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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
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  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
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  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P17/00—Drugs for dermatological disorders
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  • A61P17/00—Drugs for dermatological disorders
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  • A61P19/00—Drugs for skeletal disorders
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  • A61P27/00—Drugs for disorders of the senses
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  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• This invention is directed to substituted pyrrolopyrimidines, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of the protein kinases.
• Protein kinases participate in the signalling events which control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these kinases fall into several groups; those which preferentially phosphorylate serine and/or threonine residues and those which preferentially phosphorylate tyrosine residues [S.K.Hanks and T.Hunter, FASEB. J., 1995, 9, pages 576-596].
• the serine/threonine kinases include for example, protein kinase C isoforms [A.C.Newton, J. Biol.
• tyrosine kinases include membrane-spanning growth factor receptors such as the epidermal growth factor receptor [S.Iwashita and M.Kobayashi, Cellular Signalling, 1992, 4, pages 123-132], and cytosolic non-receptor kinases such as p56tck, p59fYn, ZAP-70 and csk kinases [C.Chan et. al., Ann. Rev. Immunol., 1994, 12, pages 555-592].
• Syk is a 72-kDa cytoplasmic protein tyrosine kinase that is expressed in a variety of hematopoietic cells and is an essential element in several cascades that couple antigen receptors to cellular responses.
• Syk plays a pivotal role in signalling of the high affinity IgE receptor, Fc ⁇ Rl, in mast cells and in receptor antigen signalling in T and B lymphocytes.
• the signal transduction pathways present in mast, T and B cells have common features.
• the ligand binding domain of the receptor lacks intrinsic tyrosine kinase activity.
• ITAMs immunoreceptor tyrosine based activation motifs
• TCR T cell receptor
• BCR B cell receptor
• Syk belongs to a unique class of tyrosine kinases that have two tandem Src homology 2 (SH2) domains and a C terminal catalytic domain. These SH2 domains bind with high affinity to ITAMs and this SH2 -mediated association of Syk with an activated receptor stimulates Syk kinase activity and localises Syk to the plasma membrane.
• SH2 domains bind with high affinity to ITAMs and this SH2 -mediated association of Syk with an activated receptor stimulates Syk kinase activity and localises Syk to the plasma membrane.
• Syk is further involved in the activation of platelets stimulated via the low-affinity IgG receptor (Fc gamma-RIIA) or stimulated by collagen [F.Yanaga et al., Biochem. J., 1995, 311, (Pt. 2) pages 471- 478].
• Fc gamma-RIIA low-affinity IgG receptor
• FAK Focal adhesion kinase
• FAK Focal adhesion kinase
• FAK is a non-receptor tyrosine kinase involved in integrin-mediated signal transduction pathways.
• FAK colocalizes with integrins in focal contact sites and FAK activation and its tyrosine phosphorylation have been shown in many cell types to be dependent on integrins binding to their extracellular ligands.
• Results from several studies support the hypothesis that FAK inhibitors could be useful in cancer treatment. For example, FAK-deficient cells migrate poorly in response to chemotactic signals and overexpression of C-terminal domain of FAK blocks cell spreading as well as chemotactic migration (Sieg et al, J. Cell Science, 1999, 112, 2677-2691; Richardson A.
• Angiogenesis is a complex multistage process which includes activation, migration, proliferation and survival of endothelial cells.
• Extensive studies in the field of tumor angiogenesis in the past two decades have identified a number of therapeutic targets including kinases, proteases and integrins resulting in the discovery of many new anti- angiogenic agents, including KDR inhibitors some of which are currently under clinical evaluation (Jekunen, et al Cancer Treatment Rev. 1997 , 23, 263-286.).
• Angiogenesis inhibitors may be used in frontline, adjuvant and even preventive settings for the emergence or regrowth of malignancies.
• kinases proteins involved in chromosome segregation and spindle assembly have been identified in yeast and drosophila. Disruption of these proteins results in chromosome missegregation and monopolar or disrupted spindles.
• Ipll and aurora kinases from S.cerevisiae and drosophila respectively, which are required for centrosome separation and chromosome segregation.
• One human homologue of yeast Ipll was recently cloned and characterized by different laboratories. This kinase termed Aurora2, STK15 or BTAK belongs to the serine/threonine kinase family.
• Aurora2 is oncogenic and is amplified in human colorectal cancers (EMBO J, 1998, 17, 3052-3065). It has also been exemplified in cancers involving epithelial tumors such as breast cancer.
