ZA200309315B - Pyrrolopyrimidines as protein kinase inhibitors. - Google Patents

Description

PYRROLOPYRIMIDINES AS PROTEIN KINASE INHIBITORS

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

Protein kinases participate in the signalling events which control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these kinases fall into several groups; those which preferentially phosphorylate serine and/or threonine residues and those which preferentially phosphorylate tyrosine residues [S.K.Hanks and

T.Hunter, FASEB. J., 1995, 9, pages 576-596]. The serine/threonine kinases include for example, protein kinase C isoforms [A.C.Newton, J. Biol. Chem., 1995, 270, pages 28495-28498] and a group of cyclin-dependent kinases such as cdc2 [J.Pines, Trends in

Biochemical Sciences, 1995, 18, pages 195-197]. The tyrosine kinases include membrane-spanning growth factor receptors such as the epidermal growth factor receptor [S.Iwashita and M.Kobayashi,

Cellular Signalling, 1992, 4, pages 123-132], and cytosolic non-receptor kinases such as p56tck, p59fYn, ZAP-70 and csk kinases [C.Chan et. al., Ann. Rev. Immunol., 1994, 12, pages 555-592]. Inappropriately high protein kinase activity has been implicated in many diseases resulting from abnormal cellular function. This might arise either directly or indirectly, for example by failure of the proper control mechanisms for the kinase, related for example to mutation, over-expression or inappropriate activation of the enzyme; or by over- or underproduction of cytokines or growth factors also participating in the transduction of signals upstream or downstream of the kinase. In all of these instances, selective inhibition of the action of the kinase might be expected to have a beneficial effect.

Syk is a 72-kDa cytoplasmic protein tyrosine kinase that is expressed in a variety of hematopoietic cells and is an essential element in several cascades that couple antigen receptors to cellular responses.

Thus, Syk plays a pivotal role in signalling of the high affinity IgE receptor, FceR1, in mast cells and . 30 in receptor antigen signalling in T and B lymphocytes. The signal transduction pathways present in mast, T and B cells have common features. The ligand binding domain of the receptor lacks intrinsic : tyrosine kinase activity. 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 present in both the 3 and y subunits of the FceR1, in the E-subunit the of T cell receptor (TCR) and in the IgGa and IgG B subunits of the B-cell receptor (BCR). [N.S.van Oers and

A. Weiss, Seminars in Immunology, 1995, 7, pages 227-236] Upon binding of antigen and multimerization, the ITAM residues are phosphorylated by protein tyrosine kinases of the Sre family.

Syk belongs to a unique class of tyrosine kinases that have two tandem Src homology 2 (SH2) domains and a C terminal catalytic domain. These SH2 domains bind with high affinity to ITAMs and this SH2 -mediated association of Syk with an activated receptor stimulates Syk kinase activity and localises 5S Syk to the plasma membrane.

In Syk deficient mice, mast cell degranulation is inhibited, suggesting that this is an important target for the development of mast cell stabilising agents [P.S.Costello, Oncogene, 1996, 13, pages 2595- 2605]. Similar studies have demonstrated a critical role 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 [L-5 and GM-CSF [S.Yousefi et al., J. Exp. Med., 1996. 183, pages 1407-1414]. Despite the key role of

Syk in mast cell, BCR and T cell signalling, little is known about the mechanism by which Syk transmits downstream effectors. Two adaptor proteins, BLNK (B cell Linker protein, SLP-65) and

SLP-76 have been shown to be substrates of Syk in B cells and mast cells respectively and have been postulated 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 Syk appears to play an important role in the CD40 signalling pathway, which plays an important role in B cell proliferation [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-affinity IgG receptor (Fc gamma-RIIA) or stimulated by collagen [F.Yanaga et al., Biochem. J., 1995, 311, (Pt. 2) pages 471- 478].

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in integrin-mediated signal transduction pathways. FAK colocalizes with integrins in focal contact sites and FAK activation and its tyrosine phosphorylation have been shown in many cell types to be dependent on integrins binding to their extracellular ligands. Results from several studies support the hypothesis that FAK inhibitors could be useful in cancer treatment. For example, FAK-deficient cells migrate poorly in response to chemotactic signals and overexpression of C-terminal domain of FAK blocks cell spreading as well as chemotactic migration (Sieg et al, J. Cell Science, 1999, 112, 2677-2691; Richardson A. and Parsons

T., Cell, 1997, 97, 221-231) ; in addition, tumor cells treated with FAK antisense oligonucleotides lost their attachment and underwent apoptosis (Xu et al, Cell Growth Differ. 1996, 4, 413-418). FAK has been reported to be overexpressed in prostate, breast, thyroid, colon and lung cancers. The level of expression of FAK is directly correlated with tumors demonstrating the most aggressive phenotype.

