WO2009136144A1

WO2009136144A1 - Purine derivatives suitable for the treatment of cancer, autoimmune and inflammatory diseases

Info

Publication number: WO2009136144A1
Application number: PCT/GB2009/001115
Authority: WO
Inventors: David Charles Festus Moffat; Kenneth William John Baker; Alistair David Graham Donald; Francesca Ann Day
Original assignee: Chroma Therapeutics Ltd
Current assignee: Chroma Therapeutics Ltd
Priority date: 2008-05-07
Filing date: 2009-05-05
Publication date: 2009-11-12
Anticipated expiration: 2010-11-07
Also published as: GB0808286D0

Abstract

The invention provides a compound which is (a) an amino acid derivative of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof: wherein R¹, R², L¹, Het, A, x, y and W are as defined herein. The compounds are useful in the treatment of diseases mediated by HSP90.

Description

PURINE DERIVATIVES SUITABLE FOR THE TREATMENT OF CANCER, AUTOIMMUNE AND INFLAMMATORY DISEASES

This invention relates to a series of amino acid derivatives, to compositions containing them, to processes for their preparation and to their use in medicine as HSP90 inhibitors. The compounds may also be of use in the treatment of cell proliferative diseases such as cancer which are mediated by inappropriate HSP90 activity as well as inflammatory and immune disorders such as rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, and disorders related to angiogenesis age related macular degeneration, diabetic retinopathy and endometriosis. The compounds may also be of use in the protection of normal cells against the action of cytotoxic agents. The present invention encompasses compounds that are derivatives of adenine.

BACKGROUND TO THE INVENTION

Cells respond to stress by increasing synthesis of a number of heat shock proteins or HSPs, also known as molecular chaperones. The heat shock proteins assist general protein folding and prevent non-functional side reactions such as non-specific aggregation of misfolded or unfolded proteins. Heat shock protein 90 (HSP90) in particular has been identified as an important mediator of cancer cell survival.

Most HSPs are ubiquitously expressed under normal conditions, their basal levels facilitating normal protein folding and guarding the proteosome from the dangers of misfolding or aggregation, [Wegele et al, Rev. Physiol. Biochem. Pharmacol., 2004, 151, 1-44]. Under non-stressed conditions HSP90 comprises as much as 1-2% of total cellular protein content, whereas in tumour cells it is expressed at levels 2- to 10-fold higher in comparison to normal cells. These chaperone proteins are required for essential housekeeping functions, such as de novo protein folding during nascent polypeptide-chain synthesis, translocation of proteins across membranes and normal protein turnover. HSPs also participate in higher-order functions such as post-translational regulation of signalling molecules [Csermelt et al, Pharmacol. Ther, 1998, 79, 129-168], the assembly and disassembly of transcriptional complexes [Science 2002, 296, 2232-2235] and the processing of immunogenic peptides by the immune system.

HSPs function as components of multi-protein complexes which contain other chaperones, co-chaperones, modulators of ATPase activity and various accessory proteins. The components of the HSP90 chaperone complex include HSP70 ,HSP40, HIP, HOP, CDC37/p50, AHAl, p23 and immunophilin. Chaperones typically interact with client proteins in a cyclical, iterative fashion which is driven by ATP hydrolysis, [Smith et al, MoI. Cell Biol. 1995, 15, 6804-6812]. Targeting the nucleotide-binding pockets of HSP90 with small molecules may therefore provide a method of modulating the activity of the chaperone complex. HSP90 is unique amongst the chaperones as it is not required for biogenesis of most polypeptides. Many of its client proteins are conformationally labile signal transducers which are critical to cell growth and survival, [Pratt et al, Proc. Soc. Exp. Biol. Med., 1998, 217, 420-431]. Post-translational interactions with its clients allows HSP90 to couple stress response to changes in signal transduction pathways and transcriptional responses, [Morimoto et al, Cell, 2002, 110, 281-284]. Studies in

Drosophila melanogaster have demonstrated that compromising the function of HSP90 can induce epigenetic alteration in gene expression as well as heritable alterations in chromatin state [Solars et al, Nature Genet. 2003, 33, 70-74 and Sangster et al, Cell Cycle, 2003, 2, 166-168]. A common feature of both solid and haematological malignancies is increased expression of one or more HSPs. Overexpression of HSP90 in breast cancer correlates with poor prognosis [Jameel et al, hit. J. Cancer 1992, 50, 409-415]. Increased chaperone expression contributes to oncogenesis at several levels. Increased abundance of HSPs in advanced cancers reflects an appropriate cytoprotective stress response to hypoxic and acidotic microenvironment of the tumour. At the molecular level increased chaperone activities appear to allow tumour cells to tolerate the deregulation in intracellular signalling associated with neoplastic transformation and thereby provide a mechanism for tumour cells to avoid apoptosis [Mosser et al, Oncogene 2004, 23, 2907]. The modulation of tumour cell apoptosis by HSP90 and its co-chaperones is mediated through effects on AKT, [Basso et al, J. Biol. Chem., 2003, 277, 39858-39866], tumour necrosis factor (TNF) receptors [Vanden Bergh et al, J. Biol. Chem. 2003, 278, 5622-5629] and NF-κB function [Chen et al, MoI. Cell, 2002, 9, 401-410].

Many kinases are client proteins of HSP90 including several which play a significant role in the progression of malignant phenotype such as HER2, AKT and RAF-I, [Neckers et al, Trends MoI. Med. 2002, 8, S55-S61]. Ligand-dependent transcription factors (e.g. steroid receptors), transcription factors (e.g. HIF- lα) containing PAS domains and mutated or chimeric signalling proteins (mutated p53, NPM-ALK kinase, p210^Bcr"AbI] are also HSP90 clients. In addition some client proteins are involved other fundamental processes of tumorigenesis, namely apoptosis evasion (e.g. Apaf-1, RIP), immortality (e.g. hTert), angiogenesis (e.g. VEGFR, Flt-3, FAK, HIF-I) and metastasis (c-Met).

HSP90 resides predominantly in the cytoplasm, where it exists at a homodimer. Each monomer is comprised of three main domains. The N-terminal domain contains an unusual adenine nucleotide-binding pocket defined by a Bergerat fold, [Dutta et al, Trends Biochem. Sci., 2000, 25, 24-28]. Structural alterations driven by the hydrolysis of ATP in this fold appear to have an essential role in the chaperoning activity of the HSP90 dimer. In eukaryotes a highly charged linker sequence connects the N-terminal domain to the 'middle region' of HSP90. The structure of this middle region indicates that is has an important role in modulating ATP hydrolysis by interacting with the γ-phosphate of ATP molecules bound to the protein, [Meyer et al, MoI. Cell 2003, 11, 647-658]. The N-terminal ATP- binding site is also the site of interaction of the structurally unrelated natural products geldanamycin and radicicol. These compounds prevent the chaperone from cycling between its ADP- and ATP-bound conformations. Drug binding at the N-terminus of HSP90 seems to recruit E3 ubiquitin ligases such as CHIP (carboxy terminus of HSP70- interacting protein) to the many client proteins that are normally expressed by HSP90 protein complexes [Xu et al, Proc. Natl. Acad. Sci., 2002, 99, 12847-12852]. This recruitment leads to proteosomal degradation of the clients and depletion of their cellular levels.

In normal and many cancer cell lines, HSP90 inhibitors induce a predominant Gl cell-cycle arrest in a p53-independent manner, [Mcllwrath et al, Cancer Chemother. Pharmacol. 1996, 37, 423-428]. Disruption of anti-apoptotic signalling in tumour cells occurs following exposure to HSP90 inhibitors and can enhance the pro-apoptotic effects of cytotoxic agents [Basso et al, Oncogene 2002, 21, 1159-1162].

We have now discovered a group of compounds which are potent and selective inhibitors of HSP90 and the isoforms and splice variants thereof. The compounds are thus of use in medicine, for example in the treatment of a variety of proliferative disease states, where inappropriate action of HSP90 may be involved such as cancer, inflammatory and immune disorders such as rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, and disorders related to angiogenesis age related macular degeneration, diabetic retinopathy and endometriosis. The compounds may also be of use in the protection of normal cells against the action of cytotoxic agents.

BRIEF DESCRIPTION OF THE INVENTION

The invention provides a compound which is (a) an amino acid derivative of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof:

wherein:

R¹ represents a hydrogen or halogen atom, or a cyano, nitro, -N₃, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_-6 alkoxy, C_2-6 alkenyloxy, hydroxyl, -SR', Ci_-6 alkylthio, C_2-6 alkenylthio, guanidine, amidine, -NR'R", -NR" OR' or -NR'"R'R" group wherein each R', R" and R'" group is the same or different and represents hydrogen or Ci_-4 alkyl, or represents a group of formula -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -SO₂NHR^A, -C0NR^AR^B, -SO₂NR^AR^B, -OCONH₂, -0C0NHR^A, -OCONR^AR^B, -NHCOR^A, NHCOOR^A, -NR^BCOOR^A, -NHSO₂R^A, -NR^BSO₂R^A, -NHSO₂OR^A, -NR⁸SO₂OH, -NR^BSO₂OR^A, -NHCONH₂, -NR^ACONH₂, -NHCONHR⁸, -NR^AC0NHR^B, -NHC0NR^AR^B or -NR^AC0NR^AR^B wherein R^A and R^B are the same or different and represent C_1-6 alkyl, C_3-6 cycloalkyl, non-fused phenyl or a non-fused 5- to 6-membered heteroaryl, or R^A and R^B when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group; R² represents a hydrogen or halogen atom, or a cyano, nitro, -N₃, Ci_-6 alkyl, Ci_-6 alkenyl, C_2-6 alkynyl group, or a group of formula -NR'R", -CO₂R', -SO₂R', -NR'OR" or -CONR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-4 alkyl, or a C_6-10 aryl, 5- to 10- membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; x and y are the same or different and represent zero or 1 ; L¹ represents C_M alkylene; Het represents -S-, -S(O)-, -S(O)₂-, -NR'- or -O- where R' represents hydrogen or unsubstituted Ci_-4 alkyl;

A represents a C_6-Io aryl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group which is optionally fused to a further C_6-I0 aryl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group;

W is a group of formula -[CH₂]_Z-Y¹ -L² -R, wherein: z is 0 or 1 ;

Y¹ represents a bond or a group of formula -S-, -O-, -(C=O)-, -(S=O)-, -S(O₂)-, -NR³-, -(C=O)NR³-, -NR³(C=0)-, -S(O₂)NR³-, -NR³S(O₂)-, -NR³(C=O)NR⁴- or -NR³(C=S)NR⁴-, wherein R³ and R⁴ are the same or different and represent hydrogen or Ci_-6 alkyl; L² is a divalent radical of formula -(Alk¹)_m(Q)_n(Alk²)_p- wherein: m, n and p are independently O or 1 ;

Q either (i) represents a phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-metnbered heterocyclyl group; or (ii) in the case where p is 0, represents a group of formula -Q¹Ot¹- wherein X¹ represents -O-, -S- or -NR⁵- wherein R⁵ is hydrogen or C_1-4 alkyl, and Q¹ represents a phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; AIk¹ and AIk² are the same or different and represent C_3-7 carbocyclyl groups, or represent Ci_-6 alkylene, C_2-6 alkenylene, or C_2-6 alkynylene groups which may optionally contain or terminate in an ether (-O-), thioether (-S-) or amino (-NR⁶-) link wherein R⁶ represents hydrogen or C_M alkyl; R is a radical of formula (X):

wherein:

R⁷ is a group -COOH or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a -COOH group; - R⁸ represents hydrogen or a C_1-6 alkyl, -(C=O)R⁹, -(C=O)OR¹⁰ or

-(C=O)NR¹⁰ group wherein R⁹ represents hydrogen, a Ci_-6 alkyl group, a phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, or R⁹ represents a group of formula

-Alk⁴-Cyc wherein AIk⁴ represents a C_1-6 alkylene group and Cyc represents a phenyl, 5- to 10-membered heteroaryl or 5- to 10- membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, and R¹⁰ represents hydrogen or Ci_-6 alkyl, or wherein R⁸ represents a phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; and

R¹⁹ represents a Ci_-6 alkyl group or a group -L³ -B where L³ represents a bond or a Ci_-6 alkylene and B represents a C_6-10 aryl or 5- to 10-membered heteroaryl group; wherein the alkyl, alkylene, alkenyl and alkynyl moieties in R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹⁹, AIk¹, AIk² and AIk³ are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C_2-4 alkenyloxy, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C_M hydroxyalkyl, C_2-4 hydroxyalkenyl, C_1-4 alkylthio, C_2-4 alkenylthio, phenyl, -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl, and groups of formula -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂,

-CONHR^A, -S0₂NHR^A, -C0NR^AR^B, -SO₂NR^AR^B, -OCONH₂, -0C0NHR^A, -0C0NR^AR^B, -NHCOR^A, NHCOOR^A, -NR^BCOOR^A, -NHS0₂0R^A, -NR⁸SO₂OH, -NR^BS0₂0R^A, -NHCONH₂, -NHC(NH)NH₂, -NHC(NH)NHR⁸, -NHC(NH)NR^AR^B, -NR^AC0NH₂, -NHCONHR⁸, -NR^AC0NHR^B, -NHC0NR^AR⁸ or -NR^ACONR^AR^B wherein R^A and R⁸ are the same or different and represent Ci_-6 alkyl, C_3-6 cycloalkyl, phenyl or a non-fused 5- to 6-membered heteroaryl, or R^A and R⁸ when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group; and - the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R¹, R², R⁸,

R⁹, R¹⁹, A, B, Q, Q¹ and D are unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_1-4 alkylene, C_2-4 alkenyl, C_1-4 alkoxy, C₂^ alkenyloxy, C 1-4 haloalkyl, C₂^ haloalkenyl, C_1-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C_1-4 hydroxyalkyl, C_2-4 hydroxyalkenyl, Ci_-4 alkylthio, C_2-4 alkenylthio, -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_M alkyl, and groups of formula -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -CONHR^A, -S0₂NHR^A, -CONR^AR^B, -SO₂NR^AR^B, -OCONH₂, -OCONHR^A, -OCONR^AR^B, -NHC0R^A, NHC00R^A, -NR^BC00R^A, -NHSO₂OR^A, -NR³SO₂OH, -NR^BSO₂OR^A, -NHCONH₂, -NR^AC0NH₂,

-NHCONHR^B, -NR^ACONHR^B, -NHCONR^AR^B or -NR^ACONR^AR^B wherein R^A and R^B are the same or different and represent Ci_-6 alkyl, C_3-6 cycloalkyl, phenyl or a non-fused 5- to 6-membered heteroaryl, or R^A and R^B when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group.

The compounds of the invention are characterised by the presence in the molecule of an amino acid motif or an amino acid ester motif which is hydrolysable by an intracellular carboxylesterase. Compounds of the invention can cross the cell membrane, and, if in the ester form, can be hydrolysed to the acid by the intracellular carboxylesterases. The polar hydrolysis product accumulates in the cell since it does not readily cross the cell membrane. Hence the HSP90 activity of the compound is prolonged and enhanced within the cell.

Preferably the compounds of the invention are compounds of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In another broad aspect the invention provides the use of a compound as defined above in the manufacture of a medicament for inhibiting the activity of HSP90. More preferably, the invention provides the use of a compound as defined above in the manufacture of a medicament for use in treating a disorder mediated by HSP90.

The compounds with which the invention is concerned may be used for the inhibition of HSP90 activity ex vivo or in vivo. In one aspect of the invention, the compounds of the invention may be used in the preparation of a composition for treatment of cancer, inflammatory and immune disorders such as rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, and disorders related to angiogenesis age related macular degeneration, diabetic retinopathy and endometriosis. The compounds may also be of use in the protection of normal cells against the action of cytotoxic agents.

In another aspect, the invention provides a method for the treatment of the foregoing disease types, which comprises administering to a subject suffering such disease an effective amount of a compound as defined above.

DETAILED DESCRIPTION QF THE INVENTION

Although the above definitions potentially include molecules of high molecular weight, it is preferable, in line with general principles of medicinal chemistry practice, that the compounds with which this invention is concerned should have molecular weights of no more than 600.

The alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene moieties in R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹⁹, AIk¹, AIk² and AIk³ are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_M alkyl, C₂-4 alkenyl, C_M alkoxy, C₂^ alkenyloxy, CM haloalkyl, C_2-4 haloalkenyl, C_M haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C_M hydroxyalkyl, C₂^ hydroxyalkenyl, C_M alkylthio, C₂_4 alkenylthio, -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or CM alkyl, and from groups of formula -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -CONHR^A, -SO₂NHR^A, -C0NR^AR^B, -SO₂NR^AR^B, -OCONH₂, -OCONHR^A, -OCONR^AR^B, -NHCOR^A, NHCOOR^A, -NR^BCOOR^A, -NHSO₂OR^A, -NR⁸SO₂OH, -NR^BSO₂OR^A, -NHCONH₂, -NR^AC0NH₂, -NHC(NH)NH₂, -NHC(NH)NHR⁸, -NHC(NH)NR^AR^B, -NHCONHR⁸, -NR^AC0NHR^B, -NHC0NR^AR⁸ and -NR^ACONR^AR^B wherein R^A and R^B are the same or different and represent Ci_-6 alkyl, non-fused C_3-O cycloalkyl, non-fused phenyl or non-fused 5- to 6- membered heteroaryl, or R^A and R^B when attached to the same nitrogen atom form a non- fused 5- or 6-membered heterocyclyl group. Unless otherwise specified, the substituents described above are preferably themselves unsubstituted.

