WO2010043865A1

WO2010043865A1 - Inhibitors of hsp90

Info

Publication number: WO2010043865A1
Application number: PCT/GB2009/002464
Authority: WO
Inventors: Francesca Ann Day; Delphine Francoise Monique Launay; Michael Hugh Charlton; David Festus Charles Moffat
Original assignee: Chroma Therapeutics Ltd
Priority date: 2008-10-17
Filing date: 2009-10-15
Publication date: 2010-04-22
Also published as: GB0819105D0

Abstract

The invention provides a compound which is (a) a pyrrolopyrimidine derivative of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof: Formula (I) wherein R¹, R², R³, R⁴ and W are as defined herein. The compounds are useful in the treatment of diseases mediated b HSP90 and also in the treatment of inflammation.

Description

INHIBITORS OF HSP90

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 aberrant HSP90 activity as well as inflammatory and immune disorders such as rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), 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.

BACKGROUND TO THE INVENTION

Cells respond to stress by increasing the synthesis of a number of molecular chaperones: cellular machines that facilitate protein folding. Heat shock proteins (Hsps) are molecular chaperones that assist general protein folding and prevent non-functional side reactions such as non-specific aggregation of misfolded or unfolded proteins, even under normal conditions. They account for 1 to 2% of total protein in unstressed cells. However, their levels of intracellular expression increase in response to protein- denaturing stressors, such as temperature change, as an evolutionarily conserved response to restore the normal protein-folding environment and to enhance cell survival. The essential chaperoning functions of Hsps are subverted during oncogenesis to make malignant transformation possible and to facilitate rapid somatic evolution.

Hsp90 (heat shock protein 90IcDa), one of the most abundant proteins expressed in cells is a member of the heat shock protein family, upregulated in response to stress. It has been identified as an important mediator of cancer cell survival. Hsp90 binds to a variety of target or "client" proteins, among them many steroids hormone receptors, protein kinases and transcription factors. It interacts with client-proteins by facilitating their stabilisation and activation or by directing them for proteasomal degradation. Thanks to its multifaceted ability to influence signal transduction, chromatin remodelling and epigenetic regulation, development and morphological evolution, it is considered as a promising target for cancer therapy.

The Hsp90 protein contains three well-defined domains, each of these plays a crucial role in the function of the protein. The N-terminal domain, binding site for ATP, is also the binding site for Geldanamycin, a representative of the ansamycin drugs that specifically target Hsp90. The middle domain completes the ATPase site and binds to client proteins. Finally, at the C-terminal dimerisation domain, Hsp90 forms homodimers where the contact sites between subunits are localised within the C- terminus in the open conformation of the dimer. During the ATPase cycle, the three domains of Hsp90 move from an ATP-free "open" state to an ATP-bound "closed" state. The N-termini also come in contact in the closed conformation of the dimer. The functions of Hsp90 include assisting in protein folding, cell signaling, and tumor repression. In unstressed cells, Hsp90 plays a number of important roles, which include assisting in folding, intracellular transport, maintenance, and degradation of proteins as well as facilitating cell signaling.

The majority of known Hsp90 inhibitors, such as the natural products belonging to the ansamycins or radicicols families or synthetic purines, bind at the ATP-site on the N-terminal domain, resulting in client protein deactivation, destabilisation and degradation. However, compounds such as Novobiocin and Cisplatin have been reported to bind to the C-terminal domain of Hsp90, resulting in anti-cancer effect as well. Inhibition of Hsp90 can also be a result of inactivation through posttranslational modifications, typically acetylation or ubiquitinylation. When Hsp90 is inhibited, its regulatory functions are disrupted. As Hsp90 is involved in many relevant oncoproteins, it is suggested that its inhibition results in a broad range of biological activities, hence the Hsp chaperone molecule is an appealing target for cancer. Cancerous cells over express a number of proteins, including PBK and AKT and inhibition of these two proteins triggers apoptosis. As Hsp90 stabilizes the PBK and AKT proteins, its inhibition appears to induce apoptosis through inhibition of the PBK/AKT signaling pathway. Together with its co-chaperones, Hsp90 modulates tumour cell apoptosis, mediated through effects on AKT, tumor necrosis factor receptors (TNFR) and nuclear factor-κB (NF- KB) function. Finally Hsp90 participates in many key processes in oncogenesis such as self-sufficiency in growth signals, stabilization of mutant proteins, angiogenesis, and metastasis.

Recent studies have shown that Hsp90 also plays an important role in regulating pro-inflammatory signalling pathways. For example, agonists that stimulate NO production were reported to activate a mechanism that recruits Hsp90 to the eNOS. Interaction between Hsp90 and eNOS enhances activation of the enzyme in cells and in intact blood vessels leading to NO production. Following this discovery, Geldanamycin, a known natural inhibitor of Hsp90, was shown to be anti-inflammatory in vivo. Geldanamycin treatment was also shown to induce a significant reduction in IKK protein levels. IKK phosphorylates IKB, marking it for subsequent proteasomal degradation. It is therefore a crucial regulator of the NF-κB pathway, which holds prominent roles in inflammation and cancer. It has been shown that Hsp90 inhibitors prolong survival, reduce or abolish systemic and pulmonary inflammation, and restore normal lung function in a murine model of sepsis. Sepsis is associated with activation of proinflammatory mediators, including NF-κB, an important proinflammatory transcription factor that mediates up-regulated expression of several proinflammatory cytokines and chemokines, such as tumour necrosis factor α (TNF- α), IL-6, IL-8 and IL- lβ, critical for amplifying the inflammatory insult. Hsp90-complexing to the glucocorticoid receptor (GR) is necessary to maintain GR in a conformation able to bind hormone. Binding of the hormone to GR causes a conformational change in the complex which results in the interaction between Hsp90 and GR to be disrupted: the receptor then translocates from the cytoplasm to the nucleus, dimerizes and binds to DNA to activate the transcription of the target genes. Hsp90 is also required for the proper functioning of several other steroid receptors, including those responsible for the binding of aldosterone, androgen, estrogen and progesterone.

HSP90 has also been implicated in a number of other conditions, such as viral infection and Alzheimer's Disease.

A group of compounds has now been identified which are potent and selective inhibitors of HSP90 and the isoforms and splice variants thereof. The compounds of the invention are related to the Hsp90 inhibtors encompassed by the disclosures in WO 2005/028434, WO 2006/105372 and WO 2007/035963 but differ from them in that the present compounds have the amino acid motif referred to above. The compounds are - A -

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, COPD, psoriasis, Crohn's disease, ulcerative colitis, systemic lupus erythmatosis, and disorders related to angiogenesis such as 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 or in the management of viral infection or Alzheimer's Disease.

BRIEF DESCRIPTION OF THE INVENTION

The invention provides a compound which is (a) a pyrrplopyrimidine 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, Ci_-6 alkoxy, C_2-6 alkenyl, C_2-6 alkynyl, C_2-6 alkenyloxy, hydroxyl, -SR', -NR'R" or -NR" 'OR' group wherein each R' and R" is the same or different and represents hydrogen or unsubstituted Ci_-4 alkyl, or R¹ represents a group of formula -COOH, -C00R^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -SO₂NHR^A, -C0NR^AR^B, -S0₂NR^AR^B, -OCONH₂, -0C0NHR^A, -OCONR^AR^B, -NHC0R^A, -NR^BCOR^A, -NHCOOR^A, -NR^BC00R^A, -NR^BC00H, -NHC00H-, -NHS0₂R^A, -NR^BS0₂R^A, -NHS0₂0R^A, -NR^BS0₂0H, -NHSO₂H, -NR^BSO₂OR^A, -NHCONH₂, -NR^AC0NH₂, -NHC0NHR^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 an unsubstituted C_1-6 alkyl group, or a 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, hydroxyl, -N₃, C_1-6 alkyl, C_1-6 alkoxy, C_2-6 alkenyl, C_2-6 alkynyl group, or a group -SR', -NR'R", -COOR', -SO₂R', -NROR" or -CONR'R" where R' and R" are the same or different and represent a hydrogen atom, an unsubstituted C_1-4 alkyl group or an unfused C_6-1O aryl, 5- to 10- membered heteroaryl, C3-7 carbocyclyl or 5- to 10-membered heterocyclyl group;

R³ represents a hydrogen or halogen atom or a cyano, nitro, -N₃, hydroxyl, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_2-6 alkenyloxy, -SR' or -NR'R" group where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-4 alkyl; R⁴ represents a group of formula -L¹ -A¹; L¹ represents C_1-4 alkylene or C_2-4 alkenylene, the alkylene and alkenylene groups optionally containing or terminating in an -O-, -S- or -NR'- link where R' represents hydrogen or unsubstituted C_1-2 alkyl; A¹ represents a Cβ-io aryl, 5- to 10-membered heteroaryl, C_3-? carbocyclyl or 5- to 10-membered heterocyclyl group which is optionally fused to a further Ce-io aryl, 5- to 10-membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; W represents a group of formula: L² (Het)_x AIk¹ R wherein:

L² represents a group -AIk³-, -Alk³-A²- or -Alk³-Alk⁵-;

AIk³ represents a bond or a C_1-4 alkylene, C_2-4 alkenylene or C_2-4 alkynylene group;

AIk⁵ represents a C]_-4 alkylene, C_2-4 alkenylene or C_2-4 alkynylene group; A² represents a phenyl or 5- to 6-membered heteroaryl group which is unfused or fused to a further phenyl or 5- to 6-membered heteroaryl group;

Het represents -O-, -S- or -NR'- where R' represents hydrogen or unsubstituted Ci_-2 alkyl; x is O or l;

AIk¹ represents a bond or Cμg alkylene, C_2-6 alkenylene or C_2-6 alkynylene group, or a group -A³-Alk⁶- where A³ represents a phenyl or 5- to 6-membered heteroaryl group which is unfused or fused to a further phenyl or 5- to 6-membered heteroaryl group, and AIk⁶ represents a Q.6 alkylene, C_2-6 alkenylene or C_2-6 alkynylene group; R represents a group of formula (X) or (Y):

(X) (Y)

R⁸, where present, represents a hydrogen atom or a Cj_-4 alkyl group; AIk² represents a group of formula -C(R⁵)(R⁶)- when R is of formula (X) or -C(R⁵)- when R is of formula (Y), wherein R⁵ and R⁶ are the same or different and represent hydrogen or the α-substituents of an α -substituted or an α,α-disubstituted glycine or glycine ester compound; ring D, where present, is a 5- to 6-membered heterocyclyl group containing AIk² and wherein R⁷ is linked to ring D via AIk², and ring D is optionally fused to a second ring comprising a phenyl, 5- to 6- membered heteroaryl, C3-₇ carbocylyl or 5- to 6-membered heterocyclyl; and

R⁷ is a group -COOH or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a -COOH group; and wherein, unless otherwise stated: the alkyl, alkenyl and alkynyl groups and moieties in R¹, R², R³, R⁵, R⁶, R⁸, L¹, AIk¹, AIk², AIk³, AIk⁴, AIk⁵ and AIk⁶ are unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C_2-4 alkenyloxy, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Cj_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Ci_-4 hydroxyalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl; and the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in A¹, A², A³, D, R¹ and R² are unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents selected from halogen atoms, and cyano, nitro, Ci_-4 alkyl, Ci_-4 alkoxy, C_2-4 alkenyl, C_2-4 alkenyloxy, C_1-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, Ci_-4 hydroxyalkyl, -SR' and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or unsubstituted Ci_-4 alkyl, or from substituents of formula -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -SO₂NHR^A, -C0NR^AR^B, -SO₂NR^AR^B, -OCONH₂, -OCONHR^A, -0C0NR^AR^B, -NHCOR^A, -NR^BC0R^A, -NHC00R^A, -NR^BC00R^A, -NR⁵COOH, -NHCOOH, -NHSO₂R^A, -NR^BSO₂R^A, -NHS0₂0R^A, -NR³SO₂OH, -NHSO₂H, -NR^BS0₂0R^A, -NHCONH₂, -NR^AC0NH₂, -NHC0NHR^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 unsubstituted Ci-β 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.

When R⁵ and/or R⁶ represent the α substituents or an α-substituted or α,α- disubstituted glycine or glycine ester compound, any functional groups in these R⁵ and R⁶ groups may be protected. It will be known to the person skilled in the art that the term "protected" when used in relation to a functional substituent in a side chain of an α-amino acid means a derivative of such a substituent which is substantially nonfunctional. Suitable protecting groups will be described later.

The compounds of the invention are characterised by the presence in the molecule of a 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.

The compounds of the invention are also particularly useful in the treatment of inflammation, for example in the treatment of rheumatoid arthritis.

In one aspect of the invention, the compounds of the invention may be used in the preparation of a composition for treatment of cancer (for example monocyte-derived cancers), 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 or in the management of viral infection or Alzheimer's Disease.

The invention also provides compounds of formula (I), tautomers thereof or pharmaceutically acceptable salts theseof for use in the prevention or treatment of the conditions mentioned above.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 OF 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, alkenyl and alkynyl groups and moieties in R¹, R², R³, R⁵, R⁶, R⁸, L¹, AIk¹, AIk² and AIk³ are unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms and C)_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C_2-4 alkenyloxy, C_1-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C_1-4 hydroxyalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl. Unless otherwise specified, the substituents described above are preferably themselves unsubstituted.

Preferred substituents include halogen atoms and Ci_-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, mercapto, cyano, nitro, Ci_-4 hydroxyalkyl, C_2-4 hydroxyalkenyl, C]_-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 preferred substituents include halogen, Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, hydroxyl, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkyloxy and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl. More preferred substituents are halogen, unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl. For example, particularly preferred substituents include unsubstituted C_1-4 alkyl, C_1-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl.

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.

As used herein, a Ci_-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_1-4 alkyl group or moiety containing from 1 to 4 carbon atoms. Examples Of C_1-4 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, 4-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 C_1-6 alkylene group or moiety is a linear or branched alkylene group or moiety, for example a C_1-4 alkylene group or moiety. Examples include methylene, n-ethylene, n-propylene and -C(CHa)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 C_2-6 alkenyloxy group is typically a said Ci-6 alkyl (e.g. a Ci_-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 C_1-4 alkylthio or C_2-4 alkenylthio group is typically a said Ci_-4 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 C_1-4 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, Cs_-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. In 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 thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl and triazinyl, e.g. pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl and triazinyl, most preferably pyridinyl. 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 benzimidazolyl, benzoxazolyl and benzothiazolyl, most preferably benzothiazolyl.

As used herein, a 5- to 10- membered heterocyclyl group or moiety is a non- aromatic, saturated or unsaturated C_5-1O 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, IH- 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 aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in A¹, A², D, R¹ and R² are unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents selected from halogen atoms, and cyano, nitro, Ci_-4 alkyl, Ci_-4 alkoxy, C_2-4 alkenyl, C_2-4 alkenyloxy, C_1-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, C_1-4 hydroxyalkyl, -SR' and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or unsubstituted Ci_-4 alkyl, or from substituents of formula -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -C0NHR^A, -SO₂NHR^A, -CONR^AR^B, -SO₂NR^AR^B, -OCONH₂, -OCONHR^A, -0C0NR^AR^B, -NHC0R^A, -NR^BC0R^A, -NHC00R^A, -NR^BC00R^A, -NR⁸COOH, -NHCOOH, -NHSO₂R^A, -NR^BSO₂R^A, -NHSO₂OR^A, -NR²SO₂OH, -NHSO₂H, -NR^BSO₂OR^A, -NHCONH₂, -NR^AC0NH₂, -NHC0NHR^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 unsubstituted Q_-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. 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 cyano and nitro. More preferably, not more than one substituent is selected from 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, -C0NHR^A, -SO₂NHR^A, -C0NR^AR^B, -SO₂NR^AR^B, -OCONH₂, -OCONHR^A, -0C0NR^AR^B, -NHCOR^A, -NR^BC0R^A, -NHC00R^A, -NR^BC00R^A, -NR⁸COOH, -NHCOOH, -NHSO₂R^A, -NR^BS0₂R^A, -NHSO₂OR^A, -NR¹⁵SO₂OH, -NHSO₂H, -NR^BSO₂OR^A, -NHCONH₂, -NR^AC0NH₂, -NHC0NHR^B, -NR^AC0NHR^B, -NHC0NR^AR^B or -NR^ACONR^AR^B.

Typically the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in A¹, A², D, R¹ and R² 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, C_2-4 alkenyl, C]_-4 alkoxy, C_2-4 alkenyloxy, CM haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, mercapto, 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 C_1-4 alkyl. Preferably the substituents are themselves unsubstituted. More preferred substituents include halogen atoms and unsubstituted C_1-4 alkyl, Ci_-4 alkoxy, hydroxyl, C_1-4 haloalkyl, Ci_-4 haloalkoxy, Ci_-4 hydroxyalkyl, cyano, nitro, -SR' and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl. More preferred substituents include halogen atoms and Ci_-2 alkyl and Ci_-2 alkoxy groups.

