WO2008024634A1 - Composés de pyrimidine utilisés en tant qu'inhibiteurs de kinase - Google Patents

Composés de pyrimidine utilisés en tant qu'inhibiteurs de kinase Download PDF

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WO2008024634A1
WO2008024634A1 PCT/US2007/075656 US2007075656W WO2008024634A1 WO 2008024634 A1 WO2008024634 A1 WO 2008024634A1 US 2007075656 W US2007075656 W US 2007075656W WO 2008024634 A1 WO2008024634 A1 WO 2008024634A1
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amino
title compound
synthesized
except
pyrimidinyl
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PCT/US2007/075656
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English (en)
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James Andrew Linn
Timothy Longstaff
Kirk Lawrence Stevens
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Smithkline Beecham Corporation
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Publication of WO2008024634A1 publication Critical patent/WO2008024634A1/fr

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    • 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
    • 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
    • C07D401/02—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
    • 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
    • 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
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 mono-anilino pyrimidine derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments.
  • Such mono-anilino pyrimidine derivatives are of potential therapeutic benefit in the treatment of diseases and conditions associated with inappropriate Syk activity, in particular in the treatment of inflammatory and allergic diseases.
  • Spleen Tyrosine Kinase is a protein tyrosine kinase which has been described as a key mediator of immunoreceptor signalling in a host of inflammatory cells including mast cells, B-cells, macrophages and neutrophils.
  • immunoreceptors including Fc receptors and the B-cell receptor, are important for both allergic diseases and antibody-mediated autoimmune diseases and thus pharmacologically interfering with Syk could conceivably treat these disorders.
  • 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 ⁇ Rl) and IgG (Fc ⁇ Rl) 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 ⁇ Rl and or Fc ⁇ Rl receptors, and is positioned early in the signalling cascade.
  • the early sequence of Fc ⁇ Rl signalling following allergen cross-linking of receptor-IgE complexes involves first Lyn (a Src family tyrosine kinase) and then Syk.
  • Inhibitors of Syk 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 et al 2004, 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.
  • FcR Fc receptor
  • the present invention relates to novel mono-anilino pyrimidine compounds, which are inhibitors of kinase activity.
  • Such mono aniline pyrimidine derivatives therefore have potential therapeutic benefit in the treatment of disorders associated with inappropriate kinase, in particular inappropriate Syk activity, in particular in the treatment and prevention of disease states mediated by kinase mechanisms, particularly those diseases mediated by Syk including inflammatory, allergic and autoimmune diseases including asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohns disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, scleroderma, urticaria, rheumatoid arthritis, multiple sclerosis, cancer, HIV and lupus.
  • COPD chronic obstructive pulmonary disease
  • ARDS adult respiratory distress syndrome
  • ulcerative colitis Crohns disease
  • bronchitis dermatitis
  • allergic rhinitis
  • R 1 is H or Ci-3 alkyl
  • R 2 is H, OH, Ci-3 alkyl or Cr 3 hydroxyalkyl
  • R 3 is pyridyl or phenyl (wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogen, C1-3 haloalkyl, C1-3 alkyl, C1-3 alkoxy);
  • a bicyclic heteroaryl group having 9-14 ring members optionally substituted by one or more substituents independently selected from -halogen, -C1-3 alkyl, oxo, - (CH 2 ) 1-3 NR a R b ,), where R a and R b are independently H or C1-3 alkyl; or
  • phenyl (optionally substituted by one or more substituents independently selected from CN, -halogen, C1-3 alkyl, -C1-3 haloalkyl,
  • X represents a bond (ie is absent), -NHCOCH 2 -, -NHCOCH 2 CH 2 -, CH 2 NHCOCH 2 -, OCH 2 CO-, SO 2 , CH 2 -, CH 2 CH 2 -, OCH 2 CH 2 -, -OCH 2 CH 2 CH 2 -, CO-, or -CH 2 SO 2 -;
  • R c and R d independently represent H, -C1-3 alkyl, -(C1-3 alkylene) NRsR h , a 6 membered heterocyclic group optionally substituted by C1-3 alkyl, or R c and R d together with the nitrogen to which they are joined form a 5 or 6 membered heterocyclic group (optionally containing a further heteroatom selected from O or N and optionally substituted by one or more substituentsl
  • R h independently represent H, C1-3 alkyl or R 9 and R h together with the nitrogen to which they are joined form a 5 or 6 membered heterocyclic group, optionally containing a further heteroatom selected from 0 or s and optionally substituted by C1-3 alkyl;
  • R e and R f are independently H, C1-3 alkyl, (C1-3 alkylene)-pyridyl
  • a pharmaceutical composition comprising a compound of formula (I), or a salt or solvate, thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.
  • a compound of formula (I) or a salt or solvate thereof for use in the treatment of a disease or condition mediated by inappropriate Syk activity, particularly inflammatory, allergic and autoimmune diseases.
