WO2007028445A1 - Composés 6-indolyl-4-ylamino-5-halogéno-2-pyrimidinylamino - Google Patents

Composés 6-indolyl-4-ylamino-5-halogéno-2-pyrimidinylamino Download PDF

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Publication number
WO2007028445A1
WO2007028445A1 PCT/EP2006/006952 EP2006006952W WO2007028445A1 WO 2007028445 A1 WO2007028445 A1 WO 2007028445A1 EP 2006006952 W EP2006006952 W EP 2006006952W WO 2007028445 A1 WO2007028445 A1 WO 2007028445A1
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Prior art keywords
alkyl
compound
ring
formula
indazol
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PCT/EP2006/006952
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English (en)
Inventor
Francis Louis Atkinson
Michael David Barker
Sebastien Andre Campos
Lee Andrew Harrison
Nigel James Parr
Vipulkumar Kantibhai Patel
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Glaxo Group Limited
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Priority claimed from GB0514580A external-priority patent/GB0514580D0/en
Priority claimed from GB0524785A external-priority patent/GB0524785D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2007028445A1 publication Critical patent/WO2007028445A1/fr

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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
    • C07D401/14—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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel chemical compounds which have activity against the spleen tyrosine kinase (Syk kinase), processes for their preparation, pharmaceutically acceptable formulations containing them and their use in therapy.
  • Syk kinase spleen tyrosine kinase
  • Allergic rhinitis and asthma are diseases associated with hypersensitivity reactions and inflammatory events involving a multitude of cell types including mast cells, eosinophils, T cells and dendritic cells.
  • high affinity immunoglobulin receptors for IgE (Fc ⁇ RI) and IgG (Fc ⁇ RI) become cross-linked and activate downstream processes in mast cells and other cell types leading to the release of pro-inflammatory mediators and airway spasmogens.
  • IgE receptor cross-linking by allergen leads to release of mediators including histamine from pre-formed granules, as well as the synthesis and release of newly synthesised lipid mediators including prostaglandins and leukotrienes.
  • Syk kinase is a non-receptor linked tyrosine kinase which is important in transducing the downstream cellular signals associated with cross-linking Fc ⁇ RI and or Fc ⁇ RI receptors, and is positioned early in the signalling cascade.
  • the early sequence of Fc ⁇ RI signalling following allergen cross-linking of receptor-lgE complexes involves first Lyn (a Src family tyrosine kinase) and then Syk kinase.
  • Inhibitors of Syk kinase activity would therefore be expected to inhibit all downstream signalling cascades thereby alleviating the immediate allergic response and adverse events initiated by the release of pro-inflammatory mediators and spasmogens (Wong, B., Grossbard, E. B. Payan, D. G & Masuda, E. S. Expert Opin. Investig. Drugs (2004) 13 (7) 743-762).
  • Rheumatoid Arthritis is an auto-immune disease affecting approximately 1% of the population. It is characterised by inflammation of articular joints leading to debilitating destruction of bone and cartilage.
  • Recent clinical studies with Rituximab, which causes a reversible B cell depletion, (J. CW. Edwards et al 2004, New Eng. J. Med. 350: 2572-2581 ) have shown that targeting B cell function is an appropriate therapeutic strategy in auto-immune diseases such as RA.
  • Clinical benefit correlates with a reduction in auto-reactive antibodies (or Rheumatoid Factor) and these studies suggest that B cell function and indeed auto-antibody production are central to the ongoing pathology in the disease.
  • WO 03/057695 (Boehringer lngelheim Pharmaceuticals, Inc.) describes substituted [1 ,6]-naphthyridines that inhibit Syk kinase.
  • WO2003/063794, WO2004/014382, WO2005/012294 and WO2005/16893 describes a series of 2,4-pyrimidinediamine compounds which inhibit Syk kinase, for use in treating autoimmune diseases.
  • WO2005/026158 (Novartis AG) describes 2,4-di (hetero)-arylamino-pyrimidine derivatives which have ZAP-70 and/or Syk inhibitory activities.
  • WO 04/035604 discloses the structural co-ordinates of the human Syk protein.
  • R 1 , R 2 and R 3 is each independently selected from hydrogen, halogen, -Co. 6 hydroxy, -C 1-6 alkyl, -NR 5 R 6 , -CN, -Co-aalkylene-COzH, OC(O)C 1-6 alkyl, C(O)C 1-6 alkoxy, -C 1-2 alkyl substituted by 1 or more fluorine atoms, -C 1-6 alkoxy, -C(O)NR 5 R 6 , -OCH 2 C(O)NR 5 R 6 , -NR 5 C(O)R 6 , -SC 1-6 alkyl, -S(O)C 1-6 alkyl, -S(O) 2 C 1-6 alkyl,- NHS(O) 2 R 7 , -S(O) 2 NR 5 R 6 or -S(O) 2 NR 5 R 8 , such that at least one of R 1 , R 2 and R 3 is hydrogen; or
  • R 4 is C 1-3 alkyl
  • R 7 is C 1-6 alkyl or phenyl optionally substituted by C 1-6 alkyl
  • R 8 is C 3-7 cycloalkyl, C ⁇ alkyl (optionally terminally substituted with hydroxyl or tetrahydrofuranyl);
  • X is halogen
  • a salt or solvate preferably a pharmaceutically acceptable salt or solvate, thereof.
  • Compounds of the present invention are useful as inhibitors of Syk kinase and thus useful in treating diseases resulting from inappropriate mast cell activation, for instance allergic and inflammatory diseases.
  • the present invention provides for a compound of formula (I) as hereinbefore defined, and excluding a compound of the formula (IA):
  • R 9a and R 1Oa is each independently hydrogen, C 1-6 alkyl or CH 2 C 3-7 cycloalkyl
  • R 4a is C 1-3 alkyl
  • X a is halogen
  • two of R 1 , R 2 and R 3 are hydrogen.
  • representative values of R 1 , R 2 and R 3 include: hydroxy, - NH 2 , methyl, -OCOCH 3 , -OCH 3 , -C 2 H 4 OH, -CONH 2 , -CONHCH 3 , -CONH(C 2 H 5 ), - SO 2 NH 2 , -SO 2 NHR 8 and -SO 2 CH 3
  • R 1 and R 3 is each hydrogen and representative examples of R 2 include:
  • R 1 and R 2 is each hydrogen and representative examples of
  • R include:
  • representative examples of the 5- or 6- membered saturated or unsaturated ring formed by R 2 and R 3 , fused with the phenyl ring include:
  • representative examples of the 5- or 6- membered saturated or unsaturated ring formed by R 2 and R 3 , fused with the phenyl ring, and including any substituents which may be present, include:
  • R 4 is ethyl or propyl.
  • R 5 and R 6 include: H, methyl, and ethyl.
  • R 8 include cyclopropyl, hydroxyethyl and tetrahydro-2-furanylmethyl
  • X include fluoro, chloro and bromo.
  • X is fluoro.
  • Representative examples of compounds of formula (I) include: / ⁇ -(i .i-dioxido ⁇ .S-dihydro-i-benzothien-e-yO- ⁇ -ethyl-S-fluoro- ⁇ -IH-indazol ⁇ -yl- 2,4-pyrimidinediamine; 3-( ⁇ 4-[ethyl(1/-/-indazol-4-yl)amino]-5-fluoro-2-pyrimidinyl ⁇ amino)benzene sulfonamide;
  • heteroaryl includes single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents.
  • Representative heteroaryl rings comprise from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heteroaryl ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • heterocyclic includes non-aromatic single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents.