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.

Preferably R¹ represents a hydrogen or halogen atom, or Ci_-4 alkyl, C_1-4 alkoxy, hydroxyl, -SR' or -NR'R" group wherein each R' and R" is the same or different and represents hydrogen or unsubstituted Ci_-4 alkyl, and wherein the alkyl groups and moieties in R¹, unless otherwise stated, are unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents selected from halogen atoms, and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, hydroxyl, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy and -NR'R" groups where R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl.

More preferably R¹ represents a hydrogen or halogen atom or an unsubstituted group selected from C]_-4 alkyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl and -NR'R" where R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl.

More preferably R¹ represents a hydrogen or halogen atom, a hydroxyl group, an unsubstituted CM alkyl or -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted methyl.

Most preferably R¹ represents a halogen atom, in particular a chlorine atom.

Preferably R² represents a hydrogen or halogen atom, or a C_1-4 alkyl, Ci_-4 alkoxy, hydroxyl, -SR' or -NR'R" group where R' and R" are the same or different and represent hydrogen or unsubstituted CM alkyl, and wherein the alkyl groups or moieties in R², unless otherwise stated, are unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents selected from halogen atoms, and Ci_-4 alkyl, C_2-4 alkenyl, Cj_-4 alkoxy, hydroxyl, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy and -NR'R" groups 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, or an unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl or -NR'R" group 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, a hydroxy group or an unsubstituted Ci_-4 alkyl or -NR'R" group where R' and R" represent hydrogen or unsubstituted C]_-2 alkyl.

More preferably R² represents -NR'R" where R' and R" represent hydrogen or unsubstituted methyl.

Most preferably R² represents -NH₂.

Preferably R³ represents a hydrogen or halogen atom or a group Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl, -SR' or -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl, and wherein the alkyl groups or moieties in R³, unless otherwise stated, are unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents selected from halogen atoms, and C_1-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, hydroxyl, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl. More preferably R³ represents a hydrogen or halogen atom or an unsubstituted C_1-4 alkyl, C_1-4 alkoxy, C_1-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl or -NR'R" group where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl.

More preferably R³ represents a hydrogen or halogen atom.

Most preferably R³ represents a hydrogen atom.

Preferred substituents on L¹ include halogen atoms and groups selected from Ci_-2 alkyl, C_1-2 alkoxy, hydroxyl and -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl.

Preferably L¹ represents Ci_-2 alkylene, said alkylene group optionally containing or terminating in -O-, -S- or -NR'- where R' is hydrogen or unsubstituted methyl, and said alkylene group being unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms, and Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted methyl.

More preferably L¹ represents a methylene group which is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms and Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl and -NH₂.

Most preferably L¹ represents an unsubstituted methylene group.

Preferably A¹ represents a phenyl, 5- to 6-membered heteroaryl, C_3-7 carbocyclyl or 5- to 6-membered heterocyclyl group which is unfused or fused to a further phenyl, 5- to 6-membered heteroaryl, C_3-7 carbocyclyl or 5- to 6-membered heterocyclyl group.

More preferably A¹ represents a phenyl or 5- to 6-membered heteroaryl group which is unfused or fused to a further phenyl or 5- to 6-membered heterocyclyl group. When A¹ represents a phenyl or 5- to 6-membered heteroaryl group which is unfused or fused to a 5- to 6-membered heterocyclyl group, the heterocyclyl group is preferably a dioxole group. For example, when A¹ represents a phenyl or 5- to 6-membered heteroaryl group which is unfused or fused to a 5- to 6-membered heterocyclyl group, a preferred A¹ group is benzodioxole.

More preferably A¹ represents a phenyl or 5- to 6-membered heteroaryl group which is unfused or fused to a further phenyl group. More preferably A¹ represents an unfused phenyl or 5- to 6-raembered heteroaryl group, more preferably an unfused 5- to 6-membered heteroaryl group such as a pyridyl group.

Preferably the A¹ group bears 0, 1, 2 or 3 substituents. Where more than one substituent is present the substituents may be the same or different. Where more than one substituent is present preferably only one substituent is a cyano or nitro group.

Preferred substituents on A¹ are selected from halogen atoms and unsubstituted Ci_-4 alkyl, C_1-4 alkoxy, hydroxyl, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, Ci_-4 hydroxyalkyl, cyano, nitro, -SR' and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl.

More preferred substituents on A¹ are selected from halogen atoms and unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl.

More preferably the substituents on A¹ are selected from halogen atoms and unsubstituted Ci_-2 alkyl and Ci_-2 alkoxy groups.

L² represents -AIk³-, -Alk³-A²- or -Alk'-Alk⁵- with AIk³, AIk⁵ and A² being as defined earlier. Preferred examples of AIk³, AIk⁵ and A² are discussed below, and it is also preferred that L² in total does not represent a bond, i.e. that AIk³ and AIk⁵ do not both represent a bond when x is zero.

Preferably AIk³ represents a bond or a Ci_-3 alkylene, C_2-3 alkenylene or C_2-3 alkynylene group. More preferably AIk³ represents a Ci_-3 alkylene, C_2-3 alkenylene or C_2-3 alkynylene group.

Preferably the AIk³ group is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents selected from halogen atoms, and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, hydroxyl, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl. More preferably the AIk³ group is unsubstituted or substituted with 1 or 2, more preferably 1, unsubstituted substituent selected from halogen atoms, and Q_-2 alkyl, Ci_-2 alkoxy, hydroxyl, Ci_-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl. Most preferably the AIk³ group is unsubstituted.

More preferably AIk³ represents an unsubstituted ethylene (-CH₂CH₂-), vinylene (-CH=CH-) or ethynylene (-C≡C-) group. Preferably AIk³ represents a C_2-3 alkynylene group, more preferably an ethynylene group. For example, when L² represents -Alk³-Alk⁵- preferably AIk³ represents an ethynylene group.

When L² represents -Alk³-A²-, preferably A² represents an unfused phenyl or unfused 5- to 6-membered heteroaryl group. More preferably A² represents an unfused phenyl group. The AIk³ and Het or AIk¹ groups can be attached to the phenyl group at any position, although it is preferred that the AIk³ and Het or AIk¹ groups are attached in a meta- or para- relationship to one another, more preferably in a para- relationship.

Preferably the A² group bears 0, 1, 2 or 3 substituents, more preferably 0, 1 or 2 substituents. Where more than one substituent is present the substituents may be the same or different. Where more than one substituent is present preferably only one substituent is a cyano or nitro group.

Preferred substituents on A² are selected from halogen atoms and unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl, C_1-4 haloalkyl, Ci_-4 haloalkoxy, C_1-4 hydroxyalkyl, cyano, nitro, -SR' and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl.

More preferred substituents on A² are selected from halogen atoms and unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl.

More preferably the substituents on A² are selected from halogen atoms and unsubstituted Ci_-2 alkyl and Ci_-2 alkoxy groups. Most preferably the A² group is unsubstituted.

When L² represents -Alk³-Alk⁵, preferably AIk⁵ represents a Ci_-4 alkylene, C_2-4 alkenylene or C_2-4 alkynylene group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms, and Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl, Ci_-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl. More preferably, AIk⁵ represents an unsubstituted Ci_-4 alkylene, C_2-4 alkenylene or C_2-4 alkynylene group. Most preferably AIk⁵ represents an unsubstituted Ci_-4 alkylene, for example a C_3-4 alkylene group, more preferably a group -CH₂-CH₂-CH₂-.

When present, the Het group is preferably -O-.

When L² is -AIk³- preferably x is 0, and preferably when x is 0 then L² is -AIk³- or -Alk³-A²-. More preferably when x is 0 then L² is -AIk³-. Preferably AIk¹ represents C_1-6 alkylene or a group -A³-Alk⁶-. When AIk¹ represents a C_1-6 alkylene group, it preferably is a Cj_-4 alkylene group, more preferably a Cμ3 alkylene group, preferably a methylene or propylene group.

When AIk¹ represents a C₁^ alkylene group preferably the AIk¹ group is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents selected from halogen atoms, and C_1-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, hydroxyl, Ci_-4 haloalkyl, C₂-₄ haloalkenyl, Ci_-4 haloalkoxy and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Cj_-2 alkyl. More preferably the AIk¹ group is unsubstituted or substituted with 1 or 2, more preferably 1, unsubstituted substituent selected from halogen atoms, and C_1-2 alkyl, Ci_-2 alkoxy, hydroxyl, Ci_-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl. Most preferably AIk¹ is unsubstituted.

When AIk¹ represents a group -A³ -AIk⁶- then A³ represents an unfused phenyl or unfused 5- to 6-membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted Ci_-4 alkyl, C_1-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl, and AIk⁶ represents a bond or an Ci_-3 alkylene, C_2-3 alkenylene or C_2-3 alkynylene group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms, and Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl, Ci_-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl.

When AIk¹ represents a group -A³-Alk⁶-, preferably A³ represents an unfused phenyl or unfused 5- to 6-membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms and unsubstituted Ci-₄ alkyl, CM alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl. More preferably A³ represents an unfused phenyl which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms and unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl. Most preferably A³ represents an unsubstituted, unfused phenyl group. When AIk¹ represents a group -A³-Alk⁶-, preferably AIk⁶ represents an unsubstituted C_1-6 alkylene group, more preferably still an unsubstituted C_1-2 alkylene group, in particular a methylene group -CH₂- or an ethylene group -CH₂-CH₂-.

Preferably only one of A² and A³ is present, i.e. it is preferred that L² is not -Alk³-A²- when AIk¹ is -A³ -AIk⁶- and vice versa.

When x is 1, preferably AIk¹ is a C3 alkylene group. When L² is -AIk³-, preferably x is 0 and AIk¹ is a C₃ alkylene group. When L² is -Alk³-A²-, preferably x is 1 and AIk¹ is a C₁ alkylene group.

R represents a group of formula (X) or (Y):

(X) (Y)

Ring D is present when group R is of formula (Y). Preferred groups (Y) include those where Ring D is a non-fused 5- to 6-membered heteroaryl or heterocyclyl group where R⁷ is linked to the group AIk², which provides the carbon atom adjacent the nitrogen atom shown in Ring D. More preferably Ring D is a non-fused 5- to 6- membered heterocyclyl group, for example a pyrrolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, morpholinyl or thiomorpholinyl group. More preferably Ring D is a pyrrolidinyl, piperazinyl or piperidinyl group, more preferably a piperidyl or piperazinyl group.

When ring D is present, -AIk²- is -C(R⁵)-. In particular, the carbon atom of AIk² forms part of the ring D, and (in addition to being bonded to two other ring atoms) bears groups R^s and R⁶. Preferred examples of R⁵ are discussed in more detail below.

Preferably Ring D, in addition to containing AIk² and bearing group R⁷, is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and Ci_-4 alkyl, C]_-4 alkoxy and hydroxyl groups. More preferably Ring D, apart from containing AIk² and bearing group R⁷, is unsubstituted.

When R represents a group of formula (X), R⁸ preferably represents a hydrogen atom or an unsubstituted Ci_-2 alkyl. More preferably R⁸ represents a hydrogen atom Preferably R represents a group of formula (X).

AIk² represents a methylene group substituted with an R⁵ and, when R represents a group of formula (X), an R⁶ group. R⁵ and R⁶ are hydrogen or the α substituents of an α-substituted or α,α-disubstituted glycine or glycine ester. These substituents may therefore be independently selected from hydrogen and the side chains of a natural or non-natural alpha-amino acid. In such side chains any functional groups may be protected.

It will be known to the person skilled in the art that the term "protected" when used in relation to a functional substituent in a side chain of an α-amino acid means a derivative of such a substituent which is substantially non-functional. For example, carboxy groups may be esterified (for example as a C₁-C₆ alkyl ester), amino groups may be converted to amides (for example as a NHCOCi-C₆ alkyl amide) or carbamates (for example as an NHC(O)OCi-C₆ alkyl or a NHC(=O)OCH₂Ph carbamate), hydroxyl groups may be converted to ethers (for example an OCi-C₆ alkyl or a 0(Ci-C₆ alkyl)phenyl ether) or esters (for example a OC(=O)Ci-C₆ alkyl ester) and thiol groups may be converted to thioethers (for example a tert-butyl or benzyl thioether) or thioesters (for example a SC(=O)Ci-C₆ alkyl thioester).

For example, examples of R⁵ and R⁶ include hydrogen, phenyl and groups of formula -CR^aR^bR^c in which:

(a) R^a, R^b and R^c are the same or different and represent a hydrogen atom or a Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, phenyl, 5- to 6-membered heteroaryl, phenyl(Ci_-6)alkyl or (C3_-8)cycloalkyl group, -OH, -SH, halogen, -CN, -CO₂H, (Ci_-4)perfluoroalkyl, -CH₂OH, -O(Ci_-6)alkyl, -O(C_2-6)alkenyl, -S(C_!-6)alkyl, -SO(C_1-6)alkyl, -SO₂(Ci_-6) alkyl, -S(C_2-6)alkenyl, -SO(C_2-6)alkenyl or -SO₂(C_2-6)alkenyl group; or

(b) two of R^a, R^b and R^e represent a group mentioned in (a) above and the other of R^a, R^b and R^c represents a group -Q-W wherein Q represents a bond or -0-, -S-, -SO- or -SO₂- and W represents a phenyl, phenyl(C]_-6)alkyl, C_3-8 carbocyclyl, C3-8 cycloalkyl(Ci_-6)alkyl, C₄..8 cycloalkenyl, C_4-8 cycloalkenyl(Ci_-6)alkyl, 5- or 6-membered heteroaryl or 5- or 6-membered heteroaryl(Ci_-6)alkyl group, which group W is unsubstituted or substituted by one or more substituents which are the same or different and represent hydroxyl, halogen, -CN, -CONH₂, - CONH(C_1-6)alkyl, -CONH(C i-₆alkyl)₂, -CHO, -CH₂OH, (C_1-4)perfluoroalkyl, -O(d_-6)alkyl, -S(C_1-6)alkyl, -SO(Ci_-6)alkyl, -SO₂(C_1-6)alkyl, -NO₂, -NH₂, -NH(C_1-6)alkyl, -N((C_1-6)alkyl)₂, -NHCO(C_1-6)alkyl, (C_1-6)alkyl, (C_2-6)alkenyl, (C_2-6)alkynyl, (C3_-8)cycloalkyl, (C_4-8)cycloalkenyl, phenyl or benzyl; or (c) one of R^a, R^b and R^c represents a group mentioned in (a) above and the other two of R^a, R^b and R^c, together with the carbon atom to which they are attached, form a 3 to 8-membered carbocyclyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl ring, or R^a, R^b and R^c, together with the carbon atom to which they are attached, form a tricyclic system; or

For example, in one embodiment each of R^a, R^b and R^c is the same or different and represents a hydrogen atom or a C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, phenyl(Ci.₆)alkyl or (C_3-8)cycloalkyl group.

In another embodiment, R^c is hydrogen and R^a and R^b are the same or different and represent phenyl or a 5- to 6-membered heteroaryl group. Particularly suitable heteroaryl groups include pyridyl.

In another embodiment R^c represents a hydrogen atom or a C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, phenyl(Ci-6)alkyl or (C₃-₈)cycloalkyl group, and R^a and R^b, together with the carbon atom to which they are attached, form a 3 to 8-membered carbocyclyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl ring.

In another embodiment R^a, R^b and R^c, together with the carbon atom to which they are attached, form a tricyclic system. A particularly suitable tricyclic system is adamantyl.

In another embodiment R^a and R^b are the same or different and represent a Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl or phenyl(C].6)alkyl group, or a group as defined for R^c below other than hydrogen, or R^a and R^b, together with the carbon atom to which they are attached, form a C_3-8 carbocyclyl or 5- or 6-membered heterocyclyl group, and R^c represents a hydrogen atom or a group selected from -OH, -SH, halogen, -CN, -CO₂H, (C_M)perfluoroalkyl, -CH₂OH, -O(C_1-6)alkyl, -O(C_2-6)alkenyl, -S(Ci_-6)alkyl₅ -SO(Ci_-6)alkyl, -SO₂(C_1-6) alkyl, -S(C_2-6)alkenyl, -SO(C_2-6)alkenyl and -SO₂(C_2-6)alkenyl, or R^c represents a group -Q-W wherein Q represents a bond or -O-, -S-, -SO- or -SO₂- and W represents a phenyl, phenyl(C_1-6)alkyl, C_3-8 carbocyclyl, C_3-8 cycloalkyl(Cj.₆)alkyl, C_4-8 cycloalkenyl, C_4-8 cycloalkenyl(C i^alkyl, 5- or 6-membered heteroaryl or 5- or 6-membered heteroaryl(Ci.₆)alkyl group, which group W is unsubstituted or substituted by one or more substituents which are the same or different and represent hydroxyl, halogen, -CN, -CONH₂, -CONH(Ci_-6)alkyl, -CONH(C_1-6alkyl)₂, -CHO, -CH₂OH, (C_1-4)perfluoroalkyl, -O(C_1-6)alkyl, -S(Ci.₆)alkyl, -SO(C_1-6)alkyl, -SO₂(Ci.₆)alkyl, -NO₂, -NH₂, -NH(Ci_-6)alkyl, -N((Ci_-6)alkyl)₂, -NHCO(C_I-6)alkyl, (C_1-6)alkyl, (C_2-6)alkenyl, (C_2-6)alkynyl, (C_3-8)cycloalkyl, (C_4-8)cycloalkenyl, phenyl or benzyl.

