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WO2010043867A1 - Pyrrolo [2, 3-d] pyrimidines as inhibitors of hsp90 - Google Patents

Pyrrolo [2, 3-d] pyrimidines as inhibitors of hsp90 Download PDF

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Publication number
WO2010043867A1
WO2010043867A1 PCT/GB2009/002466 GB2009002466W WO2010043867A1 WO 2010043867 A1 WO2010043867 A1 WO 2010043867A1 GB 2009002466 W GB2009002466 W GB 2009002466W WO 2010043867 A1 WO2010043867 A1 WO 2010043867A1
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Francesca Ann Day
Delphine Francoise Monique Launay
Michael Hugh Charlton
David Festus Charles Moffat
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Chroma Therapeutics Ltd
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Chroma Therapeutics Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

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 9OkDa
  • client protein 9OkDa heat shock protein 9OkDa
  • 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 PI3K 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 PI3K/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.
  • TNFR tumor necrosis factor receptors
  • NF- KB nuclear factor- ⁇ B
  • 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.
  • the compounds are thus of use in medicine, for example in the treatment of a variety of proliferative disease states, where inappropriate action of HSP90 may be involved such as cancer, inflammatory and immune disorders such as rheumatoid arthritis, 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 pyrrolopyrimidine 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, -COOR A , -COR A , -SO 2 R A , -CONH 2 ,
  • R A and R are the same or different and represent an unsubstituted Ci -6 alkyl group, or a C 3-6 cycloalkyl, non-fused phenyl or a non-fused 5- to 6-membered heteroaryl, or R A and R B when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group;
  • R 2 represents a hydrogen or halogen atom, or a cyano, nitro, hydroxyl, -N 3 , Ci- 6 alkyl, Ci -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, or a group -SR ' ,
  • R' and R" are the same or different and represent a hydrogen atom, an unsubstituted CM alkyl group or an unfused C 6-I0 aryl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group;
  • - R 3 represents a hydrogen or halogen atom or a cyano, nitro, -N 3 , hydroxyl,
  • R 4 represents a group of formula -L 1 -A 1 ;
  • - L 1 represents Ci -4 alkylene or C 2-4 alkenylene, the alkylene and alkenylene groups optionally containing or terminating in an -O-, -S- or -NR'- link where R' represents hydrogen or unsubstituted C] -2 alkyl;
  • a 1 represents a C ⁇ -io aryl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group which is optionally fused to a further C ⁇ -io aryl, 5- to 10-membered heteroaryl, C 3-7 carb
  • AIk 3 represents a bond or Ci -4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene group
  • AIk 5 represents a C M 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 0 or 1 ;
  • AIk 1 represents a bond or Ci -6 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
  • AIk 6 represents a bond or a Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene group
  • R represents a group of formula (X) or (Y):
  • R 12 is a hydrogen atom or a C ]-6 alkyl group
  • R 20 represents a hydrogen atom, a Ci -6 alkyl group or a group -L 3 -B where L 3 represents a bond or a Ci -6 alkylene and B represents a C ⁇ -io aryl or 5- to 10-membered heteroaryl group
  • - ring D is a 5- to 6-membered heterocyclyl group wherein R 7 is linked to a ring carbon adjacent the ring nitrogen shown, and ring D is optionally fused to a second ring comprising a phenyl, 5- to 6-membered heteroaryl, C 3 .7 carbocylyl or 5- to 6-membered heterocyclyl group in which case the bond shown intersected by a wavy line may be from a ring atom in ring D or said second ring; 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 1 ', R 12 , R 20 , L 1 , L 3 , AIk 1 , 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 C M alkyl, C 2-4 alkenyl, Ci -4 alkoxy, C 2-4 alkenyloxy, Ci -4 haloalkyl, C 2 _ 4 haloalkenyl, Ci -4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR',
  • R A and R B are the same or different and represent unsubstituted Ci -6 alkyl, C3-6 cycloalkyl, non-fused phenyl or a non-fused 5- to 6-membered heteroaryl, or R and R when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group.
  • the compounds of the invention are characterised by the presence in the molecule of 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 inflammatory lung disease.
  • 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
  • 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 11 , R 12 , R 20 , L 1 , L 3 , AIk 1 , 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, Ci -4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C )-4 hydroxyalkyl and -NR ' R " groups where R' and R" are the same or different and represent hydrogen or unsubstituted C 1-2 alkyl. Unless
  • Preferred substituents include halogen atoms and C M alkyl, C 2-4 alkenyl, CM alkoxy, C 2-4 alkenyloxy, Ci -4 haloalkyl, C 2-4 haloalkenyl, Cj -4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, mercapto, cyano, nitro, C M hydroxyalkyl, C 2-4 hydroxyalkenyl, Ci -4 alkylthio, C 2-4 alkenylthio, and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl.
  • More preferred substituents include halogen, Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, hydroxyl, Ci -4 haloalkyl, C 2-4 haloalkenyl, Ci -4 haloalkyloxy and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C] -2 alkyl.
  • 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 C] -2 alkyl.
  • particularly preferred substituents include 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.
  • 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 C ⁇ alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, for example a Ci -4 alkyl group or moiety containing from 1 to 4 carbon atoms.
  • Ci -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.
  • 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 are present in a group, they may be the same or different.
  • a Ci -6 alkylene group or moiety is a linear or branched alkylene group or moiety, for example a Ci -4 alkylene group or moiety. Examples include methylene, n-ethylene, n-propylene and -C(CHs) 2 - groups and moieties.
  • a halogen atom is typically chlorine, fluorine, bromine or iodine.
  • a Ci -6 alkoxy group or C 2-6 alkenyloxy group is typically a said Ci -6 alkyl (e.g. a C] -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 -CX 3 and -OCX 3 wherein X is a said halogen atom, for example chlorine and fluorine.
  • a C M 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 CM 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, C 3-7 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.
  • 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 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.
  • a 5- to 10- membered heterocyclyl group or moiety is a non- aromatic, saturated or unsaturated C 5 . 10 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 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).
  • 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.
  • 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 D, A 1 , A 2 , A 3 , B, R 1 , R 2 , R 11 and R 20 are unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents selected from halogen atoms, and cyano, nitro, CM alkyl, CM alkoxy, C 2-4 alkenyl, C 2-4 alkenyloxy, CM haloalkyl, C 2-4 haloalkenyl, CM haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, CM 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
  • 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 , -CONHR A , -SO 2 NHR A , -C0NR A R B , -SO 2 NR A R B , -OCONH 2 , -0C0NHR A , -OCONR A R B , -NHCOR A , -NR B COR A , -NHC00R A , -NR B C00R A , -NR 8 COOH, -NHCOOH, -NHSO 2 R A , -NR B SO 2 R A , -NHSO 2 OR A , -NR 8 SO 2 OH, -NHSO 2 H, -NR
  • phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in D, A 1 , A 2 , A 3 , B, R 1 , R 2 , R 1 1 and R 20 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, Ci -4 alkoxy, C 2-4 alkenyloxy, Ci -4 haloalkyl, C 2-4 haloalkenyl, CM 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 Ci -4 alkyl.
  • the substituents are themselves unsubstituted.
  • substituents include halogen atoms and unsubstituted C] -4 alkyl, Ci -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 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 piperidine, dibenzylamine and the like.
  • 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 C M alkyl, Ci -4 alkoxy, hydroxyl, -SR' or -NR'R" group wherein each R' and R" is the same or different and represents hydrogen or unsubstituted C !-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, CM alkoxy, hydroxyl, Ci -4 haloalkyl, C 2-4 haloalkenyl, C ]-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 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.
  • 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.
  • R 1 represents a halogen atom, in particular a chlorine atom.
  • R 2 represents a hydrogen or halogen atom, or a C M alkyl, Cj -4 alkoxy, hydroxyl, -SR' or -NR'R" group where R' and R" are the same or different and represent hydrogen or unsubstituted Ci -4 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, 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.
  • R 2 represents a hydrogen or halogen atom, or an unsubstituted C] -4 alkyl, Ci -4 alkoxy, Ci -4 haloalkyl, C] -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 C M 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 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 C] -2 alkyl.
  • R 3 represents a hydrogen or halogen atom or an unsubstituted C M alkyl, CM alkoxy, C M haloalkyl, C M haloalkoxy, hydroxyl or -NR'R" group 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.
  • R 3 represents a hydrogen atom.
  • Preferred substituents on L 1 include halogen atoms and groups selected from Ci -2 alkyl, Ci -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 C].
  • 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- ? 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 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-membered 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 CM alkyl, Ci -4 alkoxy, hydroxyl, Ci -4 haloalkyl, CM 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 C 1-2 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 Cj -2 alkyl and Ci -2 alkoxy groups.
  • AIk 3 represents a bond or an C i- 3 alkylene, C 2-3 alkenylene or C 2-3 alkynylene group. More preferably AIk 3 represents an 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, C M alkoxy, hydroxyl, C M haloalkyl, C 2-4 haloalkenyl, C M haloalkoxy and -NR'R " groups where R' and R" are the same or different and represent hydrogen or unsubstituted C] -2 alkyl.
  • the AIk 3 group is unsubstituted or substituted with 1 or 2, more preferably 1, unsubstituted substituent 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 Ci -2 alkyl. Most preferably the AIk 3 group is unsubstituted.
  • L 2 represents -AIk 3 -
  • AIk 3 represents a C 2-3 alkynylene group, more preferably an ethynylene group.
  • a 2 represents an unfused phenyl or unfused 5- to 6-membered heteroaryl group.
  • 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 M haloalkyl, C M 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 C 1-2 alkyl.
  • More preferred substituents on A 2 are 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 Ci -2 alkyl.
  • the substituents on A 2 are selected from halogen atoms and unsubstituted Cj -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. More preferably, AIk 5 represents an unsubstituted C 1 .
  • AIk 5 represents an unsubstituted C M alkylene, for example a C 3-4 alkylene group, more preferably a group -CH 2 -CH 2 -CH 2 -.
  • L 2 represents -AIk 3 - or -Alk 3 -A 2 -, more preferably -Alk 3 -A 2 -.
  • x is 1.
  • the Het group is preferably -O-.
  • x is 0.
  • L 2 and AIk 1 are different, e.g. preferably L 2 and AIk 1 are not both alkyl, L 2 and AIk 1 are not both alkenyl, or L 2 and AIk 1 are not both alkynyl.
  • AIk 1 represents a bond or a Q -6 alkylene group, more preferably a Ci-6 alkylene group, more preferably still a Ci -4 alkylene group.
  • AIk 1 group is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents selected from halogen atoms, and Ci -4 alkyl, C 2-4 alkenyl, CM alkoxy, hydroxyl, Ci -4 haloalkyl, C 2-4 haloalkenyl, CM haloalkoxy and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Ci -2 alkyl.
  • the AIk 1 group is unsubstituted or substituted with 1 or 2, more preferably 1, unsubstituted substituent 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 C] -2 alkyl. More preferably the AIk 1 group is unsubstituted.