  • Representative heterocyclic rings comprise from 4 to 7, preferably 5 to 6, ring atoms.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • Examples of "-C 1-2 alkyl substituted by 1 or more fluorine atoms" include, but is not restricted to, -CF 3 .
  • References to alkyl include references to both straight chain and branched chain aliphatic isomers of the corresponding alkyl. It will be appreciated that references to alkylene and alkoxy shall be interpreted similarly.
  • references to C 3-7 cycloalkyl include references to all alicyclic (including branched) isomers of the corresponding alkyl.
  • the term “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 the compound of the present invention may be prepared.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects.
  • compositions may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. Indeed, in certain embodiments of the invention, pharmaceutically acceptable salts may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form.
  • the compound of the present invention may contain one or more acidic functional groups.
  • suitable pharmaceutically acceptable salts include salts of such acidic functional groups.
  • Representative salts include pharmaceutically acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts; carbonates and bicarbonates of a pharmaceutically- acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; pharmaceutically acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.
  • Compounds of the present invention are basic and accordingly generally capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid.
  • Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids.
  • Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate A acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, t
  • the term “compound” refers to one or more compounds.
  • the term “a compound of the present invention” refers to one or more compounds of the present invention.
  • the compound of the present invention may exist in solid or liquid form.
  • the compound of the present invention may exist in crystalline or non- crystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, n-butanol, i-butanol, acetone, tetrahydrofuran, dioxane, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates 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.
  • polymorphs may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs.”
  • the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymophs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • the compound of the present invention may contain one or more asymmetric centers (also referred to as a chiral centre) and may, therefore, exist as individual enantiomers, diastereoisomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
  • the structure is intended to encompass any stereoisomer and all mixtures thereof.
  • the compound of the present invention containing one or more chiral centres may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • a compound of formula (I) in the form of a purified single enantiomer.
  • Individual stereoisomers of a compound according to Formula (I) which contain one or more asymmetric centre may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral envionce, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the compound of the present invention may also contain double bonds or other centres of geometric asymmetry. Where the stereochemistry of a centre of geometric asymmetry is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included the compound of the present invention whether such tautomers exist in equilibrium or predominately in one form.
  • the present invention provides a process for preparing a compound of formula (I), or a salt or solvate thereof, which process comprises:
  • the process may be performed in the presence of a solvent (for example, aqueous acetone or propan-2-ol), in the presence of concentrated hydrochloric acid, at a suitable temperature, preferably in the range of 0-170° C.
  • a solvent for example, aqueous acetone or propan-2-ol
  • concentrated hydrochloric acid at a suitable temperature, preferably in the range of 0-170° C.
  • the process may be performed in the presence of a solvent such as 2-propanol, and hydrogen chloride in ether, at a suitable temperature, preferably in the range of 0-100° C, preferably under a nitrogen atmosphere.
  • a solvent such as 2-propanol, and hydrogen chloride in ether
  • the process may be performed in the presence of a solvent such as 2-propanol, and a dilute acid such as dilute hydrochloric acid, at a suitable temperature, preferably in the range of 0- 100° C.
  • a solvent such as 2-propanol
  • a dilute acid such as dilute hydrochloric acid
  • Suitable leaving groups (L 1 ) include a halide such as chloride, bromide or iodide.
  • Other leaving groups include, but are not restricted to, an alkyl and aryl sulfide, an alkyl and aryl sulfinyl, an alkyl and aryl sulfonyl, and an alcohol derived leaving group (such as triflate, mesylate, methylsulfonate or tosylate).
  • the process may be performed in the presence of a non-nucleophilic base such as triethylamine or di-isopropylethylamine, as a melt, at a suitable temperature, preferably in the range of 0-180° C.
  • a non-nucleophilic base such as triethylamine or di-isopropylethylamine
  • Suitable amine protecting groups include, but are not restricted to, sulphonyl (such as tosyl), acyl (such as benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (such as benzyl), which may be removed by hydrolysis or hydrogenolysis as appropriate.
  • Suitable amine protecting groups include trifluoroacetyl (-C(O)CF 3 ), which may be removed by base catalysed hydrolysis, or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker) which may be removed by acid catalysed hydrolysis (using, for example, trifluoroacetic acid).
  • a solid phase resin bound benzyl group such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker) which may be removed by acid catalysed hydrolysis (using, for example, trifluoroacetic acid).
  • L 1 , and X are as hereinbefore defined, or a protected derivative thereof, by reacting with a sodium hydride in DMF, followed by adding alkyl iodide R 4 I, at a temperature of about 0° C, under a nitrogen atmosphere.
  • L 2 is a leaving group such as chloro and L 1 and X are as hereinbefore defined; in a solvent such as propan-2-ol or acetone in the presence or a base such as di-isopropylethylamine, and at a temperature in the range 120-180° C.
  • R 4 , L 1 and X are as hereinbefore defined, or a protected derivative thereof, with an organic nitrite derivative, such as, but not limited to, tert-butyl nitrite.
  • This reaction is preferably performed in the presence of an acid, such as acetic acid or hydrochloric acid.
  • the aforementioned reaction may be performed in the presence of acetic anhydride to yield a product in which an indazolyl nitrogen atom is protected.
  • L 1 and X are as hereinbefore defined, or a protected derivative thereof, with an alkyl iodide R 4 I in the presence of a base such as cesium carbonate, in an aprotic solvent such as DMF.
  • the compound of formula (II) is the following N-acetyl protected derivative:
  • L 1 , X 1 and R 4 are as defined above. This may be prepared from the corresponding N-acetyl compounds of formula (Vl), (VII) and (VIII), as hereinbefore described.
  • Compounds of the present invention are useful as inhibitors of Syk and thus useful in treating diseases resulting from inappropriate mast cell activation, for instance allergic and inflammatory diseases.
  • the present invention provides for a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.
  • the present invention provides for a method of treating of treating inappropriate mast cell activation which method comprises administering to a patient in need thereof an effective compound of formula I, or a or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method comprising administering to a patient in need thereof an effective compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, to inhibit a Syk kinase.
  • the present invention provides a method of treating an inflammatory disease which comprises administering to a patient in need thereof an effective compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of treating an allergic disorder which comprises administering to a patient in need thereof an effective compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • Syk kinase diseases and pathological conditions thought to be mediated by Syk kinase include inflammatory and allergic disorders involving mast cell activation, such as chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), asthma, ulcerative colitis, Crohn's Disease, bronchitis, conjunctivitis, psoriasis, sclerodoma, urticaria, dermatitis, and allergic rhinitis. They also include inflammatory conditions which involve B cells, for instance lupus and rheumatoid arthritis.
  • COPD chronic obstructive pulmonary disease
  • ARDS adult respiratory distress syndrome
  • asthma ulcerative colitis
  • Crohn's Disease bronchitis
  • conjunctivitis conjunctivitis
  • psoriasis psoriasis
  • sclerodoma urticaria
  • dermatitis dermatitis
  • allergic rhinitis allergic r
  • COPD chronic obstructive pulmonary disease
  • asthma asthma
  • allergic rhinitis asthma
  • the present invention provides a method of treating chronic obstructive pulmonary disease which comprises administering to a patient in need thereof an effective compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of treating asthma which comprises administering to a patient in need thereof an effective compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of treating allergic rhinitis which comprises administering to a patient in need thereof an effective compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the present invention may also be used in combination with other classes of therapeutic agents which are known in the art.
