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WO2008147831A1 - Anthranilimides - Google Patents

Anthranilimides Download PDF

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Publication number
WO2008147831A1
WO2008147831A1 PCT/US2008/064446 US2008064446W WO2008147831A1 WO 2008147831 A1 WO2008147831 A1 WO 2008147831A1 US 2008064446 W US2008064446 W US 2008064446W WO 2008147831 A1 WO2008147831 A1 WO 2008147831A1
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Prior art keywords
mmol
compound
pharmaceutically acceptable
alkyl
methyl
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Ceased
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English (en)
Inventor
Jeffrey Michael Axten
Jesus R. Medina Betancourt
Neil W. Johnson
Marcus Semones
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to anthranilamide compounds, compositions, and medicaments thereof, as well as methods of treatments therefor. These anthranalimide compounds are useful in the treatment of diseases associated with Aurora kinase activity.
  • Protein kinases catalyze the phosphorylation of hydroxylic amino acid side chains in proteins by the transfer of the ⁇ -phosphate OfATP-Mg 2+ to form a mono-phosphate ester of serine, threonine or tyrosine. Studies have shown that protein kinases are key regulators of many cell functions, including signal transduction, transcriptional regulation, cell motility and cell division. Several oncogenes have also been shown to encode protein kinases, suggesting that kinases may play a role in oncogenesis.
  • the protein kinase family of enzymes is typically classified into two main subfamilies: protein tyrosine kinases and protein serine/threonine kinases, based on the amino acid residue they phosphorylate.
  • Aberrant protein serine/threonine kinase activity has been implicated or is suspected in a number of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, cancers and other proliferative diseases.
  • Tyrosine kinases play an equally important role in cell regulation. These kinases include several receptors for molecules such as growth factors and hormones, including epidermal growth factor receptor, insulin receptor and platelet derived growth factor receptor.
  • tyrosine kinases are transmembrane proteins with their receptor domains located on the outside of the cell and their kinase domains on the inside. Accordingly, both kinase subfamilies and their signal transduction pathways are important targets for drug design.
  • Aurora-A 2
  • B 1
  • C 3
  • Aurora-A 3
  • cytokinesis cytokinesis .
  • Aurora expression is low or undetectable in resting cells, with expression and activity peaking during the G2 and mitotic phases in cycling cells.
  • substrates for the Aurora A and B kinases include histone H3, CENP-A, myosin II regulatory light chain, protein phosphatase 1, TPX2, INCENP, p53 and survivin, many of which are required for cell division.
  • Aurora kinases have been reported to be over-expressed in a wide range of human tumors. Elevated expression of Aurora- A has been detected in colorectal, ovarian and pancreatic cancers and in invasive duct adenocarcinomas of the breast. High levels of Aurora-A have also been reported in renal, cervical, neuroblastoma, melanoma, lymphoma, pancreatic and prostate tumor cell lines. Amplification/over-expression of Aurora-A is observed in human bladder cancers and amplification of Aurora-A is associated with aneuploidy and aggressive clinical behavior. Moreover, amplification of the Aurora-A locus (20ql 3) correlates with poor prognosis for patients with node- negative breast cancer.
  • allelic variant isoleucine at amino acid position 31
  • Aurora-B is also highly expressed in multiple human tumor cell lines, including leukemic cells.
  • Aurora-B increase as a function of Duke's stage in primary colorectal cancers.
  • Aurora- C which is normally only found in germ cells, is also over-expressed in a high percentage of primary colorectal cancers and in a variety of tumor cell lines including cervical adenocarinoma and breast carcinoma cells.
  • the present invention relates to a compound represented by the following Formula I:
  • R 1 is H, Ci-Ce-alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-CH 2 -, or HO-Ci -C 6 -alkyl;
  • R is CH 3 , F, or Cl
  • Het is a nitrogen-containing heterocyclic group represented by:
  • Y is CR 5 or N
  • Z is CH or N; with the proviso that at least one of X, Y, and Z is N, and with the further proviso that at least one of X and Z is not N;
  • A is NR 6 or O
  • R 3 is Ci-Ce-alkyl, OH, or -N(R 7 ) 2 ;
  • R 4 is H, CH 3 , -CH 2 N(CHs) 2 , -CH 2 -piperazinyl, -CH 2 -4-methylpiperazinyl, or l-ethyl-2- pyrrolidinyl;
  • R 5 is H or Ci-Ce-alkyl
  • R 6 is H, -CH 3 , or -CH 2 CH 3 ;
  • each R 7 is independently H, Ci-C 6 -alkyl, HO-Ci-C 6 -alkyl,
  • the present invention is a method for treating a cancer comprising administering to a patient in need thereof the compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention is a method for treating cancer comprising the step of administering to a patient in need thereof an effective amount of a composition comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof; and (b) at least one pharmaceutically acceptable excipient.