In another embodiment, when R is a group of formula (X), the substituents R⁵ and R⁶, taken together with the carbon to which they are attached, form a 3- to 6- membered saturated spiro cycloalkyl or heterocyclyl ring. Suitable spiro cycloalkyl rings include cyclopropyl, cyclopentyl and cyclohexyl ring; suitable spiro heterocyclyl rings include piperidin-4-yl rings.

Preferably at least one of the substituents R⁵ and R⁶ is a C_1-6 alkyl group, for example methyl, ethyl, or n- or iso-propyl.

Most preferably R⁵ and R⁶ are the same or different and represent a hydrogen atom an unsubstituted C_1-6 alkyl (for example methyl), phenyl, 5- to 6-membered heteroaryl, C_3-8 carbocyclyl (for example cyclohexyl), C_3-8 cycloalkyl(Ci-6)alkyl, or phenyl(Ci_6)alkyl group (for example benzyl).

Where one of R⁵ or R⁶ is hydrogen, then preferably the other of R⁵ and R⁶ is other than hydrogen. More preferably R⁵ and R⁶ are the same or different and represent hydrogen or unsubstituted C_1-6 alkyl.

Where neither R⁵ nor R⁶ are hydrogen, preferably R⁵ and R⁶ are the same or different and represent unsubstituted C_1-2 alkyl groups. More preferably when neither R⁵ nor R⁶ are hydrogen, then preferably R⁵ and R⁶ are both unsubstituted methyl groups.

R⁷ is either a carboxylic acid group -COOH or an ester group -COOR⁹. The term "ester" or "esterified carboxyl group" in connection with substituent R⁷ above means a group -(C=O)OR⁹ in which R⁹ is the group characterising the ester, notionally derived from the alcohol R⁹-OH. In one embodiment, R⁷ is preferably an ester group -COOR⁹.

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 HSP90 inhibitor. Hence, the broken cell assay described later provides a straightforward, quick and simple first screen for esters which have the required hydrolysis profile. Ester motifs selected in that way may then be re-assayed in the same carboxylesterase assay when conjugated to the HSP90 inhibitor via the chosen conjugation chemistry, to confirm that it is still a carboxylesterase substrate in that background.

Macrophages are known to play a key role in inflammatory disorders through the release of cytokines in particular TNF-α and IL-I. In rheumatoid arthritis they are major contributors to the maintenance of joint inflammation and joint destruction. Macrophages are also involved in tumour growth and development. Hence agents that selectively target macrophage cell proliferation could be of value in the treatment of cancer and autoimmune disease. Targeting specific cell types would be expected to lead to reduced side-effects. The inventors have discovered a method of targeting HSP90 inhibitors to macrophages and other cells derived from the myelo-monocytic lineage such as monocytes, osteoclasts and dendritic cells. This is based on the observation that the way in which the esterase motif is linked to the HSP90 inhibitor determines whether it is hydrolysed, and hence whether or not it accumulates in different cell types. Specifically it has been found that macrophages and other cells derived from the myelo- monocytic lineage contain the human carboxylesterase hCE-1 whereas other cell types do not. In the general formula (I) when the nitrogen of the esterase motif (X) or (Y) is not directly linked to a carbonyl (-C(=0)-), i.e. when AIk¹ does not join to N via a - C(=O), -C(=O)O- or -C(=0)NR^A- radical, the ester will only be hydrolysed by hCE-1 and hence the inhibitors will selectively accumulate in macrophage-related cells. Herein, unless "monocyte" or "monocytes" is specified, the term macrophage or macrophages will be used to denote macrophages (including tumour associated macrophages) and/or monocytes.

Subject to the requirement that they be hydrolysable by intracellular carboxylesterase enzymes, examples of particular ester groups R⁷ include those of formula -(C=O)OR¹³ wherein R¹³ is -CR¹⁴R¹⁵R¹⁶ wherein:

(i) R¹⁵ represents hydrogen or a group of formula -[C_1-4 alkylene]_b-(Z¹)_a-[C_M alkyl] or -[C_1-4 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 Ci_-4 alkyl, R¹⁶ represents hydrogen or Ci_-4 alkyl, and R¹⁴ represents hydrogen or Ci_-4 alkyl; (ii) R¹⁵ 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, R¹⁶ represents hydrogen or Ci_-4 alkyl, and R¹⁴ represents hydrogen; (iii) R¹⁵ represents a group of formula -(Alk⁴)-NR¹⁸R¹⁹ wherein AIk⁴ represents a Ci_-4 alkylene group and either (a) R¹⁸ and R¹⁹ are the same or different and represent hydrogen or Ci_-4 alkyl, or (b) R¹⁸ and R¹⁹, 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; R¹⁶ represents hydrogen or Ci_-4 alkyl, and R¹⁴ represents hydrogen; or (iv) R¹⁵ and R¹⁶, 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 R¹⁴ represents hydrogen. Preferred substituents on the alkyl, alkylene and alkenyl groups in R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and AIk⁴ groups include one or two substituents which are the same or different and are selected from halogen, C_1-4 alkyl, C_2-4 alkenyl, CM 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, 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 the alkyl, alkylene and alkenyl groups in R¹⁵, R¹⁶and AIk⁴ are unsubstituted.

Preferred substituents on the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R¹⁵, R¹⁶, R¹⁸ and R¹⁹ groups include one or two substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C]_-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 R¹⁵, R¹⁶, R¹⁸ and R¹⁹ 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 R¹⁵, R¹⁶, R¹⁸ and R¹⁹ are unsubstituted.

When R¹⁵ represents a group of formula -[Ci_-4 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 R¹⁵ represents a group of formula -[Ci_-4 alkyleneJ_b-CZ¹^- [C_1-4 alkyl], preferably Ci_-4 alkyl is a Ci_-3 alkyl group such as methyl, ethyl or n-propyl, most preferably methyl.

When R¹⁵ represents a group of formula -[CM alkyleneJ_b-CZ'VtC_M alkyl] and a is 1, Z¹ is preferably -O- or -NR¹⁷- wherein R¹⁷ is hydrogen or Ci_-2 alkyl, more preferably Z¹ is -O-.

When R¹⁵ represents a group of formula -[Ci_-4 alkyleneJ_b-CZ^_a-fC^ alkenyl], preferably either a or b is zero, more preferably 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.

When R¹⁵ represents a group of formula -[C]_-4 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 R¹⁵ represents a group of formula -[C_1-4 alkylene]_b-(Z')_a-[Ci.₄ alkenyl] and a is 1, Z¹ is preferably -O- or -NR¹⁷- wherein R¹⁷ is hydrogen or C_1-2 alkyl, more preferably Z¹ is -O-. Most preferably Z¹ is absent (i.e. a is zero).

When R¹⁵ represents hydrogen or a group of formula -[C_1-4

alkyl] or -[C_1-4 alkylenej_b-CZ^_a-fC^ alkenyl], preferably R¹⁵ represents hydrogen or a Ci-₄ alkyl or C_2-4 alkenyl group, or a group -(C_1-4 alky!)-O-(C_1-4 alkyl). More preferably R¹⁵ represents hydrogen, methyl, ethyl, n-propyl, -CH=CH₂ or -CH₂-CH₂-O-CHa, most preferably methyl.

When R¹⁵ represents hydrogen or a group of formula -[C_1-4 alkylene]_b-(Z¹)_a-[C₁-₄ alkyl] or -[C_1-4 alkylene]_b-(Z¹)_a-[C_2-4 alkenyl], preferably R¹⁶ represents hydrogen or Ci_-2 alkyl, more preferably hydrogen or methyl.

When R¹⁵ represents hydrogen or a group of formula -[Ci_-4 alkylene]_b-(Z')_a-[Ci_-4 alkyl] or -[Ci_-4 alkylene]b-(Z¹)_a-[C_2-4 alkenyl], preferably R¹⁴ represents hydrogen or Ci_-2 alkyl, more preferably R¹⁴ represents hydrogen or methyl.

When R¹⁵ 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], preferably the alkyl, alkylene and alkenyl groups in both R¹⁵ and R¹⁶ are unsubstituted.

When R¹⁵ 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 R¹⁵ 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 R¹⁵ 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, R¹⁶ preferably represents hydrogen or C]_-4 alkyl, more preferably hydrogen or Ci_-2 alkyl, most preferably hydrogen. Preferably the C]_-4 alkyl groups of R¹⁶ are unsubstituted. When R¹⁵ represents a group of formula -(Alk⁴)-NR¹⁸R¹⁹, AIk⁴ preferably represents a C_1-2 alkylene group, preferably either -CH₂- or -CH₂CH₂-.

When R¹⁵ represents a group of formula -(Alk⁴)-NR¹⁸R¹⁹ and R¹⁸ and R¹⁹ are the same or different and represent hydrogen or Ci_-4 alkyl, preferably R¹⁸ represents hydrogen or Ci_-2 alkyl, more preferably R¹⁸ represents a methyl group. When R¹⁵ represents a group of formula -(AIkVNR¹⁸R¹⁹ and R¹⁸ and R¹⁹ are the same or different and represent hydrogen or C]_-4 alkyl, preferably R¹⁹ represents hydrogen or Ci_-2 alkyl, more preferably R¹⁹ represents a methyl group.

When R¹⁵ represents a group of formula -(Alk⁴)-NR¹⁸R¹⁹ and R¹⁸ and R¹⁹, 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 R¹⁵ represents a group of formula -(AIk⁴VNR¹⁸R¹⁹, AIk⁴ preferably represents a Ci_-2 alkylene group, more preferably a group -CH₂CH₂-.

When R¹⁵ represents a group of formula -(Alk⁴)-NR¹⁸R¹⁹, R¹⁶ preferably represents hydrogen or Cj_-2 alkyl, most preferably hydrogen.

When R¹⁵ represents a group of formula -(Alk⁴)-NR¹⁸R¹⁹, preferably the alkyl and alkylene groups in AIk⁴, R¹⁸ and R¹⁹ are unsubstituted. When R¹⁵ represents a group of formula -(Alk⁴)-NR¹⁸R¹⁹, preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in R¹⁸ and R¹⁹ are unsubstituted.

When R¹⁵ represents a group of formula -(AIk^-NR¹⁸R¹⁹, preferred groups include -CH₂-CH₂-NMe₂ and -CH₂-CH₂-morpholinyl.

When R¹⁵ and R¹⁶, 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 R¹⁵ and R¹⁶ 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 R¹⁵ and R 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 R¹⁵ and R¹⁶ 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 R¹⁵ and R¹⁶ 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_1-4 alkyl, C_1-4 alkylene, C]_-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 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 Cj_-2 alkylene group (such as by a methylene group). Even more preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups so formed are unsubstituted.

Preferred R⁷ groups are -COOH and -COOR⁹ where R⁹ represents Ci_-4 alkyl groups (such as methyl, ethyl, n- or iso-propyl and n-, sec- and tert-butyl), 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-pyridylmethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl, methoxyethyl, indanyl, norbonyl, dimethylaminoethyl and morpholinoethyl groups, more preferably R⁹ represents Ci_-4 alkyl or C_3-7 carbocyclyl. When R⁷ is -COOR⁹ more preferably R⁹ represents unsubstituted Ci_-4 alkyl or C_3-7 carbocyclyl. Most preferred groups include where R⁹ is cyclopentyl or t-butyl, more preferably where R⁹ is cyclopentyl.

Compound where R⁷ represents -COOH or -COOR⁹ wherein R⁹ is Ci ₄ alkyl or C_3-7 carbocyclyl can be described by a group where R⁷ is -COOR¹⁰ and R¹⁰ is hydrogen, C_M alkyl or C_3-7 carbocyclyl. Preferably R⁷ is -COOR¹⁰ where R¹⁰ is hydrogen or C_3-7 carbocyclyl, more preferably where R¹⁰ is hydrogen or cyclopentyl. In one embodiment, R¹⁰ is other than hydrogen, i.e. is selected from C_1-4 alkyl or C_3-7 carbocyclyl as described above.

In a preferred embodiment of the invention there is provided a compound which is (a) a pyrrolopyrimidine derivative of formula (IA) 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 an unsubstituted group selected from Ci_-4 alkyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl and -NR 'R" where R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl;

L¹ represents Cj_-2 alkylene, said alkylene group optionally containing or terminating in -O-, -S- or -NR'- where R' is hydrogen or unsubstituted methyl, and said alkylene group being unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms, and Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted methyl; A¹ represents an unfused phenyl or 5- to 6-membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted Cj_-4 alkyl, Ci_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl; L² represents -AIk³-, -Alk³-A²- or -Alk³-Alk⁵-;

AIk³ represents a bond or an unsubstituted C_1-3 alkylene, C2-3 alkenylene or C_2-3 alkynylene group;

AIk⁵ represents an unsubstituted C_1-4 alkylene group; A² represents an unfused phenyl or unfused 5- to 6-membered heteroaryl group which is unsubstituted or substituted with I₅ 2 or 3 substituents selected from halogen atoms and unsubstituted C_1-4 alkyl, C_1-4 alkoxy, hydroxyl and -NR 'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl; x is O or l;

Het represents -O-, -NR' or -S- where R' represents hydrogen or unsubstituted methyl;

AIk¹ represents a bond or a C_[-4 alkylene group which is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms, and C_1-2 alkyl, Ci_-2 alkoxy, hydroxyl, C_1-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl, or AIk¹ represents a group -A³ -AIk⁶- where A³ represents an unfused phenyl or unfused 5- to 6- membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms and unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl, and AIk⁶ represents an unsubstituted Ci_-6 alkylene group; R⁸ represents a hydrogen atom or an unsubstituted Ci_-2 alkyl; AIk² represents a group of formula -C(R⁵)(R⁶)- wherein R⁵ and R⁶ are the same or different and represent a hydrogen atom or an unsubstituted Ci_-6 alkyl group; and

R⁷ represents -COOH or -COOR⁹ where R⁹ represents a Ci_-4 alkyl, C_3-7 carbocyclyl groups or C_2-4 alkenyl group, or R⁹ represents a phenyl, benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl, methoxyethyl, indanyl, norbonyl, dimethylaminoethyl or morpholinoethyl group. In the case of a compound of formula (I), preferably Het represents -O-. Preferably L¹ represents a methylene group which is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms and Ci_-2 alkyl, Cj_-2 alkoxy, hydroxyl and -NH₂. Preferably A¹ represents a 5- to 6-membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl. Preferably R⁸ represents hydrogen.

In a more preferred embodiment there is provided a compound which is (a) a pyrrolopyrimidine derivative of formula (IB) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof:

wherein:

R¹ represents a hydrogen or halogen atom, a hydroxyl group, an unsubstituted Ci_-4 alkyl or -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted methyl; n represents 0, 1, 2 or 3; each R^a is the same or different and represents a halogen atom or an unsubstituted Ci_-4 alkyl, C]_-4 alkoxy, hydroxyl or -NR'R" group where

R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl;

L² represents -AIk³-, -Alk³-Alk⁵- or -Alk³-A²;

AIk³ represents an unsubstituted ethylene, vinylene or ethynylene group; A² represents a phenyl group which is unsubstituted or substituted with 1 or 2 substituents selected from halogen atoms and unsubstituted C_1-2 alkyl and Ci_-2 alkoxy groups; x represents 0 or 1;

AIk¹ represents an unsubstituted C₁-₃ alkylene group or a group -A³-Alk⁶ where A³ represents an unfused phenyl which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms and unsubstituted CM alkyl, C_1-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl, and AIk⁶ represents an unsubstituted Ci_-2 alkylene group;

AIk² represents a group of formula -C(R⁵)(R⁶)- wherein R⁵ and R⁶ are the same or different and represent a hydrogen atom or an unsubstituted Ci-6 alkyl group; and

R¹⁰ represents a hydrogen atom or an unsubstituted Ci_-4 alkyl or C3_-7 carbocyclyl group. In this preferred embodiment preferably AUc² represents a group of formula

-C(R⁵)(R⁶)- wherein either (i) R⁵ and R⁶ are the same and represent unsubstituted Ci_-2 alkyl groups, or (ii) R⁵ and R⁶ are different and one of R⁵ and R⁶ represents hydrogen and the other of R⁵ and R⁶ represents an unsubstituted Ci_-6 alkyl group. Preferably AIk³ represents ethynylene.

