WO2012020215A1 - Amino-imidazolothiadiazoles destinés à être utilisés en tant qu'inhibiteurs de kinases protéiques ou lipidiques - Google Patents

Amino-imidazolothiadiazoles destinés à être utilisés en tant qu'inhibiteurs de kinases protéiques ou lipidiques Download PDF

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WO2012020215A1
WO2012020215A1 PCT/GB2011/001187 GB2011001187W WO2012020215A1 WO 2012020215 A1 WO2012020215 A1 WO 2012020215A1 GB 2011001187 W GB2011001187 W GB 2011001187W WO 2012020215 A1 WO2012020215 A1 WO 2012020215A1
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optionally substituted
alkyl
ring
group
methyl
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PCT/GB2011/001187
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Joaquín PASTOR FERNÁNDEZ
Guido Kurz
María del Rosario RICO FERREIRA
David SOILÁN RODRIGUEZ
Miguel Angel Ortega Soret
Wolfang Link
Obdulia Rabal Gracia
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Centro Nacional De Investigaciones Oncológicas (Cnio)
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of protein or lipid kinases (such as inhibitors of the phosphoinositide 3 ⁇ kinase (PI3 kinase) family, particularly the PI3K class I sub-type.
  • the compounds may also be useful as inhibitors of Flt3 and may optionally also be inhibitors of a PIM family kinase (e.g. PIM-3 and, especially PIM-1 ).
  • PIM family kinase e.g. PIM-3 and, especially PIM-1 .
  • the compounds are of potential utility in the treatment of diseases such as cancer.
  • the invention also relates to the use of such compounds as medicaments, to the use of such compounds for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells (or associated pathological conditions), to pharmaceutical compositions containing them, and to synthetic routes for their production.
  • PKs protein kinases
  • a large share of the oncogenes and proto-oncogenes involved in human cancers code for PKs.
  • the enhanced activities of PKs are also implicated in many non-malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.
  • Phosphatidylinositol 3-kinases are a family of lipid and serine/threonine kinases that catalyze the phosphorylation of the membrane lipid phosphatidylinositol (PI) on the 3'-OH of the inositol ring to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP 2 ) and phosphoinositol-3,4,5-triphosphate (PIP 3 ), which act as recruitment sites for various intracellular signalling proteins, which in turn form signalling complexes to relay extracellular signals to the cytoplasmic face of the plasma membrane.
  • PIP phosphoinositol-3-phosphate
  • PIP 2 phosphoinositol-3,4-diphosphate
  • PIP 3 phosphoinositol-3,4,5-triphosphate
  • PI3K isoforms categorized by their catalytic subunits, their regulation by corresponding regulatory subunits, expression patterns and signalling specific funtions ( ⁇ 1 10 ⁇ , ⁇ , ⁇ , ⁇ ) perform this enzymatic reaction (Exp. Cell. Res. 25 (1 ),. 239-54 (1999) by Vanhaesebroeck and Katso et al., 2001 , above).
  • the closely related isoforms p1 10a and ⁇ are ubiquitously expressed, while ⁇ and ⁇ are more specifically expressed in the haematopoietic cell system, smooth muscle cells, myocytes and endothelial cells (see e.g. Trends Biochem. Sci. 22 (7),. 267-72 (1997) by Vanhaesebroeck et al). Their expression might also be regulated in an inducible manner depending on the cellular, tissue type and stimuli as well as disease context. Inductibility of protein expression includes synthesis of protein as well as protein stabilization that is in part regulated by association with regulatory subunits.
  • Class la includes ⁇ 3 ⁇ , ⁇ 3 ⁇ and PI3K5. All of the class la enzymes are heterodimeric complexes comprising a catalytic subunit ( ⁇ 1 10 ⁇ , ⁇ 1 10 ⁇ or ⁇ 1 10 ⁇ ) associated with an SH2 domain containing p85 adapter subunit. Class la PI3Ks are activated through tyrosine kinase signalling and are involved in cell proliferation and survival. PI3Ka and ⁇ 3 ⁇ have also been implicated in tumorigenesis in a variety of human cancers. Thus, pharmacological inhibitors of PI3Ka and ⁇ 3 ⁇ are useful for treating various types of cancer.
  • ⁇ 3 ⁇ the only member of the Class lb PI3Ks, consists of a catalytic subunit p110y, which is associated with a p110 regulatory subunit.
  • ⁇ 3 ⁇ is regulated by G protein coupled receptors (GPCRs) via association with ⁇ subunits of heterotrimeric G proteins.
  • GPCRs G protein coupled receptors
  • ⁇ 3 ⁇ is expressed primarily in hematopoietic cells and cardiomyocytes and is involved in inflammation and mast cell function.
  • pharmacological inhibitors of ⁇ 3 ⁇ are useful for treating a variety of inflammatory diseases, allergies and cardiovascular diseases.
  • PIM-1 is the protooncogene activated by murine leucemia virus (Provirus Integration site for Moloney murine leucemia virus - MoMuLV) that induces T-cell lymphoma [Cuypers, H.T., et. al. Cell, 1984, 37, 141 -150].
  • the expression of the protooncogene produces a non-transmembrane serine/threonine kinase of 313 residues, including a kinase domain consisting of 253 amino acid residues.
  • Two isoforms are known through alternative initiation (p44 and p33) [Saris, C.J.M. et al. EMBO J. 1991 , 10, 655-664].
  • PIM-1 , PIM-2 and PIM-3 phosphorylate protein substrates that are important in cancer neogenesis and progression.
  • PIM-1 phosphorylates inter alia p21 , Bad, c-myb, Cdc 25A and elF4B (see e.g. Quian, K. C. et al, J. Biol. Chem. 2005, 280(7), 6130-6137, and references cited therein).
  • Two PIM-1 homologs have been described [Baytel, D. Biochem. Biophys. Acta 1998, 1442, 274-285; Feldman, J. et al. J. Biol. Chem. 1998, 273, 16535.16543].
  • PIM-2 and PIM-3 are respectively 58% and 69% identical to PIM-1 at the amino acid level.
  • PIM-1 is mainly expressed in thymus, testis, and cells of the hematopoietic system [Mikkers, H.; Nawijn, M.; Allen, J.; Brouwers, C; Verhoeven, E.; Jonkers, J.; Berns, Mol. Cell. Biol. 2004, 24, 6104; Bachmann, M.; Moray, T. Int. J. Biochem. Cell Biol. 2005, 37, 726-730. 61 15].
  • PIM-1 expression is directly induced by STAT (Signal Transducers and Activators of Transcription) transcription factors, and PIM-1 expression is induced by many cytokine signalling pathways such as interleukins (IL), granulocyte-macrophage colony stimulating factor (GM-CSF), a- and ⁇ -interferon, erythropoietin, and prolactin [Wang, Z et al.. J. Vet. Sci. 2001 , 2, 167-179].
  • IL interleukins
  • GM-CSF granulocyte-macrophage colony stimulating factor
  • erythropoietin erythropoietin
  • prolactin prolactin
  • PIM-1 has been implicated in lymphoma development. Induced expression of PIM-1 and the protooncogene c-myc synergise to increase the incidence of lymphomagenesis [Breuer, M. et al. Nature 1989, 340, 61-63; van Lohuizen M. et al. Cell, 1991 , 65, 737-752]. PIM-1 functions in cytokine signalling pathways and has been shown to play a role in T cell development [Schmidt, T. et al. EMBO J. 1998, 17, 5349-5359; Jacobs, H. et al.
  • PIM-1 also appears to be necessary for IL-3-stimulated growth in bone marrow-derived mast cells [Domen, J. et al., Blood, 1993, 82, 1445-1452] and survival of FDCP1 cells after IL-3 withdrawal [Lilly, M. et al., Oncogene, 1999, 18, 4022-4031]. Additionally, control of cell proliferation and survival by PIM-1 may be effected by means of its phosphorylation of the well-established cell cycle regulators cdc25 [Mochizuki, T. et al., J. Biol. Chem. 1999, 274, 18659-18666] and/or p21 (Cip1/WAF1 ) [Wang Z. et al. Biochim.
  • mice deficient for all three PIM genes showed an impaired response to hematopoietic growth factors and demonstrated that PIM proteins are required for efficient proliferation of peripheral T lymphocyes.
  • PIM function is required for efficient cell cycle induction of T cells in response to synergistic T-cell receptor and IL-2 signalling.
  • a large number of interaction partners and substrates of PIM-1 have been identified, suggesting a pivotal role for PIM-1 in cell cycle control, proliferation, as well as in cell survival.
  • chromosomal translocation of PIM-1 leads to overexpression of PIM-1 in diffuse large cell lymphoma.
  • a number of missense mutations in PIM-1 have been reported in lymphomas of the nervous system and AIDS-induced non-Hodgkins' lymphomas that probably affect PIM-1 kinase activity or stability [Pasqualucci, L. et al, Nature 2001 , 412, 341-346; Montesinos-Rongen, M. et al., Blood 2004, 103, 1869-1875; Gaidano, G. et al., Blood 2003, 102, 1833-184].
  • the strong linkage between reported overexpression data and the occurrence of PIM-1 mutations in cancer suggests a dominant role of PIM-1 in tumorigenesis.
  • Flt3 kinase FMS-like tyrosine kinase 3
  • AML acute myelogenous leukemia
  • Flt3 inhibitors may also be useful in the treatment of inflammation, as they have been shown to be effective in treating airway inflammation in mice, using a murine asthma model (Edwan ef a/., J.
  • targeted therapies are becoming more important. That is, therapy that has the effect of interfering with specific target molecules that are linked to tumor growth and/or carcinogenesis. Such therapy may be more effective than current treatments (e.g. chemotherapy) and less harmful to normal cells (e.g. because chemotherapy has the potential to kill normal cells as well as cancerous cells).
  • current treatments e.g. chemotherapy
  • targeted therapies may be selective (i.e. it may inhibit a certain targeted molecule more selectively as compared to other molecular targets, e.g. as described hereinafter), may have the benefit of reducing side effects and may also have the benefit that certain specific cancers can be treated (also selectively). The latter may in turn also reduce side effects.
