WO2012098387A1 - Dérivés de triazolo[4,3-b]pyridazines au cycle 6,7 fusionné utilisés en tant qu'inhibiteurs de pim - Google Patents

Dérivés de triazolo[4,3-b]pyridazines au cycle 6,7 fusionné utilisés en tant qu'inhibiteurs de pim Download PDF

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WO2012098387A1
WO2012098387A1 PCT/GB2012/050091 GB2012050091W WO2012098387A1 WO 2012098387 A1 WO2012098387 A1 WO 2012098387A1 GB 2012050091 W GB2012050091 W GB 2012050091W WO 2012098387 A1 WO2012098387 A1 WO 2012098387A1
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optionally substituted
pharmaceutically
alkyl
substituents selected
compound
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Joaquín PASTOR FERNÁNDEZ
Rosa María ÁLVAREZ ESCOBAR
Ana Belén GARCÍA GARCÍA
Rosario Concepción RIESCO FAGUNDO
Carmen Blanco Aparicio
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Centro Nacional De Investigaciones Oncológicas (Cnio)
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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

Definitions

  • This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of protein or lipid kinases (such as inhibitors of a member of the PIM family kinases, e.g. PIM-1 , PIM-2 or PIM-3).
  • 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, neurofibromatosis, 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.
  • 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 050091
  • 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), 6130-6 37, and references cited therein).
  • 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.; Moroy, T. Int. J.
  • 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. JEM 1999, 190, 1059-1068].
  • gp130 a subunit common to receptors of the IL-6 cytokine family, activates the transcription factor STAT3 and can lead to the proliferation of hematopioetic cells [Hirano, T. et al. Oncogene 2000, 19, 2548-2556].
  • a kinase- active PIM-1 appears to be essential for the gp130-mediated STAT3 proliferation signal. In cooperation with the c-myc PIMrl can promote STAT3-mediated cell cycle progression and antiapoptosis [Shirogane, T. et al., immunity, 1999, 11 , 709-719].
  • 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].
  • 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. Biophys. Acta 2002, 1593, 45-55] or phosphorylation of heterochromatin protein 1 , a molecule involved in chromatin structure and transcriptional regulation [Koike, N. et al, FEBS Lett. 2000, 467, 17- 21].
  • 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.
  • the oncogenic potential of this kinase has been first demonstrated in E ⁇ PIM-1 transgenic mice in which PIM-1 over-expression is targeted to the B-cell lineage which leads to formation of B-cell tumors [van Lohuizen, M.
  • PIM-1 has been reported to be over-expressed in a number of prostate cancers, erythroleukemias, and several other types of human leukemias [Roh, M. et al.; Cancer Res. 2003, 63, 8079-8084; Valdman, A. et al; Prostate 2004, 60, 367-371 ;
  • 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 1 linkage between reported overexpression data and the occurrence of PIM-1 mutations in cancer suggests a dominant role of PIM-1 in tumorigenesis.
  • International patent application WO 2005/041971 discloses inter alia fused tricyclic compounds that may bind to ⁇ 2 ⁇ -1 sub-units of Ca channels, and may therefore be useful in the treatment of inter alia psychiatric and mood disorders.
  • International patent applications WO 99/025353 and WO 98/04559 disclose various compounds that may act as ligands for GABA A receptors
  • WO 98/04560 discloses those that may act as inverse agonists of GABA A receptors
  • UK patent GB 2345443 discloses inter alia tricyclic compounds, which may be of use in treating premenstrual syndrome
  • international patent application WO 2005/041971 discloses various tricyclic compounds for use in the treatment of bipolar diseases and the like.
  • EP 0 104 506 and EP 0 029 130 both disclose inter alia tricyclic compounds that may be useful as bronchodilators, but does not disclose any that bear an aromatic substituent, nor does it disclose the potential use of those compounds as kinase inhibitors.
  • EP 0 548 923 and EP 0 562 439 disclose inter alia tricyclic compounds containing an aromatic imidazopyridazine bicyclic core or a [1 ,2,4]triazolo[1 ,5-b]pyridazine core. However, it does not disclose any tricyclic compounds containing a [1 ,2,4]triazolo[4,3-b]pyridazine core, nor does it mention that any of the compounds disclosed therein may be useful as kinase inhibitors.
  • European patent application EP 0 620 224 discloses inter alia [1 ,2,4]triazolo[4,3- bjpyridazines, but none in which such a bicycle is a sub-component of a fused tricyclic compound. Nor does this document disclose that the compounds therein may be useful as kinase inhibitors.
  • US patent application US 2003/0078277 discloses tricyclic compounds that may be useful as a corticotrophin, and therefore of use in the treatment of e.g. 12 050091 depression.
  • this document does not primiarly relate to [1,2,4]triazolo[4,3-b]pyridazines, nor does it disclose that the compounds therein may be useful as kinase inhibitors.
  • US patent application US 2007/0167453 discloses inter alia tricyclic compounds that may be useful as histamine-H3 receptor antagonists.
  • this document does not specifically relate to [1 ,2,4]triazolo[4,3-b]pyridazines substituted with an amino moiety and an aromatic group. Further, this document does not mention that the compounds disclosed therein may be useful as kinase inhibitors.
  • R and R 2 are independently selected from -0-, -S-, -S(0)-, -S(0) 2 -, -C(R 6 )(R 6a )- and -N(R 6 )-; and X represents -CH 2 -CH 2 - optionally substituted by one or more substituents selected from E 2 ; each R 6 and R 6a independently represents, on each occasion when used herein, H, -C(0)NHR d1 , -C(0)R d2 or R d3 ;
  • R d1 , R d2 and R d3 independently represent C-,. 12 (e.g. C 1-6 ) alkyl optionally substituted by one or more substituents selected from E 1 ;
  • R 3 represents heteroaryl optionally substituted by one or more substituents selected from E 3 ;
  • R 4 represents a fragment of formula IA
  • R a and R b independently represent H, C 1-12 (e.g. C -8 ) alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from Q 1 ), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Q 2 ); or R a and R b are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a (first) 3- to 7-membered cyclic group, optionally containing one further heteroatom selected from nitrogen, sulfur and oxygen, and which ring optionally:
  • (a) is fused to a second ring that is either a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen, sulfur and nitrogen (preferably oxygen and nitrogen), a 3- to 12- membered saturated carbocyclic ring, or an unsaturated 5- to 12- membered carbocyclic or heterocyclic ring (in which the heteroatoms are preferably selected from sulfur and, especially, nitrogen and oxygen); comprises a linker group -(C(R X ) 2 ) P - and/or -(C(R x ) 2 )r-0-(C(R x ) 2 ) s - (wherein p is 1 or 2; r is 0 or 1 ; s is 0 or 1 ; and each R independently represents hydrogen or C 1-6 alkyl), linking together any two non-adjacent atoms of the first 3- to 7-membered ring (i.e.
  • a bridged structure or comprises a second ring that is either a 3- to 12-membered saturated carbocyclic ring 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.
  • 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 , E 7 , E 8 and E 9 independently represents, on each occasion when used herein:
  • any relevant pair of R 50 , R 5 and R 52 may (for example when attached to the same or adjacent atoms) be linked together to form, a 3- to 8-membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, heteroatoms selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (e.g.
  • R , R and R independently represent hydrogen or C -6 alkyl optionally substituted by one or more fluoro atoms, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, which compounds, esters, amides, solvates and salts are referred to hereinafter as "the compounds of the invention".
  • 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. Specific salts that may be mentioned include carboxylic acid salts, such as formic acid salts.
  • 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 1-6 alkyl, C 5 . 0 aryl and/or C 5 .i 0 aryl-C ⁇ e alkyl- esters.
  • R z1 and R 22 independently represent optionally substituted Ci -6 alkyl, C 5- 0 aryl, or C 5- 0 aryl-C -6 alkylene-.
  • C 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 hydroxy!, 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, Elesevier, New York-Oxford (1985).
  • 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.