Angiogenesis or the formation of new blood vessels by sprouting from the preexisting vasculature is of central importance for embryonic development and organogenesis. Abnormal enhanced neovascularization is observed in rheumatoid arthritis, diabetic retinopathy and during tumor ' development (Folkman, Nat. Med., 1995, 1, 27-31.). Angiogenesis is a complex multistage process which includes activation, migration, proliferation and survival of endothelial cells. Extensive studies in the field of tumor angiogenesis in the past two decades have identified a number of therapeutic targets including kinases, proteases and integrins resulting in the discovery of many new anti- angiogenic agents, including KDR inhibitors some of which are currently under clinical evaluation (Jekunen, et al Cancer Treatment Rev. 1997 , 23, 263-286.). Angiogenesis inhibitors may be used in frontline, adjuvant and even preventive settings for the emergence or regrowth of malignancies.

Several proteins involved in chromosome segregation and spindle assembly have been identified in yeast and drosophila. Disruption of these proteins results in chromosome missegregation and monopolar or disrupted spindles. Among these kinases are the Ipll and aurora kinases from S.cerevisiae and drosophila respectively, which are required for centrosome separation and chromosome segregation. One human homologue of yeast Ipl1 was recently cloned and characterized by different laboratories. This kinase termed Aurora2, STK15 or BTAK belongs to the serine/threonine kinase family. Bischoff et al showed that Aurora? is oncogenic and is amplified in human colorectal cancers (EMBO J, 1998, 17, 3052-3065). It has also been exemplified in cancers involving epithelial tumors such as breast cancer.

This invention concerns substituted pyrrolopyrimidines of formula (I), which have the ability to inhibit one or more protein kinases, more particularly, FAK, KDR , Syk kinase or Aurora2, especially Syk kinase. rR 4 5 2 i —\_~—R ‘

N ~~ TN 3 N\ -s 6

Pe Pa 7

Ny N 2 ~~

PES

R ty) wherein

R! represents hydrogen, -C(=0)-NY1Y2, -C(=0)-OR?, -SO,-NY1Y2, -S05-R7 , -C(=O)R7, or R! may be alkenyl, alkenyloxy, alkyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl or 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 derivative thereof), -C(=0)-NY1Y2, .C(=0)-OR5, -NY1YZ, -N(R6)-C(=0)-R7, -N(R0)-C(=0)-NY3Y4,

N(R6)-SO»-R7, -N(R6)-SO»-NY3Y4, -OR7, -C(=0)-R7, hydroxy, alkoxy and carboxy;

RZ? represents one or more groups selected from hydrogen, acyl, alkylenedioxy, alkenyl, alkenyloxy, alkynyl, aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, R4, -C(=0)-NY1YZ2, -C(=0)-0R5, NY!Y2Z N(R6)-C(=0)-R7, -N(R6)-C(=0)-NY3Y4, -N(RE)-C(=0)-OR,

N(R6)-S0»-R7, -N(R%)-SO5-NY3Y4, -S05-NY YZ and -ZR%,

R3 represents H, cyano, halo, hydroxy, nitro, R4, NY1Y2, -ZR4, -C(=0)-OR3, -C(=0)-R7, -C(=0)-NY!YZ -N(R8)-C(=0)-R4, N(R8)-C(=0)-NY1Y2, N(R8)-C(=0)-OR, -S05-NY3Y¥%, or -N(R8)-50,-R7, or R3 represents aryl, heteroaryl, alkenyl or alkynyl, each optionally substituted by one or more groups selected from aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, -C(=0)-NY1Y2, -C(=0)-OR5, -NY1Y2, .N(R6)-C(=0)-R7> -N(R6)-C(=0)-NY3Y4,

N(R6)-C(=0)-OR7, N(R6)-S0»-R7, N(R®)-S02-NY3Y4, -S0»-NY1Y2 or -ZRY, .