• This invention concerns substituted pyrrolopyrimidines of formula (I), which have the ability to inhibit one or more protein kinases, more particularly, FAK, KDR , Syk kinase or Aurora2, especially Syk kinase.
• R 4 can also be optionally interspersed with a group selected from O, S(0) n , NR >;
• R5 represents hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
• R6 represents hydrogen or lower alkyl
• R 7 represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
• Y 3 and Y 4 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY Y 4 may form a cyclic amine; Z represents O or S(0) n ; n is zero or an integer 1 or 2; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and their prodrugs, and their acid bioisosteres; together with one or more pharmaceutically acceptable carriers or excipients.
• Z represents O or S(0) n ; n is zero or an integer 1 or 2; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and
• “Patient” includes both human and other mammals.
• “Acid bioisostere” means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21, p283 "Bioisosterism In Drug Design”; Yun, Hwahak Sekye, 1993, 33, pages 576-579 "Application Of Bioisosterism To New Drug Design”; Zhao, Huaxue Tongbao, 1995, pages 34-38 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design”; Graham, Theochem, 1995, 343, pages 105-109 "Theoretical Studies Applied To Drug Desig ab initio Electronic Distributions In Bioisosteres”).
• Acyl means an H-CO- or alkyl-CO- group in which the alkyl group is as described herein.
• acylamino is an acyl-NH- group wherein acyl is as defined herein.
• Alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in the chain.
• Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain.
• “Lower alkenyl” means about 2 to about 4 carbon atoms in the chain, which may be straight or branched.
• alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
• alkenyloxy is an alkenyl-O- group wherein alkenyl is as defined above.
• exemplary alkenyloxy groups include allyloxy.
• Alkoxy means an alkyl-O- group in which the alkyl group is as described herein.
• exemplary alkoxy groups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
• Alkoxycarbonyl means an alkyl-O-CO- group in which the alkyl group is as described herein.
• exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
• Alkyl means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched chain having about 1 to about 15 carbon atoms in the chain, optionally substituted by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms.
• “Lower alkyl” as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulf ⁇ nyl or lower alkylsulfonyl group means unless otherwise specified, an aliphatic hydrocarbon group which may be a straight or branched chain having 1 to about 4 carbon atoms in the chain.
• Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.
• Exemplary alkyl groups substituted by one or more halogen atoms include trifluoromethyl.
• Alkylene means an aliphatic bivalent radical derived from a straight or branched alkyl group, in which the alkyl group is as described herein.
• exemplary alkylene radicals include methylene, ethylene and trimethylene.
• Alkylenedioxy means an -O-alkylene-O- group in which alkylene is as defined above.
• exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.
• Alkylsulfinyl means an alkyl-SO- group in which the alkyl group is as previously described. Preferred alkylsulfinyl groups are those in which the alkyl group is C ⁇ alkyl.
• Alkylsulfonyl means an alkyl-S0 2 - group in which the alkyl group is as previously described.
• Preferred alkylsulfonyl groups are those in which the alkyl group is C ⁇ alkyl.
• Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is C ⁇ alkyl.
• Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
• exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
• Alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which group may be a straight or branched chain having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
• “Aroyl” means an aryl-CO- group in which the aryl group is as described herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
• Aroylamino is an aroyl-NH- group wherein aroyl is as previously defined.
• Aryl as a group or part of a group denotes: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring.
• aryl groups may be substituted with one or more aryl group substituents, which may be the same or different, where "aryl group substituent" includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or an acid bioisostere), cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, -NY Y 4 , -CON
• Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C ⁇ alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
• Arylalkyloxy means an arylalkyl-O- group in which the arylalkyl groups is as previously described.
• exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
• Arylalkyloxycarbonyl means an arylalkyl-O-CO- group in which the arylalkyl groups is as previously described.
• An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
• Arylalkylthio means an arylalkyl-S- group in which the arylalkyl group is as previously described.
• An exemplary arylalkylthio group is benzylthio.
• Aryloxy means an aryl-O- group in which the aryl group is as previously described.
• exemplary aryloxy groups include phenoxy and naphthoxy, each optionally substituted.
• exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
• Arylsulfmyl means an aryl-SO- group in which the aryl group is as previously described.
• Arylsulfonyl means an aryl-S0 - group in which the aryl group is as previously described.
• Arylthio means an aryl-S- group in which the aryl group is as previously described.
• exemplary arylthio groups include phenylthio and naphthylthio.
• Azaheteroaryl means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are selected from carbon, oxygen, sulfur, and nitrogen.