  • the present invention is a composition
  • the present invention relates to a compound of Formula I:
  • R 1 , R 2 , and Het are defined hereinabove.
  • Ci-C ⁇ -alkyl refers to a linear or branched alkyl group including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, and n-hexyl.
  • Het is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 3 is Ci-C 6 -alkyl, OH, or -N(R 7 ) 2 .
  • each R 7 together with the nitrogen atom to which they are attached may form a 5- or 6-membered heterocycloalkyl group or a 9- or 10-membered heterobicycloalkyl group.
  • 5- and 6-membered heterocycloalkyl groups include piperazinyl, 4-methylpiperazinyl, 2-oxo-piperazinyl, 4-hydroxyethylpiperazinyl, morpholino, thiomorpholino, pyrrolidinyl, and piperidinyl groups.
  • 9- or 10-membered heterobicycloalkyl groups include fused ring groups such as a hexahydropyrrolopyrazinyl group.
  • At least one of X and Z is not N, meaning that if X is N, Z must be C-H; if Z is N, X must be CR 5 . It is also permissible for neither X nor Z to be N, in which case Y must be N.
  • R 1 is Ci-C ⁇ -alkyl.
  • R 2 is methyl or F.
  • the compound of the present invention is represented by the following formula:
  • the present invention is represented by Formula Ia or a pharmaceutically acceptable salt thereof, wherein R 3 is -N(R 7 )2, where each R 7 , together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, 4-hydroxyethylpiperazinyl, morpholino, or 2-oxo- piperazinyl group.
  • the present invention is represented by a compound of Formula Ia or a pharmaceutically acceptable salt thereof, wherein each R 7 , together with the nitrogen atom to which they are attached, form a 4-methylpiperazinyl group.
  • the present invention is represented by a compound of Formula Ia or a pharmaceutically acceptable salt thereof, wherein R 1 is isopropyl and R 2 is methyl.
  • the present invention is represented by a compound having the following formula:
  • Y is N or CH, R 1 is Ci-C 6 alkyl; and R 3 is wherein R 3 is -N(R 7 ) 2 .
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts of compounds of the present invention may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable acid.
  • Suitable acids include pharmaceutically acceptable inorganic acids and organic acids.
  • Representative pharmaceutically acceptable acids include inorganic acids such as hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, and phosphoric acid, as well as organic acids such as acetic acid, trifluoroacetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, /?-toluenesulfonic acid, oleic acid, and lauric acid.
  • a compound or “the compound” refers to one or more compounds.
  • Compounds of the present invention may exist in a crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve non- aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Hydrates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates and forms.
  • reaction is advantageously carried out under reflux in the presence of an acid such as hydrochloric acid or trifluoroacetic acid (TFA), and in a suitable solvent such as isopropanol, n-butanol, 1,4-dioxane, ethanol or N,N-dimethylformamide (DMF).
  • an acid such as hydrochloric acid or trifluoroacetic acid (TFA)
  • a suitable solvent such as isopropanol, n-butanol, 1,4-dioxane, ethanol or N,N-dimethylformamide (DMF).
  • compounds of formula (VIII) can be prepared from compounds of formula (IV) and (VII) by Buchwald coupling, using a palladium catalyst such as Pd(OAc) 2 or Pd 2 (dba)3, and a ligand such as XANTPHOS, in a suitable solvent such as dioxane or toluene.
  • This coupling reaction is advantageously carried out
  • a substrate phosphorylation assay This assay examines the ability of small molecule organic compounds to inhibit the serine phosphorylation of a peptide substrate, and was run in the IMAP® technology (Molecular Devices, Sunnyvale, California) fluorescent polarization assay format. The method measures the ability of the isolated enzyme to catalyze the transfer of the gamma-phosphate from ATP onto the serine residue of a fluorescein-labeled synthetic peptide (5FAM-GRTGRRNSI-NH 2 ). In a microwell assay format, the fluorescein-labeled peptide is phosphorylated in a kinase reaction.