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 derivative thereof), -C(=0)-NY1Y2, -C(=0)-OR53, NY'Y2,

N(R6)-C(=0)-R7, -N(R6)-C(=0)-NY3Y4, -N(R6)-S0,-R7, -N(R6)-505-NY3Y4, -OR7 and -C(=0)-R7; R# can also be optionally interspersed with a group selected from O, S(O), NRO; ’ RO represents hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;

RO represents hydrogen or lower alkyl; R7 represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl,

RS represents hydrogen or lower alkyl;

Y! and Y2 are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl optionally substituted by one or more groups selected from aryl, halo, heteroaryl, hydroxy, -C(=0)-NY3Y4, -C(=0)-OR, NY3Y4, .N(R)-C(=0)-R7, -N(R®)-C(=0)-NY3Y4, N(R6)-SO»-R7,

N(R9)-SO,-NY3Y4 and -OR7; or the group -NYly2 may form a cyclic amine;

Y3 and Y4 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group NY3v4 may form a cyclic amine;

Z represents O or S(O); nis zero or an integer 1 or 2; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and their prodrugs, and their acid bioisosteres; together with one or more pharmaceutically acceptable carriers or excipients.

In the present specification, the term "compounds of the invention", and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, 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 instances ) are 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 terms, unless otherwise indicated, shall be understood to have the following meanings:- "Patient" includes both human and other mammals.

"Acid bioisostere" means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21,p283 "Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993, 33, pages 576-579 "Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995 pages 34.18 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham,

Theochem, 1995, 343, pages 105-109 "Theoretical Studies Applied To Drug Design:ab initio

Electronic Distributions In Bioisosteres"). Examples of suitable acid bioisosteres include: -C(=0)-NHOH, -C(=0)-CH)0H, -C(=0)-CH5 SH, -C(=0)-NH-CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl,

N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-1-methylpyrazolyl. "Acyl" means an H-CO- or alkyl-CO- group in which the alkyl group is as described herein. "Acylamino" is an acyl-NH- group wherein acyl is as defined herein. "Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in the chain. "Branched," as used herein and throughout the text, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain: here a linear alkenyl chain. "Lower alkenyl" means about 2 to about 4 carbon atoms in the chain, which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbuteny! and decenyl. "Alkenyloxy" is an alkeny]-O- group wherein alkenyl is as defined above. Exemplary alkenyloxy groups include allyloxy. "Alkoxy" means an alkyl-O- group in which the alkyl group is as described herein. Exemplary alkoxy groups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy ’ and heptoxy. "Alkoxycarbonyl" means an alkyl-O-CO- group in which the alkyl group is as described herein.

Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbony!.

"Alkyl" means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched chain having about 1 to about 15 carbon atoms in the chain, optionally substituted by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms. "Lower alkyl" as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group means unless otherwise specified, an aliphatic hydrocarbon group which may be a straight or branched chain having 1 to about 4 carbon atoms in the chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.

Exemplary alkyl groups substituted by one or more halogen atoms include trifluoromethyl. "Alkylene" means an aliphatic bivalent radical derived from a straight or branched alkyl group, in which the alkyl group is as described herein. Exemplary alkylene radicals include methylene, ethylene and trimethylene. "Alkylenedioxy" means an -O-alkylene-O- group in which alkylene is as defined above. Exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy. "Alkylsulfinyl" means an alkyl-SO- group in which the alkyl group is as previously described.

Preferred alkylsulfinyl groups are those in which the alkyl group is C_galkyl. "Alkylsulfonyl" means an alkyl-SO9- group in which the alkyl group is as previously described.

Preferred alkylsulfonyl groups are those in which the alkyl group is Cj_galkyl. "Alkylsulfonylcarbamoyl" means an alkyl-SO2-NH-C(=0)- group in which the alkyl group is as previously described. Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is

Cj.galkyl. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio. "Alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which . group may be a straight or branched chain having about 2 to about 15 carbon atoms in the chain.

Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.

"Aroyl" means an aryl-CO- group in which the aryl group is as described herein. Exemplary aroy! groups include benzoyl and 1- and 2-naphthoyl. "Aroylamino® is an aroyl-NH- group wherein aroyl is as previously defined. "Aryl" as a group or part of a group denotes: (1) an optionally substituted monocyciic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl! or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moicty in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Except where otherwise defined, aryl groups may be substituted with one or more aryl group substituents, which may be the same or different, where "aryl group substituent" includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or an acid bioisostere), cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, -NY3Y4, -CONY3Y4, -SO,NY3Y4, .NY3-C(=0)alkyl,

NY3 SO9alky! or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or NY3v4, "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a Cy_galkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl. "Arylalkyloxy" means an arylalkyl-O- group in which the arylalkyl groups is as previously described.

Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. "Arylalkyloxycarbonyl" means an arylalkyl-O-CO- group in which the arylalkyl groups is as previously described. An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl. "Arylalkylthio” means an arylalkyl-S- group in which the arylalkyl group is as previously described. .

An exemplary arylalkylthio group is benzylthio. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Exemplary aryloxy groups include phenoxy and naphthoxy, each optionally substituted. "Aryloxycarbonyl" means an aryl-O-C(=0)- group in which the aryl group is as previously described.

Exemplary aryloxycarbonyl groups include phenoxycarbony! and naphthoxycarbonyl.

"Arylsulfinyl" means an aryl-SO- group in which the aryl group is as previously described. ’ "Arylsulfonyl" means an aryl-SO>- group in which the aryl group is as previously described.

"Arylsulfonylcarbamoy!" means an aryl-SO-NH-C(=O)- group in which the aryl group is as previously described. "Arylthio" means an aryl-S- group in which the aryl group is as previously described.

Exemplary arylthio groups include phenylthio and naphthylthio. "Azaheteroaryl" means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are selected from carbon, oxygen, sulfur, and nitrogen.

Examples of azaheteroaryl groups include benzimidazolyl, imidazolyl, indazolinyl, indolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, quinazoliny! and tetrahydroindolizinyl. "Cyclic amine" means a 3 to 8 membered monocyclic cycloalkyl ring system wherein one of the ring carbon atoms is replaced by nitrogen and which (i) may also contain a further heteroatom-containing group selected from O, S, SO», or NY3 (where Y? is hydrogen, alkyl, aryl, arylalkyl, -C(=0)-R”, -C(=0)-OR7 or -SO,R7); and (ii) may be fused to additional ary] (e.g. phenyl), heteroaryl (e.g. pyridyl), heterocycloalky! or cycloalkyl rings to form a bicyclic or tricyclic ring system.

Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline, pyrindoline, tetrahydroquinoline and the like groups.

"Cycloalkeny!" means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.

Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl.

. "Cycloalkyl" means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms, optionally substituted by oxo.

Exemplary monocyclic cycloalkyl! rings include C3_gcycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

"Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyi, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethy!. "Halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred are fluoro and chloro. "Heteroaroyl" means a heteroaryl-C(=0)- group in which the heteroaryl group is as described herein.

Exemplary heteroaryl groups include pyridylcarbonyl. "Heteroaroylamino" means a heteroaroyl-NH- group in which the heteroaryl moiety is as previously described. "Heteroaryl" as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur (examples of such groups include benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents as defined above except where otherwise defined); (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which a heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure (examples of such groups include pyrindanyl groups, optionally substituted by one or more "aryl group substituents” as defined above, except where otherwise defined). Optional substituents include one or more "aryl group substituents” as defined above, except where otherwise defined. "Heteroarylalky!" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a Cj_galkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. Heteroarylalkyloxy" means an heteroarylalkyl-O- group in which the heteroarylalkyl group is as ’ previously described. Exemplary heteroaryloxy groups include optionally substituted pyridylimethoxy. "Heteroaryloxy" means an heteroaryl-O- group in which the heteroaryl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridyloxy.

"Heteroarylsulfonylcarbamoyl" means a heteroaryl-SOo-NH-C(=O)- group in which the heteroaryl group is as previously described. "Heterocycloalkyl" means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms or heteroatom-containing groups selected from O, S and N'Y? and mat be optionally substituted by oxo; (ii) a partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl) ring, each optionally substituted by one or more “aryl group substituents,” and a heterocycloalkyl group are fused together to form a cyclic structure. (Examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups). "Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described. "Prodrug” means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof. For example an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis_in vivo to the parent molecule.

Alternatively, an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.

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

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

Suitable esters of compounds of formula (I) containing both a carboxy group and a hydroxy group ’ 30 within the moiety -L1-Y include lactones formed by loss of water between said carboxy and hydroxy groups. Examples of such lactones include caprolactones and butyrolactones.