  • Representative clases of agents for use in such combinations include, for treating asthma, anti-inflammatory steroids (in particular corticosteroids), topical glucocorticoid agonists, PDE4 inhibitors, IKK2 inhibitors, A2a agonists, ⁇ 2 -adrenoreceptor agonists (including both slow acting and long acting ⁇ 2 -adrenoreceptor agonists), alpha 4 integrin inhibitors, and anti-muscarinics, and, for treating allergies, the foregoing agents, as well as H1 and H1/H3 antagonists.
  • Representative agents for use in combination therapy for treating severe asthma include topically acting p38 inhibitors, and IKK2 inhibitors.
  • Anti-inflammatory corticosteroids are well known in the art. Representative examples include fluticasone propionate (e.g. see US patent 4,335,121 ), beclomethasone 17- propionate ester, beclomethasone 17,21-dipropionate ester, dexamethasone or an ester thereof, mometasone or an ester thereof (e.g. mometasone furoate), ciclesonide, budesonide, and flunisolide.
  • fluticasone propionate e.g. see US patent 4,335,121
  • beclomethasone 17- propionate ester beclomethasone 17,21-dipropionate ester
  • dexamethasone or an ester thereof e.g. mometasone furoate
  • ciclesonide e.g. mometasone furoate
  • anti-inflammatory corticosteroids are described in WO 02/12266 A1 (Glaxo Group Ltd), in particular, the compounds of Example 1 ( 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy- 16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester) and Example 41 (6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-1 ,3-thiazole-5- carbonyOoxyJ-S-oxo-androsta-i ⁇ -diene- ⁇ -carbothioic acid S-fluoromethyl ester), or a pharmaceutically acceptable salt thereof.
  • ⁇ 2 -adrenoreceptor agonists examples include salmeterol (e.g. as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol.
  • Long- acting ⁇ 2 -adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 24 hour period such as salmeterol or formoterol.
  • anti-histamines examples include azelastine, levocabastine, olopatidine, methapyrilene, loratadine, cetirizine, desloratadine or fexofenadine.
  • anticholinergic compounds include muscarinic (M) receptor antagonists, in particular M-
  • M muscarinic
  • M2 M-1/M2
  • M3 receptor antagonists in particular a (selective) M3 receptor antagonist.
  • anticholinergic compounds are described in
  • muscarinic M3 antagonists include ipratropium bromide, oxitropium bromide or tiotropium bromide.
  • PDE4 or mixed PDE3/4 inhibitors that may be used in combination with compounds of the invention include AWD-12-281 (Elbion), PD-168787 (Pfizer), roflumilast, and cilomilast (GlaxoSmithKline). Further examples of PDE4 inhibitors are described in WO 2004/103998 (Glaxo Group Ltd).
  • the present invention also provides for so-called "triple combination” therapy, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with ⁇ 2 -adrenoreceptor agonist and an anti-inflammatory corticosteroid.
  • this combination is for treatment and/or prophylaxis of asthma, COPD or allergic rhinitis.
  • the ⁇ 2 -adrenoreceptor agonist and/or the anti-inflammatory corticosteroid can be as described above and/or as described in WO 03/030939 A1.
  • a representative example of such a "triple" combination comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, salmeterol or a pharmaceutically acceptable salt thereof (e.g. salmeterol xinafoate) and fluticasone propionate.
  • Preferred compounds of formula (I) for use as inhibitors of Syk kinase are those which exhibit selectivity for the Syk kinase against other key kinases such as Aurora A, Aurora B, JNK3, for instance at least 1Ox (based on either pKi or plC 50 values for the enzymes)
  • the compound of the present invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient, such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from about 0.1 to 99.9 wt.%, depending on the nature of the formulation.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically acceptable excipient means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled, such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and would result in pharmaceutically unacceptable compositions are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.
  • dosage forms include those adapted for (1 ) inhalation, such as aerosols and solutions; and (2) intranasal administration, such as solutions or sprays. It will be appreciated by the skilled person that a preferred route of administration for treating asthma and COPD is inhalation and that a preferred route of administration for treating allergic rhinitis is intranasal administration.
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound of the present invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: Diluents, fillers, lubricants, glidants, granulating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, anticaking agents, chelating agents, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • Diluents Diluents, fillers, lubricants, glidants, granulating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, anticaking agents, chelating agents, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • Dosage forms for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, drops, gels or dry powders.
  • Dosage forms for topical administration to the nasal cavity include pressurised aerosol formulations and aqueous formulations administered to the nose by pressurised pump.
  • Formulations which are non-pressurised and adapted for nasal administration are of particular interest. Suitable formulations contain water as the diluent or carrier for this purpose.
  • Aqueous formulations for administration to the nose may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like.
  • Aqueous formulations may also be administered to the nose by nebulisation.
  • dosage forms for nasal administration are provided in a metered dose device.
  • the dosage form may be provided as a fluid formulation for delivery from a fluid dispenser having a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser.
  • Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid formulation, the doses being dispensable upon sequential pump actuations.
  • the dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid formulation into the nasal cavity.
  • the fluid dispenser is of the general type described and illustrated in WO-A-2005/044354.
  • the dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid formulation.
  • the housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the formulation out of a pump stem through a nasal nozzle of the housing.
  • a particularly preferred fluid dispenser is of the general type illustrated in Figures 30-40 of WO-A- 2005/044354.
  • the compound or salt of formula (I) is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation.
  • the preferable particle size of the size-reduced (e.g. micronised) compound or salt or solvate is defined by a D50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).
  • Aerosol formulations can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted.
  • a metering valve metered dose inhaler
  • the dosage form comprises an aerosol dispenser
  • it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide or an organic propellant such as a hydrofluorocarbon (HFC).
  • suitable HFC propellants include 1 ,1 ,1 , 2,3, 3,3-heptafluoropropane and 1 ,1 ,1 ,2-tetrafluoroethane.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • the pressurised aerosol may contain a solution or a suspension of the active compound. This may require the incorporation of additional excipients e.g. co-solvents and/or surfactants to improve the dispersion characteristics and homogeneity of suspension formulations. Solution formulations may also require the addition of co-solvents such as ethanol.
  • Other excipient modifiers may also be incorporated to improve, for example, the stability and/or taste and/or fine particle mass characteristics (amount and/or profile) of the formulation.
  • the pharmaceutical composition is a dry powder inhalable composition.
  • a dry powder inhalable composition can comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, the compound of formula (I) or salt or solvate thereof (preferably in particle-size-reduced form, e.g. in micronised form), and optionally a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.
  • the dry powder inhalable composition comprises a dry powder blend of lactose and the compound of formula (I) or salt thereof.
  • the lactose is preferably lactose hydrate e.g. lactose monohydrate and/or is preferably inhalation-grade and/or fine-grade lactose.
  • the particle size of the lactose is defined by 90% or more (by weight or by volume) of the lactose particles being less than 1000 microns (micrometres) (e.g. 10-1000 microns e.g. 30-1000 microns) in diameter, and/or 50% or more of the lactose particles being less than 500 microns (e.g. 10-500 microns) in diameter. More preferably, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 300 microns (e.g.
  • the particle size of the lactose is defined by 90% or more of the lactose particles being less than 100-200 microns in diameter, and/or 50% or more of the lactose particles being less than 40-70 microns in diameter.
  • a suitable inhalation-grade lactose is E9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 JD Zwolle, Netherlands).
  • a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device.
  • the container is rupturable or peel-openable on demand and the dose of e.g. the dry powder composition can be administered by inhalation via the device such as the DISKUS TM device, marketed by GlaxoSmithKline.
