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WO2010043865A1 - Inhibitors of hsp90 - Google Patents

Inhibitors of 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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Prior art keywords
unsubstituted
alkyl
group
same
different
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PCT/GB2009/002464
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French (fr)
Inventor
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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Publication of WO2010043865A1 publication Critical patent/WO2010043865A1/en

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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

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:
Figure imgf000005_0001
wherein:
R1 represents a hydrogen or halogen atom, or a cyano, nitro, -N3, Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C2-6 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, -C00RA, -CORA, -SO2RA, -CONH2, -SO2NH2, -C0NHRA, -SO2NHRA, -C0NRARB, -S02NRARB, -OCONH2, -0C0NHRA, -OCONRARB, -NHC0RA, -NRBCORA, -NHCOORA, -NRBC00RA, -NRBC00H, -NHC00H-, -NHS02RA, -NRBS02RA, -NHS020RA, -NRBS020H, -NHSO2H, -NRBSO2ORA, -NHCONH2, -NRAC0NH2, -NHC0NHRB, -NRAC0NHRB, -NHC0NRARB or -NRAC0NRARB wherein RA and RB are the same or different and represent an unsubstituted C1-6 alkyl group, or a C3-6 cycloalkyl, non-fused phenyl or a non-fused 5- to 6-membered heteroaryl, or RA and RB 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, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 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 C1-4 alkyl group or an unfused C6-1O 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, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy, -SR' or -NR'R" group where R' and R" are the same or different and represent hydrogen or unsubstituted C1-4 alkyl; R4 represents a group of formula -L1 -A1; L1 represents C1-4 alkylene or C2-4 alkenylene, the alkylene and alkenylene groups optionally containing or terminating in an -O-, -S- or -NR'- link where R' represents hydrogen or unsubstituted C1-2 alkyl; A1 represents a Cβ-io aryl, 5- to 10-membered heteroaryl, C3-? carbocyclyl or 5- to 10-membered heterocyclyl group which is optionally fused to a further Ce-io aryl, 5- to 10-membered heteroaryl, C3-7 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 C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene group;
AIk5 represents a C]-4 alkylene, C2-4 alkenylene or C2-4 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, C2-6 alkenylene or C2-6 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, C2-6 alkenylene or C2-6 alkynylene group; R represents a group of formula (X) or (Y):
Figure imgf000007_0001
(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, C2-4 alkenyl, Ci-4 alkoxy, C2-4 alkenyloxy, Ci-4 haloalkyl, C2-4 haloalkenyl, Cj-4 haloalkoxy, C2-4 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, C2-4 alkenyl, C2-4 alkenyloxy, C1-4 haloalkyl, C2-4 haloalkenyl, Ci-4 haloalkoxy, C2-4 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, -COORA, -CORA, -SO2RA, -CONH2, -SO2NH2, -C0NHRA, -SO2NHRA, -C0NRARB, -SO2NRARB, -OCONH2, -OCONHRA, -0C0NRARB, -NHCORA, -NRBC0RA, -NHC00RA, -NRBC00RA, -NR5COOH, -NHCOOH, -NHSO2RA, -NRBSO2RA, -NHS020RA, -NR3SO2OH, -NHSO2H, -NRBS020RA, -NHCONH2, -NRAC0NH2, -NHC0NHRB, -NRAC0NHRB, -NHC0NRARB or -NRAC0NRARB wherein RA and RB are the same or different and represent unsubstituted Ci-β alkyl, C3-6 cycloalkyl, non- fused phenyl or a non-fused 5- to 6-membered heteroaryl, or RA and RB 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, C2-4 alkenyl, Ci-4 alkoxy, C2-4 alkenyloxy, C1-4 haloalkyl, C2-4 haloalkenyl, Ci-4 haloalkoxy, C2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C1-4 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, C2-4 alkenyl, Ci-4 alkoxy, C2-4 alkenyloxy, Ci-4 haloalkyl, C2-4 haloalkenyl, Ci-4 haloalkoxy, C2-4 haloalkenyloxy, hydroxyl, mercapto, cyano, nitro, Ci-4 hydroxyalkyl, C2-4 hydroxyalkenyl, C]-4 alkylthio, C2-4 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, C2-4 alkenyl, Ci-4 alkoxy, hydroxyl, Ci-4 haloalkyl, C2-4 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 C1-4 alkyl, C1-4 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 C1-4 alkyl group or moiety containing from 1 to 4 carbon atoms. Examples Of C1-4 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 C2-6 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 C2-4 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 C2-6 alkynyl group or moiety is a linear or branched alkynyl group or moiety containing from 2 to 6 carbon atoms, for example a C2-4 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 C1-6 alkylene group or moiety is a linear or branched alkylene group or moiety, for example a C1-4 alkylene group or moiety. Examples include methylene, n-ethylene, n-propylene and -C(CHa)2- groups and moieties.
