2003-11-19 2005-11-10 Marlow Allison L Heterocyclic inhibitors of MEK and methods of use thereof
US20050256123A1 (en) * 2003-11-19 2005-11-17 Marlow Allison L Heterocyclic inhibitors of MEK and methods of use thereof
US20050153942A1 (en) * 2003-11-19 2005-07-14 Eli Wallace Heterocyclic inhibitors of MEK and methods of use thereof
EP1689406A4 (en) * 2003-11-19 2007-01-17 Array Biopharma Inc HETEROCYCLIC INHIBITORS OF MEK AND METHOD FOR THEIR APPLICATION
US20070112038A1 (en) * 2003-11-19 2007-05-17 Marlow Allison L Heterocyclic inhibitors of MEK and methods of use thereof
US20050130943A1 (en) * 2003-11-19 2005-06-16 Eli Wallace 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
WO2005051300A2 (en) 2003-11-19 2005-06-09 Array Biopharma Inc. Bicyclic 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
US7772234B2 (en) 2003-11-19 2010-08-10 Array Biopharma Inc. Bicyclic inhibitors of MEK and methods of use thereof
US7732616B2 (en) 2003-11-19 2010-06-08 Array Biopharma Inc. Dihydropyridine and dihydropyridazine derivatives as 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
US7517994B2 (en) 2003-11-19 2009-04-14 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US20090131435A1 (en) * 2003-11-19 2009-05-21 Array Biopharma Inc. Heterocyclic inhibitors of mek and methods of use
US20050130976A1 (en) * 2003-11-19 2005-06-16 Eli Wallace Bicyclic inhibitors of MEK and methods of use thereof
US20110178136A1 (en) * 2003-11-19 2011-07-21 Array Biopharma Inc. Heterocyclic inhibitors of mek and methods of use thereof
US20090143389A1 (en) * 2003-11-19 2009-06-04 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
US7598383B2 (en) 2003-11-19 2009-10-06 Array Biopharma Inc. Heterocyclic inhibitors of MEK 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
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
US8211921B2 (en) 2003-11-19 2012-07-03 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use
US8101611B2 (en) 2003-11-19 2012-01-24 Array Biopharma Inc. Substituted pyridazines inhibitors of MEK
US20100168123A1 (en) * 2003-11-21 2010-07-01 Mitchell Ian S Akt protein kinase inhibitors
US8680114B2 (en) 2003-11-21 2014-03-25 Array Biopharma, Inc. AKT protein kinase inhibitors
US20050130954A1 (en) * 2003-11-21 2005-06-16 Mitchell Ian S. AKT protein kinase inhibitors
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
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
EP2364973A1 (en) 2005-05-18 2011-09-14 Array Biopharma, Inc. Heterocyclic inhibitors of MEK and Methods of use thereof
US20080280957A1 (en) * 2005-05-18 2008-11-13 Array Biopharma, Inc. Heterocyclic Inhibitors of Mek and Methods of Use Thereof
EP2361905A1 (en) 2005-05-18 2011-08-31 Array Biopharma Inc. Heterocyclic Inhibitors of MEK and methods of use thereof
CN101248060B (zh) * 2005-06-23 2014-09-10 阵列生物制药公司 用于制备苯并咪唑化合物的方法
TWI391380B (zh) * 2005-06-23 2013-04-01 Array Biopharma Inc 製備苯并咪唑化合物之方法
US8383832B2 (en) 2005-06-23 2013-02-26 Array Biopharma Inc. Process for preparing benzimidazole compounds
US8183385B2 (en) 2005-06-23 2012-05-22 Array Biopharma Inc. SNAR process for preparing benzimidazole compounds
US9024040B2 (en) 2005-06-23 2015-05-05 Array Biopharma Inc. Processes for preparing benzimidazole compounds
WO2007002157A3 (en) * 2005-06-23 2007-11-01 Array Biopharma Inc Process for preparing benzimidazole compounds
US8501956B2 (en) 2005-06-23 2013-08-06 Array Biopharma Inc. Benzimidazole compounds
AU2006262259B2 (en) * 2005-06-23 2013-03-14 Array Biopharma Inc. Process for preparing benzimidazole compounds