  • AIk 1 represents a group -A 3 -Alk 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 which are the same or different and are selected from halogen atoms and unsubstituted CM alkyl, C M 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
  • 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 C M alkyl, C M alkoxy, hydroxyl and -NR'R" groups where R ' and R" are the same or different and represent hydrogen or unsubstituted Ci -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 CM alkyl, CM alkoxy, hydroxyl and -NR ' R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Cj -2 alkyl. Most preferably A 3 represents an unsubstituted, unfused phenyl group.
  • AIk 1 represents a group -A 3 -Alk 6 -
  • AIk 6 represents a bond or an unsubstituted C] -6 alkylene group, more preferably still a bond, i.e. AIk 1 represents -A 3 -.
  • a 2 and A 3 are present, i.e. it is preferred that L 2 is not -Alk 3 -A 2 - when AIk 1 is -A 3 -Alk 6 - and vice versa.
  • AIk 1 is a C 2-3 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 a ring 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.
  • Ring D in addition to bearing group R 7 and being bonded to the rest of the molecule, is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and C 1-4 alkyl, C M alkoxy and hydroxyl groups. More preferably Ring D, apart from bearing group R 7 and being bonded to the rest of the molecule, is unsubstituted.
  • particularly preferred Ring D groups are:
  • exemplary R 20 groups include side chains of natural amino acids and close structural variants thereof.
  • R 20 is a Ci -6 alkyl group preferably it is a CM alkyl group, more preferably a C ]-2 alkyl group, most preferably a methyl group.
  • R 20 represents a group of formula -L 3 -B, preferably L 3 is a bond or a C M alkylene group, more preferably a Ci -2 alkylene group, most preferably a methylene group.
  • R 20 represents a group of formula -L 3 -B, preferably B represents a phenyl group or a 5- tolO-membered heteroaryl group.
  • B represents a 5- to 10- membered heteroaryl group
  • preferred heteroaryl groups include imidazolyl and indolyl.
  • R 20 represents a group of formula -L 3 -B
  • B represents a phenyl group.
  • R 20 is a C 1-6 alkyl group it is preferably unsubstituted or substituted with one or two, preferably one, unsubstituted substituent selected from halogen, Ci -2 alkoxy, C -2 haloalkyl, hydroxyl, -COOR', -COONR'R", -SR' and -NR'R" wherein R ' and R " are the same or different and represent hydrogen or Ci -2 alkyl.
  • R 20 is a Ci -6 alkyl group most preferably it is unsubstituted.
  • R 20 represents a group of formula -L 3 -B, preferably L 3 is unsubstituted.
  • R 20 represents a group of formula -L 3 -B
  • B is unsubstituted or substituted with one, two or three, more preferably with one or two, unsubstituted substituents selected from halogen atoms, Ci -4 alkyl, Ci -2 alkoxy, Ci -2 alkylthio and hydroxy.
  • R 20 represents a group of formula -L 3 -B, most preferably B is unsubstituted or substituted with one substituent selected from a halogen atom or a Ci -4 alkyl, Ci -2 alkoxy, C]. 2 alkylthio or hydroxy group.
  • R 20 represents an unsubstituted Ci -6 alkyl group or a Ci -6 alkyl group substituted with one halogen atom or a C] -2 alkoxy, Ci -2 haloalkyl, hydroxyl, -COOR', -COONR'R", -SR' or -NR'R” group wherein R' and R" are the same or different and represent hydrogen or Ci -2 alkyl, or R 20 represents a group -L 3 -B where L 3 represents a bond or an unsubstituted Ci -6 alkylene group and B represents an unsubstituted or substituted C ⁇ -io aryl or 5- to 10-membered heteroaryl group, the substituents on the aryl or heteroaryl group being independently selected from 1, 2, 3 or 4 halogen atoms or Ci -2 alkyl, Cj -2 alkoxy, Ci -2 alkylthio or hydroxy groups.
  • R 20 represents an unsubstituted C M alkyl group or a group -L 3 -B where L 3 represents a bond or an unsubstituted Cj -2 alkylene group and B represents an unsubstituted phenyl group or a phenyl group substituted with one substituent selected from a halogen atom or a Ci -2 alkyl, Ci -2 alkoxy, Ci -2 alkylthio or hydroxy group.
  • Most preferred R 20 groups include hydrogen atoms, unsubstituted methyl groups and unsubstituted methylphenyl groups, more preferably unsubstituted methyl groups.
  • R 20 represents hydrogen.
  • R represents a group of formula (X).
  • 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.
  • R 15 represents hydrogen or a group of formula -[C] -4 alkylene]b-(Z 1 )a-[C ]-4 alkyl] or -[Ci -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 C] -4 alkyl, R 164 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 CM alkyl, and R 14 represents hydrogen; (iii) R 15 represents a
  • 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, and R 14 represents hydrogen.
  • 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, Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci -2 alkyl. More preferred substituents are halogen, C 1 - 2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or 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 , R , R 1 and R groups include one or two substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, Ci -4 alkylene, Ci -4 alkoxy, Ci -4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C M alkyl, 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 -[C M 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 -.
  • R 15 represents a group of formula -[CM alkyleneJ b -CZ ⁇ a - ⁇ M alkyl], preferably C M alkyl is a Ci -3 alkyl group such as methyl, ethyl or n-propyl, most preferably methyl.
  • C M 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 alkylene] b -(Z') a -[Ci -4 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 -[CM alkyleneJ b -CZ ⁇ a -fC ⁇ alkenyl], preferably either a or b is zero, more preferably both a and b are zero.
  • [C M alkylene] is present, it is preferably a Ci -3 alkylene, more preferably a Ci -2 alkylene.
  • R 15 represents a group of formula -[CM alkylene]b-(Z') a -[CM alkenyl] 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-. Most preferably Z 1 is absent (i.e. a is zero).
  • R 15 represents hydrogen or a group of formula -[Ci -4 alky lene] b -(Z') a -[C M alkyl] or -[Ci -4 alkylene] b -(Z') a -[C 2-4 alkenyl]
  • R 15 represents hydrogen or a group of formula -[Ci -4 alkylene] b -(Z 1 ) a -[Ci -4 alkyl] or -[CM 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 -[C )-4 alkylene] b -(Z') a -[Ci -4 alkyl] or -[C )-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') a -[Ci4 alkyl] or -[C] -4 alkylene] t ,-(Z 1 ⁇ -[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 M alkyl, more preferably hydrogen or Ci -2 alkyl, most preferably hydrogen.
  • the C 1-4 alkyl groups of R 16 are unsubstituted.
  • AIk 4 preferably represents a Ci -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 C M 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 -(Alk 4 )-NR 18
  • R 19 and R 18 and R 19 are the same or different and represent hydrogen or Cj -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 -(Alk 4 )-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- ? 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 Ci -4 alkyl, C] -4 alkylene, Ci -4 alkoxy, CM haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C M alkyl, more preferably selected from halogen atoms or C 1-2 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 Ci -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 C M 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 C] -4 alkyl or C3.7 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 Cj -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 CJ -4 alkyl, Ci -4 alkoxy, Ci -4 haloalkyl, C] -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 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.
  • 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 C 1 .
  • L 2 represents -AIk 3 -, -Alk 3 -A 2 - or -Alk 3 -Alk 5 -;
  • AIk 3 represents an unsubstituted C 1 -3 alkylene, C 2 -3 alkenylene or C 2 -3 alkynylene group;
  • - AIk 5 represents an unsubstituted Ci -4 alkylene group;
  • a 2 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, Cj -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;
  • AIk 1 represents a C ]-4 alkylene group which is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms, and Ci -2 alkyl, Ci -2 alkoxy, hydroxyl, C] -2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C 1-2 alkyl, or AIk 1 represents a group -A 3 -Alk 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 CM alkyl, Ci -4 alkoxy, hydroxyl and -NR'R” groups where R' and
  • R 20 represents a hydrogen atom or a Ci -6 alkyl group which is unsubstituted or substituted with one or two substituents which are the same or different and represent halogen, C ]-2 alkoxy, Ci -2 haloalkyl, hydroxyl, -COOR',
  • R 20 represents a group of formula -L 3 -B where L 3 is a bond or an unsubstituted Ci -4 alkylene group and B represents a phenyl or a 5- to 10-membered heteroaryl group which is unsubstituted or substituted with one, two or three unsubstituted substituents which are the same or different and represent halogen atoms, C M alkyl, Ci -2 alkoxy, Ci -2 alkylthio and hydroxy;
  • R 1 ' represents a hydrogen atom or an unsubstituted Ci -4 alkyl group
  • 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,
  • x 1 and 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, Ci -2 alkoxy, hydroxyl and -NH 2 .
  • a 1 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 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 20 represents hydrogen.
  • 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 C 1-4 alkyl, C ]-4 alkoxy, hydroxyl or -NR'R" group where R' and R" are the same or different and represent hydrogen or unsubstituted
  • L 2 represents -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
  • AIk 1 represents an unsubstituted Ci_ 4 alkylene group
  • R 11 represents hydrogen or an unsubstituted Ci -2 alkyl group
  • R 10 represents a hydrogen atom or an unsubstituted Cj -4 alkyl or C 3-? carbocyclyl group.
  • each R a is the same or different and represents a halogen atom or an unsubstituted C 1-2 alkyl or C 1-2 alkoxy group.
  • R 10 represents a hydrogen atom or an unsubstituted t-butyl or cyclopentyl group.
  • Particularly preferred compounds of formula (I) are:
  • Cyclopentyl O-[4-( ⁇ 2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyI]-7H-pyrrolo[2,3-rf]pyrimidin-5-yl ⁇ ethynyl)phenyl]-L-homoserinate; tert-Buty ⁇ O-[4-( ⁇ 2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-
  • 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 HSP90 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.
  • 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.
  • 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 polyvinyl- pyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • 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 propel lant-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 comprising:
  • 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.
  • Boc /erf-butoxycarbonyl
  • DIPEA diisopropylethylamine
  • DMSO dimethyl sulfoxide
  • EDCI N-(3-Dimethylaminopropyl)-N l -ethylcarbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole
  • LCMS high performance liquid chromatography/mass spectrometry
  • LiAlH 4 lithium aluminium hydride
  • NaHCO 3 sodium hydrogen carbonate
  • Na 2 SO 4 sodium sulphate
  • NaH sodium hydride
  • NBS N-bromosuccinimide
  • PyBop benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TME tert-buty ⁇ methyl ether
  • Intermediate B-4 Cyclopentyl N-(fert-butoxycarbonyl)-L-homoserinate was prepared from Intermediate B-3 as follows: Intermediate B-3 (1.57 g, 3.9 mmol) was dissolved in acetic acid / THF / water
  • the precipitated mass was removed by filtration and the filtrate was added over a period of 20 minutes to a solution of sodium borohydride (2.43 g, 64.1 mmol) in THF (20 mL) and water (5 mL) at 0 0 C.
  • the reaction mixture was stirred warming to RT for 4 hours.
  • the mixture was acidified to pH 5 with IM HCl and the THF removed under reduced pressure.
  • the aqueous solution was extracted with EtOAc (3 x 100 mL) and dried (MgS ⁇ 4 ).