  • a method of treating a disease or condition mediated by inappropriate Syk activity particularly inflammatory, allergic and autoimmune diseases in a mammal comprising administering to said mammal a compound of formula (I) or a salt or solvate thereof.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • alkyl refers to a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms.
  • C1-C3 alkyl and “Ci-C ⁇ alkyl” refer to an alkyl group, as defined above, containing at least 1, and at most 3 or 6 carbon atoms respectively.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.
  • alkylene refers to a straight or branched chain divalent hydrocarbon radical having the specified number of carbon atoms.
  • C1-C3 alkylene and “Ci-C ⁇ alkylene” refer to an alkylene group, as defined above, which contains at least 1, and at most 3 or 6, carbon atoms respectively.
  • alkylene as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term “halo” refers to the halogen radicals ⁇ fluoro ("F), chloro (-Cl), bromo(-Br), and iodo(-l).
  • haloalkyl refers to an alkyl group as defined above, substituted with at least one halo group, halo being as defined herein.
  • branched or straight chained haloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more halos, e.g., fluoro, chloro, bromo and iodo.
  • heterocyclic or the term “heterocyclyl” refers to a non-aromatic heterocyclic ring, being saturated or having one or more degrees of unsaturation, containing one or more heteroatom substitutions selected from S, S(O), S(O)2, O, or N, and having the specified number of ring members.
  • alkoxy refers to the group RaO", where Ra is alkyl as defined above and the terms "C1-C3 alkoxy” and “Ci-C ⁇ alkoxy” refer to an alkoxy group as defined herein wherein the alkyl moiety contains at least 1, and at most 3 or 6, carbon atoms.
  • Exemplary "C1-C3 alkoxy” and “Ci-C ⁇ alkoxy” groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
  • haloalkoxy refers to the group RaO", where Ra is haloalkyl as defined above and the term “Ci-C ⁇ haloalkoxy” refers to a haloalkoxy group as defined herein wherein the haloalkyl moiety contains at least 1, and at most 6, carbon atoms.
  • Ci-C ⁇ haloalkoxy groups useful in the present invention include, but are not limited to, trifluoromethoxy.
  • hydroxy refers to the group —OH.
  • heteroaryl refers to an aromatic monocyclic 5-7 monitored ring group and fused bicyclic rings, having at least one aromatic ring and having the specified number of ring members (e.g. carbon and heteratoms N, O, and/or S) and containing 1, 2, 3 or 4 heteroatoms selected from N, O and S.
  • ring members e.g. carbon and heteratoms N, O, and/or S
  • heteroatoms selected from N, O and S.
  • heteroaryl groups include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiopene, benzazepine, benzimidazole, benzoimidazole, indole, oxindole and indazole.
  • hydroxyalkyl refers to an alkyl group as defined above substituted with at least one hydroxy, hydroxy being as defined herein.
  • Examples of branched or straight chained “CrC ⁇ hydroxyalkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more hydroxy groups.
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.
  • substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
  • Syk inhibitor is used to mean a compound which inhibits the Syk receptor respectively.
  • Syk mediated disease or a "disorder or disease or condition mediated by inappropriate Syk activity” is used to mean any disease state mediated or modulated by Syk kinase mechanisms, in particular inflammatory, allergic and autoimmune diseases including asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDs), ulcerative colitis, Crohns disease, bronchitis, dermatitis, allergic rhinitis, psorasis, scleroderma, urticaria, rheumatoid arthritis, multiple sclerosis, cancer, HIV and lupus.
  • COPD chronic obstructive pulmonary disease
  • ARDs adult respiratory distress syndrome
  • ulcerative colitis Crohns disease
  • bronchitis dermatitis
  • allergic rhinitis allergic rhinitis
  • psorasis scleroderma
  • urticaria rheumatoid arthritis
  • multiple sclerosis cancer
  • HIV and lupus l
  • 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.
  • a compound of the invention means a compound of formula (I) or a salt, or solvate thereof.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I), or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, acetone, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Most preferably the solvent is water.
  • the compounds of formula (I) including salts and solvates thereof may have the ability to crystallize in more than one form, a characteristic, which is known as polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of formula (I).
  • 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 polymorphs. 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, diasteroisomers, 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. Where the stereochemistry of a chiral centre is not specified 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.
  • 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 our (l) 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 environment, 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 in the compound of the present invention whether such tautomers exist in equilibrium or predominately in one form.
  • R 1 is H or -CH3. In a further embodiment R 1 is H.
  • R 2 is "OH, -CH3 or -CH2OH. In a further embodiment R 2 is -OH.
  • R 3 is phenyl (optionally substituted one or more times by substituents independently selected from -CH3, "F, -CF3, -OCH3) or R 3 is
  • R 3 is phenyl (monsubstituted in the ortho, para or meta position by -CH 3 , -F, -CH 3 or -OCH 3 ) or R 3 is
  • R 4 is a bicyclic heteroaryl group having 9-14 ring members (optionally substituted by one or more substituents independently selected from F,
  • R 4 is
  • R 4 is phenyl (optimally substituted by, one or more substituents independently selected from
  • X is as described herein above and NR c R d represents -NH 2 , -N(CHa) 2 , -NH(CH 3 ), -NH(CH 2 ) 3 , N(CHa) 2 ,
  • R 4 is phenyl which is mono substituted.
