OA12632A - Pyrrolopyrimidines as protein kinase inhibitors. - Google Patents

Abstract

This invention is directed to compounds of the formula (I) to N-oxides, prodrugs, acid bioisosteres, pharmaceutically acceptable salts or solvates of such compounds, or N-oxides, prodrugs, or acid bioisosteres of such salts or solvates, to compositions comprising such compounds, and to methods of treatment comprising administering, to a patient in need thereof, such compounds and compositions.

Description

012632 -1-

PYRROLOPYRIMIDINES AS PROTEIN KINASE INHIBITORS

This invention is directed to substituted pyrrolopyrimidines, their préparation, pharmaceutical 5 compositions containing these compounds, and their pharmaceutical use in the treatment of diseaseStates capable of being modulated by the inhibition of the protein kinases.

Protein kinases participate in the signalling events which control the activation, growth anddifférentiation of cells in response to extracellular mediators and to changes in the environment. In 10 general, these kinases fall into several groups; those which preferentially phosphoiylate serine and/orthreonine residues and those which preferentially phosphoiylate tyrosine residues [S.K.Hanks andT.Hunter, FASEB. J., 1995,9, pages 576-596]. The serineZthreonine kinases include for example,protein kinase C isoforms [A.C.Newton, J. Biol. Chem., 1995,270, pages 28495-28498] and a group ofcyclin-dependent kinases such as cdc2 [J.Pines, Trends in 15 Biochemical Sciences, 1995, 18, pages 195-197]. The tyrosine kinases include membrane-spanninggrowth 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]. 20 Inappropriately high protein kinase activity has been implicated in many diseases resulting fforn abnormal cellular fonction. This might arise either directly or indirectly, for example by failure of theproper control mechanisms for the kinase, related for example to mutation, over-expression orinappropriate activation of the enzyme; or by over- or underproduction of cytokines or growth factorsalso participating in the transduction of signais upstream or downstream of the kinase. In ail of these 25 instances, sélective inhibition of the action of the kinase might be expected to hâve a bénéficiai effect.

Syk is a 72-kDa cytoplasmic protein tyrosine kinase that is expressed in a variety of hematopoieticcells and is an essential element in several cascades that couple antigen receptors to cellular responses.Thus, Syk plays a pivotai rôle in signalling of the high affînity IgE receptor, FcsRl, in mast cells and 30 in receptor antigen signalling in T and B lymphocytes. The signal transduction pathways présent inmast, T and B cells hâve common features. The ligand binding domain of the receptor lacks intrinsictyrosine kinase activity. However, they interact with transducing subunits that contain immunoreceptor tyrosine based activation motifs (ITAMs) [M.Reth, Nature, 1989,338, pages 383-384]. These motifs are présent in both the β and γ subunits of the FcsRl, in the ξ-subunit the of T cell 35 receptor (TCR) and in the IgGa and IgG β subunits of the B cell receptor (BCR). [N.S.van Oers andA. Weiss, Seminars in Immunology, 1995,7, pages 227-236] Upon binding of antigen and 012632 -2- multimerization, the ITAM residues are phosphorylated by protein tyrosine kinases of the Src family.Syk belongs to a unique class of tyrosine kinases that hâve two tandem Src homology 2 (SH2) domainsand a C terminal catalytic domain. These SH2 domains bind with high affmity to ITAMs and this SH2-mediated association of Syk with an activated receptor stimulâtes Syk kinase activity and localisesSyk to the plasma membrane.

In Syk déficient mice, mast cell degranulation is inhibited, suggesting that this is an important targetfor the development of mast cell stabilising agents [P.S.Costello, Oncogene, 1996,13, pages 2595-2605]. Similar studies hâve demonstrated a critical rôle for Syk in BCR and TCR signalling[A.M.Cheng, Nature, 1995,378, pages 303-306, (1995) and D.H.Chu et al., Immunological Reviews,1998,165, pages 167-180]. Syk also appears to be involved in eosinophil survival in response to IL-5and GM-CSF [S.Yousefi et al., J. Exp. Med., 1996,183, pages 1407-1414]. Despite the key rôle ofSyk in mast cell, BCR and T cell signalling, little is known about the mechanism by which Syktransmits downstream effectors. Two adaptor proteins, BLNK (B cell Linker protein, SLP-65) andSLP-76 hâve been shown to be substrates of Syk in B cells and mast cells respectively and hâve beenpostulated to interface Syk with downstream effectors [M.Ishiai et al., Immunity, 1999,10, pages 117-125 and L.R.Hendricks-Taylor et al., J.Biol. Chem, 1997,272, pages 1363-1367]. In addition Sykappears to play an important rôle in the CD40 signalling pathway, which plays an important rôle in Bcell prolifération [M.Faris et al., J.Exp. Med., 1994, 179, pages 1923-1931].

Syk is further involved in the activation of platelets stimulated via the low-afïïnity IgG receptor (Fcgamma-RUA) or stimulated by collagen [F.Yanagaet al., Biochem. J., 1995,311, (Pt. 2) pages 471-478].

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in integrin-mediated signaltransduction pathways. FAK colocalizes with integrins in focal contact sites and F AK activation andits tyrosine phosphorylation hâve been shown in many cell types to be dépendent on integrins bindingto their extracellular ligands. Results from several studies support the hypothesis that FAK inhibitorscould be usefiil in cancer treatment. For example, FAK-deficient cells migrate poorly in response tochemotactic signais and overexpression of C-terminal domain of FAK blocks cell spreading as welî aschemotactic migration (Sieg et al, J. Cell Science, 1999,112,2677-2691; Richardson A. and ParsonsT., Cell, 1997, 97,221-231) ; in addition, tumor cells treated with FAK antisense oligonucleotides losttheir attachment and underwent apoptosis (Xu et al, Cell Growth Differ. 1996,4,413-418). FAK hasbeen reported to be overexpressed in prostate, breast, thyroid, colon and lung cancers. The level ofexpression of FAK is directly correlated with tumors demonstrating the most aggressive phenotype. 012632 -3-

Angiogenesis or the formation of new blood vessels by sprouting from die preexisting vascuiature is ofcentral importance for embryonic development and organogenesis. Abnormal enhancedneovascularization is observed in rheumatoid arthritis, diabetic retinopathy and during tumordevelopment (Folkman, Nat. Med., 1995, l, 27-31.). Angiogenesis is a complex multistage process 5 whîch includes activation, migration, prolifération and survival of endothélial cells. Extensive studiesin the field of tumor angiogenesis in the past two décades hâve identified a number of therapeutictargets 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 évaluation(Jekunen, et al Cancer Treatment Rev. 1997,23, 263-286.). Angiogenesis inhibitors may be used in 10 frontline, adjuvant and even préventive settings for the emergence or regrowth of malignancies.

Several proteins involved in chromosome ségrégation and spindle assembly hâve been identified inyeast and drosophila. Disruption of these proteins results in chromosome missegregation andmonopolar or disrupted spindles. Among these kinases are the Ipll and aurora kinases from 15 S.cerevisiae and drosophila respectively, which are required for centrosome séparation and chromosome ségrégation. One human homologue of yeast Ipll was recently cloned and characterizedby different laboratories. This kinase termed Aurora2, STK15 or BTAK belongs to the serine/threonine kinase family. Bischoff et al showed that Aurora2 is oncogenic and is amplified inhuman colorectal cancers (EMBO J, 1998, 17,3052-3065). It has also been exemplified in cancers 20 invôlving épithélial tumors such as breast cancer. 25 30 -4- 012632

This invention concerns substituted pyrrolopyrimidines of formula (I), which hâve the ability to inhibitone or more protein kinases, more particularfy, FAK, KDR, Syk kinase or Aurora2, especially Sykkinase.

wherein R1 represents hydrogen, -C^O^NY1 Y2, -C(=O)-OR5, -SO^NY1 Y2, -SO2-R7, -C(=O)R7, or R1 10 may be alkenyl, alkenyloxy, alkyl, alkynyl, aryl, heteroaiyl, heterocycloalkyl, cycloalkyl or cycloalkylalkyl, each optionally substituted by one or more groups selected from aiyl, cycloalkyl,cyano, halo, heteroaryl, heterocycloalkyl, -CHO (or a 5-, 6- or 7-membered cyclic acetal dérivativethereof), -0(=0)-^^2, -C(=O)-OR5, -NYÎY2, -N(R6)-C(=O>R7, -N(R6)-C(=O)-NY3Y4,-N(R6)-SO2-R7, -N(R6)-SO2-NY3Y4, -OR7, -C(=O)-R7, hydroxy, alkoxy and carboxy; 15 R2 represents one or more groups selected from hydrogen, acyl, alkylenedioxy, alkenyl, alkenyloxy,alkynyl, aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, R4, -C(=0)-NY^Y3,-C(=O)-OR5, -NY1 Y3, -N(R6)-C(=O)-R7, -N(R6)-C(=O)-NY3Y4, -N(R6)-C(=O)-OR7,-N(R6)-SO2-R7, -N(R6)-SO2-NY3Y4, -SO2-NY’y2 and -ZR4; R3 represents H, cyano, halo, hydroxy, nitro, R4, NY1 Y2, -ZR4, -C(=O)-OR3, -C(=0)-R7, 20 -Ο(=Ο)-ΝΥ! Y2, -N(R8)-C(=O>R4, -N(R8)-C(=O)·^ Y2, -N(R8)-C(=O)-OR5, -SO2-NY3Y4, or -N(R8)-SO2-R7, or R3 represents aryl, heteroaryl, alkenyl or alkynyl, each optionally substituted byone or more groups selected from aryl, cyano, halo, hydroxy, heteroaiyl, heterocycloalkyl, nitro,-0(=0)-^1 Y2, -C(=O)-OR5, -NY1 Y2, -N(R6)-C(=O)-R7> -N(R6)-C(=O)-NY3Y4, -N(R6)-C(=O)-OR7, -N(R6>SO2-R7, -N(R6>SO2-NY3Y4, -SO2-NY1Y2 or-ZR4; 25 R4 represents alkyl, cycloalkyl or cycloalkylalkyl each optionally substituted by one or more groupsselected from aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, hydroxy, -CHO (or a 5-, 6- or 7-membered cyclic acetal dérivative thereof), -C(=O)-NY1Y2 -C(=O)-OR3, -NY1 Y3, 012632 -5- -N(R6)-C(=O)-R7, -N(R6)-C(=O>NY3Y4, -N(R6)-SO2-R7, -N(R6)-SO2-NY3Y4, -OR7 and-C(=O)-R7; R4 can also be optionally interspersed with a group selected from O, S(O)n, NR^; R3 représente hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; r6 represents hydrogen or Iower alkyl; R7 represents alkyl, aiyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl or heterocycloalkylalkyl;r8 represents hydrogen or Iower alkyl; γΐ and Y7 are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl optionallysubsfituted by one or more groups selected from aryl, halo, heteroaryl, hydroxy, -C(=O)-NY3Y4,-C(=O>OR5, -NY3Y4, -N(R6)-C(=O>R7, -N(R6)-C(=O)-NY3Y4, -N(R6)-SO2-R7,-N(r6)-SO2-NY3Y4 and -OR7; or the group -NY Y7 may form a cyclic amine; Y3 and Y4 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl orheteroarylalkyl; or the group -NY3Y4 may form a cyclic amine; Z represents O or S(O)n; n is zéro or an integer 1 or 2; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceuticallyacceptable salts and solvatés (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 orexcipients.