As used herein, a C2-6 alkenylene group or moiety is a linear or branched alkenylene group or moiety, for example a C2-4 alkenylene group or moiety. Examples include -CH=CH-, -CH=CH-CH2-, -CH2-CH=CH- and -CH=CH-CH=CH-.
As used herein, a C2-6 alkynylene group or moiety is a linear or branched alkynylene group or moiety, for example a C2-4 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 C1-6 alkoxy group or C2-6 alkenyloxy group is typically a said Ci-6 alkyl (e.g. a Ci-4 alkyl) group or a said C2-6 alkenyl (e.g. a C2-4 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 C1-4 alkylthio or C2-4 alkenylthio group is typically a said Ci-4 alkyl group or a C2-4 alkenyl group respectively which is attached to a sulphur atom, for example -S-CH3.
As used herein, a C1-4 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, C3-7 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 C3-7 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 C5-1O 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 C3-7 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 C3-7 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 C3-7 carbocyclyl group or moiety also includes C3-7 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 C3-7 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, C2-4 alkenyl, C2-4 alkenyloxy, C1-4 haloalkyl, C2-4 haloalkenyl, Ci-4 haloalkoxy, C2-4 haloalkenyloxy, hydroxyl, C1-4 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, -COORA, -CORA, -SO2RA, -CONH2, -SO2NH2, -C0NHRA, -SO2NHRA, -CONRARB, -SO2NRARB, -OCONH2, -OCONHRA, -0C0NRARB, -NHC0RA, -NRBC0RA, -NHC00RA, -NRBC00RA, -NR8COOH, -NHCOOH, -NHSO2RA, -NRBSO2RA, -NHSO2ORA, -NR2SO2OH, -NHSO2H, -NRBSO2ORA, -NHCONH2, -NRAC0NH2, -NHC0NHRB, -NRAC0NHRB, -NHC0NRARB or -NRAC0NRARB wherein RA and RB are the same or different and represent unsubstituted Q-6 alkyl, C3-6 cycloalkyl, non-fused phenyl or a non-fused 5- to 6-membered heteroaryl, or RA and RB 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 RA and RB 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, -C00RA, -CORA, -SO2RA, -CONH2, -SO2NH2, -C0NHRA, -SO2NHRA, -C0NRARB, -SO2NRARB, -OCONH2, -OCONHRA, -0C0NRARB, -NHCORA, -NRBC0RA, -NHC00RA, -NRBC00RA, -NR8COOH, -NHCOOH, -NHSO2RA, -NRBS02RA, -NHSO2ORA, -NR15SO2OH, -NHSO2H, -NRBSO2ORA, -NHCONH2, -NRAC0NH2, -NHC0NHRB, -NRAC0NHRB, -NHC0NRARB or -NRACONRARB.
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, C2-4 alkenyl, C]-4 alkoxy, C2-4 alkenyloxy, CM haloalkyl, C2-4 haloalkenyl, Ci-4 haloalkoxy, C2-4 haloalkenyloxy, hydroxyl, mercapto, cyano, nitro, Ci-4 hydroxyalkyl, C2-4 hydroxyalkenyl, Ci-4 alkylthio, C2-4 alkenylthio and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C1-4 alkyl. Preferably the substituents are themselves unsubstituted. More preferred substituents include halogen atoms and unsubstituted C1-4 alkyl, Ci-4 alkoxy, hydroxyl, C1-4 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, C1-4 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, C2-4 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 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 C1-4 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, C2-4 alkenyl, Cj-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 Ci-2 alkyl.