  • B represents -S-, -S(O)- or -S0 2 -;
  • R 2 represents heteroaryl optionally substituted by one or more substituents selected from E ;
  • R a and R b are defined as follows:
  • heterocycloaikyl e.g. 3- to 7-membered heterocycloalkyl
  • ring(s) i.e. heterocycloalkyl and optional further ring
  • R 5a , R 5b and R 5c are independently hydrogen or d-e alkyl optionally substituted by one or more fluoro atoms, or, R 5b and R 5c are linked together to form a 5- or 6-membered heterocycloalkyl group);
  • heterocycloalkyl group(s) in which the heteroatoms are selected from sulfur and, preferably, nitrogen and/or in which the heterocycloalkyl group is attached to the acyclic alkyl group via a single carbon atom, which heterocycloalkyl group may comprise a further ring as defined by Z 3 ; and/or
  • T 1a represents a direct bond, -C(O)-, -S(0) 2 -, -C(0)N(R 1g )- or -C(0)0-;
  • R 1a , R 1 b , R 1c , R 1d , R 1e , R 1f , R 1g and R 1i independently represent hydrogen or d.
  • 6 alkyl optionally substituted by one or more substituents selected from halo (e.g. fluoro), -CN, -OR 6a and -N(R 6b )R 6c ) or aryl or heteroaryl (both of which are optionally substituted by one or more substituents selected from halo, -CN and Ci-6 alkyl); or
  • R 1 represents Ci -6 alkyl optionally substituted by one or more substituents selected from halo, -N(R 2h )R 3h and -OR 4h ;
  • R 2 , R 3 , R 4h , R 6a , R 5 and R 6c independently represent hydrogen or d. 6 alkyl;
  • y represent hydrogen or C i . 6 alkyl optionally substituted by one or more fluoro atoms
  • Z 1 , Z 2 , Z 3 , Z 3a and Z 4 each independently represent a moiety that results in a further ring sytem (that is present in addition to the "first ring" i.e. in addition to the monocyclic cycloalkyi or heterocycloalkyi groups, to which that Z 1 to Z 4 group is attached) that is formed by that Z 1 to Z 4 group representing:
  • a bridged structure or a second ring that is either a 3- to 12-membered saturated carbocyclic ring or or a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen and nitrogen, and which second ring is linked together with the first ring via a single carbon atom common to both rings (i.e. forming a spiro-cycle);
  • R 3 represents hydrogen, halo or C -3 alkyl optionally substituted by one or more fluoro atoms; each Q 1 , Q 2 , Q 3 , Q 4 and Q 5 independently represents, on each occasion when used herein:
  • 1 ,2-relationship or to atoms that are two atoms apart, i.e. in a 1 ,3-relationship) may be linked together to form (e.g. along with the requisite nitrogen atom to which they may be attached) a 4- to 20- (e.g. 4- to 12-) membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, e.g. (a) heteroatom(s) selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (e.g.
  • each E 1 , E 2 , E 3 , E 4 E 5 , E 6 and E 7 independently represents, on each occasion when used herein:
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • esters or amides we include salts of pharmaceutically acceptable esters or amides, and solvates of pharmaceutically acceptable esters, amides or salts.
  • pharmaceutically acceptable esters and amides such as those defined herein may be mentioned, as well as pharmaceutically acceptable solvates or salts.
  • esters and amides of the compounds of the invention are also included within the scope of the invention.
  • Pharmaceutically acceptable esters and amides of compounds of the invention may be formed from corresponding compounds that have an appropriate group, for example an acid group, converted to the appropriate ester or amide.
  • pharmaceutically acceptable esters (of carboxylic acids of compounds of the invention) include optionally substituted C 6 alky!, C 5 .i 0 aryl and/or C 5 . 10 aryl-C ⁇ e alkyl- esters.
  • R z and R 22 independently represent optionally substituted C 1 -6 alkyl, C 5 . 10 aryl, or C5-10 aryl-Ci. 6 alkylene-.
  • 0 1-6 alkyl groups that may be mentioned in the context of such pharmaceutically acceptable esters and amides are not cyclic, e.g. linear and/or branched.
  • prodrug of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
  • parenteral administration includes all forms of administration other than oral administration.
  • Prodrugs of compounds of the invention may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent.
  • Prodrugs include compounds of the invention wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” p. 1-92, E!esevier, New York-Oxford (1985).
  • compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention.
  • Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the "active" compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of the invention.
  • certain compounds of the invention including, but not limited to compounds of formula I in which there is a W 1 group present (i.e. T represents C3.12 cycloalkyl substituted by at least one W 1 substituent), which represents -0-C(0)-R h (e.g. -0-C(0)-CH 2 -NH 2 ) may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds (which may or may not be other compounds of the invention) that do possess pharmacological activity as such (e.g. corresponding compounds in which W represents -OH).
  • W 1 group i.e. T represents C3.12 cycloalkyl substituted by at least one W 1 substituent
  • -0-C(0)-R h e.g. -0-C(0)-CH 2 -NH 2
  • Such compounds may also be described as "prodrugs".
  • Compounds of the invention may contain double bonds and may thus exist as E (entussi) and Z (zusammen) geometric isomers about each individual double bond.
  • Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g. if a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention).
  • tautomer or tautomeric form
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganisation of some of the bonding electrons.
  • Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e.
  • a resolution for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
  • All stereoisomers including but not limited to diastereoisomers, enantiomers and atropisomers) and mixtures thereof (e.g. racemic mixtures) are included within the scope of the invention.
  • all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, C , 13 N, 5 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 CI, 123 l, and 1 5 l.
  • Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and C
  • Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability.
  • isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Scheme 1 and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.
  • C -q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched- chain, and/or cyclic (so forming a C 3-q -cycloalkyl group).
  • Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic.
  • Such alkyl groups may also be saturated or, when there is a sufficient number (i.e.
  • C 1-q alkylene (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number of carbon atoms, be saturated or unsaturated (so forming, for example, an alkenylene or alkynylene linker group).
  • Such Ci. q alkylene groups may be branched (if sufficient number of atoms), but are preferably straight-chained.
  • q cycloalkyl groups may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups).
  • Such cycloalkyl groups may be saturated or unsaturated containing one or more double bonds (forming for example a cycloalkenyl group). Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic.
  • halo when used herein, preferably includes fluoro, chloro, bromo and iodo.
  • Heterocycloalkyi groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyi groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between 3 and 20 (e.g. between three and ten, e.g between 3 and 8, such as 5- to 8-).
  • Such heterocycloalkyl groups may also be bridged.
  • such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2 .
  • q heterocycloalkenyl (where q is the upper limit of the range) group.
  • q heterocycloalkyl groups that may be mentioned include 7- azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1 Jheptanyl, 6-azabicyclo[3.2.1 ]- octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1 ,3-dioxolanyl), dioxanyl (including ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imid
  • heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heterocycloalkyl groups may also be in the N- or S- oxidised form.
  • Heterocycloalkyl mentioned herein may be stated to be specifically monocyclic or bicyclic.
  • bicyclic refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring.
  • bridged e.g. when employed in the context of cycloalkyl or heterocycloalkyl groups refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).
  • Aryl groups that may be mentioned include C 6 . 2 o, such as C 6 -12 (e.g. C 6 . 0 ) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 12 (e.g. 6 and 10) ring carbon atoms, in which at least one ring is aromatic. Ce-10 aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydro- naphthyl.
  • the point of attachment of aryl groups may be via any atom of the ring system. For example, when the aryl group is polycyclic the point of attachment may be via atom including an atom of a non-aromatic ring. However, when aryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring.
  • heteroaryl when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S.
  • Heteroaryl groups include those which have between 5 and 20 members (e.g. between 5 and 10) and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group).
  • the heteroaryl group is polycyclic the point of attachment may be via atom including an atom of a non-aromatic ring.
  • heteroaryl groups are polycyclic (e.g.
  • heteroaryl groups that may be mentioned include 3,4-dihydro-1 H-isoquinolinyl, 1 ,3-dihydroisoindolyl, 1 ,3-dihydroisoindolyl (e.g. 3,4- dihydro-1 H-isoquinolin-2-yl, 1 ,3-dihydroisoindol-2-yl, 1 ,3-dihydroisoindol-2-yl; i.e.
  • heteroaryl groups that are linked via a non-aromatic ring or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3- benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1 ,3- benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1 ,3- benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2/- -1 ,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2, 1 ,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl,
  • heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • the heteroaryl group is monocyclic or bicyclic.
  • the heteroaryl may be consist of a five-, six- or seven-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another a five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring).
  • Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.
  • a group e.g. a d. 12 alkyl group
  • substituents e.g. selected from E 5
  • those substituents e.g. defined by E 5
  • such groups may be substituted with the same substituent (e.g. defined by E 5 ) or different substituents (defined by E 5 ).
  • E 1 to E 7 this will be understood by the skilled person to mean E , E 2 , E 3 , E 4 , E 5 , E 6 and E 7 , inclusively.
  • Z 1 to Z 4 will be understood to mean Z 1 , Z 2 , Z 3 , Z 3a and Z 4 inclusively
  • Q 1 to Q 5 will be understood to mean Q 1 , Q 2 , Q 3 , Q 4 and Q 5 , inclusively. All individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).
  • R 2 represents a polycyclic (e.g. bicyclic) heteroaryl group
  • the first ring attached to the requisite polycyclic (e.g. bicyclic) core of compounds of formula I
  • the first ring preferably contains at least one heteroatom (and the other rings may or may not contain a heteroatom), which polycyclic heteroaryl group is optionally substituted as hereinbefore defined;
  • R 2 preferably represents a monocyclic hetereoaryl group, optionally substituted as defined herein.
  • Preferred compounds include those in which R 2 represents a moiety of formula IA:
  • R , R 2 , R 2c and R independently represent hydrogen or a substituent selected from E 1 ;
  • R 2a to R 2d represent a substituent selected from E 1 (and the other two or three represent hydrogen);
  • E 1 represents C1.3 alkyl (optionally substituted by Q 21 ; so forming e.g. a -CF 3 group), or, E 1 represents Q 20 ;
  • Q 20 represents -N(R 20 )R 21 ;
  • Q 21 represents halo (e.g. fluoro);
  • R 20 and R 2 independently represent hydrogen.