  • the DISKUS TM inhalation device is for example described in GB 2242134 A, and in such a device at least one container for the pharmaceutical composition in powder form (the container or containers preferably being a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: a means of defining an opening station for the said container or containers; a means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the pharmaceutical composition in powder form from the opened container.
  • a composition of the present invention, for intranasal administration may also be adapted for dosing by insufflation, as a dry powder formulation.
  • the compound of the present invention when administered in combination with other therapeutic agents normally administered by the inhaled, intravenous, oral or intranasal route, that the resultant pharmaceutical composition may be administered by the same routes.
  • the compound of the present invention may conveniently be administered in amounts of, for example, 1 ⁇ g to 100 mg.
  • the precise dose will of course depend on the age and condition of the patient and the particular route of administration chosen.
  • Recombinant human Syk was expressed as a His-tagged protein * .
  • the activity of Syk was assessed using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay.
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • the reaction was incubated for 40min at room temperature, then terminated by the addition of 3 ⁇ l of read reagent containing 60 mM EDTA, 15OmM NaCI, 5OnM Streptavidin APC (Prozyme, San Leandro, California, USA), 0.5nM antiphosphotyrosine antibody labelled with W-1024 europium chelate (Wallac OY, Turku, Finland) in 4OmM HEPES pH 7.4, 0.03% BSA. The reaction was further incubated for 60min at room temperature.
  • the degree of phosphorylation of Biotin- AAAEEIYGEI was measured using a BMG Rubystar plate reader (BMG LabTechnologies Ltd, Aylesbury, UK) as a ratio of specific 665 nm energy transfer signal to reference europium 620 nm signal.
  • Version B - Syk was pre-activated at room temperature for 30 mins in the presence of 16.6mM MgCI 2 , 8.3mM ATP and then diluted to 4nM in 4OmM Hepes pH 7.4, 0.01% BSA.
  • 3 ⁇ l of substrate reagent containing biotinylated peptide, Biotin- AAAEEIYGEI (0.5 ⁇ M final), ATP (30 ⁇ M final) and MgCI 2 (1OmM final) in 4OmM HEPES pH 7.4, 0.01% BSA were added to wells containing 0.1 ⁇ l of various concentrations of compound or DMSO vehicle (1.7% final) in Greiner low volume 384 well black plate.
  • the reaction was initiated by the addition of 3 ⁇ l of diluted Syk (2nM final). The reaction was incubated for 60min at room temperature, then terminated by the addition of 3 ⁇ l of read reagent containing 60 mM EDTA, 15OmM NaCI, 5OnM Streptavidin APC (Prozyme, San Leandro, California, USA), 0.5nM antiphosphotyrosine antibody labelled with W-1024 europium chelate (Wallac OY, Turku, Finland) in 4OmM HEPES pH 7.4, 0.03% BSA. The reaction was further incubated for 45min at room temperature.
  • the degree of phosphorylation of Biotin- AAAEEIYGEI was measured using a BMG Rubystar plate reader (BMG LabTechnologies Ltd, Aylesbury, UK) as a ratio of specific 665 nm energy transfer signal to reference europium 620 nm signal.
  • Compounds according to the present invention were assayed in this, or a similar Time-resolved fluorescence resonance energy transfer kinase assay, and gave IC 50 values less than 10 ⁇ M.
  • the NiNTA was packed into a column and eluted using 10 column volumes each of buffer (2OmM Tris pH ⁇ .O, 30OmM NaCI, 1OmM ⁇ McEtOH, 10% glycerol), buffer + 1 M NaCI, buffer + 2OmM Imidazole and buffer + 30OmM imidazole.
  • the 30OmM Imidazole fractions were pooled buffer exchanged using G25M (Amersham Biosciences, Buckinghamshire, UK) into 2OmM MES pH 6.0, 2OmM NaCI, 1OmM ⁇ McEtOH,10% glycerol.
  • the buffer exchanged 6His-Syk was loaded onto a Source15S column (Amersham Biosciences, Buckinghamshire, UK) and the column eluted using a NaCI gradient 0-50OmM over 50 column volumes.
  • the 6His-Syk containing fractions were pooled and concentrated by ultra-filtration. The identity of 6His-Syk was confirmed by peptide mass finger printing and intact LC-MS.
  • Cells of the mouse fibroblast cell line NIH-3T3 are stably transfected with a cFms- SYK chimera.
  • Addition of the ligand (MCSF) produces dimerisation of the chimera resulting in autophosphorylation of the SYK kinase domain.
  • MCSF ligand
  • Cells are plated at a density of 1x10 5 /well in a volume of 200 ⁇ l growth medium (DMEM containing 10% heat inactivated foetal calf serum, 1% L-glutamine, 400 ⁇ g/ml geneticin and 400 ⁇ g/ml zeocin) in 96 well Collagen 1 coated tissue culture plates. Following incubation at 37°C, 10% CO 2, for 2Oh, the cell supernatant is removed and replaced with 200 ⁇ l DMEM containing 1 % penicillin/streptomycin (serum free DMEM). The cells are incubated for an hour under the conditions described above. The medium is removed, 50 ⁇ l appropriately diluted compound solution added and the plate incubated for a further hour.
  • DMEM containing 10% heat inactivated foetal calf serum, 1% L-glutamine, 400 ⁇ g/ml geneticin and 400 ⁇ g/ml zeocin
  • Cells are stimulated with 25 ⁇ l MCSF (0.66 ⁇ g/ml final) for 20min at 37°C. After removal of the supernatant, the cells are washed with cold PBS and lysed with 100 ⁇ l lysis buffer for 4h at 4°C.
  • cell lysate 85 ⁇ L is transferred to a 96 well ELISA plate coated with goat anti human M-CSF R capture antibody and incubated for 16 hours at 4°C.
  • the plate is washed and a biotinylated anti-phosphotyrosine detection antibody added (100 ⁇ l/well) for 2 hours at room temperature. This is removed and replaced with 100 ⁇ l Streptavidin- HRP for 30min.
  • Captured phosphorylated SYK is visualised using 10O ⁇ l TMB substrate. The reaction is terminated with 50 ⁇ l 1 M sulphuric acid and the absorbance measured at 450nm.
  • Compound Preparation Compound is prepared as a 1 OmM stock in DMSO and a dilution series prepared in DMSO using 9 successive 5-fold dilutions. This dilution series is diluted a further 1 :333 with serum free DMEM to give the concentration range to be tested of 1x10 5 to 1.54x10 "11 M. Compound dilutions are prepared using the Biomek 2000 or Biomek Nx automated robotic pipetting systems.
  • the population of B cells observed in this assay are the naive mature IgM/lgD expressing population. These form at least 70% of the purified B cell population (the rest being isotype switched memory B cells) and are the only cells that proliferate as the cells are stimulated with anti-lgM.
  • Anti-lgM drives signalling through the B cell receptor which is Syk dependant. Proliferation is a functional measure of B cell signalling that can be measured by observing the incorporation of tritiated methyl thymidine into the cells.
  • Protocol Purified human tonsillar B cells are resuspended in Buckleys* medium at a concentration of 1.25 x 10 6 ml.
  • 160 ⁇ l of cells re-suspended in Buckley's medium is added to the compound and control wells of a 96 well plate.
  • the control wells are located on column 11 and 12 of the 96 well plate.
  • the background wells are located in column 12 and 20 ⁇ l of 10 ⁇ M control is added to provide an appropriate background control.
  • 20 ⁇ l of 1% DMSO is added to the wells in column 11 for the stimulated control.