  • Prodrugs of compounds of the invention that may be mentioned also include salts of compounds of the invention.
  • R 3 represents a pyridine ring
  • this also includes quaternary salts for instance those containing the following subgroup -N + -R xx (wherein the nitrogen atom is the atom that is an integral part of the pyridine ring) associated with an anion (e.g. halide, such as CI ) and in which R*" may represent optionally substituted alkyl (e.g. C 1-6 alky', such as methyl, optionally substituted by one or more (e.g.
  • R yy represents aryl/heteroaryl (optionally substituted by one or more substituents selected from halo, C 1-6 alkyl and C 1-6 alkoxy) or C -6 alkyl (optionally substituted by one or more substituents selected from halo and C -6 alkoxy)).
  • Such quaternary salts include those that may be disclosed in e.g. J. Med. Chem., 1994, 37 (26), 4423-4429 and Bioorg. Med. Chem. Lett. 15 (2005) 2491-2494.
  • Such compounds may also be described as "prodrugs".
  • Compounds of the invention may contain double bonds and may thus exist as E ⁇ ent ought) 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, including a dynamic 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.
  • derivatisation i.e. a resolution, including a dynamic resolution
  • stereoisomers including but not limited to diastereoisomers, enantiomers and atropisomers
  • mixtures thereof e.g. racemic mixtures
  • stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid 2012/050091 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, 1 C, 3 C, 14 C , 13 N, 15 0, 7 0, 8 0, 32 P, 33 P, 35 S, 8 F, 36 CI, 123 l, and 25 l.
  • Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and 1 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. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C 2-q alkenyl or a C 2-q alkynyl group).
  • 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 C 1-q alkylene groups may be branched (if sufficient number of atoms), but are preferably straight-chained.
  • C 3-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.
  • Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl 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 from 3 to 20 (i.e. 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. Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 3 .
  • q heterocycloalkenyl (where q is the upper limit of the range) group.
  • C 3 . q heterocycloalkyl groups that may be mentioned include 7-aza-spiro[3.5]non-2-ylamine, 2,9-diaza-spiro[5.5]undecane, 1-oxa-4,9- T B2012/050091 diaza-spiro[5.5]undecane, 8-diaza-spiro[4.5]decan-1-one, 2,8-diaza- spiro[4.5]decan-3-one and, particularly, 7-azabicyclo[2.2.1]heptanyl, 6- azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo- [3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5
  • 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- 2o > such as C 6-12 (e.g. C 6 .i 0 ) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have from 6 to 12 (such as between 6 and 12 (e.g. 6 and 0)) ring carbon atoms, in which at least one ring is aromatic.
  • C 6 . 0 aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl. The point of attachment of aryl groups is via any atom of 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 from 5 to 20 (such as between 5 and 20) members (e.g. from 5 to 10 (such as 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 point of attachment of such heteroaryl groups (e.g.
  • heteroaryl groups that may be mentioned include azaindolyl or, particularly, 3,4-dihydro-IW-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, ,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imi
  • 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 bicyciic.
  • 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 C 1 . 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 ).
  • R 1 does not represent -N(R 6 )- (e.g. R 1 is selected from -0-, -S-, -S(O)-, -S(0) 2 - and -C(R 6 )(R 6a )-), especially when R 2 represents -C(R 6 )(R 6a )-;
  • R 3 represents a substituted heteroaryl group (i.e. substituted by one or more E 3 substituents)
  • that/those E 3 substituent(s) are preferably not located at the position ortho to the point of attachment of the R 3 group (to the requisite triazolopyridazine bicycle of formula I).
  • R and R 2 each independently represents -O- or -N(R 6 )-.
  • Preferred heteroaryl groups include monocyclic heteroaryl groups and bicyclic heteroaryl groups (but in this case, bicyclic heteroaryl groups must be attached to the requisite triazolopyridazine of formula I via a heteroaryl ring i.e.
  • R 3 may represent include the following groups (which may be unsubstituted or substituted): azaindolyl or, particularly, pyrrole, pyrazole, triazole, tetrazole, thiazole, isothiazole, oxazole, isoxazole, isoxazole, isoindole, 1 ,3-dihydro-indol-2-one, pyridine-2-one, pyridine, pyridine-3-ol, imidazole, 1 H- indazole, 1 H-indole, indolin-2-one, 1-(indolin-1-yl)ethanone, pyrimidine, pyridazine, pyrazine and isatin groups, 1 H-benzo[d][
  • R 3 groups include those in which:
  • R 3 represents monocyclic heteroaryl (e.g. a 5- or 6-membered heteroaryl group), then that group preferably contains 1 oxygen or sulfur atom or, particularly, 1 , 2, 3 or 4 nitrogen atoms, and optionally 1 or 2 additional heteroatoms selected from oxygen and sulfur, and which heteroaryl group is optionally substituted by one or more substituents selected from E 3 ;
  • R 3 represents bicyclic heteroaryl (e.g. a 8-, 9- or 10-membered heteroaryl group)
  • that group preferably consists of a 5- or 6-membered ring fused to another 5- or 6-membered ring (in which the first ring, attached to the requisite tricycle of formula I, contains one to four heteroatoms and the second ring, fused to the first, may contain one to four (e.g. one to three) heteroatoms), in which the total number of heteroatoms is preferably one to four, and which ring (i.e. bicyclic heteroaryl group) is optionally substituted by one or more (e.g.
  • R 3 groups include those in which R 3 represents azaindolyl, benzofuranyl, benzothienyl, furanyl, isoquinolinyl, pyrazinyl, pyridyl, quinolinyl, thiazolyl or thienyl.
  • R 3 groups include those in which: R 3 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 3 substituents;
  • R 3 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 3 substituents;
  • R 3 is represented b a moiety of formula IB or IC:
  • R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R g and R 2h independently represent hydrogen or a substituent selected from E 3 ;
  • R 2a to R 2d represent a substituent selected from E 3 (and the other two or three represent hydrogen);
  • R 2e to R 2h represent a substituent selected from E 3 (and the other two or three represent hydrogen);
  • E 3 represents C 1-3 alkyl (optionally substituted by Q 5 ; so forming e.g. a -CF 3 group), or, E 3 represents Q 4 ;
  • Q 4 represents halo (e.g. fluoro), -N(R 20 )R 21 or -OR 20 ;
  • Q 5 represents halo (e.g. fluoro);
  • R 20 and R 21 independently represent hydrogen or C -2 alkyl (e.g. methyl), or, may be linked together to form a morpholinyl group.
  • Preferred monocyclic heteroaryl groups that R a or R b or Q 1 , Q 2 , Q 4 or Q 5 (if applicable) may independently represent include 5- or 6-membered rings, containing one to three (e.g. one or two) heteroatoms selected from sulfur, oxygen and nitrogen.
  • Preferred bicyclic heteroaryl groups that R 3 (provided that it is attached to be requisite bicycle of formula I via a heteroaryl ring of the bicycle), R a or R b , or Q 1 , Q 2 , Q 4 or Q 5 may represent include 8- to 12- (e.g.
  • bicyclic rings may consist of benzene rings fused with a monocyclic heteroaryl group (as hereinbefore defined), e.g. a 6- or, preferably 5- membered monocyclic heteroaryl group optionally containing two, or, preferably, one heteroatom selected from sulfur, oxygen and nitrogen.
  • Preferred heterocycloalkyi groups that R a or R b or Q , Q 2 , Q 4 or Q 5 may independently represent include 4- to 8-membered (e.g. 5- or 6-membered) heterocycloalkyi groups, which groups preferably contain one or two heteroatoms (e.g.
  • C 3 . 6 cycloalkyl groups that R a or R b or Q , Q 2 , Q 4 or Q 5 may independently represent include optionally substituted C 3-8 (e.g. C 3-6 ) cycloalkyl groups, such as cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.