More preferably R2 represents a hydrogen or halogen atom, or an unsubstituted Ci-4 alkyl, Ci-4 alkoxy, Ci-4 haloalkyl, C1-4 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 C1-4 alkyl, C2-4 alkenyl, C1-4 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 Ci-2 alkyl. More preferably R3 represents a hydrogen or halogen atom or an unsubstituted C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, hydroxyl or -NR'R" group where R' and R" are the same or different and represent hydrogen or unsubstituted C1-2 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, C1-2 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, C3-7 carbocyclyl or 5- to 6-membered heterocyclyl group which is unfused or fused to a further phenyl, 5- to 6-membered heteroaryl, C3-7 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, C1-4 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, C2-3 alkenylene or C2-3 alkynylene group. More preferably AIk3 represents a Ci-3 alkylene, C2-3 alkenylene or C2-3 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, C2-4 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 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 C1-2 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 C2-3 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, C1-4 haloalkyl, Ci-4 haloalkoxy, C1-4 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, C2-4 alkenylene or C2-4 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, C2-4 alkenylene or C2-4 alkynylene group. Most preferably AIk5 represents an unsubstituted Ci-4 alkylene, for example a C3-4 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 C1-6 alkylene or a group -A3-Alk6-. When AIk1 represents a C1-6 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 C1-4 alkyl, C2-4 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 C1-2 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, C1-4 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, C2-3 alkenylene or C2-3 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 C1-2 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 C1-6 alkylene group, more preferably still an unsubstituted C1-2 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):
Figure imgf000022_0001
(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 Rs 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 -CRaRbRc in which:
(a) Ra, Rb and Rc are the same or different and represent a hydrogen atom or a Ci-6 alkyl, C2-6 alkenyl, C2-6 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(C2-6)alkenyl, -S(C!-6)alkyl, -SO(C1-6)alkyl, -SO2(Ci-6) alkyl, -S(C2-6)alkenyl, -SO(C2-6)alkenyl or -SO2(C2-6)alkenyl group; or
(b) two of Ra, Rb and Re represent a group mentioned in (a) above and the other of Ra, Rb and Rc 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, C3-8 carbocyclyl, C3-8 cycloalkyl(Ci-6)alkyl, C4..8 cycloalkenyl, C4-8 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(C1-6)alkyl, -CONH(C i-6alkyl)2, -CHO, -CH2OH, (C1-4)perfluoroalkyl, -O(d-6)alkyl, -S(C1-6)alkyl, -SO(Ci-6)alkyl, -SO2(C1-6)alkyl, -NO2, -NH2, -NH(C1-6)alkyl, -N((C1-6)alkyl)2, -NHCO(C1-6)alkyl, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-8)cycloalkyl, (C4-8)cycloalkenyl, phenyl or benzyl; or (c) one of Ra, Rb and Rc represents a group mentioned in (a) above and the other two of Ra, Rb and Rc, 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 Ra, Rb and Rc, together with the carbon atom to which they are attached, form a tricyclic system; or
For example, in one embodiment each of Ra, Rb and Rc is the same or different and represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl(Ci.6)alkyl or (C3-8)cycloalkyl group.
In another embodiment, Rc is hydrogen and Ra and Rb 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 Rc represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl(Ci-6)alkyl or (C3-8)cycloalkyl group, and Ra and Rb, 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 Ra, Rb and Rc, together with the carbon atom to which they are attached, form a tricyclic system. A particularly suitable tricyclic system is adamantyl.
In another embodiment Ra and Rb are the same or different and represent a Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or phenyl(C].6)alkyl group, or a group as defined for Rc below other than hydrogen, or Ra and Rb, together with the carbon atom to which they are attached, form a C3-8 carbocyclyl or 5- or 6-membered heterocyclyl group, and Rc represents a hydrogen atom or a group selected from -OH, -SH, halogen, -CN, -CO2H, (CM)perfluoroalkyl, -CH2OH, -O(C1-6)alkyl, -O(C2-6)alkenyl, -S(Ci-6)alkyl5 -SO(Ci-6)alkyl, -SO2(C1-6) alkyl, -S(C2-6)alkenyl, -SO(C2-6)alkenyl and -SO2(C2-6)alkenyl, or Rc represents a group -Q-W wherein Q represents a bond or -O-, -S-, -SO- or -SO2- and W represents a phenyl, phenyl(C1-6)alkyl, C3-8 carbocyclyl, C3-8 cycloalkyl(Cj.6)alkyl, C4-8 cycloalkenyl, C4-8 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(C1-6alkyl)2, -CHO, -CH2OH, (C1-4)perfluoroalkyl, -O(C1-6)alkyl, -S(Ci.6)alkyl, -SO(C1-6)alkyl, -SO2(Ci.6)alkyl, -NO2, -NH2, -NH(Ci-6)alkyl, -N((Ci-6)alkyl)2, -NHCO(CI-6)alkyl, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-8)cycloalkyl, (C4-8)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 C1-6 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 C1-6 alkyl (for example methyl), phenyl, 5- to 6-membered heteroaryl, C3-8 carbocyclyl (for example cyclohexyl), C3-8 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 C1-6 alkyl.