In tire présent spécification, the term "compounds of the invention", and équivalent expressions, aremeant to embrace compounds of general formula (I) as hereinbefore described, which expressionincludes the prodrugs, the pharmaceutically acceptable salts, and the solvatés, e.g. hydrates, where thecontext so permits. Similarly, référencé to intermediates, whether or not they themselves are claimed,is meant to embrace their salts, and solvatés, where the context so permits. For the sake of clarity,particular instances when the context so permits are sometimes indicated in the text, but these instancesare purely illustrative and it is not intended to exclude other instances when the context so permits.

As used above, and throughout the description of the invention, the following ternis, unless otherwise indicated, shall be understood to hâve the following meanings:- 'Patient" includes both human and other mammals. 012632 -6- "Acid bioisostere" means a group which has Chemical and physical similarities producing broadlysimilar biological properties to a carboxy group (see Lipinski, Annual Reports in Médicinal 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 34-3 8"Bîoisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham,Theochem, 1995,343, pages 105-109 "Theoretical Studies Applied To Drug Design:ab initioElectronic Distributions In Bioisosteres"). Examples of suitable acid bioisosteres include:-C(=O)-NHOH, -C(=O)-CH2OH, -C(=O)-CH2SH, -C(=O)-NH-CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-l,2-dione, 3,5-dioxo-l,2,4-oxadiazolidinyl orheterocyclic phénols such as 3-hydroxyisoxazoIyl and 3-hydoxy-l-methylpyrazolyI. "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 whichmay be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenylgroups hâve 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," as used herein and throughout the text, means thatone or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here aIinear alkenyl chain. "Lower alkenyl" means about 2 to about 4 carbon atoms in the chain, which maybe straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methyIbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl. "Alkenyloxy" is an alkenyl-O- group wherein alkenyl is as defined above. Exemplaiy alkenyloxygroups include allyloxy. "Alkoxy" means an alkyl-O- group in which the alkyl group is as described herein. Exemplary alkoxygroups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxyand heptoxy. "Alkoxycarbonyl" means an alkyl-O-CO- group in which the alkyl group is as described herein.Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl. 012632 -7- "Alkyl" means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight orbranched Chain having about 1 to about 15 carbon atoms in the chain, optionally substituted by one ormore halogen atoms. Particular alkyl groups hâve from 1 to about 6 carbon atoms. "Lower alkyl" as agroup or part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl groupmeans unless otherwise specified, an aliphatic hydrocarbon group which may be a straight or branchedchain 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, inwhich the alkyl group is as described herein. Exemplary alkylene radicals include methylene, ethyleneand trimethylene. "Alkylenedioxy" means an -O-alkylene-O- group in which alkylene is as defined above. Exemplaryalkylenedioxy 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 Cj^alkyl. "Alkylsulfonyl" means an aIkyl-SO2- group in which the alkyl group is as previously described.Preferred alkylsulfonyl groups are those in which the alkyl group is Cj^alkyl. "Alkylsulfonylcarbamoyl" means an alkyl-SO2-NH-C(=O)- group in which the alkyl group is as previously described. Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group isCj^alkyl. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Exemplaryalkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio. "Alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and whichgroup may be a straight or branched chain having about 2 to about 15 carbon atoms in the chain.Preferred alkynyl groups hâve 2 to about 12 carbon atoms in the chain; and more preferably 2 to about6 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. 012632 -8- " Aroyl" means an aryl-CO- group in which the aryl group is as described herein. Exemplary aroylgroups include benzoyl and 1- and 2-naphthoyl. "Aroylamino" is an aroyl-NH- group wherein aroyl is as previously defined. "Aryl" as a group or pari of a group dénotés: (i) an optionally substituted monocyclic or multicyclicaromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) anoptionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which an aryl anda cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as atetrahydronaphthyl, indenyl or indanyl ring. Except where otherwise defined, aryl groups may besubstituted with one or more aiyl group substituents, which may be the same or different, where "arylgroup 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 acidbioisostere), cyano, halo, heteroaroyl, heteroaiyl, heteroarylalkyloxy, heteroaroylamino, heteroaiyloxy,hydroxy, nitro, trifluoromethyl, -NY3Y4, -CONY3Y4, -SO2NY3Y4, -NY3-C(=O)alkyl, -NY3SO2alkyl or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or -NY3 Y4. "Arylalkyl" means an aryl-alkyl- group in which die aryl and alkyl moieties are as previouslydescribed. Preferred arylalkyl groups contain a Cj 4 alkyl moiety. Exemplary arylalkyl groupsinclude benzyl, 2-phenethyl and riaphthlenemethyl. "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 previouslydescribed. 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. Exemplaryaryloxy groups include phenoxy and naphthoxy, each optionally substituted. "Aryloxycarbonyl" means an aryl-0-C(=0)- group in which the aryl group is as previously described.Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. 012632 -9- "Arylsulfinyl" means an aryl-SO- group in which the aryl group is as previously described. "Arylsulfonyl" means an aryl-SO2- group in which the aryl group is as previously described.

S "Aiylsulfonylcarbamoyl" means an aiyl-SO2-NH-C(=O)- group in which the aryl group is aspreviously described. "Aiylthio” means an aryl-S- group in which the aryl group is as previously described. Exemplary 10 arylthio groups include phenylthio and naphthylthio. "Azaheteroaryl" means an aromatic carbocyclic moiety of about 5 to about 10 ring members in whichone of the ring members is nitrogen and the other ring members are selected from carbon, oxygen,sulfur, and nitrogen. Examples of azaheteroaryl groups include benzimidazolyl, imidazolyl, 15 indazolinyl, indolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, quinazolinyl andtetrahydroindolizinyl. * "Cyclic amine" means a 3 to 8 membered monocyclic cycloalkyl ring System wherein one of the ringcarbon atoms is replaced by nitrogen and which (i) may also contain a further heteroatom-containing 20 group selected from O, S, SO2, or NY$ (where is hydrogen, alkyl, aryl, arylalkyl, -C(=O)-R7,-C(=O)-OR7 or -SO2R7); and (ii) may be fiised to additional aryl (e.g. phenyl), heteroaryl (e.g.pyridyl), heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring System. Exemplarycyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline, pyrindoline,tetrahydroquinoline and the like groups. 25 "Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring System contaïning at least onecarbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocycliccycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl. 30 "Cycloalkyl" means a saturated monocyclic or bicyclic ring System of about 3 to about 10 carbonatoms, optionally substituted by oxo. Exemplary monocyclic cycloalkyl rings include C3_8cycloalkylrings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. 012632 -10- "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are aspreviously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl,cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. 5 "Halo” or "haîogen" means fluoro, chloro, bromo, or iodo. Preferred are fluoro and chloro. "Heteroaroyl" means a heteroaryI-C(=O)- group in which the heteroaryl group is as described herein.Exemplary heteroaryl groups include pyridylcarbonyl. 10 "Heteroaroylamino" means a heteroaroyl-NH- group in which the heteroaryl moiety is as previouslydescribed. "Heteroaryl" as a group or part of a group dénotés: (i) an optionally substituted aromatic monocyclic ormulticyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring 15 members is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur (examples of suchgroups 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, optionallysubstituted by one or more aryl group substituents as defined above except where otherwise defmed); 20 (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which aheteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure(exampies of such groups include pyrindanyl groups, optionally substituted by one or more "aryl groupsubstituents" as defined above, except where otherwise defined). Optional substituents include one ormore "aryl group substituents" as defined above, except where otherwise defined. 25 "Heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are aspreviously described. Preferred heteroarylalkyl groups contain a C^alkyl moiety. Exemplaryheteroarylalkyl groups include pyridylmethyl. 30 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 previouslydescribed. Exempîaiy heteroaryloxy groups include optionally substituted pyridyloxy. 35 012632 -11- "Heteroarylsulfonylcarbamoyl" means a heteroaryl-S02-NH-C(=0)- group in which the heteroarylgroup is as previously described. "Heterocycloalkyl" means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one ormore heteroatoms or heteroatom-containing groups selected from O, S and NY$ and mat be optionailysubstituted by oxo; (ii) a partially saturated multicyclic heterocarbocyclic moiety in which an aryl (orheteroaryl) ring, each optionaily substituted by one or more “aryl group substituents,” and aheterocycloalkyl group are fused together to form a cyclic structure. (Examples of such groups includechromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups). "Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkylmoieties are as previously described. "Prodrug" means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of formula (I), including N-oxides thereof. For example an ester of a compound of formula(I) containing a hydroxy group may be convertible by hvdrolvsis in vivo to the parent molécule.Alternatively, an ester of a compound of formula (I) containing a carboxy group may be convertible byhydrolysis in vivo to the parent molécule.

Suitable esters of compounds of formula (I) containing a hydroxy group are, for example acétates,citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fiimarates,maleates, methylene-bis-P-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates,methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamatesand quinates.

Suitable esters of compounds of formula (I) containing a carboxy group are, for example, thosedescribed by F.J.Leinweber, Drug Metab. Res., 1987,18, page 379.

Suitable esters of compounds of formula (I) containing both a carboxy group and a hydroxy group within the moiety -iJ-Y include lactones formed by loss of water between said carboxy and hydroxygroups. Examples of such lactones include caprolactones and butyrolactones.

An especially useful class of esters of compounds of formula (I), containing a hydroxy group, may beformed 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 012632 -12- by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, moreespecially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and(4-alkylpiperazin-l-yI)benzoates, e.g. 3- or 4-(4-alkyIpiperazin-l-yl)benzoates.

Where the compound of the invention contains a carboxy group, or a sufficiently acidic bioisostere,base addition salts may be formed and are simply a more convenient form for use; in practice, use ofthe sait form inherently amounts to use of the free acid form. The bases which can be used to préparéthé 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 inpharmaceutical doses of the salts, so that the bénéficiai inhibitory effects inhérent in the free base arenot vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including thosederived from alkali and alkaline earth métal salts, within the scope of the invention include thosederived from the following bases; sodium hydride, sodium hydroxide, potassium hydroxide, calciumhydroxide, aluminium hydroxide, lithium hydroxide, magnésium hydroxide, zinc hydroxide, ammonia,ethylenediamine, N-methyl-glucamine, lysine, arginine, omithine, choline, Ν,Ν'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tétraméthylammonium hydroxide, andthe like.

Some of the compounds of the présent invention are basic, and such compounds are useful in the formof tiie free base or in the form of a pharmaceutically acceptable acid addition sait thereof.

Acid addition salts are a more convenient form for use; and in practice, use of the sait form inherentlyamounts to use of the free base form. The acids which can be used to préparé the acid addition saltsinclude preferably those which produce, when combined with the free base, pharmaceuticallyacceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of thesalts, so that the bénéficiai inhibitoiy effects inhérent in the free base are not vitiated by side effectsascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds arepreferred, ail acid addition salts are useful as sources of the free base form even if the particular sait,per se, is desired only as an intermediate product as, for example, when the sait is formed only forpurposes of purification, and identification, or when it is used as intermediate in preparing apharmaceutically acceptable sait by ion exchange procedures. Pharmaceutically acceptable salts withinthe scope ofthe invention include those derived from minerai acids and organic acids, and includehydrohalides, e.g. hydrochlorides and hydrobromides, sulfates, phosphates, nitrates, sulfamates,acétates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates,maleates, methylene-bis-beta-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, 012632 -13- methane-sulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamatesand quinates.

As well as being useful in themselves as active compounds, saits of compounds of the invention areuseful for the purposes of purification of the compounds, for example by exploitation of the solubilitydifférences between the salts and the parent compounds, side products and/or starting materials bytechniques well known to those skilled in the art.