  • R 10a , R 11a and R 12a 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 , E 7 , E 8 and/or E 9 groups may be linked together (e.g. any two E 3 substituents may also be linked togethe 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 , E 7 , E 8 and/or E 9 ) are preferably not linked together;
  • aryl e.g. phenyl; preferably unsubstituted, but which may be substituted by one to three J 5 groups
  • C 1-6 e.g. C 1-3 alky
  • 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 Ci. 6 (e.g. C 1-3 ) alkyl optionally substituted by one or more substituents selected from fluoro;
  • R 60 , R 6 and R 62 independently represent hydrogen or C 1-3 (e.g. C -2 ) alkyl optionally substituted by one or more fluoro atoms. 12 050091
  • R 3 , R 4 and the R 1 , R 2 and X-containing ring include:
  • halo e.g. fluoro, chloro or bromo
  • C 1-6 e.g. C- alkyl
  • fluoro groups (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl) or substituted with an aryl, heteroaryl or heterocycloalkyi group (which themselves may be substituted with one or more -OR z , -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 z °, -C(0)-N(R z1 l )R z12 , -N(R z9 )-C(0)-N(R z1 °), -N(R z9 )-S(0) 2 -R z1 ° and/or -N(R z9 )-S(O) 2 -N(R z10 )R
  • aryl e.g. phenyl
  • substitutent may also be present on an alkyl group, thereby forming e.g. a benzyl group
  • optionally substituted by one or more J 3 substituents
  • each R z1 to R z 2 independently represents, on each occasion when used herein, H or C 1- 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 0a and R 1a groups.
  • Preferred compounds of the invention include those in which:
  • each J 1 , J 2 , J 3 , J 4 , J 5 and J 6 independently represents C -6 alkyl (e.g. C -4 acyclic alkyl or C 3 . 5 cycloalkyl) optionally substituted by one or more substituents selected from Q 8 , or, J 1 to J 6 more preferably represent a substituent selected from Q 7 ;
  • each R 50 , R 5 , R 52 and R 53 independently represents hydrogen or C 1-6 (e.g. C 1-4 ) alkyl optionally substituted by one or more fluoro atoms; 12 050091 each R , R and R independently represents hydrogen or C 1-2 a!kyl (e.g. methyl).
  • More preferred compounds of the invention include those in which:
  • R d , R d2 and R d3 independently represent C 1-6 (e.g. C 1-3 ) alkyl optionally substituted by one or more substituents selected from E but which is preferably unsubstituted;
  • X represents unsubstituted -CH 2 -CH 2 -;
  • R a and R b when linked together, they may represent a 3- to 6-membered ring (e.g. a 5- or, preferably, 6-membered ring), optionally containing one further heteroatom selected from nitrogen and oxygen, which ring may be: (a) fused to another saturated 5- or 6-membered carbocyclic or heterocyclic ring, in which the latter contains one to four heteroatoms preferably selected from nitrogen and oxygen; (b) comprises a -(CH 2 ) n i-, -O- or -CH 2 -0-CH 2 - linker group linking any two non-adjacent atoms (n1 represents 1 or 2); or (c) comprises a further 4- to 6- membered saturated carbocyclic or heterocyclic ring, in which the latter contains one or two heteroatoms preferably selected from nitrogen and oxygen, which second ring is linked to the first via a single atom;
  • ring may be: (a) fused to another saturated 5- or 6-membered carbocyclic or hetero
  • e alkyl e.g. C 1-3 alkyl
  • fluoro atoms e.g. C 1-3 alkyl
  • each R 20 , R 2 , R 22 and R 23 independently represents hydrogen or C-M (e.g. C 1-3 ) alkyl (e.g. a C 1-4 acyclic alkyl group or a part cyclic C 4 group) optionally substituted (but preferably unsubstituted) by one or more (e.g. one) J 4 substituent(s); or
  • R 22 represents alkyl or hydrogen;
  • R 11c and R 21a independently represent C 1-3 alkyl;
  • each J 1 , J 2 , J 3 , J 4 , J 5 and J 6 independently represent a substituent selected from Q 7 , or J 1 to J 6 independently represent C -6 alkyl (e.g. C 1J ⁇ alkyl);
  • each R 50 , R 5 , R 52 and R 53 independently represents H or 0 1-4 alkyl (e.g. fBu, Me).
  • Preferred compounds of the invention include those in which:
  • R 1 and R 2 independently represent -C(R 6 )(R 6a )-, preferably, -S(O)-, -S(0) 2 -, and, more preferably, -0-, -S- or -N(R 6 )-;
  • each R 6 and R 6a independently represents, on each occasion when used herein, H or R d3 ;
  • R d3 represents C 1-6 (e.g. C 1-4 ) alkyl
  • X represents optionally substituted (i.e. by E 2 ) -CH 2 -CH 2 -;
  • R 3 represents a 5- or 6-membered monocyclic heteroaryl group (e.g. pyridyl) or a 9- or 10-membered heteroaryl group, which heteroaryl groups are optionally substituted by one or more (e.g. one to three) substituent(s) selected from E 3 ;
  • R a and R b independently represents H, C 1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more (one to three) substituent(s) selected from Q 1 ); or R a and R b may be linked together to form a 3- to 6- membered ring (e.g.
  • a 5- or, preferably, 6-membered ring preferably containing no further heteroatoms, which ring may be linked to a further 4- to 6-membered ring (e.g. 4-membered ring) via a single atom (i.e. forming a spiro cycle), all of which cyclic groups are optionally substituted by one or more substituents selected from E 4 ;
  • E 1 to E 9 independently represent Q 4 or C 1-6 (e.g. C-
  • R 20 and R 2 independently represent hydrogen, Ci. 4 alkyl, which latter group is optionally substituted by one or more (e.g. one) substituent(s) selected from J 4 ; when there is a -N(R 20 )R 21 moiety present, then one of R 20 and R 2 represents hydrogen, and the other represents hydrogen or C 1- alkyl (e.g. methyl, ethyl or isopropyl), which latter group is optionally substituted by one or more (e.g. one) substituent(s) selected from J 4 ;
  • R 22 and R 23 independently represent hydrogen or C1.3 alkyl (e.g. methyl);
  • R 21a represents C 1-3 alkyl (e.g. methyl);
  • J 3 represents Q 7 ;
  • J 4 represents Q 7 or Ci_ 6 (e.g. Ci -3 ) alkyl, which is preferably unsubstituted;
  • Q 7 represents halo (e.g. fluoro).
  • Q 7 and Q 8 independently represent halo, -N(R 50 )R 51 , -OR 50 or C 1-3 alkyl optionally substituted by one or more fluoro atoms.
  • Q 1 and Q 2 independently represent aryl (such as phenyl) (optionally substituted by one or more E 6 substituents) or, particularly, halo, -N(R 10a )R 1a , -OR 10a , -S(0) 2 .
  • halo e.g. fluoro or chloro
  • Q 7 and Q 8 independently represent halo or Ci -3 alkyl optionally substituted by one or more fluoro atoms.
  • R 1 , R 2 and X-containing rings of the compounds of the invention include:
  • squiggly lines represent the point of attachment to the requisite triazolopyridazine of the compound of formula I, and R 6 is as defined herein (the rings containing at least one oxygen atom are particularly preferred).
  • R 1 , R 2 and X-containing rings of the compounds of the invention include:
  • R 3 groups of the compounds of the invention include optionally substituted benzofuranyl (such as benzofuran-2-yl), optionally substituted benzothienyl (such as benzothien-2-yl, 4-CF 3 -benzothien-2-yl and 6-CF 3 - benzothien-2-yl), optionally substituted furanyl (such as furan-3-yl), optionally substituted pyrazinyl (such as 2-NH 2 -5-(4-fluorophenyl)-pyrazin-3-yl), optionally substituted thiazolyl (such as 4-CF 3 -thiazol-2-yl), optionally substituted thienyl (such as 2-(C(0)CH 3 )-thien-4-yl and 2-CH 3 -thienyl-3-yl), or, particularly, optionally substituted pyridyl (such as 4-pyridyl and 3-pyridyl; e.g. 2-NH 2 -4-pyridyl, 2-(
  • R 3 groups include optionally substituted pyridyl.