Preferred substituents include halogen atoms and C_1-4 alkyl, C_2^t alkenyl, C_M alkoxy, C_2-4 alkenyloxy, C_M haloalkyl, C_2-4 haloalkenyl, C_M haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C_M hydroxyalkyl, C_2-4 hydroxyalkenyl, C_M alkylthio, C_2-4 alkenylthio, and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_M alkyl.

More preferred substituents include halogen, C_1-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, hydroxyl, C_M haloalkyl, C_2-4 haloalkenyl, C_1-4 haloalkyloxy, C_2-4 haloalkenyloxy and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C_1-2 alkyl. More preferred substituents are halogen, C_1-2 alkoxy, C_1-2 haloalkyl, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C_1-2 alkyl. In particular, it is preferred that R' and R" are unsubstituted.

When the alkyl, alkylene, alkenylene and alkynylene moieties are substituted by two or three substituents, it is preferred that not more than two substituents are selected from cyano and nitro. More preferably, not more than one substituent is selected from cyano and nitro. Furthermore, when the alkyl, alkylene, alkenylene and alkynylene moieties are substituted by two or three substituents, it is preferred that not more than one substituent is selected from -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -CONHR^A, -SO₂NHR^A, -CONR^AR^B, -SO₂NR^AR^B, -OCONH₂, -OCONHR^A, -OCONR^AR^B, -NHCOR^A, NHCOOR^A, -NR^BCOOR^A, -NHSO₂OR^A, -NR^BSO₂OH, -NR^BSO₂OR^A, -NHCONH₂, -NHC(NH)NH₂, -NHC(NH)NHR³, -NHC(NH)NR^AR^B, -NR^AC0NH₂, -NHCONHR^B, -NR^AC0NHR^B, -NHCONR^AR^B and -NR^AC0NR^AR^B.

As used herein, a C_1-6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, for example a C_M alkyl group or moiety containing from 1 to 4 carbon atoms. Examples Of Ci_-4 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. For the avoidance of doubt, where two alkyl moieties are present in a group, the alkyl moieties may be the same or different.

As used herein, a C_2-6 alkenyl group or moiety is a linear or branched alkenyl group or moiety one having at least one double bond of either E or Z stereochemistry where applicable and containing from 2 to 6 carbon atoms, for example a C_2-4 alkenyl group or moiety containing from 2 to 4 carbon atoms, such as -CH=CH₂ or -CH₂-CH=CH₂, -CH₂-CH₂-CH=CH₂, -CH₂-CH=CH-CH₃ , -CH=C(CH₃)-CH₃ and -CH₂-C(CH₃)=CH₂. For the avoidance of doubt, where two alkenyl moieties are present in a group, they may be the same or different. As used herein, a C_2-6 alkynyl group or moiety is a linear or branched alkynyl group or moiety containing from 2 to 6 carbon atoms, for example a C_2-4 alkynyl group or moiety containing from 2 to 4 carbon atoms. Exemplary alkynyl groups include -C≡CH or -CH₂-C=CH, as well as 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, A- pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. For the avoidance of doubt, where two alkynyl moieties are present in a group, they may be the same or different.

As used herein, a Ci_-6 alkylene group or moiety is a linear or branched alkylene group or moiety, for example a C_M alkylene group or moiety. Examples include methylene, n-ethylene, n-propylene and -C(CH₃)₂- groups and moieties.

As used herein, a C_2-6 alkenylene group or moiety is a linear or branched alkenylene group or moiety, for example a C_2-4 alkenylene group or moiety. Examples include -CH=CH-, -CH=CH-CH₂-, -CH₂-CH=CH- and -CH=CH-CH=CH-.

As used herein, a C_2-6 alkynylene group or moiety is a linear or branched alkynylene group or moiety, for example a C_2-4 alkynylene group or moiety. Examples include -C≡C-, -C=C-CH₂- and -CH₂-C≡C-. As used herein, a halogen atom is typically chlorine, fluorine, bromine or iodine.

As used herein, a C_1-6 alkoxy group or C₂^ alkenyloxy group is typically a said C_1-6 alkyl (e.g. a C_1-4 alkyl) group or a said C_2-6 alkenyl (e.g. a C_2-4 alkenyl) group respectively which is attached to an oxygen atom.

A haloalkyl, haloalkenyl, haloalkoxy or haloalkenyloxy group is typically a said alkyl, alkenyl, alkoxy or alkenyloxy group respectively which is substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX₃ and -OCX₃ wherein X is a said halogen atom, for example chlorine and fluorine.

As used herein, a Ci_-4 alkylthio or C_2-4 alkenylthio group is typically a said C_M alkyl group or a C_2-4 alkenyl group respectively which is attached to a sulphur atom, for example -S-CH₃. As used herein, a Ci_-4 hydroxyalkyl group is a Ci_-4 alkyl group substituted by one or more hydroxy groups. Typically, it is substituted by one, two or three hydroxy groups. Preferably, it is substituted by a single hydroxy group.

When a phenyl ring is fused to a further phenyl, 5- to 10-membered heterocyclyl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group, it is preferably fused to a further phenyl, 5- to 6-membered heterocyclyl, C_3-7 carbocyclyl or 5- to 6-membered heterocyclyl group, more preferably to a 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl group. Most preferably it is fused to a 5- to 6-membered heterocyclyl group, hi this case, preferred 5- to 6-membered heterocyclyl groups include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, dithiolanyl, dioxolanyl, oxazolidinyl, imidazolyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, thioxolanyl, thiazolidinyl and isothiazolidinyl, more preferably oxazolidinyl, imidazolidinyl, thiazolidinyl, thioxolanyl, dioxolanyl and dithiolanyl, most preferably dioxolanyl.

As used herein, a 5- to 10- membered heteroaryl group or moiety is a monocyclic 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom, for example 1, 2, 3 or 4 heteroatoms, selected from O, S and N. When the ring contains 4 heteroatoms these are preferably all nitrogen atoms. Examples include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazolyl groups. Thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl groups are preferred, e.g. pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. More preferred groups are imidazolyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl and triazinyl, e.g. imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl and triazinyl. A particularly preferred group is imidazolyl.

When a heteroaryl group or moiety is fused to another group, it may be fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C_3-7 carbocyclyl group. Preferably it is preferably fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring, more preferably it is fused to a phenyl group. Examples include benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benztriazolyl, indolyl, isoindolyl and indazolyl groups. Preferred groups include indolyl, isoindolyl, benzimidazolyl, indazolyl, benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and benzisothiazolyl groups, more preferably indolyl, benzimidazolyl, benzoxazolyl and benzothiazolyl, more preferably indolyl and benzothiazolyl, most preferably indolyl. As used herein, a 5- to 10- membered heterocyclyl group or moiety is a non- aromatic, saturated or unsaturated C_5-io carbocyclic ring in which one or more, for example 1, 2, 3 or 4, of the carbon atoms are replaced with a moiety selected from N, O, S, S(O) and S(O)₂, and wherein one or more of the remaining carbon atoms is optionally replaced by a group -C(O)- or -C(S)-. When one or more of the remaining carbon atoms is replaced by a group -C(O)- or -C(S)-, preferably only one or two (more preferably two) such carbon atoms are replaced. Typically, the 5- to 10- membered heterocyclyl ring is a 5- to 6- membered ring. Suitable heterocyclyl groups and moieties include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, methylenedioxyphenyl, ethylenedioxyphenyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S,S-dioxo-thiomorpholinyl, morpholinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, trioxolanyl, trithianyl, imidazolinyl, pyranyl, pyrazolinyl, thioxolanyl, thioxothiazolidinyl, lH-pyrazol- 5-(4H)-onyl, l,3,4-thiadiazol-2(3H)-thionyl, oxopyrrolidinyl, oxothiazolidinyl, oxopyrazolidinyl, succinimido and maleimido groups and moieties. Preferred heterocyclyl groups are pyrrolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, thiomorpholinyl and morpholinyl groups and moieties. More preferred heterocyclyl groups are tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl and pyrrolidinyl groups, and variants where one or two ring carbon atoms are replaced with -C(O)- groups. Particularly preferred groups include tetrahydrofuranyl and pyrrolyl-2,5- dione.

When a heterocyclyl group or moiety is fused to another group, it may be fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C_3-7 carbocyclyl group, more preferably to a further phenyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl group. Preferably it is monocyclic (i.e. it is unfused).

For the avoidance of doubt, although the above definitions of heteroaryl and heterocyclyl groups refer to an "N" moiety which can be present in the ring, as will be evident to a skilled chemist the N atom will be protonated (or will carry a substituent as defined below) if it is attached to each of the adjacent ring atoms via a single bond.

As used herein, a C_3-7 carbocyclic group or moiety is a non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 7 carbon atoms. Preferably it is a saturated or mono-unsaturated hydrocarbon ring (i.e. a cycloalkyl moiety or a cycloalkenyl moiety) having from 3 to 7 carbon atoms, more preferably having from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and their mono- unsaturated variants, more particularly cyclopentyl and cyclohexyl. A C_3-7 carbocyclyl group or moiety also includes C_3-7 carbocyclyl groups or moieties described above but wherein one or more ring carbon atoms are replaced by a group -C(O)-. More preferably one or two ring carbon atoms (most preferably two) are replaced by -C(O)-. A preferred such group is benzoquinone.

When a carbocyclyl group or moiety is fused to another group, it may be fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C_3-7 carbocyclyl group, more preferably to a further phenyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl ring. For example it may be fused to a further phenyl ring. An exemplary fused carbocyclyl group is indanyl. More preferably carbocyclyl groups are monocyclic (i.e. non-fused).

Unless otherwise stated, the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R¹, R², R⁸, R⁹, R¹⁹, A, B, Q, Q¹ and D are unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_1-4 alkylene, C_2-4 alkenyl, C_M alkoxy, C_2-4 alkenyloxy, C_1-4 haloalkyl, C_2-4 haloalkenyl, C_1-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Ci_-4 hydroxyalkyl, C_2-4 hydroxyalkenyl, C_M alkylthio, C_2-4 alkenylthio, -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl, and groups of formula -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -S0₂NHR^A, -CONR^AR^B, -S0₂NR^AR^B, -OCONH₂, -0C0NHR^A, -0C0NR^AR^B, -NHC0R^A, NHC00R^A, -NR^BC00R^A, -NHS0₂0R^A, -NR¹³SO₂OH, -NR^BS0₂0R^A, -NHCONH₂, -NHC(NH)NH₂, -NHC(NH)NHR³, -NHC(NH)NR^AR^B, -NR^ACONH₂, -NHC0NHR^B, -NR^AC0NHR^B, -NHC0NR^AR^B and -NR^AC0NR^AR^B wherein R^A and R^B are the same or different and represent C_1-6 alkyl, non-fused C_3-6 cycloalkyl, non-fused phenyl or non-fused 5- to 6-membered heteroaryl, or R^A and R^B when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group. Unless otherwise stated, the substituents are preferably themselves unsubstituted, in particular it is preferred that R^A and R^B are unsubstituted.

When the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties are substituted by two, three or four substituents, it is preferred that not more than two substituents are selected from C_1-4 alkylene, cyano and nitro. More preferably, not more than one substituent is selected from C_1-4 alkylene, cyano and nitro. Furthermore, when the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties are substituted by two or three substituents, it is preferred that not more than one substituent is selected from -COOH, -C00R^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -CONHR^A, -SO₂NHR^A, -CONR^AR^B, -SO₂NRV³, -OCONH₂, -OCONHR^A, -0C0NR^AR^B, -NHCOR^A, NHCOOR^A,

-NR^BC00R^A, -NHS0₂0R^A, -NR³SO₂OH, -NR^BSO₂OR^A, -NHCONH₂, -NHC(NH)NH₂, -NHC(NH)NHR³, τNHC(NH)NR^AR³, -NR^AC0NH₂, -NHCONHR³, -NR^AC0NHR^B, -NHC0NR^AR^B or -NR^ACONR^AR³.

Typically the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R¹, R², R⁸, R⁹, R¹⁹, A, B, Q, Q¹ and D are unsubstituted or substituted by 1, 2, 3 or 4 substituents, for example by 1, 2 or 3 substituents. Preferred substituents include halogen atoms and Ci_-4 alkyl, C₂^ alkenyl, C_1-4 alkoxy, C_2-4 alkenyloxy, C_1-4 haloalkyl, C_2-4 haloalkenyl, C_1-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C_M hydroxyalkyl, C_2-4 hydroxyalkenyl, C_1-4 alkylthio, C_2-4 alkenylthio and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and groups of formula COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -SO₂NHR^A, -C0NR^AR^B and -SO₂NR^AR³ wherein R^A and R^B are the same or different and represent Ci_-4 alkyl. Preferably the substituents are themselves unsubstituted.

More preferred substituents on the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R¹, R², R⁸, R⁹, R¹⁹, A, B, Q, Q¹ and D include halogen atoms and Cj_-4 alkyl, Q- 4 alkoxy, Ci_-4 alkylthio, C_M haloalkyl, hydroxyl, cyano, nitro and -NR 'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_M alkyl, and groups of formula COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -SO₂NHR^A, -C0NR^AR^B and -SO₂NR^AR^B wherein R^A and R^B are the same or different and represent C_1-2 alkyl. More preferred substituents include halogen atoms and C_1-4 alkyl, C_1-4 alkoxy, Ci_-4 alkylthio and hydroxyl groups. More preferred substituents include halogen atoms, C_1-4 alkyl, Ci_-2 alkoxy, Ci_-2 alkylthio and hydroxy.

As used herein the term "salt" includes base addition, acid addition and quaternary salts. Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like. Those compounds (I) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesulfonic, glutamic, lactic, and mandelic acids and the like.

Compounds of the invention which contain one or more actual or potential chiral centres, because of the presence of asymmetric carbon atoms, can exist as a number of diastereoisomers with R or S stereochemistry at each chiral centre. The invention includes all such diastereoisomers and mixtures thereof.

The term "ester" or "esterifϊed carboxyl group" in connection with substituent R⁷ above means a group -(C=O)OR¹¹ in which R¹ ' is the group characterising the ester, notionally derived from the alcohol R¹ '-OH. Group R¹

Preferably R¹ represents a hydrogen or halogen atom, or an unsubstituted Ci_-4 alkyl, hydroxyl, C_1-4 alkoxy, -SR', Ci_-4 alkylthio, -NR'R" or -CONR^AR^B group where R', R", R^A and R^B are the same or different and represent hydrogen or unsubstituted Ci_-4 alkyl group. More preferably R¹ represents a halogen atom (preferably chlorine) or an unsubstituted Ci_-4 alkyl or -NR'R" group wherein R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl. More preferably still, R¹ represents an -NR'R" group wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl. Most preferably R¹ represents -NH₂. It is preferred that the alkyl groups and moieties in R¹ are unsubstituted or substituted by 1, 2 or 3 substituents which are themselves unsubstituted and are selected from halogen, C_M alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, hydroxyl, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkyloxy, C_2-4 haloalkenyloxy and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl. More preferably, the alkyl groups and moieties in R¹ are unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci_-2 alkoxy, Ci_-2 haloalkyl, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C_1-2 alkyl. hi particular, it is preferred that R' and R" are unsubstituted. More preferably, the alkyl groups and moieties in R¹ are unsubstituted.

Group R²

Preferably R² represents a hydrogen or halogen atom, an unsubstituted Ci_-4 alkyl group or a group of formula -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl. More preferably R² represents a hydrogen or halogen atom (preferably fluorine or chlorine) or an -NH₂ group. Most preferably R² represents a hydrogen atom.

Group -(L¹ VfHety x and y are the same or different and represent zero or 1. When x is zero, L¹ is absent, and when y is 1, Het is absent. Preferably at least one of x and y is 1. More preferably only one of x and y is 1. hi a most preferred embodiment, x is zero and y is 1. When present, L¹ preferably represents unsubstituted C_M alkylene, more preferably unsubstituted C_1-2 alkylene, most preferably -CH₂-.

When present, Het preferably represents -S-, -S(O)- or -S(O)₂-. More preferably, Het represents -S- or -S(O)-. Most preferably Het represents -S-.

Group A

Preferably A represents an unsubstituted or substituted phenyl, 5- to 6-membered heteroaryl, C_3-7 carbocyclyl or 5- to 6-membered heterocyclyl group which is optionally fused to a further phenyl, 5- to 6-membered heteroaryl, C_3-7 carbocyclyl or 5- to 6- membered heterocyclyl group. More preferably A represents an unsubstituted or substituted phenyl, 5- to 6-membered heteroaryl, C_3-7 carbocyclyl or 5- to 6-membered heterocyclyl group which is optionally fused to a further phenyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl group. More preferably A represents an unsubstituted or substituted non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non- fused C_3-7 carbocyclyl, non-fused 5- to 6-membered heterocyclyl group, a phenyl group which is fused to a further 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group which is fused to a further phenyl group.