With référencé to formula (I) above, the following are particular and preferred groupings: RJ may particularly represent: (i) hydrogen (ii) CMaIkyl [e.g. -CH3 or -CH2CH3]; (iii) C^alkyl substituted by halo [e.g. -CH2CF3]; (iv) C^alkyl substituted by hydroxy [e.g. -CH2OH, -CH2CH2OH or -CH2CH2CH2OH ]; (v) C^alkyl substituted by-N(R6)C(==O)-R7 [e.g. -CH2CH2CH2NHC <=O) CH3 ]; (vi) C 1.4 alkyl substituted by -<2(=Ο)-Νγ1γ2 [e.g. -CH—C (=O) -N O]; or (vii) cycloalkylalkyl substituted by hydroxy [e.g. Η2^Η2

—c—CHJ.I ch2oh

Compounds of formula (I) in which R^ represents hydrogen, -CH3, -CH2CH3, -CH2CF3 or -CH — C (—0) 2° are especially preferred. R^ more especially represents hydrogen. R^ may particularly represent: (i) carboxy or an acid bioisostere (e.g. N- N'

NH (ii) hydroxy; (iii) alkyl substituted by carboxy [e.g. -CH2CH2CO2H ]; 012632 -1Φ-

(iv) heteroaryl [e.g. — 10 (v) -OR4 in which R4 is alkyl [e.g. -OCH3 ]; (vi) -OR4 in which R4 is alkyl or cycloalkylalkyl substituted by one or more hydroxy groups[e.g. -OCH2CH2OH , -OCH2CH2CH2OH, -OCH (CH3) CH2OH, h2ç-çh2 -OCH2CH (OH) CH3, -o—Ç—CH2 or -OCH2CH(OH)CH2OH];ch2oh (vii) -OR4 in which R4 is alkyl substituted by one or more alkoxy groups [e.g. -och (ch3) ch2och3 ]; (viii) -OR4 in which R4 is alkyl or cycloalkyl substituted by one or more carboxy groups [e.g. h2Ç-Çh2 -OCH,CO,H, -OCH (CH_) CO,H or -O—Ç—CH, ]; co2h

HaÇ- ÇH2 (ix) -OR4 in which R4 is cycloalkyl substituted by-C(=O)-NY^ Y2 [e.g. -o—Ç—CH2 or CONH„ H2<f-ÇH2-o—ç—ch2 ]; conhch3 (x) -C(=O)-R in which R is alkyl [e.g. -c (=0) -CH3 ]; (xi) -Ο(=Ο)-ΝγΙ Y2 [e.g. -CONH2, —CONHCH,, -CONHCH (CH,OH) ,, 15 -CONHCH2CH2OH, -CONHC (CH,) ,CH,OH, CONHCH,CH,OCH, , -2^^2 3

CONHCH2CH2CONH,, -CONHCH,C (CH,) ,OH or -CONH 3' 2' 1; V® or (xii) -N(R6)-C(=O)-R7 [e.g. -NHC (=0) CH3 ]. 012632 -15-

Compounds of formula (I) in which R2 représente -OCH3 or -CONHC (CH3) 2CH2OH are especially preferred. R2 more especially représente -OCH3 · R2 may particularly represent: (i) hydrogen; (ii) cyano; (iii) optionally substituted aryl (e.g. phenyl); (iv) optionally substituted heteroaryl (e.g. optionally substituted pyridyl or optionally

MeO substituted indolyl, especially (v) alkyl (e.g. methyl or ethyl); (vi) alkyl substituted by one or more halogen atoms (e.g. trifluoromethyl); (vii) alkyl substituted by -C(=O)-NY^ Y2, especially -CH2-CH2-C(=O)NHCH3 ; (viii) alkyl substituted by -OR2 (e.g. -CH2-CH2-OCH3); (ix) -ZR4, especially -OCH3 , -OCH2CH3, -OCF2H or -OCH2-CH2-OCH3; (x) -C(=O)-OR5, especially -C(=O)-OH; (xi) -C(=O)-NYlY2, especially -C(=O)NHCH3 or -C(=0)-NH-C(CH3)2-CH2OH; and (xii) -NY *YZ, especially —.

Compounds of formula (I) in which R2 représente hydrogen, cyano, pyridyl, trifluoromethyl, -CH2-/ \ CH2-C(=O)NHCH3, -OCF2H, -C(=O)-NH-C(CH3)2-CH2OH or —are especially preferred. R2 more especially représente -OCH3. R2 is preferably attached to position 5 ofthe indole ring. 012632 -16-

The group

is preferably attached to the 3 position of the indole ring 5 It is to be understood that this invention covers ali appropriate combinations of the particular andpreferred groupings referred to herein.

10 (II) (ΙΠ)

15 012632

(XV) (XVII) (XVI) 15 01263 2 -18-

(XIX) (xvm)

(xxi) (xxii) (xxm)

(XXIV)

(XXV)

10

(XXVII) and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvatés(e.g. hydrates) of such compounds and their N-oxides and prodrugs. 15 Especially preferred compounds of the invention are:- 012632 -19-

(ΧΠ) 4-methoxy-6-(5-methoxy-lH-indol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine;and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvatés(e.g. hydrates) of such compounds and their N-oxides and prodrugs.

The compounds of the invention exhibit useful pharmacological activity and accordingly areincorporated into pharmaceutical compositions and used in the treatment of patients suffering fromcertain medical disorders. The présent invention thus provides, according to a further aspect,compounds of the invention and compositions containing compounds of the invention for use intherapy.

Compounds within the scope of the présent invention block kinase catalytic activity according to testsdescribed in the literature and in vitro procedures described hereinafter, and which tests results arebelieved to correlate to pharmacological activity in humans and other mammals. Thus, in a furtherembodiment, the présent invention provides compounds of the invention and compositions containingcompounds 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, F AK, KDR orAurora2) inhibitors, in particular a Syk kinase inhibitor. For example, compounds of the présentinvention are useful in the treatment of inflammatory diseases, for example asthma: inflammatorydermatoses (e.g. psoriasis, dematitis herpetiformis, eczema, necrotizing and cutaneous vasculitis,bullous disease); allergie rhinitis and allergie 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 alsouseful in the treatment of Chronic Obstructive Pulmonary Disease (COPD), acute synovitis,autoimmune diabètes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vasculardisease, cardiovascular disease, multiple sclerosis, restenosis, myocarditis, B cell lymphomas,systemie 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) andinflammatoty bowel disease. Additionally, the compounds are useful as tumor anti-angiogenic agents. A spécial embodiment of the therapeutic methods of the présent invention is the treating of asthma. 012632 -20-

Anotlier spécial embodiment of the therapeutic methods of the présent invention is the treating of psoriasis.

Another spécial embodiment of the therapeutic methods of the présent invention is the treating of jointinflammation.

Another spécial embodiment of the therapeutic methods of the présent invention is the treating ofinflammatory bowel disease.

Another spécial embodiment of the therapeutic methods of the présent invention is the treating ofcancers and tumours.

According to a further feature of the invention there is provided a method for the treatment of a humanor animal patient suffering from, or subject to, conditions which can be ameliorated by theadministration of a protein kinase (e.g. Syk, FAK, KDR or Aurora2) inhibitor for example conditionsas hereinbefore described, which comprises the administration to the patient of an effective amount ofa compound of the invention or a composition containing a compound of the invention. "Effectiveamount" is meant to describe an amount of compound of the présent invention effective in inhibitingthe catalytic activity a protein kinase, such as Syk, FAK, KDR or Aurora2, and thus producing thedesired therapeutic effect.

References herein to treatment should be understood to include prophylactic therapy as well astreatment of established conditions.

The présent invention also includes within its scope pharmaceutical compositions comprising at leastone of the compounds of the invention in association with a pharmaceutically acceptable carrier orexcipient.

Compounds of the invention may be administered by any suitable means. In practice, compounds ofthe présent 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, stérile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of tabîets, pills, granules, powders, aqueous solutions or suspensions, injectable 012632 -21- solutions, élixirs or syrups, and can contain one or more agents chosen from the group comprisingsweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptablepréparations. The choice of vehicle and the content of active substance in the vehicle are generallydetermined in accordance with the solubility and Chemical properties of the active compound, theparticular mode of administration and the provisions to be observed in pharmaceutical practice. Forexample, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate anddisintegrating agents such as starch, alginic acids and certain complex silicates combined withlubricants such as magnésium stéarate, sodium lauryl sulfate and talc may be used for preparing tablets.To préparé a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols.When aqueous suspensions are used they can contain emulsifying agents or agents which facilitatesuspension. Diluents such as sucrose, éthanol, polyethylene glycol, propylene glycol, glycerol andchloroform or mixtures thereof may also be used.

For parentéral administration, émulsions, suspensions or solutions of the products according to theinvention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organicsolutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well asstérile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the saltsof the products according to the invention are especially useful for administration by intramuscular orsubcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilledwater, may be used for intravenous administration with the proviso that their pH is suitably adjusted,that they are judiciously buffered and rendered isotonie with a sufRcient quantity of glucose or sodiumchloride and that they are sterilised by heating, irradiation or microfiltration.

For topical administration, gels (water or alcohol based), creams or ointments containing compounds ofthe invention may be used. Compounds of the invention may also be incorporated in a gel or matrixbase for application in a patch, which would allow a controlled release of compound through thetransdermal barrier.

For administration by inhalation compounds of the invention may be dissolved or suspended in asuitable carrier for use in a nebuliser or a suspension or-solution aérosol, or may be absorbed oradsorbed 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. -22- 012632

The percentage of active ingrédient in the compositions of the invention may be varied, it beingnecessaiy that it should constitute a proportion such that a suitable dosage shall be obtained.

Obviousîy, several unit dosage forms may be admînistered at about the same time. The dose employedwill be determined by the physicien, and dépends upon the desired therapeutic effect, the route ofadministration and the duration of the treatment, and the condition of the patient.

In the adult, the doses are generally from about 0.001 to about 50, preferabiy about 0.001 to about 5,mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferabiy 0.1 to 70, moreespecially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about10, preferabiy 0.01 to 1, mg/kg body weight per day by intravenous administration. ïn each particularcase, the doses will be determined in accordance with the factors distinctive to the subject to be treated,such as âge, weight, general State of health and other characteristics which can influence the efficacy ofthe médicinal product.

The compounds according to the invention may be admînistered as frequently as necessary in order toobtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose andmay find much weaker maintenance doses adéquate. For other patients, it may be necessary to hâvelong-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiologicalrequirements of each particular patient. Generally, the active product may be admînistered orally 1 to4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one ortwo doses per day.

Compounds of the invention may be prepared by the application or adaptation of known methods, bywhich is meant methods used heretofore or described in the literature, for example those described byR.C.Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

In the reactions described hereinafter it may be necessary to protect reactive functional groups, forexample hydroxy, amino, imino, thio or carboxy groups, whére these are desired in the final product, toavoid their unwanted participation in the reactions. Conventional protecting groups may be used inaccordance with standard practice, for examples see T.W. Greene and P.G.M.Wuts in "ProtectiveGroups in Organic Chemistry" John Wiley and Sons, 1991.