  • Examples 1 — 284 as described in the Examples section below.
  • the compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
  • suitable salts see Berge et al, J. Pharm. Sci. 1977, 66, 1-19.
  • the salts of the present invention are pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal un desired toxicological effects. 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 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.
  • Suitable pharmaceutically acceptable salts can include acid or base additions salts.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2 -naphthalene sulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • a suitable inorganic or organic acid such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic,
  • a pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formarate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethane sulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfbnate) or hexanoate salt.
  • a hydrobromide hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formarate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-
  • a pharmaceutically acceptable base addition salt may, where there is a suitable acidic group, be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration.
  • a suitable inorganic or organic base e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine
  • a suitable solvent such as an organic solvent
  • compositions include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the compound of formula (I).
  • pharmaceutically acceptable metal salts for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the compound of formula (I).
  • non-pharmaceutically acceptable salts e.g. oxalates or trifluoroacetates
  • oxalates or trifluoroacetates may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.
  • the invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the compounds of formula (I).
  • the compounds of formula (I) and salts and solvates thereof are believed to be inhibitors of Syk activity, and thus be potentially useful in the treatment of diseases and conditions associated with inappropriate Syk activity.
  • the invention thus provides compounds of formula (I) and salts and solvates thereof for use in therapy, and particularly in the treatment of diseases and conditions mediated by inappropriate Syk activity.
  • the invention further provides a pharmaceutical composition, which comprises a compound of formula (I) and salts and solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • a pharmaceutical composition which comprises a compound of formula (I) and salts and solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of the formula (I) and salts and solvates thereof, are as described above.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical composition including admixing a compound of the formula (I), or salts and solvates thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 5 ⁇ g to Ig, preferably lmg to 700mg, more preferably 5mg to lOOmg of a compound of the formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient.
  • Such unit doses may therefore be administered more than once a day.
  • Preferred unit dosage compositions are those containing a daily dose or sub- dose (for administration more than once a day), as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, inhaled, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets! powders or granules! solutions or suspensions in aqueous or non-aqueous liquids! edible foams or whips! or oiHn-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit compositions for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of formula (I), and salts, solvates and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of formula (I) and salts, solvates and physiological functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • compositions are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oiHn-water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • Dosage forms for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, drops, gels or dry powders.
  • 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).
  • 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 Lrleucine or another amino acid, cellobiose octaacetate 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.
  • the compound of formula (I) or pharmaceutically acceptable salts or solvates thereof may be formulated as a fluid formulation for delivery from a fluid dispenser, for example 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.
  • a fluid dispenser for example 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.
  • a fluid dispenser of the aforementioned type is described and illustrated in WOA-2005/044354, the entire content of which is hereby incorporated herein by reference.
  • 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 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.
  • compositions adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti- oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian
  • an effective amount of a compound of formula (I) for the treatment of diseases or conditions associated with inappropriate Syk activity will generally be in the range of 5 ⁇ g to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 5 ⁇ g to 10 mg/kg body weight per day. This amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt or solvate, thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and the use of at least one other pharmaceutically active agent.
  • combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and at least one other pharmaceutically active agent.
  • the compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the compounds of formula (I) and salts, solvates and physiological functional derivatives thereof, are believed to have therapeutic potential particularly in inflammatory, allergy and autoimmune diseases as a result of inhibition of the protein kinase Syk.
  • the invention provides a compound of formula (I) or a pharmasceutically acceptable salt or solvate thereof for use in therapy.
  • the present invention also provides compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof, or physiologically functional derivatives thereof for use in the treatment of disorders mediated by inappropriate Syk activity.
  • the inappropriate Syk activity referred to herein is any Syk activity that deviates from the normal Syk activity expected in a particular mammalian subject.
  • Inappropriate Syk activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of Syk activity.
  • Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation.
  • the present invention is directed to methods of regulating, modulating, or inhibiting Syk for the prevention and/or treatment of disorders related to unregulated Syk activity.
  • a further aspect of the invention provides a method of treatment of a mammal suffering from a disorder mediated by Syk activity, which includes administering to said subject a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof.
  • a further aspect of the present invention provided the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, in the preparation of a medicament for the treatment of a disorder mediated by Syk activity.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and the use of at least one other pharmaceutically active agent.
  • combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and at least one other pharmaceutically active agent.
  • the compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a further therapeutic agent, pharmaceutical compositions containing said combination and use of such combinations and compositions in therapy.
  • Compounds of the present invention may also be used in combination with other classes of therapeutic agents which are known in the art.