When A represents a phenyl group which is fused to a further 5- to 6-membered heterocyclyl group, preferred 5- to 6-membered heterocyclyl groups include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, dithiolanyl, dioxolanyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, thioxolanyl, thiazolidinyl and isothiazolidinyl, more preferably oxazolidinyl, imidazolidinyl, thiazolidinyl, thioxolanyl, dioxolanyl and dithiolanyl, most preferably dioxolanyl.

When A represents a non-fused 5- to 6-membered heteroaryl group, preferred groups include pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

When A is a 5- to 6-membered heteroaryl group fused to a phenyl group, preferred groups include indolyl, isoindolyl, benzimidazolyl, indazolyl, benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, more preferably benzimidazolyl, benzoxazolyl or benzothiazolyl, most preferably benzothiazolyl. When A represents a non-fused 5- to 6-membered heterocyclyl group, suitable groups include 5- to 6-membered heterocyclyl groups where 1, 2, 3 or 4, of the carbon atoms are replaced with a moiety selected from N, O, S, S(O) and S(O)₂, and wherein one or more of the remaining carbon atoms is optionally replaced by a group -C(O)- or -C(S)-. When one or more of the remaining carbon atoms is replaced by a group -C(O)- or -C(S)-, preferably only one or two (more preferably two) such carbon atoms are replaced. More preferably two of the carbon atoms of the heterocyclyl group are replaced by -C(O)- groups. Thus, suitable 5- to 6-membered heterocyclyl groups include tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl and thiomorpholinyl, and variants where one or two of the ring carbon atoms are replaced with -C(O)- groups. Particularly preferred 5- to 6-membered heterocyclyl groups include tetrahydrofuranyl and pyrrolyl-2,5-dione.

When A is a non-fused C_3-7 carbocyclyl group, preferred groups include C_3-7 carbocyclyl groups wherein one or two ring carbon atoms are replaced by -C(O)- or -S(O)-, more preferably wherein two ring carbon atoms are replaced by -C(O)-. More preferably, when A is a non-fused C_3-7 carbocyclyl group it is a benzoquinone group.

In a most preferred embodiment, A represents an unsubstituted or substituted phenyl ring, wherein the phenyl ring is optionally fused to a further phenyl, 5- to 6- membered heteroaryl or 5- to 6-membered heterocyclyl group. When A is fused, it is preferably fused to a further 5- to 6-membered heterocyclyl group, more preferably to an imidazolidinyl, thiazolidinyl, thioxolanyl, dioxolanyl or dithiolanyl group, most preferably to a dioxolanyl group. Preferably A represents an unsubstituted or substituted phenyl ring.

Preferably group A is unsubstituted or substituted by 1, 2, 3 or 4 substituents which are themselves unsubstituted, which are the same or different, and which are selected from halogen atoms and C_1-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C₂^ alkenyloxy, C_M haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Ci_-4 hydroxyalkyl, C_2-4 hydroxyalkenyl, Ci_-4 alkylthio, C_2-4 alkenylthio and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and groups of formula COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -S0₂NHR^A, -C0NR^AR^B and -S0₂NR^AR^B wherein R^A and R^B are the same or different and represent Ci_-4 alkyl. More preferred substituents on group A include 1, 2, 3 or 4 unsubstituted substituents which are the same or different and represent halogen atoms and C_1-4 alkyl, C_M alkoxy, C_M alkylthio, Ci_-4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_M alkyl. Even more preferred substituents include halogen atoms, C_M alkyl, C_1-2 alkoxy, Ci_-2 alkylthio and hydroxy. Preferred halogen substituents include fluorine, chlorine, bromine and iodine atoms, most preferably iodine atoms. Preferred C_1-2 alkoxy substituents include methoxy groups. Preferred C_1-4 alkyl substituents include methyl, ethyl and propyl, more preferably ethyl and propyl. Preferred Ci_-2 alkylthio substituents include -S-CH₃. In a most preferred embodiment, group A is substituted by a single halogen atom (preferably a fluorine or bromine atom, more preferably a bromine atom) and a C_1-2 alkoxy group (preferably a methoxy group).

Group W

W is a group of formula -[CH₂]_Z-Y¹-L²-R. The group W contains the alpha amino acid or alpha amino acid ester moiety of formula (X) linked through a linker radical to ring A. Where W terminates in an ester group, the compounds of the invention are converted by intracellular esterases to the corresponding carboxylic acid. Both the esters and carboxylic acids may have HSP90 inhibitory activity in their own right. The compounds of the invention therefore include not only the ester, but also the corresponding carboxylic acid hydrolysis products.

Group R

The group R is represented by formula (X):

Group R⁷

R⁷ is either a carboxylic acid group -COOH or an ester group -COOR¹¹. Where R⁷ is an ester group, it must be one which in the compound of the invention is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group. Intracellular carboxylesterase enzymes capable of hydrolysing the ester group of a compound of the invention to the corresponding acid include the three known human enzyme isotypes hCE-1, hCE-2 and hCE-3. Although these are considered to be the main enzymes other enzymes such as biphenylhydrolase (BPH) may also have a role in hydrolysing the conjugates. In general, if the carboxylesterase hydrolyses the free amino acid ester to the parent acid it will also hydrolyse the ester motif when covalently conjugated to the modulator. Hence, the study of hydrolysis rates by recombinant human carboxylesterases and the broken cell assay described later provides a straightforward, quick and simple first screens for esters which have the required hydrolysis profile. Ester motifs selected in that way may then be re-assayed in the same carboxylesterase assays when conjugated to the HSP90 inhibitor via the chosen conjugation chemistry, to confirm that it is still a carboxylesterase substrate in that background. A quantitative measure of the amount of intracellular parent amino acid produced by hydrolysis of esters is provided by the cellular accumulation assay described later.

Subject to the requirement that they be hydrolysable by intracellular carboxylesterase enzymes, examples of particular ester groups R⁷ include those of formula -(C=O)OR¹¹ wherein R¹¹ is -CR¹²R¹³R¹⁴ wherein:

(i) R¹³ represents hydrogen or a group of formula -[C_1-4 alkylene]_b-(Z¹)_a-[C_1-4 alkyl] or -[Ci_-4 alkylene]b-(Z¹)_a-[C_2-4 alkenyl] wherein a and b are the same or different and represent 0 or 1, and Z¹ represents -O-, -S-, or -NR¹⁷- wherein R¹⁷ is hydrogen or Ci_-4 alkyl, R¹⁴ represents hydrogen or Ci_-4 alkyl, and R¹² represents hydrogen or Ci_-4 alkyl;

(ii) R¹³ represents a phenyl or a 5- to 10-membered heteroaryl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group, R¹⁴ represents hydrogen or C_M alkyl, and R¹² represents hydrogen; (iii) R¹³ represents a group of formula -(Alk³)-NR¹⁵R¹⁶ wherein AIk³ represents a C_M alkylene group and either (a) R¹⁵ and R¹⁶ are the same or different and represent hydrogen or C_M alkyl, or (b) R¹⁵ and R¹⁶, together with the nitrogen atom to which they are bonded, form a 5- to 10- membered heteroaryl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; R¹⁴ represents hydrogen or C_1-4 alkyl, and R¹² represents hydrogen; or (iv) R¹³ and R¹⁴, together with the carbon atom to which they are bonded, form a phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group which is optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, and R¹² represents hydrogen. Preferred substituents on the alkyl, alkylene and alkenyl groups in R¹², R¹³, R¹⁴, R¹⁵,

R¹⁶, R¹⁷ and AIk³ groups include one or two substituents which are the same or different and are selected from halogen, CM alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, hydroxyl and -NR 'R" wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl. More preferred substituents are halogen, C_1-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C_1-2 alkyl. Most preferably the alkyl, alkylene and alkenyl groups in R¹³, R¹⁴ and AIk³ are unsubstituted.

Preferred substituents on the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R¹³, R¹⁴, R¹⁵ and R¹⁶ groups include one or two substituents which are the same or different and are selected from halogen atoms and Cj_-4 alkyl, C_1-4 alkylene, Ci_-4 alkoxy, Ci_-4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, more preferably halogen atoms and Ci_-2 alkyl, Ci_-2 alkylene, Ci_-2 alkoxy and hydroxyl groups. More preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R¹³, R¹⁴, R¹⁵ and R¹⁶ are unsubstituted or substituted by a Ci_-2 alkylene group, in particular a methylene group. Most preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R¹³, R¹⁴, R¹⁵, R¹⁶ are unsubstituted.

When R¹³ represents a group of formula -[C_M alkylene]_b-(Z¹)_a-[Ci_-4 alkyl], preferably either a or b is zero, for example both a and b are zero. When [Ci_-4 alkylene] is present, it is preferably a Ci_-3 alkylene, more preferably a Ci_-2 alkylene such as a group -CH₂-CH₂-. When R¹³ represents a group of formula -[CM alkylene]b-(Z')_a-[Cι-4 alkyl], preferably C_M alkyl is a Ci_-3 alkyl group such as methyl, ethyl or n-propyl, most preferably methyl.

When R¹³ represents a group of formula -[C_M

alkyl] and a is 1, Z¹ is preferably -O- or -NR¹⁷- wherein R¹⁷ is hydrogen or C_1-2 alkyl, more preferably Z¹ is -O-.

When R¹³ represents a group of formula -[C_1-4 alkylene]_b-(Z¹)_a-[C₂.₄ alkenyl], preferably either a or b is zero, more preferably both a and b are zero. When [C_M alkylene] is present, it is preferably a C_1-3 alkylene, more preferably a Ci_-2 alkylene. When R¹³ represents a group of formula -[CM alkylene]b-(Z¹)_a-[C_2-4 alkenyl], preferably C_2-4 alkenyl is a C_2-3 alkenyl group, in particular -CH=CH₂.

When R¹³ represents a group of formula -[C_M alkylene]_b-(Z ¹^-[Ci_-4 alkenyl] and a is 1, Z¹ is preferably -O- or -NR¹⁷- wherein R¹⁷ is hydrogen or Ci_-2 alkyl, more preferably Z¹ is -O-. Most preferably Z¹ is absent (i.e. a is zero). When R¹³ represents hydrogen or a group of formula -[Ci_-4

alkyl] or -[C_M alkylene]_b-(Z¹)_a-[C_2-4 alkenyl], preferably R¹³ represents hydrogen or a C_M alkyl or C_2-4 alkenyl group, or a group -(C_M alkyl)-0-(CM alkyl). More preferably R¹³ represents hydrogen, methyl, ethyl, n-propyl, -CH=CH₂ or -CH₂-CH₂-O-CH₃, most preferably methyl. When R¹³ represents hydrogen or a group of formula -[CM alkylene]b-(Z¹)_a-[CM alkyl] or -[C_M alkylene]_b-(Z¹)_a-[C_2-4 alkenyl], preferably R¹⁴ represents hydrogen or Ci_-2 alkyl, more preferably hydrogen or methyl, most preferably hydrogen.

When R¹³ represents hydrogen or a group of formula -[Ci_-4 alkylene]b-(Z¹)_a-[CM alkyl] or -[C_M alkylene]_b-(Z¹)_a-[C_2-4 alkenyl], preferably R¹² represents hydrogen or Ci_-2 alkyl, more preferably R¹² represents hydrogen or methyl, most preferably hydrogen.

When R¹³ represents hydrogen or a group of formula -[Ci_-4 alkylene]b-(Z¹)_a-[Ci_-4 alkyl] or -[C_M alkylene]_b-(Z¹)_a-[C_2-4 alkenyl], preferably the alkyl, alkylene and alkenyl groups in both R¹³ and R¹⁴ are unsubstituted.

When R¹³ represents a phenyl or a 5- to 10-membered heteroaryl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, preferably it represents a non-fused phenyl or a non-fused 5- to 6-membered heteroaryl group. Preferred heteroaryl groups include pyridyl, pyrrolyl, isothiazolyl, pyrazolyl and isoxazolyl, most preferably pyridyl.

When R¹³ represents a phenyl or a 5- to 10-membered heteroaryl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in R¹³ are unsubstituted .

When R¹³ represents a phenyl or a 5- to 10-membered heteroaryl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, R¹⁴ preferably represents hydrogen or C_1-4 alkyl, more preferably hydrogen or C_1-2 alkyl, most preferably hydrogen. Preferably the C_1-4 alkyl groups of R¹⁴ are unsubstituted.

When R¹³ represents a group of formula -(Alk³)-NR¹⁵R¹⁶, AIk³ preferably represents a C_1-2 alkylene group, preferably either -CH₂- or -CH₂CH₂-.

When R¹³ represents a group of formula -(Alk^-NR¹⁵R¹⁶ and R¹⁵ and R¹⁶ are the same or different and represent hydrogen or C_1-4 alkyl, preferably R¹⁵ represents hydrogen or C_1-2 alkyl, more preferably R¹⁵ represents a methyl group. When R¹³ represents a group of formula -(Alk³)-NR¹⁵R¹⁶ and R¹⁵ and R¹⁶ are the same or different and represent hydrogen or C₁^ alkyl, preferably R¹⁶ represents hydrogen or C_1-2 alkyl, more preferably R¹⁶ represents a methyl group. When R¹³ represents a group of formula -(Alk³)-NR^l5R¹⁶ and R¹⁵ and R¹⁶, together with the nitrogen atom to which they are bonded, form a 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10- membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group, preferably they form a non-fused 5- to 6-membered heteroaryl or non-fused 5- to 6- membered heterocyclyl group. More preferably they form a 5- to 6-membered heterocyclyl group. Preferred heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl, most preferably morpholinyl.

When R¹³ represents a group of formula -(Alk³)-NR¹⁵R¹⁶, AIk³ preferably represents a C_1-2 alkylene group, more preferably a group -CH₂CH₂-. When R¹³ represents a group of formula -(Alk³)-NR¹⁵R¹⁶, R¹⁴ preferably represents hydrogen or Ci_-2 alkyl, most preferably hydrogen. When R¹³ represents a group of formula -(Alk³)-NR^I5R¹⁶, preferably the alkyl and alkylene groups in AIk³, R¹⁵ and R¹⁶ are unsubstituted. When R¹³ represents a group of formula -(Alk³)-NR¹⁵R¹⁶, preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in R¹⁵ and R¹⁶ are unsubstituted. When R¹³ represents a group of formula -(Alk³)-NR¹⁵R¹⁶, preferred groups include

-CH₂-CH₂-NMe₂ and -CH₂-CH₂-morpholinyl.

When R¹³ and R¹⁴, together with the carbon atom to which they are bonded, form a phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group which is optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group, preferred groups include non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non-fused 5- to 6-membered heterocyclyl, non-fused C_3-7 carbocyclyl and C_3-7 carbocyclyl fused to a phenyl ring, more preferably non-fused phenyl, non-fused 5- to 6-membered heterocyclyl, non-fused C_3-7 carbocyclyl and C_3-7 carbocyclyl fused to a phenyl ring. When R¹³ and R¹⁴ form a cyclic group together with the carbon atom to which they are bonded, preferred non-fused 5- to 6-membered heterocyclyl groups include piperidinyl, tetrahydrofuranyl, piperazinyl, morpholinyl and pyrrolidinyl groups, more preferably piperidinyl and tetrahydrofuranyl groups. When R¹³ and R¹⁴ form a cyclic group together with the carbon atom to which they are bonded, preferred non-fused C_3-7 carbocyclyl groups include cyclopentyl and cyclohexyl, more preferably cyclopentyl. When R¹³ and R¹⁴ form a cyclic group together with the carbon atom to which they are bonded, preferred C_3-7 carbocyclyl groups fused to a phenyl ring include indanyl.

When R¹³ and R¹⁴ form a cyclic group together with the carbon atom to which they are bonded, preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups formed are unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen atoms and C_M alkyl, C_1-4 alkylene, C_1-4 alkoxy, C_M haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_M alkyl, more preferably selected from halogen atoms or Ci_-2 alkyl, Ci_-2 alkylene, Ci_-2 alkoxy and hydroxyl groups. Most preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups formed are unsubstituted or substituted by a Ci_-2 alkyl group (such as a methyl group) or by a Ci_-2 alkylene group (such as by a methylene group). Even more preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups so formed are unsubstituted.

Particularly preferred R¹¹ groups include C_1-4 alkyl groups (such as methyl, ethyl, n- or iso-propyl and n-, sec- and tert-butyl, most preferably methyl), C_3-7 carbocyclyl groups (such as cyclopentyl and cyclohexyl), C_2-4 alkenyl groups (such as allyl), and also phenyl, benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridyhnethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl, methoxyethyl, indanyl, norbonyl, dimethylaminoethyl and moφholinoethyl groups, more preferably R¹¹ represents C_1-4 alkyl or C_3-7 carbocyclyl. Most preferred groups include where R¹¹ is methyl, cyclopentyl or t-butyl, more preferably where R¹¹ is methyl or cyclopentyl, most preferably where R^{1 !} is methyl.