  • the product was purified by column chromatography (100% DCM to 5 % MeOH in DCM) and isolated as a clear oil (5.0 g, 78 %).
  • Building Block D was prepared from Intermediate D-I as follows: To a slurry of N-bromosuccinimide (1.67 g, 9.38 mmol) in DCM (30 mL) was added triphenylphosphine (2.30 g, 8.76 mmol). The solution was stirred at RT for 5 minutes and then treated with pyridine (304 ⁇ L, 3.76 mmol) and Intermediate D-I (2 g, 3.13 mmol). The resulting solution was stirred at RT for 16 hours. The solvent was then removed under reduced pressure and the resulting black oil was purified by column chromatography (Heptane / EtOAc 7:3) to afford the desired product as a clear oil (521 mg, 49 %).
  • Building Block E - tert-Buty ⁇ N-(terf-butoxycarbonyl)-5-bromo-L-norvalinate was prepared from N-Boc-glutamic acid tert-buty ⁇ ester using the same methodology described for Building Block D.
  • Intermediate Ic Cyclopentyl N-(tert-butoxycarbonyl)-0-(4-ethynylphenyl)-L- homoserinate was prepared from Intermediate Ib as follows: To a solution of Intermediate Ib (694 mg, 1.50 mmol) in THF (10 mL) was added tetrabutylammonium fluoride (434 ⁇ L, 1.50 mmol) and the reaction mixture was stirred at RT for 15 minutes. The crude was poured into EtOAc (50 mL) and washed with water (3 x 50 mL) then brine (50 mL).
  • reaction mixture was heated at reflux for 2 hours. It was then diluted with DCM (10 mL), washed with sat. NaHCO 3 (10 mL) then brine (10 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The product was purified by flash chromatography (Heptane / EtOAc 6:4 to 4:6) to afford the desired product (253 mg, 58 %).
  • Example 1 was prepared from Intermediate Id as follows:
  • Example 8 resulted as the by-product of the reduction of Intermediate Id when the preparation of Example 7 was undertaken.
  • Example 9 O-[4-( ⁇ 2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3- ⁇ pyrimidin-5-yl ⁇ ethynyl)phenyl]-L-homoserine was prepared from Example 1 as follows:
  • Example 1 To Example 1 (50 mg, 0.082 mmol) in dry T ⁇ F (1 mL) was added potassium trimethylsilanolate (76 mg, 0.59 mmol) and the reaction mixture was left stirring for 18 hours at RT under an atmosphere of nitrogen. The crude was concentrated under reduced pressure, MeOH was added (1 mL) to give a suspension, and the filtrate was purified by preparative ⁇ PLC. The desired product was isolated as a clear oil.
  • HTRF 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, # 61 OSAXLB, lot: 089).
  • Unlabeled GM or compounds compete with the bio-GM for binding to HSP90 resulting in reduced fluorescence energy transfer/assay signal.
  • 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, 4OnM 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).
  • 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 5OLVmI 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 lOO ⁇ l at a density of 4xlO 4 cells / well in V-bottomed 96 well tissue culture treated plates and incubated at 37°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).
  • IC 50 values are allocated to one of three ranges as follows: Range A: IC 50 ⁇ 10OnM
  • Range B 10OnM ⁇ IC 50 ⁇ 100OnM Range C: IC 50 > 100OnM
  • Examples 9-13 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 compound which is (a) a pyrrolopyrimidine derivative of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof: wherein R1, R2, R3, R4 and W are as defined herein. The compounds are useful in the treatment of diseases mediated by HSP90, and also in the treatment of inflammation.

Description

PYRROLO [2 , 3-D] PYRIMIDINES AS 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 9OkDa), 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 PI3K 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 PI3K/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 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 pyrrolopyrimidine 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, -COORA, -CORA, -SO2RA, -CONH2,
-SO2NH2, -C0NHRA, -SO2NHRA, -C0NR AArR>BB, -SO2NR ,AΛrR» BB, -OCONH2,
-0C0NHRA, -0C0NR ,AAnRBD, -NHCORA, -NRBC0RA, -NHCOORA, -NRBCOORA, -NRBC00H, -NHCOOH-, -NHSO2RA, -NRBSO2RA, -NHSO2ORA, -NRBSO2OH, -NHSO2H, -NRBSO2ORA, -NHCONH2, -NRAC0NH2, -NHCONHRB, -NRAC0NHRB, -NHC0NRARB or
,AnB
-NRAC0NRAR° wherein RA and R 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 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, Ci-6 alkyl, Ci-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 C6-I0 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,
Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Q-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 C]-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 Cβ-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 Ci-4 alkylene, C2-4 alkenylene or C2-4 alkynylene group;
AIk5 represents a CM 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 Ci-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 bond or a Ci-6 alkylene, C2-6 alkenylene or C2-6 alkynylene group; and
R represents a group of formula (X) or (Y):
Figure imgf000007_0001
(X) (Y) ;
- R11 represents a hydrogen atom or a Ci-6 alkyl, C3-? carbocyclyl, C6-Io aryl or 5- to 6-membered heteroaryl group, or a group of formula -(C=O)R12,
-(C=O)OR12, or -(C=O)NR12 wherein R12 is a hydrogen atom or a C]-6 alkyl group; R20 represents a hydrogen atom, a Ci-6 alkyl group or a group -L3 -B where L3 represents a bond or a Ci-6 alkylene and B represents a Cβ-io aryl or 5- to 10-membered heteroaryl group; - ring D is a 5- to 6-membered heterocyclyl group wherein R7 is linked to a ring carbon adjacent the ring nitrogen shown, 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 group in which case the bond shown intersected by a wavy line may be from a ring atom in ring D or said second ring; 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, R1 ', R12, R20, L1, L3, AIk1, 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 CM 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, CM 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 D, A1, A2, A3, B, R1, R2, R11 and R20 are unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents selected from halogen atoms, and cyano, nitro, CJ-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, -CONRARB, -SO2NRARB, -OCONH2, -OCONHRA, -0C0NRARB, -NHCORA, -NRBCORA, -NHCOORA, -NRBCOORA, -NR8COOH, -NHCOOH, -NHSO2RA, -NRBS02RA, -NHSO2ORA, -NR8SO2OH, -NHSO2H, -NRBSO2ORA, -NHCONH2,
-NRACONH2, -NHCONHR13, -NRAC0NHRB, -NHCONRARB or -NRACONRAR8 wherein RA and RB are the same or different and represent unsubstituted Ci-6 alkyl, C3-6 cycloalkyl, non-fused phenyl or a non-fused 5- to 6-membered heteroaryl, or R and R when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group.
The compounds of the invention are characterised by the presence in the molecule of 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 inflammatory lung disease. 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, R11, R12, R20, L1, L3, AIk1, 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, C)-4 hydroxyalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C1-2 alkyl. Unless otherwise specified, the substituents described above are preferably themselves unsubstituted.
Preferred substituents include halogen atoms and CM alkyl, C2-4 alkenyl, CM alkoxy, C2-4 alkenyloxy, Ci-4 haloalkyl, C2-4 haloalkenyl, Cj-4 haloalkoxy, C2-4 haloalkenyloxy, hydroxyl, mercapto, cyano, nitro, CM 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 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 C]-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 C]-2 alkyl. For example, particularly preferred substituents include 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.
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 C^ alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, for example a Ci-4 alkyl group or moiety containing from 1 to 4 carbon atoms. Examples Of Ci-4 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. For the avoidance of doubt, where two alkyl moieties are present in a group, the alkyl moieties may be the same or different.
As used herein, a 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 Ci-6 alkylene group or moiety is a linear or branched alkylene group or moiety, for example a Ci-4 alkylene group or moiety. Examples include methylene, n-ethylene, n-propylene and -C(CHs)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 Ci-6 alkoxy group or C2-6 alkenyloxy group is typically a said Ci-6 alkyl (e.g. a C]-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 CM 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 CM 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, C3-7 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 C5.10 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.-? 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 D, A1, A2, A3, B, R1, R2, R11 and R20 are unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents selected from halogen atoms, and cyano, nitro, CM alkyl, CM alkoxy, C2-4 alkenyl, C2-4 alkenyloxy, CM haloalkyl, C2-4 haloalkenyl, CM haloalkoxy, C2-4 haloalkenyloxy, hydroxyl, CM 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, -CONHRA, -SO2NHRA, -C0NRARB, -SO2NRARB, -OCONH2, -OCONHRA, -OCONRARB, -NHCORA, -NRBC0RA, -NHCOORA, -NRBCOORA, -NR8COOH, -NHCOOH, -NHSO2RA, -NRBSO2RA, -NHS020RA, -NR8SO2OH, -NHSO2H, -NRBSO2ORA, -NHCONH2, -NRACONH2, -NHCONHR8, -NRACONHRB, -NHC0NRARB or -NRACONRARB wherein RA and RB are the same or different and represent unsubstituted Ci-6 alkyl, C3-6 cycloalkyl, non-fused phenyl or a non-fiised 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. 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, -CONHRA, -SO2NHRA, -C0NRARB, -SO2NRARB, -OCONH2, -0C0NHRA, -OCONRARB, -NHCORA, -NRBCORA, -NHC00RA, -NRBC00RA, -NR8COOH, -NHCOOH, -NHSO2RA, -NRBSO2RA, -NHSO2ORA, -NR8SO2OH, -NHSO2H, -NRBSO2ORA, -NHCONH2, -NRAC0NH2, -NHCONHR8, -NRAC0NHRB, -NHC0NRARB or -NRACONRARB.
Typically the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in D, A1, A2, A3, B, R1, R2, R1 1 and R20 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, Ci-4 alkoxy, C2-4 alkenyloxy, Ci-4 haloalkyl, C2-4 haloalkenyl, CM 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 Ci-4 alkyl. Preferably the substituents are themselves unsubstituted. More preferred substituents include halogen atoms and unsubstituted C]-4 alkyl, Ci-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 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 CM alkyl, Ci-4 alkoxy, hydroxyl, -SR' or -NR'R" group wherein each R' and R" is the same or different and represents hydrogen or unsubstituted C!-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, CM alkoxy, hydroxyl, Ci-4 haloalkyl, C2-4 haloalkenyl, C]-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 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.
More preferably 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.
Most preferably R1 represents a halogen atom, in particular a chlorine atom. Preferably R2 represents a hydrogen or halogen atom, or a CM alkyl, Cj-4 alkoxy, hydroxyl, -SR' or -NR'R" group where R' and R" are the same or different and represent hydrogen or unsubstituted Ci-4 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, 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 R2 represents a hydrogen or halogen atom, or an unsubstituted C]-4 alkyl, Ci-4 alkoxy, Ci-4 haloalkyl, C]-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 CM 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 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 C]-2 alkyl.