An especially useful class of esters of compounds of formula (I), containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32 page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3~ or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-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 of the salt form inherently amounts to use of the frec acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline,

N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.

Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.

Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition saits include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for : purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-beta-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates,

methane-sulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.

As well as being useful in themselves as active compounds, salts of compounds of the invention are

S useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.

With reference to formula (I) above, the following are particular and preferred groupings:

RI may particularly represent: (i) hydrogen (ii) Cj_galkyl [e.g. -CH3 or -CHyCH3]; (iii) Cj.galkyl substituted by halo [e.g. -CHyCF3]; (iv) Cjp_galkyl substituted by hydroxy [e.g. -CH,OH, —CH,CH,OH or -CH,CH,CH,OH IR (v) Ci4alkyl substituted by -N(R®)C(=0)-R7 [e.g. ~CH,CH,CH,NHC (=0) CH, J; (vi) Cp_galkyl substituted by -C(=0)-NY1Y2 [e.g. ~CH;-C (=0) -N oJ; or wil (vii) cycloalkylalkyl substituted by hydroxy [e.g. (cH 2 ].

CH,OH

Compounds of formula (I) in which Rl represents hydrogen, -CH3, -CHpCHj3, -CHyCF3 or -CH;—C (=0) -N O are especially preferred. R1 more especially represents hydrogen. ) RZ may particularly represent: : Co J NE (i) carboxy or an acid bioisostere (e.g. — I); nN (i) hydroxy; (iti) alkyl substituted by carboxy [e.g. -CH,CH,CO,H];

WO (3/000695 PCT/GBO2/02835

N_ CH, ~~ (iv) heteroaryl e.g. — = or pyridyl];

N° (v) -OR%in which R% is alkyl e.g. OCH. 1; (vi) -OR% in which R4 is alkyl or cycloalkylalkyl substituted by one or more hydroxy groups [e.g —~OCH,CH,OH » —OCH,CH,CH,OH >» —OCH (CH,) CH,OH »

H,C—CH, —OCH,CH (OH) CH, , RR or —OCH,CH (OH) CH,OH I;

CH_OH (vii) -OR% in which R4 is alkyl substituted by one or more alkoxy groups [e.g. -OCH (CH,) CH,OCH, |; (viii) -OR# in which R# is alkyl or cycloalkyl substituted by one or more carboxy groups [e.g.

NN

~OCH,CO,H, —~OCH (CH,) COH or i I;

CO, H yf (ix) -OR# in which R% is cycloalkyl substituted by -C(=0)-NY 1Y2 [e.g. oe, or

CONH,

H,C—CH,

RE k

CONHCH, (x) -C(=O)-R in which R is alkyl [e.g. -C(=0) -CH, |; (xi) -C(=0)-NY!YZ|eg -CONH,, —CONHCH,,~CONHCH (CH,OH) , ~CONHCH,CH,OH , ~CONHC (CH,) ,CH,0H, ——CONHCH,CH,OCH, -

N= —CONHCH,CH,CONH, . ——CONHCH,C (CH,) ,0H or —cont— xo

NT

(xii) -N(R®)-C(=0)-R7 [e.g. -NHC (=O) CH, ].

Compounds of formula (I) in which R2 represents ~OCH, or —~CONHC (CH,) ,CH,OH are especially preferred. R2 more especially represents -OCH, - } R3 may particularly represent: (i) hydrogen; (i) cyano; (iii) optionally substituted aryl (e.g. phenyl); (iv) optionally substituted heteroaryl (e.g. optionally substituted pyridyl or optionally

MeO substituted indolyl, especially or % \ 4 NN

N H

(v) alkyl (e.g. methyl or ethyl); (vi) alkyl substituted by one or more halogen atoms (e.g. trifluoromethyl); (vii) alkyl substituted by -C(=0)-NY1y2 especially ~CH5-CH,-C(=0)NHCHj3; (viii) alkyl substituted by -OR” (e.g. -CHy-CH,-OCH3j); (ix) -ZR4, especially -OCHj3 , -OCH,»CHj3, ~OCF,H or -OCH»-CH,-OCHj3; (x) -C(=0)-OR3, especially -C(=0)-OH; (xi) -C(=0)-NY1Y2, especially -C(=0)NHCH3 or -C(=0)-NH-C(CH3)»-CHoOH; and (xii) -NY1Y2, especially —N 0. —/

Compounds of formula (I) in which R3 represents hydrogen, cyano, pyridyl, trifluoromethyl, -CHo-

CH5-C(=0)NHCH3, -OCF2H, -C(=0)-NH-C(CH3),-CHoOH or —N O are especially preferred. R3 more especially represents -OCHj3.