  • the substrate phosphorylation assays use recombinant human full-length Aurora A kinase expressed in baculovirus/Sf9 system. An N-terminal His-Thr-affmity tag was fused to the amino terminus of amino acids 2 through 403 of Aurora A. 5nM okadaic acid was added during the last 4 hours of expression (experimentally determined to enhance Aurora A's enzymatic activity). The enzyme was purified to approximately 70% purity by metal-chelate affinity chromatography.
  • Assays were performed in 384-well low volume black polystyrene plates (Greiner Bio- One, Longwood, FL). 5 ⁇ Lof a 4 nM Aurora A enzyme was added to the wells containing 0.1 ⁇ l of test compound in 100% DMSO and incubated for 30 minutes followed by the addition of 5 ⁇ L reaction mixture resulting in a final assay volume of 10 ⁇ L containing 1 mM magnesium chloride, 2 ⁇ M ATP, 1 ⁇ M peptide substrate, 40 nM microtubule associated protein TPX2 peptide (1-43), 1.5 mM DTT, 25 mM NaCl, 0.15 mg/mL BSA and 0.01% Tween-20 in 5OmM HEPES, pH 7.2.
  • the reaction was allowed to proceed for 120 minutes at room temperature and was terminated by the addition of 1 O ⁇ L of a 1 :500 dilution of Progressive Binding Reagent (nanoparticles beads) in the Molecular Devices proprietary 90% buffer A and 10% buffer B. After a 120 minute incubation time the plates were read in a Analyst GT (Molecular Devices) in fluorescence polarization mode with excitation at 485 nM, emission at 530 nM and using the 505 nM dichroic lens.
  • Progressive Binding Reagent nanoparticles beads
  • the substrate phosphorylation assay use recombinant human full-length Aurora B kinase expressed in baculovirus/Sf9 system. Following expression the culture is incubated with 50 nM okadaic acid for 1 hour prior to purification. An N-terminal His-affinity tag was fused to the amino terminus of amino acids 1 through 344 of Aurora B. The expressed protein was purified by metal-chelate affinity chromatography.
  • 5 ⁇ M Aurora B was activated in 5OmM Tris-HCl pH 7.5, O.lmM EGTA, 0.1% 2-mercaptoethanol, O.lmM sodium vanadate, 1OmM magnesium acetate, O.lmM ATP with O.lmg/ml GST-INCENP [826 - 919] at 30 0 C for 30 minutes. Following activation the enzyme is then dialyzed into enzyme storage buffer and stored at -70 0 C.
  • Assays were performed in 384-well low volume black polystyrene plates (Greiner Bio- One, Longwood, FL). 5 ⁇ L of a 4nM Aurora B/INCENP was added to the wells containing 0.1 ⁇ l of test compound in 100% DMSO and incubated for 30 minutes followed by the addition of 5 ⁇ L of a reaction mixture resulting in a final assay volume of lO ⁇ L containing 2mM magnesium chloride, 2.5 ⁇ M ATP, 1.25 ⁇ M peptide substrate (5FAM-GRTGRRNSI-NH 2 ), 2 mM DTT, 25 mM NaCl, 0.15mg/mL BSA, 0.01% Tween-20 in 5OmM HEPES, pH 7.5.
  • the reaction was allowed to proceed for 120 minutes at room temperature and was terminated by the addition of lO ⁇ L of a 1 :500 dilution of Progressive Binding Reagent (nanoparticles beads) in the Molecular Devices proprietary 95% buffer A and 5% buffer B. After a 120-minute incubation time the plates were read in a Analyst GT in fluorescence polarization mode with excitation at 485 nM, emission at 530 nM and using the 505 nM dichroic lens.
  • a PE Sciex API 150 single quadrupole mass spectrometer (PE Sciex, Thornhill, Ontario, Canada) was operated using electrospray ionization in the positive ion detection mode.
  • the nebulizing gas was generated from a zero air generator (Balston Inc., Haverhill, MA) and delivered at 65 psi and the curtain gas was high purity nitrogen delivered from a Dewar liquid nitrogen vessel at 50 psi.
  • the voltage applied to the electrospray needle was 4.8 kV.
  • the orifice was set at 25 V and mass spectrometer was scanned at a rate of 0.5 scan/sec using a step mass of 0.2 amu and collecting profile data.