Compounds where R⁷ represents -COOH or -COOR¹¹ wherein R¹¹ is C_1-4 alkyl or C_3-7 carbocyclyl can be described by a group where R⁷ is -COOR¹⁸ and R¹⁸ is hydrogen, Ci_-4 alkyl or C_3-7 carbocyclyl. Preferably R⁷ is -COOR¹⁸ where R¹⁸ is hydrogen, methyl or C_3-7 carbocyclyl, more preferably where R¹⁸ is hydrogen, methyl or cyclopentyl, most preferably where R¹⁸ is hydrogen or methyl.

Group R⁸

R⁸ preferably represents hydrogen or a C_1-6 alkyl, -(C=O)R⁹ or -(C=O)OR¹⁰ wherein R⁹ and R¹⁰ are as defined above, or R⁸ represents a non-fused phenyl, non-fused 5- to 6- membered heteroaryl, non-fused C_3-7 carbocyclyl or non-fused 5- to 6-membered heterocyclyl group. More preferably R preferably represents hydrogen or a C_1-6 alkyl, -(C=O)R⁹ or -(C=O)OR¹⁰ wherein R⁹ and R¹⁰ are as defined above, or R⁸ represents a non- fused phenyl, non-fused 5- to 6-membered heteroaryl or a non-fused C_3-7 carbocyclyl group. When R⁸ represents a Ci_-6 alkyl group, it is preferably a Ci_-4 alkyl group such as methyl, ethyl or n-or iso-propyl.

When R represents a C_3-7 carbocyclyl group, it is preferably a C_3-6 carbocyclyl group, more preferably a C_3-6 cycloalkyl group such as cyclopropyl, cyclopentyl or cyclohexyl. When R⁸ represents a 5- to 6-membered heteroaryl group preferred groups include pyridyl. When R⁸ represents -(C=O)R⁹, preferably R⁹ is Ci_-6 alkyl, non-fused phenyl, non- fused 5- to 6-membered heteroaryl, non-fused C_3-7 carbocyclyl or a group -Alk⁴-Cyc. When R⁹ is Ci_-6 alkyl, it is preferably a C_1-4 alkyl group such as methyl, ethyl, n- or iso- propyl, or n-, iso- or sec-butyl. When R⁹ is C_3-7 carbocyclyl it is preferably C_3-6 carbocyclyl, more preferably C_3-6 cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl. When R⁹ is 5- to 6-membered heteroaryl, preferred groups include pyridyl and thienyl. When R⁹ is -Alk⁴-Cyc, AIk⁴ is preferably a C_1-4 alkylene group, more preferably C_1-2 alkylene, most preferably methylene. When R⁹ is -Alk⁴-Cyc, Cyc is preferably a non- fused phenyl, a non-fused 5- to 6-membered heteroaryl or a non-fused 5- to 6-membered heterocyclyl group. When Cyc is a 5- to 6-membered heteroaryl it is preferably thienyl or pyridyl. Preferred -Alk⁴-Cyc groups include benzyl, 4-methoxyphenylmethylcarbonyl, thienylmethyl and pyridylmethyl.

When R⁸ represents -(C=O)OR¹⁰ or -(C=O)NHR¹⁰, preferably R¹⁰ is hydrogen or C i-₄ alkyl, more preferably hydrogen, methyl, ethyl, or n- or iso-propyl. The alkyl and alkylene groups in R⁸, R⁹, R¹⁰ and AIk⁴ are preferably unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, C_1-4 alkyl, C_2-4 alkenyl, C_M alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C_1-2 alkyl, more preferably selected from halogen, C_1-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C_1-2 alkyl. Most preferably the alkyl and alkylene groups in R⁸, R⁹, R¹⁰ and AIk⁴ are unsubstituted.

The phenyl, heteroaryl, heterocyclyl, carbocyclyl and heterocyclyl in R⁸ and R⁹ are preferably unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, Ci_-4 alkoxy, C_1-4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl, more preferably the substituents are selected from halogen atoms and C_1-2 alkyl, C_1-2 alkoxy and hydroxyl groups. Most preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in R⁸ are unsubstituted. Most preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in R⁹ are unsubstituted or substituted by a single Ci_-2 alkoxy group, more preferably by a single methoxy group. In a most preferred embodiment, R⁸ is hydrogen.

For compounds of the invention which are to be administered systemically, esters with a slow rate of esterase cleavage are preferred, since they are less susceptible to pre-systemic metabolism. Their ability to reach their target tissue intact is therefore increased, and the ester can be converted inside the cells of the target tissue into the acid product. However, for local administration, where the ester is either directly applied to the target tissue or directed there by, for example, inhalation, it will often be desirable that the ester has a rapid rate of esterase cleavage, to minimise systemic exposure and consequent unwanted side effects. If a carbon atom to which the group R is attached is unsubstituted, i.e. R is attached to a methylene (-CH₂-) radical, then the esters tend to be cleaved more rapidly than if that carbon is substituted, or is part of a ring system such as a phenyl or cyclohexyl ring. Thus, if (i) p is 1 and AIk² terminates in a methylene radical, (ii) n and p are both zero, m is 1 and AIk¹ terminates in a methylene radical, or (iii) m, n and p are zero, Y¹ is a bond and z is 1, then the ester (i.e. when R⁷ is not -COOH) is likely to be cleaved more rapidly.

Group -rCH^-Y¹-!,²-

The group (or bond, when m, n, p and z are zero and Y¹ represents a bond)

-[CH₂]_Z-Y¹-].,²- arises from the particular chemistry strategy chosen to link the amino acid motif R in substituent Y to the rest of the molecule. Clearly the chemistry strategy for that coupling may vary widely, and thus many combinations of the variables Y¹, L², and z are possible. However, when a compound of the invention is bound to an enzyme at its active site, the amino acid motif generally extends in a direction away from the enzyme, and thus minimises or avoids interference with the binding mode of the inhibitor. Hence the precise combination of variables making up the linking chemistry between the amino acid motif and the rest of the molecule will often be irrelevant to the primary binding mode of the compound as a whole.

The subscript z may be 0 or 1, so that a methylene group linked to ring A is optional. Preferably z is zero and the methylene group is absent.

Group Y¹ Y¹ preferably represents a bond or a group of formula -O-, -S-, -O-(C=O)-, -(C-O)-O-, -(C=O)-, -(S=O)-, -S(O₂)-, -NR³-, -(C=O)NR³-, -NR³(C=0)-, -S(O₂)NR³- and -NR³S(O₂)-, wherein R³ represents hydrogen or C_1-6 alkyl. When R³ is Ci_-6 alkyl, it is preferably Ci_-2 alkyl, more preferably ethyl. When R³ is an alkyl group, it is preferably unsubstituted or substituted by one or two substituents which are the same or different and are selected from Ci_-4 alkyl, C₂^ alkenyl, C_M alkoxy, C_2-4 alkenyloxy, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Ci_-4 hydroxyalkyl, C_2-4 hydroxyalkenyl, Ci_-4 alkylthio, C_2-4 alkenylthio, and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, more preferably selected from halogen, Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C_1-2 alkyl. Most preferred substituents are halogen, Ci_-2 alkoxy and hydroxyl, in particular hydroxyl.

More preferably Y¹ is a bond or represents a group of formula -0-, -S-, -NR³-, -C(O)-O-, -0-(C=O)-, -(C=O)NR³- or -NR³(C=0)- wherein R³ is as defined above. More preferably Y¹ is a bond or represents a group of formula -0-, -S-, -NH-, -O-(C=O)-,

-NH(C=O)- or -(C=O)NH-. When Y¹ represents -0-, -S- or -NR³-, preferably either m is zero (i.e. AIk¹ is absent) and n is 1 (i.e. Q is present), or m is 1 (i.e. AIk¹ is present) and n and p are zero (i.e. Q and AIk² are absent). Most preferably Y¹ is a bond.

Group L²

L² represents a group of formula -(Alk¹)_m-(Q)_n-(Alk²)_p-. The subscripts m, n and p are independently zero or 1. Specifically, in some embodiments of the invention, m and p may be O with n being 1. In other embodiments, n and p may be O with m being 1. In further embodiments, m, n and p may be all O. In still further embodiments m may be O, n may be 1 with Q being a monocyclic aryl, heteroaryl, carbocyclyl or heterocyclyl radical, and p may be O or 1 , more preferably p is 1. Most preferably either n and p are zero and m is 1; or m is zero, n is 1 with Q being a monocyclic aryl, heteroaryl, carbocyclyl or heterocyclyl radical, and p is 1 ; for example n and p are zero and m is 1.

Preferred AIk¹ groups include C_3-6 cycloalkyl groups and Ci_-4 alkylene, C_2-4 alkenylene and C_2-4 alkynylene groups which may optionally contain or terminate in an ether, thioether or amino -NR⁶- link wherein R⁶ represents hydrogen or Ci_-2 alkyl. When R⁶ is Ci_-2 alkyl, it is preferably unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl and -NR 'R" wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl. Most preferred substituents on the R⁶ group are halogen, Ci_-2 alkoxy and hydroxyl, in particular hydroxyl.

When AIk¹ is a C_3-6 cycloalkyl group, preferred groups include divalent cyclopropyl, cyclopentyl and cyclohexyl groups which optionally contain an ether, thioether or amino -NR⁶- link wherein R⁶ represents hydrogen or Ci_-2 alkyl. Preferably the group R⁶, when present, is unsubstituted. More preferably, when AIk¹ is a C_3-6 cycloalkyl group it is a 5- or 6-membered ring optionally containing an ether or amino -NR⁶- link. Suitable examples include cyclopentyl, cyclohexyl and heterocyclic groups selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl. More preferred examples include cyclopentyl, cyclohexyl and pyrrolidinyl. When AIk¹ is a Ci_-4 alkylene group, preferred groups include -CH₂-, -CH₂CH₂-,

-CH₂CH₂CH₂- and -CH₂CH₂CH₂CH₂-, as well as branched variants such as -CH(CH₃)-, -C(CH₃)₂-, or in either orientation -CH₂CH(CH₃)-, -CH₂C(CH₃)₂-. When AIk¹ is a C_2-4 alkenylene group, preferred groups include -CH=CH-, -CH=CHCH₂-, -CH₂CH=CH- and -CH₂CH=CHCH₂- as well as branched variants. When AIk¹ is a C_2-4 alkynylene group, preferred groups include -C=C-, -C=CCH₂-, -CH₂C=C- and -CH₂C=CCH₂- as well as branched variants.

When AIk¹ is a Ci_-4 alkylene, C_2-4 alkenylene or C_2-4 alkynylene group terminating in an ether (-O-), thioether (-S-) or amino (-NR⁶)- wherein R⁶ represents hydrogen or Ci_-2 alkyl, preferred groups include (in either orientation) -CH₂W-, -CH₂CH₂W-, -CH₂CH₂WCH₂-, -CH₂CH₂WCH(CH₃) -, -CH₂WCH₂CH₂-, -CH₂WCH₂CH₂WCH₂-, and -WCH₂CH₂- where W is -O-, -S-, -NH-, -N(CH₃)-, or -CH₂CH₂N(CH₂CH₂OH)CH₂-. Thus suitable groups include -0-CH₂-, -S-CH₂- and -0-CH₂-CH₂-. When AIk¹ terminates in an ether, thioether or amino group, preferably Y¹ is a bond or a group -(C=O)-, -0(C=O)-, -S(O)-, -SO₂-, -NR³(C=O)- or NR³S(O₂)-, more preferably Y¹ is a bond or a group -C(=O)-. More preferably AIk¹ does not terminate in or contain an ether, thioether or amino group. Most preferably AIk¹ is a C_1-4 alkylene group, more preferably it is selected from -CH₂-, -CH₂CH₂- and -CH₂-CH₂-CH₂-, more preferably AIk¹ is -CH₂CH₂- or -CH₂CH₂CH₂-, most preferably AIk¹ is -CH₂CH₂-.

AIk¹ groups are preferably unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C₂^ alkenyl, C_1-4 alkoxy, C_2-4 alkenyloxy, C_1-4 haloalkyl, C_2-4 haloalkenyl, C_1-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C_1-4 hydroxyalkyl, C_2-4 hydroxyalkenyl, C_M alkylthio, C_2-4 alkenylthio, and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl. More preferably, AIk¹ groups are unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, C_1-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C_1-2 alkyl. Most preferably AIk¹ groups are unsubstituted.

Preferred Q groups include phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl and 5- to 10-membered heterocyclyl groups optionally fused to a further phenyl, 5- to 10- membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group. More preferably Q represents a phenyl optionally fused to a further phenyl, a 5- to 10-membered heteroaryl optionally fused to a further phenyl, a non-fused C_3-7 carbocyclyl or a non-fused 5- to 10-membered heterocyclyl group. When Q represents a phenyl optionally fused to a further phenyl, it represents phenyl or naphthyl, with phenyl groups being preferred. When Q represents a phenyl it is preferably linked to the rest of the molecule in a 1,4-relationship.

When Q represents a C_3-7 carbocyclyl group it is preferably a cyclopropyl, cyclopentyl or cyclohexyl group, more preferably a cyclohexyl group. When Q represents a 5- to 10-membered heteroaryl group optionally fused to a further phenyl it is preferably a 5- to 6-membered heteroaryl group optionally fused to a further phenyl. When Q represents a non-fused 5- to 6-membered heteroaryl group it is preferably a pyridyl, thienyl, furyl or pyrrolyl group, more preferably a pyridyl, thienyl or pyrrolyl group. When Q represents a 5- to 6-membered heteroaryl group fused to a phenyl, it is preferably an indolyl, benzimidazolyl, benzofuryl or benzothienyl group, more preferably an indolyl group. When Q represents a 5- to 10-membered heterocyclyl group it is preferably a non- fused 5- to 6-membered heterocyclyl group, for example a piperidinyl or piperazinyl group.

Most preferred Q groups, when present, include phenyl, pyridinyl, thienyl and cyclohexyl, e.g. phenyl and cyclohexyl, more preferably phenyl. However, in one preferred embodiment subscript n is zero and the group Q is absent.

Q groups are preferably unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_1-4 alkoxy, C_1-4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and groups of formula COR^Λ, -SO₂R^A, -CONH₂, -SO₂NH₂, -CONHR^A, -SO₂NHR^A, -C0NR^AR^B, -SO₂NR^AR^B wherein R^A and R^B are the same or different and represent Ci_-2 alkyl. More preferably Q groups are unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_M alkoxy and hydroxyl groups. Most preferably Q groups are unsubstituted. Preferred AIk² groups include C_3-6 cycloalkyl groups, and Ci_-4 alkylene, C_2-4 alkenylene and C_2-4 alkynylene groups which may optionally contain or terminate in an ether, thioether or amino -NR⁶- link wherein R⁶ represents hydrogen or C_1-2 alkyl. When R⁶ is Ci_-2 alkyl, it is preferably unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, C_1-2 alkyl, C_1-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl. Most preferred substituents on the R⁶ group are halogen, Ci_-2 alkoxy and hydroxyl, in particular hydroxyl.

When AIk² is a C_3-6 cycloalkyl group, preferred groups include divalent cyclopropyl, cyclopentyl and cyclohexyl groups. When AIk² is a Ci_-4 alkylene group, preferred groups include -CH₂-, -CH₂CH₂-,

-CH₂CH₂CH₂- and -CH₂CH₂CH₂CH₂-, as well as branched variants such as -CH(CH₃)-, -C(CH₃)₂-, or in either orientation -CH₂CH(CH₃)-, -CH₂C(CH₃)₂-. Most preferred groups are -CH₂- and -CH₂-CH₂-. When AIk² is a C_2-4 alkenylene group, preferred groups include -CH=CH-, -CH=CHCH₂-, -CH₂CH=CH- and -CH₂CH=CHCH₂- as well as branched variants. When AIk² is a C_2-4 alkynylene group, preferred groups include -C≡C-, -C=CCH₂-, -CH₂C=C- and -CH₂C=CCH₂- as well as branched variants. When AIk² is a Ci_-4 alkylene, C_2-4 alkenylene or C_2-4 alkynylene group terminating in an ether (-O-), thioether (-S-) or amino (-NR⁶- wherein R⁶ represents hydrogen or Ci_-2 alkyl), preferred groups include (in either orientation) -CH₂W-, -CH₂CH₂W-, -CH₂CH₂WCH₂-, -CH₂CH₂WCH(CH₃) -, -CH₂WCH₂CH₂-, -CH₂WCH₂CH₂WCH₂-, and -WCH₂CH₂- where W is -O-, -S-, -NH-, -N(CH₃)-, or -CH₂CH₂N(CH₂CH₂OH)CH₂-. More preferably AIk² does not terminate in or contain an ether, thioether or amino group.