  • Preferred R 4 roups of compounds of the invention include:
  • the squiggly line represents the point of attachment to the requisite triazolopyridazine of the compound of formula I
  • R 3 " 3 represents R a or R
  • the other integers e.g. E 4 , E 5 and Q 1 ; which are optional substituents that may be attached to specific atoms, or, may be depicted as 'floating', in which case the 50091 relevant group is optionally substituted by one or more of those E 5 /Q 1 /E 4 substituents
  • the depiction of a substituent in brackets signifies that that substituent is optionally present, and may therefore be absent (i.e. N-(E 5 ) may signify N-E 5 or N-H).
  • More preferred compounds of the invention include those in which:
  • each of R and R 2 independently represents -O- or, particularly, one of R 1 and R 2 represents -N(R 6 )- and the other represents -O- or -N(R 6 )-;
  • R 6 represents H or R d3 ;
  • R d3 represents C -3 alkyl (e.g. methyl or ethyl);
  • X represents unsubstituted -CH 2 -CH 2 -;
  • R a and R represents H or Ci -3 alkyl (e.g. methyl) and the other represents a substituent other than hydrogen (or the foregoing groups);
  • R a and R when either of R a and R represents a substituent (other than hydrogen; see above), then it may be:
  • C-,-6 alkyl e.g. Ci. 3 acyclic alkyl or C 3 . 6 cycloalkyl
  • C-,-6 alkyl e.g. Ci. 3 acyclic alkyl or C 3 . 6 cycloalkyl
  • substituents e.g. methyl, ethyl, n-propyl, cyclobutyl or cyclohexyl
  • Q 1 e.g. one substituent
  • heterocycloalkyl e.g. a 5- to 11-membered heterocycloalkyl group containing one or two (e.g. one) heteroatom(s) in which one is preferably nitrogen or oxygen, which 5- to 11-membered heterocycloalkyl group may be formed of two rings linked together via a single atom (i.e. forming a spiro cycle, which is preferably a [3.5], [5.3] or [5.5] spiro-cycle) or, particularly, a 5- or, preferably 6-membered heterocycloalkyl group containing one or two (e.g. one) heteroatom(s) in which one is preferably nitrogen or oxygen, so forming e.g.
  • heterocycloalkyl e.g. a 5- to 11-membered heterocycloalkyl group containing one or two (e.g. one) heteroatom(s) in which one is preferably nitrogen or oxygen
  • piperidinyl or tetrahydropyranyl such as 4-piperidinyl or 4-tetrahydropyranyl
  • which heterocycloalkyl group is optionally substituted by one or more substituents (e.g. one; which substituent(s) may be attached to a nitrogen heteroatom) selected from Q 1 ; or
  • Q may represent (for instance, when it is attached to a heterocycloalkyi group) C-i-6 (e.g. C1.3) alkyl (e.g. methyl) (which alkyl group is optionally substituted by one or more substituents selected from E 5 ), -N(R 10a )R 1a (e.g. -N(CH 3 ) 2 ), -OR 10a (e.g. -OH) or -S(O) 2 R 0a ;
  • C 1-6 alkyl e.g. cycloalkyl, such as cyclopropyl or cyclohexyl
  • substituents selected from 0 and, preferably E 5
  • heterocycloalkyi e.g. a 5- or, preferably 6- membered heterocycloalkyi group
  • two non-adjacent atoms (which may be in a 1 ,4-relationship) of the first ring may be linked together with -(CH 2 ) n i- (where n1 is 2 or, preferably, 1), so forming for example a 1-aza-bicyclo[2.2.1]hept-4-yl group); aryl (e.g. phenyl) (which is optionally substituted by one or more substituents selected from E 6 ); or heteroaryl (e.g. a 5- or, preferably, a 6-membered heteroaryl group preferably containing one nitrogen heteroatom, so forming e.g. pyridyl, such as 3-pyridyl), which group is preferably unsubstituted;
  • aryl e.g. phenyl
  • heteroaryl e.g. a 5- or, preferably, a 6-membered heteroaryl group preferably containing one nitrogen heteroatom, so forming e.g. pyri
  • two E 3 groups may be linked together to form an aromatic (e.g. 5-membered) ring, preferably containing one or two (e.g. one) heteroatom(s) (selected from sulfur, oxygen and, preferably nitrogen), but two E 3 groups are preferably not linked together;
  • E 4 represents Q 4 , or, C -3 alkyl (e.g. methyl) optionally substituted by one or more (e.g. one) Q 5 substituent;
  • E 5 represents Q 4 or Ci. 6 (e.g. d. 4 ) alkyl (acyclic or part-cyclic; so forming e.g. methyl or cyclopropylmethyl, i.e. C 1-2 alkyl (e.g. methyl) substituted by cycloalkyl (e.g. cyclopropyl)), which is preferably unsubstituted;
  • E 6 represents Q 4 ;
  • R 10a and R 11a independently represent H or Ci -3 alkyl (e.g. methyl);
  • R 20 represents H or C -4 alkyl (e.g. ethyl or, preferably, methyl, isopropyl or tert- butyl) optionally substituted by one or more J 4 substituents (in particular J 4 may represent halo, such as fluoro, and hence R 20 may represent a trifluoromethyl group);
  • R 21 represents hydrogen or C 1-4 (e.g. C -3 ) alkyl (e.g. isopropyl or, preferably, methyl);
  • R 22 represents hydrogen
  • J 4 represents Q 7 ;
  • Q 7 represents halo (e.g. fluoro).
  • Particularly preferred compounds of the invention include those in which:
  • R 1 and R 2 represents -N(R 6 )- and the other represents -O- or -N(R 6 )-;
  • R 6 represents H or, more preferably, R d3 ;
  • R d3 represents C -3 alkyl (e.g. methyl or ethyl, preferably methyl);
  • X represents unsubstituted -CH 2 -CH 2 -;
  • R 3 represents a monocyclic 5- or 6-membered heteroaryl group (e.g. pyridyl) or a 9- or 10-membered bicyclic heteroaryl group (e.g. isoquinolinyl or azaindolyl, such as 3-isoquinolinyl and 7-azaindol-4-yl), which heteroaryl groups are optionally substituted by one or more (e.g. one or two) substituents selected from E 3 ;
  • a monocyclic 5- or 6-membered heteroaryl group e.g. pyridyl
  • a 9- or 10-membered bicyclic heteroaryl group e.g. isoquinolinyl or azaindolyl, such as 3-isoquinolinyl and 7-azaindol-4-yl
  • heteroaryl groups are optionally substituted by one or more (e.g. one or two) substituents selected from E 3 ;
  • R a and R represents hydrogen or C -3 alkyl (e.g. methyl) and the other represents a substituent other than hydrogen, or, R a and R are linked together as defined herein; 50091 when R a or R b represents a substituent other then hydrogen, then it is preferably: C-,.6 alkyl (e.g. acyclic Ci -3 alkyl or C 3-6 cycloalkyl) optionally (and preferably) substituted by one or more (e.g. one) substituent(s) selected from Q 1 ; or a 5- or preferably 6-membered heterocycloalkyl group (e.g. containing one heteroatom, so forming e.g. piperidinyl or tetrahydropyranyl) optionally substituted by one or more (e.g. one) substituent(s) selected from Q ;
  • C-,.6 alkyl e.g. acyclic Ci -3 alkyl or C 3-6 cycloalkyl
  • R a and R b when R a and R b are linked together, they form a 5- or, preferably, a 6-membered ring optionally containing one further heteroatom (e.g. nitrogen; so forming e.g. a piperazinyl group), which ring may further comprise a 3- to 6- membered cycloalkyl group (e.g. cyclobutyl) or heterocycloalkyl group (e.g. a 5- or, preferably, 6-membered group containing one heteroatom, so forming e.g. piperazinyl) linked via a single atom (so forming a spiro-cycle), all of which rings are optionally substituted by one or more substituents selected from E 4 ;
  • a 3- to 6- membered cycloalkyl group e.g. cyclobutyl
  • heterocycloalkyl group e.g. a 5- or, preferably, 6-membered group containing one heteroatom, so
  • Q 1 (e.g. when present on an alkyl/cycloalkyl group) represents -N(R 10a )R 1 a or a 5- or 6-membered heterocycloalkyl group (e.g. containing two or preferably one nitrogen atom; so forming e.g. a piperidinyl group, which may be attached to a cycloalkyl group via a single carbon atom so forming a spiro-cycle), which is optionally substituted by one or more (e.g. one) substituent(s) selected from E 5 ;
  • Q (e.g. when present on a heterocycloalkyl group) represents -S(O) 2 R 10a (which is preferably attached to a nitrogen heteroatom);
  • E 3 represents Q 4 or d. 3 alkyl (e.g. methyl) optionally substituted by one or more substituents selected from Q 5 (e.g. fluoro; so forming a -CF 3 group);
  • E 4 represents Q 4 or Ci. 3 alkyl (e.g. methyl or ethyl) optionally substituted by one or more (e.g. one) substituent(s) selected from Q 5 ;
  • E 5 represents C -3 alkyl (e.g. methyl);
  • Q 4 represents halo (e.g. fluoro or chloro), -OR 20 or -N(R 20 )R 21 ;
  • Q 5 represents halo (e.g. fluoro) or -N(R 20 )R 21 ;
  • R 0a and R 11a independently represent hydrogen or preferably C 1-3 alkyl (e.g. methyl or ethyl);
  • R 20 and R 21 independently represent hydrogen or C 1-6 (e.g. C 1-3 ) alkyl (e.g. methyl or ethyl); or R and R are linked together to form a 5- or preferably 6-membered ring optionally containing one further heteroatom (e.g. nitrogen or oxygen; so forming e.g. a morpholinyl group).