More preferably R3 represents a hydrogen or halogen atom or an unsubstituted CM alkyl, CM alkoxy, CM haloalkyl, CM 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 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, Ci-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 C].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-? 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 A 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-membered 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 CM alkyl, Ci-4 alkoxy, hydroxyl, Ci-4 haloalkyl, CM 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 C1-2 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 Cj-2 alkyl and Ci-2 alkoxy groups.Preferably AIk3 represents a bond or an C i-3 alkylene, C2-3 alkenylene or C2-3 alkynylene group. More preferably AIk3 represents an 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, CM alkoxy, hydroxyl, CM haloalkyl, C2-4 haloalkenyl, CM haloalkoxy and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C]-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 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 Ci-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. When L2 represents -AIk3-, preferably AIk3 represents a C2-3 alkynylene group, more preferably an ethynylene group.
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, CM haloalkyl, CM 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 C1-2 alkyl. More preferred substituents on A2 are 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 Ci-2 alkyl.
More preferably the substituents on A2 are selected from halogen atoms and unsubstituted Cj-2 alkyl and Ci-2 alkoxy groups. Most preferably the A2 group is unsubstituted.
When L2 represents -Alk3-Alks, 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 C 1.4 alkylene, C2-4 alkenylene or C2-4 alkynylene group. Most preferably AIk5 represents an unsubstituted CM alkylene, for example a C3-4 alkylene group, more preferably a group -CH2-CH2-CH2-.
It is preferred that L2 represents -AIk3- or -Alk3-A2-, more preferably -Alk3-A2-. In a preferred embodiment, x is 1.
When present, the Het group is preferably -O-.
In an alternative embodiment, x is 0. In particular, when L2 is -AIk3- preferably x is 0. In addition, when x is 0 preferably L2 and AIk1 are different, e.g. preferably L2 and AIk1 are not both alkyl, L2 and AIk1 are not both alkenyl, or L2 and AIk1 are not both alkynyl.
When L2 is -Alk3-A2- preferably x is 1.
When L2 is -Alk3-Alk5- preferably x is 1.
Preferably AIk1 represents a bond or a Q-6 alkylene group, more preferably a Ci-6 alkylene group, more preferably still a Ci-4 alkylene group. Preferably the AIk1 group is unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents selected from halogen atoms, and Ci-4 alkyl, C2-4 alkenyl, CM alkoxy, hydroxyl, Ci-4 haloalkyl, C2-4 haloalkenyl, CM 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 AIk1 group is unsubstituted or substituted with 1 or 2, more preferably 1, unsubstituted substituent 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 C]-2 alkyl. More preferably the AIk1 group is unsubstituted.
Alternatively, 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 which are the same or different and are selected from halogen atoms and unsubstituted CM alkyl, CM 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 C]-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 CM alkyl, CM 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 A3 represents an unfused phenyl which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms and unsubstituted CM alkyl, CM alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted Cj-2 alkyl. Most preferably A3 represents an unsubstituted, unfused phenyl group.
When AIk1 represents a group -A3-Alk6-, preferably AIk6 represents a bond or an unsubstituted C]-6 alkylene group, more preferably still a bond, i.e. AIk1 represents -A3-.
Preferably only one of A2 and A3 is present, i.e. it is preferred that L2 is not -Alk3-A2- when AIk1 is -A3-Alk6- and vice versa. Preferably AIk1 is a C2-3 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 a ring 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. Preferably Ring D, in addition to bearing group R7 and being bonded to the rest of the molecule, is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and C1-4 alkyl, CM alkoxy and hydroxyl groups. More preferably Ring D, apart from bearing group R7 and being bonded to the rest of the molecule, is unsubstituted. Thus, particularly preferred Ring D groups are:
Figure imgf000022_0002
When R represents a group of formula (X), R11 preferably represents a hydrogen atom or an unsubstituted Ci-4 alkyl group, or a group of formula -(C=O)R12, -(C=O)OR12, or -(C=O)NR12 wherein R12 is a hydrogen atom or an unsubstituted C1-4 alkyl group. More preferably R11 represents a hydrogen atom or an unsubstituted Ci-2 alkyl group. Most preferably R11 represents a hydrogen atom.
In one embodiment, exemplary R20 groups include side chains of natural amino acids and close structural variants thereof. When R20 is a Ci-6 alkyl group preferably it is a CM alkyl group, more preferably a C]-2 alkyl group, most preferably a methyl group. When R20 represents a group of formula -L3-B, preferably L3 is a bond or a CM alkylene group, more preferably a Ci-2 alkylene group, most preferably a methylene group. When R20 represents a group of formula -L3-B, preferably B represents a phenyl group or a 5- tolO-membered heteroaryl group. When B represents a 5- to 10- membered heteroaryl group preferred heteroaryl groups include imidazolyl and indolyl. When R20 represents a group of formula -L3-B, preferably B represents a phenyl group. When R20 is a C1-6 alkyl group it is preferably unsubstituted or substituted with one or two, preferably one, unsubstituted substituent selected from halogen, Ci-2 alkoxy, C-2 haloalkyl, hydroxyl, -COOR', -COONR'R", -SR' and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci-2 alkyl. When R20 is a Ci-6 alkyl group most preferably it is unsubstituted. When R20 represents a group of formula -L3 -B, preferably L3 is unsubstituted.
When R20 represents a group of formula -L3 -B, preferably B is unsubstituted or substituted with one, two or three, more preferably with one or two, unsubstituted substituents selected from halogen atoms, Ci-4 alkyl, Ci-2 alkoxy, Ci-2 alkylthio and hydroxy. When R20 represents a group of formula -L3 -B, most preferably B is unsubstituted or substituted with one substituent selected from a halogen atom or a Ci-4 alkyl, Ci-2 alkoxy, C].2 alkylthio or hydroxy group.
In one embodiment R20 represents an unsubstituted Ci-6 alkyl group or a Ci-6 alkyl group substituted with one halogen atom or a C]-2 alkoxy, Ci-2 haloalkyl, hydroxyl, -COOR', -COONR'R", -SR' or -NR'R" group wherein R' and R" are the same or different and represent hydrogen or Ci-2 alkyl, or R20 represents a group -L3 -B where L3 represents a bond or an unsubstituted Ci-6 alkylene group and B represents an unsubstituted or substituted Cβ-io aryl or 5- to 10-membered heteroaryl group, the substituents on the aryl or heteroaryl group being independently selected from 1, 2, 3 or 4 halogen atoms or Ci-2 alkyl, Cj-2 alkoxy, Ci-2 alkylthio or hydroxy groups. In a preferred embodiment R20 represents an unsubstituted CM alkyl group or a group -L3-B where L3 represents a bond or an unsubstituted Cj-2 alkylene group and B represents an unsubstituted phenyl group or a phenyl group substituted with one substituent selected from a halogen atom or a Ci-2 alkyl, Ci-2 alkoxy, Ci-2 alkylthio or hydroxy group. Most preferred R20 groups include hydrogen atoms, unsubstituted methyl groups and unsubstituted methylphenyl groups, more preferably unsubstituted methyl groups. Most preferably R20 represents hydrogen. Preferably R represents a group of formula (X).
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 R9-0H. 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.
Subject to the requirement that they be hydrolysable by intracellular carboxylesterase enzymes, examples of particular ester groups R include those of formula -(C=O)OR13 wherein R13 is -CR14R15R16 wherein:
(i) R15 represents hydrogen or a group of formula -[C]-4 alkylene]b-(Z1)a-[C]-4 alkyl] or -[Ci-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 C]-4 alkyl, R164 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 CM 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, Ci-4 alkyl, C2-4 alkenyl, Ci-4 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci-2 alkyl. More preferred substituents are halogen, C1-2 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 R , R , R1 and R groups include one or two substituents which are the same or different and are selected from halogen atoms and Ci-4 alkyl, Ci-4 alkylene, Ci-4 alkoxy, Ci-4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or CM 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 -[CM
Figure imgf000026_0001
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 -[CM alkyleneJb-CZ^a-^M alkyl], preferably CM 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 alkylene]b-(Z')a-[Ci-4 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 -[CM alkyleneJb-CZ^a-fC^ alkenyl], preferably either a or b is zero, more preferably both a and b are zero. When [CM alkylene] is present, it is preferably a Ci-3 alkylene, more preferably a Ci-2 alkylene.
When R15 represents a group of formula -[CM alkylene]b-(Z')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 -[CM alkylene]b-(Z')a-[CM alkenyl] and a is 1, Z1 is preferably -O- or -NR17- wherein R17 is hydrogen or Ci-2 alkyl, more preferably Z1 is -O-. Most preferably Z1 is absent (i.e. a is zero).
When R15 represents hydrogen or a group of formula -[Ci-4 alky lene]b-(Z')a-[C M alkyl] or -[Ci-4 alkylene]b-(Z')a-[C2-4 alkenyl], preferably R15 represents hydrogen or a CM alkyl or C2-4 alkenyl group, or a group -(Ci-4 alkyl)-O-(CM alkyl). More preferably R15 represents hydrogen, methyl, ethyl, n-propyl, -CH=CH2 or -CH2-CH2-O-CH3, most preferably methyl.
When R15 represents hydrogen or a group of formula -[Ci-4 alkylene]b-(Z1)a-[Ci-4 alkyl] or -[CM 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 -[C)-4 alkylene]b-(Z')a-[Ci-4 alkyl] or -[C)-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-(Z')a-[Ci4 alkyl] or -[C]-4 alkylene]t,-(Z 1^-[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 CM alkyl, more preferably hydrogen or Ci-2 alkyl, most preferably hydrogen. Preferably the C1-4 alkyl groups of R16 are unsubstituted.
When R15 represents a group of formula -(Alk4)-NR18R19, AIk4 preferably represents a Ci-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 CM alkyl, preferably R18 represents hydrogen or Ci-2 alkyl, more preferably R18 represents a methyl group. When R15 represents a group of formula -(Alk4)-NR18R19 and R18 and R19 are the same or different and represent hydrogen or Cj-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 -(Alk4)-NRI8R19, AIk4 preferably represents a Ci-2 alkylene group, more preferably a group -CH2CH2-. When R15 represents a group of formula -(AIk4^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 -(Alk4)-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-? 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 R16 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 Ci-4 alkyl, C]-4 alkylene, Ci-4 alkoxy, CM haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or CM alkyl, more preferably selected from halogen atoms or C1-2 alkyl, Ci-2 alkylene, Ci-2 alkoxy and hydroxyl groups. Most preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups formed are unsubstituted or substituted by a Ci-2 alkyl group (such as a methyl group) or by a Ci-2 alkylene group (such as by a methylene group). Even more preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups so formed are unsubstituted.
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 CM alkyl or C3-7 carbocyclyl. Most preferred groups include where R9 is cyclopentyl or t-butyl, more preferably where R9 is cyclopentyl.