  • the compound titrations are located between columns 1 and 10. Three compounds are run in duplicate on each plate and row A and B are used for the control compound titration.
  • the final concentration of DMSO is 0.1 % in the assay.
  • the cells are left for 45min, after 4 min the proliferative stimulus is added to the first 1 1 wells of the 96 well plate and 20 ⁇ l of medium is added to column 12.
  • F(ab')2 fragments of a polyclonal goat anti-sera raised to human IgM is used at a final concentration of 15 ⁇ g/ ml to stimulate the cells. (Biosource. Cat no: AMI 4601 ).
  • Tritiated methyl thymidine is added to the cells at a concentration of 1 ⁇ Ci per well. (Amersham, TRK 758). The radioactivity is added 65 hours after the initial stimulus and is left on the cells for 6 to 8 hours. After pulsing with methyl thymidine the cells are harvested on a Skatron 96 well cell harvester onto glass fibre mats. Once these have dried these are counted on a Wallac 1450 Microbeta scintillation counter.
  • Data is downloaded as an XL file and IC50's determined using Activity base.
  • Buckleys Medium 450 ml Iscoves (Sigma I 3390), 50ml FCS, 2.5 g BSA, 5ml Pen/ strep, 5ml Glutamine (20OmM), 500 ⁇ l Apo transferrin (50mg/ml) Sigma (T 1147), 100 ⁇ l Bovine Insulin (10mg/ml) Sigma (I 1882).
  • Compound is prepared as a 1OmM stock in DMSO and a dilution series prepared in DMSO using 9 successive 3-fold dilutions.
  • This dilution series is diluted a further 1 :100 with Buckleys medium to give the concentration range to be tested of 100 ⁇ M to 5nM.
  • This is added as 20 ⁇ l to 96 well plates in duplicate to generate two IC50's for each compound tested. Each plate is run in the presence of a control compound, which acts as an internal standard. .
  • LAD2 is a stem cell factor (SCF)-dependent human mast cell line that was established by the NIH from bone marrow aspirates from a patient with mast cell sarcoma/leukaemia.
  • SCF stem cell factor
  • LAD2 cells resemble CD34+-derived human mast cells and express functional Fc ⁇ RI.
  • the Fc ⁇ RI is up-regulated in the presence of IL-4, SCF and IgE, subsequent cross linking of cell-bound IgE results in degranulation which can be measured as hexosaminidase release.
  • LAD2 cells to up-regulate Fc ⁇ RI LAD2 cells are re-suspended at 1x10 5 /ml in complete stem pro-34SFM (Gibco Cat 10640-019 media containing Stem Pro-34 nutrient supplement (1 :40), glutamine (2mM), penicillin (100 ⁇ g/ml), streptomycin (100 ⁇ g/ml)) with additional supplements of human recombinant SCF (100ng/ml; R&D systems), human recombinant Interleukin- 4 (6ng/ml; R&D Systems) and IgE (100 ⁇ g/ml; Calbiochem). Cells are then maintained for 5 days at 37°C, 5% CO2 in a humidified atmosphere.
  • Primed LAD2 cells are centrifuged (30Og, 5min), the supernatant discarded and the cell pellet re-suspended at 1x10 4 cells/ml in RPMI supplemented with glutamine (2mM). Following a further centrifugation (30Og, 5min) the cells are re-suspended in fresh RPMI with glutamine (2mM), adjusted to a density of 2.85x10 5 /ml, and pipetted into sterile V-well plates (70 ⁇ l/well; Greiner) containing 20 ⁇ l diluted compound (prepared as detailed above).
  • Cells are then incubated for 1h (37°C, 5% CO 2 in a humidified atmosphere) before activating with a sub-maximal concentration of anti- lgE (10 ⁇ l volume to give a final assay dilution of 1 :2700; Sigma).
  • a sub-maximal concentration of anti- lgE 10 ⁇ l volume to give a final assay dilution of 1 :2700; Sigma.
  • plates are centrifuged (120Og, 10min, 4°C) and the supernatant removed for hexosaminidase assay.
  • the cell pellet is lysed in 100 ⁇ l/well triton-X (0.5% in RPMI 2mM glutamine) at 37°C for 30 min.
  • LAD2 cells are centrifuged (400g, 5min), the supernatant discarded and the cell pellet re-suspended at 1x10 4 cells/ml in RPMI supplemented with glutamine (2mM). Following a further centrifugation (40Og, 5min) the cells are re-suspended in fresh RPMI with glutamine (2mM), adjusted to a density of 5.7 x10 5 /ml, and pipetted into sterile V-well plates (70 ⁇ l/well; Greiner) containing 20 ⁇ l diluted compound (prepared as detailed above).
  • Cells are then incubated for 1 h (37°C, 5% CO 2 in a humidified atmosphere) before activating with a sub-maximal concentration of anti- lgE (10 ⁇ l volume to give a final assay dilution of 1 :2700; Sigma).
  • a sub-maximal concentration of anti- lgE 10 ⁇ l volume to give a final assay dilution of 1 :2700; Sigma.
  • plates are centrifuged (120Og, 10min, 4 C C) and the supernatant removed for hexosaminidase assay.
  • the cell pellet is lysed in 100 ⁇ l/well triton-X (0.5% in RPMI 2mM glutamine) at 37°C for 30min.
  • Beta-hexosaminidase assay Beta-hexosaminidase activity is measured by the conversion of 4-methylumbelliferyl N-acetyl- ⁇ -D glucosaminide (Sigma) to a fluorescent product.
  • a useful screening strategy comprises assay 1 (enzyme assay (pKi), assay 2 and then assay 3 (B Cell Proliferation) or assay 4 (LAD2).
  • DCM refers to dichloromethane
  • DMSO dimethylsulfoxide
  • DMF refers to ⁇ /, ⁇ /-dimethylformamide
  • IPA refers to propan-2-ol
  • TFA refers to trifluoroacetic acid
  • THF refers to tetrahydrofuran
  • HPLC refers to high performance liquid chromatography.
  • ADDP refers to 1 ,1'(azodicarbonyl)dipiperidine
  • SPE refers to solid phase extraction cartridges marketed by lsolute TBTU refers to O-benzotriazol-1-yl- ⁇ /, ⁇ /, ⁇ /', ⁇ /',-bis(tetramethylene)uronium tetrafluoroborate
  • HOBt refers to N-hydroxybenzotriazole hydrate
  • LC/MS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HCO2H and 0.01 M ammonium acetate in water (solvent A) and 0.05% HCO2H 5% water in acetonitrile (solvent B), using the following elution gradient 0.0-7min 0%B, 0.7-4.2min 100%B, 4.2-5.3min 0%B, 5.3-5.5min 0%B at a flow rate of 3ml/min.
  • the mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
  • Mass directed autoprep / "preparative mass directed HPLC” was conducted on a system such as; a Waters FractionLynx system comprising of a Waters 600 pump with extended pump heads, Waters 2700 autosampler, Waters 996 diode array and Gilson 202 fraction collector on a 10 cm 2.54 cm ID ABZ+ column, eluting with either 0.1% formic acid or trifluoroacetic acid in water (solvent A) and 0.1 % formic or trifluoroacetic acid in acetonitrile (solvent B) using the appropriate elution gradient.
  • Mass spectra were recored on Micromass ZMD mass spectrometer using electrospray positive and negative mode, alternate scans. The software used was MassLynx 3.5 with OpenLynx and FractionLynx optio or using equivalent alternative systems.