Where neither R5 nor R6 are hydrogen, preferably R5 and R6 are the same or different and represent unsubstituted C1-2 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)NRA- 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 -[C1-4 alkylene]b-(Z1)a-[CM alkyl] or -[C1-4 alkylene]b-(Z1)a-[C2-4 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, C3-7 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, C3-7 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, C3-7 carbocyclyl or 5- to 10-membered heterocyclyl group which is optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C3-7 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, C1-4 alkyl, C2-4 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 alkyleneJb-CZ1^- [C1-4 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 alkyleneJb-CZ'VtCM 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 alkyleneJb-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-[C2-4 alkenyl], preferably C2-4 alkenyl is a C2-3 alkenyl group, in particular -CH=CH2. When R15 represents a group of formula -[C1-4 alkylene]b-(Z')a-[Ci.4 alkenyl] and a is 1, Z1 is preferably -O- or -NR17- wherein R17 is hydrogen or C1-2 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 -[C1-4
Figure imgf000029_0001
alkyl] or -[C1-4 alkylenejb-CZ^a-fC^ alkenyl], preferably R15 represents hydrogen or a Ci-4 alkyl or C2-4 alkenyl group, or a group -(C1-4 alky!)-O-(C1-4 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 -[C1-4 alkylene]b-(Z1)a-[C1-4 alkyl] or -[C1-4 alkylene]b-(Z1)a-[C2-4 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-[C2-4 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-[C2-4 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, C3-7 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, C3-7 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, C3-7 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 C1-2 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, C3-7 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, C3-7 carbocyclyl or 5- to 10-membered heterocyclyl group which is optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C3-7 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 C3-7 carbocyclyl and C3-7 carbocyclyl fused to a phenyl ring, more preferably non-fused phenyl, non-fused 5- to 6-membered heterocyclyl, non-fused C3-7 carbocyclyl and C3-7 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 C3-7 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 C3-7 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 C1-4 alkyl, C1-4 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), C3-7 carbocyclyl groups (such as cyclopentyl and cyclohexyl), C2-4 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 C3-7 carbocyclyl. When R7 is -COOR9 more preferably R9 represents unsubstituted Ci-4 alkyl or C3-7 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 C3-7 carbocyclyl can be described by a group where R7 is -COOR10 and R10 is hydrogen, CM alkyl or C3-7 carbocyclyl. Preferably R7 is -COOR10 where R10 is hydrogen or C3-7 carbocyclyl, more preferably where R10 is hydrogen or cyclopentyl. In one embodiment, R10 is other than hydrogen, i.e. is selected from C1-4 alkyl or C3-7 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:
Figure imgf000032_0001
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 C1-2 alkyl; L2 represents -AIk3-, -Alk3-A2- or -Alk3-Alk5-;
AIk3 represents a bond or an unsubstituted C1-3 alkylene, C2-3 alkenylene or C2-3 alkynylene group;
AIk5 represents an unsubstituted C1-4 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 C1-4 alkyl, C1-4 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 C1-2 alkyl, Ci-2 alkoxy, hydroxyl, C1-2 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, C3-7 carbocyclyl groups or C2-4 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:
Figure imgf000034_0001
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 Ra 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 C1-2 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 C1-2 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, C1-4 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;
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)-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;
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-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", 4th Edition (Wiley), J March, "Comprehensive Organic Transformation", 2nd Edition (Wiley), R.C. Larock , "Handbook of Heterocyclic Chemistiy", 2nd 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:
Figure imgf000043_0001
e.g. R13-OH, EDC
Esterification HOBt, DCM
Figure imgf000043_0002
Route 2:
Figure imgf000043_0003
Route 3:
Figure imgf000043_0004
• 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):
Figure imgf000044_0001
POCI3, BTEACI
N,N-diethylaniline
Acetonitrile
Figure imgf000044_0002
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):
Figure imgf000045_0001
CuI, Pd(PPh3),, TEA, DCM
Figure imgf000045_0002
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):
Figure imgf000045_0003
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,6b and R10 are as defined herein):
Figure imgf000046_0001
Figure imgf000046_0002