Compounds of formula (I), wherein RÏ, R^ and are as hereinbefore defined, are prepared byreaction of compounds of formula (XXVIII).·- 012632 -23-

(ΧΧΥΙΠ) wherein is as hereinbefore defined and is a halogen, preferably iodine, atom or a triflate group,with compounds of formula (XXIX):-

(XXIX) wherein and R^ are as defined hereinbefore. The coupling reaction may conveniently be carriedout, for example, in the presence of a complex métal catalyst such as tetrakis(triphenylphosphine)palladîum(0) and sodium bicarbonate, in aqueous dimethylformamide at atempérature up to reflux température. This reaction is conveniently carried out with the pyrrole NH incompound (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 formula (I) wherein and R^ are as hereinbefore defined and R^ is optionallysubstituted alkyl are prepared by reaction of the corresponding compounds of formula (I) wherein R^and are as hereinbefore defined and R^ is hydrogen with the appropriate alkyl halide R^_x2 jn which R^ is optionally substituted alkyl and X^ is halo. This reaction is particularîy suitable for thepréparation of compounds of formula (I) wherein RI is morpholinoacetyl.

Compounds of the invention may also be prepared by interconversion of other compounds of theinvention.

Thus, for example, 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 012632 -24- hydroiysis using a base, such as an alkali métal hydroxide, e.g. lithium hydroxide, or an alkali métalcarbonate, e.g. potassium carbonate, in the presence of an aqueous/organic solvent mixture, usingorganic solvents such as dioxan, tetrahydrofuran or methanol, at a température from about ambient toabout reflux. The hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganicacid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, usingorganic solvents such as dioxan or tetrahydrofuran, at a température from about 50°C to about 80°C.

As another example compounds of formula (I) containing a carboxy group may be prepared by acidcatalysed removal of the ierf-butyl group of the corresponding ierZ-butyl esters using standard reactionconditions, for example reaction with trifluoroacetic acid at a température at about room température.

As another example compounds of formula (I) containing a carboxy group may be prepared byhydrogénation of the corresponding benzyl esters. The reaction may be carried out in the presence ofammonium formate and a suitable métal catalyst, e.g. palladium, supported on an inert carrier such ascarbon, preferably in a solvent such as methanol or éthanol and at a température at about refluxtempérature. The reaction may altematively be carried out in the presence of a suitable métal catalyst,e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in asolvent such as methanol or éthanol.

As another example of tire interconversion process, compounds of formula (I) containing a -C(=O)-NY^ group may be prepared by coupling compounds of formula (I) containing a carboxygroup with an amine of formula HNY^ Y^ to give an amide bond using standard peptide couplingprocedures, for example coupling in the presence of O-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate and triethylamine (or diisopropylethylamine) intetrahydrofuran (or dimethylformamide) at room température. This procedure is particularly useful forthe préparation of (i) compounds of formula (I) wherein represents -C(=O)-NY^ Y^ or (ii) compounds of formula (I) wherein represents -C(=O)-NY^ Y^. The coupling may also be brought about by reaction of compounds of formula (I) containing a carboxy group withN-{(dimethylamino)(lH-l,2,3-triazaolo[4,5-b]pyridin-l-yl)methylene}-N-methylmethanaminiumhexafluorophosphate N-oxide in the presence of a suitable base, such as diisopropylethylamine, in aninert solvent, such as dimethylformamide, and at a température at about room température, followed byreaction with an amine of formula HNY^Y^ (ammonium chloride can be used for the préparation ofcompounds of formula (I) containing a -C(=O)-NH9 group). The coupling may also be brought aboutby reaction of compounds of formula (I) containing a carboxy group with 2-(lH-benzotriazole-l- 012632 -25- yl)l,l,3,3-tetramethyluronium hexafluorophosphate, in dry dimethylformamide, followed by reactionwith an amine of formula HNY^Y^ in tbe presence of diisopropylethylamine.

As another example of the interconversion process, compounds of formula (I) containing a -CH2OHgroup may be prepared by the réduction of corresponding compounds of formula (I) containing a -CHOor -CO2R.7 (in which R^ is lower alkyl) group. For example, the réduction may conveniently becarried out by means of reaction with lithium aluminium hydride, in an inert solvent, such astetrahydrofuran, and at a température from about room température to about reflux température.

As another example of the interconversion process, compounds of formula (I) in which is hydroxymay be prepared by reaction of the corresponding compounds of formula (I) in which RHs methoxywith a Lewis acid, such as boron tribromide, in an inert βοϊνβηζ such as dichloromethane and at atempérature from about 0°C to about room température.

As another example of the interconversion process, compounds of formula (I) in which R^ is -OR4 (inwhich R4 is optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl orheterocycloalkylalkyl) may be prepared by alkylation the corresponding compounds of formula (I) inwhich is hydroxy, with compounds of formula (XXX):- R4-X3 (XXX) wherein R4 is as just hereinbefore defined and X3 is a halogen, preferably bromo, atom, or a tosylgroup, using standard alkylation conditions. The alkylation may for example be carried out in thepresence of a base, such as an alkali métal carbonate (e.g. potassium carbonate or césium carbonate),an alkali métal alkoxide (e.g. potassium tertiaiy butoxide) or alkali métal hydride (e.g. sodiumhydride), in dimethylformamide, or dimethyl sulfoxide, at a température from about 0°C to about100°C.

As another example of the interconversion process, compounds of formula (I) in which R^ is alkyl,alkenyl, cycloalkyl, heterocycloalkyl, or alkyl substituted by -C(=O)NY^ Y3, -OR?, -C(=O)-OR7,-ΝΥΐγ3 may be prepared by alkylation of the corresponding compounds of formula (la) in which R^ ishydrogen, with the appropriate halide of formula (XXXI):- r!-X4 (XXXI) 012632 -26- wherein R^ is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, or alkyl substituted by -C(=O)NY^Y^,-OR^, -C(=O)-OR7, -Νγΐ γ2 and χ4 ;s a halogen, preferably bromine, atom, using standard alkylationconditions for example those described hereinbefore.

As another example of the interconversion process, compounds of formula (I) containing sulfoxidelinkages may be prepared by the oxidation of corresponding compounds containing -S- linkages. Forexample, 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 nearroom température, or altematively by means of potassium hydrogen peroxomonosulfate in a mediumsuch as aqueous methanol, buffered to about pH5, at températures between about 0°C and roomtempérature. This latter method is preferred for compounds containing an acid-labile group.

As another example of the interconversion process, compounds of formula (I) containing sulfonelinkages may be prepared by the oxidation of corresponding compounds containing -S- or sulfoxidelinkages. For example, the oxidation may conveniently be carried out by means of reaction with aperoxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent e.g. dichloromethane,preferably at or near room température.

As another example of the interconversion process, compounds of formula (I) containing a cyano groupmay be prepared by reaction of the corresponding compounds of formula (I) containing a-C(=O)-NH2group with phosphorus pentachloride in the presence of triethylamine. The reaction may convenientlybe carried out in an inert solvent, such as tetrahydrofuran, and at a température at about refluxtempérature.

As another example of the interconversion process, compounds of formula (I) containing a-C(=O)-NH2 group may be prepared by reaction of the corresponding compounds of formula (I)containing a cyano group with hydrogen peroxide in the presence of sodium hydroxide. The reactionmay conveniently be carried out in methanol at a température at about room température.

As another example of the interconversion process, compounds of formula (I) in which R^ is -Νγ1γ2(wherein Y^ and are as hereinbefore defined), may be prepared by reaction of the correspondingcompounds of formula (I) in which Rp is halo (e.g. chloro) with an amine of formula HNY^ Y^(wherein Y^ and Y^ are as immediately hereinbefore defined). 012632 -27-

As another example of the interconversion process, compounds of formula (I) in which Rp is cyano may be prepared by reaction of compounds of formula (I) in which is halo, preferably chloro, withzinc cyanide in the présence of zinc powder, [ri-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex and dichloromethane (catalytic amount) and Ν,Ν-dimethylacetamide at S a température up to about 150°C.

As another example of the interconversion process, compounds of formula (I) containing a -C(=O)-OR5 group (in which R$ is as hereinbefore defined) may be prepared by reaction of thecorresponding compounds of formula (I) containing a -C(=O)-OH group with alcohols of formula 10 R^-OH. For example when R$ is teri-butyl the reaction may conveniently be carried out in the presence of Ι-Γ-carbonyldiimidazole and 1,8-diazabicyclo[5.4.0]undec-7-ene at a température at aboutroom température.

It will be appreciated that compounds of the présent invention may contain asymmetric centres. These 15 asymmetric centres may independently be in either the R or S configuration. ït will be apparent tothose skilled in the art that certain compounds of the invention may also exhibit geometricalisomerism. It is to be understood that the présent invention includes individual geometrical isomersand 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 20 known methods, for example chromatographie techniques and recrystallisation techniques, or they areseparately prepared from the appropriate isomers of their intermediates.

According to a further feature of the invention, acid addition salts of the compounds of this inventionmay be prepared by reaction of the free base with the appropriate acid, by the application or adaptation 25 of known methods. For example, the acid addition salts of the compounds of this invention may beprepared either by dissolving the free base in water or aqueous alcohol solution or other suitablesolvents containing the appropriate acid and isolating the sait by evaporating the solution, or byreacting the free base and acid in an organic solvent, in which case the sait séparâtes directly or can beobtained by concentration of the solution. 30

The acid addition salts of the compounds of this invention can be regenerated from the salts by theapplication or adaptation of known methods. For example, parent compounds of the invention can beregenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonatesolution or aqueous ammonia solution. 35 012632 -28-

Compounds of this invention can be regenerated from their base addition salts by the application oradaptation of known methods. For example, parent compounds of the invention can be regeneratedfrom their base addition salts by treatment with an acid, e.g. hydrochloric acid.

Compounds of the présent invention may be conveniently prepared, or formed during the process of theinvention, as solvatés (e.g. hydrates). Hydrates of compounds of the présent invention may beconveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organicsolvents such as dioxan, tetrahydrofuran or methanol.

According to a further feature of the invention, base addition salts of the compounds of this inventionmay be prepared by reaction of the free acid with the appropriate base, by the application or adaptationof known methods. For example, the base addition salts of the compounds of this invention may beprepared either by dissolving the free acid in water or aqueous alcoho! solution or other suitablesolvents containing the appropriate base and isolating the sait by evaporating the solution, or byreacting the free acid and base in an organic solvent, in which case the sait séparâtes directly or can beobtained by concentration of the solution.

The starting materials and intermediates may be prepared by the application or adaptation of knownmethods, for example methods as described in the Reference Examples or their obvious Chemicaléquivalents.

Intermediates of formula (XXVIII) wherein is as hereinbefore defmed, Xbs iodo and the pyrrole NH is protected with a tosyl group may be prepared as shown in scheme l. SCHEME 1

(XXXII)

(ΧΧΧΠΙ)

(XXXIV)

Thus for example compounds of formula (XXXIV) may be prepared by: (i) réaction of compounds of formula (XXXII) with /x?ra-to!uenesulfonyl chloride in the presence ofaqueous sodium hydroxide and tetrabutyl ammonium sulfate in an inert solvent, such as toluene, and atroom température; 01263 2 -29- (ii) subséquent treatment of the resulting compound of formula (ΧΧΧΙΠ) with butyl lithium intetrahydrofuran, at a température at about -78°C; (iii) reaction of the resulting anion with iodine.

Intermediates of formula (ΧΧΧΠΙ) wherein R^ is heteroaiyl may be prepared by reaction ofcompounds of formula (ΧΧΧΠΙ) wherein R$ is halo, e.g. chloro, with a borane of formula R^BEt2 wherein R^ is heteroaiyl. The reaction may conveniently be carried out in the presence oftetrakis(triphenylphosphine)palladium(0) and potassium carbonate, in tetrahydrofuran at a températureup to reflux température. This reaction is particularly suitable for the préparation of compounds offormula (ΧΧΧΙΠ) wherein R^ is pyridyl.