  • “Hydrophobic frits” refers to filtration tubes sold by Whatman. SPE (solid phase extraction) refers to the use of cartridges sold by International Sorbent Technology Ltd.
  • the Flashmaster Il is an automated multi-user flash chromatography system, available from Argonaut Technologies Ltd, which utilises disposable, normal phase, SPE cartridges (2 g to 100 g). It provides quaternary on-line solvent mixing to enable gradient methods to be run. Samples are queued using the multi-functional open access software, which manages solvents, flow-rates, gradient profile and collection conditions.
  • the system is equipped with a Knauer variable wavelength uv-detector and two Gilson FC204 fraction-collectors enabling automated peak cutting, collection and tracking.
  • Silica chromatography techniques include either automated (Flashmaster) techniques or manual chromatography on pre-packed cartridges (SPE) or manually- packed flash columns.
  • Microwave chemistry was typically performed in sealed vessels, irradiating with a suitable microwave reactor system, such as a Biotage InitiatorTM Microwave Synthesiser.
  • the second portion was absorbed onto a 75Og silica cartridge before being purified using a CombiFlash ® CompanionTM system eluting with a gradient of ethyl acetate in cyclohexane (0-100%).
  • the required pure fractions were combined and the solvent was evaporated in vacuo to give a further quantity of the ⁇ /-(2-chloro-5-fluoro-4- pyrimidinyl)-1 -( ⁇ [2-(trimethylsilyl)ethyl]oxy ⁇ methyl)-1 H-indazol-4-amine as an orange/brown solid (10.96g).
  • a microwave vessel was charged with ⁇ /-(2-chloro-5-fluoro-4-pyrimidinyl)- ⁇ /-ethyl-1- ( ⁇ [2-(trimethylsilyl)ethyl]oxy ⁇ methyl)-1H-indazol-4-amine (0.05g) and aniline (0.2mmol), followed by and a solution of acetone / water / cone, hydrochloric acid (150:100:1 , 3ml) and N-methyl pyrrolidinone (0.1ml) The mixture was heated by microwave irradiation in a sealed vessel at 15O 0 C for 60min. The crude material was added to an SCX cartridge (10g), primed with methanol. The cartridge was eluted with 3x column volumes of methanol and then flushed with 2x column volumes ammonia in methanol solution (2M). The basic fractions were combined and concentrated and the residue purified by preparative mass directed HPLC to afford the title compound.
  • Example 12 formic acid - 6-((4-rethyl(1/-/-indazol-4-yl)aminol-5-fluoro-2- pyrimidinyl)amino)-2,3-dihvdro-1/-/-isoindol-1-one (1:1)
  • 6-Nitro-2,3-dihydro-1H-isoindol-1-one (33mg) was dissolved in glacial acetic acid (2ml) and added to 10% palladium on carbon (6mg). The mixture was stirred under a hydrogen atmosphere (1Atm.) for 72h. The mixture was filtered through a celite cartridge (10g), and the filtrate diluted with ethanol and loaded onto a SPE cartridge (SCX-2, 5g). The product was eluted with ammonia in methanol (2N). The appropriate ammonical fractions were combined and evaporated in vacuo to give 6- amino-2,3-dihydro-1/-/-isoindol-1-one (20mg). LC/MS; Rt O.74min.
  • Methyl 2-methyl-5-nitrobenzoate (1.0g, Salor) was dissolved in dry chloroform (40ml). N-Bromosuccinimide (1.09g) was added, followed by benzoyl peroxide (200mg) and the mixture was heated at reflux for 18h. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residual solid was purified by chromatography on a silica cartridge (10Og) and eluting with an ethyl acetate / cyclohexane gradient (0 to 50%) over 60min.
  • N-(2,5-dichloro-4-pyrimidinyl)-N-ethyl-1-( ⁇ [2-(trimethylsilyl)ethyl]oxy ⁇ methyl)-1 H- indazol-4-amine (520mg) in 5M hydrochloric acid / IPA (2:1 ; 15ml) was heated at 55 0 C for 6.5h. The cooled mixture was evaporated to dryness in vacuo and the crude residue was left at room temperature overnight. The residue was basified with saturated sodium carbonate solution (20ml) and extracted with ethyl acetate (3x 30ml). The combined organic extracts were washed with water (2x 20ml), dried (MgSO 4 ) and the solvent evaporated in vacuo.
  • the residue was purified by chromatography on a silica cartridge (5Og) eluting with an ethyl acetate / cyclohexane gradient (0-50%) over 40min. Then product fractions were combined and reduced to dryness in vacuo. The residue was purified by mass directed autoprep to give, after evaporation of the solvents, ⁇ /-(2,5-dichloro-4-pyrimidinyl)- ⁇ /-ethyl-1H-indazol-4- amine (79mg). LC/MS; Rt 3.33min. MH + 308, 310.
  • N-(2,5-dichloro-4-pyrimidinyl)-1-( ⁇ [2-(trimethylsilyl)ethyl]oxy ⁇ methyl)-1 H-indazol-4- amine 870mg was dissolved in DMF (20ml) at room temperature under nitrogen. Cesium carbonate (760mg) was added and the mixture stirred for 30min. Ethyl iodide (255 ⁇ l) was added and the mixture was left to stir at 60 0 C for 1.5h. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The organic extract was washed with water (3x 15ml), dried (MgSO 4 ) and reduced to dryness.
  • Example 36 - ⁇ / 4 -ethyl-5-fluoro-/v 4 -1H-indazol-4-yl- ⁇ / 2 -r3-(methylsulfonvnphenyll-2,4- pyrimidinediamine trifluoroacetate
  • ⁇ /-(2-chloro-5-fluoro-4-pyrimidinyl)- ⁇ /-ethyl-1/-/-indazol-4-amine (16.3mg) was placed in a microwaveable vessel, suspended in water (1.5ml), acetone (1ml) and hydrochloric acid (2N, 20 ⁇ l) and treated with 5-amino-1 ,3-dihydro-2H-benzimidazol- 2-one (12.5mg, ASINEX-REAG).
  • the sealed vessel was irradiated in a biotage microwave at 70 0 C for 1h.
  • the reaction was treated with 5-amino-1 ,3-dihydro-2H- benzimidazol-2-one (8.3mg, ASINEX-REAG), and irradiated at 100°C for 1h.
  • the reaction was transferred to a greenhouse tube and heated at 70 0 C under reflux conditions over the weekend.
  • the reaction mixture was allowed to cool, then evaporated to dryness, dissolved in methanol and applied to a SCX-2 column (500mg) that had been preconditioned with methanol.
  • the column was washed with methanol (2ml) and the crude product was eluted with methanolic ammonia solution (2N, 2ml).
  • the solution was evaporated to dryness, dissolved in DMSO and purified by Mass Directed HPLC.
  • the fractions containing product were evaporated to dryness to give the title compound (0.0057g) LC/MS; Rt 2.63min, MH + 404.95.
  • the orange mixture was treated cautiously with 1 M aqueous potassium carbonate (259ml) over 20min, stirred for a further 30min and the layers were separated.
  • the organic layer was washed with water (150ml) and concentrated to ca 110ml under reduced pressure.
  • the residue was diluted by addition of propan-1-ol (296ml) and the organic layer was concentrated to ca 110ml under reduced pressure. Further propan-1-ol (222ml) was added and the organic layer was concentrated to ca 110ml under reduced pressure.
  • the residue was diluted with further propan-1-ol (1 10ml), warmed to 40-50 0 C, and treated with water (222ml) over 20min.
  • the slurry was aged at ca 50 0 C for 15min, then cooled to 5°C over 3h.