  • Samples are introduced into the mass spectrometer using a CTC PAL autosampler (LEAP Technologies, Carrboro, NC) equipped with a hamilton 10 uL syringe which performed the injection into a Valco 10-port injection valve.
  • the HPLC pump was a Shimadzu LC-10ADvp (Shimadzu Scientific Instruments, Columbia, MD) operated at 0.3 mL/min and a linear gradient 4.5% A to 90% B in 3.2 min. with a 0.4 min. hold.
  • the mobile phase was composed of 100% (H2O 0.02% TFA) in vessel A and 100% (CH3CN 0.018% TFA) in vessel B.
  • the stationary phase is Aquasil (C18) and the column dimensions are 1 mm x 40 mm. Detection was by UV at 214 nm, evaporative light- scattering (ELSD) and MS.
  • an Agilent 1100 analytical HPLC system with an LC/MS was used and operated at 1 mL/min and a linear gradient 5% A to 100% B in 2.2 min with a 0.4 min hold.
  • the mobile phase was composed of 100% (H 2 O 0.02% TFA) in vessel A and 100% (CH 3 CN 0.018% TFA) in vessel B.
  • the stationary phase was Zobax (C8) with a 3.5 um partical size and the column dimensions were 2.1 mm x 50 mm. Detection was by UV at 214 nm, evaporative light-scattering (ELSD) and MS.
  • NMR 1 H-NMR
  • Analytical HPLC Products were analyzed by Agilent 1100 Analytical Chromatography system, with 4.5 x 75 mm Zorbax XDB-C 18 column (3.5 ⁇ m) at 2 mL/min with a 4 min gradient from 5% CH 3 CN (0.1% formic acid) to 95% CH 3 CN (0.1% formic acid) in H 2 O (0.1% formic acid) and a 1 min hold.
  • Preparative HPLC Products were purified using a Gilson preparative chromatography system with a 75 x 30 mm L D. YMC CombiPrep ODS-A column (5 ⁇ m) at 50 mL/min with a 10 min gradient from 5% CH 3 CN (0.1% formic acid) to 95% CH 3 CN (0.1% formic acid) in H 2 O (0.1% formic acid) and a 2 min hold; alternatively, products were purified using an Agilent 1100 Preparative Chromatography system, with 100 x 30 mm Gemini Cl 8 column (5 ⁇ m) at 60 mL/min with a 10 min gradient from 5% CH 3 CN (0.1 % formic acid) to 95% CH 3 CN (0.1 % formic acid) in H 2 O (0.1 % formic acid) and a 2 min hold.
  • N-( 1 -methylethyl)-2-[(5 -methyl-2- ⁇ [6-(substituted)-3 -pyridinyl] amino ⁇ -A- pyrimidinyl)amino]benzamide compounds were prepared from the corresponding 2-[(2- chloro-5-methyl-4-pyrimidinyl)amino]-N-(l-methylethyl)benzamide Intermediate 6 and the corresponding pyridinamine (prepared substantially as shown for Intermediates 5 or 11) using a procedure similar to Example 3.
  • the dashed bond for the groups in the table represents the point of attachment to the pyridine ring.
  • a sealed tube was charged with 2,4-dichloro-5-methylpyrimidine (10 g, 61.3 mmol), 2- amino-iV-methylbenzamide (9.2 g, 61.3 mmol), di-isopropyl-ethylamine (21 mL, 122 mmol) and n-butanol (50 mL).
  • the reaction vessel was sealed and heated with stirring at 95° C for 18 h.
  • the reaction was cooled to room temperature, whereupon a white solid precipitated in the reaction mixture.
  • the solid was filtered, washed with cold isopropanol, and collected. About 1/3 of the mother liquid was removed in vacuo and the concentrated mother liquid was heated and cooled as before, upon which further precipitation occurred.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de formule I ou un sel pharmaceutiquement acceptable de celui-ci, R1, R2 et Het sont tels que définis ici. Les composés de la présente invention sont utiles en tant qu'inhibiteurs de kinase de l'aurore.