• azaheteroaryl groups include benzimidazolyl, imidazolyl, indazolinyl, indolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, quinazolinyl and tetrahydroindolizinyl.
• cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline, pyrindoline, tetrahydroquinoline and the like groups.
• Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
• Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl.
• Cycloalkyl means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms, optionally substituted by oxo.
• Exemplary monocyclic cycloalkyl rings include C ⁇ .gcycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
• Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described.
• Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
• Halo or "halogen” means fluoro, chloro, bromo, or iodo. Preferred are fluoro and chloro.
• exemplary heteroaryl groups include pyridylcarbonyl.
• Heteroaroylamino means a heteroaroyl-NH- group in which the heteroaryl moiety is as previously described.
• Heteroaryl as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur (examples of such groups include benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents as defined above
• Heteroarylalkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C ⁇ alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
• Heteroarylalkyloxy means an heteroarylalkyl-O- group in which the heteroarylalkyl group is as previously described.
• exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.
• Heteroaryloxy means an heteroaryl-O- group in which the heteroaryl group is as previously described.
• exemplary heteroaryloxy groups include optionally substituted pyridyloxy.
• Heterocycloalkyl means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms or heteroatom-containing groups selected from O, S and NY ⁇ and mat be optionally substituted by oxo; (ii) a partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl) ring, each optionally substituted by one or more "aryl group substituents,” and a heterocycloalkyl group are fused together to form a cyclic structure.
• aryl or heteroaryl
• aryl group substituents each optionally substituted by one or more "aryl group substituents”
• heterocycloalkyl group include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).
• Heterocycloalkylalkyl means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
• Prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof.
• an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
• an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
• Suitable esters of compounds of formula (I) containing a hydroxy group are, for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
• Suitable esters of compounds of formula (I) containing a carboxy group are, for example, those described by F.J.Leinweber, Drug Metab. Res., 1987, j_8, page 379.
• Suitable esters of compounds of formula (I) containing both a carboxy group and a hydroxy group within the moiety -L ⁇ -Y include lactones formed by loss of water between said carboxy and hydroxy groups. Examples of such lactones include caprolactones and butyrolactones.
• esters of compounds of formula (I), containing a hydroxy group may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32 , page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-l-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-l-yl)benzoates.
• substituted (aminomethyl)-benzoates for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by
• base addition salts may be formed and are simply a more convenient form for use; in practice, use of the salt form inherently amounts to use of the free acid form.
• the bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations.
• Pharmaceutically acceptable salts including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline,
• N,N'-dibenzylethylenediamine chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
• Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
• Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form.
• the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions.
• compositions are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.
• Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g.
• salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
• Rl may particularly represent: (i) hydrogen (ii) C ! _ 4 alkyl [e.g. -CH 3 or -CH 2 CH 3 ];
• R 1 more especially represents hydrogen.
• R 2 may particularly represent:
• alkyl substituted by carboxy e.g. -CH 2 CH 2 CO,H
• heteroaryl e.g.
• R 4 is alkyl or cycloalkylalkyl substituted by one or more hydroxy groups [e.g. -OCH 2 CH 2 OH , -OCH 2 CH 2 CH 2 OH , -OCH (CH 3 ) CH 2 OH ,
• R 4 is alkyl substituted by one or more alkoxy groups [e.g. -OCH (CH 3 ) CH 2 OCH 3 ];
• R 4 is alkyl or cycloalkyl substituted by one or more carboxy groups [e.g.
• R 2 more especially represents -OCH 3 .
• R 3 may particularly represent: (i) hydrogen; (ii) cyano;
• optionally substituted heteroaryl e.g. optionally substituted pyridyl or optionally
• substituted indolyl especially (v) alkyl (e.g. methyl or ethyl);
• alkyl substituted by one or more halogen atoms e.g. trifluoromethyl
• alkyl substituted by -OR 7 e.g. -CH -CH 2 -OCH 3 ;
• R 3 more especially represents -OCH 3 .
• R 2 is preferably attached to position 5 of the indole ring.
• the group is preferably attached to the 3 position of the indole ring
• Especially preferred compounds of the invention are:-
• the compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders.
• the present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
• the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of protein kinase (e.g. Syk, FAK, KDR or Aurora2) inhibitors, in particular a Syk kinase inhibitor.
• protein kinase e.g. Syk, FAK, KDR or Aurora2
• compounds of the present invention are useful in the treatment of inflammatory diseases, for example asthma: inflammatory dermatoses (e.g.