  • the product was isolated by filtration, washed with water / propan-1-ol (1 :1 , 2x 75ml), and dried in vacuo to give the title product as a yellow solid (34.91 g).
  • This material was chromatographed on a silica cartridge (100g) eluting with a gradient of 0-30% methanol, 1% triethylamine, in DCM over an 80min period. Concentration of the appropriate fractions afforded material which still required further purification. This material was split into 2 portions. The first portion was chromatographed on a silica cartridge (100g) eluting with DCM / MeOH / triethylamine (94:5:1). The pure fractions were reduced to dryness to give the title compound as a pale yellow solid (1.25g). LC/MS; Rt 2.92min, MH + 445.
  • the impure fractions were reduced to dryness, combined with the second portion of material and chromatographed on a silica cartridge (100g) eluting with DCM / MeOH / triethylamine (94:5:1).
  • the resulting impure product fractions from the second column were combined, concentrated and dried in vacuo. This material was dissolved in 10ml of DMF to give approx 14ml of solution.
  • 9 chromatographic separations were performed by taking 1.6ml of sample solution and adding 3.4ml of DMF and 0.7ml of TFA for each separation.
  • a column of 7micron Kromasil C8 (25 x 5cm) was used with a gradient of 0 to 50%B in 40min (where A is water +0.25% TFA and B is acetonitrile +0.25% TFA).
  • the peaks at retention time 35.5 to 37mins were bulked from all the chromatographic separations.
  • the bulked fraction was evaporated to remove acetonitrile and divided into 2 portions. Each portion was applied to an Amberchrom CG161 column (25cm x 2 cm) to adsorb the compound.
  • the column was washed in turn with water, 0.2M ammonium hydroxide, water, and IPA and the compound eluted with acetone.
  • the acetone elution samples were bulked and dried.
  • 6-Aminoindazole (5g, Aldrich) was dissolved in methanol (100ml) and benzaldehyde (4.22ml) was added. The reaction mixture was stirred at room temperature under nitrogen for 1 h. The solvent was removed under vacuum and the resulting white solid was dissolved in dry DMF (50ml). Sodium hydride (1.77g, 60% in mineral oil) was added and the reaction mixture was stirred in a cold water bath under a nitrogen atmosphere for 10min. [(3-Bromopropyl)oxy](1 ,1-dimethylethyl)dimethylsilane (10.17ml, Aldrich) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 1h.
  • the mixture was seeded with ⁇ /- ⁇ 3-r(2-chloro-5-fluoro-4- pyrimidinyl)(ethyl)aminol-2-methylphenyl)acetamide. aged for 30min at 6O 0 C and treated with further water (100ml) over 30min. The yellow suspension was aged for 1h, cooled to 10 0 C and aged for 2h. The product was isolated by filtration, washed with water / DMF (2:1 , 60ml) and then water (2x 60ml). The product was dried in vacuo at 55-60°C to give the title product as a yellow solid (20.1g).
  • the solution was heated in a sealed vessel at 150 0 C for 1 h by microwave irradiation.
  • the reaction mixture was partitioned between ethyl acetate and water.
  • the aqueous extracted with ethyl acetate (x2).
  • the organic phases were combined, dried (MgSO 4 ) and evaporated to dryness .
  • the crude residue was purified on a silica cartridge (5g), eluting with an ethyl acetate / cyclohexane gradient (0 to 100%) over 30min.
  • the appropriate fractions were combined and evaporated in vacuo to give the title compound (43mgJ. LC/MS; MH + 556, Rt 4.0min.
  • the eluting product second was purified further by trituation with cyclohexane and filtration to give 2-(3- ⁇ [(1 ,1-dimethylethyl)(dimethyl)silyl]oxy ⁇ propyl)-3-methyl-6-nitro- 2H-indazole (2.08g).
  • the reaction mixture was diluted with methanol and filtered through an aminopropyl SPE cartridge (10g), the cartridge washed with methanol and the combined filtrate and washings reduced to dryness.
  • the residue was applied to a silica cartridge and eluted with an (1% Et3N / 50%MeOH / 50%EtOAc) / cyclohexane gradient (0 to 50%). The eluted fractions were combined and reduced to dryness.
  • the residue was purified by mass directed autoprep to give the title compound (24mg). LC/MS; MH + 461 , Rt 2.98min.
  • 6-Aminoindazole (1g) was dissolved in anhydrous methanol (30ml) and treated with benzaldehyde (0.92ml). The reaction mixture was stirred under nitrogen at room temperature for 90min. The solvent was evaporated in vacuo, the residue dissolved in anhydrous DMF (15ml) and stirred in an ice/water bath under nitrogen. Sodium hydride (60% in mineral oil, 360mg) was added and stirring continued for 15min before addition of the tert-butyl(4-iodobutoxy)-dimethylsilane (1.94ml). The reaction mixture was stirred at room temperature for 45min before quenching with hydrochloric acid (5M, 5ml) and stirring at room temperature overnight.
  • hydrochloric acid 5M, 5ml
  • the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution.
  • the aqueous phase was extracted with ethyl acetate and the combined organic extracts dried (MgSO 4 ), filtered and reduced to dryness.
  • the residue was dissolved in DCM, loaded on to a silica cartridge (7Og) and the cartridge eluted with an ethyl acetate / cyclohexane gradient (0 - 100%), then methanol / DCM (0 - 25%) over 30min. Appropriate fractions were combined, reduced to dryness and the residue dried in vacuo to give the title compound (520 mg).
  • N,N-Diisopropylethylamine (2.55ml) was added to a solution of 5-nitroindoline (2g, Aldrich) in DCM (20ml). The solution was cooled to 0°C (ice/salt water bath), trifluoroacetic anhydride (2.60ml) added and the mixture left to stir at 0 0 C for 10min. The solution was poured into saturated sodium bicarbonate (100ml) and extracted with DCM (2x 100ml). The combined organic extracts were washed with water (100ml), dried (hydrophobic frit) and concentrated under reduced pressure.

Abstract

Les composés de type Bisanilinopyrimidine de formule (I) de l’invention peuvent être employés en tant qu'inhibiteurs de Syk kinase et sont donc utiles dans le traitement de maladies résultant de l'activation inappropriée des mastocytes, par exemple les maladies allergiques et inflammatoires.