Intermediates of formula (ΧΧΧΙΠ) wherein R^ is heteroaiyl may also be prepared by reaction ofcompounds of formula (ΧΧΧΙΠ) wherein R^ is halo, e.g. chloro, with heteroaryl-boronic acids offormula R^B(OH)2 in the presence of tetrakis(triphenylphosphine)palladium(0) and aqueous sodiumbicarbonate, in dimethylformamide at a température up to reflux température. This reaction is particularly suitable for the préparation of compounds of formula (ΧΧΧΙΠ) wherein R^ is optionallysubstituted indolyl.

Intermediates of formula (ΧΧΧΙΠ) wherein R^ is OR^, in which R^ is as hereinbefore defined, may beprepared by reaction of compounds of formula (ΧΧΧΠΙ) wherein is halo, e.g. chloro, with compounds of formula R^ONa (prepared by reacting alcohols of formula R^OH with sodium) at atempérature up to about 65°C. This réaction is particularly suitable for the préparation of compoundsof formula (ΧΧΧΠΙ) wherein R^ is OMe.

The présent invention is further exemplified but not limited by the following illustrative Examples andRéférencé Examples.

High Pressure Liquid Chromatography - Mass Spectrometry (LC-MS) conditions for détermination ofrétention times (Ry) were as follows:-

Method A: Hypersil BDS C-18 column (4.6 mm x 50 mm) reverse phase operated under gradientelution conditions with mixtures of (A) water containing 0.05% trifluoroacetic acid and (B) acetonitrilecontaining 0.05% trifluoroacetic acid as the mobile phase gradient : (0.00 minutes 100%A:0%B; linear 012632 -30- gradientto 100% B at 2 minutes; then hold until 3.5 minutes); flow rate lmL/minute with approximately 0.25mL/minute split to the Mass Spectrometer; injection volume 10 pL; Hewlett

Packard Model HP1100 Sériés UV detector wavelength 200nm; Evaporative light scattering (ELS) détection - température 46°C, nitrogen pressure 4bar.

Method B: Gilson 215 injecter model using a Hypersil HyPURITY C-18 -5 μ column (4.6 mm x 50mm) operated under gradient elution conditions with mixtures of (A) water containing 0.05%trifluoroacetic acid and (B) acetonitriîe containing 0.05% trifluoroacetic acid as the mobile phasegradient : (0.00 minutes 95%A:5%B; linear gradient to 95% B at 4 minutes; then to 5% B at 4.5minutes, then hold until 6 minutes); injection volume 5 pL and flow rate lmL/minute to UV (DAD)detector followed by approximately O.lOOmLZminute split to the Mass Spectrometer (positiveelectrospray) with remainder to ELS detector. METHOD C: Micromass instrument model LCT linked to an HP 1100 model instrument. Compoundabundance were detected using an HP model G1315A photodiode array detector in the 200-600 nmwavelength range and a Sedex model 65 evaporative light scattering detector. Mass spectra wereacquired in the 180 to 800 range. Data were analysed using the Micromass MassLynx software.Séparation were carried out on a Hypersil BDS Cl 8,3 pm particle size column (50 x 4.6 mm) elutedby a linear gradient of 5 to 90% acetonitriîe containing 0.05% (v/v) trifluoroacetic acid in watercontaining 0.05% (v/v) trifluoroacetic acid in 3.5 minutes at a flow rate of 1 ml/minute. The totalruntime including column reequilibration was 7 minutes. EXAMPLE 1 2-r5-Methoxv-3-f4-trifluoromethvl-7H-pvrroloi2.3-blpvrimidin-6-vn-indol-l-vl1-l-morpholin-4-vl- ethanone

The compound of formula (I), wherein R^ is ~CH2 N j , R2 is -OMe, R^ is -CF 3, the

k /O group is attached to the 3 position of the indole ring and the group R^ is N' attached to the 5 position of the indole ring, represented by formula (H): 012632 -31-

(Π) is prepared as shown in the following scheme:

(IX) -32- 012632 (i) treatment of 7H-pyrrolo[2,3-b]pyrimidine (1) with 3-chIoroperbenzoic acid indichloromethane at about 0°C to give 7H-pyrrolo[2,3-b]pyrimidine-N-oxide (2); (ii) reaction of (2) with phosphorous oxybromide at about 50°C to give 4-bromo-7H-pyrrolo[2,3-b]pyrimidine (3); (iii) réaction of (3) with 4-toluene sulfonyl chloride in the presence of tetrabutylammoniumsulfate and aqueous sodium hydroxide in toluene, to give 4-bromo-7H-pyrrolo[2,3-b]pyrimidine (4); (iv) reaction of (4) with trifluoromethyltrimethylsilane in the presence of potassium fluorideand copper(I) iodide in dimethylformamide at about 60°C, to give 7-(toluene-4-sulfonyl)-4-trifluoromethyl-7H-pyrcoIo[2,3-b]pyrimidine (5); (v) treatment of (5) with lithium diisopropylamide in tetrahydrofuran, at about -78°C,followed by reaction of the resulting anion with iodine to give 6-iodo-7-(toluene-4-sulfonyl)-4-trifluoromethyl-7H-pyrrolo[2,3-b]pyrimidine (6). (vi) coupling of (6) with l-tert-butyloxycarbonyl-5-methoxy-lH-indole-3-boronic acid in thepresence of tetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in aqueousdimethylformamide at about reflux température and removal of the tert-butyloxycarbonylprotecting group followed by treatment with methyl iodide in the presence of sodium hydride,in tetrahydrofuran, to give 6-(5-methoxy-IH-indol-3-yl)-7-(toIuene-4-suIfonyl)-4-trifluoromethyl-7H-pyrrolo[2,3-b]pyrimidine (7); (viii) removal of the tosyl protecting group in (7) by treatment with potassium hydroxide inmethanol to give 6-(5-methoxy-lH-indoI-3-yl)-4-trifluoromethyl-7H-pyrroIo[2,3-b]pyrimidine(8); and (ix) alkylation of (8) with 4-(2-chloroacetyl)morpholine in die presence of sodium hydride, indimethylformamide to give 2-[5-methoxy-3-(4-trifluoromethyl-7H-pyrrolo[2,3-b]pyrimidin-6-yl)-indol-1 -yl]-1 -morpholin-4-yl-ethanone (Π). EXAMPLE 2 1 -Methyl-3-(7H-pvrrolor2,3-b3pvrimidine-6-vb-lH-indole-5-carboxvlic acid f2-hvdroxv-l, 1 -dimethyl- ethvO-amide 012632 -33-

it^ch oh ’ r3 îs 'H,Λβ SW H 2 O Me Me

The compound of formula (I), wherein RJ is -CH3, is

the 5 position of the indole ring, represented by formula (III):

is prepared as shown in the following scheme: 10 012632

(i) reaction of (9) with 4-toluene sulfonyl chloride in the presence of tetrabutylammoniumsulfate and aqueous sodium hydroxide in toluene, to give (10); 5 (ii) treatment of (10) with lithium diisopropylamide in tetrahydrofuran, at about -78°C,followed by reaction of the resulting anion with iodine to give (II); (iii) coupling of (11) with l-tert-bu1yloxycarbonyl-5-methoxy-lH-indole-3-boronic acid (12) in 10 the presence of tetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in aqueous dimethylformamide at about reflux température and removal of the tert-butyloxycarbonylprotecting group followed by treatment with methyl iodide in the presence of sodium hydride,in tetrahydrofuran, to give 6-[(l-methyI-5-carbomethoxyindole)3-yI]-7H-pyrrolo[2,3-b]pyrimidine (13); 15 (iv) treatment of (13) with aqueous methanolic potassium hydroxide at reflux to give 6-[(l-methyl-5-carboxyindole)3-yl]-7H-pyrroIo[2,3-b]pyrimidine (14); and 012632 -35- (v) coupling of (14) with 2-hydroxy-l,î-dimethylethy lamine in the presence of O-(7-azabenzotria2ol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide to give l-methyl-3-(7H-pyrrolo[2,3- 5 b]pyrimidine-6-yl)-lH-indole-5-carboxylic acid (2-hydroxy-l, l-dimethyl-ethyî)-amide (ΙΠ). EXAMPLE 3 2-ïf5-Methoxv-3-f7H-pvrroloi2,3-b]pvrimidine-6-vn-indoi-l-vn-l-moroholin-4-yl)-ethanone

O

The compound of formula (I), wherein RJ is “CH

, R.2 is -OMe, R.3 is -H, die group 10

is attached to the 3 position of the indole ring and the group R^ is attached to die 5 position of die indole ring, represented by formula (IY):

is prepared as shown in the following scheme: 15 012632 10 15

(i) coupling of 6-iodo-7-(toIuene-4-sulfonyl)-7H-pyrroio[2,3-b3pyrimidine (11) 1-tert-butyIoxycarbony1-5-methoxyindole-3-boronic acid (15) in the presence oftetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in aqueousdimethylformamide at about reflux température and removal of the tert-butyloxycarbonylprotecting group, to give 6-[(5-methoxyindole)-3-yI]-7-(toluene-4-sulfonyl)-7H-pyrroIo[2,3-bjpyrimidine (16); (ii) ) treatment of (16) with aqueous methanolic potassium hydroxide at reflux to give 6-((5-methoxyindole)3-yl]-7H-pyrrolo[2,3-b]pyrimidine (17); and (iii) reaction of (17) with sodium hydride in dimethylformamide followed by reaction with 2·bromoacetic acid morpholineamide to give 2-{[5-methoxy-3-(7H-pyrrolo[2,3-b]pyrimidine-6yl)-indol-1 -y 1]-1 -morpholin-4-y l}-ethanone (IV). 012632 -37- EXAMPLE4

The compound of formula (I), wherein RÏ is -CH2CF3, R^ is -OMe, Rp is-CN, the group

îs attached to the 3 position of the indole ring and the group r2 is attached to the 5 position of the indole ring, represented by formula (VH):5

is prepared as shown in the following scheme: 012632 • 38- (18) ♦ NC^^COjEt

Nal K,CO,

EtO CO,Et (18) (20)

NaOEt

BOH

ElO^^OEtOH ηρ T~* Il η,ν-Ινη, hsAAnh,(21)

(i) reaction of (18) and (19) in the presence of potassium carbonate and sodium iodide to give(20); 5 (Îi) reaction of (20) with thiourea in the presence of sodium ethoxide in éthanol to give (21); (iii) cyclisation of (21) by heating in toluene at about reflux to give (22); 10 (iv) reaction of (22) with phosphorus oxybromide to give 4-bromo-7H-pyrrolo[2,3- bjpyrimidine (23); (v) réaction of (23) with 4-toluenesulfonyl chloride in the presence of tetrabutylammonium sulfate and aqueous sodium hydroxide in toluene to give (24); 15 012632 -39- (vi) treatment of (24) with lithium diisopropylamide in tetrahydro&amp;ran, at about -78°C,followed by reaction of the resulting anion with iodine to give (25); (vii) coupling of (25) with l-tert-butyloxycarbonyl-5-methoxyindole-3-boronic acid in the 5 présence of tetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in aqueous dimethylformamide at about reflux température and removal of the tert-butyloxycarbonylprotecting group, to give 4-bromo-6-[(5-methoxyindole)3-yl]-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-b]pyrimidine (26); 10 (viii) reaction of (26) with sodium hydride in tetrahydro&amp;ran followed by reaction with 2- trifluoro-iodoethane to give (27); (ix) reaction of (27) with zinc cyanide in the presence of palladium in N’N-dimethylaniline atabout 140°C to give (28); and 15 (x) treatment of (28) with aqueous methanolic potassium hydroxide at reflux to give (VII). EXAMPLE 5 9 Me Me