• psoriasis dematitis herpetiformis, eczema, necrotizing and cutaneous vasculitis, bullous disease
• allergic rhinitis and allergic conjunctivitis joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis.
• the compounds are also useful in the treatment of Chronic Obstructive Pulmonary Disease (COPD), acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, restenosis, myocarditis, B cell lymphomas, systemic lupus erythematosus, graft v host disease and other transplant associated rejection events, cancers and tumours (such as colorectal, prostate, breast, thyroid, colon and lung cancers) and inflammatory bowel disease. Additionally, the compounds are useful as tumor anti-angiogenic agents.
• COPD Chronic Obstructive Pulmonary Disease
• acute synovitis autoimmune diabetes
• autoimmune encephalomyelitis collitis
• atherosclerosis peripheral vascular disease
• cardiovascular disease multiple sclerosis
• restenosis myocarditis
• B cell lymphomas systemic lupus erythematosus
• graft v host disease and other transplant associated rejection events
• a special embodiment of the therapeutic methods of the present invention is the treating of asthma.
• Another special embodiment of the therapeutic methods of the present invention is the treating of psoriasis.
• Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
• Another special embodiment of the therapeutic methods of the present invention is the treating of inflammatory bowel disease.
• Another special embodiment of the therapeutic methods of the present invention is the treating of cancers and tumours.
• a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of a protein kinase (e.g. Syk, FAK, KDR or Aurora2) inhibitor for example conditions as hereinbefore described which comprises the administration to the patient of an effective amount of a compound of the invention or a composition containing a compound of the invention.
• Effective amount is meant to describe an amount of compound of the present invention effective in inhibiting the catalytic activity a protein kinase, such as Syk, FAK, KDR or Aurora2, and thus producing the desired therapeutic effect.
• references herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
• the present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
• compounds of the invention may be administered by any suitable means.
• compounds of the present invention may be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
• compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients.
• the adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents.
• the compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptable preparations.
• excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets.
• lactose and high molecular weight polyethylene glycols When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
• Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
• emulsions, suspensions or solutions of the products according to the invention in vegetable oil for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used.
• vegetable oil for example sesame oil, groundnut oil or olive oil
• aqueous-organic solutions such as water and propylene glycol
• injectable organic esters such as ethyl oleate
• sterile aqueous solutions of the pharmaceutically acceptable salts are used.
• the solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection.
• aqueous solutions also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilised by heating, irradiation or microfiltration.
• gels water or alcohol based
• creams or ointments containing compounds of the invention may be used.
• Compounds of the invention may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
• inhalation compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
• Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
• the percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained.
• several unit dosage forms may be administered at about the same time.
• the dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient.
• the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration.
• the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
• the compounds according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
• R 3 is as hereinbefore defined and ⁇ is a halogen, preferably iodine, atom or a triflate group, with compounds of formula (XXIX):-
• the coupling reaction may conveniently be carried out, for example, in the presence of a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in aqueous dimethylformamide at a temperature up to reflux temperature.
• a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate
• This reaction is conveniently carried out with the pyrrole NH in compound (XXVIII) protected with for example a tosyl group and the indole NH in compound (XXIX) protected with, for example, a tert-butyloxycarbonyl group.
• Compounds of the invention may also be prepared by interconversion of other compounds of the invention.
• compounds of formula (I) containing a carboxy group may be prepared by hydrolysis of the corresponding esters.
• the hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, e.g. lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux.
• a base such as an alkali metal hydroxide, e.g. lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate
• organic solvents such as dioxan, tetrahydrofuran or methanol
• the hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50°C to about 80°C.
• an inorganic acid such as hydrochloric acid
• an aqueous/inert organic solvent mixture using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50°C to about 80°C.
• compounds of formula (I) containing a carboxy group may be prepared by acid catalysed removal of the tert-butyl group of the corresponding tert-butyl esters using standard reaction conditions, for example reaction with trifluoroacetic acid at a temperature at about room temperature.
• compounds of formula (I) containing a carboxy group may be prepared by hydrogenation of the corresponding benzyl esters.
• the reaction may be carried out in the presence of ammonium formate and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature at about reflux temperature.
• a suitable metal catalyst e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
• a suitable base such as diisopropylethylamine
• an inert solvent such as dimethylformamide
• the coupling may also be brought about by reaction of compounds of formula (I) containing a carboxy group with 2-(lH-benzotriazole-l- yl)l,l,3,3-tetramethyluronium hexafluorophosphate, in dry dimethylformamide, followed by reaction with an amine of formula HNY ⁇ 2 in the presence of diisopropylethylamine.