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
Figure imgf000046_0003
Figure imgf000046_0004
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:
Figure imgf000049_0001
Building Block A Building Block B Building Block C Building Block D
Figure imgf000049_0002
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
Figure imgf000052_0001
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
Figure imgf000052_0002
Intermediate 1b
Figure imgf000052_0003
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
Figure imgf000054_0001
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
Figure imgf000054_0002
Scheme 8 - Methodology for the preparation of Example 3 from Building Block A and Building Block D:
Figure imgf000055_0001
Bulding Block A TEA, Pd(PPh3).,, CuI, DCM
Figure imgf000055_0002
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
Figure imgf000056_0001
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
Figure imgf000056_0002
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
Figure imgf000057_0001
Scheme 9 - Methodology for the preparation of Example 6 from Building Block A and Building Block D: Building Block D Me-Si Λ
Figure imgf000057_0002
STAB, DCE
Figure imgf000057_0003
Intermediate 6a
Figure imgf000057_0004
Figure imgf000057_0005
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
Figure imgf000059_0001
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
Figure imgf000060_0001
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
Figure imgf000060_0002
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
Figure imgf000061_0001
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
Figure imgf000062_0001
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
Figure imgf000062_0002
Scheme 10 - Methodology for the preparation of Example 6 from Building Block A and Building Block B: Building Block B jJU>
K2CO3, NaI, DMF
Figure imgf000063_0001
Intermediate 12a
Intermediate 12b
Figure imgf000063_0002
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
Figure imgf000065_0001
Scheme 11 - Methodology for the preparation of Example 7 from Building Block A and Building Block B:
Figure imgf000065_0002
Intermediate 13a Intermediate 13b Block B
Figure imgf000065_0003
[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
Figure imgf000067_0001
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
Figure imgf000068_0001
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
Figure imgf000069_0001
Scheme 12 - Methodology for the preparation of Example 16 from Building Block A and Building Block D:
JULO
Me3Si'
Figure imgf000069_0002
Intermediate 16a Intermediate 16b
TBAF /THF
Intermediate 16c
Figure imgf000069_0004
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-pyrroloPjS-cTIpyrimidin-S-yllethy^benzy^-L- alaninate
Figure imgf000070_0001
Scheme 13 - Methodology for the preparation of Example 17:
Figure imgf000070_0002
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
Figure imgf000071_0001
Scheme 14 - Methodology for the preparation of Example 18 from Building Block A and Building Block B:
Building Block B
Figure imgf000071_0002
Intermediate 18a
A CuI
Figure imgf000071_0003
Figure imgf000071_0004
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
Figure imgf000073_0001
Scheme 15 - Methodology for the preparation of Example 19 from Example 1.
Figure imgf000073_0002
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:
Figure imgf000074_0001
Figure imgf000075_0001
- "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
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
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:
Figure imgf000082_0001
wherein:
R1 represents a hydrogen or halogen atom, or a cyano, nitro, -N3, C]-6 alkyl, Q-6 alkoxy, C2-6 alkenyl, C2-6 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, -COORA, -CORA, -SO2RA, -CONH2, -SO2NH2, -CONHRA, -S02NHRA, -CONRARB, -SO2NRARB, -OCONH2, -0C0NHRA, -0C0NRARB, -NHCORA, -NRBC0RA, -NHC00RA, -NRBC00RA, -NR5COOH, -NHC00H-, -NHSO2RA, -NRBSO2RA, -NHSO2ORA, -NR6SO2OH, -NHSO2H, -NRBSO2ORA, -NHCONH2, -NRAC0NH2, -NHC0NHRB, -NRAC0NHRB, -NHC0NRARB or -NRAC0NRARB wherein RA and RB 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 RΛ and RB 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, C1-6 alkoxy, C2-6 alkenyl, C2-6 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 Cδ-jo aryl, 5- to 10- membered heteroaryl, C3-7 carbocyclyl or 5- to 10-raembered heterocyclyl group;
R3 represents a hydrogen or halogen atom or a cyano, nitro, -N3, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C]-6 alkoxy, C2-6 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 C2-4 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, C3-7 carbocyclyl or 5- to 10-membered heterocyclyl group which is optionally fused to a further C6-Io aryl, 5- to 10-membered heteroaryl, C3-7 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, C2-4 alkenylene or C2-4 alkynylene group;
AIk5 represents a Ci-4 alkylene, C2-4 alkenylene or C2-4 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 C1-6 alkylene, C2-6 alkenylene or C2-6 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, C2-6 alkenylene or C2-6 alkynylene group; R represents a group of formula (X) or (Y):