PCT/US2008/064446 2007-05-23 2008-05-22 Anthranilimides Ceased WO2008147831A1 (fr)

Applications Claiming Priority (2)

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US93962407P 2007-05-23 2007-05-23
US60/939,624 2007-05-23

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WO2008147831A1 true WO2008147831A1 (fr) 2008-12-04

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010144468A1 (fr) * 2009-06-10 2010-12-16 Abbott Laboratories 2-(lh-pyrazol-4-ylamino)-pyrimidine en tant qu'inhibiteurs de kinase
WO2012020060A1 (fr) 2010-08-11 2012-02-16 Bayer Cropscience Ag Dérivés d'hétéroarylpipéridine et d'hétéroarylpipérazine utilisés comme fongicides
EP2423210A1 (fr) 2010-08-25 2012-02-29 Bayer CropScience AG Dérivés d'hétéroarylpipéridine et -pipérazine comme fongicides
WO2012025557A1 (fr) 2010-08-25 2012-03-01 Bayer Cropscience Ag Dérivés hétéroarylpipéridine et hétéroarylpipérazine en tant que fongicides
WO2012055837A1 (fr) 2010-10-27 2012-05-03 Bayer Cropscience Ag Hétéroarylpipéridine et dérivés d'hétéroarylpipéridine comme fongicide
WO2013098229A2 (fr) 2011-12-27 2013-07-04 Bayer Intellectual Property Gmbh Dérivés d'hétéroarylpipéridine et d'hétéroarylpipérazine utilisés comme fongicides
US20140228322A1 (en) * 2013-02-08 2014-08-14 Celgene Avilomics Research, Inc. Erk inhibitors and uses thereof
US10005760B2 (en) 2014-08-13 2018-06-26 Celgene Car Llc Forms and compositions of an ERK inhibitor
CN108586362A (zh) * 2018-07-09 2018-09-28 郭秦 一种二氯代吡唑酰胺中间体合成方法
WO2022270994A1 (fr) 2021-06-25 2022-12-29 한국화학연구원 Nouveau composé hétérocyclique bifonctionnel ayant une fonction de dégradation de btk par l'intermédiaire d'une voie de protéasome d'ubiquitine, et son utilisation
JP2023113615A (ja) * 2019-03-15 2023-08-16 ザ ジェネラル ホスピタル コーポレイション Ｔｅａｄ転写因子の新規小分子阻害剤
WO2024024962A1 (fr) 2022-07-29 2024-02-01 住友ファーマ株式会社 Dérivé à noyau hétérocyclique saturé contenant de l'azote

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6932161B2 (en) * 2001-09-26 2005-08-23 Weatherford/Lams, Inc. Profiled encapsulation for use with instrumented expandable tubular completions
US7122544B2 (en) * 2000-12-06 2006-10-17 Signal Pharmaceuticals, Llc Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto
US7148357B2 (en) * 2002-07-31 2006-12-12 Schering Ag VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridines
US7338957B2 (en) * 2003-08-28 2008-03-04 Irm Llc Compounds and compositions as protein kinase inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7122544B2 (en) * 2000-12-06 2006-10-17 Signal Pharmaceuticals, Llc Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto
US6932161B2 (en) * 2001-09-26 2005-08-23 Weatherford/Lams, Inc. Profiled encapsulation for use with instrumented expandable tubular completions
US7148357B2 (en) * 2002-07-31 2006-12-12 Schering Ag VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridines
US7338957B2 (en) * 2003-08-28 2008-03-04 Irm Llc Compounds and compositions as protein kinase inhibitors

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102498110A (zh) * 2009-06-10 2012-06-13 雅培制药有限公司 作为激酶抑制剂的2-(lh-吡唑-4-基氨基)-嘧啶
US8426408B2 (en) 2009-06-10 2013-04-23 Abbvie Inc. Pyrimidine inhibitors of kinases
WO2010144468A1 (fr) * 2009-06-10 2010-12-16 Abbott Laboratories 2-(lh-pyrazol-4-ylamino)-pyrimidine en tant qu'inhibiteurs de kinase
JP2012529522A (ja) * 2009-06-10 2012-11-22 アボット・ラボラトリーズ キナーゼ阻害剤としての２−（１ｈ−ピラゾール−４−イルアミノ）−ピリミジン
WO2012020060A1 (fr) 2010-08-11 2012-02-16 Bayer Cropscience Ag Dérivés d'hétéroarylpipéridine et d'hétéroarylpipérazine utilisés comme fongicides
WO2012025557A1 (fr) 2010-08-25 2012-03-01 Bayer Cropscience Ag Dérivés hétéroarylpipéridine et hétéroarylpipérazine en tant que fongicides