Compounds where R7 represents -COOH or -COOR9 wherein R9 is C]-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 Cj-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 imgf000029_0001
wherein:
R1 represents a hydrogen or halogen atom or an unsubstituted group selected from CJ-4 alkyl, Ci-4 alkoxy, Ci-4 haloalkyl, C]-4 haloalkoxy, hydroxyl and -NR'R" where R' and R" are the same or different and represent hydrogen or Ci-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 C 1.4 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; L2 represents -AIk3-, -Alk3-A2- or -Alk3-Alk5-; AIk3 represents an unsubstituted C1-3 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 Ci-4 alkyl, Cj-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 C]-4 alkylene group which is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen atoms, and Ci-2 alkyl, Ci-2 alkoxy, hydroxyl, C]-2 haloalkyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C1-2 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 CM alkyl, Ci-4 alkoxy, hydroxyl and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted d-2 alkyl, and AIk6 represents an unsubstituted Ci-6 alkylene group;
R20 represents a hydrogen atom or a Ci-6 alkyl group which is unsubstituted or substituted with one or two substituents which are the same or different and represent halogen, C]-2 alkoxy, Ci-2 haloalkyl, hydroxyl, -COOR',
-COONR'R", -SR' and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci-2 alkyl, or R20 represents a group of formula -L3-B where L3 is a bond or an unsubstituted Ci-4 alkylene group and B represents a phenyl or a 5- to 10-membered heteroaryl group which is unsubstituted or substituted with one, two or three unsubstituted substituents which are the same or different and represent halogen atoms, CM alkyl, Ci-2 alkoxy, Ci-2 alkylthio and hydroxy;
R1 ' represents a hydrogen atom or an unsubstituted Ci-4 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 this preferred embodiment, preferably x represents 1 and 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, Ci-2 alkoxy, hydroxyl and -NH2. Preferably 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 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 R20 represents hydrogen. In a more preferred embodiment there is provided a compound which is (a) a pyrrolopyrimidine derivative of formula (IC) 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, 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 C1-4 alkyl, C]-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 -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 Ci-2 alkyl and
Ci-2 alkoxy groups;
AIk1 represents an unsubstituted Ci_4 alkylene group;
R11 represents hydrogen or an unsubstituted Ci-2 alkyl group; and
R10 represents a hydrogen atom or an unsubstituted Cj-4 alkyl or C3-? carbocyclyl group. In this preferred embodiment preferably each Ra is the same or different and represents a halogen atom or an unsubstituted C1-2 alkyl or C1-2 alkoxy group.
Preferably R10 represents a hydrogen atom or an unsubstituted t-butyl or cyclopentyl group. Particularly preferred compounds of formula (I) are:
Cyclopentyl O-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyI]-7H-pyrrolo[2,3-rf]pyrimidin-5-yl}ethynyl)phenyl]-L-homoserinate; tert-Buty\ O-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-
7H-pyrrolo[2,3-J]pyrimidin-5-yl}ethynyl)phenyl]-L-homoserinate; Cyclopentyl 5-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-
7Η-pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenoxy]-L-norvalinate; tert-Butyl 5-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-
7H-pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenoxy]-L-norvalinate;
Cyclopentyl O-[3-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenyl]-L-homoserinate;
Cyclopentyl 5-(4-{[2-amino-4-chloro-7-(pyridin-2-ylmethyl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]ethynyl}phenoxy)-L-norvalinate;
Cyclopentyl O-[4-(2-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}ethyl)phenyl]-L-homoserinate; Cyclopentyl O-{4-[(Z)-2-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}vinyl]phenyl}-L-homoserinate;
0-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenyl]-L-homoserine;
5-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenoxy]-L-norvaline;
O-[3-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)ιnethyl]-7H- pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenyl]-L-homoserine;
5-(4-{[2-Amino-4-chloro-7-(pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5- yl]ethynyl}phenoxy)-L-norvaline; O-[4-(2-{2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-d]pyrimidin-5-yl}ethyl)phenyl]-L-homoserine.
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 HSP90 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 polyvinyl- pyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. For topical application to the skin, the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
For topical application by inhalation, the drug may be formulated for aerosol delivery for example, by pressure-driven jet atomizers or ultrasonic atomizers, or preferably by propel lant-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 Chemistiγ", 2n 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 "Beilsteiή".
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 intermediates (AIk1 and R10 are as defined herein, P is a suitable protecting group). Additional literature references relating to this route can be found within J. Org. Chem., 1984, 49,
3527-3534.
Figure imgf000038_0001
R1°-0H EDCI, DMAP DCM
Figure imgf000038_0002
It will be apparent to the individual skilled in the art that the chosen synthetic route is one of a number available. The silyl protection of the hydroxyl must be compatible with the chosen protecting group for the amino functionality. Equally, there are a number of possible methods for the esterification of the acid moiety; the decision of which one to use will be depend upon the chosen protecting group strategy.
Scheme 2 - Generic scheme for the preparation of the pyrrolo-pyrimidine building blocks (R3 and R4 are as defined herein):
Figure imgf000039_0001
POCI3, BTEACI
N,N-dιethylanιlιne
Acetonitπle
Figure imgf000039_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.
Scheme 3 - Generic scheme for the preparation of compounds where L is an acetylene
(R >3j, D R44, D R7', R1 ', R >220υ, Het, x and AIk' are as defined herein):
Figure imgf000040_0001
CuI, Pd(PPh3),, TEA, DCM
Figure imgf000040_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 AIk is an alkene and A2 is phenyl (AIk1, R3, R4, R7, R11 and R20 are as defined herein):
Figure imgf000040_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 AIk3 is an alkyl chain (AIk ,11, r R>3J, r R>44, „ R7', „ R1"1 and R 2^0 are as defined herein):
Figure imgf000041_0001
Figure imgf000041_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, R7, R11 and R20 are as defined herein):
Saponification
Figure imgf000041_0004
Figure imgf000041_0003
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
Boc = /erf-butoxycarbonyl
«BuLi = n-butyllithium
CO2 = carbon dioxide
DCE = dichloroethane DCM = dichloromethane
DIPEA = diisopropylethylamine
DMAP = 4-Dimethylaminopyridine
DMF = dimethylformamide
DMSO = dimethyl sulfoxide EDCI = N-(3-Dimethylaminopropyl)-Nl-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
Na2CCh = sodium carbonate
NaHCO3 = sodium hydrogen carbonate
Na2SO4 = sodium sulphate NaH = sodium hydride
NaOH = sodium hydroxide
NBS = N-bromosuccinimide
NH3 = ammonia
NH4Cl = ammonium chloride NMR = nuclear magnetic resonance
NMM = N-methylmorpholine
Pd/C = palladium on carbon
PyBop = 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-buty\ 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 C18 columns
(10 μm, 100 x 21.2 mm), gradient 0-100 % B (A = water + 0.05 % TFA, B = acetonitrile) over 10 min, flow = 25 mL/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 F2S4 (Merck) plates and visualized using UV light.
5 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 Gl 315B DAD detector. Mass spectra were obtained over the range m/z 150 to 800 on a LC/MSD SL G1956B 10 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 imgf000044_0001
Building Block A Building Block B Building Block C
Figure imgf000044_0002
\ 5 Building Block D Building Block E Building Block F
Building Block A - 4-Chloro-5-iodo-7-[(4-methoxy-3,5-dirnethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-J]pyrimidin-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), 20 5.28 (2H, s), 3.72 (3H, s), 2.25 (3H, s), 2.16 (3H, s). Building Block B - Cyclopentyl (2S)-4-bromo-2-[(fert-butoxycarbonyl)amino] butanoate was prepared using the following methodology:
Figure imgf000045_0001
Intermediate B-1 Intermediate B-2
Cyclopentanol EDC, DMAP, DCM
Figure imgf000045_0002
Building Block B Intermediate B-4 Intermediate B-3
Intermediate B-I - <9-[terr-Butyl(dimethyl)silyl]-L-homoserine was prepared as follows:
To a suspension of L-homoserine (1.00 g, 8.4 mmol) in ACN (10 mL) at 0 0C was added l,8-diazabicyclo[5.4.0]undec-7-ene (1.32 mL, 8.8 mmol). fert-Butyl- dimethyl-silyl chloride (1.33 g, 8.8 mmol) was then added portionwise over 5 minutes and the reaction mixture allowed to warm to RT and stirred for 16 hours. A white precipitate had formed, which was filtered off and washed with acetonitrile before drying under reduced pressure. The title compound was isolated as a white solid (1.80 g, 92 %). 1H NMR (300MHz, dfe-DMSO) δ: 7.50 (IH, br s), 3.70 (IH, m), 3.35 (4H, br m), 1.95 (IH, m), 1.70 (IH, m), 0.90 (9H, s), 0.10 (6H, s).
Intermediate B-2 - N-(/erf-Butoxycarbonyl)-O-[/er/-butyl(dimethyl)silyl]-L- homoserine was prepared from Intermediate B-I as follows:
A suspension of Intermediate B-I (1.80 g, 7.7 mmol) in DCM (100 mL) at 0 0C was treated with TEA (2.15 mL, 15.4 mmol) and di-terf-butyl dicarbonate (1.77 g, 8.1 mmol). The reaction mixture was stirred at RT for 16 hours. The DCM was removed under reduced pressure and the mixture was separated between EtOAc and brine. The EtOAc layer was dried (MgSO4) and concentrated under reduced pressure. The crude product was taken forward to the next step without further purification (2.53 g, 99 %). 1H NMR (300 MHz, CDCl3) δ: 7.50 (IH, br s), 5.85 (IH, d, J=6.5 Hz), 4.30 (IH, m), 3.75 (2H, m), 1.95 (2H, m), 1.40 (9H, s), 0.85 (9H, s), 0.10 (6H, s).
Intermediate B-3 - Cyclopentyl N-(ferf-butoxycarbonyl)-0[rert-butyl(dimethyl)silyl]- L-homoserinate was prepared from Intermediate B-2 as follows:
To a solution of Intermediate B-2 (2.53 g, 7.6 mmol) in DCM (50 mL) at 0 0C was added cyclopentanol (1.39 mL, 15.3 mmol), EDC (1.61 g, 8.4 mmol) and DMAP (93 mg, 0.76 mmol). The reaction mixture was stirred for 16 hours at RT before evaporation under reduced pressure. The crude residue was dissolved in EtOAc (100 mL) and washed with IM HCl, IM Na2CO3 and brine. The organic layer was then dried (MgSθ4) and evaporated under reduced pressure. The crude was purified by column chromatography (EtOAc /heptane 1:4) to afford the title compound (2.24 g, 73 %). m/z = 402 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 5.2 (IH, d, J=6.3 Hz), 5.15 (IH, m), 4.20 (IH, m), 3.60 (2H, m), 2.00 (IH, m), 1.95-1.55 (9H, br m), 1.40 (9H, s), 0.85 (9H, s), 0.10 (6H, s).
Intermediate B-4 — Cyclopentyl N-(fert-butoxycarbonyl)-L-homoserinate was prepared from Intermediate B-3 as follows: Intermediate B-3 (1.57 g, 3.9 mmol) was dissolved in acetic acid / THF / water
(3: 1 :1, 100 mL). The reaction mixture was stirred at 30 0C for 16 hours. EtOAc (200 mL) was added and washed with IM Na2CO3, IM HCl and brine. The EtOAc layer was dried (MgSO4) and concentrated under reduced pressure to afford the title compound as a clear oil which solidified on standing (1.00 g, 95 %). m/z = 310 [M+Na]+. 1H NMR (300 MHz, CDCl3) δ: 5.40 (IH, d, J=6.5 Hz), 5.20 (IH, m), 4.40 (IH, m), 3.65 (2H, m), 2.15 (IH, m), 1.90-1.55 (9H, br m), 1.45 (9H, s).