  • Representative classes of agents for use in such combinations include, for treating asthma, anti-inflammatory steroids (in particular corticosteroids), anticholinergic agents, 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 Hl 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 dexamethasone or an ester thereof
  • mometasone or an ester thereof e.g. mometasone furoate
  • ciclesonide e.g. mometasone furoate
  • ciclesonide esonide
  • anti-inflammatory corticosteroids are described in WO 02/12266 Al (Glaxo Group Ltd), in particular, the compounds of Example 1 ( 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-ll ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-andr osta-l,4-diene-17 ⁇ -carbothioic acid * S L fluoromethyl ester) and Example 41 (6 ⁇ ,9 ⁇ -difluoro-ll ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyM,3-thiazole-5-carbonyl)o xy]-3-oxo-androsta-l,4-diene-17 ⁇ -carbothioic acid AS'-fluoromethyl ester), or a pharmaceutically acceptable salt thereof.
  • ⁇ 2-adrenoreceptor agonists 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.
  • antihistamines examples include methapyrilene, olopatadine, or loratadine, cetirizine, desloratadine or fexofenadine.
  • anticholinergic compounds examples include muscarinic (M) receptor antagonists, in particular Mi, M2, M1M2, or M3 receptor antagonists, in particular a (selective) M3 receptor antagonist.
  • M muscarinic
  • anticholinergic compounds are described in WO 03/011274 A2 and WO 02/069945 A2 / US 2002/0193393 Al and US 2002/052312 Al.
  • muscarinic M3 antagonists include ipratropium bromide, oxitropium bromide or tiotropium bromide.
  • Representative 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).
  • the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimise the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
  • These combinations are of particular interest in respiratory diseases and are conveniently adapted for inhaled or intranasal delivery.
  • Rheumatoid arthritis is a further inflammatory disease where combination therapy may be contemplated.
  • the present invention provides a compound of formula (I) or a salt or solvate thereof in combination with a further therapeutic agent useful in the treatment of rheumatoid arthritis, said combination being useful for the treatment of rheumatoid arthritis.
  • the compound and pharmaceutical compositions according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from NSAIDS, corticosteroids, COX-2 inhibitors, cytokine inhibitors, anti-TNF agents, inhibitors of oncostatin M, antimalarials, immunosuppressivess and cytostatics
  • Two classes of medication are contemplated for the treatment of RA, these may be classified as “fast acting” and “slow acting” or “second line” drugs (also referred to as Disease Modifying Antirheumatic Drugs or DMARDS).
  • the first line drugs such as typical NSAIDs (e.g. aspirin, ibuprofen, naproxen, etodolac), corticosteroids (e.g. prednisone).
  • Second line drugs include COX-2 inhibitors and anti-TNF agents. Examples of COX-2 inhibitors are celecoxib (Celebrex), etoricoxib and rofecoxib (Vioxx).
  • Anti-TNF agents include infliximab (Remicade), etanercept (Enbrel) and adalimumab (Humira).
  • Other "biological" treatments include anakinra (Kineret), Rituximab, Lymphostat-B, BAFF/APRIL inhibitors and CTLA-4-Ig or mimetics thereof.
  • Other cytokine inhibitors include leflunomide (Arava).
  • Further second line drugs include gold preparations (Auranofin (Ridaura tablets) or Aurothiomalate (Myocrisin injection)), medicines used for malaria: (Hydroxychloroquine (Plaquenil)), medicines that suppress the immune system (Azathioprine (Imuran, Thioprine), methotrexate (Methoblastin, Ledertrexate, Emthexate), cyclosporin (Sandimmun, Neoral)), Cyclophosphamide (Cycloblastin), Cytoxan, Endoxan), D-Penicillamine (D-Penamine), Sulphasalazine (Salazopyrin), nonsteroidal anti inflammatory drugs (including aspirin and ibuprofen).
  • the present invention also provides for so-called "triple” 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 described above and/or as described in WO 03/030939 Al.
  • 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.
  • the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions.
  • the individual compounds will be administered simultaneously in a combined pharmaceutical composition.
  • Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
  • the compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the Working Examples.
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • a compound When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wileylnterscience, 1994). SCHEME 1
  • TFA trifluoroacetic acid
  • DMSO dimethylsulfoxide
  • DCM diichloromethane
  • DMAP 4-dimethylaminopyridine
  • ATP adenosine triphosphate
  • DMEM Dulbecco's modified Eagle medium
  • TBAF tetra-irbutylammonium fluoride
  • HEPES (4-(2-hydroxyethyl)-l-piperazine ethane sulfonic acid);
  • DPPA diphenylphosphoryl azide
  • EDTA ethylenediaminetetraacetic acid
  • TMEDA ⁇ NHetramethyl-l ⁇ -ethanediamine
  • NBS jV-bromosuccinimide
  • HATU O-(7azabenzobenzotriazol-l-yl)-AfAfA/ " 'A ⁇ etramethyluronium hexafluorophosphate
  • DIPEA diisopropylethylamine
  • dppf l,l'-bis(diphenylphosphino)ferrocene
  • PTFE (poly)tetrafluoroethylene
  • IPA isopropanol
  • atm atmosphere
  • BSA bovine serum albumin
  • HRP horseradish peroxidase
  • LC/MS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HCO2H and 0.01M 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 or a Waters ZQ 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 or a Waters 2525 pump with extended pump heads, Waters 2700 or Waters 2767 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.