The compound of formula (I), wherein Rl is -CH3, is -OMe, R^ is anx , tire

N

H ch2oh

attached to the 5 position of the indole ring, represented by formula (IX);

(ix) 012632 -40- is préparée! as shown in the following scheme:

5 (ii) reaction of (26) with sodium hydride in tetrahydrofuran followed by reaction with methyl iodide to give (29); (ii) reaction of (29) with carbon monoxide in the presence of palladium in methanol at reflux togive (30); 10 (iii) treatment of (30) with aqueous methanolic potassium hydroxide at reflux to give (31); and (iv) coupl ing of (31 ) with 2-hydroxy-1,1 -dimethylethylam ine in the presence of0-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate and 15 diisopropylethylamine in dimethylformamide to give (IX). 012632 EXAMPLE 6

The compound of formula (I), wherein Rl is

is -OMe, R^ is

.CH 2^ch NHMe

, the group “ is attached to the 3 position of the indole ring and the group R^ is attached to the 5 position of the indole ring, represented by formula (V):

M 012632 -42- (i) reaction of (26) with methyl acrylate in the presence of palladium acetate, triphenylphosphine and triethylamine at about 110°C to give (32); 5 (ii) hydrogénation of (32) in the presence of palladium on carbon to give (33); (iii) treatment of (33) with aqueous methanolic potassium hydroxide at reflux to give the acid(34); 10 (iv) coupling of (34) with methylamine in the presence of O-(7-azabenzotriazol-l-y 1)-1,1,3,3- . tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide to give (35); and (v) alkylation of (35) with 4-(2-chloroacetyl)morpholine in the presence of sodium hydride, in15 dimethylformamide to give (V). EXAMPLE 7

The compound of formula (I), wherein R^ is

O

X -CHflÎ

, is -OMe, r3 is

is attached to the 3 position of the indole ring 20 the group R^ is attached to the 5 position of the indole ring, represented by formula (VI): 01263 2

(i) coupling of (26) with pyridine-3-boronic acid in the presence oftetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in aqueous 10 dimethylformamide at about reflux température to give 4-(pyridin-3-yI)-6-[(5- methoxyindoIe)3-yl]-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-b]pyrimidine (36); (ii) treatment of (36) with aqueous methanolic potassium hydroxide at reflux to give (37,Example 9); and 15 012632 -44- (iii) alkylation of (37, Example 9) with 4-(2-chloroacetyl)morpholine in the presence of sodiumhydride, in dimethylformamide to give 2-[5-methoxy-3-(4-(pyridin-3-yl)-7H-pyrrolo[2,3-b]pyrimidin-6-yl)-indol-l-yl]-l -morpholin-4-yl-ethanone (VI). EXAMPLE 8

The compound of formula (I), wherein is -CH2CH3, R^ is -OMe, is \ , the group \_y

is attached to the 3 position of the indole ring and the group is attached to the 5 position of the indole ring, represented by formula (VIH):

(VIII) (39) 012632 -45- (i) alkylation of (26) with ethyl iodide in the presence of sodium hydride, in dimethylfonnamide to give (38); (ii) reaction of (38) with morpholine, in a microwave oven at about 200°C in α,α,α-trifluorotoluene to give (39); and (iii) treatment of (39) with aqueous methanolic potassium hydroxide at reflux to give (VIII). EXAMPLE 9

A solution of 6-iodo-7-[(4-methylphenyl)sulfonyl]-4-pyridin-3-yl-7H-pyrrolo[2,3-d]pyrimidine[260mg, Référencé Example 1] and l-tert-butyl-carboxyl-5-methoxy-17/-indole-3-boronic acid[178mg, Référencé Example 12] in dimethylformamide (lOmL) was treated with palladium tetrakistriphenyl phosphine (13mg) and sodium hydrogen carbonate (8mg). The reaction mixture was stirred atreflux for 2 hours and allowed to cool to room température. The solution was evaporated underreduced pressure and the residue partitioned between water and ethyl acetate. The organic phase wasseparated, then dried over magnésium sulfate and then evaporated under reduced pressure. The residuewas subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate andmethanol (95:5, v/v) to give 6-f5-Methoxy-lH-indol-3-vD-4-pvridin-3-vl-7H-pyrrolo(2,3-dlpyrimidine(20mg) as an amorphous solid. MS: 342 [MH]+, LCMS (Method A) RT = 2.57 minutes. EXAMPLE 10 4-Methoxy-6-(5-methoxv-l-methyl-lH-indol-3-vn-7H-pyrrolof2.3-d]pvrimidine 012632 -46-

A solution of 4-methoxy-6-(5-methoxy-l-methyl-lH-indol-3-yl)-7-((4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [361mg, Référencé Example 4] in methanol (20mL) was treated withpotassium hydroxide (1.53g). The reaction mixture was stirred for 16 hours at room température and 5 refluxed 1 hour. The solution was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was separated, then dried over magnésium sulfateand evaporated under reduced pressure. The residue was triturated with diethyl ether to give 4-methoxy-6-f5-methoxy-l-methvl-lH-indol-3-vl)-7H-pynOlor2.3-dlpyrimidine (155mg) as a solidm.p. = Î84°C. MS: 309 [MH]+. 10 EXAMPLE 11 4-Methoxv-6-f5-methoxy-1 H-indol-3-vl)-7H-pynOlor2.3-d1pvrimidine

A solution of 4-methoxy-6-(5-methoxy-lH-indol-3-yl)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-15 djpyrimidine [448mg, Reference Example 5] in methanol (15mL) was treated with potassium hydroxide (1.96g). The réaction mixture was stirred for 2 hours at room température and the solventwas evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate.The organic phase was separated, then dried over magnésium sulfate and then evaporated underreduced pressure. The residue was subjected to flash column chromatography on silica eluting with a 20 mixture of ethyl acetate and cyclohexane (80:20, v/v) to give 4-methoxv-6-(5-methoxy-1 H-indol-3 -yl)-7H-pyrroloi2,3-d1pvrimidine (320mg) as a yellow solid m.p. > 260°C. MS: 295 [MH]+. r EXAMPLE 12 4-(5-Methoxv- l/f-indol^-vD-ô-fS-methoxy-l -methyl-1 f/~-indol-3-vl)-777-pyrroloi2,3-fflpyrimidine 012632 -47-

A solution of 4-(5-methoxy-l-[(4-methylphenyl)sulfonyl]-l/f-indol-3-yl)-6-(5-methoxy-l-methyl-lff-indol-3-yl)-7-[(4-inethylphenyl)sulfonyl]-777-pyrrolo[2,3-i/]pyrimidine [93mg, Référencé Example 9]in methanoi (5mL) was treated with potassium hydroxide (249mg). The reaction mixture was stirredfor 16 hours at room température. The solution was evaporated under reduced pressure and the residuepartitioned between ethyl acetate and water. The organic phase was separated, then dried overmagnésium sulfate and then evaporated under reduced pressure. The residue was purified by HPLC togive 4-f5-methoxv-î7jr-indol-3-vl)-6-f5-methoxv-l-methvl-177-indol-3-vl>)-777-pvrroloi2.3-<flpvrimidine (9mg) as a gum. MS: 424 [MH]+. LCMS (Method B) RT - 3.15 minutes. REFERENCE EX AMPLE 1 6-Iodo-7-rf4-nrethvlphenynsulfonvfl-4-pyridin-3-yl-7H-Pvrrolor2.3-dlpyrimidine

To a solution of 7-[(4-methylphenyl)sulfonyî]-4-pyridin-3-yl-7H-pyrrolo[2,3-d]pyrimidine [lg,Reference Example 2] in tetrahydrofuran (20mL) at-78°C was added drop wise a solution of butyllithium in hexane (2mL, 1.6M) under inert atmosphère. The solution was stirred at that température for 1.5 hour and iodine (796mg) was added. The reaction mixture was stirred at -78°C for another l hourand allowed to reach room température. The reaction mixture was partitioned between ethyl acetateand aqueous sodium sulfite solution. The organic phase was separated, then dried over magnésiumsulfate and then evaporated under reduced pressure. The residue was subjected to flash columnchromatography 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. MS: 477 [MH]+. LCMS (Method B) Rp =3.26 minutes. REFERENCE EXAMPLE 2 7-i(4-Methvlphenvl')sulfonyl1-4-pvridin-3-yl-7H-pvrrolor2.3-dlpyrimidine A solution of 4-chIoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [4g, ReferenceExample 3] and diethyl-3-pyridyl-borane (2.1g) in tetrahydrofuran (180mL) was treated with palladiumtetrakis triphenylphosphine (0.65g) and potassium carbonate (3.59g). The solution was stirred at refluxfor 24 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetateand brine. The organic phase was separated, then dried over magnésium sulfate and then evaporatedunder reduced pressure. The residue was subjected twice to flash column chromatography on silica 012632 -48- eluting with a mixture of ethyl acetate and methanol (90:10, v/v) and a mixture of ethyl acetate and cyclohexane (50:50, v/v) to give the title compound (2.5g) as an amorphous solid. MS: 351 [MH]+. LCMS (Method B) Ry = 3.05 minutes. REFERENCE EXAMPLE 3 4-ChlorO“7-r(4-methvlphenyBsulfonvl1-7H-pvrrolof2.3-d1pyrimidine A solution of 4-chloro-7H-pyrrolo{2,3-d]pyrimidine (Reference: Gerster, John F. ; Hinshaw, BarbaraC.; Robins, Roland K.; Townsend, Leroy B. Study of electrophylic substitution in the pyrrolo[2,3-djpyrimidine ring. J. Heterocycl. Chem. (1969), -(2), 207-213) (20g) and pcra-toluene sulfonylchloride(28.6g) in toluene (IL) was treated with a solution of sodium hydroxide (50g) in water (800mL), andtetrabutyl ammonium sulfate (462mg). The solution was stirred vigorousîy at room température for 2hours and partitioned between etliyl acetate and brine. The organic phase was separated, then driedover magnésium sulfate and then evaporated under reduced pressure. The residue was subjected toflash column chromatography on sîlica eluting with a gradient of ethyl acetate and cyclohexane (50:50to 80:20, v/v) to give the title compound (2.5g) as a solid m.p. = 143°C. LCMS (Method B) Ry = 2.78minutes. REFERENCE EXAMPLE 4 4-Methoxy-6-(5-methoxv-l-methyl-lH-indol-3-vl)-7-IY4-methylphenybsulfonyri-7H- pvrrolor2.3dlpvrimidine