• compounds of formula (I) containing a -CH 2 OH group may be prepared by the reduction of corresponding compounds of formula (I) containing a -CHO or -C0 2 R 7 (in which R 7 is lower alkyl) group.
• the reduction may conveniently be carried out by means of reaction with lithium aluminium hydride, in an inert solvent, such as tetrahydrofuran, and at a temperature from about room temperature to about reflux temperature.
• compounds of formula (I) in which R 2 is hydroxy may be prepared by reaction of the corresponding compounds of formula (I) in which R is methoxy with a Lewis acid, such as boron tribromide, in an inert solvent, such as dichloromethane and at a temperature from about 0°C to about room temperature.
• a Lewis acid such as boron tribromide
• an inert solvent such as dichloromethane
• compounds of formula (I) in which R 2 is -OR 4 may be prepared by alkylation the corresponding compounds of formula (I) in which R 2 is hydroxy, with compounds of formula (XXX):-
• R 4 is as just hereinbefore defined and X 3 is a halogen, preferably bromo, atom, or a tosyl group, using standard alkylation conditions.
• the alkylation may for example be carried out in the presence of a base, such as an alkali metal carbonate (e.g. potassium carbonate or cesium carbonate), an alkali metal alkoxide (e.g. potassium tertiary butoxide) or alkali metal hydride (e.g. sodium hydride), in dimethylformamide, or dimethyl sulfoxide, at a temperature from about 0°C to about 100°C.
• a base such as an alkali metal carbonate (e.g. potassium carbonate or cesium carbonate), an alkali metal alkoxide (e.g. potassium tertiary butoxide) or alkali metal hydride (e.g. sodium hydride), in dimethylformamide, or dimethyl sulfoxide, at a temperature from about 0
• -NY'Y 2 may be prepared by alkylation of the corresponding compounds of formula (la) in which R is hydrogen, with the appropriate halide of formula (XXXI):-
• R -X 4 (XXXI) wherein R is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, or alkyl substituted by -C( 0)NYl ⁇ 2 ,
• compounds of formula (I) containing sulfoxide linkages may be prepared by the oxidation of corresponding compounds containing -S- linkages.
• the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulfate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0°C and room temperature.
• a peroxyacid e.g. 3-chloroperbenzoic acid
• an inert solvent e.g. dichloromethane
• potassium hydrogen peroxomonosulfate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0°C and room temperature.
• This latter method is preferred for compounds containing an acid-labile group
• compounds of formula (I) containing sulfone linkages may be prepared by the oxidation of corresponding compounds containing -S- or sulfoxide linkages.
• the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.
• the reaction may conveniently be carried out in an inert solvent, such as tetrahydrofuran, and at a temperature at about reflux temperature.
• the reaction may conveniently be carried out in methanol at a temperature at about room temperature.
• compounds of formula (I) in which R 3 is -NY ⁇ Y 2 may be prepared by reaction of the corresponding compounds of formula (I) in which R 3 is halo (e.g. chloro) with an amine of formula HNY ⁇ 2 (wherein ⁇ and Y 2 are as immediately hereinbefore defined).
• compounds of formula (I) in which R 3 is cyano may be prepared by reaction of compounds of formula (I) in which X* is halo, preferably chloro, with zinc cyanide in the presence of zinc powder, [l'l-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex and dichloromethane (catalytic amount) and N,N-dimethylacetamide at a temperature up to about 150°C.
• R ⁇ is tert-butyl the reaction may conveniently be carried out in the presence of l-l'-carbonyldiimidazole and l,8-diazabicyclo[5.4.0]undec-7-ene at a temperature at about room temperature.
• compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates.
• acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods.
• the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
• the acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods.
• parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
• Co pounds of this invention can be regenerated from their base addition salts by the application or adaptation of known methods.
• parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
• Hydrates of compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol.
• base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods.
• the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
• the starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
• the present invention is further exemplified but not limited by the following illustrative Examples and Reference Examples.
• Method A Hypersil BDS C-18 column (4.6 mm x 50 mm) reverse phase operated under gradient elution conditions with mixtures of (A) water containing 0.05% trifluoroacetic acid and (B) acetonitrile containing 0.05% trifluoroacetic acid as the mobile phase gradient : (0.00 minutes 100%A:0%B; linear gradient to 100% B at 2 minutes; then hold until 3.5 minutes); flow rate ImL/minute with approximately 0.25mL/minute split to the Mass Spectrometer; injection volume 10 ⁇ L; Hewlett Packard Model HP 1100 Series UV detector wavelength 200nm; Evaporative light scattering (ELS) detection - temperature 46°C, nitrogen pressure 4bar.