  • a Waters FractionLynx system comprising of a Waters 600 or a Waters 2525 pump with extended pump heads, Waters 2700 or Waters 2767 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 trifluor
  • Mass spectra were recorded on a Micromass ZMD or a Waters ZQ mass spectrometer using electrospray positive and negative mode, alternate scans.
  • the software used was MassLynx 3.5 with OpenLynx and FractionLynx options or using equivalent alternative systems.
  • Method A refers to use of a water / acetonitrile gradient containing 0.1% formic acid.
  • Method B refers to use of a water / acetonitrile gradient containing 0.1% trifluoroacetic acid.
  • “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.
  • Flash silica chromatography techniques include either automated (Flashmaster/ISCO SQ16X) techniques or manual chromatography on pre-packed cartridges (SPE/Redisep) or manually-packed flash columns.
  • the ISCO SQ16X is an automated multi-user flash chromatography system, available from Presearch, which utilises disposable, normal phase, RedisepTM cartridges (4 g to 33Og). 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 Microwave chemistry was typically performed in sealed vessels, irradiating with a suitable microwave reactor system, such as a Biotage InitiatorTM Microwave Synthesiser.
  • a suitable microwave reactor system such as a Biotage InitiatorTM Microwave Synthesiser.
  • the phases were separated and the aqueous phase extracted with ethyl acetate.
  • Trimethylsilylcyanide (l5.6mL, 117mmol) was added to neat 2-fluorobenzaldehyde (4.24mL, 40.3mmol) under a flow of nitrogen.
  • a catalytic amount of zinc iodide (0.154g, 0.484mmol) was added in one portion to the stirring mixture (exothermic) and the reaction was stirred overnight for 18 hours. The volatiles were removed under vacuum at 7O 0 C.
  • the residual oil was dissolved in ether (3OmL) and the TMS-protected cyanohydrin/ether solution added to IM lithium aluminum hydride in ether (l22mL) over 20 minutes, maintaining mild reflux. After three hours reflux, the reaction was cooled to ambient temperature.
  • the reaction was carried out in a 6 L 3-necked RB flask, equipped with a mechanical stirrer, thermometer, condenser and CaCb tube.
  • the reduction was carried out in a 2 1 3-necked flask provided with magnetic stirring.
  • the filter cake was again washed with further hot methanol (1.5 L, 50 0 C) and the filtrate used to slurry wash the crude product.
  • Example 3 4-[3'( ⁇ 4-[(2'hvdroxy2'phenylethyl)amino]'2'Pyrimidinyl ⁇ amino)phenyl]'5'methyl' 2.4-dihvdro-3,ffl.2.4-triazol-3-one
  • Example 7 l-[4-( ⁇ 4-[(2'hvdroxy2'phenylethyl)amino]'2'Pyrimidinyl ⁇ amino)phenyl]'4-(l-meth ylethyl)-2-piperazinone
  • Example 2Q 2' ⁇ [2'( ⁇ 3''[(dimethylamino)methyl]'4-biphenylyl ⁇ amino)'4-pyrimidinyl] amino ⁇ ' I-P henylethanol
  • the title compound was synthesized using the procedure recited in Example 1, except 3' "[(dimethylamino) methyl] -4-biphenylamine (65mg, 0.30mmol) was used to give solid (31mg, 0.070mmol).