  • R 1 groups that may be mentioned include esters e.g. in which R 1h represents methyl or ethyl or aminoesters, i.e. in which R h represents -CH 2 -NH 2 .
  • esters e.g. in which R 1h represents methyl or ethyl or aminoesters, i.e. in which R h represents -CH 2 -NH 2 .
  • Such compounds may be prodrugs of corresponding compounds in which W 1 represents -OH.
  • R a and R are linked together as hereinbefore defined.
  • one of R a and R b represents T and the other is as hereinbefore defined.
  • heterocycloalkyl group in which the heteroatoms are selected nitrogen; and in which the heterocycloalkyl group is preferably not attached to the acyclic alkyl group via a single carbon atom, which heterocycloalkyl group may comprise a further ring as defined herein by Z 3 (but preferably does not comprise such a further ring); or
  • T 1 represents (i) heterocycloalkyi (optionally substituted as defined herein) or (iii) cycloalkyl (which comprises a further Z 4 ring and is optionally substituted, as defined herein) (either embodiments (i) or (iii) may be preferred); and
  • T 1 represents substituted acyclic C 12 alkyl as defined herein (most preferably, when T 1 represents acyclic C t _ 12 alkyl, then it is substituted with a heterocycloalkyi group as the requisite substituent).
  • T 1 represents acyclic d.12 alkyl
  • it is preferably substituted by (a) one -N(R 5a )-T-R 5t> substituent; (b) one 4- to 8- (e.g. 5- or 6-) membered heterocycloalkyi group (containing one or two nitrogen heteroatoms) and which does not comprise a further ring (as defined by Z 3 ; or (c) one C3.12 (e.g.
  • C3- 7 ) cycloalkyl group which comprises a further ring as defined by Z 3a , which acyclic CM 2 alkyl group, 4- to 8-membered heterocycloalkyi group and C3-12 cycloalkyl group (and further Z 3a ring) are optionally substituted by one or more substituents selected from Q 2 .
  • Z 3a which acyclic CM 2 alkyl group, 4- to 8-membered heterocycloalkyi group and C3-12 cycloalkyl group (and further Z 3a ring) are optionally substituted by one or more substituents selected from Q 2 .
  • Any of the foregoing embodiments (a), (b) and (c) may be preferred, however, it is particularly preferred that when T 1 represents acyclic C-,.- ⁇ alkyl, then it is preferably substituted by (a) or, especially, (c).
  • R a and R b represents T 1 and the other represents hydrogen or optionally substituted C 1- 2 alkyl, then, for the specific embodiment (B), it is preferred that:
  • T 1 represents C3-12 cycloalkyl substituted by one W 1 substituent
  • W 1 represents -OR 1i or, preferably, -N(R 1a )-T 1a -R lb (in which T 1a , R 1a , R 1 and R 1c are as defined herein);
  • R 2 is substituted by one (requisite) substituent as defined herein (e.g. by fluoro, chloro, -CN, -N(R 5e )R 5f , -C(0)R 5g or d. 6 alkyl (optionally, and preferably, substituted by one or more fluoro atoms)) and is further optionally substituted by one or more E 1 substituents (but, preferably, R 2 has a maximum of two substituents, e.g. one requisite substituent as hereinbefore defined and one optional substituent defined by E 1 ).
  • R a and R represents T 1 and the other represents hydrogen or optionally substituted Ci -12 alkyl
  • W 1 represents -0-C(0)-R 1h , which compounds may metabolise to corresponding compounds in which W represents -OH (hence, compounds in which W represents -0-C(0)-R 1h may be prodrugs).
  • each Q 1 , Q 2 , Q 3 , Q 4 and Q 5 independently represents, on each occasion when used herein:
  • R 10a , R 11a and R 1 a may be linked together as defined herein (although they are preferably not linked);
  • any two E 1 , E 2 , E 3 , E 4 , E 5 , E 6 and/or E 7 groups may be linked together (e.g. any two E 3 substituents may also be linked together as defined herein, for example when attached to the same or, preferably, adjacent carbon atoms), but (e.g. any two E , E 2 , E 4 , E 5 , E 6 and/or E 7 ) are preferably not linked together;
  • aryl e.g. phenyl; preferably unsubstituted, but which may be substituted by one to three J 5 groups
  • halo e.g. fluoro
  • each R 50 , R 51 , R 52 and R 53 substituent independently represents, on each occasion when used herein, hydrogen or C 1-6 (e.g. d-3) alkyl optionally substituted by one or more substituents selected from fluoro;
  • R 60 , R 61 and R 62 independently represent hydrogen or -3 (e.g. C 1-2 ) alkyl optionally substituted by one or more fluoro atoms.
  • Preferred optional substituents on the requisite R 2 ring include:
  • halo e.g. fluoro, chloro or bromo
  • d-e alkyl
  • alkyl group may be cyclic, part-cyclic, unsaturated or, preferably, linear or branched (e.g. d-4 alkyl (such as ethyl, n-propyl, isopropyl, t- butyl or, preferably, n-butyl or methyl), all of which are optionally substituted with one or more halo (e.g.
  • fluoro groups (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl) or substituted with an aryl, heteroaryl or heterocycloalkyl group (which themselves may be substituted with one or more -OR z1 , -C(0)R z2 ) -C(0)OR z3 , -N(R z4 )R z5 , -S(0) 2 R z6 , -S(0) 2 N(R z7 )R z8 ; -N(R z9 )-C(0)-R z1 °, -C(0)-N(R z 1 )R z12 , -N(R z9 )-C(0)-N(R z1 °) and/or -N(R z9 )-S(0) 2 - N(R Z1 °) substituents);
  • aryl e.g. phenyl
  • substitutent may also be present on an alkyl group, thereby forming e.g. a benzyl group
  • each R z1 to R z12 independently represents, on each occasion when used herein, H or alkyl (e.g. ethyl, n-propyl, f-butyl or, preferably, n-butyl, methyl, isopropyl or cyclopropylmethyl (i.e. a part cyclic alkyl group)) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a trifluoromethyl group).
  • any two R z groups e.g. R z4 and R z5 ), when attached to the same nitrogen heteroatom may also be linked together to form a ring such as one hereinbefore defined in respect of corresponding linkage of R 10a and R 11a groups.
  • More preferred compounds of the invention include those in which:
  • Z ⁇ Z 2 , Z 3 , Z 3a and Z 4 independently represent either: (a) a 4- to 7- (e.g. 5- or 6-) membered saturated heterocycloalkyl group fused to the first ring (so forming e.g. a 5,5-fused or 6,6-fused bicycle); or (b) a 4- to 7- (e.g. 4- to 6-)-membered saturated carbocyclic group or a 4- to 7- (e.g. 4- to 6-)-membered saturated heterocycloalkyl group linked together with the first 4- to 7- (e.g. 4- to 6-)- membered ring via a single common carbon atom to form a spiro-cycle;
  • each R 10a , R 11a and R 12a independently represent, on each occasion when used herein, hydrogen or d-12 (e.g. d. 6 ) alkyl;
  • any relevant pair of R 0a , R 11a and R 1 a is preferably not linked together;
  • any relevant pair of R 20 , R 21 and R 22 is preferably not linked together;
  • each J 1 , J 2 , J 3 , J 4 , J 5 and J 6 independently represents Q 30 ;
  • each Q 30 and Q 31 independently represents, on each occasion when used herein: halo, -N(R 50 )R 51 , -OR 50 or d- 3 (e.g. d. 2 ) alkyl optionally substituted by one or more fluoro atoms;
  • R 60 , R 61 and R 62 independently represent hydrogen or C 1-3 alkyl optionally substituted by one or more fluoro atoms.
  • R a and R include those in which:
  • R a and R b represents hydrogen or d. 3 alkyl (e.g. methyl) and the other represents T 1 (in another instance, both R a and R b may represent T 1 ) in which T 1 may represent:
  • optionally substituted C 3 . 12 e.g. C 4 . 7
  • cycloalkyl which comprises a further (optionally substituted) ring as defined by Z 4
  • optionally substituted heterocycloalkyi optionally comprising a further ring
  • the squiggly line represents the point of attachment to the requisite imidazodiathiazole of the compound of formula I
  • R a t> (if present) represents R a or R
  • E 2 , Q 1 , Q 2 and Q 3 each independently represent one or more optional E 2 , Q 1 , Q 2 and/or Q 3 substituents (where they are depicted as 'floating'; or Q 2 may represent a requisite substituent) or the depiction of those substituents in brackets signifies that that substituent is optionally present, and may therefore be absent (i.e. N-(E 2 ) may signify N-E 2 or N-H).
  • the cyclic groups depicted i.e.
  • T represents -C(0)0- or, preferably, a direct bond, -S(0) 2 - or -C(0)-N(R c )-;
  • R a represents hydrogen;
  • R 5b represents hydrogen or C,. 6 (e.g. C 1- ) alkyi
  • R 5c represents hydrogen
  • R 5b and R 5c are linked together to form a 5- or, preferably, 6-membered heterocydoalkyl group (e.g. piperazinyl optionally substituted by methyl);
  • T 1a represents a direct bond, -C(O)-, -S(0) 2 -, -C(0)-N(R 19 )- or -C(0)0-;
  • R 1b represents hydrogen or C v3 alkyi (e.g. methyl);
  • R a represents hydrogen, C 1-6 (e.g. C 1-4 ) alkyi or aryl (e.g. phenyl; optionally substituted by one or more substituents selected from fluoro);
  • R 1c represents Ci. 2 alkyi (e.g. ethyl) optionally substituted by fluoro (so forming e.g. a -CH 2 -CH 2 F moiety);
  • R 1d represents alkyi (e.g. ethyl);
  • R ' represents hydrogen or d. 3 alkyi (e.g. methyl);
  • R 19 represents hydrogen
  • R represents Ci -3 alkyi (e.g. methyl) optionally substituted by -NH 2 (so forming e.g. -CH 2 -NH 2 );
  • Q 4 represents C -3 alkyi (e.g. methyl);
  • E 1 represents Q 20 or C 1-6 (e.g. d- 3 ) alkyi (e.g. methyl) optionally substituted by one or mere Q 21 (e.g. fluoro) substituents (so forming e.g. -CF 3 );
  • E 2 represents Q 20 or Ci. 3 alkyi (e.g. methyl) optionally substituted by one or more (e.g. one) Q 21 group;
  • R 10a represents hydrogen or d_6 (e.g. C ⁇ ) alkyl or heterocycloalkyl (e.g. a 4- to 6-membered group such as azetidinyl; optionally substituted by one or more substituents selected from E 5 );
  • E 5 represents Q 20 ;
  • R 20 represents hydrogen or C ⁇ e (e.g. C ⁇ ) alkyl (e.g. ierf-butyi or methyl);
  • R 21 represents hydrogen or C 1-6 (e.g. C 1-4 ) alkyl
  • R 20 and R 2 are (e.g. in the case of -N(R 20 )R 21 ) linked together to form a 5- or 6-membered ring optionally containing one further nitrogen or oxygen heteroatom (e.g. so forming piperazinyl) and which ring is optionally substituted by one or more C 3 alkyl (e.g. methyl) group;
  • R 22 represents hydrogen
  • R 2 represents heteroaryl (e.g. a monocyclic 5- or, preferably 6-membered group, preferably containing one or two (e.g. one) nitrogen heteroatom(s), so forming e.g. pyridyl such as 3-pyridyl) substituted by one or two E 1 substituents;
  • heteroaryl e.g. a monocyclic 5- or, preferably 6-membered group, preferably containing one or two (e.g. one) nitrogen heteroatom(s), so forming e.g. pyridyl such as 3-pyridyl) substituted by one or two E 1 substituents;
  • At least E 1 substituent is present at the meta or para position (if substitution is available on that position) relative to the point of attachment of any 6-membered heteroaryl group;
  • R 2a to R 2d represent hydrogen
  • R 2a to R 2d represents a substituent selected from E 1 ;
  • R 2b , R 2c and R 2d represent a substituent other than hydrogen, i.e. there is at least one substituent that is meta or para relative to the point of attachment of the 3-pyridyl group;
  • E 1 represents Q 20 or d. 3 alkyl (e.g. methyl) optionally substituted by one or more Q 21 groups (so forming e.g. a -CF 3 group);
  • Q 20 when E 1 represents Q 20 , then Q 20 preferably represents halo or, more preferably, -CN, -OR 20 , -N(R 20 )R 21 or -C(0)R 20 (in which instances, R 20 and R 21 may represent hydrogen or C 1-3 alkyl optionally substituted by one or more fluoro atoms); when E 1 represents Q 20 , then Q 20 more preferably represents a 5- or 6-membered heterocyc oalkyl group (optionally substituted by d. 3 alkyl) or, preferably, -CN, -OR 20 or -N(R 20 )R 21 ;
  • Q 21 represents halo (e.g. fluoro);
  • E 1 groups include -CN, -CH 3 , -CF 3 , -OCF 3l -OH, -OCH 3 , -N(CH 3 ) 2 , -NH 2 , 1-piperazinyl, 4-methyl-1-piperazinyl and -C(0)-CH 3 (e.g. -NH 2 , -CF 3l -OCH 3 , -CN, -CH 3 , 1-piperazinyl and 4-methyl-1-piperazinyl; the especially preferred substituents are -CF 3 and -NH 2 , for instance R 2 may represent 5-CF 3 ,6- NH 2 -pyrid-3-yl).
  • R 3 represents hydrogen, halo (e.g chloro) or methyl
  • R a and R b are linked together as hereinbefore defined, or, one of R a and R represents hydrogen or C 1-3 alkyl (e.g. methyl) and the other represents T ;
  • R a and R when R a and R are linked together, they preferably:
  • Z 1 represents either: (a) a 4- to 7- (e.g. 5- or 6-) membered saturated heterocycloalkyi (e.g. containing one or two nitrogen heteroatoms) group fused to the first ring (so forming e.g. a 5,5-fused bicycle or a 6,6-fused bicycle); or (b) a 4- to 7- (e.g. 4- to 6-)-membered saturated carbocyclic group (e.g. cyclobutyl) or a 4- to 7- (e.g. 4- to 6-)-membered saturated heterocycloalkyi group (e.g. pyrrolidinyl or, preferably, piperidinyl) linked together with the first ring 4- to 7- (e.g. 4- to 6-)- membered via a single common carbon atom to form a spiro-cycle (e.g. a [5.3], [3.5] or [5.5] spiro-cycle);
  • E 2 represents Q 20 or C 1-6 (e.g. Ci -3 ) alkyl (e.g. methyl) optionally substituted by one or more (e.g. one) substituent(s) selected from Q 21 ;
  • T may represent: (i) heterocycloalkyl (e.g. a 4- to 6-membered group, containing one or two heteroatoms preferably selected from nitrogen and oxygen, so forming e.g. piperidinyl) optionally substituted by one or more (e.g. one) Q substituent(s);
  • heterocycloalkyl e.g. a 4- to 6-membered group, containing one or two heteroatoms preferably selected from nitrogen and oxygen, so forming e.g. piperidinyl
  • C 4 . 7 e.g. C 4 . 6
  • cycloalkyl e.g. cyclohexyl
  • Z 4 which rings are optionally substituted by one or more (e.g. one) Q 3 substituent(s);
  • acyclic alkyl e.g. methyl or ethyl substituted by one of either: a 5- or preferably 6-membered heterocycloalkyl group containing one or two heteroatoms preferably selected from nitrogen (so forming e.g. piperidinyl or piperazinyl) optionally substituted by one or more (e.g. one) Q 2 substituent(s); a C 3 . 12 cycloalkyl group, which is substituted by Q 2 ; or -N(R 5a )-T-R 5t> ; or
  • C 4 . 7 e.g. C 4 . 6
  • cycloalkyl e.g cyclohexyl substituted by one or more (e.g. one) substituent selected from W 1 as hereinbefore defined (and further optionally substituted by one or more substituents as defined by Q 4 ), provided that R 2 is substituted by at least one certain substituent as defined hereinbefore;
  • Z 3a and Z' independently represent a 4- to 7- (e.g. 4- to 6-) membered saturated heterocycloalkyl group (e.g. piperidinyl) that is attached to the first ring via a common carbon atom to form, together with the first ring to which these second rings are attached, a spiro-cycle (e.g. a [3.5] spiro-cycle, such as 7-aza- spiro[3.5]nonane-2-yl);
  • a spiro-cycle e.g. a [3.5] spiro-cycle, such as 7-aza- spiro[3.5]nonane-2-yl
  • E 2 substituents that are preferred include -C(0)0-iert-butyl, -C(0)0-CH 3 , -C(0)OCH 2 CH 3 , -OH, -C(0)0-ethyl, -CH 2 -N(H)-C(0)-0-fert-butyl, -N(H)-C(0)-0-tert-butyl, -NH 2 , -C(0)OH and -CH 2 -NH 2 ;
  • E 1 groups include -CN, -CF 3 , -CH 3 , -OCFs, -OH, -OCHs, -NH 2 , -N(CH3) 2 , 1 -piperazinyl, 4-methy 1-1 -piperazinyl and -C(0)-CH 3 (particularly preferred are -OCH 3 , -CH 3 and, especially, -NH 2 and -CF 3 ).
  • particularly preferred compounds of the invention include those in which:
  • R 2 represents heteroaryl (e.g. a monocyclic 5- or, preferably 6-membered group, preferably containing one or two (e.g. one) nitrogen heteroatom(s), so forming e.g. pyridyl such as 3-pyridyl) substituted by one or two E substituents;
  • heteroaryl e.g. a monocyclic 5- or, preferably 6-membered group, preferably containing one or two (e.g. one) nitrogen heteroatom(s), so forming e.g. pyridyl such as 3-pyridyl) substituted by one or two E substituents;
  • R 2 represents a moiet of formula IA:
  • R , R , R and R independently represent hydrogen or a substituent selected from E 1 ;
  • R 2a to R 2d represent a substituent selected from E 1 (and the other two or three represent hydrogen);
  • E 1 represents C,. 3 alkyl (optionally substituted by Q 21 ; so forming e.g. a -CF 3 group), or, E represents Q 20 ;
  • R 3 represents hydrogen or halo (e.g chloro);
  • R a and R b are linked together as hereinbefore defined, or, more preferably, one of R a and R represents hydrogen or C 1-3 alkyl (e.g. methyl) and the other represents T 1 ;
  • one further heteroatom e.g. oxygen or, preferably, nitrogen; so forming e.g. tetrahydropyrimidinyl
  • ring is preferably monocyclic (i.e. it may not contain a further ring as defined by Z ) and is are optionally substituted
  • R a and R b may be linked together to form: when ones of R a and R represents hydrogen or C 1 .3 alkyl (e.g. methyl) (or in some instances, T 1 ) and the other represents T 1 , then T may represent:
  • heterocycloalkyi e.g. a 6-membered group, preferably containing one heteroatom (e.g. a nitrogen heteroatom), so forming e.g. 4-piperidinyl
  • Q 1 substituent(s) in which Q 1 is preferably iocated on the nitrogen heteroatom, e.g. it may represent:
  • C 4 . 7 e.g. C 4 . 6
  • cycloalkyl e.g. cyclohexyl
  • Z 4 which rings are optionally substituted by one or more (e.g. one) Q 3 substituent(s) (but is preferably not substituted by a Q 3 substituent), e.g. it may represent:
  • acyclic C 1-4 alkyl e.g. C 1-2 alkyl such as methyl
  • acyclic C 1-4 alkyl e.g. C 1-2 alkyl such as methyl
  • Q 2 may represent an optional or requisite substituent (as applicable) (most preferably when T represents acyclic alkyl, then it is substituted with a heterocycloalkyi group as the requisite substituent); or (iv) (e.g. in a separate embodiment of the invention), C4-7 (e.g. C 4 . 6 ) cycloalkyl (e.g cyclohexyl) substituted by one or more (e.g. one) substituent selected from W 1 (and further optionally substituted by one or more substituents as defined by Q 4 ), provided that R 2 is substituted by at least one (e.g.
  • R 2 represents 3-pyridyl
  • R 2c or R 2 preferably represents the E 1 substituent as defined herein
  • R 2 may further be optionally substituted as defined herein
  • W 1 is located at the 4-position of a cyclohexyl group
  • Z 4 represents a 4- to 6- (e.g. 6-) membered saturated heterocycloalkyi group (e.g. piperidinyl) that is attached to the first ring via a common carbon atom to form, together with the first ring to which these second rings are attached, a spiro-cycle (e.g. a [3 5] spiro-cycle, such as 7-aza-spiro[3.5]nonane-2-yl);
  • a spiro-cycle e.g. a [3 5] spiro-cycle, such as 7-aza-spiro[3.5]nonane-2-yl
  • W 1 represents -N(R 1a )-T 1a -R 1b , -0-C(0)-R 1 or -OR 1 ';
  • T 1a represents a direct bond, -C(O)- or -S(0) 2 -;
  • R 1a , R b and R 1 ' independently represent hydrogen or d. 6 (e.g. C 1 .3) alkyl (e.g methyl) (or R 3 may represent aryl, e.g. phenyl, optionally substituted by one or more halo, e.g. fluoro, atoms);
  • R 1tl represents Ci. 6 (e.g. C ⁇ ) alkyl (e.g. methyl) optionally substituted by one or more substituents selected from -N(R 2h )R 3h (e.g. -NH 2 , so forming e.g. -CH 2 -NH 2 ); specific W 1 substituents include -N(H)-S(0) 2 -phenyl (e.g.
  • R ' represents hydrogen or C 1-3 alkyl (e.g. methyl);
  • Q 1 represents -S(O) 2 R 10a ;
  • Q 2 represents -OR 10a ;
  • Q 4 represents C z alkyl (e.g. methyl);
  • E 1 repre ents Q 20 or C 1-6 (e.g. C 1-3 ) alkyl (e.g. methyl) optionally substituted by one or more Q 21 (e.g. fluoro) substituents (so forming e.g. -CF 3 );
  • Q 21 e.g. fluoro
  • Q 20 when E 1 represents Q 20 , then Q 20 preferably represents -N(R 20 )R 21 ;
  • Q 21 represents halo (e.g. fluoro);
  • R 10a rep-esents hydrogen or Ci. 6 (e.g. C 1- ) alkyl or heterocycloalkyi (e.g. azetidiny ; optionally substituted by one or more substituents selected from E 5 );
  • E 5 represents Q 20 ;
  • R 20 represents C 1-3 alkyl (e.g. methyl) or, preferably, hydrogen;
  • R 21 represents C 1-6 (e.g. C 1-4 ) alkyl or, preferably, hydrogen;
  • R 22 represents hydrogen
  • Particularly preferred compounds of the invention include those of the examples described hereinafter.
  • I. 1 represents a suitable leaving group, such as iodo, bromo, chloro or a sulfonate group (e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 or -OS(0) 2 PhMe), and B, R 2 and R 3 are as hereinbefore defined, with a compound of formula III,
  • This reaction may be carried out under microwave irradiation reaction conditions or, alternatively, the reaction may be performed in the absence of other reagents such as catalyst, base and even solvent.
  • Such a reaction may be accompanied by a rearrangement reaction, for instance if the compound of formula III is 2,7-diaza- spiro[3.5]nonane (or the 7-protected derivative thereof, e.g. the corresponding 7- carboxylic acid tert-butyl ester thereof), then such a spiro-cyclic amine may undergo ring-opening to form a 1-aza-bicyclo[2.2.1]hept-4-ylmethyl-amino moiety (i.e. a bridged amine) so forming a corresponding compound of formula I in which there is a 1-aza-bicyclo[2.2.1]hept-4-ylmethyl-amino moiety present;
  • L 3 represents a suitable leaving group such as one hereinbefore defined in respect of L (e.g. halo, such as chloro or, preferably, bromo), and R 3 , R b , B and R 3 are as hereinbefore defined, with a compound of formula V, L"-R 2 V wherein l_ 4 represents a suitable group, such as -B(OH) 2 , -B(OR w ) 2 or -Sn(R wx )3, in which each R w independently represents a C ⁇ e alkyl group, or, in the case of -B(OR w ) 2 , the respective R"TM groups may be linked together to form a 4- to 6- membered cyclic group (such as a 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl group), thereby forming e.g.
  • halo such as chloro or, preferably, bromo
  • a pinacolato boronate ester group (or L 4 may represent iodo, bromo or chloro, provided that L 3 and L 4 are mutually compatible) and R 2 is as hereinbefore defined.
  • the reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2 , Pd(Ph 3 P) 4 (i.e.
  • a suitable catalyst system e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2 , Pd(Ph 3 P) 4 (i.e.
  • L 5 represents a suitable leaving group, such as one hereinbefore defined in respect of the V definition (e.g. chloro or, preferably, bromo), and R* represents R 10a or R 20 (or R 50 ; as appropriate), provided that they do not represent hydrogen (and preferably represent Cm or C ⁇ e al yl optionally substituted as defined herein), under reaction conditions known to those skilled in the art, the reaction may be performed at around room temperature or above (e.g. up to 40-180°C), optionally in the presence of a suitable base (e.g.
  • Compounds of formula IV or VII in which L 3 represents halo may be prepared by reaction of a compound of formula VIII, wherein X a represents -N(R a )R b (in the case of preparation of compounds of formula IV) or L 1 (in the case of preparation of compounds of formula VII) and L 1 , R a , R and R 3 are as hereinbefore defined, with a source of halide ions, for instance an electrophile that provides a source of iodide ions includes iodine, diiodoethane, diiodotetrachloroethane or, preferably, /V-iodosuccinimide, a source of bromide ions includes /V-bromosuccinimide and bromine, and a source of chloride ions includes /V-chlorosuccinimide, chlorine and iodine monochloride.
  • a source of halide ions for instance an electrophile that provides
  • Other compounds of formula IV may also be prepared under standard conditions, for instance such as those described herein.
  • L 3 represents a sulfonate group
  • reaction of a compound corresponding to a compound of formula IV but in which L 3 represents -OH with an appropriate sulfonyl halide under standard reaction conditions, such as in the presence of a base (e.g. as hereinbefore described in respect of preparation of compounds of formula I (process step (iii)).
  • Ci-CH 2 -C(0)-R X wherein R preferably represents hydrogen or C-,. 3 alkyl optionally substituted by one or more fluoro atoms (most preferably R 3a represents hydrogen or methyl), under standard conditions known to those skilled in the art.
  • R preferably represents hydrogen or C-,. 3 alkyl optionally substituted by one or more fluoro atoms (most preferably R 3a represents hydrogen or methyl), under standard conditions known to those skilled in the art.
  • the compound of formula X may already be present in water, and hence, the reaction may be performed in the presence of water as a solvent, optionally in the presence of a further solvent, such as an alcohol (e.g. n-butanol), for example at room temperature or, preferably, elevated temperature such as at reflux.
  • an alcohol e.g. n-butanol
  • halide ions e.g. in the case of bromide ions, bromine
  • a suitable solvent such as an alcohol (e.g. methanol)
  • a suitable base such as a weak inorganic base, e.g. sodium bicarbonate.
  • a reducing agent such as a chemoselective one mentioned above or NaBH 4 , AIH , or the like
  • a reducing agent such as sodium cyanaoborohydride (i.e. overall a reductive amination)
  • amide coupling reactions i.e. the formation of an amide from a carboxylic acid (or ester thereof), for example when R 2 represents -C(0)OH (or an ester thereof), it may be converted to a -C(O)N(R 0b )R 11b group (in which R 10b and R 11 are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g. when R 2 represents -C(O)OH) be performed in the presence of a suitable coupling reagent (e.g.
  • R 2 represents an ester (e.g. -C(0)OCH 3 or -C(0)OCH 2 CH 3 ), in the presence of e.g.
  • the -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), and, in all cases, the relevant compound is reacted with a compound of formula HN(R 103 )R , 1a (in which R 10a and R 11a are as hereinbefore defined), under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere);
  • acyl halide e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like
  • nucleophilic substitution reactions where any nucleophile replaces a leaving group, e.g. methylsulfonylpiperazine may replace a chloro leaving group;
  • alkylation, acylation or sulfonylation reactions which may be performed in the presence of base and solvent (such as those described hereinbefore in respect of preparation of compounds of formula I, process step (iv) above, for instance, a -N(H)- or -OH or -NH 2 (or a protected version of the latter) moiety may be alkylated, acylated or sulfonylated by employing a reactant that is an alkyl, acyl or sulfonyl moiety attached to a leaving group (e.g. C 1-6 alkyl-halide (e.g. ethylbromide), d. 6 alkyl-C(0)-halide (e.g.
  • a leaving group e.g. C 1-6 alkyl-halide (e.g. ethylbromide), d. 6 alkyl-C(0)-halide (e.g.
  • H 3 C-C(0)CI an anhydride (e.g. H 3 C- C(0)-0-C(0)-CH 3 , i.e. "-0-C(0)-CH 3 " is the leaving group), dimethylformamide (i.e. -N(CH 3 ) 2 is the leaving group) or a sulfonyl halide (e.g. H 3 C-S(0) 2 CI) and the like);
  • anhydride e.g. H 3 C- C(0)-0-C(0)-CH 3 , i.e. "-0-C(0)-CH 3 " is the leaving group
  • dimethylformamide i.e. -N(CH 3 ) 2 is the leaving group
  • a sulfonyl halide e.g. H 3 C-S(0) 2 CI
  • a urea functional group by reaction of an amine (e.g. a secondary amine, such as a -NH moiety that is a part of a heterocyclic group) with an alkyl isocyanate (e.g. ethyl isocyanate) to form a -N-C(0)-N(H)-alkyl (e.g. -N-C(0)-N(H)-CH 2 CH 3 moiety), which transformation may be performed in the presence of a suitable solvent (e.g. acetonitrile) and base (e.g. N,N- diisopropylethylamine);
  • a suitable solvent e.g. acetonitrile
  • base e.g. N,N- diisopropylethylamine
  • R a , R b , R 2 , R 3 and B in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations or nitrations. Such reactions may result in the formation of a symmetric or asymmetric final compound of the invention or intermediate.
  • the precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.
  • transformation steps include: the reduction of a nitro or azido group to an amino group; the hydrolysis of a nitrile group to a carboxylic acid group; and standard nucleophilic aromatic substitution reactions, for example in which an iodo-, preferably, fluoro- or bromo-phenyl group is converted into a cyanophenyl group by employing a source of cyanide ions (e.g. by reaction with a compound which is a source of cyano anions, e.g. sodium, copper (I), zinc or potassium cyanide, optionally in the presence of a palladium catalyst) as a reagent (alternatively, in this case, palladium catalysed cyanation reaction conditions may also be employed).
  • a source of cyanide ions e.g. by reaction with a compound which is a source of cyano anions, e.g. sodium, copper (I), zinc or potassium cyanide, optionally in the presence of a palladium catalyst
  • transformations that may be mentioned include: the conversion of a halo group (preferably iodo or bromo) to a 1-alkynyl group (e.g. by reaction with a 1- alkyne), which latter reaction may be performed in the presence of a suitable coupling catalyst (e.g. a palladium and/or a copper based catalyst) and a suitable base (e.g. a tri-(Ci.
  • a suitable coupling catalyst e.g. a palladium and/or a copper based catalyst
  • a suitable base e.g. a tri-(Ci.
  • 6 alkyl)amine such as triethylamine, tributylamine or ethyldiisopropylamine
  • introduction of amino groups and hydroxy groups in accordance with standard conditions using reagents known to those skilled in the art; the conversion of an amino group to a halo, azido or a cyano group, for example via diazotisation (e.g. generated in situ by reaction with NaN0 2 and a strong acid, such as HCI or H 2 S0 4 , at low temperature such as at 0°C or below, e.g. at about -5°C) followed by reaction with the appropriate nucleophile e.g.
  • diazotisation e.g. generated in situ by reaction with NaN0 2 and a strong acid, such as HCI or H 2 S0 4 , at low temperature such as at 0°C or below, e.g. at about -5°C
  • reaction with the appropriate nucleophile e.g.
  • a source of the relevant anions for example by reaction in the presence of a halogen gas (e.g. bromine, iodine or chlorine), or a reagent that is a source of azido or cyanide anions, such as NaN 3 or NaCN; the conversion of -C(0)OH to a -NH 2 group, under Schmidt reaction conditions, or variants thereof, for example in the presence of HN 3 (which may be formed in by contacting NaN 3 with a strong acid such as H 2 S0 4 ), or, for variants, by reaction with diphenyl phosphoryl azide ((PhO) 2 P(0)N 3 ) in the presence of an alcohol, such as ferf-butanol, which may result in the formation of a carbamate intermediate; the conversion of -C(0)NH 2 to -NH 2 , for example under Hofmann rearrangement reaction conditions, for example in the presence of NaOBr (which may be formed by contacting NaOH and Br 2 ) which may result in the formation of a
  • Compounds of the invention bearing a carboxyester functional group may be converted into a variety of derivatives according to methods well known in the art to convert carboxyester groups into carboxamides, N-substituted carboxamides, ⁇ , ⁇ -disubstituted carboxamides, carboxylic acids, and the like.
  • the operative conditions are those widely known in the art and may comprise, for instance in the conversion of a carboxyester group into a carboxamide group, the reaction with ammonia or ammonium hydroxide in the presence of a suitable solvent such as a lower alcohol, dimethylformamide or a mixture thereof; preferably the reaction is carried out with ammonium hydroxide in a methanol/dimethyl- formamide mixture, at a temperature ranging from about 50°C to about 100°C.
  • Analogous operative conditions apply in the preparation of N-substituted or N,N- disubstituted carboxamides wherein a suitable primary or secondary amine is used in place of ammonia or ammonium hydroxide.
  • carboxyester groups may be converted into carboxylic acid derivatives through basic or acidic hydrolysis conditions, widely known in the art.
  • amino derivatives of compounds of the invention may easily be converted into the corresponding carbamate, carboxamido or ureido derivatives.
  • Compounds of the invention may be isolated from their reaction mixtures using conventional techniques (e.g. recrystallisations).
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenylmethyleneoxycarbonyl (Fmoc) and 2,4,4-trimethylpentan-2-yl (which may be deprotected by reaction in the presence of an acid, e.g. HCI in water/alcohol (e.g. MeOH)) or the like.
  • an acid e.g. HCI in water/alcohol (e.g. MeOH)
  • the need for such protection is readily determined by one skilled in the art.
  • the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
  • a compound of the invention for use as a pharmaceutical and/or in isolated (i.e. ex vivo) form.
  • Compounds of the invention may inhibit protein or lipid kinases, such as a PI3 kinase (especially a class I PI3K), for example as may be shown in the tests described below (for example, the test for PI3Ka inhibition described below) and/or in tests known to the skilled person.
  • the compounds of the invention may also inhibit Flt3.
  • the compounds of the invention may be useful in the treatment of those disorders in an individual in which the inhibition of such protein or lipid kinases (e.g. PI3K, particularly class I PI3K, and/or Flt3) is desired and/or required (for instance compounds of the invention may inhibit PI3K, particularly class I PI3K and, optionally, may also inhibit Flt3).
  • compounds of the invention may inhibit both PI3K (e.g. class I PI3K, also referred to as PI3Ka) and Flt3 (such compounds may be referred to herein as "dual inhibitors”.
  • compounds of the invention may also inhibit a PIM family kinase (e.g. PIM--1 , PIM-2 and/or PIM-3; in particular, PIM-1 and/or PIM-3 and, especially PIM-1 ).
  • PIM family kinase e.g. PIM--1 , PIM-2 and/or PIM-3; in particular, PIM-1 and/or PIM-3 and, especially PIM-1 .
  • certain compounds of the invention may exhibit “triple inhibition", for instance, they may inhibit PI3-K (e.g. PI3-Ka), Flt3 and a PIM family kinase (e.g. PIM-2 and/or, especially PIM-1 and/or PIM-3; the most preferred PIM family kinase is PIM-1 ).
  • Such compounds may be referred to herein as "triple inhibitors” and are essentially “dual inhibitors" as hereinbefore defined, which further inhibit a PIM family kinase (e.g. PIM
  • inhibitor may refer to any measurable reduction and/or prevention of catalytic kinase (e.g. PI3K, particularly class I PI3K, Flt3 and/or a PIM family kinase) activity.
  • the reduction and/or prevention of kinase activity may be measured by comparing the kinase activity in a sample containing a compound of the invention and an equivalent sample of kinase (e.g. PI3 , particularly class I PI3K, Flt3 and/or a PIM family kinase) in the absence of a compound of the invention, as would be apparent to those skilled in the art.
  • the measurable change may be objective (e.g.
  • Compounds of the invention may be found to exhibit 50% inhibition of a protein or lipid kinase (e.g. PI3 , such as class I PI3K, and/or Flt3) at a concentration of 100 ⁇ or below (for example at a concentration of below 50 ⁇ , or even below 10 ⁇ , such as below 1 ⁇ ), when tested in an assay (or other test), for example as described hereinafter, or otherwise another suitable assay or test known to the skilled person.
  • PI3 protein or lipid kinase
  • PIM family kinases e.g. PIM1-, PIM-2 and/or PIM-3 (in particular PIM-3 and, especially P!M-1 ), for instance the compounds of the invention may further inhibit a PIM family kinase.
  • Compounds of the invention are thus expected to be useful in the treatment of a disorder in which a protein or lipid kinase (e.g. PI3K, such as class I PI3 , and/or Flt3, and, optionally (e.g.
  • a PIM family kinase is known to play a role and which are characterised by or associated with an overall elevated activity of that kinase (due to, for example, increased amount of the kinase or increased catalytic activity of the kinase).
  • compounds of the invention are expected to be useful in the treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with the protein or lipid kinase (e.g. PI3K, such as class I PI3K, and/or Flt3 and, optionally (e.g. the compounds of the invention further inhibit), a PIM family kinase).
  • diseases/disorders include cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders and neurological disorders.
  • the disorders/conditions that the compounds of the invention may be useful in treating hence includes cancer (such as lymphomas, solid tumours or a cancer as described hereinafter), obstructive airways diseases, allergic diseases, inflammatory diseases ⁇ such as asthma, allergy and Chrohn's disease), immunosuppression (such as transplantation rejection and autoimmune diseases), disorders commonly connected with organ transplantation, AIDS- related diseases and other associated diseases.
  • cancer such as lymphomas, solid tumours or a cancer as described hereinafter
  • obstructive airways diseases such as lymphomas, solid tumours or a cancer as described hereinafter
  • allergic diseases e.g. asthma, allergy and Chrohn's disease
  • immunosuppression such as transplantation rejection and autoimmune diseases
  • disorders commonly connected with organ transplantation AIDS- related diseases and other associated diseases.
  • Other associated diseases that may be mentioned (particularly due to the key role of kinases in the regulation of cellular proliferation) include other cell proliferative disorders and/or non- malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, bone disorders, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • non- malignant diseases such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, bone disorders, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • cardiovascular disease cardiovascular disease
  • stroke diabetes
  • diabetes hepatomegaly
  • Alzheimer's disease cystic fibrosis
  • hormone-related diseases immunodeficiency disorders
  • destructive bone disorders infectious diseases
  • conditions associated with cell death thrombin-induced platelet aggregation
  • chronic myelogenous leukaemia liver disease
  • pathologic immune conditions involving T cell activation and CNS disorders.
  • the compounds of the invention may be useful in the treatment of cancer. More, specifically, the compounds of the invention may therefore be useful in the treatment of a variety of cancer including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including non-small cell cancer and small cell lung cancer), esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, skin, squamous cell carcinoma, testis, genitourinary tract, larynx, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small ceil lung carcinoma, small cell lung carcinoma, lung adenocarcinoma, bone, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papilliary carcinoma, seminona, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary
  • protein or lipid kinases may also be implicated in the multiplication of viruses and parasites. They may also play a major role in the pathogenesis and development of neurodegenerative disorders. Hence, compounds of the invention may also be useful in the treatment of viral conditions, parasitic conditions, as well as neurodegenerative disorders.
  • a disease e.g. cancer or another disease as mentioned herein
  • a disease which is associated with the inhibition of protein or lipid kinase (e.g. PI3K, such as class I PI3K, and/or Flt3 and, optionally, a PIM family kinase), i.e. where such inhibition is desired and/or required (for example, a method of treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with protein or lipid kinases, e.g.
  • protein or lipid kinase e.g. PI3K, such as class I PI3K, and/or Flt3 and, optionally, a PIM family kinase
  • PI3K such as class I PI3K, and/or Flt3 and, optionally, a PIM family kinase
  • Patients include mammalian (including human) patients.
  • the method of treatment discussed above may include the treatment of a human or animal body.
  • effective amount refers to an amount of a compound, which confers a therapeutic effect on the treated patient.
  • the effect may be objective (e.g. measurable by some test or marker) or subjective (e.g. the subject gives an indication of or feels an effect).
  • Compounds of the invention may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • the type of pharmaceutical formulation may be selected with due regard to the intended route of administration and standard pharmaceutical practice.
  • Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.
  • Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques and/or in accordance with standard and/or accepted pharmaceutical practice.
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1 % (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1 :99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
  • the amount of compound of the invention in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
  • the invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Compounds of the invention may also be combined with other therapeutic agents that are inhibitors of protein or lipid kinases (e.g. PI3K, such as class I PI3K, Flt3, a PI family kinase (e.g.
  • PI -1, PIM-2- and/or PI -3 PI-1, PIM-2- and/or PI -3
  • EGFR EGFR
  • mTOR mTOR
  • MEK MEK
  • useful in the treatment of a cancer and/or a proliferative disease Compounds of the invention may also be combined with other therapies (e.g. radiation).
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • a pharmaceutically-acceptable adjuvant, diluent or carrier Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
  • a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
  • the invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with the other therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
  • the two components of the kit of parts may be: (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or
  • compounds of the invention may be administered at varying therapeutically effective doses to a patient in need thereof.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe.
  • the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
  • Administration may be continuous or intermittent (e.g. by bolus injection).
  • the dosage may also be determined by the timing and frequency of administration. In the case of oral or parenteral administration the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of the invention.
  • the medical practitioner or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Compounds of the invention may have the advantage that they are effective inhibitors of protein or lipid kinases (e.g. PI3K, such as class I PI3K, and/or Flt3 and, optionally, a PIM family kinase).
  • compounds of the invention may inhibit (e.g. selectively) certain protein or lipid kinases (e.g. PI3K, such as class I PI3K), without exhibiting inhibition (or significant inhibition) of other protein or lipid kinases.
  • the compounds of the invention may selectively inhibit only one protein or lipid kinase (e.g. PI3K, such as class I PI3K).
  • Compounds of the invention may also be "dual inhibitors”, e.g. they may inhibit both PI3-K (such as class I PI3-K) and Flt3. Further, advantageously, certain compounds of the invention may also be “triple inhibitors”, e.g. in addition to inhibiting PI3- (such as class I PI3- ) and Flt3, they may also inhibit a PIM family kinase (e.g. PI -3 and/or, especially, PIM-1). Such dual inhibitors and especially triple inhibitors may have the advantage that they are more efficacious in treating certain diseases (such as those mentioned herein).
  • dual inhibitors and especially triple inhibitors may have the advantage that they are more efficacious in treating certain diseases (such as those mentioned herein).
  • Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above- stated indications or otherwise.
  • pharmacokinetic profile e.g. higher oral bioavailability and/or lower clearance
  • Compounds of the invention may also benefit from improved metabolic stability or improved activity.
  • Such metabolic stability may be tested in standard methods known to those skilled in the art and may constitute an improvement over the known compounds in this respect
  • Compounds of the invention may be beneficial as they are medicaments with targeted therapy, i.e. which target a particular molecular entity by inferring or inhibiting it (e.g. in this case by inhibiting one or more protein or lipid kinases as hereinbefore described). Compounds of the invention may therefore also have the benefit that they have a new effect (for instance as compared to known compounds in the prior art), for instance, the new effect may be a particular mode of action or another effect resultant of the targeted therapy.
  • Targeted therapies may be beneficial as they may have the desired effect (e.g. reduce cancer, by reducing tumor growth or carcinogenisis) but may also have the advantage of reducing side effects (e.g.
  • compounds of the invention may selectively target particular protein or lipid kinases (e.g. the ones described herein) compared to other known protein or lipid kinases (as may be shown experimentally hereinafter). Accordingly, compounds of the invention may have the advantage that certain, specific, cancers may be treated selectively, which selective treatment may also have the effect of reducing side effects.
  • Compounds of the invention may have the advantage that they may exhibit multiple kinase inhibitory activity. In this respect, advantageously, compounds of the invention may be considered as multi-targeted kinase inhibitors. Compounds of the invention that exhibit single selectivity for a kinase may have the additional benefit that they exhibit less side effects, whereas compounds of the invention that exhibit multiple kinase selectivity may have the additional benefit that they exhibit better potency and/or efficacy.
  • the compounds of the invention may have the benefit that they inhibit multiple targets (or even multiple pathways).
  • compounds of the invention may be considered to have an improved kinase inhibition cross-reactivity profile, e.g. by being selective against multiple kinases of therapeutic interest, for instance compared to compounds known in the prior art.
  • Compounds of the invention may therefore additionally act on other key kinases, thereby allowing single-agent administration (or, potentially, combination products with reduced dosages) and providing the associated benefits, e.g. reducing the risk of drug-drug interactions, etc.
  • PI3 kinase activity of compounds of the invention is possible by a number of direct and indirect detection methods.
  • Certain exemplary compounds described herein were prepared, characterized, and tested for their PI3K binding activity and in vitro activity against tumor cells.
  • the range of PI3K binding activities was about 1 n to about 50 ⁇ (i.e. certain compounds of the examples/invention had PI3K binding activity IC 5o values of less than 10 nM). See Table below.
  • the kinase activity was measured by using the commercial ADP HunterTM Plus assay available from DiscoveR* (#33-016), which is a homogeneous assay to measure the accumulation of ADP, a universal product of kinase activity.
  • the enzyme, PI3K p1 10a/p85q was purchased from Carna Biosciences (#07CBS- 0402A).
  • the assay was done following the manufacturer recommendations with slight modifications: Mainly the kinase buffer was replace by 50 mM HEPES, pH 7.5, 3 mM MgCI 2 , 100 mM NaCl, 1 mM EGTA, 0.04% CHAPS, 2 mM TCEP and 0.01 mg/ml BGG.
  • the PI3K was assayed in a titration experiment to determine the optimal protein concentration for the inhibition assay.
  • serial 1 :5 dilutions of the compounds were added to the enzyme at a fixed concentration (2.5 ⁇ g/ml).
  • the enzyme was preincubated with the inhibitor and 30 ⁇ PIP 2 substrate (P9763, Sigma) for 5 min and then ATP was added to a final 50 ⁇ concentration. Reaction was carried out for 1 hour at 25°C. Reagent A and B were sequentially added to the wells and plates were incubated for 30 min at 37 °C.
  • Cell culture The cell lines are obtained from the American Type Culture Collection (ATCC). U20S (human osteosarcoma) is cultured in Dulbecco's modified Eagle's medium (DME ). PC3 (human prostate carcinoma), MCF7 (human breast cardinoma), HCT116 (human colon carcinoma), 768-0 (human neuroblastoma), U251 (human glyoblastoma) are grown in RPMI. All media are supplemented with 10% fetal bovine serum (FBS) (Sigma) and antibiotics- antimycotics. Cells are maintained in a humidified incubator at 37°C with 5% C0 2 and passaged when confluent using trypsin/EDTA.
  • DME Dulbecco's modified Eagle's medium
  • PC3 human prostate carcinoma
  • MCF7 human breast cardinoma
  • HCT116 human colon carcinoma
  • 768-0 human neuroblastoma
  • U251 human glyoblastoma
  • FBS fetal bovine serum
  • U2foxRELOC and U2nesRELOC assay The U2nesRELOC assay and the U2foxRELOC assay have been described. Briefly, cells are seeded at a density of 1.0* 10 5 cells/ml into black-wall clear-bottom 96-well microplates (BD Biosciences). After incubation at 37°C with 5% CC1 ⁇ 2 for 12 hours, 2 ⁇ of each test compound are transferred from the mother plates to the assay plates. Cells are incubated in the presence of the compounds for one hour. Then cells are fixed and the nucleus stained with DAPI (Invitrogen). Finally the plates are washed with 1X PBS twice and stored at 4°C before analysis.
  • DAPI Invitrogen
  • Image acquirement and processing Assay plates are read on the BD PathwayTM 855 Bioimager equipped with a 488/10 nm EGFP excitation filter, a 380/10 nm DAPI excitation filter, a 515LP nm EGFP emission filter and a 435LP nm DAPI emission filter. Images are acquired in the DAPI and GFP channels of each well using 10x dry objective. The plates are exposed 0.066 ms (Gain 31 ) to acquire DAPI images and 0.55 ms (Gain 30) for GFP images.
  • the BD Pathway Bioimager outputs its data in standard text files. Data are imported into the data analysis software BD Image Data Explorer.
  • the nuclear/cytoplasmic (Nuc/Cyt) ratios of fluorescence intensity are determined by dividing the fluorescence intensity of the nucleus by the cytoplasmic.
  • a threshold ratio of greater than 1.8 is employed to define nuclear accumulation of fluorescent signal for each cell. Based on this procedure we calculate the percentage of cells per well displaying nuclear translocation or inhibition of nuclear export. Compounds that induce a nuclear accumulation of the fluorescent signal greater than 60% of that obtained from wells treated with 4nM LMB are considered as hits.
  • AKT phosphorylation Inhibition-Western Blot Analysis Subconfluent cells are incubated under different conditions and are washed twice with TBS prior to lysis. Lysis buffer is added containing 50 mM Tris HCI, 150 m NaCI, 1 % NP-40, 2mM Na 3 V0 4 , 100 mM NaF, 20 mM Na 4 P 2 0 7 and protease inhibitor cocktail (Roche Molecular Biochemicals). The proteins are resolved on 10% SDS-PAGE and are transferred to nitrocellulose membrane (Schleicher & Schuell, Dassel, Germany).
  • the membranes are incubated overnight at 4°C with antibodies specific for Akt, phospho-Ser-473-Akt (Cell Signaling Technology) and a-tubulin (Sigma), they are washed and then incubated with IRDye800 conjugated anti- mouse and Alexa Fluor 680 goat anti-rabbit IgG secondary antibodies. The bands are visualized using an Odyssey infrared imaging system (Li-Cor Biosciences).
  • the compounds are tested on 96-well trays.