US8039637B2 (en) 2005-06-23 2011-10-18 Array Biopharma Inc. Process for preparing benzimidazole compounds
US20100145065A1 (en) * 2005-06-23 2010-06-10 Array Biopharma Inc. Process for preparing benzimidazole compounds
US20100130748A1 (en) * 2005-06-23 2010-05-27 Array Biopharma Inc. Snar process for preparing benzimidazole compounds
US20100016393A1 (en) * 2005-12-21 2010-01-21 Demattei John Novel hydrogen sulfate salt
US9156795B2 (en) 2005-12-21 2015-10-13 Array Biopharma, Inc. Hydrogen sulfate salt
US9562017B2 (en) 2005-12-21 2017-02-07 AsrtaZeneca AB Hydrogen sulfate salt
US20090030058A1 (en) * 2005-12-21 2009-01-29 Mohammed Pervez 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
US20080058327A1 (en) * 2006-07-06 2008-03-06 Mitchell Ian S Pyrimidyl cyclopentanes as akt protein kinase inhibitors
US20080051399A1 (en) * 2006-07-06 2008-02-28 Mitchell Ian S Hydroxylated and methoxylated pyrimidyl cyclopentanes 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
US8329701B2 (en) 2006-07-06 2012-12-11 Array Biopharma Inc. Dihydrofuro pyrimidines as AKT protein kinase inhibitors
US9303040B2 (en) 2006-07-06 2016-04-05 Array Biopharma Inc. Substituted piperazines as AKT inhibitors
US8853199B2 (en) 2006-07-06 2014-10-07 Array Biopharma, Inc. Hydroxylated and methoxylated 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
US8063050B2 (en) 2006-07-06 2011-11-22 Array Biopharma Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8003651B2 (en) 2006-07-06 2011-08-23 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8492378B2 (en) 2006-08-03 2013-07-23 Takeda Pharmaceutical Company Limited GSK-3β inhibitor
US20100069381A1 (en) * 2006-08-03 2010-03-18 Fumio Itoh Gsk-3betainhibitor
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
US20110160221A1 (en) * 2007-07-05 2011-06-30 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
US9409886B2 (en) 2007-07-05 2016-08-09 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US20100292244A1 (en) * 2008-01-09 2010-11-18 Array Biopharma Inc. Hydroxylated pyrimidyl cyclopentane as akt protein kinase inhibitor
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
US20110065716A1 (en) * 2008-01-09 2011-03-17 Array Biopharma Inc. Hydroxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors
WO2010051933A2 (en) 2008-11-10 2010-05-14 Bayer Schering Pharma Aktiengesellschaft Substituted sulphonamido phenoxybenzamides
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
WO2012055953A1 (en) 2010-10-29 2012-05-03 Bayer Pharma Aktiengesellschaft Substituted phenoxypyridines
WO2012085244A1 (fr) 2010-12-23 2012-06-28 Sanofi Derives de pyrimidinone, leur preparation et leur utilisation pharmaceutique
US9150549B2 (en) 2011-04-01 2015-10-06 Genentech, Inc. Combinations of AKT inhibitor compounds and erlotinib, and methods of use
US9150548B2 (en) 2011-04-01 2015-10-06 Genentech, Inc. Combinations of AKT inhibitor compounds and vemurafenib, and methods of use
US9346789B2 (en) 2011-04-01 2016-05-24 Genentech, Inc. Combinations of AKT inhibitor compounds and abiraterone, 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
US9682082B2 (en) 2011-04-01 2017-06-20 Genentech, Inc. Combinations of AKT and MEK inhibitor compounds, 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
US10092567B2 (en) 2011-04-01 2018-10-09 Genentech, Inc. Combinations of AKT inhibitor compounds and chemotherapeutic agents, and methods of use

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