  • Example 32 iV L -[3-( ⁇ 4-[(2-hvdroxy-2-phenylethyl)amino]-2-pyrimidinyl ⁇ amino)phenyl]-. ⁇ .. ⁇ -di methylglycinamide
  • Example 36 ⁇ [4-( ⁇ 4-[(2'hvdroxy2'phenylethyl)amino]'2'pyrimidinyl ⁇ amino)phenyl]'2'(4-mor pholinvDacetamide
  • Example 4Q iV L -(3- ⁇ [4-( ⁇ 2-hvdroxy-2-[3-(methyloxy)phenyl]ethyl ⁇ amino)-2-pyrimidinyl]amino ⁇ p henyl)-. ⁇ .. ⁇ 'dimethylglvcinamide
  • Example 42 iV L -(3- ⁇ [4-( ⁇ 2-hvdroxy-2-[3-(trifluoromethyl)phenyl]ethyl ⁇ amino)-2-pyrimidinyl]am ino ⁇ phenyl)-.r ⁇ ,. ⁇ ft-dimethylglvcinamide
  • Example 43 iV L -(3- ⁇ [4-( ⁇ 2-hvdroxy-2-[4-(trifluoromethyl)phenyl]ethyl ⁇ amino)-2-pyrimidinyl]am ino ⁇ phenyl)-. ⁇ .. ⁇ 'dimethylglvcinamide
  • Example 44 iV L - ⁇ 3-[(4- ⁇ [2-hvdroxy-2-(2-pyridinyl)ethyl]amino ⁇ -2-pyrimidinyl)amino]phenyl ⁇ -. ⁇ . ⁇ E-dimethylglvcinamide
  • Step A jV-(2-Fluoro-4-nitrophenyl)-N,N-dimethyl-l,3-propanediamine[3-(dimethylamino) propyl] (2-fluoro-4-nitrophenyl)amine
  • Example 48 l'phenyl'2'[(2' ⁇ [3.4.5'tris(methyloxy)phenyl]amino ⁇ '4-pyrimidinyl)amino]ethanol
  • Example 58 l-(2-methylphenyl)-2- ⁇ [2-( ⁇ 4-[(methylsulfonyl)methyl]-phenyl ⁇ amino)-4-pyrimidin yl] aminolethanol
  • Example 72 l-(3-methylphenyl)-2- ⁇ [2-( ⁇ 4-[(methylsulfonyl)methyl]phenyl ⁇ -amino)-4-pyrimidin yl] aminolethanol
  • Example 78 l-(3-methylphenyl)-2-( ⁇ 2-[(3-methylphenyl)amino]-4-pyrimidinyl ⁇ amino)ethanol
  • Example 81 2-[(2- ⁇ [3-(methyloxy)phenyl]aniino ⁇ -4-pyrimidinyl) amino] -l-(3-methylphenyl)etha nol
  • Example 83 2-( ⁇ 2-[(2-chlorophenvl)amino]-4-pvrimidinvl ⁇ amino)-l-(3-methvlphenvl)ethanol
  • Example 84 2-( ⁇ 2-[(3-chlorophenvl)amino]-4-pvrimidinvl ⁇ amino)-l-(3-methvlphenvl)ethanol
  • Example 9Q l'(4-methylphenyl)'2'[(2' ⁇ [3'(2'methyl'1.3'thiazol-4-yl)phenyl]amino ⁇ '4-pyrimidi nypamino] ethanol
  • Example 92 l"(4-methvli3henvl)"2"( ⁇ 2"r(3"methvliDhenvl)aminol"4- ⁇ )vrimidinvl ⁇ amino)ethanol
  • Example 104 l'(3'fluorophenyl)'2'[(2' ⁇ [3.4.5'tris(methyloxy)phenyl]amino ⁇ '4-pyrimidinyl)amin o]ethanol
  • Example 106 l'(3'fluorophenyl)'2'[(2' ⁇ [3'(2'methyl'1.3'thiazol-4-yl)phenyl]amino ⁇ '4-pyrimidin vDamino] ethanol
  • Example 108 l'(3'fluorophenyl)'2'( ⁇ 2'[(2'methylphenyl) amino] '4-pyrimidinyl ⁇ amino)ethanol
  • Example 109 l-(3-fluorophenyl)-2-( ⁇ 2-[(3-methylphenyl) amino] -4-pyrimidinyl ⁇ amino)ethanol
  • Example HQ l-(3-fluorophenyl)-2-( ⁇ 2-[(4-methylphenyl) amino] -4-pyrimidinyl ⁇ -amino)ethanol
  • Example 113 l-(3-fluorophenyl)-2-[(2- ⁇ [4-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)amino]ethan ol
  • Example 116 2-( ⁇ 2-[(4-chlorophenvl)amino]-4-pvrimidinvl ⁇ amino)-l-(3-fluorophenvl)ethanol
  • Example 118 l-[3-(methyloxy)phenyl]-2- ⁇ r2-( ⁇ 4-[(methylsulfonyl)methyl] -phenyl ⁇ amino) -4-pyri midinyl] amino ⁇ ethanol
  • Example 12Q l-[3-(methyloxy)phenyl]-2-[(2- ⁇ [3,4,5-tris(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl
  • Example 122 l-[3-(methyloxy)phenyl]-2-[(2- ⁇ [3-(2-methyl-1.3-thiazol-4-yl)phenyl]amino ⁇ -4-pyri midinv ⁇ amino] ethanol
  • Example 124 l-[3-(methyloxy)phenyl]-2-( ⁇ 2-[(2-methylphenyl) amino] -4-pyrimidinyl ⁇ amino)etha nol
  • Example 126 l-[3-(methyloxy)phenyl]-2-( ⁇ 2-[(4-methylphenyl) amino] -4-pyrimidinyl ⁇ amino)etha nol
  • Example 127 l-[3-(methyloxy)phenyl]-2-[(2- ⁇ [2-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)amino ]ethanol
  • Example 128 l-[3-(methyloxy)phenyl]-2-[(2- ⁇ [3-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)amino ]ethanol
  • Example 129 l-[3-(methyloxy)phenyl]-2-[(2- ⁇ [4-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)amino ]ethanol
  • Example 132 2-( ⁇ 2- [(4-chlorophenyl)amino] -4-pyrimidinyl ⁇ amino)- 1 - [3-(methyloxy)phenyl] etha nol
  • Example 135 3- ⁇ [4-( ⁇ 2-hvdroxy-2-[2-(trifluoromethyl)phenyl]ethyl ⁇ amino)-2-pyrimidinyl] amino ⁇ benzenesulfonamide
  • Example 136 l-[2-(trifluoromethyl)phenyl]-2-[(2- ⁇ [3,4,5-tris(methyloxy)phenyl]amino ⁇ -4-pyrimi dinvOamino] ethanol
  • Example 152 l-[3-(trifluoromethyl)phenyl]-2-[(2- ⁇ [3,4,5-tris(methyloxy)phenyl]amino ⁇ -4-pyrimi dinvDamino] ethanol
  • Example 153 The title compound was synthesized using the procedure recited in Example 150, except 3,4,5-tris(methyloxy)aniline (55mg, 0.30mmol) was used to give solid (43mg, 0.093mmol). MS m/z 465 (M+l) + Example 153:
  • Example 150 The title compound was synthesized using the procedure recited in Example 150, except 3-aminobenzonitrile (35mg, 0.30mmol) was used to give solid (38mg, 0.096mmol).