Figure imgf000084_0001
(X) (Y)
R8, where present, represents a hydrogen atom or a C1-4 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, 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, C2-4 alkenyl, Ci-4 alkoxy, C2-4 alkenyloxy, Ci-4 haloalkyl, C2-4 haloalkenyl, Ci-4 haloalkoxy, C2-4 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, C2-4 alkenyl, C2-4 alkenyloxy, Ci-4 haloalkyl, C2-4 haloalkenyl, Ci-4 haloalkoxy, C2-4 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, -COORA, -CORA, -SO2RA, -CONH2, -SO2NH2, -CONHRA, -SO2NHRA, -C0NRARB, -SO2NRARB, -OCONH2, -OCONHRA, -0C0NRARB, -NHCORA, -NRBC0RA, -NHC00RA, -NRBCOORA, -NRBCOOH, -NHCOOH5 -NHSO2RA, -NRBS02RA, -NHSO2ORA, -NRBSO2OH, -NHSO2H, -NRBSO2ORA, -NHCONH2, -NRACONH2, -NHCONHRB, -NRAC0NHRB, -NHC0NRARB or -NRACONRARB wherein RA and RB are the same or different and represent unsubstituted Cj-6 alkyl, C3-6 cycloalkyl, non- fused phenyl or a non-fused 5- to 6-membered heteroaryl, or RA and RB 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 C1-4 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, C2-4 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 C1-4 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 C1-2 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 C1-4 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, C2-3 alkenylene or C2-3 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, C2-4 alkenylene or C2-4 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, C1-2 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 C1-4 alkyl, C1-4 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 ;
Het represents -O-, -NR' or -S- where R' represents hydrogen or unsubstituted methyl;
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, C2-4 alkenyl, Cj-4 alkoxy, hydroxyl, Cj-4 haloalkyl, C2-4 haloalkenyl, C1-4 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 C2-3 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, C1-2 alkoxy, hydroxyl, Ci-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C1-2 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, C2-4 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 Ci-2 alkyl;
R2 represents a hydrogen or halogen atom, or an unsubstituted Cj-4 alkyl, Ci-4 alkoxy, Ci-4 haloalkyl, C1-4 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, C1-4 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 C1-2 alkyl;
L2 represents -AIk3-, -Alk3-A2- or -Alk3-Alk5-; AIk3 represents a bond or an C1-3 alkylene, C2-3 alkenylene or C2-3 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 C1-2 alkyl; AIk5 represents a Ci-4 alkylene, C2-4 alkenylene or C2-4 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 ;
Het represents -O-, -NR' or -S- where R' represents hydrogen or unsubstituted methyl;
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, C2-4 alkenyl, Ci-4 alkoxy, hydroxyl, C]-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 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 C1-4 alkyl, C1-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C1-2 alkyl, and AIk6 represents a bond or an C1-3 alkylene, C2-3 alkenylene or C2-3 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, C1-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C1-2 alkyl;
R represents a group of formula (X) or (Y);
R8 , where present, represents a hydrogen atom or an unsubstituted C1-2 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
R7 is a group -COOH or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a -COOH group.
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:
Figure imgf000091_0001
wherein:
R1 represents a hydrogen or halogen atom or an unsubstituted group selected from Ci-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, Ci-4 haloalkoxy, hydroxyl and -NR'R" where R' and R" are the same or different and represent hydrogen or C1-2 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 C1-2 alkyl;
L2 represents -AIk3-, -Alk3-A2- or -Alk3-Alk5-;
AIk3 represents a bond or an unsubstituted Ci-3 alkylene, C2-3 alkenylene or C2-3 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 ;
Het represents -O-, -NR' or -S- where R' represents hydrogen or unsubstituted methyl;
AIk1 represents a bond or a C1-4 alkylene group which is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms, and C1-2 alkyl, C1-2 alkoxy, hydroxyl, C1-2 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 C1-2 alkyl; AIk2 represents a group of formula -C(RS)(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 C1-4 alkyl, C3-7 carbocyclyl groups or C2-4 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, C1-2 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 C1-4 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:
Figure imgf000093_0001
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 Ra 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;
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 C1-2 alkyl and Ci-2 alkoxy groups; x represents 0 or 1;
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;
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.
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-3s5-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.
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