Most preferable AIk² groups are Ci_-4 alkylene groups, in particular -CH₂- and -CH₂CH₂-. However, in one preferred embodiment subscript p is zero and the group AIk² is absent. AIk² groups are preferably unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen atoms and C_M alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C_2-4 alkenyloxy, C_M haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Ci_-4 hydroxyalkyl, C₂^ hydroxyalkenyl, C_M alkylthio, C_2-4 alkenylthio, and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably, AIk² groups are preferably unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, Ci_-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl. Most preferably AIk² groups are unsubstituted. In a preferred embodiment, m is 1, n andp are zero and L² preferably represents

Ci_-4 alkylene, more preferably -CH₂-, -CH₂CH₂- or -CH₂CH₂CH₂-, more preferably -CH₂CH₂- or -CH₂CH₂CH₂-, most preferably -CH₂CH₂-. hi another embodiment m is zero, n and p are 1 and L² represents -Cyc'-Alk²- wherein Cyc' represents a non-fused phenyl or a non-fused C_3-6 cycloalkyl group, substituted as described for Q above and AIk² represents Ci_-4 alkylene, more preferably -CH₂- or -CH₂CH₂-. In another preferred embodiment, m is zero, n andp are 1 and L² represents -Cyc'-Alk² - wherein Cyc' represents a non-fused phenyl or a non-fused 5- to 10- membered heteroaryl and AIk² represents Ci_-4 alkylene, more preferably -CH₂- Or -CH₂CH₂-. Preferred examples of the group -[CH₂]_Z-Y¹ -L²- in its entirety include -CH₂CH₂-,

-CH₂CH₂CH₂-, -(C=O)NH-(CH₂)₂-, -(C=O)NH-(CH₂)₃-, -NH-(CH₂)₃-, -NH-C(O)-CH₂-, -NH-CC=O)-CH₂-CH₂-, -O-C(=O)-CH₂-, -0-CC=O)-CH₂CH₂-, -S-CH₂-, -S-CH₂-CH₂-, -NH-(CH₂)₄-, -Q-CH₂- and -0-CH₂-CH₂-, and groups of formula:

A further preferred example of the group -[CH₂]_Z-Y 1 - τL2 - in its entirety is

More preferred examples of the group -[CH₂]_Z-Y¹-!.,²- in its entirety include

-CH₂CH₂-, -CH₂CH₂CH₂- and

, for example -CH₂CH₂- and -CH₂CH₂CH₂-, more preferably -CH₂CH₂-.

Group R » 1¹9

In one embodiment, exemplary R¹⁹ groups include side chains of natural amino acids and close structural variants thereof. When R¹⁹ is a C_1-4 alkyl group preferably it is a C_1-4 alkyl group, more preferably a C_1-2 alkyl group, most preferably a methyl group. When R¹⁹ represents a group of formula -L³-B, preferably L³ is a bond or a C_1-4 alkylene group, more preferably a Ci_-2 alkylene group, most preferably a methylene group. When R¹⁹ represents a group of formula -L³ -B, preferably B represents a phenyl group or a 5- tolO-membered heteroaryl group. When B represents a 5- to 10-membered heteroaryl group preferred heteroaryl groups include imidazolyl and indolyl. When R¹⁹ represents a group of formula -L³-B, preferably B represents a phenyl group.

When R¹⁹ is a Ci_-6 alkyl group it is preferably unsubstituted or substituted with one or two, preferably one, unsubstituted substituent selected from halogen, Ci_-2 alkoxy, C_1-2 haloalkyl, hydroxyl, -COOR', -COONR'R", -SR' and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C_1-2 alkyl. When R¹⁹ is a C_1-6 alkyl group most preferably it is unsubstituted.

When R¹⁹ represents a group of formula -L³-B, preferably L³ is unsubstituted.

When R¹⁹ represents a group of formula -L³-B, preferably B is unsubstituted or substituted with one, two or three, more preferably with one or two, unsubstituted substituents selected from halogen atoms, C_M alkyl, C_1-2 alkoxy, C_1-2 alkylthio and hydroxy. When R¹⁹ represents a group of formula -L³-B, most preferably B is unsubstituted or substituted with one substituent selected from a halogen atom or a C_1-4 alkyl, C_1-2 alkoxy, C_1-2 alkylthio or hydroxy group. In one embodiment R¹⁹ represents an unsubstituted C_1-6 alkyl group or a C_1-6 alkyl group substituted with one halogen atom or a C_1-2 alkoxy, C_1-2 haloalkyl, hydroxyl,

-COOR', -COONR'R", -SR' or -NR'R" group wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl, or R¹⁹ represents a group -L³ -B where L³ represents a bond or an unsubstituted Ci_-6 alkylene group and B represents an unsubstituted or substituted C_6-Io aryl or 5- to 10-membered heteroaryl group, the substituents on the aryl or heteroaryl group being independently selected from 1, 2, 3 or 4 halogen atoms or Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 alkylthio or hydroxy groups.

In a preferred embodiment R¹⁹ represents an unsubstituted Ci_-4 alkyl group or a group -L³-B where L³ represents a bond or an unsubstituted Ci_-2 alkylene group and B represents an unsubstituted phenyl group or a phenyl group substituted with one substituent selected from a halogen atom or a Ci_-2 alkyl, C_1-2 alkoxy, Ci_-2 alkylthio or hydroxy group. Most preferred R¹⁹ groups include unsubstituted methyl groups and unsubstituted methylphenyl groups, more preferably unsubstituted methyl groups.

Preferred compounds of the invention are (a) amino acid derivatives of formula (I) above or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof, wherein:

R¹ represents hydrogen or halogen atom, or an unsubstituted Ci_-4 alkyl, hydroxyl, C_M alkoxy, -SR', Ci_-4 alkylthio, -NR'R" or -CONR^AR^B group where R', R", R^A and R^B are the same or different and represent hydrogen or unsubstituted Ci_-4 alkyl group, and wherein the alkyl groups or moieties in R¹ are unsubstituted or substituted by 1, 2 or 3 substituents which are themselves unsubstituted and are selected from halogen, C_M alkyl, C_2-4 alkenyl, C_M alkoxy, hydroxyl, C_M haloalkyl, C_2-4 haloalkenyl, C_1-4 haloalkyloxy, C₂_4 haloalkenyloxy and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C_1-2 alkyl;

R² represents a hydrogen or halogen atom, an unsubstituted C_1-4 alkyl group or a group of formula -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl; x is zero and y is one; - Het represents -S-, -S(O)- or -S(O)₂-;

- A represents an unsubstituted or substituted group selected from non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non-fused C_3-7 carbocyclyl, non-fused 5- to 6-membered heterocyclyl group, a phenyl group which is fused to a further 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group which is fused to a further phenyl group, and wherein the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties are unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected from halogen atoms and C_M alkyl, C_2-4 alkenyl, C_M alkoxy, C₂^ alkenyloxy, C_M haloalkyl, C_2-4 haloalkenyl, C_M haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C_1-4 hydroxyalkyl, C_2-4 hydroxyalkenyl, C_1-4 alkylthio, C_2-4 alkenylthio and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_M alkyl, and groups of formula COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -SO₂NHR^A, -C0NR^AR^B and -S0₂NR^AR^B wherein R^A and R^B are the same or different and represent C_1-4 alkyl; z is zero;

- Y¹ is a bond or represents a group of formula -O-, -S-, -0-(C=O)-, -(C=O)-O-, -(C=O)-, -(S=O)-, -S(O₂)-, -NR³-, -(C=O)NR³-, -NR³(C=O)-, -S(O₂)NR³- and -NR³S(O₂)-, wherein R³ represents hydrogen or C₁^ alkyl; - m, n and p are the same or different and represent zero or 1 ; AIk¹ represents a C_1-4 alkylene group which is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, Ci_-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl; - Q represents phenyl optionally fused to a further phenyl, a 5- to 10-membered heteroaryl optionally fused to a further phenyl, a non-fused C_3-7 carbocyclyl or a non-fused 5- to 10-membered heterocyclyl group, and wherein the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups of Q are unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, Ci_-4 alkoxy and hydroxyl groups;

- AIk² represents a Ci_-4 alkylene group which is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, Ci_-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl; - R⁷ represents -COOH or is an ester group -COOR¹ ' wherein the ester group is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group;

- R⁸ represents hydrogen or a Ci_-6 alkyl, -(C=O)R⁹ or -(C=O)OR¹⁰ wherein R⁹ and R¹⁰ are as defined above; and - R¹⁹ represents an unsubstituted Ci_-6 alkyl group or a Ci_-6 alkyl group substituted with one halogen atom or a Ci_-2 alkoxy, Ci_-2 haloalkyl, hydroxyl, -COOR', -COONR'R", -SR' or -NR'R" group wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl, or R¹⁹ represents a group -L³ -B where L³ represents a bond or an unsubstituted Ci_-6 alkylene group and B represents an unsubstituted or substituted C_6-I0 aryl or 5- to 10-membered heteroaryl group, the substituents on the aryl or heteroaryl group being independently selected from 1, 2, 3 or 4 halogen atoms or Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 alkylthio or hydroxy groups. Further preferred compounds of the invention are (a) amino acid derivatives of formula (IA) below or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof:

wherein:

R represents a hydrogen or halogen atom, an unsubstituted C]_-4 alkyl group or a group of formula -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl;

A represents an unsubstituted or substituted group selected from non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non-fused C_3-7 carbocyclyl, non-fused 5- to 6-membered heterocyclyl group, a phenyl group which is fused to a further 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group which is fused to a further phenyl group, and wherein the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties are unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C₂^ alkenyl, C_1-4 alkoxy, C_2-4 alkenyloxy, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Ci_-4 hydroxyalkyl, C_2-4 hydroxyalkenyl, Ci_-4 alkylthio, C_2-4 alkenylthio and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and groups of formula COR^A, -SC>2R^A, -CONH₂, -SO₂NH₂, -CONHR^A, -S0₂NHR^A, -CONR^AR^B and -S0₂NR^AR^B wherein R^A and R^B are the same or different and represent Ci_-4 alkyl; W is a group of formula -Y'-L²-R;

Y¹ is a bond or represents a group of formula -O-, -S-, -0-(C=O)-, -(C=O)-O-, -(C=O)-, -(S=O)-, -S(O₂)-, -NR³-, -(C=O)NR³-, -NR³(C=0)-, -S(O₂)NR³- and -NR³S(O₂)-, wherein R³ represents hydrogen or Ci_-6 alkyl; either (i) m is 1, n and p are zero, and L² represents a group -AIk¹- wherein AIk¹ represents a C_M alkylene group which is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, C_1-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C_1-2 alkyl; or (ii) m is zero, n and p are 1, L² represents non-fused phenyl or a non-fused 5- to 10- membered heteroaryl group and AIk² represents a C_1-4 alkylene group;

R⁷ represents -COOH or is an ester group -COOR¹¹ wherein the ester group is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group;

- R⁸ represents hydrogen or a C_1-6 alkyl, -(C=O)R⁹ or -(C=O)OR¹⁰ wherein R⁹ is C_1-6 alkyl, non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non-fused C_3-7 carbocyclyl or a group -Alk⁴-Cyc, and R¹⁰ is hydrogen or C₁^ alkyl; and R¹⁹ represents an unsubstituted C_1-4 alkyl group or a group -L³ -B where L³ represents a bond or an unsubstituted Ci_-2 alkylene group and B represents an unsubstituted phenyl group or a phenyl group substituted with one substituent selected from a halogen atom or a C_1-2 alkyl, C_1-2 alkoxy, C]_-2 alkylthio or hydroxy group.

Preferably in formula (IA), R² represents a hydrogen or halogen atom or an -NH₂ group, more preferably a hydrogen atom.

Preferably in formula (IA), A represents a group selected from phenyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, pyrrolyl-2,5-dione and benzoquinone, or A represent a phenyl ring fused to a 5- to 6- membered heterocyclyl group selected from oxazolidinyl, imidazolidinyl, thiazolidinyl, thioxolanyl, dioxolanyl and dithiolanyl, and wherein A is unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and represent halogen atoms or C_M alkyl, C_1-2 alkoxy, Ci_-2 alkylthio or hydroxy groups, more preferably A represents a non- fused phenyl ring or a phenyl ring fused to a dioxolanyl ring, and wherein A is unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and represent halogen atoms or C_1-4 alkyl, C_1-2 alkoxy, Ci_-2 alkylthio or hydroxy groups.

Preferably in formula (IA), Y¹ is a bond or represents a group of formula -O-, -S-, -NR³-, -C(=O)-O-, -0-(C=O)-, -(C=O)NR³- or -NR³(C=O)- wherein R³ is hydrogen or Cj_-6 alkyl, more preferably Y¹ is a bond.

Preferably in formula (IA), R⁷ represents a group -COOH or -COOR¹¹, wherein R¹¹ represents -CR¹²R¹³R¹⁴ and:

(i) R¹³ represents hydrogen or a group of formula -[Ci_-4 alkylene]_b-(Z¹)_a-[Ci_-4 alkyl] or -[Ci_-4 alkylene]b-(Z¹)_a-[C_2-4 alkenyl] wherein a and b are the same or different and represent O or 1, and Z¹ represents -0-, -S-, or -NR¹⁷- wherein R¹⁷ is hydrogen or C_M alkyl, R¹⁴ represents hydrogen or Ci^ alkyl, and R¹² represents hydrogen or C_1-4 alkyl;

(ii) R¹³ represents a phenyl or a 5- to 10-membered heteroaryl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group, R¹⁴ represents hydrogen or Ci_-4 alkyl, and R¹² represents hydrogen;

(iii) R¹³ represents a group of formula -(Alk³)-NR¹⁵R¹⁶ wherein AIk³ represents a C_M alkylene group and either (a) R¹⁵ and R¹⁶ are the same or different and represent hydrogen or Ci_-4 alkyl, or (b) R¹⁵ and R¹⁶, together with the nitrogen atom to which they are bonded, form a 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group; R¹⁴ represents hydrogen or C_M alkyl, and R¹² represents hydrogen; or (iv) R¹³ and R¹⁴, together with the carbon atom to which they are bonded, form a phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group which is optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group, and R¹² represents hydrogen. Preferably in formula (IA), R¹ ' represents -CR¹²R¹³R¹⁴, and either: (i) R¹² represents hydrogen or C_1-2 alkyl; R¹³ represents hydrogen, C_1-4 alkyl, C_2-4 alkenyl or a group -(Ci_-4 alkyl)-O-(Ci-4 alkyl); and R¹⁴ represents hydrogen or Ci_-2 alkyl; or

(ii) R¹² represents hydrogen or Ci_-2 alkyl, and R¹³ and R¹⁴ form a cyclic group together with the carbon atom to which they are bonded, form a non-fused

C_3-7 carbocyclyl groups which is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_1-4 alkylene, Ci_-4 alkoxy, C_1-4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl.

More preferably in formula (IA) R⁷ represents a group -COOR¹⁸ where R¹⁸ is hydrogen, C_1-4alkyl or C_3-7 carbocyclyl. Preferably in formula (IA) R¹⁹ represents an unsubstituted Ci_-4 alkyl group.

Further preferred compounds of the invention are (a) amino acid derivatives of formula (IB) above or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof:

wherein:

- A represents a non-fused phenyl ring or a phenyl ring fused to a dioxolanyl ring, and wherein A is unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and represent halogen atoms or Ci_-4 alkyl, Ci_-2 alkoxy,

Ci_-2 alkylthio or hydroxy groups; and W represent a group of formula -Y'-IAR wherein:

Y¹ is a bond or represents a group -O-, -S-, -NR³-, -C(=O)-O-, -0-(C=O)-, -(C=O)NR³- or -NR³(C=0)- wherein R³ is hydrogen or C_1-6 alkyl; L² represents a group -AIk¹- or a group -Q-AIk²-, and -AIk¹- represents an unsubstituted C_1-4 alkylene group, Q represents a non-fused phenyl ring or a non-fused pyridinyl or thienyl ring and AIk² represents an unsubstituted C_1-4 alkylene group; and - R⁷ represents -COOH or -COOR¹ ' wherein R^{1 !} represents

-CR¹²R¹³R¹⁴, and either:

(i) R¹² represents hydrogen or C_1-2 alkyl; R¹³ represents hydrogen, C_1-4 alkyl, C_2-4 alkenyl or a group -(Ci_-4 alkyl)-O-(C_1-4 alkyl); and R¹⁴ represents hydrogen or Ci_-2 alkyl; or (ii) R¹² represents hydrogen or Ci_-2 alkyl, and R¹³ and R¹⁴ form a cyclic group together with the carbon atom to which they are bonded, form a non-fused C_3-7 carbocyclyl groups which is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen atoms and C_M alkyl, Ci_-4 alkylene, C_M alkoxy, Cj_-4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_M alkyl;

- R⁸ represents hydrogen or a Ci_-6 alkyl, -(C=O)R⁹ or -(C=O)OR¹⁰ wherein R⁹ is Ci_-6 alkyl, non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non-fused

C_3-7 carbocyclyl or a group -Alk⁴-Cyc, and R¹⁰ is hydrogen or C_M alkyl; and

- R¹⁹ represents an unsubstituted C_M alkyl group or a group -L³ -B where L³ represents an unsubstituted Ci_-2 alkylene group and B represents an unsubstituted phenyl group or a phenyl group substituted with one substituent selected from a halogen atom or a Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 alkylthio or hydroxy group.

Preferably in formula (IB) A represents a phenyl ring which is unsubstituted or substituted by 1 or 2 substituents which are the same or different and represent halogen atoms or C i-₄ alkyl, Ci_-2 alkoxy, Ci_-2 alkylthio or hydroxy groups. Preferably in formula (IB) Y¹ is a bond. Preferably in formula (IB) R⁷ represents -COOH or -COOR¹ ' and R^{1 !} represents a C_M alkyl or a C_3-7 carbocyclyl group. Preferably in formula (IB) R⁸ represents hydrogen. In one embodiment in formula (IB) L² represents a group -AIk¹- and AIk¹ represents an unsubstituted Ci_-4 alkylene group.