  • Example 150 The title compound was synthesized using the procedure recited in Example 150, except aniline (28mg, 0.30mmol) was used to give solid (22mg, O.O ⁇ Ommol).
  • Example 168 l'[4-(trifluoromethyl)phenyl]'2'[(2' ⁇ [3.4.5'tris(methyloxy)phenyl]amino ⁇ '4-pyrimi dinvOamino] ethanol

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

Abstract

L'invention concerne un composé représenté par la formule (I) ou un sel ou un solvate de ce composé : Formule (I) des compositions et des médicaments contenant ceux-ci, ainsi que des procédés pour la préparation et l'utilisation de tels composés, compositions et médicaments. De tels dérivés de mono-anilino pyrimidine sont d'un avantage thérapeutique potentiel dans le traitement de maladies et de conditions associées à l'activité Syk inappropriée, en particulier dans le traitement de maladies inflammatoires et allergiques.
PCT/US2007/075656 2006-08-25 2007-08-10 Composés de pyrimidine utilisés en tant qu'inhibiteurs de kinase WO2008024634A1 (fr)

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Cited By (12)

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WO2011075515A1 (fr) * 2009-12-17 2011-06-23 Merck Sharp & Dohme Corp. Aminopyrimidines en tant qu'inhibiteurs de la syk
EP2387572A2 (fr) * 2009-01-15 2011-11-23 Rigel Pharmaceuticals, Inc. Inhibiteurs de la protéine kinase c et leurs utilisations
WO2012101013A1 (fr) * 2011-01-28 2012-08-02 Boehringer Ingelheim International Gmbh Pyridinyl-pyrimidines substituées et leur utilisation en tant que médicaments
WO2013037705A3 (fr) * 2011-09-16 2013-06-06 Fovea Pharmaceuticals Dérivés d'aniline, leur préparation et leur application thérapeutique
AU2012204063B2 (en) * 2009-12-17 2014-03-13 Merck Canada Inc. Aminopyrimidines as Syk inhibitors
EP2711365A1 (fr) 2012-09-21 2014-03-26 Chemilia AB 4-Indazolylamino-2-(2-(indol-3-yl)éthyl)aminopyrimidines utiles pour le traitement du cancer
EP2711364A1 (fr) 2012-09-21 2014-03-26 Chemilia AB 4-(Indolyl ou benzimidazolyl)amino-2-(2-(indol-3-yl)éthyl)aminopyrimidines utiles pour le traitement du cancer
US8735417B2 (en) 2009-12-17 2014-05-27 Merck Sharp & Dohme Corp. Aminopyrimidines as 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
US9290490B2 (en) 2011-05-10 2016-03-22 Merck Sharp & Dohme Corp. Aminopyrimidines as Syk inhibitors
EP2884982A4 (fr) * 2012-08-20 2016-03-30 Merck Sharp & Dohme Inhibiteurs de la phényle tyrosine kinase de la rate (syk) substitués

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US6881740B1 (en) * 1998-07-08 2005-04-19 Monash University Pharmaceutical agents

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CN102292333B (zh) * 2009-01-15 2015-05-13 里格尔药品股份有限公司 蛋白激酶c抑制剂及其用途
EP2387572A2 (fr) * 2009-01-15 2011-11-23 Rigel Pharmaceuticals, Inc. Inhibiteurs de la protéine kinase c et leurs utilisations
CN102292333A (zh) * 2009-01-15 2011-12-21 里格尔药品股份有限公司 蛋白激酶c抑制剂及其用途
JP2012515206A (ja) * 2009-01-15 2012-07-05 ライジェル ファーマシューティカルズ， インコーポレイテッド プロテインキナーゼｃ阻害剤とその使用
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
US9095593B2 (en) 2009-01-15 2015-08-04 Rigel Pharmaceuticals, Inc. Protein kinase C inhibitors and uses thereof
US8759366B2 (en) 2009-12-17 2014-06-24 Merck Sharp & Dohme Corp. Aminopyrimidines as SYK inhibitors