• ELS Evaporative light scattering
• Method B Gilson 215 injector model using a Hypersil HyPURITY C-18 -5 ⁇ column (4.6 mm x 50 mm) operated under gradient elution conditions with mixtures of (A) water containing 0.05%> trifluoroacetic acid and (B) acetonitrile containing 0.05%) trifluoroacetic acid as the mobile phase gradient : (0.00 minutes 95%A:5%B; linear gradient to 95% B at 4 minutes; then to 5% B at 4.5 minutes, then hold until 6 minutes); injection volume 5 ⁇ L and flow rate ImL/minute to UV (DAD) detector followed by approximately 0.1 OOmL/minute split to the Mass Spectrometer (positive electrospray) with remainder to ELS detector.
• DAD flow rate ImL/minute to UV
• METHOD C Micromass instrument model LCT linked to an HP 1 100 model instrument. Compound abundance were detected using an HP model G1315A photodiode array detector in the 200-600 nm wavelength range and a Sedex model 65 evaporative light scattering detector. Mass spectra were acquired in the 180 to 800 range. Data were analysed using the Micromass MassLynx software.
• the reaction mixture was stirred at -78°C for another 1 hour and allowed to reach room temperature.
• the reaction mixture was partitioned between ethyl acetate and aqueous sodium sulfite solution.
• the organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure.
• the residue was subjected to flash column chromatography on silica eluting with a gradient of ethyl acetate and cyclohexane (50:50, to 100, v/v) to give the title compound (260mg) as an amorphous solid.
• LCMS (Method B) R ⁇ 3.26 minutes.
• reaction mixture was stirred at -78°C for 2 hours, and allowed to reach room temperature.
• the reaction mixture was partitioned between ethyl acetate and aqueous sodium sulfite solution, dried over magnesium sulfate and the solvent was evaporated under reduced pressure.
• the residue was subjected to flash column chromatography on silica eluting with a gradient of ethyl acetate and cyclohexane (50:50, to 100, v/v) to give the title compound (1.52g) as an amorphous solid.
• the catalytic domain of Syk kinase (residues A340-N635 ) was expressed as a fusion protein in yeast cells and purified to homogeneity.
• Kinase activity was determined in 50mM Tris-HCl buffer pH 7.0 containing 50mM NaCl, 5mM MgCl2, 5mM MnCl2, l ⁇ M adenosine triphosphate and lO ⁇ M synthetic peptide Biotin-( ⁇ -Alanine) -DEEDYEIPP-NH2.
• Enzyme reactions were terminated by the addition of buffer containing 0.4M KF, 133mM EDTA, pH 7.0, containing a streptavidin-XL665 conjugate and a monoclonal phosphospecf ⁇ c antibody conjugated to a europium cryptate (Eu-K).
• buffer containing 0.4M KF, 133mM EDTA, pH 7.0 containing a streptavidin-XL665 conjugate and a monoclonal phosphospecf ⁇ c antibody conjugated to a europium cryptate (Eu-K).
• Eu-K europium cryptate
• Inhibition of syk activity with compounds of the invention was expressed as percentage inhibition of control activity exhibited in the absence of test compounds.
• Particular preferred compounds of the invention inhibit syk activity with IC50S in the range 100 micromolar to 100 nanomolar.
• Especially preferred compounds of the invention inhibit syk activity with IC50S in the range 1 micromolar to 100 nanomolar.
• RBL-2H3 cells are maintained in T75 flasks at 37°C and 5%C ⁇ 2, and passaged every 3-4 days.
• 5 ml trypsin-EDTA is used to rinse the flask once, then 5 ml trypsin is added to each flask, and incubated at room temperature for 2 minutes.
• Cells are transferred to a tube with 14ml medium, spun down at 1100 rpm RT for 5 minutes and resuspended at 2xl0 ⁇ /ml.
• Cells are sensitized by adding l ⁇ l of DNP-specif ⁇ c IgE to every 10 ml of cells. 200 ⁇ l of cells are added to each well of a flat-bottom 96 well plate (40,000 cells/well), and the plate incubated overnight at 37°C and 5%C ⁇ 2-
• the supernatants are transferred to a new 96-well plate.
• RBL Rat Basophilic leukemia

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