Preferably in formula (IB) R¹⁹ represents an unsubstituted C_M alkyl group.

Further preferred compounds of the invention are (a) amino acid derivatives of formula (IC) above or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof:

wherein:

A represents a non-fused phenyl ring or a phenyl ring fused to a dioxolanyl ring, and wherein A is unsubstituted or substituted by 1 or 2 substituents which are the same or different and represent halogen atoms or C_M alkyl, C_1-2 alkoxy, C_1-2 alkylthio or hydroxy groups; AIk¹ represents a Ci_-4 alkylene group; and R¹⁸ represents hydrogen, Ci_-4 alkyl or a C_3-7 carbocyclyl. More preferably in formula (IC) R¹⁸ represents hydrogen, t-butyl or cyclopentyl, most preferably hydrogen or cyclopentyl. More preferably in formula (IC) AIk¹ represents -CH₂-, -CH₂CH₂- or -CH₂CH₂CH₂-, most preferably -CH₂CH₂- or -CH₂CH₂CH₂-. More preferably in formula (IC) R¹⁹ represents an unsubstituted Ci_-4 alkyl group.

Particularly preferred compounds of formula (I) are: - Methyl 4- {6-amino-8-[(2 -bromo-5-methoxyphenyl)thio]-9H-purin-9- yl}isovalinate; and 4-{6-Amino-8-[(2-bromo-5-methoxyphenyl)thio]-9H-purin-9-yl}isovaline. The compounds of the invention comprise a derivatised purine core, with a side chain (W) which terminates in an amino acid or amino acid ester end group. The purine cores of the compounds are similar to a number of known purine analogues which have HSP90 inhibition activity. The binding of such compounds to HSP90 has been characterised by x-ray crystallography (Immormino et al, J. Med. Chem. 2006, 49, 4953-4960, PDB code 2FWZ). Such studies indicate that the side chain W will not interfere with the ability of the compounds to inhibit HSP90, and instead acts as a group which can be enzymatically modified to alter the compounds ability to enter and exit a cell. Accordingly, despite addition of the side chain W, the compounds of the invention will still be useful as HSP90 inhibitors, and will therefore be useful in the treatment of conditions which are mediated by inappropriate HSP90 activity. A suitable assay for assessing the activity of the compounds of the invention is as follows:

Cell inhibition Assay

Cancer cell lines (e.g. U937 and HUT) can be grown in log phase then harvested and seeded at 1000 cells/well (200μl final volume) into 96- well tissue culture plates.

Following 24h of cell growth, cells can be treated with the claimed compounds (final concentration of 20μM). Plates can then be re-incubated for a further 72h before a sulphorhodamine B (SRB) cell viability assay is conducted according to Skehan 1990 J

Natl. Cane. Inst. 82, 1107-1112.

Data from the assay can be expressed as a percentage inhibition of the control, measured in the absence of inhibitor, as follows:

% inhibition = 100-((SVS°)xl00) where S¹ is the signal in the presence of inhibitor and S⁰ is the signal in the presence of

DMSO. IC50 can then be determined by non-linear regression analysis, for example after fitting the results of eight data points to the equation for sigmoidal dose response with variable slope (% activity against log concentration of compound), using Graphpad Prism software. As mentioned above, the compounds with which the invention is concerned are inhibitors of HSP90 activity and are therefore of use for treatment of cancer, autoimmune and inflammatory diseases, including chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, diabetes, atopic dermatitis, graft versus host disease, systemic lupus erythematosis and others. A preferred utility of the compounds of the invention is for use in the treatment of cancer.

It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial, but an exemplary dosage would be 0.1-lOOOmg per day

The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. For topical application to the skin, the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia. For topical application by inhalation, the drug may be formulated for aerosol delivery for example, by pressure-driven jet atomizers or ultrasonic atomizers, or preferably by propellant-driven metered aerosols or propellant-free administration of micronized powders, for example, inhalation capsules or other "dry powder" delivery systems. Excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavourings, and fillers (e.g. lactose in the case of powder inhalers) may be present in such inhaled formulations. For the purposes of inhalation, a large number of apparata are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is appropriate for the patient. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhalers for example as described in European Patent Application EP 0 505 321). For topical application to the eye, the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.

The active ingredient may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. The compounds of the invention may be used in conjunction with a number of known pharmaceutically active substances. For example, the compounds of the invention may be used with cytotoxics, HDAC inhibitors, kinase inhibitors, aminopeptidase inhibitors and monoclonal antibodies (for example those directed at growth factor receptors). Preferred cytotoxics include, for example, taxanes, platins, anti-metabolites such as 5- fluoracil, topoisomerase inhibitors and the like. The medicaments of the invention comprising amino acid derivatives of formula (I), tautomers thereof or pharmaceutically acceptable salts, N-oxides, hydrates or solvates thereof therefore typically further comprise a cytotoxic, an HDAC inhibitor, a kinase inhibitor, an aminopeptidase inhibitor and/or a monoclonal antibody.

Further, the present invention provides a pharmaceutical composition comprising: (a) an amino acid derivative of formula (I), a tautomer thereof or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof;

(b) a cytotoxic agent, an HDAC inhibitor, a kinase inhibitor, an aminopeptidase inhibitor and/or a monoclonal antibody; and

(c) a pharmaceutically acceptable carrier or diluent. Also provided is a product comprising:

(a) an amino acid derivative of formula (I), a tautomer thereof or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof; and

(b) a cytotoxic agent, an HDAC inhibitor, a kinase inhibitor, an aminopeptidase inhibitor and/or a monoclonal antibody, for the separate, simultaneous or sequential use in the treatment of the human or animal body.

Synthesis

There are multiple synthetic strategies for the synthesis of the compounds (I) with which the present invention is concerned, but all rely on known chemistry, known to the synthetic organic chemist. Thus, compounds according to formula (I) can be synthesised according to procedures described in the standard literature and are well-known to those skilled in the art. Typical literature sources are "Advanced organic chemistry", 4^th Edition (Wiley), J March, "Comprehensive Organic Transformation", 2^nd Edition (Wiley), R.C. Larock , "Handbook of Heterocyclic Chemistry", 2^nd Edition (Pergamon), A.R. Katritzky), review articles such as found in "Synthesis", "Ace. Chem. Res." , "Chem. Rev", or primary literature sources identified by standard literature searches online or from secondary sources such as "Chemical Abstracts" or "Beilstein".

The compounds of the invention may be prepared by a number of processes generally described below and more specifically in the Examples hereinafter. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxyl, amino and carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions [see for example Greene, T. W., "Protecting Groups in Organic Synthesis", John Wiley and Sons, 1999]. Conventional protecting groups may be used in conjunction with standard practice. In some instances deprotection may be the final step in the synthesis of a compound of general formula (T), and the processes according to the invention described herein after are understood to extend to such removal of protecting groups.

Thus, in one aspect of the invention amino acid ester intermediates may be prepared by, but not restricted to, the methods outlined in Scheme 1.

Scheme 1

herein

The amino acid ester compounds of the invention may be prepared by, but not restricted to, the methods outlined in Scheme 2. Scheme 2

Alkylation

In Scheme 2 the linking group (W) between the central purine core and the R⁷ group is an ethylene group. A large number of other linking groups are, of course, encompassed by formula (I). The skilled person would readily be able to choose suitable starting materials in order to produce amino acid ester compounds of the invention having a wide range of other W groups, and the ethylene group of Scheme 2 is used for clarity purposes only.

Scheme 3 shows a generic scheme for preparing the amino acids derivatives according to the invention, starting from the corresponding amino acid ester.

Scheme 3: Saponification e.g. LiOH₁ THF / water

HCE-I Carboxylesterase Assay

Hydrolysis of esters to the corresponding carboxylic acids by hCE-1 can be measured using the following procedure. At zero time, lOOμl of recombinant hCE-1 at a concentration of 6μg/ml in phosphate assay buffer (K₂PO₄ 10OmM, KCl 4OmM, PH 7.4) was added to an equal volume of assay buffer containing 5μM ester substrate. After thorough mixing, triplicate samples were incubated for 0, 20 or 80minutes at 37⁰C. At the appropriate time, hydrolysis was stopped by the addition of 600μl of acetonitrile. For zero time samples, the acetonitrile was added prior to the enzyme. The samples were analysed for the ester and its corresponding carboxylic acid at room temperature by LCMS (Sciex API 3000, HPl 100 binary pump, CTC PAL). Chromatography was based on an AcCN (75x2. lmm) column and a mobile phase of 5-95 % acetonitrile in water /0.1 % formic acid. Levels of the acid, the hydrolysis product, after 80 minutes are expressed in ng/ml.

Broken Cell Assay

In order to determine whether a compound containing a particular group R⁷ is hydrolysable by one or more intracellular carboxylesterase enzymes to a -COOH group, the compound may be tested in the following assay: Preparation of cell extract

U937 or HCT 116 tumour cells (~ 109) were washed in 4 volumes of Dulbeccos PBS (~ 1 litre) and pelleted at 525 g for 10 min at 4 ⁰C. This was repeated twice and the final cell pellet was resuspended in 35 ml of cold homogenising buffer (Trizma 10 mM, NaCl 130 mM, CaCl₂ 0.5 mM pH 7.0 at 25 ⁰C). Homogenates were prepared by nitrogen cavitation (700 psi for 50 min at 4 ⁰C). The homogenate was kept on ice and supplemented with a cocktail of inhibitors at final concentrations of: Leupeptin 1 μM Aprotinin 0.1 μM E64 8 μM

Pepstatin 1.5 μM Bestatin 162 μM Chymostatin 33 μM

After clarification of the cell homogenate by centrifugation at 525 g for 10 min, the resulting supernatant was used as a source of esterase activity and was stored at -80⁰C until required.

Measurement of ester cleavage

Hydrolysis of esters to the corresponding carboxylic acids can be measured using the cell extract, prepared as above. To this effect cell extract (~30 μg / total assay volume of 0.5 ml) was incubated at 37 ⁰C in a Tris- HCl 25 mM, 125 mM NaCl buffer, pH 7.5 at 25 ⁰C. At zero time the ester (substrate) was then added at a final concentration of 2.5 mM and the samples were incubated at 37 ⁰C for the appropriate time (usually 0 or 80 min). Reactions were stopped by the addition of 3 x volumes of acetonitrile. For zero time samples the acetonitrile was added prior to the ester compound. After centrifugation at 12000 g for 5 min, samples were analysed for the ester and its corresponding carboxylic acid at room temperature by LCMS (Sciex API 3000, HPl 100 binary pump, CTC PAL). Chromatography was based on an AceCN (75*2. lmm) column and a mobile phase of 5-95 % acetonitrile in water/0.1 % formic acid.

Cell Accumulation Assay

Cells (8xlO⁴/ml) were incubated at 37⁰C in culture medium containing 6μM compound in a 5% (v/v) CO₂-humidified atmosphere. Incubations were terminated after 6h by centrifugation of 25ml aliquots of the cell suspension at 300g for 5 minutes at 4 ⁰C.

0.2ml samples of the culture media supernatants were added to 4 volumes of acetonitrile (Sigma-Aldrich). After decanting the supernatant, the residual cell pellet (2xlO⁶ cells) was extracted into ImI of acetonitrile. Samples were then analysed for the ester and acid metabolite at room temperature by LC/MS/MS (Sciex API3000). Chromatography was based on an AcCN (75x2 lmm) column with a 5-95% (v/v) acetonitrile, 0.1% (v/v) formic acid mobile phase. For the zero time samples, the cell suspension was chilled and centrifuged as soon as the ester had been added and then extracted into acetonitrile as described. Levels in cells are expressed as ng/ml.

EXAMPLES

Abbreviations MeOH = methanol; EtOH = ethanol; EtOAc = ethyl acetate; Boc = tert- butoxycarbonyl; DCM = dichloromethane; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; DMAP = dimethylamino pyridine; DEAD = diethylazodicarboxylate; EDC = 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide; TFA = trifluoroacetic acid; THF = tetrahydrofuran; Na₂CO₃ = sodium carbonate; HCl = hydrochloric acid; DIPEA = diisopropylethylamine; NaH = sodium hydride; NaOH = sodium hydroxide; NaHCO₃ = sodium hydrogen carbonate; Pd/C = palladium on carbon; EDC = l-ethyl-3-(3- dirnethylaminopropyl)carbodiimide; ml = millilitre; g = gram(s); mg = milligram(s); mol = moles; mmol = millimole(s); Sat = saturated; LC/MS = high performance liquid chromatography/mass spectrometry; NMR = nuclear magnetic resonance.

Reagents and Apparatus

Commercially available reagents and solvents (HPLC grade) were used without further purification. Solvents were removed using a Buchi rotary evaporator. Purification of compounds by flash chromatography column was performed using silica gel, particle size 40-63 μm (230-400 mesh) obtained from Silicycle. Purification of compounds by preparative HPLC was performed on Gilson systems using reverse phase ThermoHypersil-Keystone Hyperprep HS C18 columns (12 μm, 100 X 21.2 mm), gradient 20-100% B ( A= water/ 0.1% TFA, B= acetonitrile/ 0.1% TFA) over 9.5 min, flow = 30 ml/min, injection solvent 2:1 DMSO:acetonitrile (1.6 ml), UV detection at 215 nm. 1H NMR spectra were recorded on a Bruker 400 MHz AV spectrometer in deuterated solvents. Chemical shifts δ are in parts per million. Thin-layer chromatography (TLC) analysis was performed with Kieselgel 60 F₂₅₄ (Merck) plates and visualized using UV light.

Analytical HPLC/MS was performed on an Agilent HPl 100 LC system using reverse phase Hypersil BDS Cl 8 columns (5 μm, 2.1 X 50 mm), gradient 0-95% B (A= water/ 0.1% TFA, B= acetonitrile/ 0.1% TFA) over 2.10 min, flow = 1.0 ml/min. UV spectra were recorded at 215 nm using a G1214A single wavelength UV detector. Mass spectra were obtained over the range m/z 150 to 850 at a sampling rate of 2 scans per second or 1 scan per 1.2 seconds using LC/MSD Quad SW ESI interface. Data were integrated and reported using OpenLynx and OpenLynx Browser software.

Intermediates

Intermediate 1: 2-Amino-4-(benzyloxy)-2-methylbutanenitrile

98% Sodium cyanide (1.81g, 36.9mmol) in water (3ml) was treated with ammonium chloride (2.17g, 40.6mmol) in lukewarm water (5ml). Ammonium hydroxide (2.88ml, 73.8mmol) was then added, followed by 4-benzyloxy-2-butanone (6.58g, 36.9mmol) in ethanol (1 ImI). The resulting mixture was stirred at RT for 15 min, then at 60 °C for 2 hours. After cooling to RT the reaction mixture was concentrated under reduced pressure and partitioned between water (100ml) and DCM (100ml). The aqueous layer was extracted with DCM (3 x 75ml). The combined organic layers were dried (MgSO₄), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc in heptane) to afford the title compound as a colourless oil (4.7Og, 62%). m/z 205 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.36 (2H, br s), 7.33-7.25 (3H, m), 4.56-4.49 (2H, m), 3.73 (2H, t, J=6.1 Hz), 2.67-2.27 (2H, m), 1.49 (3H, s). Intermediate 2: Methyl 4-fbenzyloxy)isovalinate

Anhydrous methanol (5ml) was cooled to 0 °C and then saturated with HCl (g) for

5 min. Intermediate 1 (2.Og, 9.8mmol) in methanol (7ml) was added and the reaction mixture stirred at 65 °C for 48 hours. The reaction mixture was cooled to RT, concentrated under reduced pressure and partitioned between water (50ml) and EtOAc (50ml). The aqueous layer was isolated, diluted with saturated NaHCO₃ and extracted with EtOAc (3 x 50ml). The combined organic layers were dried (MgSO₄), filtered and concentrated under reduced pressure to afford the crude product as a dark yellow oil (2.32g, 100%). m/z 238 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.35-7.26 (5H, m), 5.39 (IH, br s), 4.57 (2H, d, J=5.8 Hz), 3.64 (3H, s), 3.61-3.52 (2H, m), 2.28-2.14 (2H, m), 1.53 (3H, s).

Intermediate 3: Methyl 4-fbenzyloxy)-N-(tert-butoxycarbonyl)isovalinate

To a solution of Intermediate 2 (2.32g, 9.78mmol) in DCM (20ml) was added Et₃N (6.8ml, 48.9mmol). The reaction mixture was cooled to 0 ⁰C and to it was added BoC₂O (2.56g, 11.7mmol) in 2 portions. The reaction was stirred at RT for 24 hours and the product was extracted onto silica under reduced pressure. Purification was performed by automated column chromatography (EtOAc in heptane) to afford the title compound as a colourless oil (0.37g, 15%). m/z 360 [M+Na]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.46-7.18 (5H, m), 6.03 (IH, br s), 4.45 (2H, m), 3.64 (3H, s), 3.55 (2H, t, J=5.6 Hz), 2.41-2.07 (2H, m), 1.58 (3H, s), 1.44 (9H, s).