RZ is preferably attached to position 5 of the indole ring.

rR

The group § Pu J ts preferably attached io the 3 position of the indole ring

NS

NTR

H

Itisto be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.

Particular preferred compounds of the invention are:-

MeO o Je he © fe

CF, CH, OH <

NTN \ 0

Iq \ NT \ ns

Fn N , I \ bu N N EN

Lo } h CH, ¢1)) (II)

OMe CONHMe MeO \ “I dd 2

IS IN vo

CY CY pz

N N N § Pa \_N

N N

A C2

H o

TN [0] FN (J . (4 B (Iv) Vv) ~n MeO =

MeO =

N AN CN =

NP Nan I 0G fo) il Ny N \ ™ (eo H CF ; *;

Claims (3)

1. WHAT IS CLAIMED IS:

   I. A compound of the formula 3 R 4 5 2 R 6 gg Nn NN 27N Ew R wherein R! represents hydrogen, -C(=0)-NY YZ, -C(=0)-OR5, -S0,-NY1Y2 | .50,-R7 , -C(=O)R7, or R! represents alkenyl, alkenyloxy, alkyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl or 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 derivative of such —CHO, -C(=0)-NY1Y2, .C(=0)-OR3, NY 1Y2, ;N(R6)-C(=0)-R7, -N(R6)-C(=0)-NY3Y4, N(R6)-S0»-R7, -N(R0)-S0,-NY3Y4, -OR7, -C(=0)-R7, hydroxy, alkoxy and carboxy; 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!Y2, -C(=0)-OR3, -NY1Y2, .N(R6)-C(=0)-R7, -N(R6)-C(=0)-NY3Y4, -N(R6)-C(=0)-OR’, N(R6)-S0,-R7, -N(R®)-S0,-NY3Y4, -SO,-NY1Y2 and -ZR4, R3 represents H, cyano, halo, hydroxy, nitro, R4, NY1Y2, -ZR4, -C(=0)-OR5, -C(=0)-R’, -C(=0)-NY1YZ2, -N(R8)-C(=0)-R4, N(R8)-C(=0)-NY YZ, .N(R8)-C(=0)-OR3, -SO»-NY3Y4, or -N(R$)-SO,-R7, or R3 represents aryl, heteroaryl, alkenyl or alkynyl, each optionally substituted by one or more groups selected from aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, -C(=0)-NY1Y2, -C(=0)- . OR3, NY1Y2, N(R8)-C(=0)-R7> -N(RS)-C(=0)-NY3Y4, -N(R6)-C(=0)-OR7, -N(R9)-805-R7, N(R6)-S0,-NY3Y4, -S0,-NY1Y2 and -ZR4,; 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 derivative of such -CHO, -C(=0)-NY YZ, -C(=0)-OR3, -NY!Y2,

   N(R®)-C(=0)-R7, -N(R6)-C(=0)-NY3Y4, -N(R6)-SO5-R7, -N(R6)-S05-NY3Y4, -OR7 and -C(=0)-R7 where R% is optionally interspersed with a group selected from O, S(O), and NRS; ’ RS represents hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; RO represents hydrogen or lower alkyl; R7 represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; RS represents hydrogen or lower alkyl; Y1 and Y2 are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl optionally substituted by one or more groups selected from aryl, halo, heteroaryl, hydroxy, -C(=0)-NY3Y4, -C(=0)-OR>, NY3Y4, N(R®)-C(=0)-R7, NRS)-C(=0)-NY3Y4, N(R6)-SO»-R7, N(R6)-SO,-NY3Y4 and -OR7; or the group NYly2 may form a cyclic amine; Y3 and Y4 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group NY3Y4 may form a cyclic amine; Z represents O or S(O)p; nis zero or an integer 1 or 2; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
2. 2. A compound according to claim 1 wherein RI is hydrogen, Cj-4alkyl, Cy_salkyl substituted by halo, C;_galkyl substituted by hydroxy, Cj_galkyl substituted by -N(R®)C(=0)-R7, C1_galkyl substituted by -C(=0)-NY YZ, or cycloalkylalkyl substituted by hydroxy.
3. 3. A compound according to claim 1 wherein R! is hydrogen, -CHj3, -CHoCH3, -CH,CF3 or -CH;~C(=0) +p .