EP2423210A1 (fr) 2010-08-25 2012-02-29 Bayer CropScience AG Dérivés d'hétéroarylpipéridine et -pipérazine comme fongicides
EP3109248A1 (fr) 2010-08-25 2016-12-28 Bayer Intellectual Property GmbH Dérivés d'hétéroarylpipéridine et de pipérazine utilisés comme fongicides
EP3241829A1 (fr) 2010-08-25 2017-11-08 Bayer Intellectual Property GmbH Dérivés d'hétéroarylpipéridine et de pipérazine utilisés comme fongicides
WO2012055837A1 (fr) 2010-10-27 2012-05-03 Bayer Cropscience Ag Hétéroarylpipéridine et dérivés d'hétéroarylpipéridine comme fongicide
US9975889B2 (en) 2010-10-27 2018-05-22 Bayer Intellectual Property Gmbh Heteroaryl piperidine and heteroaryl piperazine derivatives as fungicides
US9512117B2 (en) 2010-10-27 2016-12-06 Bayer Intellectual Property Gmbh Heteroaryl piperidine and heteroaryl piperazine derivatives as fungicides
US9914728B2 (en) 2010-10-27 2018-03-13 Bayer Intellectual Property Gmbh Heteroaryl piperidine and heteroaryl piperazine derivatives as fungicides
EP2921485A1 (fr) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Dérivés d'isoxazole
EP2921484A1 (fr) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Dérivés d'oxazole
EP2921494A1 (fr) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Dérivés d'hétéroarylpipéridine et -pipérazine
EP2921492A1 (fr) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Dérivés d'hétéroarylpipéridine et -pipérazine
EP2921495A1 (fr) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Dérivés d'hétéroarylpipéridine et -pipérazine comme fongicides
EP2921491A1 (fr) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Produits intermédiaires pour la production des dérivés d'hétéroarylpipéridine et -pipérazine comme fongicides
EP2921481A1 (fr) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Dérivés d'acide de 4-piperidine
EP2921493A1 (fr) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Dérivés d'hétéroarylpipéridine et -pipérazine
WO2013098229A2 (fr) 2011-12-27 2013-07-04 Bayer Intellectual Property Gmbh Dérivés d'hétéroarylpipéridine et d'hétéroarylpipérazine utilisés comme fongicides
US9145387B2 (en) * 2013-02-08 2015-09-29 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9561228B2 (en) 2013-02-08 2017-02-07 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9504686B2 (en) 2013-02-08 2016-11-29 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US20140228322A1 (en) * 2013-02-08 2014-08-14 Celgene Avilomics Research, Inc. Erk inhibitors and uses thereof
US9980964B2 (en) 2013-02-08 2018-05-29 Celgene Car Llc ERK inhibitors and uses thereof
US9796700B2 (en) 2013-02-08 2017-10-24 Celgene Car Llc ERK inhibitors and uses thereof
US10202364B2 (en) 2014-08-13 2019-02-12 Celgene Car Llc Forms and compositions of an ERK inhibitor
US10005760B2 (en) 2014-08-13 2018-06-26 Celgene Car Llc Forms and compositions of an ERK inhibitor
CN108586362A (zh) * 2018-07-09 2018-09-28 郭秦 一种二氯代吡唑酰胺中间体合成方法
JP2023113615A (ja) * 2019-03-15 2023-08-16 ザ ジェネラル ホスピタル コーポレイション Ｔｅａｄ転写因子の新規小分子阻害剤
JP7605892B2 (ja) 2019-03-15 2024-12-24 ザ ジェネラル ホスピタル コーポレイション Ｔｅａｄ転写因子の新規小分子阻害剤
US12187722B2 (en) 2019-03-15 2025-01-07 The General Hospital Corporation Small molecule inhibitors of TEAD transcription factors
WO2022270994A1 (fr) 2021-06-25 2022-12-29 한국화학연구원 Nouveau composé hétérocyclique bifonctionnel ayant une fonction de dégradation de btk par l'intermédiaire d'une voie de protéasome d'ubiquitine, et son utilisation
US12161722B2 (en) 2021-06-25 2024-12-10 Korea Research Institute Of Chemical Technology Bifunctional heterocyclic compound having BTK degradation function via ubiquitin proteasome pathway, and use thereof
WO2024024962A1 (fr) 2022-07-29 2024-02-01 住友ファーマ株式会社 Dérivé à noyau hétérocyclique saturé contenant de l'azote

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