Building Block B - Cyclopentyl (2S)-4-bromo-2-[(tert-butoxycarbonyl)amino] butanoate was prepared from Intermediate B-4 as follows: To a suspension of N-bromo succinimide (1.86 g, 10.4 mmol) in DCM (16 mL) was added a solution of triphenyl phosphine (2.56 g, 9.7 mmol) in DCM (7 mL). The solution was stirred for 5 minutes. Pyridine (0.34 mL, 4.2 mmol) was added, followed by a solution of Intermediate B-4 (1.00 g, 3.5 mmol) in DCM (9 mL). The solution was stirred at RT for 18 hours, concentrated under reduced pressure and the residual solvent azeotroped with toluene (3 x 16 mL). The residue was triturated with diethyl ether (10 mL) and EtOAc / heptane (1 :9, 2 x 10 mL). The combined organic solutions were concentrated onto silica and purified by column chromatography (EtOAc / heptane 1 :9 to 2:8) to afford the title compound (1.02 g, 84 %). 1H NMR (300 MHz, CZ)Cl3) δ: 5.30-5.05 (2H, m), 4.45-4.30 (IH, m), 3.45 (2H, t, J=7.3 Hz), 2.50-2.30 (IH, m), 2.25- 2.10 (IH, m), 1.95- 1.60 (8H, br m), 1.47 (9H, s).
Building Block C - Cyclopentyl 5-bromo-L-norvalinate was prepared using the following methodology:
Figure imgf000047_0001
Intermediate C-1 Intermediate C-2
DCM
Figure imgf000047_0003
Figure imgf000047_0002
Building Block C Intermediate C-3
Intermediate C-I - 5-Benzyl 1 -cyclopentyl N-(tert-butoxycarbonyl)-L-glutamate was prepared as follows:
To a solution of (2S)-5-(benzyloxy)-2-[tert-butoxycarbonyl)amino]-5- oxopentanoic acid (15 g, 44.5 mmol) in DCM (220 mL) in an ice-bath, was added cyclopentanol (4.8 mL, 53.3 mmol), EDCI (9.4 g, 48.9 mmol) and DMAP (543 mg, 4.4 mmol). The reaction mixture was allowed to warm to RT and stirred for 12 hours for complete reaction. The reaction mixture was diluted with DCM (200 mL) and washed with IM HCl, IM Na2CO3 and brine. The organic layer was then dried (MgSO4) and evaporated under reduced pressure. The product was purified by column chromatography (EtOAc / heptane 1 :4) to afford the title compound as a white solid (12.4 g, 69 %). 1H NMR (300 MHz, CDCl3) δ: 7.38 (5H, m), 5.70 (IH, m), 5.10 (2H, s), 5.05 (IH, m), 4.25 (IH, m), 2.47 (2H, m), 2.15 (IH, m), 1.95-1.55 (9H, m), 1.47 (9H, s).
Intermediate C-2 - (4S)-4-[(ferr-Butoxycarbonyl)amino]-5-(cyclopentyloxy)-5- oxopentanoic acid was prepared from Intermediate C-I as follows:
Intermediate C-I (12.4 g, 30.5 mmol) was dissolved in EtOAc (200 mL) and purged with nitrogen before addition of 20 % Pd(OH)2 on carbon (1.3 g). The reaction flask was then purged with hydrogen gas for a period of 5 minutes before stirring under an atmosphere of hydrogen for 5 hours for complete reaction. The catalyst was removed by filtration, washed with EtOAc (50 mL) and the combined filtrates were evaporated under reduced pressure. The title compound was isolated as a clear oil (7.73 g, 85 %) and required no further purification. 1H NMR (300 MHz, CZ)Cl3) δ: 10.0 (IH, br s), 5.70 (2H, m), 4.28 (IH, m), 2.47 (2H, m), 2.15 (IH, m), 1.95-1.55 (9H, m), 1.47 (9H, s).
Intermediate C-3 - Cyclopentyl N-(ter/-butoxycarbonyl)-5-hydroxy-L-norvalinate was prepared from Intermediate C-2 as follows:
Ethyl chloroformate (2.45 mL, 25.6 mmol) was added at -20 0C to a stirred solution of Intermediate C-2 (6.73 g, 21.4 mmol) and N-methyl morpholine (3.05 mL, 27.8 mmol) in THF (50 mL). The reaction mixture became very thick with precipitation of a white solid. The reaction was therefore diluted further with THF (100 mL) to aid mixing and left stirring at -20 0C for 2 hours. The precipitated mass was removed by filtration and the filtrate was added over a period of 20 minutes to a solution of sodium borohydride (2.43 g, 64.1 mmol) in THF (20 mL) and water (5 mL) at 0 0C. The reaction mixture was stirred warming to RT for 4 hours. The mixture was acidified to pH 5 with IM HCl and the THF removed under reduced pressure. The aqueous solution was extracted with EtOAc (3 x 100 mL) and dried (MgSθ4). The product was purified by column chromatography (100% DCM to 5 % MeOH in DCM) and isolated as a clear oil (5.0 g, 78 %). 1H ΝMR (300 MHz, CDCl3) δ: 5.20 (2H, m), 4.25 (IH, m), 3.65 (2H, m), 2.00-1.57 (12H, m), 1.47 (9H, s). Building Block C was prepared from Intermediate C-3 as follows:
To a slurry of N-bromosuccinimide (3.54 g, 19.9 mmol) in DCM (30 mL) was added a solution of triphenylphosphine (4.87 g, 18.8 mmol) in DCM (15 mL). The solution was stirred for 5 minutes before addition of pyridine (644 μL, 7.96 mmol) and a solution of Intermediate C-3 (2.0 g, 6.64 mmol) in DCM (20 mL). The solution was stirred for 18 hours, concentrated in vacuo and the residual solvent azeotroped with toluene (3 x 30 mL). The residue was triturated with Et2O (30 mL) and EtOAc / heptane (1 :9, 2 x 30 mL). The combined organic solutions were concentrated onto silica and purified by column chromatography (EtOAc / heptane 1:9 to 2:8) to afford the title compound as a clear oil (1.34 g, 55 %). 1H ΝMR (300 MHz, CDCl3) δ: 5.25 (IH, m), 5.05 (IH, br d), 3.45 (2H, m), 2.00-1.55 (12H, m), 1.45 (9H, s).
Building Block D - tert-Butyl (25)-4-bromo-2-[(/e^-butoxycarbonyl)amino] butanoate was prepared using the following methodology:
Figure imgf000049_0001
Intermediate D-1
NBS, PPh3 pyridine
DCM
Figure imgf000049_0002
Building Block D
Intermediate D-I - tert-butyl N-(tert-butoxycarbonyl)-L-homoserinate was prepared as follows:
To a solution of N-Boc-aspartic acid tert-butyl ester (5 g, 17.3 mmol) in anhydrous THF (20 mL) was added ΝMM (2.85 mL, 26 mmol) at 0 0C. After 30 minutes at 0 0C, isobutyl chloro formate (3.14 mL, 24 mmol) was added and the reaction stirred at RT for 3 hours. The reaction was then treated with NaBH4 (1.31 g, 34.6 mmol) and anhydrous MeOH (2 mL) and stirred for a further 16 hours. The reaction mixture was then dissolved in EtOAc (100 mL) and washed with water (100 mL) and brine (100 mL), then dried (MgSO4) and concentrated under reduced pressure. The crude was purified by column chromatography (EtOAc / heptane 1 :1) to afford the desired product (3.76 g, 79 %). m/z = 276 [M+H]+.
Building Block D was prepared from Intermediate D-I as follows: To a slurry of N-bromosuccinimide (1.67 g, 9.38 mmol) in DCM (30 mL) was added triphenylphosphine (2.30 g, 8.76 mmol). The solution was stirred at RT for 5 minutes and then treated with pyridine (304 μL, 3.76 mmol) and Intermediate D-I (2 g, 3.13 mmol). The resulting solution was stirred at RT for 16 hours. The solvent was then removed under reduced pressure and the resulting black oil was purified by column chromatography (Heptane / EtOAc 7:3) to afford the desired product as a clear oil (521 mg, 49 %). 1H NMR (300 MHz, CDCl3) δ: 5.20-5.04 (IH, m), 4.36-4.23 (IH, m), 3.49- 3.39 (2H, m), 2.46-2.31 (IH, m), 2.25-2.11 (IH, m), 1.50 (9H, s), 1.47 (9H, s).
Building Block E - tert-Buty\ N-(terf-butoxycarbonyl)-5-bromo-L-norvalinate was prepared from N-Boc-glutamic acid tert-buty\ ester using the same methodology described for Building Block D.
1H ΝMR (300 MHz, CDCl3) δ: 5.21-5.07 (IH, m), 4.40-4.23 (IH, m), 3.49-3.42 (2H, m), 2.46-2.30 (IH, m), 2.28-2.09 (3H, m), 1.50 (9H, s), 1.45 (9H, s).
Building Block F - 4-Chloro-5-iodo-7-(pyridin-2-ylmethyl)-7H-pyrrolo[2,3-
<5?]pyrimidin-2-amine was prepared using the methodology outlined in Scheme 2 and as described in WO2006105372. m/z = 386 [M+Η]+ Example 1 - Cyclopentyl O-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin^-yOmethyll-VH-pyrrolop.S-cdpyrimidin-S-ylJethynyOphenylJ-L- homoserinate
Figure imgf000051_0001
Scheme 6 - Methodology for the preparation of Example 1:
Figure imgf000051_0002
Figure imgf000051_0003
Intermediate Ia - Cyclopentyl N-(ferr-butoxycarbonyl)-0-(4-iodophenyl)-L- homoserinate was prepared as follows: To a solution of 4-iodophenol (660 mg, 3 mmol) in DMF (10 rnL) were added
Building Block B (1.05 g, 3 mmol) and K2CO3 (456 mg, 3.3 mmol). The reaction mixture was stirred at RT for 15 hours. The DMF was removed under vacuum, 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 product was purified by flash chromatography (Heptane / EtOAc 8:2) to yield the desired product as a white solid (1.35 g, 92 %). m/z = 512.3 [M+Νa]+; 1H NMR (300 MHz, d6-OMSO) δ: 7.58 (2H, d, J=8.9 Hz), 7.34 (IH, d, J=7.7 Hz), 6.77 (2H, d, J=8.9 Hz), 5.1 1-5.05 (IH, m), 4.11-4.03 (IH, m), 4.04-3.94 (2H, m), 2.12-1.91 (2H, m), 1.83- 1.69 (2H, m), 1.66-1.48 (6H, m), 1.37 (9H, s).