  • Cells growing in a flask are harvested just before they became confluent, counted using a haemocytometer and are diluted down with media adjusting the concentration to the required number of cells per 0.2 ml (volume for each well).
  • Cells are then seeded in 96- well trays at a density between 1000 and 4000 cells/well, depending of the cell size. Cells are left to plate down and grow for 24 hours before adding the drugs.
  • Drugs are weighed out and diluted with DMSO to get them into solution to a concentration of 10mM. From here a "mother plate" with serial dilutions is prepared at 200X the final concentration in the culture.
  • the final concentration of DMSO in the tissue culture media should not exceed 0.5%.
  • the appropriate volume of the compound solution (usually 2 microlitres) is added automatically (Beckman FX 96 tip) to media to make it up to the final concentration for each drug.
  • the medium is removed from the cells and replaced with 0.2 ml of medium dosed with drug.
  • Each concentration is assayed in triplicate.
  • Two sets of control wells are left on each plate, containing either medium without drug or medium with the same concentration of DMSO.
  • a third control set is obtained with the cells untreated just before adding the drugs (seeding control, number of cells starting the culture). Cells are exposed to the drugs for 72 hours and then processed for MTT colorimetric read-out.
  • the biochemical assay to measure FLT3 activity relies on the ADP Hunter assay kit (DiscoveRx Corp., Cat. # 90-0077), that determines the amount of ADP as direct product of the kinase enzyme activity. Assay conditions were as indicated by the kit manufacturers with the following adaptations for the kinase activity step:
  • ABLtide substrate peptide EAIYAAPFAKKK
  • DMSO concentration below 2% during the kinase reaction Assays were performed in either 96 or 384-well plates (corning 3575 or 3573).
  • the final outcome of the coupled reactions provided by the kit is the release of the fluorescent product Resorufin and has been measured with a multilabel HTS counter VICTOR V or ENVISION (PerkinElmer) using an excitation filter at 544 nm and an emission filter at 580 nm.
  • the biochemical assay to measure PIM-1 activity relies on the ADP Hunter assay kit (DiscoveRx Corp., Cat. # 90-0077), that determines the amount of ADP as direct product of the kinase enzyme activity.
  • the enzyme has been expressed and purified in-house as a recombinant human protein with a C-terminal histidine tag. The protein is active and stable. Assay conditions were as indicated by the kit manufacturers with the following adaptations for the kinase activity step:
  • PIM-1 substrate peptide PIMtide (ARKRRRHPSGPPTA)
  • the biochemical assay to measure PIM-2 activity relies on the ADP Hunter assay kit (DiscoveRx Corp., Cat. # 90-0077), that determines the amount of ADP as direct product of the kinase enzyme activity.
  • the enzyme has been expressed and purified in-house as a recombinant human protein with a N-terminal histidine tag.
  • the protein is active and stable.
  • PIM-1 substrate peptide PIMtide (ARKRRRHPSGPPTA)
  • Assays were performed in either 96 or 384-well plates.
  • the final outcome of the coupled reactions provided by the kit is the release of the fluorescent product Resorufin and has been measured with a multilabel HTS counter VICTOR V (PerkinE!mer) using an excitation filter at 544 nm and an emission filter at 580 nm.
  • the biochemical assay to measure PIM-3 activity relies on the ADP Hunter assay kit (DiscoveRx Corp., Cat. # 90-0077), that determines the amount of ADP as direct product of the kinase enzyme activity.
  • the enzyme has been bought from Millipore (# 14-738).
  • the protein is active and stable.
  • PIM-1 substrate peptide PIMtide (ARKRRRHPSGPPTA)
  • Assays were performed in either 96 or 384-well plates.
  • the final outcome of the coupled reactions provided by the kit is the release of the fluorescent product Resorufin and has been measured with a multilabel HTS counter VICTOR V (PerkinElmer) using an excitation filter at 544 nm and an emission filter at 580 nm.
  • Certain exemplary compounds of Formula I described herein were prepared, characterized and assayed for their PI3K alpha and Flt3 enzymatic activities.
  • DCM dichloromethane
  • CHCI 3 means chloroform
  • MeOH means methanol
  • EtOH means ethanol
  • EtOAc means ethyl acetate
  • THF means tetrahydrofuran
  • MeCN or “ACN” means acetonitrile
  • DIPEA means diisopropylethy!amine
  • D AP means 4,4- dimethylaminopyridine
  • D F means dimethylformamide
  • DME means dimetoxyethane
  • DMSO means dimethylsulfoxide
  • Et 2 0 means diethyl ether
  • Hex means hexane
  • EtOAc means ethyl acetate
  • BA BE means boronic acid/ester
  • EDC means N-(dimethylaminopropyl)-N'-ethylcarbodiimide
  • NMR spectra were recorded on a Bruker Avance II 300 spectrometer and Bruker Avance II 700 spectrometer fitted with 5mm QXI 700 S4 inverse phase, Z-gradient unit and variable temperature controller.
  • HPLC measurements were performed using a HP 1 100 from Agilent Technologies comprising a pump (binary) with degasser, an autosampler, a column oven, a diode-array detector (DAD) and a column as specified in the respective methods below.
  • Flow from the column was split to a MS spectrometer.
  • the MS detector was configured with an electrospray ionization source or API/APCI. Nitrogen was used as the nebulizer gas.
  • Data acquisition was performed with ChemStation LC/MSD quad, software.
  • Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5um), Solvent A: water with 0.1 % formic acid; Solvent B: acetonitrile with 0.1 % formic acid. Gradient: 5% of B to 100% of B within 8 min at 50 °C, DAD.
  • Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5um), Solvent A: water with 0.1 % formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 50% of B to 100% of B within 8 min at 50 °C, DAD.
  • Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5um), Solvent A: water with 0.1 % formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 5% of B to 40% of B within 8 min at 50 °C, DAD.
  • Reversed phase HPLC was carried out on a Gemini C18 column (50 x 2 mm, 3 urn); Solvent A: water with 0.1 % formic acid; Solvent B: acetonitrile with 0.1 % formic acid. Gradient: 10-95 % of B within 4 min at a flow rate of 0.5 mUmin followed by 2 min of 100 % of B at 0.8 mUmin, controlled temperature at 50 °C, DAD.
  • Reversed phase HPLC was carried out on a Gemini C18 column (50 x 2 mm, 3 urn); Solvent A: water with 10mM ammonium bicarbonate; Solvent B: acetonitrile. Gradient: 20-100 % of B within 3 min at a flow rate of 0.5 mUmin followed by 2 min of 100 % of B at 0.8 mL/min, controlled temperature at 40 °C, DAD.
  • Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5um), Solvent A: water with 0.1 % formic acid; Solvent B: acetonitrile with 0.1 % formic acid. Gradient: 0% of B to 30% of B within 8 min at 50 °C, DAD.
  • “Found mass” refers to the most abundant isotope detected in the HPLC-MS. Compound preparation.
  • Acetic anhydride (0.15 mL, 1.4 mmol. 1.5 eq) was added at RT to a mixture of 4-(5- lodo-imidazo[2, 1-b][1 ,3,4]thiadiazol-2-ylamino)-ira 7s-cyclohexanol (0.34 g, 0.9 mmol), TEA (0.4 mL, 2.8 mmol, 3.0 eq) and DMAP (0.025 g, 0.2 mmol, 0.2 eq) in dry DCM (10 mL), and the mixture was stirred for 3h. The reaction mixture was quenched with sat aq NaHC0 3 and extracted with DCM, the organic phase was dried and concentrated to give the desired product as a crude solid (0.25 g; 66% yield) that was used in the subsequent step without further purification.
  • N-Chlorosuccinimide (0.023 g, 0.1 mmol, 1.1 eq) was added at RT to a solution of acetic acid 4-(5-iodo-imidazo[2, 1-b][1 ,3,4]thiadiazol-2-ylamino)-irans-cyclohexyl ester (0.050 g, 0.1 mmol) in dry D F (1 ml_).
  • the mixture was stirred overnight at 60 °C (sand bath temp), diluted with EtOAc and quenched with a very diluted aq solution of sodium thiosulfate.
  • the aq. phase was extracted with EtOAc, and the organic phase was washed with sat aq. NH CI, water and brine, dried and concentrated to afford the desired product as a crude solid that was used as such.
  • Step 1 (4-Dimethylamino-irans-cyclohexyl)-carbamic acid tert-butyl ester
  • Step 2 N,N-Dimethyl-£rans-cyclohexane-1 ,4-diamine hydrochloride
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3- trifluoromethyl-pyridin-2-ylamine.
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3- trifluoromethyl-pyridin-2-ylamine.
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3- trifluoromethyl-pyridin-2-ylamine.
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3- trifluoromethyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3- trifluoromethyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 )2.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3- trifluoromethyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Palladium catalyst Pd(PPh 3 ) 4 .
  • Boronic reagent 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-2,3-dihydro-1 H- indazole.
  • Palladium catalyst Pd(PPh 3 ) 4 .
  • Palladium catalyst Pd(PPh 3 ) 4 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3- trifluoromethyl-pyridin-2-ylamine.
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3- trifluoromethyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent tert-butyl 4-(3-(trifluoromethyl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3- trifluoromethyl-pyridin-2-ylamine.
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3- trifluoromet yl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 2-amino-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine.
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3- trifluoromethyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3- trifluoromethyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .
  • Boronic reagent 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoro- methyl-pyridin-2-ylamine.
  • Palladium catalyst PdCI 2 (PPh 3 ) 2 .

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Abstract

Cette invention concerne des composés de formule (I) - Ra, Rb, R2 et R3 ayant les significations indiquées dans la description, et des esters, amides, solvates ou sels de ceux-ci pharmaceutiquement acceptables, lesdits composés étant utiles pour traiter les maladies dans lesquelles l'inhibition d'une kinase protéique ou lipidique (par exemple, PI3-K et/ou Flt3, et, éventuellement, une kinase de la famille des PIM) est recherchée et/ou requise, et en particulier, pour traiter le cancer ou une maladie proliférative.
PCT/GB2011/001187 2010-08-09 2011-08-09 Amino-imidazolothiadiazoles destinés à être utilisés en tant qu'inhibiteurs de kinases protéiques ou lipidiques WO2012020215A1 (fr)

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