To a solution of 4-methoxy-6-(5-methoxy-lH-indol-3-yl)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [448mg, Reference Example 5) in dimethylformamide (20mL) was added thesodium hydride (44mg, 60% dispersion in oil) and methyl iodide_(156mg) under inert atmosphère. Thesolution was stirred for 1 hour at room température and the solvent was evaporated under reducedpressure. The residue was partitioned between water and ethyl acetate. The organic phase wasseparated, then dried over magnésium sulfate and then evaporated under reduced pressure. The residuewas subjected to flash column chromatography on sîlica eluting with a mixture of ethyl acetate and cyclohexane (30:70, v/v) to give the title compound (260mg) as an amorphous solid. MS: 464 [MH]+.LCMS (Method B) Ry = 4.39 minutes. REFERENCE EXAMPLE 5 4-Methoxv-6-(5-methoxv-lH-indol-3-vb-7-[f4-methvlphenvl')sulfonv11-7H-pvrrolo[2.3-d1pvrimidine A solution of 6-iodo-4-methoxy-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [1.98g,Reference Example 6] and l-Zeri-butyl-carboxyl-5-methoxy-177-indole-3-boronic acid [1.26g,Reference Example 12] in dimethylformamide (40mL) was treated successïvely with a saturatedaqueous solution of sodium bicarbonate (lOmL) and palladium tetrakis triphenylphosphine (165mg). 01263 2 -49-

The reaction mixture was stirred at reflux for 3 hours and the solvent was evaporated under reducedpressure. The residue was partitioned between ethyl acetate and water. The organic phase wasseparated, then dried over magnésium sulfate and then evaporated under reduced pressure. The residuewas subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and 5 cyclohexane (50:50, v/v) to give the title compound ( 1,8g) as a grey solid. m.p.= 131°C. MS: 450[MH]+. REFERENCE EXAMPLE 6 6-Iodo-4-methoxy-7-r(4-methvlphenynsulfonvll-7H-pvrroloi2.3-d1pyrimidine 10 To a solution of 4-methoxy-7-[(4-methylphenyI)suifonyI]-7H-pyrroIo[2,3-d]pyrimidine [2.23 g, Référencé Example 7] in tetrahydrofùran (35mL) at -78°C was added drop wise a solution of butyllithium in hexane (5mL, 1.6M) under inert atmosphère. The solution was stirred at -70°C for 1 hourand iodine (2.05g) was added. The reaction mixture was stirred at -70°C for another 1 hour, allowed toreach room température and partitioned between ethyl acetate and aqueous sodium sulfite solution. The 15 organic phase was separated, then dried over magnésium sulfate and then evaporated under reduced pressure to give the title compound (2.64g) as an amorphous solid. MS: 430 [MH]+. LCMS (MethodB) Ry = 4.15 minutes. REFERENCE EXAMPLE 7 20 4-Methoxv-7-rf4-methvlphenvl)sulfonvn-7H-pvrrolor2.3-d1nvrimidine A solution of 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine [1.2g, Reference Example 8] and para-toluenesulfonylchloride (1.77g) in toluene (60mL) was treated with a solution of sodium hydroxide (3.2g) inwater (30mL), and tetrabutyl ammonium sulfate (27mg). The solution was stirred vigorously at roomtempérature for 4 hours and partitioned between ethyl acetate and brine. The organic phase was 25 separated, then dried over magnésium sulfate and then evaporated under reduced pressure. The residuewas subjected to flash column chromatography on silica eluting with a gradient of ethyl acetate andcyclohexane (50:50 to 80:20, v/v) to give the title compound (2.23g) as an amorphous solid. MS: 304[MH]+. LCMS (Method B) Ry = 3.88 minutes. 30 REFERENCE EXAMPLE 8 4-Methoxv-7H-pvrroloi2,3-dlpvrimidine

To a solution of sodium methoxide prepared by adding portion wise the sodium (2g) in methanol(lOOmL) under an inert atmosphère, was added 4-chloro-7H-pyrroIo[2J3-d]pyrimidine (Reference:Gerster, John F. ; Hinshaw, Barbara C.; Robins, Roland K.; Townsend, Leroy B. Study of electrophylic 35 substitution in the pyrrolo[2,3-d]pyrimidine ring. J. Heterocycl. Chem. ( 1969), -(2), 207-13.) (3.5g).

The solution was stirred at 65°C for 16 hours and then partitioned between ethyl acetate and brine. 1 012632 -50-

The organic phase was separated, then dried over magnésium sulfate and then evaporated underreduced pressure. The residue v/as subjected to flash column chromatography on silica eluting with amixture of ethyl acetate and çyclohexane (50:50, v/v) to give the title compound (1.2g) as anamorphous solid. MS: 150 [MH]+. LCMS (Method B) Ry - 2.39 minutes. REFERENCE EXAMPLE 9 4-(5-Methoxv-l-r(4-niethvlphenvï')sulfonvl1-Îiy-indol-3-vn-6-f5-methoxv-l-methvl-l Zf-indol-3-vl)-7- f(4-methylphenvl)sulfonvl]-77?-pvreoloi2.3-</|pyrimidine

To a solution of 4-(5-methoxy-l-[(4-methylphenyl)sulfonyl]-l//-indol-3-yl)-6-(5-methoxy-l/7-indol-3~yl)-7-[(4-rnethylphenyl)sulfonyI]-7JY-pynOlo[2,3-£?lpyrimidine [270mg, Référencé Example 10] indimethylformamide (lOmL) was added the sodium hydride (lOmg, 60% dispersion in oil) and methyliodide (0.025mL) under inert atmosphère. The solution was stirred for 16 hours at room températureand the solvent was evaporated under reduced pressure. The residue was partitioned between water andethyl acetate The organic phase was separated, then dried over magnésium sulfate and then evaporatedunder reduced pressure. The residue was subjected to flash column chromatography on silica elutingwith a mixture of ethyl acetate and cyclohexane (50:50, v/v) to give the title compound (93mg) as anamorphous solid. MS: 732 [MH]+. LCMS (Method B) Ry = 4.68 minutes. REFERENCE EXAMPLE 10 4-f5-Methoxv-l-rf4-methy]phenyl')sulfonyl'l-]V7’-indol-3-yl~)-6-f5-methoxy-1//'-indol-3-viy7-[Y4- methvlphenvilsulfonvn-7H-pvrrolof2.3-Jlpvrimidine A solution of 4-chloro-6-iodo-7-[(4-methylphenyl)sulfonyl]-7Z/-pyrrolo[2,3-d]pyrimidine [1.72g,Référencé Example 11] and l-teri-butyl-carboxyl-5-methoxy-l//-indole-3-boronic acid [1.26g,Référencé Example 12] in dimethylformamide (36.5mL) was treated successively with a saturatedaqueous solution of sodium bicarbonate (9.1mL) and palladium tetrakis triphenylphosphine (0.3g). Thereaction mixture was stirred at reflux for 2 hours and the solvent was evaporated under reducedpressure. The residue was partitioned between ethyl acetate and water. The organic phase wasseparated, then dried over magnésium sulfate and then evaporated under reduced pressure. The residuewas subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and

cyclohexane (30:70, v/v) to give the title compound (270mg) as a gum. MS: 718 [MH]+. LCMS (Method B) Ry = 4.44 minutes. REFERENCE EXAMPLE 11 44Zhloro-6-iodo-7-rf4-methvlphenvl)sulfonyl1-77ï-pvrrolo!~2.3-</Ipyrimidine 012632 -51-

To a solution of 4-chIoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [5.4g, ReferenceExample 3], in tetrahydrofuran (96mL) at-78°C was added drop wise a solution of butyl lithium inhexane (12.1mL, 1,6M) under inert atmosphère. The solution was stirred at -78°C for 3 hours andiodine (8.9g) was added. The reaction mixture was stirred at -78°C for 2 hours, and allowed to reachroom température. The reaction mixture was partitioned between ethyl acetate and aqueous sodiumsulfite solution, dried over magnésium sulfate and the solvent was evaporated under reduced pressure.The residue was subjected to flash column chromatography on silica eluting with a gradient of ethylacetate and cyclohexane (50:50, to 100, v/v) to give the title compound (1.52g) as an amorphous solid.MS: 434 [MH]+. LCMS (Method B) RT = 4.26 minutes. REFERENCE EXAMPLB 12l-ferr-butvl-carboxvl-5-methoxv-lÆ-indole-3-boronic acid A stirred solution of 3-bromo-5-methoxy-indole-l~carboxylic acid, ier/-butyl ester [50g, ReferenceExample 13)] in tetrahydrofuran (800 mL), under nitrogen, was treated with tributylborate (49.5 mL)then cooled to -100°C and then treated with a solution of n-butyllithium in hexanes (94 mL, 2.5M)whilst keeping the température below -90°C. Once the addition was complété the mixture was allowedto warm slowly to room température over 1 hour and quenched by the addition of ice (10g). Theorganics were removed under reduced pressure and the residue was partitioned between ethyl acetate(500 mL) and water (400 mL). The organic layer was dried over magnésium sulfate and thenevaporated to afford the title compound as a cream coloured solid (28g). MS: 314 [M+Na]+. LCMS(Method C) RT = 4.07 minutes. REFERENCE EXAMPLE 13 3-Bromo-S-methoxy-indole-l-carboxvlic acid, tert-butyl ester A solution of 5-methoxyindole (10g) in dry dimethylformamide (150 mL) at ambient température wastreated with bromine (4 mL) dropwise ensuringthe température did not rise above 30°C. The mixturewas treated immediately with triethylamine (28 mL) and 4-dimethylaminopyridine (0.5g) followed by asolution of di-te/7-butyldicarbonate (18g) in dry dimethylformamide (80 mL) and stirring wascontinued for a further 4 hours. The réaction mixture was evaporated and the residue was partitionedbetween ethyl acetate (250 mL) and water (200 mL). The aqueous layer was extracted with ethylacetate (100 mL). The combined organic phases were washed with water (100 mL), then with brine(100 mL), then dried over magnésium sulfate and then evaporated. The residue was subjected to flashcolumn chromatography on silica eluting with a mixture of pentane and ethyl acetate (19/1, v/v) to givethe title compound (23.4g) as a colourless solid, m.p. 111-112°C. .,, 01263 2

IN VITRO TEST PROCEDURES FOR SYK 1. Inhibitorv effects of compounds on Svk kinase

Inhibitory effects of compounds on Syk kinase were determined using a time-resolved fluorescentassay.