PCT/EP2006/006952 2005-07-15 2006-07-13 Composés 6-indolyl-4-ylamino-5-halogéno-2-pyrimidinylamino WO2007028445A1 (fr)

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GB0524785A GB0524785D0 (en) 2005-12-05 2005-12-05 Novel compounds

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WO2008132505A1 (fr) * 2007-04-27 2008-11-06 Astrazeneca Ab Nouveaux dérivés de n' - (phényl) -n- (morpholin-4-yl-pyridin-2-yl) -pyrimidine-2, 4-diaminepyrimidine en tant qu'inhibiteurs de ephb4 kinase pour le traitement d'états prolifératifs
WO2009010789A2 (fr) * 2007-07-16 2009-01-22 Astrazeneca Ab Dérivés pyrimindines 934
EP2387572A2 (fr) * 2009-01-15 2011-11-23 Rigel Pharmaceuticals, Inc. Inhibiteurs de la protéine kinase c et leurs utilisations
US8148391B2 (en) 2006-10-23 2012-04-03 Cephalon, Inc. Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors
EP2489663A1 (fr) 2011-02-16 2012-08-22 Almirall, S.A. Composés en tant qu'inhibiteurs de la syk kinase
US8987456B2 (en) 2011-10-05 2015-03-24 Merck Sharp & Dohme Corp. 3-pyridyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
US9006444B2 (en) 2011-10-05 2015-04-14 Merck Sharp & Dohme Corp. Phenyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
US9120785B2 (en) 2011-05-10 2015-09-01 Merck Sharp & Dohme Corp. Pyridyl aminopyridines as Syk inhibitors
US9145391B2 (en) 2011-05-10 2015-09-29 Merck Sharp & Dohme Corp. Bipyridylaminopyridines as Syk inhibitors
US9216173B2 (en) 2011-10-05 2015-12-22 Merck Sharp & Dohme Corp. 2-Pyridyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
US9242984B2 (en) 2012-06-20 2016-01-26 Merck Sharp & Dohme Corp. Pyrazolyl derivatives as Syk inhibitors
US9290490B2 (en) 2011-05-10 2016-03-22 Merck Sharp & Dohme Corp. Aminopyrimidines as Syk inhibitors
US9353066B2 (en) 2012-08-20 2016-05-31 Merck Sharp & Dohme Corp. Substituted phenyl-Spleen Tyrosine Kinase (Syk) inhibitors
US9376418B2 (en) 2012-06-22 2016-06-28 Merck Sharp & Dohme Corp. Substituted pyridine spleen tyrosine kinase (SYK) inhibitors
US9416111B2 (en) 2012-06-22 2016-08-16 Merck Sharp & Dohme Corp. Substituted diazine and triazine spleen tyrosine kinease (Syk) inhibitors
US9487504B2 (en) 2012-06-20 2016-11-08 Merck Sharp & Dohme Corp. Imidazolyl analogs as syk inhibitors
US9499534B2 (en) 2013-04-26 2016-11-22 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyrimidines as spleen tyrosine kinase inhibitors
US9586931B2 (en) 2012-09-28 2017-03-07 Merck Sharp & Dohme Corp. Triazolyl derivatives as Syk inhibitors
US9598405B2 (en) 2012-12-21 2017-03-21 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyridines as spleen tyrosine kinase inhibitors
US9624210B2 (en) 2012-12-12 2017-04-18 Merck Sharp & Dohme Corp. Amino-pyrimidine-containing spleen tyrosine kinase (Syk) inhibitors
US9670196B2 (en) 2013-12-20 2017-06-06 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as Spleen Tyrosine Kinase inhibitors
US9745295B2 (en) 2013-04-26 2017-08-29 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9775839B2 (en) 2014-03-13 2017-10-03 Merck Sharp & Dohme Corp. 2-pyrazine carboxamides as spleen tyrosine kinase inhibitors
US9783531B2 (en) 2013-12-20 2017-10-10 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9822107B2 (en) 2013-12-20 2017-11-21 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation

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WO2003030909A1 (fr) * 2001-09-25 2003-04-17 Bayer Pharmaceuticals Corporation 2- et 4-aminopyrimidines n-substituees par un noyau bicyclique utilisees comme inhibiteurs de kinases dans le traitement du cancer
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WO2004080980A1 (fr) * 2003-03-14 2004-09-23 Novartis Ag 2,4-di(phenylamino)pyrimidines utilisees pour traiter des maladies neoplasiques, des troubles inflammatoires et des troubles du systeme immunitaire
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US8552186B2 (en) 2006-10-23 2013-10-08 Cephalon, Inc. Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-MET inhibitors
US8148391B2 (en) 2006-10-23 2012-04-03 Cephalon, Inc. Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors
JP2010525047A (ja) * 2007-04-27 2010-07-22 アストラゼネカ アクチボラグ 増殖状態の処置のためのＥｐｈＢ４キナーゼ阻害剤としてのＮ’−（フェニル）−Ｎ−（モルホリン−４−イル−ピリジン−２−イル）−ピリミジン−２，４−ジアミン誘導体
WO2008132505A1 (fr) * 2007-04-27 2008-11-06 Astrazeneca Ab Nouveaux dérivés de n' - (phényl) -n- (morpholin-4-yl-pyridin-2-yl) -pyrimidine-2, 4-diaminepyrimidine en tant qu'inhibiteurs de ephb4 kinase pour le traitement d'états prolifératifs
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EP2387572A2 (fr) * 2009-01-15 2011-11-23 Rigel Pharmaceuticals, Inc. Inhibiteurs de la protéine kinase c et leurs utilisations
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EP2387572A4 (fr) * 2009-01-15 2012-07-25 Rigel Pharmaceuticals Inc Inhibiteurs de la protéine kinase c et leurs utilisations
US9453028B2 (en) 2009-01-15 2016-09-27 Rigel Pharmaceuticals, Inc. Protein kinase C inhibitors and uses thereof
EP2489663A1 (fr) 2011-02-16 2012-08-22 Almirall, S.A. Composés en tant qu'inhibiteurs de la syk kinase
US9290490B2 (en) 2011-05-10 2016-03-22 Merck Sharp & Dohme Corp. Aminopyrimidines as Syk inhibitors
US9145391B2 (en) 2011-05-10 2015-09-29 Merck Sharp & Dohme Corp. Bipyridylaminopyridines as Syk inhibitors
US9120785B2 (en) 2011-05-10 2015-09-01 Merck Sharp & Dohme Corp. Pyridyl aminopyridines as Syk inhibitors
US8987456B2 (en) 2011-10-05 2015-03-24 Merck Sharp & Dohme Corp. 3-pyridyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
US9216173B2 (en) 2011-10-05 2015-12-22 Merck Sharp & Dohme Corp. 2-Pyridyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
US9006444B2 (en) 2011-10-05 2015-04-14 Merck Sharp & Dohme Corp. Phenyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
US9487504B2 (en) 2012-06-20 2016-11-08 Merck Sharp & Dohme Corp. Imidazolyl analogs as syk inhibitors
US9242984B2 (en) 2012-06-20 2016-01-26 Merck Sharp & Dohme Corp. Pyrazolyl derivatives as Syk inhibitors
US9376418B2 (en) 2012-06-22 2016-06-28 Merck Sharp & Dohme Corp. Substituted pyridine spleen tyrosine kinase (SYK) inhibitors
US9416111B2 (en) 2012-06-22 2016-08-16 Merck Sharp & Dohme Corp. Substituted diazine and triazine spleen tyrosine kinease (Syk) inhibitors
US9353066B2 (en) 2012-08-20 2016-05-31 Merck Sharp & Dohme Corp. Substituted phenyl-Spleen Tyrosine Kinase (Syk) inhibitors
US9586931B2 (en) 2012-09-28 2017-03-07 Merck Sharp & Dohme Corp. Triazolyl derivatives as Syk inhibitors
US9624210B2 (en) 2012-12-12 2017-04-18 Merck Sharp & Dohme Corp. Amino-pyrimidine-containing spleen tyrosine kinase (Syk) inhibitors
US9598405B2 (en) 2012-12-21 2017-03-21 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyridines as spleen tyrosine kinase inhibitors
US9499534B2 (en) 2013-04-26 2016-11-22 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyrimidines as spleen tyrosine kinase inhibitors
US9745295B2 (en) 2013-04-26 2017-08-29 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9670196B2 (en) 2013-12-20 2017-06-06 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as Spleen Tyrosine Kinase inhibitors
US9783531B2 (en) 2013-12-20 2017-10-10 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9822107B2 (en) 2013-12-20 2017-11-21 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9775839B2 (en) 2014-03-13 2017-10-03 Merck Sharp & Dohme Corp. 2-pyrazine carboxamides as spleen tyrosine kinase inhibitors
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation

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