  • the compound of formula I may be represented as a compound of formula ID,
  • R 1d and R 2d are independently selected from -0-, -S-, and -N(R 6d )-;
  • R 6d represents, on each occasion when used herein, H, or R d3d ;
  • R d3d represents linear or branched C 1-4 alkyl optionally substituted by one or more substituents selected from E 1d ;
  • R 3 represents a mono- or bicyclic aromatic group containing from 5 to 10 skeleton atoms, in which from 1 to 3 of the skeleton atoms are heteroatoms selected from N, O and S, which aromatic group is optionally substituted by one or more substituents selected from E 3 ;
  • R represents a fragment of formula ⁇ '
  • R a and R ' independently represent H, linear or branched Ci -e alkyl, heterocycloalkyl (particularly a 4- to 6-membered saturated heterocycloalkyl ring 1 containing at least one heteroatom selected from 0, S and N, or two 4- to 6- membered rings linked together via a single carbon atom common to both rings (i.e.
  • R a' and R b are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a (first) 3- to 7-membered cyclic group, optionally containing one further heteroatom selected from nitrogen, sulfur and oxygen, and which ring optionally:
  • (a) is fused to a second ring that is either a 4- to 6-membered saturated heterocycloalkyl group containing one to three heteroatoms selected from oxygen, sulfur and nitrogen (preferably oxygen and nitrogen), a 4- to 10- membered saturated carbocyclic ring, or an unsaturated 4- to 10- membered carbocyclic or heterocyclic ring (in which the heteroatoms are preferably selected from sulfur and, especially, nitrogen and oxygen);
  • (b) comprises a linker group -C(R ) 2 - (wherein each R independently represents hydrogen or linear or branched C 1-4 alkyl), linking together any two non-adjacent atoms of the first 3- to 7-membered ring (i.e.
  • (c) comprises a second ring that is either a 4- to 10-membered saturated carbocyclic ring 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.
  • each Q 1d and Q 2d independently represents, on each occasion when used herein: halo, -CN, -N0 2 , -N(R )R , -OR d1 , -C(0)-R d , -C(0)-OR d , -C(0)N(R d )R d2 , -OC(0)-R d , -OS(0) 2 OR d1 , -N(R d3 )C(0)R d2 , -NR d3 S(0) 2 R d1 , -S(0) 2 N(R d1 )R d2 , -S(0) 2 R d , -SR d1 , -S(0)R d , C ⁇ 2 alkyl, heterocycl
  • Q 7d represents, on each occasion when used herein:
  • each R and R independently represents, on each occasion when used herein, hydrogen or linear or branched d -6 alkyl; or a pharmaceutically acceptable ester, amide, solvate or salt thereof.
  • Preferred compounds of formula ID include those in which:
  • R 1d and R 2d are independently selected from -0-, and -N(R 6d )-; R 6d represents, on each occasion when used herein, H, or methyl;
  • R 3d represents a mono- or bicyclic aromatic group containing from 5 to 10 skeleton atoms, in which from 1 to 3 of the skeleton atoms are heteroatoms selected from N, O and S, which aromatic group is optionally substituted by one or more substituents selected from E 3d ;
  • R represents a fragment of formula ⁇ '
  • R a and R b independently represent H, linear or branched C 1-6 alkyl, heterocycloalkyl (particularly a 4- to 6-membered saturated heterocycloalkyl ring containing at least one heteroatom selected from O, S and N, or two 4- to 6- membered rings linked together via a single carbon atom common to both rings (i.e.
  • a spiro-cycle wherein at least one of said two rings contains from 1 to 3 heteroatoms selected from O, S and N), which Ci -6 alkyl and heterocycloalkyl groups are optionally substituted by one or more substituents selected from Q d ); or R a' and R b' are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a (first) 3- to 7-membered cyclic group, optionally containing one further heteroatom selected from nitrogen, sulfur and oxygen, and which ring optionally comprises a second ring that is either a 4- to 8- membered saturated carbocyclic ring or a 3- to 7-membered saturated heterocycloalkyi 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), which cyclic group, defined by the linkage of R a and R
  • each R d1 and R d2 independently represents, on each occasion when used herein, hydrogen, linear or branched C- 4 alkyl; each E 3d , E 4d , E 5d and E 6d independently represents, on each occasion when used herein:
  • each R d7 and R d8 independently represents, on each occasion when used herein, hydrogen or C 1-2 alky'; or a pharmaceutically acceptable ester, amide, solvate or salt thereof.
  • the compound of formula I may be represented as a compound of formula IE,
  • R e and R 2e is -O- and the other is selected from -0-, and -N(CH 3 )-;
  • R 3e represents a mono- or bicyclic aromatic group containing from 5 to 10 skeleton atoms, in which from 1 to 3 of the skeleton atoms are heteroatoms selected from N, O and S, which aromatic group is optionally substituted by one or more substituents selected from E 3e ;
  • R 4e represents a fragment of formula IA
  • R a and R b independently represent H, linear or branched C -6 alkyl or heterocycloalkyi (particularly a 4- to 6-membered saturated heterocycloalkyi ring B2012/050091 containing at least one heteroatom selected from O, S and N, or two 4- to 6- membered rings linked together via a single carbon atom common to both rings (i.e. forming a spiro-cycle) wherein at least one of said two rings contains from 1 to 3 heteroatoms selected from O, S and N), which C 1-6 alkyl and heterocycloalkyl groups are optionally substituted by one or more substituents selected from Q e ; or
  • R a" and R b are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a (first) 3- to 7-membered cyclic group, optionally containing one further heteroatom selected from nitrogen, sulfur and oxygen, and which ring optionally comprises a second ring that is either a 4- to 6- membered (particularly 4-membered) saturated carbocyclic ring or a 4- to 6- membered (particularly 5- or 6-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.