The catalytic domain of Syk kinase (residues A340-N635 ) was expressed as a fusion protein in yeastcells and purifïed to homogeneity. Kinase activity was determined in 50mM Tris-HCl buffer pH 7.0containing 50mMNaCl, 5mM MgCl2, 5mM MnCl2, ΙμΜ adenosine triphosphate and 10μΜ syntheticpeptide Biotin-( P-Alanine^-DEEDYEIPP-NHo. Enzyme reactions were terminated by the addition of buffer containing 0.4M KF, 133mM EDTA, pH 7.0, containing a streptavidin-XL665 conjugate and amonoclonal phosphospecfic antibody conjugated to a europium cryptate (Eu-K). Features of the twofluorophores, XL-665 and Eu-K are given in G.Mathis et al., Anticancer Research, 1997,17, pages3011-3014. The spécifie long time signal of XL-665, produced only when the synthetic peptide isphosphorylated by Syk, was measured on an LJL Biosystems Analyst AD microplate reader. Inhibitionof syk activity with compounds of the invention was expressed as percentage inhibition of controlactivity exhibited in the absence of test compounds. Particular preferred compounds of the inventioninhibit syk activity with IC50S in the range 100 micromolar to 100 nanomolar. Especially preferredcompounds of the invention inhibit syk activity with IC5QS in the range 1 micromolar to 100nanomolar. 2, Antigen-induced degranulation of Rat Basophilie leukemia (RBL) cells 2.1 Cell culture, labelling of RBL-2H3 cells and performance of assay. RBL-2H3 cells are maintained in T75 flasks at 37°C and 5%CO2, and passaged every 3-4 days. To harvest cells, 5 ml trypsin-EDTA is used to rinse the flask once, then 5 ml trypsin is added to eachflask, and incubated at room température for 2 minutes. Cells are transferred to a tube with 14mlmedium, spun down at 1100 rpm RT for 5 minutes and resuspended at 2xl0^/ml. Cells are sensitizedby adding 1 μΐ of DNP-specific IgE to every 10 ml of cells. 200μΙ of cells are added to each well of aflat-bottom 96 well plate (40,000 cells/well), and the plate incubated ovemight at 37°C and 5%CC>2.The next day compounds are prepared in 100% DMSO at lOmM. Each compound is then diluted1:100 in assay buffer and then diluted further in 1% DMSO-assay buffer to obtain final concentrationsof 0.03-30μΜ. δΟμΙ assay buffer is added to each well, followed by 1 Ομί of diluted compound.Incubation follows for 5 minutes. 10μΙ of DNP-HSA (lOOng/ml) is added to each well and incubated -53- 07 263 2 at 37°C (no CO2) for 30 minutes. As one control, 1% DMSO alone (no compound) is added to a set of wells to détermine total release. As another control, add buffer instead of DNP-HSA to another set ofwells to détermine the assay background. After the 30 minutes incubation, the supematants aretransferred to a new 96-well plate. Add 50μ1 supematantto each well of an assay plate. Add ΙΟΟμΙ of 5 substrate solution to each well and incubate at 37°C for 90 minutes. Add 50μ1 of 0.4 M glycinesolution to stop the reaction and the plate is read at 405 nm on a Molecular Devices SpectraMax 250plate reader. 2.2 Calculation of results 10 (i) The mean ± SD of each set of triplicate wells was calculated. (ii) Maximum response was the positive control wells containing antigen (lOOng/mL) but nocompound. (iii) Minimum response was the control wells containing buffer (no antigen) and no compound. 15 (iv) Using these values as the maximum (100%) and minimum (0%) values respectively, the experimental data was calculated to yield a percentage of the maximum response (designated %control). (v) A dose response curve was plotted and the IC5Q of the compound was calculated using PrismGraphPad software and nonlinear least squares régression analysis. 20

Compounds of the invention inhibit antigen-induced degranulation of Rat Basophilie leukemia (RBL)cells with EC50S in the range 100 micromolar to 1 micromolar.

Claims (18)

1. 01263 2 : -54- WHATIS CLAIMEDIS:

   1. A compound of the formula

   wherein R1 represents hydrogen, -0(=0)-1^^2, -C(=O)-OR5, -SO^NY^2, -SO2-R7, -C(=0)R7, or R1 represents alkenyl, alkenyloxy, alkyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl or 10 cycloalkylalkyl, each optionally substituted by one or more groups selected from aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, -CHO or a 5-, 6- or 7-membered cyclic acetal dérivative ofsuch -CHO, -C(=O)-NY^y2, -C(=O)-OR5, -NY1 Y2, -N(R6)-C(=O)-R7, -N(R6)-C(=O)-NY3Y4,-N(r6)-S02-R7, -N(R6)-S02-NY3Y4, -OR7, -C(=O)-R7, hydroxy, alkoxy and carboxy; R- represents one or more groups selected from hydrogen, acyl, alkylenedioxy, alkenyl, alkenyloxy, 15 alkynyl, aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, R4, -C(=O)-NY1 Y2,-C(=0)-0R5, -NY1 Y2, -N(R6>C(=O)-R7, -N(R6)-C(=O)-NY3Y4, -N(R6)-C(=O)-OR7,-N(R6)-SO2-R7, -N(R6)-SO2-NY3Y4, -SO2-NYIY2 and -ZR4; R3 represents H, cyano, halo, hydroxy, nitro, R4, NY^Y2, -ZR4, -C(=O)-0R3, -C(=O)-R7,-C^O^NY1 Y2, -N(r8)-C(=O)-R4, -N(R8>C(K>)-NYlY2, -N(R8)-C(=O)-OR5, -SO2-NY3Y4, or 20 -N(R8)-SO2-R7, or R3 represents aryl, heteroaryl, alkenyl or alkynyl, each optionally substituted by one or more groupsselected from aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, -C(=O)-NY1 Y2, -C(=O)-OR5, -NY1 Y2, -N(R6)-C(=O)-R2> -N(R6)-C(=O)-NY3Y4, -N(R6)-C(=O)-OR7, -N(R6)-SO2-R7,-N(R6)-SO2-NY3Y4, -SO2-NYÏY2 and -ZR4; 25 R4 represents alkyl, cycloalkyl or cycloalkylalkyl each optionally substituted by one or more groups selected from aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, hydroxy, -CHO or a 5-, 6- or 7-membered cyclic acetal dérivative of such -CHO, -C(=0)-NY ίγ2, -C(=O)-OR^, -NY1 Y2, 012632 -55- -N(R6)-C(=O)-R7, -N(R6)-C(=O)-NY2 3Y4, -N(R6)-SO2-R7, -N(R6)-SO2-NY3Y4, -OR7 and-C(=O)-R7 where R4 is optionally interspersed wïth a group selected from O, S(O)n, and NR^;r5 représente hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaiyl or heteroarylalkyl;r6 represents hydrogen or lower alkyl; R7 represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaiyl, heteroarylalkyl,heterocycloalkyl or heterocycloalkylalkyl;r8 represents hydrogen or lower alkyl; γΐ and Y^ are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaiyl or alkyl optionallysubstituted by one or more groups selected from aryl, halo, heteroaiyl, hydroxy, -C(=O)-NY3Y4,-C(=O)-OR5, -NY3Y4, -N(R6)-C(=O>R7, -N(R6)-C(=O)-NY3Y4, -N(R6)-SO2-R7,-N(R^)-SO2-NY3Y4 and -OR7; or the group -NY^Y^ may form a cyclic amine; Y3 and Y4 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl orheteroarylalkyl; or the group -NY3 Y4 may form a cyclic amine; Z represents O or S(O)n; n is zéro or an integer l or 2; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable sait or solvaté of such compound;or an N-oxide, prodrug, or acid bioisostere of such sait or solvaté.
2. 2. A compound according to claim 1 wherein Rl is hydrogen, C^alkyl, C^alkyl substituted by halo, Cj^alkyt substituted by hydroxy, Cj^alkyl substituted by -Ν^)Ό(“Ο^7, Cj^alkyl substituted by -C(=O)-NY^ Y^, or cycloalkylalkylsubstituted by hydroxy.
3. 3. A compound according to claim 1 wherein R^ is hydrogen, -CH3, -CH2CH3, -CH2CF3 or -CH—C (=0) -l/ \> .
4. 4. A compound according to claim 1 wherein R^ is hydrogen.
5. 5. A compound according to any one of daims 1 to 4 wherein R^ is carboxy or an acid bioisostere, hydroxy, alkyl substituted by carboxy, heteroaryl, or R^ is -OR4in which R4 is alkyl, -OR4 in which R4 is alkyl or cycloalkylalkyl substituted by one or more hydroxy 012632 -56- groups, -OR4 in which R4 is alkyl substituted by one or more alkoxy groups, -OR4 in which R4 is alkylor cycloalkyl substituted by one or more carboxy groups, -OR4 in which R4 is cycloalkyl substitutedby -0(=0)-14^1 Y2 or R2 is -C(=O)-R in which R is alkyl, or R2 is -C(=O)-NY^ Y2 , or -N(R6)-C(=O)-R7. A compound according to any one of daims 1 to 4 wherein R2 is -och3 or —CONHC (CH3) 2CH2OH
6. 7. A compound according to any one of daims 1 to 4 wherein R2 is -OCH3
7. 8. A compound according to any one of daims 1 to 7 wherein 10 R2 is hydrogen, cyano, optionally substituted aryl, optionally substituted heteroaryl, alkyl, alkyl substituted by one or more halogen atoms, alkyl substituted by -C(=O)-NY1 Y2, alkyl substituted by-OR7, or R3 is -ZR4, -C(=O>0R5, -CCOJ-NY^2, or -NY1 Y2.
8. 9. A compound according to any one of daims 1 to 7 wherein R3 is hydrogen, cyano, pyridyl, 15 trifluoromethyl, -0Η2-ΟΗ2-Ο(=Ο)ΝΗ0Η3, -OCF2H, -C(=O)-NH-C(CH3)2-CH2OH or
9. 10. A compound according to any one of daims 1 to 7 wherein R3 is -OCH3.
10. 11. A compound according to daim any one of daims 1 to 10 wherein R2 is attached at the 5-20 position of the indole ring.
11. 12. A compound according to any one of daims 1 to 11 wherein the group N' is attached to the 3-position of the indole ring. 25 13. A compound according to daim 1 which is 012632

    012632 -58-

    10 012632 -59-

    an N-oxide, prodrug, pharmaceutïcally acceptable sait or solvaté of such compound; or an N-oxide orprodrug of such sait or solvaté.

    an N-oxide, prodrug, pharmaceutically acceptable sait or solvaté of such compound; or an N-oxide orprodrug of such sait or solvaté.
12. 15. A pharmaceutical composition comprising a pharmaceutically effective amount of a compoundaccording to any one of daims 1 to 14, together with one or more pharmaceutically acceptable carriersor excipients.
13. 16- Use of a compound according to any one of daims 1 to 14, or a pharmaceuticallyeffective amount of a composition according to daim 15 in the manufacture of amédicament for treating a patient suffering from, or subject to, conditions which can beameliorated by the administration of an inhibitor of the catalytic activity of Syk.
14. 17. Use of a compound according to any one of daims 1 to 14, or a pharmaceuticallyeffective amount of a composition according to daim 15 in the manufacture of amédicament for treating inflammatory disease in a patient in need thereof. 18· Use of a compound according to any one of daims 1 to 14, or a pharmaceutically effective amount of a composition according to daim 15 in the manufacture of a médicament for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of F AK. 012632 -60-
15. 19. Use of a compound according to any one of daims 1 to 14, or a pharmaceuticallyeffective amount of a composition according to claim 15 in the manufacture of amédicament for treating a patient suffering ffom, or subject to, conditions which can beameliorated by the administration of an inhibitor of the catalytic activity of KDR. 20· Use of a compound according to any one of daims 1 to 14, or a pharmaceuticallyeffective amount of a composition according to claim 15 in the manufacture of amédicament for treating a patient suffering ffom, or subject to, conditions which can beameliorated by the administration of an inhibitor of the catalytic activity of Aurora2. 21 · Use of a compound according to any one of daims 1 to 14, or a pharmaceuticallyeffective amount of a composition according to claim 15 in the manufacture of amédicament for treating cancer in a patient in need thereof.
16. 22. A use according to claim 17 wherein the inflammatory disease is asthma,inflammatory dermatosis, allergie rhinitis, allergie conjunctivitis or joint inflammation.
17. 23. A use according to claim 17 wherein the inflammatory disease is asthma, psoriasis, dermatitis herpetiformis, eczema, necrotizing vasculitis, cutaneous vasculitis, bullous disease, allergie rhinitis, allergie conjunctivitis, arthritis, rheumatoid arthritis, rubella arthritis, psoriatic arthritis or osteoarthritis.
18. 24. Use of a compound according to any one of daims 1 to 14, or a pharmaceuticallyeffective amount of a composition according to claim 15 in the manufacture of amédicament for treating Chronic Obstructive Pulmonary Disease, in a patient in needthereof. 25· A use according to claim 21 wherein the cancer being treating is colorectal, Ρρ^θΜΓβΗδί’thyroid’ skin’ colon or lung cancer Aventis Pharmaoeutioals Ino. Par procuration