AU2014200138A8 (en) * 2009-12-17 2015-10-29 Merck Canada Inc. Aminopyrimidines as Syk inhibitors
JP2013155182A (ja) * 2009-12-17 2013-08-15 Merck Sharp & Dohme Corp Ｓｙｋ阻害剤としてのアミノピリミジン類
US8551984B2 (en) 2009-12-17 2013-10-08 Merck Sharp & Dohme Corp. Aminopyrimidines as SYK inhibitors
AU2010331927B2 (en) * 2009-12-17 2013-10-10 Merck Canada Inc. Aminopyrimidines as Syk inhibitors
AU2012204063B2 (en) * 2009-12-17 2014-03-13 Merck Canada Inc. Aminopyrimidines as Syk inhibitors
CN102858767B (zh) * 2009-12-17 2015-08-19 默沙东公司 作为syk抑制剂的氨基嘧啶
CN102858767A (zh) * 2009-12-17 2013-01-02 默沙东公司 作为syk抑制剂的氨基嘧啶
AU2014200138B2 (en) * 2009-12-17 2015-06-18 Merck Canada Inc. Aminopyrimidines as Syk inhibitors
JP2013514370A (ja) * 2009-12-17 2013-04-25 メルク・シャープ・エンド・ドーム・コーポレイション Ｓｙｋ阻害剤としてのアミノピリミジン類
US8735417B2 (en) 2009-12-17 2014-05-27 Merck Sharp & Dohme Corp. Aminopyrimidines as Syk inhibitors
WO2011075515A1 (fr) * 2009-12-17 2011-06-23 Merck Sharp & Dohme Corp. Aminopyrimidines en tant qu'inhibiteurs de la syk
KR101445012B1 (ko) * 2009-12-17 2014-09-26 머크 샤프 앤드 돔 코포레이션 Ｓｙｋ 억제제로서의 아미노피리미딘
US20140243290A1 (en) * 2009-12-17 2014-08-28 Michael D. Altman Aminopyrimidines as SYK Inhibitors
US8772305B2 (en) 2011-01-28 2014-07-08 Boehringer Ingelheim International Gmbh Substituted pyridinyl-pyrimidines and their use as medicaments
JP2014507417A (ja) * 2011-01-28 2014-03-27 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 置換ピリジニル−ピリミジン及び医薬としてのその使用
WO2012101013A1 (fr) * 2011-01-28 2012-08-02 Boehringer Ingelheim International Gmbh Pyridinyl-pyrimidines substituées et leur utilisation en tant que médicaments
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
US9290490B2 (en) 2011-05-10 2016-03-22 Merck Sharp & Dohme Corp. Aminopyrimidines as Syk inhibitors
CN103930396A (zh) * 2011-09-16 2014-07-16 弗维亚医药品公司 苯胺衍生物，其制备及其治疗应用
EA026702B1 (ru) * 2011-09-16 2017-05-31 Санофи Производные анилина, их получение и терапевтическое применение
US9624159B2 (en) 2011-09-16 2017-04-18 Sanofi Aniline derivatives, their preparation and their therapeutic application
CN103930396B (zh) * 2011-09-16 2016-11-16 赛诺菲 苯胺衍生物，其制备及其治疗应用
WO2013037705A3 (fr) * 2011-09-16 2013-06-06 Fovea Pharmaceuticals Dérivés d'aniline, leur préparation et leur application thérapeutique
US9249085B2 (en) 2011-09-16 2016-02-02 Fovea Pharmaceuticals Aniline derivatives, their preparation and their therapeutic application
US9353066B2 (en) 2012-08-20 2016-05-31 Merck Sharp & Dohme Corp. Substituted phenyl-Spleen Tyrosine Kinase (Syk) inhibitors
EP2884982A4 (fr) * 2012-08-20 2016-03-30 Merck Sharp & Dohme Inhibiteurs de la phényle tyrosine kinase de la rate (syk) substitués
EP2711365A1 (fr) 2012-09-21 2014-03-26 Chemilia AB 4-Indazolylamino-2-(2-(indol-3-yl)éthyl)aminopyrimidines utiles pour le traitement du cancer
EP2711364A1 (fr) 2012-09-21 2014-03-26 Chemilia AB 4-(Indolyl ou benzimidazolyl)amino-2-(2-(indol-3-yl)éthyl)aminopyrimidines utiles pour le traitement du cancer
WO2014044754A1 (fr) 2012-09-21 2014-03-27 Chemilia Ab 4-indazolylamino -2- (2- (indol-3-yl) éthyl) aminopyrimidines utiles pour le traitement du cancer

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