Intermediate 4: Methyl N-(tert-butoxycarbonylV4-hvdroxyisovalinate

To a solution of Intermediate 3 (370mg, l.lOmmol) in EtOAc (15ml) was added 10% PdVC (74mg, 20% w.w.). The system was evacuated and put under a hydrogen atmosphere. It was then allowed to stir for 24 hours at RT under a hydrogen atmosphere. The system was evacuated of hydrogen and the palladium residues removed by filtration over Celite. The Celite was washed thoroughly with EtOAc and the solvent removed under reduced pressure. The crude residue was purified by column chromatography (50% EtOAc in heptane) to afford the title compound as a colourless oil (251mg, 93%). m/z 270 [MH-Na]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 5.84 (IH, br. s.), 3.80-3.64 (5H, s), 2.30-2.07 (2H, m), 1.58 (3H, s), 1.43 (9H, s).

Intermediate 5: Methyl 4-bromo-N-ftert-butoxycarbonyl^*)isovalinate

To a solution of Intermediate 4 (1.22g, 4.94mmol) in DCM (70 ml) was added triphenylphosphine (1.37g, 5.22mmol) and carbon tetrabromide (1.83g, 5.51mmol). The mixture was stirred for 90 minutes and then loaded directly onto a silica gel and purified by column chromatography (50% EtOAc in heptane) to yield the title compound as a white solid (1.025g, 67%). m/z 332/334 [M+Na]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 3.79 (3H, s), 3.22-3.44 (2H, m), 2.69-2.86 (IH, m), 2.44-2.56 (IH, m), 1.57 (3H, s), 1.45 (9H, s).

Intermediate 6: Methyl 4-(6-amino-9H-purin-9-yl)-N-(tert- butoxycarbonvDisovalinate

To a solution of adenine (200mg, 1.48mmol) in DMF (5ml) was added cesium carbonate (1.1 Og, 3.38mmol) and Intermediate 5 (41 lmg, 1.32mmol). The mixture was stirred at RT for 4 hours and then poured into EtOAc (200ml) and washed with water (4 x 50ml). The crude product was carried forward to the next stage without any further purification, m/z 365.25 [M+H]⁺.

Intermediate 7: Methyl 4-(6-amino-8-bromo-9H-purin-9-vD-N-(tert- butoxycarbonvDisovalinate

To the crude Intermediate 6 (1.48mmol) in DCM (10ml) was added N- bromosuccinimide (329mg, 1.84mmol). The solution was stirred at RT for 18 hours and then concentrated under vacuum. The residue was dissolved in EtOAc and purified by flash column chromatography (EtOAc in heptane) to yield the title compound as a colourless oil (73mg, 11%). m/z 443/445 [M+H]⁺; ¹H NMR (300 MHz, CZ)Cl₃) δ: 8.27 (IH, s), 6.26 (2H, br s), 5.62 (IH, br s), 4.21 (2H, t, J=7.5 Hz), 3.66 (3H, s), 2.49-2.65 (2H, m), 1.57 (3H, s), 1.41 (9H, s).

Intermediate 8: Methyl 4-(6-amino-8-r(2-bromo-5-methoxyphenyl^')thio]-9H-purin-9-yU-N- (tert-butoxycarbonyl)isovalinate

To a solution of 2-bromo-5-methoxy-benzenethiol (55mg, 0.25mmol - prepared as described in J. Med. Chem., 2006, 49, 817-828) in DMF (2ml) and potassium tert-butoxide (39mg, 0.34mmol) was added Intermediate 7 (73mg, O.lόmmol) as a solution in DMF (2ml). The solution was then heated at 120⁰C for 1 hour. The mixture was poured into diethyl ether (200ml) and washed with water (4 x 50ml). The extracts were dried (MgSO₄), concentrated and purified by flash column chromatography (EtOAc) to yield the title compound (17mg, 18%). m/z 581/583 [M+H]⁺. Example 1: Methyl 4- j6-amino-8-IY2 -bromo-5-methoxyphenyl)tMo]-9H-purin-9- vUisovalinate

To Intermediate 8 (14mg, 0.02mmol) was added 4M HCl in dioxane (4ml). The mixture was stirred for 1 hour and then concentrated under vacuum. The solid obtained was washed with diethyl ether (2 x 20ml) and dried under vacuum to yield the title compound as an off-white solid (5mg, 36%). m/z 481 [M+H]⁺; ¹H NMR (300 MHz, CD₃OD) δ: 8.45 (IH, s), 7.69 (IH, d, J=8.8 Hz), 7.22 (IH, d, J=3.0 Hz), 7.01 (IH, dd, J=3.0, 8.8 Hz), 4.52^.63 (IH, m), 4.36-4.48 (IH, m), 3.93 (3H, s), 3.81 (3H, s), 2.51 (2H, t, J=7.9 Hz), 1.73 (3H, s).

Example 2: 4- |6-Amino-8-r(2-bromo-5-methoxyphenyl)thiol-9H-purin-9-yl}isovaline

Example 2 was prepared from Example 1 using the methodology described in scheme 3 above. To a solution of Example 1 (17mg, 0.029mmol) in diethyl ether (5ml) was added potassium trimethyl silanolate (32mg, 0.25mmol). The mixture was heated at 40 ⁰C for 12 hours, cooled to RT and then concentrated. The mixture was purified by preparative HPLC to yield the title compound as a white solid (2.6mg, 19%). m/z 467/469 [M+H]⁺; ¹H NMR (300 MHz, d₆-OMSO) δ: 8.55 (3H, br s), 8.24 (IH, s), 7.71 (2H, br s), 7.62 (IH, d, J=8.7 Hz), 6.87 (IH, d, J=3.0,9.0 Hz), 6.50 (IH, d, J=2.1 Hz), 4.40-4.36 (IH, m), 4.21-4.35 (IH, m), 3.64 (3H, s), 2.24-2.32 (2H, m).

Example 3: Biological Data Hsp90 Assay

An HTRP (homogeneous time resolved fluorescence assay) assay was used to measure the interaction of the compounds with HSP90. The assay measures binding of biotinylated GM (bio-GM; Biomol, # EI-341, lot:

A9199a) to human recombinant his-tagged HSP90α (HSP90; Prospec Technogene, #HSP90, lot: 260HSP9001). A signal is generated by fluorescence resonance energy transfer from an Europium-cryptate labeled anti-his antibody (anti-his-K; Cisbio International, # 6 IHISKLA, lot: 33V) via the HSP90-GM-biotin complex to a fluorescence acceptor (allophycocyanin) linked to streptavidin (SA-XL; Cisbio International, # 61 OSAXLB, lot: 089).

Unlabeled GM or compounds compete with the bio-GM for binding to HSP90 resulting in reduced fluorescence energy transfer/assay signal.

For the assay a preformed (Ih incubation) complex of HSP90 with the anti-his-K is added to the compound solution in a 384 well microplate (Corning, # 3710) and incubated for 15 min. A preformed (Ih incubation) complex of bio-GM with the SA-XL was added to the wells and incubated for 20 h. All incubations were performed at room temperature. The final assay volume was 50 μl/well. The final concentrations in the assay were: 50 mM Hepes pH 7.3, 50 mM NaCl, 100 mM KF, 1 mM EDTA, 1 mM DTT, 0.1% Triton-X-100, 1 nM anti-his-K, 40 nM HSP90, 40 nM SA-XL, 40 nM bio-GM. Test compounds were dissolved in DMSO, prediluted in assay buffer and tested at a final concentration between 5000 nM and 0.3 nM. The resulting DMSO concentration was 0.5% and included in all controls. High controls were without test compounds, low controls without test compounds, without HSP90 and without bio-GM. As a reference inhibitor unlabeled GM was used in the same concentrations as the test compounds. Inhibition was calculated compared to the assay controls using an Excel spreadsheet (Microsoft). IC₅₀ values were calculated by non-linear least squares fitting to the standard dose-response model using GraphPad Prism (GraphPad Software Inc).

Cell inhibition Assay

The corresponding cancer cell lines (U937 and HUT) growing in log phase were harvested and seeded at 1000 cells/well (200μl final volume) into 96- well tissue culture plates. Following 24h of cell growth cells were treated with compounds (final concentration of 20μM). Plates were then re-incubated for a further 72h before a sulphorhodamine B (SRB) cell viability assay was conducted according to Skehan 1990 J Natl Cane Inst 82, 1107-1112.

Data were expressed as a percentage inhibition of the control, measured in the absence of inhibitor, as follows:-

% inhibition = 100-((SVS°)xl 00) where S¹ is the signal in the presence of inhibitor and S⁰ is the signal in the presence of DMSO.

IC50 values were determined by non-linear regression analysis, after fitting the results of eight data points to the equation for sigmoidal dose response with variable slope (% activity against log concentration of compound), using Graphpad Prism software.

IC50 results were allocated to one of 3 ranges as follows:

Range A: IC50<1000nM,

Range B: IC50 from 100OnM to 500OnM; and Range C: IC50 >5000nM.

NT = Not tested

Claims

1. A compound which is (a) an amino acid derivative of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof:

wherein:

R¹ represents a hydrogen or halogen atom, or a cyano, nitro, -N₃, Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_2-6 alkenyloxy, hydroxyl, -SR', C_1-6 alkylthio, C_2-6 alkenylthio, guanidine, amidine, -NR'R", -NR" OR' or -NR'"R'R" group wherein each R', R" and R'" group is the same or different and represents hydrogen or C_1-4 alkyl, or represents a group of formula -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -CONHR^A, -SO₂NHR^A,

-CONR >A^AR_DB^B, -SO₂NR ,A^A _nRB^B, -OCONH₂, -0C0NHR^A, -0C0NR A^ATR₃B^B, -NHCOR^A, NHCOOR^A, -NR^BCOOR^A, -NHSO₂R^A, -NR^BSO₂R^A, -NHSO₂OR^A, -NR⁸SO₂OH, -NR^BSO₂OR^A, -NHCONH₂, -NR^ACONH₂, -NHCONHR^B, -NR^AC0NHR^B, -NHC0NR^AR^B or -NR^AC0NR^AR^B wherein R^A and R^B are the same or different and represent C_1-6 alkyl, C_3-6 cycloalkyl, non-fused phenyl or a non-fused 5- to 6-membered heteroaryl, or R^A and R^B when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group; R² represents a hydrogen or halogen atom, or a cyano, nitro, -N₃, C_1-6 alkyl, Ci_-6 alkenyl, C_2-6 alkynyl group, or a group of formula -NR'R", -CO₂R', -SO₂R', -NR'OR" or -CONR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-4 alkyl, or a C_6-I0 aryl, 5- to 10- membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; x and y are the same or different and represent zero or 1 ; L¹ represents Ci_-4 alkylene;

Het represents -S-, -S(O)-, -S(O)₂-, -NR'- or -O- where R' represents hydrogen or unsubstituted C_1-4 alkyl; A represents a C_6- io aryl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to

10-membered heterocyclyl group which is optionally fused to a further C_6-Io aryl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group;

W is a group of formula -[CH₂]_Z-Y¹-L²-R, wherein: - z is O or l;

Y¹ represents a bond or a group of formula -S-, -O-, -(C=O)-, -(S=O)-, -S(O₂)-, -NR³-, -(C=O)NR³-, -NR³(C=O)-, -S(O₂)NR³-, -NR³S(O₂)-, -NR³(C=O)NR⁴- or -NR³(C=S)NR⁴-, wherein R³ and R⁴ are the same or different and represent hydrogen or C_1-6 alkyl; - L² is a divalent radical of formula -(Alk'^Q^Alk^_p- wherein: m, n and p are independently O or 1 ;

Q either (i) represents a phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; or (ii) in the case where p is O, represents a group of formula -Q¹Ot¹- wherein X¹ represents -0-, -S- or -NR⁵- wherein R⁵ is hydrogen or Ci^ alkyl, and Q¹ represents a phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl,

C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; AIk¹ and AIk² are the same or different and represent C_3-7 carbocyclyl groups, or represent Ci_-6 alkylene, C_2-6 alkenylene, or C_2-6 alkynylene groups which may optionally contain or terminate in an ether (-O-), thioether (-S-) or amino (-NR⁶-) link wherein R⁶ represents hydrogen or Ci_-4 alkyl; R is a radical of formula (X):

wherein:

R⁷ is a group -COOH or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a -COOH group;

R⁸ represents hydrogen or a Ci^ alkyl, -(C=O)R⁹, -(C=O)OR¹⁰ or -(C=O)NR¹⁰ group wherein R⁹ represents hydrogen, a C_1-6 alkyl group, a phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, or R⁹ represents a group of formula -Alk⁴-Cyc wherein AIk⁴ represents a C_1-6 alkylene group and Cyc represents a phenyl, 5- to 10-membered heteroaryl or 5- to 10- membered heterocyclyl group optionally fused to a further phenyl,

5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, and R¹⁰ represents hydrogen or C_1-6 alkyl, or wherein R represents a phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; and

R¹⁹ represents a C₁^ alkyl group or a group -L³ -B where L³ represents a bond or a Ci_-6 alkylene group and B represents a C_6-10 aryl or 5- to 10-membered heteroaryl group; wherein the alkyl, alkylene, alkenyl and alkynyl moieties in R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹⁹, AIk¹, AIk² and AIk³ are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_M alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C_2-4 alkenyloxy, C_M haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Ci_-4 hydroxyalkyl, C_2-4 hydroxyalkenyl, C_M alkylthio, C_2-4 alkenylthio, phenyl, -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl, and groups of formula -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -S0₂NHR^A, -CONR^AR^B, -SO₂NR^AR^B, -OCONH₂, -0C0NHR^A, -OCONR^AR^B, -NHC0R^A, NHC00R^A, -NR^BC00R^A, -NHS0₂0R^A, -NR⁸SO₂OH, -NR^BSO₂OR^A, -NHCONH₂, -NR^ACONH₂, -NHCONHR⁸,

-NR^AC0NHR^B, -NHC0NR^AR^B or -NR^AC0NR^AR^B wherein R^A and R^B are the same or different and represent C_1-6 alkyl, C_3-6 cycloalkyl, phenyl or a non-fused 5- to 6-membered heteroaryl, or R^A and R^B when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R¹, R², R⁸, R⁹, R¹⁹, A, B, Q, Q¹ and D are unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected from halogen atoms and C_M alkyl, C_1-4 alkylene, C_2-4 alkenyl, C_M alkoxy, C_2-4 alkenyloxy, C_M haloalkyl, C₂^ haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C_M hydroxyalkyl, C_2^» hydroxyalkenyl, Ci_-4 alkylthio, C_2-4 alkenylthio, -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C_M alkyl, and groups of formula -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -S0₂NHR^A, -C0NR^AR^B, -S0₂NR^AR^B, -OCONH₂,

-0C0NHR^A, -0C0NR^AR^B, -NHCOR^A, NHC00R^A, -NR^BC00R^A, -NHSO₂OR^A, -NR⁸SO₂OH, -NR^BS0₂0R^A, -NHCONH₂, -NR^AC0NH₂, -NHC(NH)NH₂, -NHC(NH)NHR⁸, -NHC(NH)NR^AR^B, -NHCONHR⁸, -NR^AC0NHR^B, -NHC0NR^AR⁸ or -NR^ACONR^AR^B wherein R^A and R⁸ are the same or different and represent C_1-6 alkyl, C_3-6 cycloalkyl, phenyl or a non-fused 5- to 6-membered heteroaryl, or R^A and R^B when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group.

2. A compound as claimed in claim 1 wherein R¹ represents a hydrogen or halogen atom, or an unsubstituted C_M alkyl, hydroxyl, Ci_-4 alkoxy, -SR', Ci_-4 alkylthio, -NR'R" or -CONR^AR^B group where R', R", R^A and R^B are the same or different and represent hydrogen or unsubstituted Ci_-4 alkyl group, and wherein the alkyl groups or moieties in R¹ are unsubstituted or substituted by 1, 2 or 3 substituents which are themselves unsubstituted and are selected from halogen, C_M alkyl, C_2-4 alkenyl, CM alkoxy, hydroxyl, C_M haloalkyl, C_2-4 haloalkenyl, C_M haloalkyloxy, C_2-4 haloalkenyloxy and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl.

3. A compound as claimed in claim 1 or claim 2 wherein R² represents a hydrogen or halogen atom, an unsubstituted C_M alkyl group or a group of formula -NR'R" where R' and R' ' are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl.

4. A compound as claimed in any one of the preceding claims wherein x is zero and y is one.

5. A compound as claimed in any one of the preceding claims wherein Het represents -S-, -S(O)- or -S(O)₂-.

6. A compound as claimed in any one of the preceding claims wherein A represents an unsubstituted or substituted group selected from non-fused phenyl, non-fused 5- to 6- membered heteroaryl, non-fused C_3-7 carbocyclyl, non-fused 5- to 6-membered heterocyclyl group, a phenyl group which is fused to a further 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group which is fused to a further phenyl group, and wherein the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties are unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, C_M alkoxy, C_2-4 alkenyloxy, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Q_-4 hydroxyalkyl, C_2-4 hydroxyalkenyl, Ci_-4 alkylthio, C₂^ alkenylthio and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and groups of formula COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -S0₂NHR^A, -C0NR^AR^B and -SO₂NR^AR^B wherein R^A and R^B are the same or different and represent Ci_-4 alkyl.