Particularly preferred compounds of formula (I) are:

Cyclopentyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-

7H-pyrrolo[2,3-^pyrimidin-5-yl}pent-4-yn-l-yl)-L-leucinate;

7H-pyrrolo[2,3-</|pyrimidin-5-yl}pent-4-yn-l-yl)-2-methylalaninate;

Cycloρentyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-

7H-pyrrolo [2, 3 -£/]pyrimidin-5 -y 1 } pent-4-yn- 1 -yl)-L-alaninate; ter?-Butyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-

7H-pyrrolo[2,3 -d]pyrimidin-5~yl} pent-4-yn- 1 -yl)-L-alaninate;

7H-pyrrolo[2,3-(i]pyrimidin-5-yl}pent-4-yn-l-yl)-L-phenylalaninate; Cyclopentyl N-[4-( {2-amino-4-chloro-7-[(4-methoxy-3 , 5 -dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-c(]pyrimidin-5-yl}ethynyl)benzyl]-L-alaninate; Cyclopentyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-(f]pyrimidin-5-yl}ethynyl)benzyl]-L-leucinate; ϊert-Butyl iV-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylρyridin-2-yl)niethyl]- 7H-pyrrolo[2,3-^pyrimidin-5-yl}ethynyl)benzyl]-L-alaninate; Cyclopentyl (25)-{[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-^pyrimidin-5-yl}ethynyl)benzyl] amino} (phenyl)acetate; Cyclopentyl (25)-{[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-cf]pyrimidin-5-yl}ethynyl)benzyl] amino} (cyclohexyl)acetate;

Cyclopentyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-<i]pyrimidin-5-yl}ethynyl)benzyl]-2-methylalaninate; Cyclopentyl N- { 3 -[4-( {2-amino-4-chloro-7- [(4-methoxy-3 , 5 -dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-c(]pyrimidin-5-yl}ethynyl)phenoxy]propyl}-L-leucinate; Cyclopentyl N-{2-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-rf]pyrimidin-5-yl}ethynyl)phenyl]ethyl}-L-leucinate; Cyclopentyl N-{2-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-c(|pyrimidin-5-yl}ethynyl) phenyl] ethyl} -L-alaninate; tert-buty\ N- {2-[4-( {2-amino-4-chloro-7-[(4-methoxy-3 , 5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-rf]pyrimidin-5-yl}ethynyl)phenyl]ethyl}-L-alaninate; Cyclopentyl N-[3 -( {2-amino-4-chloro-7- [(4-methoxy-3 , 5 -dimethylpyridin-2-yl)methy 1] - 7H-pyrrolo[2,3-(flpyrimidin-5-yl}ethynyl)benzyl]-L-alaninate; Cyclopentyl N-[4-(2-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-cf]pyrimidin-5-yl}ethyl)benzyl]-L-alaninate; Cyclopentyl N- {4-[(5- {2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- y^methylj^H-pyrroloP^-cdpyrimidin-S-ylJpent^-yn-l-y^oxyJbenzylJ-L-leucinate; N-(5-{2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-</]pyrimidin-5-yl}pent-4-yn-l-yl)-L-leucine; N-(5-{2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2₅3-c(lpyrimidin-5-yl}pent-4-yn-l-yl)-2-methylalanine; N-(5 - {2-amino-4-chloro-7-[(4-methoxy-3 , 5 -dimethylpyridin-2-yl)methyl] -7H- pyrrolo [2,3 --i]pyrimidin-5 -yl} pent-4-yn- 1 -yl)-L-alanine; ^-[4_({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-c?]pyrimidin-5-yl}ethynyl)benzyl]-L-alanine; jV-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)benzyl]-L-leucine;

(25)-{[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-£/]pyrimidin-5-yl} ethynyl)benzyl] amino} (phenyl)acetic acid; N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo [2,3-<f]pyrimidin-5-yl}ethynyl)benzyl]-2-methylalanine;

N-{3-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-«f]pyrimidin-5-yl}ethynyl)phenoxy]propyl}-L-leucine; N-{2-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-<i]pyrimidin-5-yl} ethynyl)phenyl] ethyl} -L-leucine; N-{2-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-c(]pyrimidin-5-yl}ethynyl) phenyl]ethyl}-L-alanine;

Cyclopenty 1 N-[3 -( {2-amino-4-chloro-7- [(4-methoxy-3 , 5 -dimethy lpyridin-2-y l)methyl] - 7H-pyrrolo[2,3-c(]pyrimidin-5-yl} ethynyl) benzyl]-L-alaninate; N-[4-(2-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-c(]pyrimidin-5-yl} ethyl)benzyl]-L-alanine; and

N-{4-[(5-{2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-cdpyrimidin-5-yl}pent-4-yn-l-yl)oxy]benzyl}-L-leucine.

More particularly preferred compounds of formula (I) are:

Cyclopentyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo [2, 3 -β(]pyrimidin-5 -yl } pent-4-yn- 1 -yl)-L-leucinate;

Cyclopentyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-<i]pyrimidin-5-yl}pent-4-yn-l-yl)-2-methylalaninate; Cyclopentyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-cdpyrimidin-5-yl}ethynyl)benzyl]-L-alaninate;

Cyclopentyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3_>5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-_f]pyrimidin-5-yl}ethynyl)benzyl]-L-leucinate; tert-Butyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo [2,3 -<f]pyrimidm-5 -yl} ethynyl)benzyl] -L-alaninate; Cyclopentyl N-{3-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-c(]pyrimidin-5-yl}ethynyl)phenoxy]propyl}-L-leucinate; Cyclopentyl N-{2-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-c(]pyrimidin-5-yl}ethynyl)phenyl]ethyl}-L-leucinate; Cyclopentyl N- {4-[(5- {2-amino-4-chloro-7-[(4-methoxy-3 ,5 -dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-_<f]pyrimidin-5-yl}pent-4-yn-l-yl)oxy]benzyl}-L-leucinate; N-(5-{2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-<f|pyrimidm-5-yl}pent-4-yn-l-yl)-L-leucine; N-(5-{2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-c/]pyrimidin-5-yl}pent-4-yn-l-yl)-2-methylalanine; N-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-(i]pyrimidin-5-yl}ethynyl)benzyl]-L-alanine; N-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-<flpyrimidin-5-yl}ethynyl)benzyl]-L-leucine;

N-{3-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-<^pyrimidin-5-yl}ethynyl)phenoxy]propyl}-L-leucine; N-{2-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-J]pyrimidin-5-yl} ethynyl)phenyl]ethyl} -L-leucine; N-{4-[(5-{2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-J]pyrimidin-5-yl}pent-4-yn-l-yl)oxy]benzyl}-L-leucine.

The compounds of the invention comprise a derivatised pyrrolopyrimidine core, with a side chain (W). The pyrrolopyrimidine cores of the compounds are similar to a number of known purine analogues which have ΗSP90 inhibition activity. The binding of a number of compounds to HSP90 has been characterised by x-ray crystallography (See over 100 structures of HSP90 in the PDB). The existing crystal structures, combined with commercially available docking software packages have allowed us to determine the binding mode of the compounds described herein. 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 pending group which can contain the esterase sensitive motif described herein, in order to modulate 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. Suitable assays for assessing the activity of the compounds of the invention are described later in this application.

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, viral infection, Alzheimer's disease and others. A preferred utility of the compounds of the invention is for use in the treatment of cancer. Another preferred utility of the compounds of the invention is for use in the treatment of inflammation.

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 polyvinylpyrrolidone; 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) a pyrrolopyrimidine 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) a pyrrolopyrimidine 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 of formula (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 Chemistiy", 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 (I), and the processes according to the invention described herein after are understood to extend to such removal of protecting groups.

Scheme 1 - Generic scheme for the preparation of the amino acid ester building blocks (R⁵, R⁶ and R¹³ are as defined herein, P is a suitable protecting group): Route 1:

e.g. R¹³-OH, EDC

Esterification HOBt, DCM

Route 2:

Route 3:

^• The amino acid ester building blocks can be prepared in a number of ways. Scheme 1 illustrates the main routes employed for their preparation for the purpose of this application. To the chemist skilled in the art it will be apparent that there are other methodologies that will also achieve the preparation of these intermediates. Scheme 2 - Generic scheme for the preparation of the pyrrolo-pyrimidine building blocks (R³ and R⁴ are as defined herein):

POCI₃, BTEACI

N,N-diethylaniline

Acetonitrile

It will be apparent to the individual skilled in the art that the nature of the side groups R³ and R⁴ will have an impact on the reagents chosen for the steps above. Suitable protecting strategies may have to be employed.

Exemplified in scheme 2 is the case where R¹ is a chlorine and R² is NH₂. In order to allow for different substitutions, an alternative starting material may have to be employed, together with a suitable protecting group strategy. The methods shown for the preparation of the bicyclic ring system and the iodination of the pyrrole, however should apply to a number of possible R¹ and R² substitutions.

ϋcheme 3 - Generic scheme for the preparation of compounds where L² is an acetylene (R³, R⁴, R⁷, R⁸, Het, x, AIk¹ and AIk² are as defined herein):

CuI, Pd(PPh₃),, TEA, DCM

The pyrrolo-pyrimidine core can be coupled to acetylene side-chains via a Sonogashira reaction. Transformations to the side chain can be carried out either before or after the Sonogashira coupling, depending on the lability of its components.

Scheme 4 - Generic scheme for the preparation of compounds where AIk³ is an alkene and A² is phenyl (AIk¹, R³, R⁴, R⁵, R⁶ and R¹⁰ are as defined herein):

The pyrrolo-pyrimidine core can be coupled to alkene side chains via a Heck reaction. As with the Sonogashira coupling described in Scheme 3, side chain modifications can be carried out either before or after the Heck coupling. Scheme 5 - Generic scheme for the preparation of compounds where AIk is an alkyl chain (AIk Λ¹, R τ>3", R -r>4", R τ>5⁵, R τ,6^b and R¹⁰ are as defined herein):

Direct coupling of an alkyl chain to the pyrrolo-pyrimidine core is challenging, so this type of linker can be prepared by the catalytic reduction of either the acetylene or the alkene compounds. To the chemist skilled in the art it will be apparent that there exist a number of possible reducing agents which could be employed in the process.

Scheme 6 - Generic scheme for the preparation of acids from their corresponding esters (L², x, AIk¹, R³, R⁴, R⁵, R⁶ and R¹⁰ are as defined herein):

Saponification

The carboxylic acid derivatives of the esters described herein can be easily prepared from their parent esters by hydrolysis. To the chemist skilled in the art it will be apparent that depending on the ester group to be removed, either basic or acidic conditions may be employed. EXAMPLES

The following examples illustrate the preparation and properties of some specific compounds of the invention. The following abbreviations are used:

ACN = acetonitrile

Boe = fert-butoxycarbonyl nBuLi = n-butyllithium

CO₂ = carbon dioxide

DCE = dichloroethane

DCM = dichloromethane

DIPEA = diisopropylethylamine

DMAP = 4-Dimethylaminopyridine

DMF = dimethylformamide

DMP = Dess-Martin periodinane

DMSO = dimethyl sulfoxide

EDCI = N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

Et₂O = diethyl ether

EtOAc = ethyl acetate

EtOH = ethanol

Et₃N or TEA = triethylamine

ELS = Evaporative Light Scattering g = gram(s)

HCl = hydrochloric acid

HOBt = 1-hydroxybenzotriazole

LCMS = high performance liquid chromatography/mass spectrometry

LiAlH₄ = lithium aluminium hydride

LiOH = lithium hydroxide

MeOH = methanol

MgSO₄ = magnesium sulfate mg = milligram(s) mol = moles mmol = millimole(s) mL = millilitre N₂ = nitrogen

Na₂CO₃ = sodium carbonate NaHCO₃ = sodium hydrogen carbonate Na₂SO₄ = sodium sulphate NaH = sodium hydride NaOH = sodium hydroxide NH₃ = ammonia NH₄Cl = ammonium chloride NMR = nuclear magnetic resonance Pd/C = palladium on carbon

PyB op = benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate pyBrOP = Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate RT = room temperature sat. = saturated aqueous solution STAB = Sodium triacetoxyborohydride TBAF = Tetrabutylammonium fluoride TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography TME = tert-butyl methyl ether TMSCl = trimethylchlorosilane

Commercially available reagents and solvents (HPLC grade) were used without further purification. Solvents were removed using a Buchi rotary evaporator or a VirTis Benchtop SLC Freeze-dryer. Microwave irradiation was carried out using a Biotage Initiator™ Eight microwave synthesizer. Purification of compounds by flash chromatography column was performed using silica gel, particle size 40-63 μm (230- 400 mesh) obtained from Fluorochem. Purification of compounds by preparative HPLC was performed on Gilson systems using reverse phase Axia™ prep Luna Cl 8 columns (10 μm, 100 x 21.2 mm), gradient 0-100 % B (A = water + 0.05 % TFA, B = acetonitrile) over 10 min, flow = 25 niL/min, UV detection at 254 nm. ¹H NMR spectra were recorded on a Bruker 300 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 Luna Cl 8 columns (3 μm, 50 x 4.6 mm), gradient 5-95 % B ( A = water + 0.1 % Formic acid, B = acetonitrile + 0.1 % Formic acid) over 2.25 min, flow = 2.25 mL/min. UV spectra were recorded at 220 and 254 nm using a G1315B DAD detector. Mass spectra were obtained over the range m/z 150 to 800 on a LC/MSD SL G1956B detector. Data were integrated and reported using ChemStation and ChemStation Data Browser softwares.

Figure 1 - The following building blocks were employed in the synthesis of the examples described herein:

Building Block A Building Block B Building Block C Building Block D

Building Block E Building Block F Building Block G Building Block H

Building Block A - 4-Chloro-5-iodo-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-(fjpyrimidin-2-amine was prepared using the methodology outlined in Scheme 2 and as described in WO2006105372.

¹H NMR (300 MHz, J₆-DMSO) δ: 8.06 (IH, s), 7.27 (IH, s), 6.75 (2H, br s), 5.28 (2H, s), 3.72 (3H, s), 2.25 (3H, s), 2.16 (3H, s). Building Block B - Cyclopentyl L-leucinate was prepared using the methodology outlined in Scheme 1, Route 3:

To a slurry of L-Leucine (5 g, 30.5 mmol) in cyclohexane (150 mL) were added cyclopentanol (27.5 mL, 305 mmol) andp-toluene sulfonic acid (6.33 g, 33.3 mmol). The reaction was fitted with a Dean-Stark receiver and heated with stirring to 135 ⁰C for complete dissolution. This temperature was maintained for a period of 12 hours after which time the reaction was complete. The reaction was cooled to RT with precipitation of a white solid. The solid was filtered and washed with EtOAc before drying under reduced pressure. The required product was isolated as the tosylate salt (10.88 g, 85 %). m/z = 200 [M+H]⁺; ¹HNMR (300 MHz, CD₃OD) δ: 1.01 (6H, t, J=5.8 Hz), 1.54-2.03 (HH, m), 2.39 (3H, s), 3.96 (IH, t, J=6.5 Hz), 5.26-5.36 (IH, m), 7.25 (2H, d, J=7.9 Hz), 7.72 (2H, d, J=8.3 Hz).

Building Block C - Cyclopentyl 2-methylalaninate was prepared using the methodology outlined in Scheme 1, Route 2:

2-Aminoisobutyric acid (10 g, 97 mmol) was dissolved in cyclopentanol (100 mL) and treated with cone, sulfuric acid (5.7 mL, 107 mmol). The stirred reaction mixture was heated to 70 ⁰C for 18 hours. The reaction was then cooled to RT and the solvents removed in vacuo to afford an amber oil. This was separated between EtOAc and sat. NaHCO₃. The organic was washed with water, then brine, then dried (MgSO₄) and concentrated in vacuo. The resulting yellow oil was crystallized from EtOAc / heptane to afford the desired product as a white solid (5.96 g, 36 %). m/z = 172 [M+H]⁺; ¹HNMR (300 MHz, CDCl₃) δ: 7.93 (2H, br s), 4.91 (IH, m), 2.43-1.52 (14H, m).