   4. A compound according to claim 1 wherein R1 is hydrogen.

   5. A compound according to any one of claims 1 to 4 wherein RZ is carboxy or an acid bioisostere, hydroxy, alkyl substituted by carboxy, heteroaryl, or R2 is -OR% in which R% is alkyl, -OR4 in which R% is alkyl or cycloalkylalkyl substituted by one or more hydroxy groups, -OR# in which R4 is alky! substituted by one or more alkoxy groups, -OR% in which R? is alkyl or cycloalkyl substituted by one or more carboxy groups, -OR# in which R% is cycloalkyl substituted by -C(=0)-NY1Y2 or R” is -C(=0)-R in which R is alkyl, or R* is -C(=0)-NY 'Y?2 | or -N(R6)-C(=0)-

   R7.

   6. A compound according to any one of claims 1 to 4 wherein R2 is —OCH_ or —CONHC (CH,) ,CH,OH

   7. A compound according to any one of claims 1 to 4 wherein R2 is ~OCH 5

   8. A compound according to any one of claims 1 to 7 wherein R3is hydrogen, cyano, optionally substituted aryl, optionally substituted heteroaryl, alkyl, alkyl substituted by one or more halogen atoms, alkyl substituted by -C(=0)-NY1ly2, alkyl substituted by -OR7, or R3 is -ZR4, -C(=0)-0OR>, -C(=0)-NY1Y2, or NY1Y2Z.

   9. A compound according to any one of claims 1 to 7 wherein R3 is hydrogen, cyano, pyridyl, trifluoromethyl, -CH»-CH>-C(=O)NHCH3, -OCF;H, -C(=0)-NH-C(CH3)>-CH,OH or —N 0

   10. A compound according to any one of claims 1 to 7 wherein R3 is —OCHs.

   11. A compound according to claim any one of claims i to 10 wherein R” is attached at the 3- position of the indole ring. R> A

   12. A compound according to any one of claims 1 to 11 wherein the group | i J Sey H is attached to the 3-position of the indole ring.

   13. A compound according to claim 1 which is

   M MeQ 0 BN / ‘Me CF, CH,OH NT fo) LL Dan x NSN N | \ N { x § Ay N H (_o ) ) “er . . H 3 . OMe CONHMe MeO NT N\ = N N N Xx \_N N N +2 J. Io) Y [o} FN Ld (4 SN MeO pz MeO 2 N | N CN N \_~ N N NN“ H ks N \

   [0] NN Ny N ™ (_ B

   °. cr, o aN ( ) MeO MeO . o NH NN“ = OU (PRS NN p NT TN BN \

   H . H . A MeO MeO MeO = OMe OMe \ N\_N \_~ LO, Rd, LR H } H } H }

   NN A / N MeO MeO MeO \\ Pp OCHF, 74 \ CE CNA an LA Nn LA Nn NN "Me NN H MeO MeO MeO OCHF, MeO (CH,) ,0 H NTN SEE A GA NA \ 3 i y SNA NN ~~ = / NAN « PP 7 NN N N H N N H N N H bi 9 2 MeO MeO MeO CH, CH,CH, CH,CH,OMe iP N\ i N\ iP N\

   \ N. p \ N. ~ \ N. N N ~H N N SH N | SH bd hd b

   \. _.CH,OH MeO — “Meo ms o NH o NHCH By \. } NIN hi ne TN = a Ue ii | i ) [ i Za Nn. N J \_~ N An oR H oon “nm NA H HO ore J \ \ MeO o NH o NH CN ) OMe OMe 7 \ NT > SE EA NN N N N yh (§ = N \ No § = N \ Nek

   H . N H BE N H . ; : ; or

   : PCT/GB02/02835

   H . / N OMe MeO CJ y ~ : NTR . Pa 4 NN H 8 ; or an N-oxide, prodrug, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide or prodrug of such salt or solvate.

   14. A compound according to claim 1 which is MeO OMe Pha ~g : 8 or an N-oxide, prodrug, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide or prodrug of such salt or solvate.

   15. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1 to 14, together with one or more pharmaceutically acceptable carriers : or excipients.

   16. Use of a compound according to any one of claims 1 to 14, in the manufacture of a medicament 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 Syk.