7. A compound as claimed in any one of the preceding claims wherein z is zero and the methylene group in W is absent.

8. A compound as claimed in any one of the preceding claims wherein Y¹ is a bond or represents a group of formula -O-, -S-, -0-(C=O)-, -(C=O)-O-, -(C=O)-, -(S=O)-, -S(O₂)-, -NR³-, -(C=O)NR³-, -NR³(C=O)-, -S(O₂)NR³- and -NR³S(O₂)-, wherein R³ represents hydrogen or Ci_-6 alkyl.

9. A compound as claimed in any one of the preceding claims wherein L² represents a group of formula -(Alk¹)_m-(Q)_n-(Alk²)_p- wherein: m, n and p are the same or different and represent zero or 1 ; AIk¹ represents a Ci_-4 alkylene group;

Q represents phenyl optionally fused to a further phenyl, a 5- to 10-membered heteroaryl optionally fused to a further phenyl, a non-fused C_3-7 carbocyclyl or a non-fused 5- to 10-membered heterocyclyl group; and AIk² represents a Ci_-4 alkylene group; and wherein the alkylene groups in L² are unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, Ci_-2 alkoxy, hydroxyl and -NR'R' ' wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl, and wherein the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in L² are unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, Ci_-4 alkoxy and hydroxyl groups.

10. A compound as claimed in any one of the preceding claims wherein: R⁷ represents -COOH or is an ester group -COOR¹ ' wherein the ester group is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group; and

R⁸ represents hydrogen or a C_1-6 alkyl, -(C=O)R⁹ or -(C=O)OR¹⁰ wherein R⁹ and R¹⁰ are as defined in claim 1.

11. A compound as claimed in any one of the preceding claims wherein R¹⁹ represents an unsubstituted C_1-6 alkyl group or a C_1-6 alkyl group substituted with one halogen atom or a Ci_-2 alkoxy, C_1-2 haloalkyl, hydroxyl, -COOR', -COONR R", -SR' or -NR'R" group wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl, or R¹⁹ represents a group -L³-B where L³ represents a bond or an unsubstituted Ci_-6 alkylene group and B represents an unsubstituted or substituted C_6-I0 aryl or 5- to 10-membered heteroaryl group, the substituents on the aryl or heteroaryl group being independently selected from 1, 2, 3 or 4 halogen atoms or Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 alkylthio or hydroxy groups.

12. A compound as claimed in any one of the preceding claims wherein:

- R¹ represents hydrogen or halogen atom, or an unsubstituted Ci_-4 alkyl, hydroxyl, Ci_-4 alkoxy, -SR', Ci_-4 alkylthio, -NR'R" or -CONR^AR^B group where R', R", R^A and R^B are the same or different and represent hydrogen or unsubstituted Ci_-4 alkyl group, and wherein the alkyl groups or moieties in R¹ are unsubstituted or substituted by 1, 2 or 3 substituents which are themselves unsubstituted and are selected from halogen, C_M alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, hydroxyl, C_M haloalkyl, C_2-4 haloalkenyl, C_M haloalkyloxy, C_2-4 haloalkenyloxy and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Cj_-2 alkyl;

R² represents a hydrogen or halogen atom, an unsubstituted C_M alkyl group or a group of formula -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl; - x is zero and y is one;

- Het represents -S-, -S(O)- or -S(O)₂-; - A represents an unsubstituted or substituted group selected from non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non-fused C_3-7 carbocyclyl, non-fused 5- to 6-membered heterocyclyl group, a phenyl group which is fused to a further 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group which is fused to a further phenyl group, and wherein the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties are unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, C_2-4 alkenyloxy, C_1-4 haloalkyl, C_2-4 haloalkenyl, C_M haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Ci_-4 hydroxyalkyl, C_2-4 hydroxyalkenyl, Ci_-4 alkylthio, C_2-4 alkenylthio and -NR 'R" groups wherein each R' and R" is the same or different and represents hydrogen or C₁^ alkyl, and groups of formula COR^A, -SC>2R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -SO₂NHR^A, -C0NR^AR^B and -SO₂NR^AR^B wherein R^A and R^B are the same or different and represent Ci_-4 alkyl; z is zero;

Y¹ is a bond or represents a group of formula -O-, -S-, -0-(C=O)-, -(C=O)-O-, -(C=O)-, -(S=O)-, -S(O₂)-, -NR³-, -(C=O)NR³-, -NR³(C=O)-, -S(O₂)NR³- and -NR³S(O₂)-, wherein R³ represents hydrogen or C_1-6 alkyl; - m, n and p are the same or different and represent zero or 1 ;

AIk¹ represents a C_1-4 alkylene group which is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, Ci_-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl; - Q represents phenyl optionally fused to a further phenyl, a 5- to 10-membered heteroaryl optionally fused to a further phenyl, a non-fused C_3-7 carbocyclyl or a non-fused 5- to 10-membered heterocyclyl group, and wherein the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups of Q are unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_M alkoxy and hydroxyl groups; AIk² represents a Ci_-4 alkylene group which is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, Ci_-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl;

R⁸ represents hydrogen or a Ci_-6 alkyl, -(CO)R⁹ or -(C=O)OR¹⁰ wherein R⁹ and R¹⁰ are as defined in claim 1 ; and

R¹⁹ represents an unsubstituted Ci_-6 alkyl group or a Ci_-6 alkyl group substituted with one halogen atom or a Ci_-2 alkoxy, Ci_-2 haloalkyl, hydroxyl, -COOR', -COONR'R", -SR' or -NR'R" group wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl, or R¹⁹ represents a group -L³ -B where L³ represents a bond or an unsubstituted Ci_-6 alkylene group and B represents an unsubstituted or substituted C_6-Io aryl or 5- to 10-membered heteroaryl group, the substituents on the aryl or heteroaryl group being independently selected from 1, 2, 3 or 4 halogen atoms or Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 alkylthio or hydroxy groups.

13. A compound as claimed in any one of the preceding claims which is (a) an amino acid derivative of formula (IA) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof:

wherein: - R² represents a hydrogen or halogen atom, an unsubstituted C_M alkyl group or a group of formula -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl;

A represents an unsubstituted or substituted group selected from non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non-fused C_3-7 carbocyclyl, non-fused 5- to 6-membered heterocyclyl group, a phenyl group which is fused to a further 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group which is fused to a further phenyl group, and wherein the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties are unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, C_2-4 alkenyloxy, C_M haloalkyl, C₂^ haloalkenyl, C_M haloalkoxy, C₂^ haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C_1-4 hydroxyalkyl, C_2-4 hydroxyalkenyl, C_1-4 alkylthio, C_2-4 alkenylthio and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and groups of formula COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -SO₂NHR^A, -CONR^AR^B and -SO₂NR^AR^B wherein R^A and R^B are the same or different and represent Ci_-4 alkyl; - W is a group of formula - Y¹ -L²-R; - Y¹ is a bond or represents a group of formula -O-, -S-, -0-(C=O)-, -(C=O)-O-,

-(C=O)-, -(S=O)-, -S(O₂)-, -NR³-, -(C=O)NR³-, -NR³(C=0)-, -S(O₂)NR³- and -NR³S(O₂)-, wherein R³ represents hydrogen or Ci_-6 alkyl;

<- - either (i) m is 1, n and p are zero, and L² represents a group -AIk¹- wherein AIk¹ represents a C_M alkylene group which is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, Ci_-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl; or (ii) m is zero, n and p are 1, L² represents non-fused phenyl or a non-fused 5- to 10- membered heteroaryl group and AIk² represents a C_M alkylene group; R⁷ represents -COOH or is an ester group -COOR¹¹ wherein the ester group is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group;

- R⁸ represents hydrogen or a C_1-6 alkyl, -(C=O)R⁹ or -(C=O)OR¹⁰ wherein R⁹ is C_1-6 alkyl, non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non-fused

C_3-7 carbocyclyl or a group -Alk⁴-Cyc, and R¹⁰ is hydrogen or C_1-4 alkyl; and

- R¹⁹ represents an unsubstituted C_1-4 alkyl group or a group -L³ -B where L³ represents a bond or an unsubstituted C_1-2 alkylene group and B represents an unsubstituted phenyl group or a phenyl group substituted with one substituent selected from a halogen atom or a Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 alkylthio or hydroxy group.

14. A compound as claimed in claim 13 wherein R² represents a hydrogen or halogen atom or an -NH₂ group.

15. A compound as claimed in claim 14 wherein R² represents a hydrogen atom.

16. A compound as claimed in any one of claims 13 to 15 wherein A represents a group selected from phenyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, pyrrolyl-2,5-dione and benzoquinone, or A represent a phenyl ring fused to a 5- to 6-membered heterocyclyl group selected from oxazolidinyl, imidazolidinyl, thiazolidinyl, thioxolanyl, dioxolanyl and dithiolanyl, and wherein A is unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and represent halogen atoms or Ci_-4 alkyl, Ci_-2 alkoxy, Ci_-2 alkylthio or hydroxy groups.

17. A compound as claimed in claim 16 wherein A represents a non-fused phenyl ring or a phenyl ring fused to a dioxolanyl ring, and wherein A is unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and represent halogen atoms or C_M alkyl, Ci_-2 alkoxy, Ci_-2 alkylthio or hydroxy groups.

18. A compound as claimed in any one of claims 13 to 18 wherein Y¹ is a bond or represents a group of formula -O-, -S-, -NR³-, -C(O)-O-, -0-(C=O)-, -(C=O)NR³- or -NR³(C=O)- wherein R³ is hydrogen or C_1-6 alkyl.

19. A compound as claimed in any one of claims 13 to 18 wherein R⁷ represents a group -COOH or -COOR¹¹, wherein R¹¹ represents -CR¹²R¹³R¹⁴ and:

(i) R¹³ represents hydrogen or a group of formula -[Ci_-4 alkylene]b-(Z¹)_a-[Ci-4 alkyl] or -[C_M alkylene]_b-(Z¹)_a-[C_2-4 alkenyl] wherein a and b are the same or different and represent O or 1, and Z¹ represents -0-, -S-, or -NR¹⁷- wherein R¹⁷ is hydrogen or C_M alkyl, R¹⁴ represents hydrogen or C_M alkyl, and R¹² represents hydrogen or C_M alkyl; (ii) R¹³ represents a phenyl or a 5- to 10-membered heteroaryl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group, R¹⁴ represents hydrogen or C_M alkyl, and R¹² represents hydrogen; (iii) R¹³ represents a group of formula -(Alk³)-NR¹⁵R¹⁶ wherein AIk³ represents a CM alkylene group and either (a) R¹⁵ and R¹⁶ are the same or different and represent hydrogen or C_M alkyl, or (b) R¹⁵ and R¹⁶, together with the nitrogen atom to which they are bonded, form a 5- to 10- membered heteroaryl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; R¹⁴ represents hydrogen or C_M alkyl, and R¹² represents hydrogen; or (iv) R¹³ and R¹⁴, together with the carbon atom to which they are bonded, form a phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group which is optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, and R¹² represents hydrogen.

20. A compound as claimed in claim 19 wherein R¹¹ represents -CR¹²R¹³R¹⁴, and either: (i) R¹² represents hydrogen or C_1-2 alkyl; R¹³ represents hydrogen, C_1-4 alkyl,

C_2-4 alkenyl or a group -(C_1-4 3UCyI)-O-(C_1-4 alkyl); and R¹⁴ represents hydrogen or C_1-2 alkyl; or

(ii) R¹² represents hydrogen or Ci_-2 alkyl, and R¹³ and R¹⁴ form a cyclic group together with the carbon atom to which they are bonded, form a non-fused C_3-7 carbocyclyl groups which is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, Ci_-4 alkylene, C_M alkoxy, Ci_-4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl.

21. A compound as claimed in any one of the preceding claims which is (a) an amino acid derivative of formula (EB) or a tautomer thereof, or (V) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof:

wherein:

A represents a non-fused phenyl ring or a phenyl ring fused to a dioxolanyl ring, and wherein A is unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and represent halogen atoms or C ₁-₄ alkyl, Ci_-2 alkoxy, C_1-2 alkylthio or hydroxy groups; and W represent a group of formula -Y'-L^-R wherein:

Y¹ is a bond or represents a group -O-, -S-, -NR³-, -Q=O)-O-, -0-(C=O)-, -(C=O)NR³- or -NR³(C=O)- wherein R³ is hydrogen or Ci_-6 alkyl; L² represents a group -AIk¹- or a group -Q-AIk²- and -AIk¹- represents an unsubstituted Ci_-4 alkylene group, Q represents a non-fused phenyl ring or a non-fused pyridinyl or thienyl ring and AIk² represents an unsubstituted C_1-4 alkylene group; and - R⁷ represents -COOH or -COOR¹¹ wherein R¹¹ represents

-CR¹²R¹³R¹⁴, and either:

(i) R¹² represents hydrogen or Ci_-2 alkyl; R¹³ represents hydrogen, Ci_-4 alkyl, C_2-4 alkenyl or a group -(Ci_-4 3UCyI)-O-(Ci_-4 alkyl); and R¹⁴ represents hydrogen or Ci_-2 alkyl; or

(ii) R¹² represents hydrogen or Ci_-2 alkyl, and R¹³ and R¹⁴ form a cyclic group together with the carbon atom to which they are bonded, form a non-fused C_3-7 carbocyclyl groups which is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, Ci_-4 alkylene, Ci_-4 alkoxy, C_M haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl; - R⁸ represents hydrogen or a Ci_-6 alkyl, -(C=O)R⁹ or -(C=O)OR¹⁰ wherein R⁹ is Ci_-6 alkyl, non-fused phenyl, non-fused 5- to 6- membered heteroaryl, non-fused C_3-7 carbocyclyl or a group -Alk⁴-Cyc, and R¹⁰ is hydrogen or Ci_-4 alkyl; and R¹⁹ represents an unsubstituted Ci_-4 alkyl group or a group -L³ -B where L³ represents a bond or an unsubstituted Ci_-2 alkylene group and

B represents an unsubstituted phenyl group or a phenyl group substituted with one substituent selected from a halogen atom or a Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 alkylthio or hydroxy group.

22. A compound as claimed in claim 21 wherein A represents a phenyl ring which is unsubstituted or substituted by 1 or 2 substituents which are the same or different and represent halogen atoms or C_M alkyl, Ci_-2 alkoxy, C_1-2 alkylthio or hydroxy groups.

23. A compound as claimed in claim 21 or claim 22 wherein Y¹ is a bond.

24. A compound as claimed in any one of claims 21 to 23 wherein R⁷ represents -COOH or -COOR¹¹ and R¹¹ represents a C_1-4 alkyl or a C_3-7 carbocyclyl group.

25. A compound as claimed in any one of claims 21 to 24 wherein R represents hydrogen.

26. A compound as claimed in any one of claims 20 to 25 wherein R¹⁹ represents an unsubstituted C_1-4 alkyl group.

27. A compound as claimed in any one of the preceding claims which is (a) an amino acid derivative of formula (IC) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof:

wherein: A represents a non-fused phenyl ring or a phenyl ring fused to a dioxolanyl ring, and wherein A is unsubstituted or substituted by 1 or 2 substituents which are the same or different and represent halogen atoms or Ci_-4 alkyl, C_1-2 alkoxy, Ci_-2 alkylthio or hydroxy groups; - AIk¹ represents a Ci_-4 alkylene group;

R represents hydrogen, C_M alkyl or a C_3-7 carbocyclyl; and R¹⁹ represents an unsubstituted Ci_-4 alkyl group or a group -L³ -B where L³ represents a bond or an unsubstituted Ci_-2 alkylene group and B represents an unsubstituted phenyl group or a phenyl group substituted with one substituent selected from a halogen atom or a Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 alkylthio or hydroxy group.

28. A compound as claimed in any one of the preceding claims which is selected from:

Methyl 4-{6-amino-8-[(2-bromo-5-methoxyphenyl)thio]-9H-purin-9- yl}isovalinate; and

4- {6-Amino-8-[(2-bromo-5-methoxyphenyl)thio]-9H-purin-9-yl} isovaline.

29. A compound as defined in any one of the preceding claims, for use in treating the human or animal body.

30. A pharmaceutical composition which comprises a compound as defined in any one of claims 1 to 28 and a pharmaceutically acceptable carrier or diluent.

31. Use of a compound as claimed in any one of claims 1 to 28 in the manufacture of a medicament for use in treating or preventing disorders mediated by ΗSP90.

32. Use as claimed in claim 31 wherein the medicament is for use in the treatment or prevention of cancer.

33. Use as claimed in claim 31 wherein the medicament is for use in the treatment or prevention of inflammation.

34. A method of treating a patient suffering from or susceptible to a disorder mediated by HSP90 which method comprises administering to said patient an effective amount of a compound as defined in any one of claims 1 to 28.

35. A method as claimed in claim 34 wherein the patient is suffering from or susceptible to cancer.

36. A method as claimed in claim 34 wherein the patient is suffering from or susceptible to inflammation.

37. A compound as claimed in any one of claims 1 to 28 for use in treating or preventing disorders mediated by HSP90.

38. A compound according to claim 37 for use in the treatment or prevention of cancer.

39. A compound according to claim 38 for use in the treatment or prevention of inflammation.