Building Block D - Cyclopentyl L-alaninate was prepared using the methodology outlined in Scheme 1, Route 3 and as described for Building Block B:

¹H NMR (300 MHz, _f₆-DMSO) δ: 8.22 (3H, br s), 7.47 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=7.7 Hz), 5.24-5.13 (IH, m), 4.06 (IH, q, J=7.2 Hz), 2.29 (3H, s), 1.93-1.80 (2H, m), 1.71-1.51 (6H, m), 1.36 (3H, d, J=7.2 Hz). Building Block E - tert-Butyl L-alaninate is commercially available (Novabiochem, catalog number: 04-12-5019).

Building Block F - Cyclopentyl L-phenylalaninate was prepared using the methodology outlined in Scheme 1, Route 3 and as described for Building Block B: 1HNMR (300 MHz, J₆-DMSO) δ: 8.40 (3H, br s), 7.49 (2H, d, J=8.1 Hz), 7.61-7.20 (5H, br m), 7.12 (2H, d, J=7.8 Hz), 5.07 (IH, m), 4.25 (IH, dd, J=6.0, 8.4 Hz), 3.15 (IH, dd, J=6.0, 14.1 Hz), 2.97 (IH, dd, J=8.7, 14.1Hz), 2.29 (3H, s), 1.81- 1.60 (2H, br m), 1.49-1.25 (6H, br m).

Building Block G - Cyclopentyl (25)-amino(phenyl)acetate was prepared was using the methodology outlined in Scheme 1, Route 3 and as described for Building Block B:

¹H NMR (300 MHz, J₆-DMSO) δ: 8.82 (2H, br s), 8.73 (IH, br s), 7.47 (7H, br m), 7.11 (2H, d), 5.25 (IH, br s), 5.18 (IH, m), 2.29 (3H, s), 1.87-1.36 (8H, m).

Building Block H - Cyclopentyl (25)-amino(cyclohexyl)acetate was prepared was using the methodology outlined in Scheme 1, Route 1:

Stage 1- Preparation of cyclopentyl (2S)-[tert-butoxycarbonyl)amino](cyclohexyl) acetate

To a solution of (S)-2-fert-butoxycarnonylamino-3-cyclohexyl-propionic acid (5.0 g, 19.4 mmol) in DMF (50 niL) at 0 ⁰C was added cyclopentanol (8.8 mL, 97.2 mmol), EDCI (4.09 g, 21.4 mmol) and finally DMAP (237 mg, 1.9 mmol). The reaction mixture was warmed to RT and stirred for 18 hours. The DMF was removed in vacuo to give a clear oil. This was separated between water and EtOAc. The organic phase was dried (MgSO₄) and concentrated in vacuo. The crude extract was purified by column chromatography (25 % EtOAc in heptane) to yield the desired product as a clear oil (14.87 g, 55 %).

¹H NMR (300 MHz, J₆-DMSO) δ: 7.09 (IH, d), 5.08 (IH, t), 3.76 (IH, t), 1.50- 1.85 (1OH, br m), 1.39 (9H, s), 1.00-1.25 (9H, br m).

Stage 2 - Preparation of cyclopentyl (25)-amino(cyclohexyl)acetate

Stage 1 product (14.87 g, 45.7 mmol) was dissolved in DCM (100 mL) and treated with 4M HCl/dioxane (22.8 mL, 91.4 mmol), and the reaction mixture was stirred at RT for 24 hours. The crude mixture was concentrated under reduced pressure to give an orange oil. This was triturated with Et₂O to give the desired product as a white powder (7.78 g, 65 %).

¹H NMR (300 MHz, J₆-DMSO) δ: 8.45 (3H, br s), 5.22 (IH, t), 3.28 (IH, d), 1.95-1.50 (1OH, br m), 1.30 - 0.90 (9H, br m).

Example 1 - Cyclopentyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-cdpyrimidin-5-yl}pent-4-yn-l-yl)-L- leucinate

Scheme 7 - Methodology for the preparation of Example 1 from Building Block A and Building Block B:

MSCI₁ TEEA₁ DCM Building Block B

OH OMs

TEA, Acetonitrile Intermediate 1a

Intermediate 1b

Example 1

Intermediate Ia - Pent-4-yn-l-yl methanesulfonate was prepared as follows:

To a stirred solution of 4-pentyn-l-ol (278 μL, 3.0 mmol) in DCM (2 mL) at 0 ⁰C were added TEA (543 μL, 3.9 mmol) and methane sulfonyl chloride (279 μL, 3.6 x-nmol). After 1 hour, the crude mixture was poured into water (20 mL). DCM (20 mL) was added and the organic layer was washed with sat. NaHCO₃ (10 mL) then brine (20 mL), dried (Na2SO₄) and concentrated under reduced pressure to afford the desired product as a yellow oil (485 mg, 100 %).¹H NMR (300 MHz₅ CDCl₃) δ: 4.39 (2H, t, J=6.1 Hz), 3.05 (3H, s), 2.39 (2H, td, J=6.9, 2.6 Hz)₅ 1.99 (2H, t, J=6.5 Hz), 1.65 (IH, s).

Intermediate Ib - Cyclopentyl N-pent-4-yn-l-yl-L-leucinate was prepared from Intermediate Ia as follows:

To Intermediate Ia (162 mg,l mmol) in acetonitrile (3 mL) were added Building Block B (372 mg, 1 mmol) and TEA (278 μL, 2 mmol). The reaction mixture was stirred at reflux for 3 hours then heated at 50 ⁰C for 15 hours. The crude was concentrated in vacuo, poured into EtOAc (20 mL), washed with sat. NaHCO₃ (20 mL) then brine (20 mL), dried (Na₂SO^ and concentrated in vacuo to afford the desired product. This was used directly in the preparation of Example 1 without further purification or characterization.

Example 1 was prepared from Intermediate Ib as follows:

To a solution of Building Block A (133 mg, 0.3 mmol) in DCM (2 mL) were added Intermediate Ib (265 mg, 1 mmol), TEA (139 μL, 1 mmol), tetrakis(triphenylphosphine) palladium (17 mg, 0.015 mmol) and copper iodide (6 mg, 0.03 mmol). The reaction mixture was stirred at reflux for 2 hours. It was then diluted with DCM (10 mL), washed with sat. NaHCO₃ (10 mL) then brine (10 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude was purified by preparative HPLC to yield the desired product as a TFA salt (9 mg, 5 %). LCMS purity = 97 %; m/z = 581/583 (3:1) [M+H]⁺; ¹H NMR (300 MHz, CD₃OD) δ: 8.37 (IH, br s), 7.28 (IH, s), 5.51 (2H, d, J=0.9Hz), 5.36-5.28 (IH, m), 4.04 (3H, s), 4.04-4.01 (IH, m), 3.28-3.25 (2H, m), 3.24-3.21 (IH, m), 2.63 (2H, t, JMJ. \ Hz), 2.43 (3H, s), 2.37 (3H, s), 2.06-1.94 (2H, m), 1.93-1.81 (2H, m), 1.78-1.55 (6H, m). O3 -

Example 2 - CyclopentylN-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl] -7H-pyrrolo[2, 3 -d]pyrimidin-5 -yl } pent-4-yn- 1 -y l)-2- methylalaninate

Example 2 was prepared from Building Block A and Building Block C using the same methodology as described for Example 1. LCMS purity = 100 %; m/z = 553/555 (3:1) [M+H]⁺; ¹H NMR (300 MHz, CD₃OD) δ: 8.38 (IH, br s), 7.31 (IH, s), 5.56 (2H, s), 5.32-5.25 (IH, m), 4.08 (3H, s), 3.20 (2H, d, ./=7.5 Hz), 2.65 (2H, t, J=6.7 Hz), 2.45 (3H, s), 2.39 (3H, s), 2.11-1.97 (2H, m), 1.95-1.85 (2H, m), 1.82-1.65 (6H, m), 1.61 (6H, s).

Example 3 -Cyclopentyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dirnethylpyridin- 2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}pent-4-yn-l-yl)-L-alaninate

Scheme 8 - Methodology for the preparation of Example 3 from Building Block A and Building Block D:

Bulding Block A TEA, Pd(PPh₃).,, CuI, DCM

Example 3

Intermediate 3 - Cyclopentyl N-pent-4-yn-l-yl-L-alaninate was prepared as follows:

To 5-chloropent-l-yne (157 μL, 1.5 mmol) in ACΝ (2 mL) was added Building Block D (494 mg, 1.5mmol), and K₂CO₃ (311 mg, 2.3 mmol) and the mixture microwaved at 140 ⁰C for 10 minutes. The crude was concentrated in vacuo, poured into EtOAc (20 mL), washed with sat. NaHCO₃ (20 mL) then brine (20 mL), dried (Na₂SO₄) and concentrated in vacuo to afford the desired product. This was used directly in the preparation of Example 3 without further purification or characterization.

Example 3 was prepared from Intermediate 3 using the same procedure as described are in the final step for Example 1, Scheme 7. LCMS purity = 100 %; m/z =539/541 (3:1) [M+H]⁺; ¹HNMR (300 MHz, CD₃OZ)) δ: 8.14 (IH, s), 6.93 (IH, s), 5.22 (2H, s), 5.16- 5.05 (2H, m), 4.88 (2H, br. s.), 3.67 (3H, s), 3.65-3.63 (IH, m), 3.29-3.15 (IH, m), 2.74- 2.51 (2H, m), 2.40 (2H, t, J=6.4 Hz), 2.18 (3H, s), 2.11 (3H, s), 1.86-1.72 (2H, m), 1.71- 1.45 (8H, m), 1.19 (2H, d, J=6.8 Hz).

Example 4 - ferf-Butyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-fi?]pyrimidin-5-yl}pent-4-yn-l-yl)-L-alaninate

Example 4 was prepared from Building Block A and Building Block E using the same methodology as described for Example 3. LCMS purity = 94 %; m/z = 527/529 (3:1) [M+H]⁺; ¹H NMR (300 MHz, CD₃OD) δ: 8.38 (IH, br s), 7.29 (IH, s), 5.53 (2H, s), 4.07 (3H, s), 4.05-3.98 (IH, m), 3.28-3.20 (2H, m), 2.64 (2H, t, J=6.8 Hz), 2.44 (3H, s), 2.37 (3H, s), 2.08-1.94 (2H, m), 1.59-1.55 (3H, m), 1.52 (9H₅ s).

Example 5- Cyclopentyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin- 2-yl)methyl]-7H-pyrrolo[2,3-(i]pyrimidin-5-yl}pent-4-yn-l-yl)-L-phenyIalaninate

Example 5 was prepared from Building Block A and Building Block F using the same methodology as described for Example 3. LCMS purity = 100 %; m/z = 615/617 (3:1) [M+Η]⁺; ¹HNMR (300 MHz, CD₃OD) δ: 8.16 (IH, s), 7.40-7.23 (5H, m), 7.19 (IH, s), 5.43 (2H, s), 5.29-5.21 (IH, m), 5.18 -5.08 (IH, m), 4.26 (IH₅ 1, J=7.2 Hz), 3.92 (3H₅ s), 3.28-3.05 (4H, m), 2.68-2.55 (2H, m), 2.35 (3H₅ s), 2.33 (3H₅ s), 2.11-1.95 (2H, m), 1.91-1.78 (2H,m), 1.76-1.51 (6H, m). Example 6 - Cyclopentyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-<i]pyrimidin-5-yl}ethynyl)benzyl]-L- alaninate

Scheme 9 - Methodology for the preparation of Example 6 from Building Block A and Building Block D: Building Block D Me-Si Λ

STAB, DCE

Intermediate 6a

Intermediate 6a - Cyclopentyl N-(4-iodobenzyl)-L-alaninate was prepared as follows:

To 4-iodobenzaldehyde (500 mg, 2.15 mmol) in DCE (5 mL) were added Building Block D (593 mg, 2.15 mmol) and STAB (456 mg, 2.15 mmol) and the reaction mixture was stirred overnight at RT under N₂ atmosphere. The crude was poured onto DCM (20 mL) and washed with sat. NaHCO₃ (20 mL). The organic layer was separated, washed with brine (20 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude was purified by flash chromatography (0.5 % MeOH in DCM) to afford the desired product (480 mg, 60 %). m/z = 374 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.66 (2H₃ d, J=8.3 Hz), 7.10 (2H, d, J=8.3 Hz), 5.27-5.19 (IH₅ m), 3.77 (IH, d, J=13.0 Hz), 3.61 (IH, d, J=13.0 Hz), 3.30 (1 H₅ q, J=7.0 Hz), 1.97-1.80 (2H, m), 1.77-1.56 (6H, m), 1.30 (3H, d, J=7.0 Hz).

Intermediate 6b — Cyclopentyl N-{4-[(trimethylsilyl)ethynyl]benzyl}-L-alaninate was prepared from Intermediate 6a as follows:

To a solution of Intermediate 6a (480 mg, 1.29 mmol) in DCM (5 mL) were added ethynyltrimethylsilane (356 μL, 2.57 mmol), TEA (358 μL, 2.57 mmol), tetrakis(triphenylphosphine) palladium (75 mg, 0.06 mmol) and copper iodide (19 mg, 0.13 mmol). The reaction mixture was heated at reflux for 2 hours. It was then diluted with DCM (20 mL), washed with sat. NaHCO₃ (20 mL) then brine (20 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude was purified by flash chromatography (0.5 % MeOH in DCM) to afford the desired product (321 mg, 72 %). m/z = 344 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.44 (2H, d, J=8.3 Hz), 7.28 (2H, d, /=8.3 Hz), 5.28-5.20 (IH, m), 3.81 (IH, d, J=13.0 Hz)₅ 3.66 (IH₅ d, J=13.0 Hz)₅ 3.30 (IH, q, J=7.0 Hz), 1.98-1.83 (2H, m), 1.78-1.53 (6H, m), 1.30 (3H, d₅ J=7.0 Hz), 0.26 (9H, s).

Intermediate 6c - Cyclopentyl N-(4-ethynylbenzyl)-L-alaninate was prepared from Intermediate 6b as follows:

Intermediate 6b (321 mg, 0.93 mmol) was treated with TBAF (0.93 mL, 0.93 mmol, IM in THF) in THF (5 mL) for 30 minutes at RT. The crude was poured onto EtOAc (50 mL) and washed three times with water (50 mL) and brine (50 mL) then dried (Na₂SO₄) and concentrated under reduced pressure to afford the desired product (252 mg, 100 %). m/z = 272 [M+H]⁺; ¹H NMR (300 MHz₅ C-DCl₃) δ: 7.44 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 5.28-5.20 (IH, m), 3.81 (IH, d, J=13.0 Hz), 3.66 (IH₅ d, J=13.0 Hz)₅ 3.30 (IH, q, J=7.0 Hz), 1.98-1.83 (2H₅ m), 1.78-1.53 (6H₅ m), 1.30 (3H, d, J=7.0 Hz). Example 6 was prepared from Intermediate 6c as follows:

To a solution of Building Block A (204 mg, 0.46 mmol) in DCM (3 mL) were added Intermediate 6c (125 mg, 0.46 mmol), TEA (128 μL, 0.92 mmol), tetrakis(triphenylphosphine) palladium (27 mg, 0.02 mmol) and copper iodide (10 mg, 0.05 mmol). The reaction mixture was heated at reflux for 2 hours. It was then diluted with DCM (15 mL), washed with sat. NaHCO₃ (15 mL) then brine (15 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude was purified by preparative HPLC to afford the desired product as a TFA salt (15 mg, 6 %). LCMS purity = 97 %; m/z = 587/589 (3:1) [M+H]⁺; ¹HNMR (300 MHz, CD₃OD) δ: 8.35 (IH, br s), 7.62-7.57 (2H, m), 7.56-7.50 (2H, m), 7.47 (IH, s), 5.57 (2H, s), 5.38-5.31 (IH, m), 4.28 (2H, s), 4.15 (IH, q, J=7.3Hz), 4.04 (3H, s), 2.43 (3H, s), 2.40 (3H, s), 2.03- 1.89 (2H, m), 1.86-1.64 (6H, m), 1.62 (3H, d, J=7.2Hz).