Intermediate Ib - Cyclopentyl N-(terf-butoxycarbonyl)-0-{4-[(trimethylsilyl) ethynyl]phenyl}-L-homoserinate was prepared from Intermediate Ia as follows:
To a solution of Intermediate Ia (756 mg, 1.54 mmol) in DCM (10 mL) were added ethynyltrimethylsilane (428 μL, 3.09 mmol), TEA (430 μL, 3.09 mmol), tetrakis(triphenylphosphine) palladium (92 mg, 0.08 mmol) and copper iodide (28 mg, 0.15 mmol). The reaction mixture was heated at reflux for 2 hours. It was then washed with sat. NaHCO3 (10 mL) then brine (20 mL), dried (MgSO4) and concentrated under reduced pressure. The product was purified by flash chromatography (Heptane / EtOAc 8:2) to afford the desired product (694 mg, 98 %). m/z = 482.2 [M+Νa]+; 1H NMR (300 MHz, CDCl3) δ: 7.40 (2H, d, J=8.7 Hz), 6.82-6.77 (2H, m), 5.27-5.20 (IH, m), 4.50-4.41 (IH, m), 4.05 (2H, t, J=6.1 Hz), 2.38-2.20 (2H, m), 1.90-1.79 (2H, m), 1.75- 1.61 (6H, m), 1.45 (9H, s), 0.25 (9H, s).
Intermediate Ic - Cyclopentyl N-(tert-butoxycarbonyl)-0-(4-ethynylphenyl)-L- homoserinate was prepared from Intermediate Ib as follows: To a solution of Intermediate Ib (694 mg, 1.50 mmol) in THF (10 mL) was added tetrabutylammonium fluoride (434 μL, 1.50 mmol) and the reaction mixture was stirred at RT for 15 minutes. The crude was poured into EtOAc (50 mL) and washed with water (3 x 50 mL) then brine (50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the desired product, m/z = 410.2 [M+Νa]+; 1H NMR (300 MHz, CDCl3) δ: 7.40 (2H, d, J=8.7 Hz), 6.82-6.77 (2H, m), 5.27-5.20 (IH, m), 4.50-4.41 (IH, m), 4.05 (2H, t, J=6.1 Hz), 2.38-2.20 (2H, m), 1.90- 1.79 (2H, m), 1.75-1.61 (6H, m), 1.45 (9H, s).
Intermediate Id - Cyclopentyl <9-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-cf]pyrimidin-5-yl}ethynyl)phenyl]-N- (te/"f-butoxycarbonyl)-L-homoserinate was prepared from Intermediate Ic as follows: To a solution of Intermediate Ic (275 mg, 0.62 mmol) in DCM (5 mL) were added Building Block A (240 mg, 0.62 mmol), TEA (86 μL, 0.62 mmol), tetrakis(triphenylphosphine) palladium (35 mg, 0.03 mmol) and copper iodide (11 mg, 0.06 mmol). The reaction mixture was heated 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 product was purified by flash chromatography (Heptane / EtOAc 6:4 to 4:6) to afford the desired product (253 mg, 58 %). m/z = 703/705 (3:1) [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 8.34 (IH, s), 7.43 (2H, d, J=8.9 Hz), 7.28 (IH, s), 7.15 (IH, s), 6.87-6.81 (2H, m), 5.48 (2H, s), 5.27-5.20 (IH, m), 4.44-4.37 (IH, m), 4.06 (2H, t, J=6.0 Hz), 3.78 (3H, s), 2.30 (3H, s), 2.26 (3H, s), 1.90-1.81 (2H, m), 1.76-1.64 (6H, m), 1.63-1.56 (2H, m), 1.45 (9H, s).
Example 1 was prepared from Intermediate Id as follows:
To Intermediate Id (253 mg, 0.36 mmol) was added 4M HCl/dioxane (2 mL) and the reaction mixture was stirred at RT for 1 hour. The solvent was removed under reduced pressure. Water (1 mL) was added and the residual solvent was removed by freeze-drying the sample for 18 hours. The desired product was obtained as the HCl salt (141 mg, 65 %). LCMS purity = 99 %; m/z = 603/605 (3:1) [M+H]+; 1H NMR (300MHz, J6-DMSO) δ: 8.63 (2H, br s), 7.63 (IH, s), 7.44 (2H, d, J=8.5 Hz), 6.95 (2H, d, J=8.7 Hz), 5.58 (2H, s), 5.23-5.13 (IH, m), 4.21-4.09 (3H, m), 3.98 (3H, s), 2.38 (3H, s), 2.31 (3H, s), 2.29-2.18 (2H, m), 1.90-1.72 (2H, m), 1.68-1.45 (6H, m).
The following examples were prepared using the same methodology as described for Example 1 :
Figure imgf000053_0001
Figure imgf000054_0003
The final deprotection step in Examples 2 and 4 was carried out at 0 0C in order to avoid hydrolysis of the tert-butyl ester.
Example 7 - Cyclopentyl O-[4-(2-{2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-£/|pyrimidin-5-yl}ethyl)phenyl]-L- homoserinate and
Example 8 - Cyclopentyl O-{4-[(Z)-2-{2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-c(]pyrimidin-5-yl}vinyl]phenyl}-L- homoserinate
^H2
Figure imgf000054_0001
Example 8
Figure imgf000054_0002
Example 8 resulted as the by-product of the reduction of Intermediate Id when the preparation of Example 7 was undertaken.
Scheme 7 - Methodology for the preparation of Example 7 and Example 8 from Intermediate Id:
Figure imgf000055_0001
Intermediate 7a - Cyclopentyl O-[4-(2-{2-amino-4-chloro-7-[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-J]pyrimidin-5-yl}ethyl)phenyl]-N-(tert- butoxycarbonyl)-L-homoserinate and Intermediate 8a - Cyclopentyl 0-{4-[(Z)-2-{2- amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3- d\ pyr im idin-5 -y 1 } viny l]pheny 1 } -N-(tert-butoxycarbony l)-L-homoserinate were prepared from Intermediate Id as follows:
To Intermediate Id (436 mg, 0.62 mmol) in EtOΗ/DCM 1/1 (10 mL) under N2 was added palladium hydroxide (168 mg, 1.2 mmol). The reaction mixture was degassed, hydrogen was added and the reaction was stirred at 80 0C for 18 hours. The catalyst was removed by filtration through a pad of Celite, the filtrate was concentrated under reduced pressure to give a mixture Intermediate 7a and Intermediate 8a. The mixture was carried forward to the next stage without separation. Example 7 and Example 8 were prepared from the mixture of Intermediate 7a and
Intermediate 8a as follows:
The mixture of Intermediate 7a and Intermdiate 8a (437 mg, 0.62 mmol) was treated with HCl in dioxane (4M, 1 mL) and stirred for 30 min at RT. The crude was concentrated under reduced pressure and the two products were purified by preparative
HPLC.
Example 7: 15 mg, 5 %; LCMS purity = 95 %; m/z = 607/609 (3:1) [M+H]+; 1H NMR
(300 MHz, CD3OD) δ: 8.16 (IH, s), 6.93 (2H, d, J=8.5 Hz), 6.65 (2H, d, J=8.7 Hz), 6.61 (IH, s), 5.26 (2H, s), 5.14-5.03 (IH, m), 4.00 (IH, t, J=6.4 Hz), 3.93 (2H, t, J=5.7
Hz), 3.84 (3H, s), 2.84-2.76 (2H, m), 2.72-2.64 (2H, m), 2.22 (3H, s), 2.16 (2H, q, J=6.0
Hz), 2.10 (3H, s), 1.75-1.61 (2H, m), 1.58-1.35 (6H, m).
Example 8: 26 mg, 8 %; LCMS purity = 92 %; m/z = 605/607 (3:1) [M+H]+; 1H NMR
(300 MHz, CD3OD) δ: 8.39 (IH, s), 7.24 (2H, d, J=8.7 Hz), 6.83-6.78 (3H, m), 6.72 (IH, d, J=12.1 Hz), 6.58 (IH, d, J=12.1 Hz), 5.45 (2H, s), 5.27-5.35 (IH, m), 4.26-4.13
(3H, m), 4.06 (3H, s), 2.45 (3H, s), 2.44-2.35 (2H, m), 2.29 (3H, s), 1.98-1.83 (2H, m),
1.81-1.57 (6H, m).
Example 9 - 0-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-^pyrimidin-5-yl}emynyl)phenyl]-L-homoserine
Figure imgf000056_0001
Scheme 9 - Methodology for the preparation of Example 9 from Example 1:
Figure imgf000057_0001
Example 1 Example 9
Example 9 - O-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-^pyrimidin-5-yl}ethynyl)phenyl]-L-homoserine was prepared from Example 1 as follows:
To Example 1 (50 mg, 0.082 mmol) in dry TΗF (1 mL) was added potassium trimethylsilanolate (76 mg, 0.59 mmol) and the reaction mixture was left stirring for 18 hours at RT under an atmosphere of nitrogen. The crude was concentrated under reduced pressure, MeOH was added (1 mL) to give a suspension, and the filtrate was purified by preparative ΗPLC. The desired product was isolated as a clear oil. LCMS purity = 100 %; m/z = 535/537 (3:1) [M+Η]+; 1H NMR (300 MHz, CD3OD) δ: 7.43 (2H, d, J=8.5 Hz), 7.30 (IH, s), 6.99 (2H, d, J=8.7 Hz), 5.51 (2H, s), 4.27-4.20 (2H, m), 4.19-4.14 (IH, m), 3.94 (3H, s), 2.50-2.44 (2H, m), 2.38 (6H, s).
The following examples were prepared using the same methodology as described for Example 9:
Figure imgf000058_0001
BIOLOGICAL ASSAYS
HSP90 enzyme assay
An HTRF (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, # 61 OSAXLB, lot: 089).
Unlabeled GM or compounds compete with the bio-GM for binding to HSP90 resulting in reduced fluorescence energy transfer/assay signal. 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, 4OnM 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 5OLVmI 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 4xlO4 cells / well in V-bottomed 96 well tissue culture treated plates and incubated at 37°C 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 37 0C 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 RPMI 1640 tissue culture media (Sigma). lOOμl is then plated in V-bottomed 96 well tissue culture treated plates. 2 Hours after the addition of the inhibitor in lOOμl of RPMI 1640 media, the blood is stimulated with LPS (E. CoIi strain 005 :B5, Sigma) at a final concentration of 100ng/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).
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 1 μM, Aprotinin O.lμM, 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 -8O0C 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 37°C in a Tris- HCl 25mM, 125mM NaCl buffer, pH 7.5 at 25°C. 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. lmm) 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 Range C: IC50 > 100OnM
Figure imgf000061_0001
Figure imgf000062_0001
NT = Not Tested.