  • each Q e independently represents, on each occasion when used herein:
  • each R d1 and R d2 independently represents, on each occasion when used herein, hydrogen or Ci. 2 alkyl, (which latter group is optionally substituted by one or more fluoro atoms); each E 3e , E 4e and E 5e independently represents, on each occasion when used herein:
  • each Q 4e and Q 5e independently represents, on each occasion when used herein: halo, -N0 2> -NKR ⁇ R 65 , -OR e4 , -SR e4 , aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from halo atoms); and each R 64 and R independently represents, on each occasion when used herein, hydrogen, or C 1-2 alkyl, (which latter group is optionally substituted by one or more halo atoms); or a pharmaceutically acceptable ester, amide, solvate or salt thereof.
  • Particularly preferred compounds of the invention include those of the examples described hereinafter.
  • L 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 R 1 , R 2 , R 3 and X are as hereinbefore defined, with a compound of formula III,
  • R 4 -H III wherein R 4 is as hereinbefore defined, under standard conditions, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc) 2 , Cul (or Cul/diamine complex), copper tris(triphenyl-phosphine)bromide, Pd(OAc) 2 , tris(dibenzylideneacetone)- dipalladium(O) (Pd 2 (dba) 3 ) or NiCI 2 and an optional additive such as Ph 3 P, 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et 3 N, pyridine, ⁇ /,/V-dimethylethylenediamine, Na 2 C0 3 , K 2 C0 3 , K 3 P0 , Cs 2
  • This reaction may be carried out under microwave irradiation reaction conditions and/or the reaction may be performed in the absence of other reagents such as catalyst, base and even solvent (e.g.
  • the reaction may be performed under microwave irradiation conditions, in the presence of an alcohol, such as n-butanol, for instance at elevated temperature such as at above 100°C, e.g. at about 150-200°C).
  • an alcohol such as n-butanol
  • 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 terf-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.
  • L 4 represents a suitable group, such as H, -B(OH) 2 , -B(OR wx ) 2 or -SniRTM ⁇ , in which each R m independently represents a C 1-6 alkyl group, or, in the case of -B(OR wx ) 2 , the respective R wx 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.
  • a suitable group such as H, -B(OH) 2 , -B(OR wx ) 2 or -SniRTM ⁇
  • each R m independently represents a C 1-6 alkyl group
  • the respective R wx 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
  • reaction may be performed under Heck reaction conditions (e.g. with a compound of formula V in which L 4 represents H).
  • the reaction may also 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.
  • Pd 2 (dba) 3 and/or NiCI 2 palladium
  • Pd 2 (dba) 3 and/or NiCI 2 palladium
  • a ligand such as PdCI 2 (dppf).DCM, f-Bu 3 P, (C 6 Hn) 3 P, Ph 3 P, AsPh 3 , P(o-Tol) 3 , 1 ,2-bis(diphenylphosphino)ethane, 2,2'-bis(di-tert-butyl- phosphino)-1 , 1 '-biphenyl, 2,2'-bis(diphenylphosphino)-1 , 1 '-bi-naphthyl, 1 ,1'- bis(diphenyl-phosphino-ferrocene), 1 ,3-bis(diphenylphosphino)propane, xantphos, or a mixture thereof
  • the reaction may be carried out for example at room temperature or above (e.g. at a high temperature such as at about the reflux temperature of the solvent system).
  • Alternative reaction conditions include microwave irradiation conditions, for example at elevated temperature of, e.g. above 70°C, e.g. between about 100 and 120°C or at about 130°C;
  • R 4 L 1 represents either L 1 or R 4
  • R 1 , R 2 , R 4 , X and each L 1 (which are independent of each other) are as hereinbefore defined, with a compound of formula VII,
  • base such as an organic base (e.g. triethylamine or the like)
  • an acid such as an organic acid (e.g. para-toluenesulfonic acid or the like)
  • the base and acid are preferably in a ratio of about 1:1.
  • the reaction may also take place in the presence of a suitable solvent, such as a polar solvent (e.g.
  • reaction may be heated at room termperature, or, preferably, above room temperature, e.g. above 50°C, such as at about 100°C.
  • room temperature e.g. above 50°C, such as at about 100°C.
  • reaction may be proceeded by reaction with a compound of formula III, for example as defined in respect of process step (i) above;
  • R a and R 2a independently represent -0-, -S- and -NR. 6 -, and R 3 and R 4 are as hereinbefore defined, with a compound of formula IX,
  • L 5 and L 6 independently represent a suitable leaving group, such as one hereinbefore defined in respect of L 1 (e.g. halo, such as chloro), and X is as hereinbefore defined, under standard reaction conditions (to promote the nucleophilic substitution reactions), for example in the presence of a suitable base, such as Na 2 C0 3 , K 3 P0 4 , Cs 2 C0 3 , NaOH, KOH, 2 C0 3 , CsF, Et 3 N, (/-Pr) 2 NEt, f-BuONa or f-BuOK (or mixtures thereof) in a suitable solvent such as dioxane, toluene, ethanol, fert-butanol, dimethylformamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, A/-methylpyrrolidinone, tetrahydrofuran or mixtures thereof.
  • Preferred bases include
  • L x represents a suitable leaving group (e.g. chloro) and R 1a , R 2a , X, R , R 2 , R 3 and R 4 are as hereinbefore defined, for example in the presence of a suitable base, e.g. an inorganic metal alkoxide, such as an alkali metal alkoxide (in which the alkali metal may be sodium or potassium and the alkoxide may be a d.6 alkyl oxide, such as fert-butyl; hence the base is preferably potassium tert- butoxide).
  • a suitable base e.g. an inorganic metal alkoxide, such as an alkali metal alkoxide (in which the alkali metal may be sodium or potassium and the alkoxide may be a d.6 alkyl oxide, such as fert-butyl; hence the base is preferably potassium tert- butoxide).
  • Compounds of formula II may be prepared by reaction of a compound of formula VI as hereinbefore defined but in which R 4 L 1 represents L and a compound of formula VII as hereinbefore defined, for example under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (iii)).
  • Compounds of formula IV may be prepared by reaction of a compound of formula X as hereinbefore defined with a compound of formula III as hereinbefore defined, for example under reaction conditions such as those described in respect of preparation of compounds of formula I (process step (i) above).
  • bromide) 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, for instance in the presence of a suitable solvent, such as an alcohol (e.g. methanol), a halogenated solvent (e.g. chloroform) or e.g.
  • a suitable solvent such as an alcohol (e.g. methanol), a halogenated solvent (e.g. chloroform) or e.g.
  • L 4 and L 5 independently represent a suitable leaving group (e.g. chloro), and R 4 L 1 , L 1 are as hereinbefore defined, with a compound of formula XIII,
  • R 1a , R 2a and X are as hereinbefore defined, under standard aromatic nucleophilic reaction conditions, for example in the presence of a base and solvent (such as one hereinbefore described in respect of process step (iv) above, e.g. NaO/-Bu in the presence of a solvent such as acetonitrile) or under reaction conditions such as those described in respect of process step (ii) above.
  • a base and solvent such as one hereinbefore described in respect of process step (iv) above, e.g. NaO/-Bu in the presence of a solvent such as acetonitrile
  • reaction conditions such as those described in respect of process step (ii) above.
  • L 1 , R 1a , R 2a , X, R 1 , R 2 and L** are as hereinbefore defined, for example under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (v) above), e.g. an intramolecular reaction in the presence of base (e.g. sodium or potassium rert-butoxide).
  • base e.g. sodium or potassium rert-butoxide
  • L xy represents a suitable leaving group, such as one defined in respect of L** (e.g. chloro), with a compound of formula XVII,
  • R a , X, R 2 , R 2a and R 1 are as hereinbefore defined, for instance under reaction conditions such as those hereinbefore described, e.g. in respect of preparation of compounds of formula I (process step (i) above), or e.g. the reaction may take place simply in the presence of an appropriate solvent (e.g. an alcohol, e.g. methanol).
  • an appropriate solvent e.g. an alcohol, e.g. methanol
  • Compounds of formula II may alternatively be prepared by reaction of a compound of formula XVIII, 12 050091 wherein L 1 , R 3 , R 1 , R 2 and X are as hereinbefore defined, in the presence of an appropriate base such as NaH, Et 3 N, pyridine, /N/,/V-dimethylethylenediamine, Na 2 C0 3 , K 2 C0 3 , K3PO4, Cs 2 C0 3 , f-BuONa or f-BuOK (or a mixture thereof, optionally in the presence of 4A molecular sieves), in a suitable solvent (e.g.
  • an appropriate base such as NaH, Et 3 N, pyridine, /N/,/V-dimethylethylenediamine, Na 2 C0 3 , K 2 C0 3 , K3PO4, Cs 2 C0 3 , f-BuONa or f-BuOK (or a mixture thereof, optionally in the presence of 4A molecular sieves
  • acetonitrile dichloromethane, dioxane, toluene, dimethylformamide, ethylene glycol dimethyl ether, dimethylsulfoxide, dimethylacetamide, /V-methylpyrrolidinone, tetrahydrofuran or a mixture thereof; which solvent may be degassed), op tionally in the presence of a halogenating agent (e.g. a triarylphenylphosphine dihalide such as triphenylphosphine dibromide).
  • a halogenating agent e.g. a triarylphenylphosphine dihalide such as triphenylphosphine dibromide.
  • R 3 is as hereinbefore defined and L aa is a leaving group such as one hereinbefore defined in respect of L 3 , in the presence of a suitable coupling reagent (e.g. 1 ,1'-carbonyldiimidazole, .A/'-dicyclohexylcarbodiimide, 0-(7-azabenzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HATU), or the like), 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).
  • a suitable coupling reagent e.g. 1 ,1'-carbonyldiimidazole, .A/'-dicyclohexylcarbodiimide, 0-(7-azabenzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium
  • L b is a leaving group such as one hereinbefore defined in respect of L 1 , with hydrazine, or a salt, solvate or derivative thereof, under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent and/or in an inert atmosphere).
  • a reducing agent such as a chemoselective one mentioned above or NaBH 4 , AIH l 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 Q 1 or Q 2 represents -C(0)OH (or an ester thereof), it may be converted to a -C(O)N(R 10a )R 1 a group (in which R 10a and R 1a are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g. when Q 1 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 0a )R a (in which R 0a 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. 0 1-6 alkyl-halide (e.g. ethylbromide), C 1-6 alkyl-C(0)-halide (e.g.
  • a leaving group e.g. 0 1-6 alkyl-halide (e.g. ethylbromide), C 1-6 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); (x) specific deprotection steps, such as deprotection of an /V-Boc protecting group by reaction in the presence of an acid, or, a hydroxy group protected as a silyl ether (e.g.
  • a feri-butyl-dimethylsilyl protecting group may be deprotected by reaction with a source of fluoride ions, e.g. by employing the reagent tetrabutylammonium fluoride (TBAF).
  • TBAF reagent tetrabutylammonium fluoride
  • Wiley &Sons Ltd Chichester, UK, 2002, and references cited therein;
  • the substituents R 1 , R 2 , R 3 , R 4 and X 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 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-(C-
  • a suitable coupling catalyst e.g. a palladium and/or a copper based catalyst
  • a suitable base e.g. a tri-(C-
  • 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 ierf-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)
  • 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.
  • protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
  • the type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.
  • Compounds of the invention may inhibit protein or lipid kinases, such as a PI M family kinase such as PIM-1 , PIM-2 and/or PIM-3, for example as may be shown in the tests described below and/or in tests known to the skilled person.
  • 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. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) is desired and/or required.
  • the term "inhibit” may refer to any measurable reduction and/or prevention of catalytic kinase (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) 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. a PIM family kinase such as PIM-1, PIM-2 and/or PIM-3) 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.
  • test or marker for example in an in vitro or in vivo assay or test, such as one described hereinafter, or otherwise another suitable assay or test known to those skilled in the art) or subjective (e.g. the subject gives an indication of or feels an effect).
  • Compounds of the invention may be found to exhibit 50% inhibition of a protein or lipid kinase (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) 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.
  • a protein or lipid kinase e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3
  • a concentration of 100 ⁇ or below for example at a concentration of below 50 ⁇ , or even below 10 ⁇ , such as below 1 ⁇
  • an assay or other test
  • 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. a PIM family kinase such as PIM-1, PIM-2 and/or PIM-3) is known to play a role and which are characterised by or associated with an overall elevated activity of that protein kinase (due to, for example, increased amount of the kinase or increased catalytic activity of the kinase).
  • a protein or lipid kinase e.g. a PIM family kinase such as PIM-1, PIM-2 and/or PIM-3
  • Compounds of the invention (alone or in combination with another active) may be shown to be active e.g. in the biochemical assays described herein, may be shown to have predictive activity based on e.g.
  • the phosphorylation assay described herein may reduce the rate of cell proliferation e.g. as may be shown in the cell proliferation assays described herein (for instance using cancer cell lines (e.g. known commercially available ones), such as those described herein).
  • cancer cell lines e.g. known commercially available ones
  • 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. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3).
  • a disease/disorder arising from abnormal cell growth, function or behaviour associated with the protein or lipid kinase (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3).
  • 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 such as asthma, allergy and Chrohn's disease
  • immunosuppression such as transplantation rejection and autoimmune diseases
  • disorders commonly connected with organ transplantation such as asthma, allergy and Chrohn's disease
  • 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 cell 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 passage
  • carcinoma
  • 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
  • protein or lipid kinase e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3
  • a method of treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with protein or lipid kinases e.g.
  • PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3
  • PIM-1 a PIM family kinase
  • PIM-2 a PIM-2 and/or PIM-3
  • PIM-3 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.
  • the term "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. a PIM family kinase, such as PIM-1, PIM-2 and/or PIM-3, preferably PI3K, such as class I PI3K, Flt3, EGFR, mTOR and/or MEK) and/or 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). For instance, compounds of the invention may be combined (e.g.
  • compounds of the invention may be combined (e.g. sequentially, concomitantly or simultaneously administered) with an agent that modulates the Ras/Raf/Mek pathway (e.g. an inhibitor of MEK), the Jak/Stat pathway (e.g. an inhibitor of Jak), the PI3K Akt pathway (e.g. an inhibitor of Akt), 012 050091 the DNA damage response mechanism (e.g. an inhibitor of ATM or ATR) or the stress signaling pathway (e.g. an inhibitor of p38 or NF-KB).
  • an agent that modulates the Ras/Raf/Mek pathway e.g. an inhibitor of MEK
  • the Jak/Stat pathway e.g. an inhibitor of Jak
  • the PI3K Akt pathway e.g. an inhibitor of Akt
  • 012 050091 the DNA damage response mechanism (e.g. an inhibitor of ATM or ATR) or the stress signaling pathway (e.g. an inhibitor of p38 or NF-KB).
  • RTK receptor tyrosine kinase
  • an Akt or PI3-K inhibitor such as GDC-0941;
  • a therapeutic monoclonal antibody such as the HER2 inhibitor trastuzumab
  • a MEK inhibitor such as PD-0325901
  • a B-Raf inhibitor such as GDC-0879 or PLX-4720;
  • an anthracyclin such as doxorubicin
  • (x) a taxane, such as paclitaxel or, particularly, docetaxel (Taxotere);
  • a platin such as carboplatin or, particularly, cisplatin
  • nucleotide analog such as 5-fluorouracil (5-FU) or gemcitabine
  • a hormone therapeutic agent such as an estrogen receptor antagonist e.g. tamoxifen;
  • an mTOR inhibitor such as rapamycin
  • a cyclin dependent kinase inhibitor e.g. a CDK6 or CDK4 inhibitor, such as PD-0332991
  • a CDK6 or CDK4 inhibitor such as PD-0332991
  • xix an agent that modulates the DNA damage response mechanism and/or the stress signaling pathway, e.g. an inhibitor of ATM or ATR, an inhibitor of p38 and/or NF-KB.
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with 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.