Example 7- Cyclopentyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin- 2-yl)methyl]-7H-pyrrolo[2,3-c(]pyrimidin-5-yl}ethynyl)benzyl]-L-leucinate

Example 7 was prepared from Building Block A and Building Block B using the same methodology as described for Example 6. LCMS purity = 95 %; m/z = 629/631 (3:1) [M+Η]⁺; ¹HNMR (300 MHz, CD₃OD) δ: 7.73-7.63 (IH, m), 7.59 (2H, d, J=8.3 Hz), 7.52 (2H, d, J=8.3 Hz), 7.45 (IH₅ s), 5.60 (2H, br s), 5.36-5.30 (IH, m), 4.33-4.19 (2H, m), 4.10-4.05 (IH, m), 4.02 (3H, s), 2.45 (6H, s), 2.01-1.88 (3H, m), 1.87-1.67 (8H, m), 1.03 (3H, d, J=5.8 Hz), 1.00 (3H, d, J=5.8 Hz). JSxample 8- tert-Butyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dirnethylpyridin- 2-yl)methyl]-7H-pyrrolo[2,3-^pyrimidm-5-yl}ethynyl)benzyl]-L-alaninate

Example 8 was prepared from Building Block A and Building Block E using the same methodology as described for Example 6. LCMS purity = 96 %; m/z = 575/577 (3:1) [M+Η]⁺; ¹HNMR (300 MHz, J₆-DMSO) δ: 9.51-9.31 (2H, m), 8.12 (IH, s), 7.62- 7.56 (2H, m), 7.54-7.48 (2H, m), 7.48-7.41 (IH, m), 6.82 (2H, br. s.), 5.37 (2H, s), 4.31- 4.11 (2H, m), 4.08-3.98 (IH, m), 3.77 (3H, s), 2.28 (3H, s), 2.20 (3H, s), 1.51-1.49 (2H, m), 1.48 (9H, s).

Example 9- Cyclopentyl (25)-{[4-({2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-y l)methy 1] -7H-pyrrolo [2, 3 -d\ pyrimidin-5 -yl } ethyny l)benzy 1] amino} (phenyl)acetate

Example 9 was prepared from Building Block A and Building Block G using the same methodology as described for Example 6. LCMS purity = 99 %; m/z = 649/651 (3:1) [M+H]⁺; ¹H NMR (SOO MHZ, J₆-DMSO) δ: 10.05 (2H, br. s.), 8.14 (IH, s), 7.60-7.42 (1OH, m), 6.81 (IH, br. s.), 5.37 (2H, s), 5.28 (IH, s), 5.20-5.13 (IH₅ m), 4.17 (IH, d, J=13.5 Hz), 4.04 (IH, d, J=13.5 Hz)₅ 3.78 (3H, s), 2.28 (3H, s), 2.20 (3H, s), 1.90-1.26 (8H, m).

Example 10- Cyclopentyl (2₁S)-{[4-({2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-^]pyrimidin-5-yl}ethynyl)benzyl] amino} (cyclohexyl)acetate

Example 10 was prepared from Building Block A and Building Block Η using the same methodology as described for Example 6. LCMS purity = 95 %; m/z = 655/657 (3:1) [M+Η]⁺; ¹HNMR (300 MHz, CD₃OD) δ: 8.20 (IH, s), 7.49 (2H, d, J=8.5 Hz), 7.42 (2H, d, J=8.5 Hz), 7.31 (IH₅ s), 5.41 (2H, s), 5.21-5.13 (IH, m), 4.19 (2H, d, J=4.1 Hz)₅ 3.87 (3H, s), 3.78 (IH, d, J=4.0 Hz), 2.29 (6H, s), 2.01-1.52 (14H, m), 1.36- 0.88 (5H₅ m).

Example 11- Cyclopentyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-(i]pyrimidin-5-yl}ethynyl)benzyl]-2- methylalaninate

Example 11 was prepared from Building Block A and Building Block C using the same methodology as described for Example 6. LCMS purity = 91 %; m/z = 601/603 (3:1) [M+H]⁺; ¹HNMR (300 MHz, CD₃OD) δ: 8.35 (IH, s), 7.58 (4H, q, J=8.5 Hz), 7.44 (IH, s), 5.55 (2H, s), 5.43-5.31 (IH, m), 4.25 (2H, s), 4.03 (3H, s), 2.42 (3H, s), 2.40 (3H, s), 2.07-1.70 (8H, m), 1.68 (6H, s).

Example 12 - Cyclopentyl N-{3-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-c(]pyrimidin-5-yl}ethynyl)phenoxy] propyl} -L-leucinate

Scheme 10 - Methodology for the preparation of Example 6 from Building Block A and Building Block B: Building Block B ^jJU>

K₂CO₃, NaI, DMF

Intermediate 12a

Intermediate 12b

Example 12

Intermediate 12a - l-(3-Chloropropoxy)-4-iodobenzene 3-chloropropyl 4-iodophenyl ether was prepared as follows:

To 4-iodophenol (660 mg, 3 mmol) in DMF (10 mL) were added l-bromo-3- chloropropane (297 μL, 3 mmol) and K₂CO₃ (415 mg, 3 mmol). The reaction mixture was stirred overnight at RT. The crude was poured into EtOAc (50 mL), washed with water (50 mL) then brine (50 mL). The organic layer was dried (MgSO₄) and concentrated under reduced pressure. The crude was purified by flash chromatography (Heptane / EtOAc 9:1) to afford the desired product (775 mg, 87 %). m/z = 296/298 (3:1) [M+H]⁺; ¹H NMR (300 MHz, CZ)Cl₃) δ: 7.61-7.54 (2H, m), 6.74-6.66 (2H, m), 4.10 (2H, t, J=5.8 Hz), 3.76 (2H, t, J=6.2 Hz), 2.25 (2H₅ quin, J=6.0 Hz).

Intermediate 12b - Cyclopentyl N-[3-(4-iodophenoxy)propyl]-L-leucinate was prepared from Intermediate 6a as follows:

To Intermediate 12a (400 mg, 1.35 mmol) in DMF (5 mL) were added Building Block B (501 mg, 1.35 mmol), K₂CO₃ (374 mg, 2.70 mmol) andΝal (100 mg, 0.65 -ϊimol). The reaction mixture was stirred at 70 ⁰C for 2 days. The crude was poured into EtOAc (30 mL), washed with water (30 mL) then brine (30 mL). The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The crude was purified by flash chromatography (Heptane / EtOAc 5:5) to afford the desired product (360 mg, 58 %). m/z = 460 [M+H]⁺; ¹R NMR (300 MHz, CDCl₃) δ: 7.60-7.53 (2H, m), 6.72- 6.65 (2H₅ m), 5.31-5.20 (IH, m), 4.04 (2H, t, J=6.1 Hz), 3.49-3.36 (IH, m), 2.26-2.09 (2H, m), 1.94-1.82 (2H, m), 1.80-1.54 (8H, m), 1.32-1.23 (3H, m), 1.02-0.83 (6H, m).

Intermediate 12c - Cyclopentyl N-[3-(4-ethynylphenoxy)propyl]-L-leucinate was prepared from Intermediate 12b as follows:

To a solution of Intermediate 12b (360 mg, 0.78 mmol) in DCM (5 mL) were added ethynyltrimethylsilane (217 μL, 1.57 mmol), TEA (219 μL, 1.57 mmol), tetrakis(triphenylphosphine) palladium (45 mg, 0.04 mmol) and copper iodide (15 mg, 0.08 mmol). The reaction mixture was stirred at reflux for 2 hours. It was then diluted with DCM (20 mL), washed with sat. NaHCO₃ (20 mL) then brine (20 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude was purified by flash chromatography (Heptane / EtOAc 6:4) and then treated with TBAF (0.45 mL, 0.45 mmol, IM in THF) in THF (3 mL) for 30 minutes at RT. The crude was poured onto EtOAc (50 mL) and washed three times with water (50 mL) then brine (50 mL) then dried (Na₂SO₄) and concentrated under reduced pressure to afford the desired product (160 mg, 100 %). m/z = 358 [M+H]⁺.

Example 12 was prepared from Intermediate 6c as follows:

To a solution of Building Block A (200 mg, 0.45 mmol) in DCM (3 mL) were added Intermediate 12c (160 mg, 0.45 mmol), TEA (63 μL, 0.45 mmol), tetrakis(triphenylphosphine) palladium (25 mg, 0.02 mmol) and copper iodide (9 mg, 0.04 mmol). The reaction mixture was stirred at reflux for 2 hours. It was then diluted with DCM (15 mL), washed with sat. NaHCO₃ (15 mL) then brine (15 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude was purified by preparative HPLC to yield the desired product as a TFA salt (24 mg, 8 %). LCMS purity = 99 %; m/z = 673/675 (3:1) [M+H]⁺; ¹H NMR (300 MHz, ^₆-DMSO) δ: 9.14 (2H, br s), 8.09 (IH, br s), 7.45 (2H, d, J=8.7 Hz), 7.42 (IH, s), 6.97 (2H, d, ./=8.9 Hz), j.77 (2H, br s), 5.33 (2H, s), 5.25 (IH, t, J=5.2 Hz), 4.10 (3H, t, J=5.8 Hz), 3.75 (3H₅ s), 3.25-3.13 (IH, m), 3.11-3.00 (IH, m), 2.27 (3H, s), 2.18 (3H, s), 2.13-2.05 (2H, m), 1.95-1.82 (2H, m), 1.75-1.57 (8H, m), 0.93 (6H, d, J=4.5 Hz).

Example 13- Cyclopentyl N-{2-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3- JJpyriraidin-5-yl} ethynyl)phenyl] ethyl} - L-leucinate

Scheme 11 - Methodology for the preparation of Example 7 from Building Block A and Building Block B:

Intermediate 13a Intermediate 13b Block B

[ntermediate 13a - 2-{4-[(Trimethylsilyl)ethynyl]phenyl}ethanol was prepared as follows:

To a solution of 2-(4-bromophenyl)ethanol (703 μL, 5 mmol) in THF (10 mL) were added ethynyltrimethylsilane (693 μL, 5 mmol), TEA (696 μL, 5 mmol), tetrakis(triphenylphosphine) palladium (289 mg, 0.25 mmol) and copper iodide (95 mg, 0.5 mmol). The reaction mixture was stirred at reflux for 24 hours. It was then diluted with EtOAc (30 mL), washed with sat. NaHCO₃ (30 mL) then brine (30 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude was purified by flash chromatography (Heptane / EtOAc 8:2) to afford the desired product (1.03 g, 94 %). m/z = 219 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.51-7.38 (2H, m), 7.23-7.07 (2H, m), 3.87 (2H, t, J=6.6 Hz), 3.30-3.11 (IH, m), 2.93-2.78 (2H, m), 0.26 (9H, s).

Intermediate 13b - {4-[(Trimethylsilyl)ethynyl]phenyl}acetaldehyde was prepared from Intermediate 13a as follows:

To Intermediate 13a (360 mg, 1.65 mmol) in DCM (10 mL) was added Dess- Martin periodinane (839 mg, 1.98 mmol) and the resulting mixture was stirred at RT for 1 hour. A solution of sat. NaHCO₃ / sat. Na₂S₂O₃ (1:1, 25 mL) was added and the mixture stirred vigorously for a further 30 minutes at RT. The product was extracted with DCM (25 mL), the organic layer was washed with brine (25 mL), dried (MgSO₄) and concentrated to afford the desired product (357 mg, 100 %). m/z = 217 [M+H]⁺.

Intermediate 13c - Cyclopentyl N-[2-(4-ethynylphenyl)ethyl]-L-leucinate was prepared from Intermediate 13b as follows:

To Intermediate 13b (357 mg, 1.65 mmol) in DCE (10 mL) were added Building Block B (613 mg, 1.65 mmol), STAB (349 mg, 1.65 mmol) and TEA (230 μL, 1.65 mmol) and the reaction mixture was stirred overnight at RT under N₂ atmosphere. The crude was poured onto DCM (20 mL) and washed with sat. NaHCO₃ (20 mL). The organic layer was separated, washed with brine (20 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude was purified by flash chromatography (1 % MeOH in DCM). It was then dissolved in THF (10 mL) treated with TBAF (620 μL, IM in THF) and the reaction mixture was stirred at RT for 30 minutes. The crude was poured into EtOAc (30 mL) and washed with water (3 x 50 mL) then brine (50 raL), dried (MgSO₄) and concentrated in vacuo to afford the desired product (225 mg, 38 %). ra/z = 400 [MH-H]⁺.

Example 13 was prepared from Intermediate 13c as follows:

To a solution of Building Block A (225 mg, 0.51 mmol) in DCM (3 mL) were added Intermediate 13c (166 mg, 0.51 mmol), TEA (71 μL, 0.51 mmol), tetrakis(triphenylphosphine) palladium (29 mg, 0.03 mmol) and copper iodide (10 mg, 0.05 mmol). The reaction mixture was heated at reflux for 2 hours. It was then diluted with DCM (15 mL), washed with sat. NaHCO₃ (15 mL) then brine (15 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude was purified by preparative HPLC to yield the desired product as a TFA salt (4 mg, 1 %). LCMS purity = 100 %; m/z = 643/645 (3:1) [M+H]⁺; ¹H NMR (300 MHz, CD₃OD) δ: 8.32 (IH, br s), 7.49 (2H, d, J=8.3 Hz), 7.38 (IH, s), 7.31 (2H, d, J=8.1 Hz), 5.53 (2H₅ br s), 5.39-5.32 (IH, m), 4.06-4.00 (IH, m), 3.99 (3H, s), 3.29-3.23 (2H, m), 3.09-3.02 (2H, m), 2.40 (3H, s), 2.39 (3H₅ s), 2.03-1.88 (2H, m), 1.88-1.67 (9H₅ m), 1.03 (3H, d, J=3.4 Hz), 1.01 (3H, d₅ J=3.6 Hz).

Example 14- Cyclopentyl N-{2-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-tflpyrimidin-5-yl}ethynyl) phenyl] ethyl} -L-alaninate

Example 14 was prepared from Building Block A and Building Block D using the same methodology as described for Example 13. LCMS purity = 97 %; m/z = 601/603 (3:1) [MH-H]⁺; ¹H NMR (300 MHz, J₆-DMSO) δ: 9.46-9.08 (2H, m), 8.17 (IH, br. s.), 7.53- 7.43 (3H, m), 7.31 (2H, d, J=8.1 Hz), 5.38 (2H, s), 5.27-5.17 (IH₅ m), 4.20-4.09 (IH, m), 3.80 (3H₅ s), 3.33-3.14 (2H₅ m), 3.05-2.91 (2H, ra), 2.28 (3H, s), 2.22 (3H₅ s), 1.95- 1.81 (2H₅ m), 1.76-1.54 (6H, m), 1.45 (3H, d, J=7.2 Hz).

Example 15- tert-butyl N-{2-[4-({2-amino-4-chloro-7.-[(4-methoxy-3₅5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-<i]pyrimidin-5-yl}ethynyl)phenyl]ethyl}-

L-alaninate

Example 15 was prepared from Building Block A and Building Block E using the same methodology as described for Example 13. LCMS purity = 98 %; m/z = 589/591 (3:1) [M+Η]⁺; ¹H ΝMR (300 MHz, CD₃OD) δ: 8.16 (IH₅ br. s.), 7.42 (2H₅ d, J=8.1 Hz), 7.26-7.20 (3H, m), 5.38 (2H, s), 3.80 (3H₅ s), 3.26 (IH, q, J=7.0 Hz)₅ 2.88-2.73 (4H₅ m), 2.31 (3H₅ s), 2.27 (3H₅ s), 1.46 (9H₅ s), 1.26 (3H, d, J=7.0 Hz).

Example 16- Cyclopentyl N-[3-({2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-cT]pyrimidin-5-yl}ethynyl)benzyl]-L- alaninate

Scheme 12 - Methodology for the preparation of Example 16 from Building Block A and Building Block D:

JULO

Me₃Si'

Intermediate 16a Intermediate 16b

TBAF /THF

Intermediate 16c

Example 16

Example 16- Cyclopentyl N-[3-({2-amino-4-chloro-7-[(4-methoxy-3,5~ dimethylpyridin-2-yl)methyl] -7H-pyrrolo [2, 3 -d]pyrimidin-5 -y 1 } ethynyl)benzy I]-L- alaninate

Example 16 was prepared using the same conditions as for Example 6, Scheme 9 using 3-iodobenzaldehyde instead of 4-iodobenzaldehyde. LCMS purity = 97 %; m/z = 587/589 (3:1) [M+Η]⁺; ¹H ΝMR (300 MHz, CDCl₃) δ: 8.25 (IH, s), 7.47 (IH, s), 7.42- 7.37 (IH, m), 7.30 (2H, s), 7.18 (IH, s), 5.35 (2H, s), 5.28-5.20 (IH, m), 5.00 (2H, br. s.), 4.99 (IH, s), 3.81 (IH, d, J=13.0 Hz), 3.77 (3H, s), 3.66 (IH, d, J=13.0 Hz), 3.33 (IH, q, J=7.0 Hz), 2.28 (3H₅ s), 2.23 (3H, s), 1.96-1.56 (8H, m), 1.31 (3H, d, J=7.0 Hz). Example 17- Cyclopentyl N-[4-(2-{2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-l-y^methyll-VH-pyrroloP_jS-cTIpyrimidin-S-yllethy^benzy^-L- alaninate

Scheme 13 - Methodology for the preparation of Example 17:

Example 6 Example 17

Example 6 (lOO.Omg, 0.17 mmol) in 1:1 EtOAc / EtOH (5 mL) was degassed before the addition of 10% Pd / C catalyst (20 mg). The mixture was stirred at RT under an atmosphere of Hα_(g) for 18 hours. The catalyst was removed by filtering the mixture through Celite and the filtrate concentrated in vacuo and purified by preparative HPLC to yield the desired product as a TFA salt (38 mg, 21 %). LCMS purity = 100 %; m/z = 591/593 (3:1) [M+H]⁺; ¹H NMR (300 MHz, CD₃OD) 8.39 (IH, s), 7.43 (2H, d, J=8.1 Hz), 7.36 (2H, d, J=8.1 Hz), 6.89 (IH, s), 5.49 (2H, s), 5.37-5.29 (IH, m), 4.23 (2H, s), 4.14-4.09 (IH, m), 4.08 (3H, s), 3.13-2.97 (4H, m), 2.46 (3H, s), 2.35 (3H, s), 2.06- 1.90 (2H, m), 1.83-1.67 (6H, m), 1.60 (3H, d, J=7.2 Hz).

Example 18 - Cyclopentyl N-{4-[(5-{2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl] -7H-pyrrolo [2, 3 -d]pyrimidin-5 -yl} pent-4-yn- 1 - yl)oxy]benzyl} -L-leucinate

Scheme 14 - Methodology for the preparation of Example 18 from Building Block A and Building Block B:

Building Block B

Intermediate 18a

A CuI

Intermediate 18b

Example 18

Intermediate 18a - 4-(Pent-4-yn-l-yloxy)benzaldehyde was prepared as follows:

To 4-hydroxybenzaldehyde (1 g, 8.2 mmol) in acetonitrile (20 mL) were added 5-chloro-l-pentyne (859 μL, 8.2 mmol) and K₂CO₃ (1.13 g, 8.2 mmol). The reaction mixture was stirred overnight at 90 ⁰C. The solvent was removed under reduced pressure. The crude was diluted with EtOAc (100 mL), washed with water (100 mL) then brine (100 mL). The organic layer was dried (MgSO₄) and concentrated under reduced pressure. The crude was used directly in the following step. Intermediate 18b - Cyclopentyl N-[4-(pent-4-yn-l-yloxy)benzyl]-L-leucinate was prepared from Intermediate 8a as follows:

To Intermediate 18a (520 mg, 2.75 mmol) in DCE (6 mL) were added Building Block B (1.02 g, 2.75 mmol), STAB (583 mg, 2.75 mmol) and TEA (371 μL, 2.75 mmol) and the reaction mixture was stirred overnight at RT under N₂ atmosphere. The crude was poured onto DCM (20 mL) and washed with sat. NaHCO₃ (20 mL). The organic layer was separated, washed with brine (20 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude was purified by flash chromatography (DCM to 0.5 % MeOH in DCM) to afford the desired product (176 mg, 17 % yield), m/z = 372 [M+H]⁺; ¹HNMR (300 MHz, CDCl₃) δ: 7.30-7.19 (2H, m), 6.91-6.81 (2H, m), 5.28-5.20 (IH, m), 4.07 (2H, t, J=6.0 Hz), 3.74 (IH, d, J=12.4 Hz), 3.56 (IH, d, J=12.4 Hz), 3.24 (IH, t, J=7.3 Hz), 2.42 (2H, td, J=7.0, 2.6 Hz), 2.04-1.96 (3H, m), 1.95-1.83 (2H, m), 1.82-1.61 (7H, m), 1.45 (2H, t, J=7.3 Hz), 0.93 (3H, d, J=6.6 Hz), 0.87 (3H, d, J=6.6 Hz).

Example 18 was prepared from Intermediate 8b as follows:

To a solution of Building Block A (209 mg, 0.47 mmol) in DCM (3 mL) were added Intermediate 18b (176 mg, 0.47 mmol), TEA (98 μL, 0.71 mmol), tetrakis(triphenylphosphine) palladium (29 mg, 0.03 mmol) and copper iodide (10 mg, 0.05 mmol). The reaction mixture was stirred at reflux for 2 hours. It was then diluted with DCM (15 mL), washed with sat. NaHCO₃ (15 mL) then brine (15 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude was purified by preparative HPLC to yield the desired product as a TFA salt (7 mg, 2 %). LCMS purity = 97 %; m/z = 687/689 (3:1) [M+H]⁺; ¹H NMR (300 MHz, J₆-DMSO) δ: 9.34 (2H, br s), 8.08 (IH, s), 7.39 (2H, d, J=8.7 Hz), 7.27 (IH, s), 7.03 (2H, d, J=8.7 Hz), 6.71 (2H, br s), 5.29 (2H, s), 5.21-5.12 (IH, m), 4.21-4.12 (4H, m), 3.75 (3H, s), 2.60 (2H, t, J=6.8 Hz), 2.25 (3H, s), 2.18 (3H, s), 2.07-1.94 (2H, m), 1.89-1.76 (2H, m), 1.72-1.55 (6H, m), 0.91 (3H, s), 0.89 (3H₅ s). 19 - N-(5-{2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- /l)raethyl]-7H-pyrrolo[2,3-c/lpyrimidin-5-yl}pent-4-yn-l-yl)-L-leucine

Scheme 15 - Methodology for the preparation of Example 19 from Example 1.

Example 1 Example 19

Example 19 was prepared from Example 1 as follows:

To Example 1 (87 mg, 0.15 mmol) in THF (2 mL) was added potassium trimethylsilanolate (96 mg, 0.75 mmol) and the reaction mixture was stirred at RT overnight. The THF was removed under reduced pressure and the crude was purified by preparative HPLC to afford the desired product as a TFA salt (1 mg, 2 %). LCMS purity = 100%; m/z = 513/515 (3:1) [M+H]⁺; ¹HNMR (300 MHz, CD₃OD) δ: 8.33-8.06 (IH, m), 7.16 (IH, s), 5.40 (2H, s), 4.00-3.90 (IH, m), 3.88 (3H, s), 3.28-3.23 (2H, m), 2.62 (2H, t, J=6.8 Hz), 2.33 (6H, s), 2.05-1.95 (2H, m), 1.92-1.77 (2H₅ m), 1.77-1.68 (IH, m), 1.01 (6H, t, J=5.7 Hz). - 15 -

The following examples were prepared using the same methodology as described for Example 19:

- "7 C -

BIOLOGICAL ASSAYS

HSP90 enzyme assay

An HTRP (homogeneous time resolved fluorescence) assay is used to measure the interaction of the compounds with HSP90. The assay measures binding of biotinylated Geldanamycin (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, # 610SAXLB, lot: 089).

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

A preformed (1 hour 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 minutes. A preformed (1 hour incubation) complex of bio-GM with the SA-XL is added to the wells and incubated for 20 hours. All incubations are performed at room temperature. The final assay volume is 50μl/well. The final concentrations in the assay are: 5OmM Hepes pH 7.3, 5OmM NaCl, 10OmM KF, ImM EDTA, ImM DTT, 0.1% Triton-X-100, InM anti-his-K, 40nM HSP90, 4OnM SA-XL, 4OnM bio-GM. Test compounds are dissolved in DMSO, prediluted in assay buffer and tested at a final concentration between 500OnM and 0.3nM. The resulting DMSO concentration is 0.5% and included in all controls. High controls are without test compounds, low controls without test compounds, without HSP90 and without bio-GM. As a reference inhibitor unlabeled GM is used in the same concentrations as the test compounds.

Inhibition is calculated compared to the assay controls using an Excel spreadsheet (Microsoft). ICs₀ values are calculated by non-linear least squares fitting to the standard dose-response model using GraphPad Prism (GraphPad Software Inc). Proliferation assay

Cells are seeded in 96 well tissue culture plates (1 well = 30mm²) at an appropriate density (2000 cells per well for U937 cells, 2250 cells per well for HUT-78 and MINO cells) in 50μl of culture medium (see below for details). 24 Hours later 50μl of the compound prepared in the same medium is added as 3 fold dilutions to give final concentrations in the range 5-10,00OnM (n=6 for each concentration). The plates are then incubated at 37⁰C, 5% CO₂ for 72 hours. Cell proliferation is assessed using WST- 1 (a metabolic indicator dye, Roche Cat no. 11644807001) according to the manufacturer's instructions. The results are calculated as a percentage of vehicle response and plotted as a dose-response curve. IC₅₀ values represent the concentration of compound that inhibits the vehicle response by 50%.

Culture medium for U937 and HUT-78 cells is RPMI1640 (Sigma R0883) with 10% heat inactivated fetal calf serum (Hyclone SH30071, Perbio), plus 2mM glutamine (Sigma G7513) and 50U/ml penicillin and streptomycin sulphate (Sigma P0781). MINO cell culture medium is as for U937 and HUT-78 but supplemented with sodium pyruvate (Sigma S8636) to a final concentration of ImM.

LPS-stimulation of THP-I cells

THP-I cells are plated in lOOμl at a density of 4x10⁴ cells / well in V-bottomed 96 well tissue culture treated plates and incubated at 37⁰C in 5% CO₂ for 16 hours. 2 Hours after the addition of the inhibitor in lOOμl of tissue culture media, the cells are stimulated with LPS (E. CoIi strain 005 :B5, Sigma) at a final concentration of lμg/ml and incubated at 37⁰C in 5% CO₂ for 6 hours. TNF-α levels are measured from cell-free supernatants by sandwich ELISA (R&D Systems #QTA00B).

LPS-stimulation of human whole blood

Whole blood is taken by venous puncture using heparinised vacutainers (Becton Dickinson) and diluted in an equal volume of RPMI1640 tissue culture media (Sigma). 1 OOμl is then plated in V-bottomed 96 well tissue culture treated plates. 2 Hours after the addition of the inhibitor in lOOμl of RPMI1640 media, the blood is stimulated with LPS (E. CoIi strain 005 :B5, Sigma) at a final concentration of lOOng/ml and incubated it 37⁰C in 5% CO₂ for 6 hours. TNF-α levels are measured from cell-free supernatants by sandwich ELISA (R&D Systems #QTA00B).

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 HUT78 tumour cells (-109) are washed in 4 volumes of Dulbeccos PBS (~1 litre) and pelleted at 525g for 10 minutes at 4⁰C. This is repeated twice and the final cell pellet is resuspended in 35ml of cold homogenising buffer (Trizma 1OmM, NaCl 13OmM, CaCl₂ 0.5mM pH 7.0 at 25⁰C). Homogenates are prepared by nitrogen cavitation (700psi for 50 minutes at 4⁰C). The homogenate is kept on ice and supplemented with a cocktail of inhibitors at final concentrations of Leupeptin lμM, Aprotinin 0.1 μM, E64 8μM, Pepstatin 1.5μM, Bestatin 162μM, Chymostatin 33μM.

After clarification of the cell homogenate by centrifugation at 525g for 10 minutes, the resulting supernatant is used as a source of esterase activity and is 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 (~30μg / total assay volume of 0.5ml) is incubated at 37⁰C in a Tris- HCl 25mM, 125mMNaCl buffer, pH 7.5 at 25⁰C. At zero time the ester (substrate) is then added at a final concentration of 2.5mM and the samples were incubated at 37⁰C for the appropriate time (usually 0 or 80 minutes). Reactions are stopped by the addition of 2 x volumes of acetonitrile. For zero time samples the acetonitrile is added prior to the ester compound. After centrifugation at 1200Og for 5 minutes, samples are 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*2.1mm) column and a mobile phase of 5-95 % acetonitrile in water / 0.1 % formic acid. Results:

IC50 values are allocated to one of three ranges as follows:

Range A: IC50 < 10OnM

Range B: 10OnM <IC₅₀ < 100OnM

RangeC:IC₅₀>1000nM

NT = Not Tested.

NR = Not Relevant. Examples 19-31 are the resultant carboxylic acid analogues of the amino acid esters that are cleaved inside cells. When these carboxylic acids are contacted with the cells, they do not penetrate into the cells and hence do not inhibit cell proliferation or TNF-α production in these assays.

Claims

1. A compound which is (a) a pyrrolopyrimidine 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]_-6 alkyl, Q_-6 alkoxy, C2-6 alkenyl, C_2-6 alkynyl, C2-6 alkenyloxy, hydroxy 1, -SR', -NR'R" or -NR" OR' group wherein each R' and R" is the same or different and represents hydrogen or unsubstituted Ci_-4 alkyl, or R¹ represents a group of formula -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -CONHR^A, -S0₂NHR^A, -CONR^AR^B, -SO₂NR^AR^B, -OCONH₂, -0C0NHR^A, -0C0NR^AR^B, -NHCOR^A, -NR^BC0R^A, -NHC00R^A, -NR^BC00R^A, -NR⁵COOH, -NHC00H-, -NHSO₂R^A, -NR^BSO₂R^A, -NHSO₂OR^A, -NR⁶SO₂OH, -NHSO₂H, -NR^BSO₂OR^A, -NHCONH₂, -NR^AC0NH₂, -NHC0NHR^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 an unsubstituted Ci_-6 alkyl group, or a C₃.₆ cycloalkyl, non-fused phenyl or a non-fused 5- to 6-membered heteroaryl, or R^Λ 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, hydroxyl, -N3, Ci-6 alkyl, C_1-6 alkoxy, C_2-6 alkenyl, C_2-6 alkynyl group, or a group -SR', -NR'R", -COOR', -SO₂R', -NR'OR" or -CONR'R" where R' and R" are the same or different and represent a hydrogen atom, an unsubstituted CM alkyl group or an unfused C_δ-jo aryl, 5- to 10- membered heteroaryl, C_3-7 carbocyclyl or 5- to 10-raembered heterocyclyl group;

R³ represents a hydrogen or halogen atom or a cyano, nitro, -N₃, hydroxyl, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_]-6 alkoxy, C_2-6 alkenyloxy, -SR' or -NR'R" group where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-4 alkyl; R⁴ represents a group of formula -L¹ -A¹ ; L¹ represents Ci_-4 alkylene or C_2-4 alkenylene, the alkylene and alkenylene groups optionally containing or terminating in an -O-, -S- or -NR'- link where R' represents hydrogen or unsubstituted Ci_-2 alkyl; A¹ represents a Cβ-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 represents a group of formula: L² (Het)_x AIk¹ R wherein:

L² represents a group -AIk³-, -Alk'-A²- or -Alk³-AIk⁵-;

AIk³ represents a bond or a Q_-4 alkylene, C_2-4 alkenylene or C_2-4 alkynylene group;

AIk⁵ represents a Ci_-4 alkylene, C_2-4 alkenylene or C_2-4 alkynylene group;

A² represents a phenyl or 5- to 6-membered heteroaryl group which is unfused or fused to a further phenyl or 5- to 6-membered heteroaryl group;

Het represents -O-, -S- or -NR'- where R' represents hydrogen or unsubstituted Ci_-2 alkyl; x is 0 or 1 ;

AIk¹ represents a bond or C_1-6 alkylene, C_2-6 alkenylene or C_2-6 alkynylene group, or a group -A³-Alk⁶- where A³ represents a phenyl or

5- to 6-membered heteroaryl group which is unfused or fused to a further phenyl or 5- to 6-membered heteroaryl group, and AIk⁶ represents a Ci_-6 alkylene, C_2-6 alkenylene or C_2-6 alkynylene group; R represents a group of formula (X) or (Y):

(X) (Y)

R⁸, where present, represents a hydrogen atom or a C_1-4 alkyl group; AIk² represents a group of formula -C(R⁵)(R⁶)- when R is of formula (X) or -C(R⁵)- when R is of formula (Y), wherein R⁵ and R⁶ are the same or different and represent hydrogen or the α-substituents of an α-substituted or α,α-disubstituted glycine or glycine ester compound; ring D, where present, is a 5- to 6-membered heterocyclyl group containing AIk² and wherein R⁷ is linked to ring D via AIk², and ring D is optionally fused to a second ring comprising a phenyl, 5- to 6- membered heteroaryl, C_3-7 carbocylyl or 5- to 6-membered heterocyclyl; and

R⁷ is a group -COOH or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a -COOH group; and wherein, unless otherwise stated: the alkyl, alkenyl and alkynyl groups and moieties in R¹, R², R³, R⁵, R⁶, R⁸, L¹, AIk¹, AIk², AIk³, AIk⁴, AIk⁵ and AIk⁶ are unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms and Ci_-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, Ci_-4 hydroxyalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl; the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in A¹, A², A³, D, R¹ and R² are unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents selected from halogen atoms, and cyano, nitro, C)_-4 alkyl, Ci_-4 alkoxy, C_2-4 alkenyl, C_2-4 alkenyloxy, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, Ci_-4 hydroxyalkyl, -SR' and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or unsubstituted CM alkyl, or from substituents of formula -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -CONHR^A, -SO₂NHR^A, -C0NR^AR^B, -SO₂NR^AR^B, -OCONH₂, -OCONHR^A, -0C0NR^AR^B, -NHCOR^A, -NR^BC0R^A, -NHC00R^A, -NR^BCOOR^A, -NR^BCOOH, -NHCOOH₅ -NHSO₂R^A, -NR^BS0₂R^A, -NHSO₂OR^A, -NR^BSO₂OH, -NHSO₂H, -NR^BSO₂OR^A, -NHCONH₂, -NR^ACONH₂, -NHCONHR^B, -NR^AC0NHR^B, -NHC0NR^AR^B or -NR^ACONR^AR^B wherein R^A and R^B are the same or different and represent unsubstituted Cj_-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.

2. A compound as claimed in claim 1 wherein R¹ represents a hydrogen or halogen atom, or Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl, -SR' or -NR'R" group wherein each R' and R" is the same or different and represents hydrogen or unsubstituted C_1-4 alkyl, and wherein the alkyl groups and moieties in R¹, unless otherwise stated, are unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents selected from halogen atoms, and Ci-₄ alkyl, QM alkenyl, C]_-4 alkoxy, hydroxyl, CM haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy and -NR'R" groups where 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, or an unsubstituted C_1-4 alkyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl or -NR'R" group 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 R³ represents a hydrogen or halogen atom or an unsubstituted Cj_-4 alkyl, Ci_-4 alkoxy, C]_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl or -NR'R" group where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl.

5. A compound as claimed in any one of the preceding claims wherein L¹ represents C_1-2 alkylene, said alkylene group optionally containing or terminating in -O-, -S- or -NR'- where R' is hydrogen or unsubstituted methyl, and said alkylene group being unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms, and Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl and -NR 'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted methyl; and wherein A¹ represents phenyl or 5- to 6-membered heteroaryl group which is unfused or fused to a further phenyl or 5- to 6-membered heterocyclyl group, said A¹ group being unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected halogen atoms and unsubstituted C_1-4 alkyl, CM alkoxy, hydroxyl, C]_-4 haloalkyl, Ci_-4 haloalkoxy, Ci_-4 hydroxyalkyl, cyano, nitro, -SR' and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl.

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

L² represents -AIk³-, -Alk³-A²- or -Alk³-Alk⁵-; AIk³ represents a bond or an Ci_-3 alkylene, C_2-3 alkenylene or C_2-3 alkynylene group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms, and Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl, Ci_-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl; AIk⁵ represents a Ci_-4 alkylene, C_2-4 alkenylene or C_2-4 alkynylene group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms, and Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl, C_1-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl; and

A² represents an unfused phenyl or unfused 5- to 6-membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted C_1-4 alkyl, C_1-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl.

7. A compound as claimed in any one of the preceding claims wherein: x is 0 or 1 ;

AIk¹ represents a bond or a Ci_-6 alkylene group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents selected from halogen atoms, and Ci_-4 alkyl, C_2-4 alkenyl, Cj_-4 alkoxy, hydroxyl, Cj_-4 haloalkyl, C_2-4 haloalkenyl, C_1-4 haloalkoxy and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C]_-2 alkyl, or AIk¹ represents a group -A³ -AIk⁶- where A³ represents an unfused phenyl or unfused 5- to 6-membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl, and AIk⁶ represents a bond or an C₁.3 alkylene, C₂-3 alkenylene or C_2-3 alkynylene group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms, and Ci_-2 alkyl, C_1-2 alkoxy, hydroxyl, Ci_-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl; R represents a group of formula (X) or (Y);

R⁸, where present, represents a hydrogen atom or an unsubstituted Ci_-2 alkyl group;

R⁵ and R⁶, which are the same or different, represent hydrogen or the α substituents of an α-substituted or α,α-disubstituted glycine or glycine ester; Ring D, where present, represents an unfϊised 5- to 6-membered heterocyclyl group; and

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

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

R¹ represents a hydrogen or halogen atom, or C₁^ alkyl, Cj_-4 alkoxy, hydroxyl, -SR' or -NR 'R" group wherein each R' and R" is the same or different and represents hydrogen or unsubstituted Ci_-4 alkyl, and wherein the alkyl groups and moieties in R¹, unless otherwise stated, are unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents selected from halogen atoms, and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, hydroxyl, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy and -NR'R" groups where R' and R" are the same or different and represent hydrogen or Ci_-2 alkyl;

R² represents a hydrogen or halogen atom, or an unsubstituted Cj_-4 alkyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl or -NR'R" group where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl;

R³ represents a hydrogen or halogen atom or an unsubstituted C]_-4 alkyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl or -NR'R" group where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl;

L¹ represents Ci_-2 alkylene, said alkylene group optionally containing or terminating in -0-, -S- or -NR'- where R' is hydrogen or unsubstituted methyl, and said alkylene group being unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms, and Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted methyl; and wherein A¹ represents phenyl or 5- to 6-membered heteroaryl group which is unfused or fused to a further phenyl group, said A¹ group being unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected halogen atoms and unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl, Cj_-4 haloalkyl, Ci_-4 haloalkoxy, C]_-4 hydroxyalkyl, cyano, nitro, -SR' and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl;

L² represents -AIk³-, -Alk³-A²- or -Alk³-Alk⁵-; AIk³ represents a bond or an C_1-3 alkylene, C_2-3 alkenylene or C_2-3 alkynylene group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms, and C]_-2 alkyl, Ci_-2 alkoxy, hydroxyl, Ci_-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl; AIk⁵ represents a Ci_-4 alkylene, C_2-4 alkenylene or C_2-4 alkynylene group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms, and Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl, Ci_-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl;

A² represents an unfused phenyl or unfused 5- to 6-membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl; x is 0 or 1 ;

AIk¹ represents a bond or a Ci-6 alkylene group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents selected from halogen atoms, and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, hydroxyl, C]_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl, or AIk¹ represents a group -A³ -AIk⁶- where A³ represents an unfused phenyl or unfused 5- to 6-membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted C_1-4 alkyl, C_1-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl, and AIk⁶ represents a bond or an C_1-3 alkylene, C_2-3 alkenylene or C_2-3 alkynylene group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms, and Ci_-2 alkyl, C ₁-₂ alkoxy, hydroxyl, C_1-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl;

R represents a group of formula (X) or (Y);

R⁸ , where present, represents a hydrogen atom or an unsubstituted C_1-2 alkyl;

R⁵ and R⁶, which are the same or different, represent hydrogen or the α substituents of an α-substituted or α,α-disubstituted glycine or glycine ester;

Ring D, where present, represents an unfused 5- to 6-membered heterocyclyl group; and

9. A compound as claimed in any one of the preceding claims which is (a) a pyrrolopyrimidine derivative of formula (IA) 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 an unsubstituted group selected from Ci_-4 alkyl, C_1-4 alkoxy, C_1-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl and -NR'R" where R' and R" are the same or different and represent hydrogen or C_1-2 alkyl;

L¹ represents Ci_-2 alkylene, said alkylene group optionally containing or terminating in -O-, -S- or -NR'- where R' is hydrogen or unsubstituted methyl, and said alkylene group being unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms, and Ci_-2 alkyl, Ci_-2 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted methyl;

A¹ represents an unfused phenyl or 5- to 6-membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C_1-2 alkyl;

L² represents -AIk³-, -Alk³-A²- or -Alk³-Alk⁵-;

AIk³ represents a bond or an unsubstituted Ci_-3 alkylene, C_2-3 alkenylene or C_2-3 alkynylene group;

AIk⁵ represents an unsubstituted Ci_-4 alkylene group;

A² represents an unfused phenyl or unfused 5- to 6-membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms and unsubstituted Cj_-4 alkyl, Ci_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Cj_-2 alkyl; x is 0 or 1 ;

AIk¹ represents a bond or a C_1-4 alkylene group which is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms, and C_1-2 alkyl, C_1-2 alkoxy, hydroxyl, C_1-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl, or AIk¹ represents a group -A³-Alk⁶- where A³ represents an unfused phenyl or unfused 5- to 6- membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms and unsubstituted Cj_-4 alkyl, Ci_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl, and AIk⁶ represents an unsubstituted C₁^ alkylene group; R⁸ represents a hydrogen atom or an unsubstituted C_1-2 alkyl; AIk² represents a group of formula -C(R^S)(R⁶)- wherein R⁵ and R⁶ are the same or different and represent a hydrogen atom or an unsubstituted Ci-6 alkyl group; and

R⁷ represents -COOH or -COOR⁹ where R⁹ represents a C_1-4 alkyl, C_3-7 carbocyclyl groups or C_2-4 alkenyl group, or R⁹ represents a phenyl, benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl, methoxyethyl, indanyl, norbonyl, dimethylaminoethyl or morpholinoethyl group.

10. A compound as claimed in claim 9 whereinx is 1 and Het represents -O-.

11. A compound as claimed in claim 9 or claim 10 wherein L¹ represents a methylene group which is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms and Ci_-2 alkyl, C_1-2 alkoxy, hydroxyl and -NH₂.

12. A compound as claimed in any one of claims 9 to 11 wherein A¹ represents 5- to 6-membered heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted C_1-4 alkyl, C]_-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl.

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

wherein:

R¹ represents a hydrogen or halogen atom, a hydroxyl group, an unsubstituted C]_-4 alkyl or -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted methyl; n represents 0, 1, 2 or 3; each R^a is the same or different and represents a halogen atom or an unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxyl or -NR'R" group where

R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl;

L² represents -AIk³-, -Alk³-Alk⁵- or -Alk³-A²;

AIk¹ represents an unsubstituted Cj_-3 alkylene group or a group -A³-Alk⁶ where A³ represents an unfused phenyl which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms and unsubstituted Ci_-4 alkyl, Ci_-4 alkoxy, hydroxy! and -NR 'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci_-2 alkyl, and AIk⁶ represents an unsubstituted C_]-2 alkylene group;

R¹⁰ represents a hydrogen atom or an unsubstituted Ci_-4 alkyl or C_3-7 carbocyclyl group.

14. A compound as claimed in claim 13 wherein AIk² represents a group of formula -C(R⁵)(R⁶)- wherein either (i) R⁵ and R⁶ are the same and represent unsubstituted C]_-2 alkyl groups, or (ii) R⁵ and R⁶ are different and one of R⁵ and R⁶ represents hydrogen and the other of R⁵ and R⁶ represents an unsubstituted Ci .6 alkyl group.

15. A compound as claimed in claim 13 or claim 14 wherein AIk³ represents an unsubstituted ethynylene group.

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

Cyclopentyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-^pyrimidin-5-yl}pent-4-yn-l-yl)-L-leucinate;

Cyclopentyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyriOlo[2,3-cripyrimidin-5-yl}pent-4-yn-l-yl)-2-methylalaninate; ]yclopentyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl] -7H-pyrrolo[2, 3 -J]pyrimidin-5 -yl} pent-4-yn- 1 -yl)-L-alaninate; tert-Butyl N-(5 - {2-amino-4-chloro-7-[(4-methoxy-3 , 5 -dimethy lpyridin-2-yl)methyl] - 7H-pyrrolo[2,3-<flpyrimidm-5-yl}pent-4-yn-l-yl)-L-alaninate;

Cyclopentyl N-(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-cT|pyrimidin-5-yl}pent-4-yn-l-yl)-L-phenylalaninate; Cyclopentyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-c(]pyrimidin-5-yl}ethynyl)benzyl]-L-alaninate;

Cyclopentyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-J]pyrimidin-5-yl}ethynyl)benzyl]-L-leucinate; ^ert-Butyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo [2,3 -<i]pyrimidin-5 -yl } ethynyl)benzyl] -L-alaninate; Cyclopentyl (25)-{[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2₅3-(/lpyrimidin-5-yl}ethynyl)benzyl] amino} (phenyl)acetate; Cyclopentyl (25)-{[4-({2-amino-4-chloro-7-[(4-methoxy-3_s5-dimethylpyridin-2- y l)methyl] -7H-pyrrolo[2, 3 -<f]pyrimidin-5 -yl} ethynyl)benzyl] amino} (cyclohexyl)acetate;

Cyclopentyl N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-J]pyrimidin-5-yl}ethynyl)benzyl]-2-methylalaninate; Cyclopentyl N-{3-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2₅3-c(lpyrimidin-5-yl}ethynyl)phenoxy]propyl}-L-leucinate; Cyclopentyl N-{2-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-(f]pyrimidin-5-yl}ethynyl)phenyl]ethyl}-L-leucinate; Cyclopentyl N-{2-[4-({2-amino-4-chloro-7-[(4-methoxy-3, 5 -dimethy lpyridin-2- yl)methyl]-7H-pyrrolo[2,3-cT]pyrimidin-5-yl}ethynyl) phenyl] ethyl} -L-alaninate; /e^-butyl N-{2-[4-({2-amino-4-chIoro-7-[(4-methoxy-3,5-dimethyIpyridin-2- yl)methyl]-7H-pyrrolo[2,3-</|pyrimidin-5-yl}ethynyl)phenyl]ethyl}-L-alaninate; Cyclopentyl N-[3-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-(i]pyrimidin-5-yl}ethynyl)benzyl]-L-alaninate; Cyclopentyl N-[4-(2-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-(f]pyrimidin-5-yl}ethyl)benzyl]-L-alaninate; Cycloρentyl iV-{4-[(5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylρyridin-2- yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}pent-4-yn-l-yl)oxy]benzyl}-L-leucinate; N-(5-{2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo [2,3 --7]pyrimidin-5 -yl} pent-4-yn- 1 -yl)-L-leucine; N-(5-{2-Amlno-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo [2,3 -</]pyrimidin-5 -yl} pent-4-yn- 1 -yl)-2-methylalanine; N-(5 - {2-amino-4-chloro-7-[(4-methoxy-3 , 5 -dimethylpyridin-2-yl)methy 1] -7H- pyrrolo[2,3-β]pyrimidin-5-yl}pent-4-yn-l-yl)-L-alanine; N-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2₅3-^pyrimidin-5-yl}ethynyl)benzyl]-L-alanine; N-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo [2, 3 -</]pyrimidin-5 -yl} ethynyl)benzyl]-L-leucine;

(25}-{[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-(f]pyrimidin-5-yl}ethynyl)benzyl] amino} (phenyl)acetic acid; N-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo [2,3-ή(]pyrimidin-5-yl}ethynyl)benzyl]-2-methylalanine;

N-{3-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-(^Ipyrimidin-5-yl}ethynyl)phenoxy]propyl}-L-leucine; N-{2-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-(i]pyrimidin-5-yl}ethynyl)phenyl]ethyl}-L-leucine; N-{2-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-c(]pyrimidin-5-yl} ethynyl) phenyljethyl} -L-alanine;

Cyclopentyl N-[3-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-c(]pyrimidin-5-yl} ethynyl) benzyl]-L-alaninate; N-[4-(2-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)raethyl]-7H- pyrrolo[2,3-</Ipyrimidin-5-yl} ethyl)benzyl]-L-alanine; and N-{4-[(5-{2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-£/lpyrimidin-5-yl}pent-4-yn-l-yl)oxy]benzyl}-L-leucine.

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

18. A pharmaceutical composition which comprises a compound as defined in any one of claims 1 to 16 and a pharmaceutically acceptable carrier or diluent.

19. Use of a compound as claimed in any one of claims 1 to 16 in the manufacture of a medicament for use in treating or preventing disorders mediated by HSP90.

20. Use as claimed in claim 19 wherein the medicament is for use in the treatment or prevention of cancer, or for use in the treatment or prevention of inflammation.

21. Use as claimed in claim 19 wherein the medicament is for use in the treatment or prevention of inflammation, more preferably for use in the treatment or prevention of rheumatoid arthritis.

22. Use as claimed in claim 19 wherein the medicament is for use in the treatment or prevention of a viral infection.

23. Use as claimed in claim 19 wherein the medicament is for use in the treatment or prevention of Alzheimer's disease.

24. Use as claimed in claim 19 wherein the medicament is for use in the treatment or prevention of cancer, more preferably for use in the treatment or prevention of monocyte-derived cancers.

25. 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 16.

26. A method as claimed in claim 25 wherein the patient is suffering from or susceptible to (i) cancer, (ii) inflammation, (iii) a viral infection, or (iv) Alzheimer's disease.

27. A compound as claimed in any one of claims 1 to 16 for use in treating or preventing disorders mediated by HSP90.

28. A compound as claimed in claim 27 for use in the treatment or prevention of (i) cancer, (ii) inflammation, (iii) a viral infection, or (iv) Alzheimer's disease.