   17. Use of a compound according to any one of claims 1 to 14, in the manufacture of a : medicament for treating inflammatory disease in a patient in need thereof.

   18. Use of a compound according to any one of claims 1 to 14, in the manufacture of a medicament 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 FAK. AMENDED SHEET

   PCT/GB02/02835

   19. Use of a compound according to any one of claims 1 to 14, in the manufacture of a medicament 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 KDR.

   20. Use of a compound according to any one of claims 1 to 14, in the manufacture of a medicament 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 Aurora2.

   21. Use of a compound according to any one of claims 1 to 14, in the manufacture of a medicament for treating cancer in a patient in need thereof, oo

   22. Use according to claim 17 wherein the inflammatory disease is asthma, inflammatory dermatosis, allergic rhinitis, allergic conjunctivitis or joint inflammation.

   23. Use according to claim 17 wherein the inflammatory disease is asthma, psoriasis, dermatitis herpetiformis, eczema, necrotizing vasculitis, cutaneous vasculitis, bullous disease, allergic rhinitis, allergic conjunctivitis, arthritis, rheumatoid arthritis, rubella arthritis, psoriatic arthritis or osteoarthritis.

   24. Use of a compound according to any one of claims 1 to 14, in the manufacture of a medicament for treating Chronic Obstructive Pulmonary Disease, in a patient in need thereof.

   25. Use according to claim 21 wherein the cancer being treated is colorectal, prostate, breast, thyroid, skin, colon or lung cancer.

   26. A substance or composition for use in a method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of Syk, said substance or composition comprising a compound according to any one of claims 1 to 14, and said method comprising administering to said patient a pharmaceutically : effective amount of said substance or composition. AMENDED SHEET

   PCT/GB02/02835

   217. A substance or composition for use in a method of treating inflammatory disease in a patient in need thereof, said substance or composition comprising a compound according to any one of claims 1 to 14, and said method comprising administering to said patient a pharmaceutically effective amount of said substance or composition.

   28. A substance or composition for use in a method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of FAK, said substance or composition comprising a compound according to any one of claims 1 to 14, and said method comprising administering to said patient.a pharmaceutically effective amount of said substance or composition.

   29. A substance or composition for use in a method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of KDR, said substance or composition comprising a compound according to any one of claims 1 to 14, and said method comprising administering to said patient a pharmaceutically effective amount of said substance or composition.

   30. A substance or composition for use in a method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of Aurora2, said substance or composition comprising a compound according to any one of claims 1 to 14, and said method comprising administering to said patient a pharmaceutically effective amount of said substance or composition.

   31. A substance or composition for use in a method of treating cancer in a patient in need thereof, said substance or composition comprising a compound according to any one of claims 1 to 14, and said method comprising administering to said patient a pharmaceutically effective amount of said substance or composition. :

   32. A substance or composition for use in a method of treatment according to claim 27 wherein the inflammatory disease is asthma, inflammatory dermatosis, allergic rhinitis, allergic conjunctivitis or joint inflammation. AMENDED SHEET

   PCT/GB02/02835

   33. A substance or composition for use in a method of treatment according to claim 27 wherein the inflammatory disease is asthma, psoriasis, dermatitis herpetiformis, eczema, necrotizing vasculitis, cutaneous vasculitis, bullous disease, allergic rhinitis, allergic conjunctivitis, arthritis, rheumatoid arthritis, rubella arthritis, psoriatic arthritis or osteoarthritis.

   34. A substance or composition for use in a method of treating Chronic Obstructive Pulmonary Disease, in a patient in need thereof, said substance or composition comprising a compound according to any one of claims 1 to 14, and said method comprising administering to said patient a pharmaceutically effective amount of said substance or composition.

   35. A substance or composition for use in a method of treatment according to claim 31 wherein the cancer being treated is colorectal, prostate, breast, thyroid, skin, colon or lung cancer.

   36. A compound according to any one of claims 1 to 14, substantially as herein described and illustrated.

   37. A composition according to claim 15, substantially as herein described and illustrated.

   38. Use according to any one of claims 16 to 25, substantially as herein described and illustrated.

   39. A substance or composition for use in a method of treatment according to any one of claims 26 to 35, substantially as herein described and illustrated.

   40. A new compound, a new composition, a new use of a compound as claimed in any one of claims 1 to 14, a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET