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WO2010043865A1 - Inhibiteurs d’hsp90 - Google Patents

Inhibiteurs d’hsp90 Download PDF

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Publication number
WO2010043865A1
WO2010043865A1 PCT/GB2009/002464 GB2009002464W WO2010043865A1 WO 2010043865 A1 WO2010043865 A1 WO 2010043865A1 GB 2009002464 W GB2009002464 W GB 2009002464W WO 2010043865 A1 WO2010043865 A1 WO 2010043865A1
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unsubstituted
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Francesca Ann Day
Delphine Francoise Monique Launay
Michael Hugh Charlton
David Festus Charles Moffat
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Chroma Therapeutics Ltd
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Chroma Therapeutics Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • 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.
  • COPD chronic obstructive pulmonary disease
  • psoriasis 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
  • Hsps 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.
  • 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.
  • Hsp90 forms homodimers where the contact sites between subunits are localised within the C- terminus in the open conformation of the dimer.
  • the three domains of Hsp90 move from an ATP-free "open" state to an ATP-bound "closed” state.
  • Hsp90 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.
  • 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.
  • 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.
  • Hsp90 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- ⁇ B (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.
  • 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.
  • 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- ⁇ B pathway, which holds prominent roles in inflammation and cancer.
  • 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- ⁇ B, an important proinflammatory transcription factor that mediates up-regulated expression of several proinflammatory cytokines and chemokines, such as tumour necrosis factor ⁇ (TNF- ⁇ ), IL-6, IL-8 and IL- l ⁇ , critical for amplifying the inflammatory insult.
  • NF- ⁇ B an important proinflammatory transcription factor that mediates up-regulated expression of several proinflammatory cytokines and chemokines, such as tumour necrosis factor ⁇ (TNF- ⁇ ), IL-6, IL-8 and IL- l ⁇ , 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.
  • Hsp90 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 -
  • 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.
  • 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:
  • R 1 represents a hydrogen or halogen atom, or a cyano, nitro, -N 3 , 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 R 1 represents a group of formula -COOH, -C00R A , -COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -C0NHR A , -SO 2 NHR A , -C0NR A R B , -S0 2 NR A R B , -OCONH 2 , -0C0NHR A , -OCONR A R B , -NHC0R A ,
  • R 3 represents a hydrogen or halogen atom or a cyano, nitro, -N 3 , 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;
  • R 4 represents a group of formula -L 1 -A 1 ;
  • L 1 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;
  • a 1 represents a C ⁇ -io aryl, 5- to 10-membered heteroaryl, C 3- ?
  • W represents a group of formula: L 2 (Het) x AIk 1 R wherein:
  • L 2 represents a group -AIk 3 -, -Alk 3 -A 2 - or -Alk 3 -Alk 5 -;
  • AIk 3 represents a bond or a C 1-4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene group
  • AIk 5 represents a C] -4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene group;
  • a 2 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;
  • AIk 1 represents a bond or C ⁇ g alkylene, C 2-6 alkenylene or C 2-6 alkynylene group, or a group -A 3 -Alk 6 - where A 3 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 AIk 6 represents a Q.6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene group; R represents a group of formula (X) or (Y):
  • R 8 represents a hydrogen atom or a Cj -4 alkyl group
  • AIk 2 represents a group of formula -C(R 5 )(R 6 )- when R is of formula (X) or -C(R 5 )- when R is of formula (Y), wherein R 5 and R 6 are the same or different and represent hydrogen or the ⁇ -substituents of an ⁇ -substituted or an ⁇ , ⁇ -disubstituted glycine or glycine ester compound
  • ring D where present, is a 5- to 6-membered heterocyclyl group containing AIk 2 and wherein R 7 is linked to ring D via AIk 2 , 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
  • R 7 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 R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , L 1 , AIk 1 , AIk 2 , AIk 3 , AIk 4 , AIk 5 and AIk 6 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',
  • R 5 and/or R 6 represent the ⁇ substituents or an ⁇ -substituted or ⁇ , ⁇ - disubstituted glycine or glycine ester compound
  • any functional groups in these R 5 and R 6 groups may be protected.
  • the term "protected" when used in relation to a functional substituent in a side chain of an ⁇ -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.
  • the compounds of the invention are compounds of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • the alkyl, alkenyl and alkynyl groups and moieties in R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , L 1 , AIk 1 , AIk 2 and AIk 3 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.
  • the substituents described above are preferably themselves unsubstitute
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • C 1-4 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
  • the alkyl moieties may be the same or different.
  • two alkenyl moieties may be the same or different.
  • 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.
  • two alkynyl moieties may be the same or different.
  • 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.
  • 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.
  • a halogen atom is typically chlorine, fluorine, bromine or iodine.
  • 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 -OCX 3 wherein X is a said halogen atom, for example chlorine and fluorine.
  • 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.
  • 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.
  • a phenyl ring 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.
  • 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.
  • 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.
  • 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.
  • phenyl 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.
  • phenyl groups 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.
  • a 5- to 10- membered heterocyclyl group or moiety is a non- aromatic, saturated or unsaturated C 5-1 O 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)-.
  • 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-
  • 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.
  • 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.
  • heterocyclyl group or moiety 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).
  • 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.
  • a C 3-7 carbocyclic group or moiety is a non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 7 carbon atoms.
  • 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.
  • a carbocyclyl group or moiety 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).
  • the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in A 1 , A 2 , D, R 1 and R 2 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 , -SO 2 R A , -CONH 2
  • 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.
  • 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 , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -C0NHR A , -SO 2 NHR A , -C0NR A R B , -SO 2 NR A R B , -OCONH 2 , -OCONHR A , -0C0NR A R B , -NHCOR A , -NR B C0R A , -NHC00R A , -NR B C00R A , -NR 8 COOH, -NHCOOH, -NHSO 2 R A , -NR B S0 2 R A , -NHSO 2 OR A , -NR 15 SO 2 OH, -NHSO 2 H,
  • phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in A 1 , A 2 , D, R 1 and R 2 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.
  • the substituents are themselves unsubstituted.
  • 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.
  • 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.
  • 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 pipe
  • hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
  • 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.
  • R 1 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 R 1 , 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.
  • R 1 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.
  • R 1 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.
  • R 1 represents a halogen atom, in particular a chlorine atom.
  • R 2 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 R 2 , 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.
  • R 2 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.
  • R 2 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.
  • R 2 represents -NR'R" where R' and R" represent hydrogen or unsubstituted methyl.
  • R 2 represents -NH 2 .
  • R 3 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 R 3 , 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.
  • R 3 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.
  • R 3 represents a hydrogen or halogen atom.
  • R 3 represents a hydrogen atom.
  • Preferred substituents on L 1 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.
  • L 1 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.
  • L 1 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 -NH 2 .
  • L 1 represents an unsubstituted methylene group.
  • a 1 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.
  • a 1 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.
  • the heterocyclyl group is preferably a dioxole group.
  • a preferred A 1 group is benzodioxole.
  • a 1 represents a phenyl or 5- to 6-membered heteroaryl group which is unfused or fused to a further phenyl group. More preferably A 1 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.
  • the A 1 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 A 1 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 A 1 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.
  • the substituents on A 1 are selected from halogen atoms and unsubstituted Ci -2 alkyl and Ci -2 alkoxy groups.
  • L 2 represents -AIk 3 -, -Alk 3 -A 2 - or -Alk'-Alk 5 - with AIk 3 , AIk 5 and A 2 being as defined earlier.
  • Preferred examples of AIk 3 , AIk 5 and A 2 are discussed below, and it is also preferred that L 2 in total does not represent a bond, i.e. that AIk 3 and AIk 5 do not both represent a bond when x is zero.
  • AIk 3 represents a bond or a Ci -3 alkylene, C 2-3 alkenylene or C 2-3 alkynylene group. More preferably AIk 3 represents a Ci -3 alkylene, C 2-3 alkenylene or C 2-3 alkynylene group.
  • the AIk 3 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.
  • the AIk 3 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 AIk 3 group is unsubstituted.
  • AIk 3 represents a C 2-3 alkynylene group, more preferably an ethynylene group.
  • L 2 represents -Alk 3 -Alk 5 -
  • AIk 3 represents an ethynylene group.
  • a 2 represents an unfused phenyl or unfused 5- to 6-membered heteroaryl group. More preferably A 2 represents an unfused phenyl group.
  • the AIk 3 and Het or AIk 1 groups can be attached to the phenyl group at any position, although it is preferred that the AIk 3 and Het or AIk 1 groups are attached in a meta- or para- relationship to one another, more preferably in a para- relationship.
  • the A 2 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 A 2 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 A 2 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.
  • the substituents on A 2 are selected from halogen atoms and unsubstituted Ci -2 alkyl and Ci -2 alkoxy groups. Most preferably the A 2 group is unsubstituted.
  • AIk 5 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.
  • AIk 5 represents an unsubstituted Ci -4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene group. Most preferably AIk 5 represents an unsubstituted Ci -4 alkylene, for example a C 3-4 alkylene group, more preferably a group -CH 2 -CH 2 -CH 2 -.
  • the Het group is preferably -O-.
  • AIk 1 represents C 1-6 alkylene or a group -A 3 -Alk 6 -.
  • AIk 1 represents a C 1-6 alkylene group, it preferably is a Cj -4 alkylene group, more preferably a C ⁇ 3 alkylene group, preferably a methylene or propylene group.
  • AIk 1 represents a C 1 ⁇ alkylene group
  • AIk 1 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, 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 Cj -2 alkyl.
  • AIk 1 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 AIk 1 is unsubstituted.
  • a 3 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 AIk 6 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
  • AIk 1 represents a group -A 3 -Alk 6 -, preferably A 3 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.
  • a 3 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 A 3 represents an unsubstituted, unfused phenyl group.
  • AIk 1 represents a group -A 3 -Alk 6 -
  • AIk 6 represents an unsubstituted C 1-6 alkylene group, more preferably still an unsubstituted C 1-2 alkylene group, in particular a methylene group -CH 2 - or an ethylene group -CH 2 -CH 2 -.
  • AIk 1 is a C3 alkylene group.
  • L 2 is -AIk 3 -, preferably x is 0 and AIk 1 is a C 3 alkylene group.
  • L 2 is -Alk 3 -A 2 -, preferably x is 1 and AIk 1 is a C 1 alkylene group.
  • R represents a group of formula (X) or (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 R 7 is linked to the group AIk 2 , which provides the carbon atom adjacent the nitrogen atom shown in Ring D.
  • 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.
  • -AIk 2 - is -C(R 5 )-.
  • the carbon atom of AIk 2 forms part of the ring D, and (in addition to being bonded to two other ring atoms) bears groups R s and R 6 .
  • R s and R 6 Preferred examples of R 5 are discussed in more detail below.
  • Ring D in addition to containing AIk 2 and bearing group R 7 , 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 AIk 2 and bearing group R 7 , is unsubstituted.
  • R 8 preferably represents a hydrogen atom or an unsubstituted Ci -2 alkyl. More preferably R 8 represents a hydrogen atom Preferably R represents a group of formula (X).
  • AIk 2 represents a methylene group substituted with an R 5 and, when R represents a group of formula (X), an R 6 group.
  • R 5 and R 6 are hydrogen or the ⁇ substituents of an ⁇ -substituted or ⁇ , ⁇ -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.
  • examples of R 5 and R 6 include hydrogen, phenyl and groups of formula -CR a R b R c in which:
  • 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, -CO 2 H, (Ci -4 )perfluoroalkyl, -CH 2 OH, -O(Ci -6 )alkyl, -O(C 2-6 )alkenyl, -S(C !-6 )alkyl, -SO(C 1-6 )alkyl, -SO 2 (Ci -6 ) alkyl, -S(C 2-6 )alkenyl, -SO(C 2-6 )alkenyl or -SO 2 (C 2-6 )alkenyl group
  • 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 -SO 2 - and W represents a phenyl, phenyl(C] -6 )alkyl, C 3-8 carbocyclyl, C3-8 cycloalkyl(Ci -6 )alkyl, C 4 ..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, -CONH 2 , - CONH(C 1-6
  • 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.
  • 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.
  • 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 (C 3 - 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.
  • 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.
  • 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, -CO 2 H, (C M )perfluoroalkyl, -CH 2 OH, -O(C 1-6 )alkyl, -O(C 2-6 )alkenyl, -S(Ci -6 )alkyl 5 -SO(Ci -6 )alkyl, -SO 2 (C 1-6 ) alkyl, -S(C 2-6 )alken
  • R is a group of formula (X)
  • the substituents R 5 and R 6 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.
  • At least one of the substituents R 5 and R 6 is a C 1-6 alkyl group, for example methyl, ethyl, or n- or iso-propyl.
  • R 5 and R 6 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).
  • R 5 or R 6 is hydrogen
  • R 5 and R 6 are the same or different and represent hydrogen or unsubstituted C 1-6 alkyl.
  • R 5 and R 6 are the same or different and represent unsubstituted C 1-2 alkyl groups. More preferably when neither R 5 nor R 6 are hydrogen, then preferably R 5 and R 6 are both unsubstituted methyl groups.
  • R 7 is either a carboxylic acid group -COOH or an ester group -COOR 9 .
  • R 7 is preferably an ester group -COOR 9 .
  • R 7 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.
  • BPH biphenylhydrolase
  • 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.
  • 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- ⁇ 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.
  • R 15 represents hydrogen or a group of formula -[C 1-4 alkylene] b -(Z 1 ) a -[C M alkyl] or -[C 1-4 alkylene] b -(Z 1 ) a -[C 2-4 alkenyl] wherein a and b are the same or different and represent O or 1, and Z 1 represents -0-, -S-, or -NR 17 - wherein R 17 is hydrogen or Ci -4 alkyl, R 16 represents hydrogen or Ci -4 alkyl, and R 14 represents hydrogen or Ci -4 alkyl; (ii) R 15 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, R 16 represents hydrogen or Ci -4 alkyl, and R 14 represents hydrogen; (iii) R 15 represents a group of formula -[C
  • Preferred substituents on the alkyl, alkylene and alkenyl groups in R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and AIk 4 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 R 15 , R 16 and AIk 4 are unsubstituted.
  • Preferred substituents on the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R 15 , R 16 , R 18 and R 19 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.
  • the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R 15 , R 16 , R 18 and R 19 are unsubstituted or substituted by a Ci -2 alkylene group, in particular a methylene group.
  • the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R 15 , R 16 , R 18 and R 19 are unsubstituted.
  • R 15 represents a group of formula -[Ci -4 alkylene] b -(Z 1 ) a -[Ci -4 alkyl], preferably either a or b is zero, for example both a and b are zero.
  • [Ci -4 alkylene] is present, it is preferably a Ci -3 alkylene, more preferably a Ci -2 alkylene such as a group -CH 2 -CH 2 -.
  • Ci -4 alkyl is a Ci -3 alkyl group such as methyl, ethyl or n-propyl, most preferably methyl.
  • R 15 represents a group of formula -[CM alkyleneJ b -CZ'VtC M alkyl] and a is 1, Z 1 is preferably -O- or -NR 17 - wherein R 17 is hydrogen or Ci -2 alkyl, more preferably Z 1 is -O-.
  • R 15 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.
  • [Ci -4 alkylene] is present, it is preferably a Ci -3 alkylene, more preferably a Ci -2 alkylene.
  • R 15 represents a group of formula -[C 1-4 alkylene] b -(Z') a -[Ci. 4 alkenyl] and a is 1
  • Z 1 is preferably -O- or -NR 17 - wherein R 17 is hydrogen or C 1-2 alkyl, more preferably Z 1 is -O-. Most preferably Z 1 is absent (i.e. a is zero).
  • R 15 represents hydrogen or a group of formula -[C 1-4 alkyl] or -[C 1-4 alkylenej b -CZ ⁇ a -fC ⁇ alkenyl]
  • R 15 represents hydrogen or a group of formula -[C 1-4 alkylene] b -(Z 1 ) a -[C 1 - 4 alkyl] or -[C 1-4 alkylene] b -(Z 1 ) a -[C 2-4 alkenyl]
  • R 16 represents hydrogen or Ci -2 alkyl, more preferably hydrogen or methyl.
  • R 15 represents hydrogen or a group of formula -[Ci -4 alkylene] b -(Z') a -[Ci -4 alkyl] or -[Ci -4 alkylene]b-(Z 1 ) a -[C 2-4 alkenyl]
  • R 14 represents hydrogen or Ci -2 alkyl, more preferably R 14 represents hydrogen or methyl.
  • R 15 represents hydrogen or a group of formula -[Ci -4 alkylene]b-(Z 1 ) a -[Ci -4 alkyl] or -[Ci -4 alkylene] b -(Z 1 ) a -[C 2-4 alkenyl], preferably the alkyl, alkylene and alkenyl groups in both R 15 and R 16 are unsubstituted.
  • R 15 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.
  • R 15 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 R 13 are unsubstituted .
  • R 15 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
  • R 16 preferably represents hydrogen or C] -4 alkyl, more preferably hydrogen or Ci -2 alkyl, most preferably hydrogen.
  • the C] -4 alkyl groups of R 16 are unsubstituted.
  • AIk 4 preferably represents a C 1-2 alkylene group, preferably either -CH 2 - or -CH 2 CH 2 -.
  • R 15 represents a group of formula -(Alk 4 )-NR 18 R 19 and R 18 and R 19 are the same or different and represent hydrogen or Ci -4 alkyl, preferably R 18 represents hydrogen or Ci -2 alkyl, more preferably R 18 represents a methyl group.
  • R 15 represents a group of formula -(AIkVNR 18 R 19 and R 18 and R 19 are the same or different and represent hydrogen or C] -4 alkyl, preferably R 19 represents hydrogen or Ci -2 alkyl, more preferably R 19 represents a methyl group.
  • R 15 represents a group of formula -(Alk 4 )-NR 18 R 19 and R 18 and R 19 , 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.
  • AIk 4 preferably represents a Ci -2 alkylene group, more preferably a group -CH 2 CH 2 -.
  • R 16 preferably represents hydrogen or Cj -2 alkyl, most preferably hydrogen.
  • R 15 represents a group of formula -(Alk 4 )-NR 18 R 19
  • R 18 and R 19 are unsubstituted.
  • R 15 represents a group of formula -(Alk 4 )-NR 18 R 19
  • preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in R 18 and R 19 are unsubstituted.
  • R 15 represents a group of formula -(AIk ⁇ -NR 18 R 19
  • preferred groups include -CH 2 -CH 2 -NMe 2 and -CH 2 -CH 2 -morpholinyl.
  • R 15 and R 16 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.
  • preferred non-fused 5- to 6-membered heterocyclyl groups include piperidinyl, tetrahydrofuranyl, piperazinyl, morpholinyl and pyrrolidinyl groups, more preferably piperidinyl and tetrahydrofuranyl groups.
  • preferred non-fused C 3-7 carbocyclyl groups include cyclopentyl and cyclohexyl, more preferably cyclopentyl.
  • preferred C 3-7 carbocyclyl groups fused to a phenyl ring include indanyl.
  • R 15 and R 16 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.
  • 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.
  • R 7 groups are -COOH and -COOR 9 where R 9 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 R 9 represents Ci -4 alkyl or C 3-7 carbocyclyl.
  • Ci -4 alkyl groups such as methyl, ethyl, n- or iso-propy
  • R 9 represents unsubstituted Ci -4 alkyl or C 3-7 carbocyclyl.
  • Most preferred groups include where R 9 is cyclopentyl or t-butyl, more preferably where R 9 is cyclopentyl.
  • R 7 represents -COOH or -COOR 9 wherein R 9 is Ci 4 alkyl or C 3-7 carbocyclyl
  • R 10 is hydrogen, C M alkyl or C 3-7 carbocyclyl.
  • R 7 is -COOR 10 where R 10 is hydrogen or C 3-7 carbocyclyl, more preferably where R 10 is hydrogen or cyclopentyl.
  • R 10 is other than hydrogen, i.e. is selected from C 1-4 alkyl or C 3-7 carbocyclyl as described above.
  • 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:
  • R 1 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;
  • L 1 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;
  • a 1 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 unsubstitute
  • AIk 3 represents a bond or an unsubstituted C 1-3 alkylene, C2-3 alkenylene or C 2- 3 alkynylene group;
  • AIk 5 represents an unsubstituted C 1-4 alkylene group
  • a 2 represents an unfused phenyl or unfused 5- to 6-membered heteroaryl group which is unsubstituted or substituted with I 5 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
  • AIk 1 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 AIk 1 represents a group -A 3 -AIk 6 - where A 3 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 AIk 6 represents an unsub
  • R 7 represents -COOH or -COOR 9 where R 9 represents a Ci -4 alkyl, C 3-7 carbocyclyl groups or C 2-4 alkenyl group, or R 9 represents a phenyl, benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl, methoxyethyl, indanyl, norbonyl, dimethylaminoethyl or morpholinoethyl group.
  • Het represents -O-.
  • L 1 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 -NH 2 .
  • a 1 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.
  • R 8 represents hydrogen.
  • 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:
  • R 1 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
  • L 2 represents -AIk 3 -, -Alk 3 -Alk 5 - or -Alk 3 -A 2 ;
  • AIk 3 represents an unsubstituted ethylene, vinylene or ethynylene group
  • a 2 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;
  • AIk 1 represents an unsubstituted C 1 - 3 alkylene group or a group -A 3 -Alk 6 where A 3 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 AIk 6 represents an unsubstituted Ci -2 alkylene group;
  • AIk 2 represents a group of formula -C(R 5 )(R 6 )- wherein R 5 and R 6 are the same or different and represent a hydrogen atom or an unsubstituted Ci-6 alkyl group;
  • R 10 represents a hydrogen atom or an unsubstituted Ci -4 alkyl or C3 -7 carbocyclyl group.
  • AUc 2 represents a group of formula
  • R 5 and R 6 are the same and represent unsubstituted Ci -2 alkyl groups, or (ii) R 5 and R 6 are different and one of R 5 and R 6 represents hydrogen and the other of R 5 and R 6 represents an unsubstituted Ci -6 alkyl group.
  • AIk 3 represents ethynylene.
  • 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
  • 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 ⁇ SP90 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.
  • 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.
  • 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.
  • 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
  • almond oil fractionated coconut oil
  • oily esters such as glycerine, propylene
  • 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.
  • 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.
  • 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.
  • the drug can either be suspended or dissolved in the vehicle.
  • 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.
  • 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).
  • 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.
  • composition comprising:
  • a cytotoxic agent an HDAC inhibitor, a kinase inhibitor, an aminopeptidase inhibitor and/or a monoclonal antibody
  • a cytotoxic agent for the separate, simultaneous or sequential use in the treatment of the human or animal body.
  • the compounds of the invention may be prepared by a number of processes generally described below and more specifically in the Examples hereinafter.
  • 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.
  • 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.
  • 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.
  • the pyrrolo-pyrimidine core can be coupled to alkene side chains via a Heck reaction.
  • side chain modifications can be carried out either before or after the Heck coupling.
  • DIPEA diisopropylethylamine
  • EDCI N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole
  • LiAlH 4 lithium aluminium hydride
  • Na 2 CO 3 sodium carbonate
  • NaHCO 3 sodium hydrogen carbonate
  • Na 2 SO 4 sodium sulphate
  • NaH sodium hydride
  • NaOH sodium hydroxide
  • NH 3 ammonia
  • NH 4 Cl 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
  • STAB Sodium triacetoxyborohydride
  • TBAF Tetrabutylammonium fluoride
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TLC thin layer chromatography
  • TME tert-butyl methyl ether
  • TMSCl trimethylchlorosilane
  • 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.
  • 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 Et 2 O to give the desired product as a white powder (7.78 g, 65 %).
  • Example 1 was prepared from Intermediate Ib as follows:
  • Example 2 was prepared from Building Block A and Building Block C using the same methodology as described for Example 1.
  • Example 3 was prepared from Intermediate 3 using the same procedure as described are in the final step for Example 1, Scheme 7.
  • Example 4 was prepared from Building Block A and Building Block E using the same methodology as described for Example 3.
  • Example 5 was prepared from Building Block A and Building Block F using the same methodology as described for Example 3.
  • Example 7 was prepared from Building Block A and Building Block B using the same methodology as described for Example 6.
  • Example 8 was prepared from Building Block A and Building Block E using the same methodology as described for Example 6.
  • Example 9 was prepared from Building Block A and Building Block G using the same methodology as described for Example 6.
  • Example 10 was prepared from Building Block A and Building Block ⁇ using the same methodology as described for Example 6.
  • Example 11 was prepared from Building Block A and Building Block C using the same methodology as described for Example 6.
  • Example 12 was prepared from Intermediate 6c as follows:
  • Example 13 was prepared from Intermediate 13c as follows:
  • Example 15 was prepared from Building Block A and Building Block E using the same methodology as described for Example 13.
  • Example 16 was prepared using the same conditions as for Example 6, Scheme 9 using 3-iodobenzaldehyde instead of 4-iodobenzaldehyde.
  • 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 H ⁇ (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 %).
  • Example 18 was prepared from Intermediate 8b as follows:
  • Example 19 was prepared from Example 1 as follows:
  • Example 1 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 %).
  • HTRP homogeneous time resolved fluorescence
  • 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 50 ⁇ l/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.
  • ICs 0 values are calculated by non-linear least squares fitting to the standard dose-response model using GraphPad Prism (GraphPad Software Inc). Proliferation assay
  • WST- 1 a metabolic indicator dye, Roche Cat no. 11644807001
  • 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.
  • THP-I cells are plated in lOO ⁇ l at a density of 4x10 4 cells / well in V-bottomed 96 well tissue culture treated plates and incubated at 37 0 C in 5% CO 2 for 16 hours. 2 Hours after the addition of the inhibitor in lOO ⁇ l of tissue culture media, the cells are stimulated with LPS (E. CoIi strain 005 :B5, Sigma) at a final concentration of l ⁇ g/ml and incubated at 37 0 C in 5% CO 2 for 6 hours. TNF- ⁇ levels are measured from cell-free supernatants by sandwich ELISA (R&D Systems #QTA00B).
  • the compound may be tested in the following assay:
  • U937 or HUT78 tumour cells (-109) are washed in 4 volumes of Dulbeccos PBS ( ⁇ 1 litre) and pelleted at 525g for 10 minutes at 4 0 C. This is repeated twice and the final cell pellet is resuspended in 35ml of cold homogenising buffer (Trizma 1OmM, NaCl 13OmM, CaCl 2 0.5mM pH 7.0 at 25 0 C). Homogenates are prepared by nitrogen cavitation (700psi for 50 minutes at 4 0 C).
  • the homogenate is kept on ice and supplemented with a cocktail of inhibitors at final concentrations of Leupeptin l ⁇ M, Aprotinin 0.1 ⁇ M, E64 8 ⁇ M, Pepstatin 1.5 ⁇ M, Bestatin 162 ⁇ M, Chymostatin 33 ⁇ M.
  • the resulting supernatant is used as a source of esterase activity and is stored at -80 0 C until required.
  • IC50 values are allocated to one of three ranges as follows:
  • 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- ⁇ production in these assays.

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Abstract

L’invention concerne un composé qui est (a) un dérivé de pyrrolopyrimidine de formule (I) ou un de ses tautomères, ou (b) un de ses sels, N-oxydes, hydrates ou solvates pharmaceutiquement acceptables : Formule (I), dans laquelle R1, R2, R3, R4 et W sont tels que définis dans la description. Les composés sont utiles pour le traitement de maladies médiées par HSP90, et également pour le traitement de l’inflammation.
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* Cited by examiner, † Cited by third party
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WO2013052417A1 (fr) * 2011-10-03 2013-04-11 The University Of North Carolina At Chapel Hill Composés pyrrolopyrimidines pour le traitement du cancer
WO2013108809A1 (fr) * 2012-01-19 2013-07-25 大鵬薬品工業株式会社 Composé d'alkynylbenzène 3,5-disubstitué et un sel de celui-ci
WO2015008839A1 (fr) * 2013-07-18 2015-01-22 大鵬薬品工業株式会社 Médicament antitumoral pour l'administration intermittente d'inhibiteur de fgfr
WO2015008844A1 (fr) 2013-07-18 2015-01-22 大鵬薬品工業株式会社 Agent thérapeutique pour un cancer résistant à un inhibiteur de fgfr
US9416136B2 (en) 2008-08-22 2016-08-16 Novartis Ag Pyrrolopyrimidine compounds and their uses
US9555030B2 (en) 2014-04-11 2017-01-31 The University Of North Carolina At Chapel Hill Therapeutic uses of selected pyrazolopyrimidine compounds with anti-Mer tyrosine kinase activity
US9562047B2 (en) 2012-10-17 2017-02-07 The University Of North Carolina At Chapel Hill Pyrazolopyrimidine compounds for the treatment of cancer
US9567326B2 (en) 2012-05-22 2017-02-14 The University Of North Carolina At Chapel Hill Pyrimidine compounds for the treatment of cancer
US9744172B2 (en) 2010-05-19 2017-08-29 The University Of North Carolina At Chapel Hill Pyrazolopyrimidine compounds for the treatment of cancer
US9771330B2 (en) 2012-11-27 2017-09-26 The University Of North Carolina At Chapel Hill Pyrimidine compounds for the treatment of cancer
US10434103B2 (en) 2015-03-31 2019-10-08 Taiho Pharmaceutical Co., Ltd. Crystal of 3,5-disubstituted benzene alkynyl compound
US10709708B2 (en) 2016-03-17 2020-07-14 The University Of North Carolina At Chapel Hill Method of treating cancer with a combination of MER tyrosine kinase inhibitor and an epidermal growth factor receptor (EGFR) inhibitor
US11833151B2 (en) 2018-03-19 2023-12-05 Taiho Pharmaceutical Co., Ltd. Pharmaceutical composition including sodium alkyl sulfate
US11883404B2 (en) 2016-03-04 2024-01-30 Taiho Pharmaceuticals Co., Ltd. Preparation and composition for treatment of malignant tumors
US11975002B2 (en) 2016-03-04 2024-05-07 Taiho Pharmaceutical Co., Ltd. Preparation and composition for treatment of malignant tumors

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US10179133B2 (en) 2011-10-03 2019-01-15 The University Of North Carolina At Chapel Hill Pyrrolopyrimidine compounds for the treatment of cancer
RU2631655C2 (ru) * 2011-10-03 2017-09-26 Зэ Юниверсити Оф Норд Каролина Эт Чапель Хилл Пирролопиримидиновые соединения для лечения злокачественной опухоли
WO2013052417A1 (fr) * 2011-10-03 2013-04-11 The University Of North Carolina At Chapel Hill Composés pyrrolopyrimidines pour le traitement du cancer
RU2576384C1 (ru) * 2012-01-19 2016-03-10 Тайхо Фармасьютикал Ко., Лтд. 3,5-дизамещенное алкинилбензольное соединение и его соль
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WO2013108809A1 (fr) * 2012-01-19 2013-07-25 大鵬薬品工業株式会社 Composé d'alkynylbenzène 3,5-disubstitué et un sel de celui-ci
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US10835536B2 (en) 2013-07-18 2020-11-17 Taiho Pharmaceutical Co., Ltd. Therapeutic agent for FGFR inhibitor-resistant cancer
RU2664118C2 (ru) * 2013-07-18 2018-08-15 Тайхо Фармасьютикал Ко., Лтд. Противоопухолевое лекарственное средство для прерывистого введения ингибитора fgfr
US10894048B2 (en) 2013-07-18 2021-01-19 Taiho Pharmaceutical Co., Ltd. Antitumor drug for intermittent administration of FGFR inhibitor
WO2015008844A1 (fr) 2013-07-18 2015-01-22 大鵬薬品工業株式会社 Agent thérapeutique pour un cancer résistant à un inhibiteur de fgfr
WO2015008839A1 (fr) * 2013-07-18 2015-01-22 大鵬薬品工業株式会社 Médicament antitumoral pour l'administration intermittente d'inhibiteur de fgfr
JP6084291B2 (ja) * 2013-07-18 2017-02-22 大鵬薬品工業株式会社 Ｆｇｆｒ阻害剤の間歇投与用抗腫瘍剤
JP6084292B2 (ja) * 2013-07-18 2017-02-22 大鵬薬品工業株式会社 Ｆｇｆｒ阻害剤耐性癌の治療薬
US10124003B2 (en) 2013-07-18 2018-11-13 Taiho Pharmaceutical Co., Ltd. Therapeutic agent for FGFR inhibitor-resistant cancer
US9555030B2 (en) 2014-04-11 2017-01-31 The University Of North Carolina At Chapel Hill Therapeutic uses of selected pyrazolopyrimidine compounds with anti-Mer tyrosine kinase activity
US10004755B2 (en) 2014-04-11 2018-06-26 The University Of North Carolina At Chapel Hill Therapeutic uses of selected pyrrolopyrimidine compounds with anti-mer tyrosine kinase activity
US9649309B2 (en) 2014-04-11 2017-05-16 The University Of North Carolina At Chapel Hill Therapeutic uses of selected pyrimidine compounds with anti-Mer tyrosine kinase activity
US9555031B2 (en) 2014-04-11 2017-01-31 The University Of North Carolina At Chapel Hill Therapeutic uses of selected pyrrolopyrimidine compounds with anti-mer tyrosine kinase activity
US9603850B2 (en) 2014-04-11 2017-03-28 The University Of North Carolina At Chapel Hill MerTK-specific pyrazolopyrimidine compounds
US10434103B2 (en) 2015-03-31 2019-10-08 Taiho Pharmaceutical Co., Ltd. Crystal of 3,5-disubstituted benzene alkynyl compound
US11883404B2 (en) 2016-03-04 2024-01-30 Taiho Pharmaceuticals Co., Ltd. Preparation and composition for treatment of malignant tumors
US11975002B2 (en) 2016-03-04 2024-05-07 Taiho Pharmaceutical Co., Ltd. Preparation and composition for treatment of malignant tumors
US10709708B2 (en) 2016-03-17 2020-07-14 The University Of North Carolina At Chapel Hill Method of treating cancer with a combination of MER tyrosine kinase inhibitor and an epidermal growth factor receptor (EGFR) inhibitor
US11833151B2 (en) 2018-03-19 2023-12-05 Taiho Pharmaceutical Co., Ltd. Pharmaceutical composition including sodium alkyl sulfate

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