NR = Not Relevant. Examples 9-13 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 imgf000063_0001
wherein:
R1 represents a hydrogen or halogen atom, or a cyano, nitro, -N3, Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkenyl, C2-S 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 Q4 alkyl, or R! represents a group of formula -COOH, -COORA, -CORA, -SO2RA, -CONH2, -SO2NH2, -CONHRA, -SO2NHRA, -CONRARB, -SO2NRARB, -OCONH2, -0C0NHRA, -0C0NRARB, -NHCORA, -NRBC0RA, -NHC00RA, -NRBC00RA, -NRBCOOH, -NHC00H-, -NHSO2RA, -NRBS02RA, -NHSO2ORA, -NR13SO2OH, -NHSO2H, -NRBSO2ORA, -NHCONH2, -NRAC0NH2, -NHCONHR8, -NRACONHRB, -NHC0NRARB or -NRACONRARB 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 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, Ci-6 alkyl, Ci_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 CM alkyl group or an unfused C6-Io 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, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cj-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 CM 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-, -Alk3-A2- or -Alk3-Alk5-;
AIk3 represents a bond or C1-4 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 Ci-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 bond or a Ci-6 alkylene, C2-6 alkenylene or C2-6 alkynylene group; and R represents a group of formula (X) or (Y):
Figure imgf000065_0001
(X) (Y) ;
- R11 represents a hydrogen atom or a Ci-6 alkyl, C3-7 carbocyclyl, Cβ-io aryl or 5- to 6-membered heteroaryl group, or a group of formula -(C=O)R12, -(C=O)OR12, or -(C=O)NR12 wherein R12 is a hydrogen atom or a Ci-6 alkyl group;
- ring D is a 5- to 6-membered heterocyclyl group wherein R7 is linked to a ring carbon adjacent the ring nitrogen shown, 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 group in which case the bond shown intersected by a wavy line may be from a ring atom in ring D or said second ring;
- R20 represents a hydrogen atom, a Ci-6 alkyl group or a group -L3 -B where L3 represents a bond or a Ci-6 alkylene and B represents a C6-I o aryl or 5- to 10-membered heteroaryl 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; and wherein, unless otherwise stated: the alkyl, alkenyl and alkynyl groups and moieties in R1, R2, R3, R11, R12, R20, L1, L3, AIk1, 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, C]-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 D, A1, A2, A3, B, R1, R2 , R11 and R20 are unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents selected from halogen atoms, and cyano, nitro, C1-4 alkyl, CM alkoxy, C2-4 alkenyl, C2-4 alkenyloxy, Ci-4 haloalkyl, C2-4 haloalkenyl, C1-4 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, -CONRARB, -SO2NRARB, -OCONH2, -0C0NHRA, -0C0NRARB, -NHCORA, -NRBCORA, -NHCOORA, -NRBC00RA, -NRBCOOH, -NHCOOH, -NHSO2RA, -NRBSO2RA, -NHS020RA, -NR3SO2OH, -NHSO2H, -NRBS020RA, -NHCONH2, -NRAC0NH2, -NHCONHR3, -NRAC0NHRB, -NHC0NRARB or
-NRAC0NRARB wherein RA and RB are the same or different and represent unsubstituted C]-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 CM 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 CM alkyl, C2-4 alkenyl, CM alkoxy, hydroxyl, C]-4 haloalkyl, C2-4 haloalkenyl, CM 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 CM alkyl, CM alkoxy, CM haloalkyl, CM 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 Ci-4 alkyl, Ci-4 alkoxy, CM 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 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; 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 Ci-4 alkyl, CM 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.
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, Ci-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, 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.
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 Cj-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, 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, 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 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 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 Cj-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; R represents a group of formula (X) or (Y); R1 ' represents a hydrogen atom or an unsubstituted Ci-4 alkyl group, or a group of formula -(C=O)R12, -(C=O)OR12, or -(C=O)NR12 wherein R12 is a hydrogen atom or an unsubstituted CM alkyl group; R20 represents a hydrogen atom or a Ci_6 alkyl group which is unsubstituted or substituted with one or two substituents which are the same or different and represent halogen, Ci-2 alkoxy, Ci-2 haloalkyl, hydroxyl, -COOR', -COONR'R", -SR' and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci-2 alkyl, or R20 represents a group of formula -L3-B where L3 is a bond or an unsubstituted Ci-4 alkylene group and B represents a phenyl or a 5- to 10-membered heteroaryl group which is unsubstituted or substituted with one, two or three unsubstituted substituents which are the same or different and represent halogen atoms, Ci-4 alkyl, Ci-2 alkoxy, Ci-2 alkylthio and hydroxy; ring D represents an unfused 5- to 6-membered heterocyclyl group wherein R7 is linked to a ring carbon adjacent the ring nitrogen shown; 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 CM alkyl, CM alkoxy, hydroxyl, -SR' or -NR'R" group wherein each R' and R" is the same or different and represents hydrogen or unsubstituted CM 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, CM alkoxy, hydroxyl, Ci-4 haloalkyl, C2-4 haloalkenyl, CM 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 CM alkyl,
CM alkoxy, CM haloalkyl, CM 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 Ci-4 alkyl, CM alkoxy, CM haloalkyl, CM 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 -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 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, Ci-4 haloalkyl, Ci-4 haloalkoxy, Cj-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; 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;
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 O or l ;
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 Cj-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, 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 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; R represents a group of formula (X) or (Y); - R11 represents a hydrogen atom or an unsubstituted Ci-4 alkyl group, or a group of formula -(C=O)R12, -(C=O)OR12, or -(C=O)NR12 wherein R12 is a hydrogen atom or an unsubstituted CM alkyl group; R20 represents a hydrogen atom or a Ci-6 alkyl group which is unsubstituted or substituted with one or two substituents which are the same or different and represent halogen, Ci-2 alkoxy, Ci-2 haloalkyl, hydroxyl, -COOR',
-COONR'R", -SR' and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci-2 alkyl, or R represents a group of formula -L3 -B where L3 is a bond or an unsubstituted Ci-4 alkylene group and B represents a phenyl or a 5- to 10-membered heteroaryl group which is unsubstituted or substituted with one, two or three unsubstituted substituents which are the same or different and represent halogen atoms, Ci-4 alkyl, Ci-2 alkoxy, Ci-2 alkylthio and hydroxy; ring D represents an unfused 5- to 6-membered heterocyclyl group wherein R7 is linked to a ring carbon adjacent the ring nitrogen shown; and - R7 is a group -COOH or an ester group which is hydroly sable 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 imgf000072_0001
wherein:
R1 represents a hydrogen or halogen atom or an unsubstituted group selected from CM alkyl, Ci-4 alkoxy, CM 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 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, Cj-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 Ci-2 alkyl;
L2 represents -AIk3-, -Alk3-A2- or -Alk3-Alk5-; AIk3 represents an unsubstituted Ci-3 alkylene, C2-3 alkenylene or C2-3 alkynylene group; AIk5 represents an unsubstituted CM 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 C1-4 alkyl, CM 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 CM 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, Ci-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, 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, and AIk6 represents an unsubstituted Ci-6 alkylene group;
R20 represents a hydrogen atom or a Ci-6 alkyl group which is unsubstituted or substituted with one or two substituents which are the same or different and represent halogen, Ci-2 alkoxy, Cj-2 haloalkyl, hydroxyl, -COOR',
-COONR'R", -SR' and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci-2 alkyl, or R20 represents a group of formula -L3 -B where L3 is a bond or an unsubstituted Ci-4 alkylene group and B represents a phenyl or a 5- to 10-membered heteroaryl group which is unsubstituted or substituted with one, two or three unsubstituted substituents which are the same or different and represent halogen atoms, CM alkyl, Ci-2 alkoxy, Ci-2 alkylthio and hydroxy
R11 represents a hydrogen atom or an unsubstituted CM 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.
10. A compound as claimed in claim 9 wherein x represents 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, Ci-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 CM 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.
13. A compound as claimed in any one of claims 1 to 12 which is (a) a pyrrolopyrimidine derivative of formula (IC) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof:
Figure imgf000074_0001
wherein: 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; 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, CM 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 -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 Ci-2 alkyl and
C)-2 alkoxy groups;
AIk1 represents an unsubstituted CM alkylene group; - R1 ' represents hydrogen or an unsubstituted Ci-2 alkyl group; and
R10 represents a hydrogen atom or an unsubstituted CM alkyl or C^ carbocyclyl group.
14. A compound as claimed in claim 13 wherein each Ra is the same or different and represents a halogen atom or an unsubstituted Ci-2 alkyl or Cj-2 alkoxy group.
15. A compound as claimed in claim 13 or claim 14 wherein R10 represents a hydrogen atom or an unsubstituted t-butyl or cyclopentyl group.
16. A compound as claimed in any one of the preceding claims which is selected from:
Cyclopentyl 0-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-(f]pyrimidin-5-yl}ethynyl)phenyl]-L-homoserinate; tert-Butyl O-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]- 7H-pyrrolo[2,3-J]pyrimidin-5-yl}ethynyl)phenyl]-L-homoserinate;
Cyclopentyl 5-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-
7Η-pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenoxy]-L-norvalinate; tert-Butyl 5-[4-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-
7H-pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenoxy]-L-norvalinate;
Cyclopentyl O-[3-({2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenyl]-L-homoserinate; Cyclopentyl 5-(4-{[2-amino-4-chloro-7-(pyridin-2-ylmethyl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]ethynyl}phenoxy)-L-norvalinate;
Cyclopentyl O-[4-(2-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}ethyl)phenyl]-L-homoserinate;
Cyclopentyl O-{4-[(Z)-2-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}vinyl]phenyl}-L-homoserinate;
O-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenyl]-L-homoserine;
5-[4-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenoxy]-L-norvaline; O-[3-({2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenyl]-L-homoserine;
5-(4-{[2-Amino-4-chloro-7-(pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5- yl]ethynyl}phenoxy)-L-norvaline;
O-[4-(2-{2-Amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H- pyrrolo[2,3-d]pyrimidin-5-yl}ethyl)phenyl]-L-homoserine.
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 inflammatory lung disease.
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. 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.
25. A method as claimed in claim 24 wherein the patient is suffering from or susceptible to (i) cancer, (ii) inflammation, (iii) a viral infection, or (iv) Alzheimer's disease.
26. A compound as claimed in any one of claims 1 to 16 for use in treating or preventing disorders mediated by HSP90.
27. A compound as claimed in claim 26 for use in the treatment or prevention of (i) cancer, (ii) inflammation, (iii) a viral infection, or (iv) Alzheimer's disease.
PCT/GB2009/002466 2008-10-17 2009-10-15 Pyrrolo [2, 3-d] pyrimidines as inhibitors of hsp90 Ceased WO2010043867A1 (en)

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US20050107343A1 (en) * 2003-09-18 2005-05-19 Conforma Therapeutics Corporation Pyrrolopyrimidines and related analogs as HSP90-inhibitors
WO2006105372A2 (en) * 2005-03-30 2006-10-05 Conforma Therapeutics Corporation Alkynyl pyrrolopyrimidines and related analogs as hsp90-inhibitors
WO2008049105A2 (en) * 2006-10-19 2008-04-24 Wyeth Sulfamoyl-containing derivatives and uses thereof

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US20050107343A1 (en) * 2003-09-18 2005-05-19 Conforma Therapeutics Corporation Pyrrolopyrimidines and related analogs as HSP90-inhibitors
WO2006105372A2 (en) * 2005-03-30 2006-10-05 Conforma Therapeutics Corporation Alkynyl pyrrolopyrimidines and related analogs as hsp90-inhibitors
WO2008049105A2 (en) * 2006-10-19 2008-04-24 Wyeth Sulfamoyl-containing derivatives and uses thereof

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CN106046047B (en) * 2016-05-26 2018-10-02 清华大学 The method for preparing phosphorylation serine phosphonic acids analogies

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