  • compounds of the invention may be combined (e.g. sequentially, concomitantly or simultaneously administered) with other therapeutic agents (e.g. chemotherapeutic agents), and such combinations may be useful as medicaments.
  • other therapeutic agents e.g. chemotherapeutic agents
  • Compounds of the invention may be combined (e.g. sequentially, concomitantly or simultaneously administered) with other therapeutic agents for use in the treatment of a disease or condition as mentioned herein, such as a disease or condition in which the inhibition of growth of cancer cells are required and/or desired.
  • a disease or condition such as a disease or condition in which the inhibition of growth of cancer cells are required and/or desired.
  • Such disease or conditions include hyperproliferative disorders, particularly, cancer (e.g. cancer in mammals, particularly, humans).
  • cancers e.g. cancer in mammals, particularly, humans.
  • Specific cancers that may be mentioned include those mentioned above.
  • Such active ingredients in combinations may act in synergy.
  • compounds of the invention may be combined (e.g. sequentially, concomitantly or simultaneously administered) with known chemotherapeutic agents (as may be demonstrated by the examples, for instance where a compound of the examples is employed in combination and inhibits cellular proliferation in vitro), for instance:
  • a PI3K inhibitor such as GDC-0941 ;
  • an EGFR inhibitor such as Lapatinib
  • a MEK inhibitor such as PD-0325901 ;
  • a CDK4/6 inhibitor such as PD-0332991.
  • GDC-0941 is a lead phosphatidylinositol-3 kinase (PI3K) inhibitor from a series of oral, small-molecule PI3K and/or mTOR inhibitors, for the potential oral treatment of cancer (see, for example, WO 2006/046031 , US 7872003, WO 2007/129161 , WO 2009/036082, WO 2009/055730, WO 2009/117277, WO 2010/105008, WO 2010/ 10782, WO 20 1/054620 and WO 2011/130654).
  • PI3K lead phosphatidylinositol-3 kinase
  • GDC-0941 is named as 2-(1 H-lndazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl- thieno[3,2-d]pyrimidine and has the structure:
  • Lapatinib (TY ERB®, GW572016, Glaxo SmithKline) has been approved for use in combination with capecitabine (XELODA®, Roche) for the treatment of patients with advanced or metastatic breast cancer whose tumors over-express HER2 050091
  • Lapatinib is an ATP-competitive epidermal growth factor (EGFR) and HER2/neu (ErbB-2) dual tyrosine kinase inhibitor (see, for example, US 6727256; US 6713485; US 7109333; US 6933299; US 7084147; US 7157466; US 7141576) which inhibits receptor autophosphorylation and activation by binding to the ATPbinding pocket of the EGFRIHER2 protein kinase domain.
  • EGFR epidermal growth factor
  • HER2/neu HER2/neu
  • Lapatinib is named as [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6- ⁇ 5-[(2- methanesulfonyl-ethylamino)-methyl]-furan-2-yl ⁇ -quinazolin-4-yl)-amine- quinazolin-4-yl amine), and has the structure:
  • GDC-0879 is a B-Raf kinase inhibitor that is being investigated by Array BioPharma and Genentech for the potential treatment of cancer (see, for example, WO 2006/084015, WO 2011/028540). GDC-0879 stabilizes B-Raf/C- Raf heterodimers and is believed to effectively block the MAPK signaling pathway and decrease tumor growth. GDC-0879 is named as 5-[1-(2-hydroxy-ethyl)-3- pyridin-4-yl-1 H-pyrazol-4- -indan-1-one oxime and has the structure:
  • the MEK inhibitor PD-0325901 (CAS RN 391210-10-9, Pfizer) is a second- generation, non-ATP competitive, allosteric MEK inhibitor for the potential oral tablet treatment of cancer (see, for example: US 6960614; US 6972298; US 2004/1147478; and US 2005/085550).
  • PD-0325901 is named N-((R)-2,3- dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and has the structure:
  • PD-332991 is a lead from a series of cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) inhibitors that is being developed for the potential oral treatment of cancer including diffuse large B-cell lymphoma (see, for example, WO 03/062236, WO 2005/005426, WO 2005/094830 and WO 2008/032157).
  • PD-332991 is named as 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H- pyrido[2,3-d]pyrimidin-7-one and has the structure:
  • a method of treatment of a disease which is associated with the inhibition of protein or lipid kinase (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) 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.
  • a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3
  • PIM-1 a PIM family kinase
  • PIM-2 a PIM-2 and/or PIM-3
  • PIM-3 a PIM family kinase
  • 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.
  • bringing into association we mean that the two components are rendered suitable for administration in conjunction with each other.
  • kits of parts as hereinbefore defined, by bringing the two components "into association with” each other, we include that the two components of the kit of parts may be:
  • 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. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3).
  • a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3.
  • 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
  • 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.
  • 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.
  • 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-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)
  • H1299 cells overexpressing PIM1 H1299Pim1
  • DMSO Plates 96-well- Polystyrene, Untreated, Round-Bottom plates from Costar (Cat #3797)
  • Antibodies phosphor Bad S112 antibody from Cell Signaling (cat. #9291S), anti rabbit conjugated with peroxidise from Amersham (cat.#3619)
  • MTT proliferation assays
  • Table 5 shows the combination index (CI) of combinations of certain example compounds and various chemotherapeutic agents in the MTT in vitro cell proliferarion assays.
  • a combination index score is calculated by the Chou and Talalay method (CalcuSyn software, Biosoft). The strength of synergy is scored using the ranking system Chou and Talalay: CI less than 0.8 indicates synergy, CI between 0.8 and 1.2 indicates additivity and CI greater than 1.2 indicates antagonism.
  • the EC50 values of representative combinations were also calculated.
  • the individually measured EC50 values of the chemotherapeutic agent and the example compounds are compared to the EC50 value of the combination.
  • the cell lines are characterized by tumor type.
  • DCM dichloromethane
  • MeOH means methanol
  • THF means tetrahydrofuran
  • DMA means dimethylacetamide
  • DMF means dimethylformamide
  • DME means 1 ,2-dimethoxyethane
  • EtOAc means ethyl acetate
  • Pd(PPh 3 ) means tetrakis(triphenylphosphine)palladium
  • DIPEA means diisopropylethylamine
  • TEA means triethylamine
  • HATU means 0-(7-azabenzotriazole-1 -yl)-1 , 1 ,3,3-tetramethyiuronium hexafluorophosphate
  • BINAP means (R)/(+J-2,2'-bis(diphenylphosphino)-1,r-binaphtyl
  • min means minutes
  • NMR spectra were recorded in 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 1100 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% 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% to 40% of B within 8 min at 50 °C, DAD.
  • Solvent A water with 0.1% formic acid
  • Solvent B acetonitrile with 0.1% formic acid. Gradient: 0% to 30% 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% to 95% of B within 4 min at 50°C, DAD.
  • Reversed phase HPLC was carried out on a Gemini C18 column (50 x 2 mm, 3 um).
  • Solvent A water with 0.1% formic acid
  • Solvent B acetonitrile with 0.1% formic acid.
  • Gradient 0% to 30% of B within 4 min at 50°C, DAD.
  • “Found mass” refers to the most abundant isotope detected in the HPLC-MS.
  • the crude product was purified by flash chromatography Biotage eluting with DCM-EtOAc 0-100% or by CCTLC on a chromatotron (eluent: DCM/MeOH, 96/4) to give the desired product.
  • the intermediate compounds of Table 2 were prepared according to the general procedure F.
  • Biological activity in PIM1 , PIM2 and PIM3 for certain examples is represented in Table 4 by semi-quantative results: IC50 >1 ⁇ (*), IC50 ⁇ 100 nM (***) > 100 nM ⁇
  • CDCI3 ⁇ 8.43 (s, 1H), 8.28 (d, J 5.7 Hz, 1 H), 7.91 (m, 2H), 4.40 (m, 2H), 3.98 (s, 3H),

Abstract

L'invention concerne des composés de formule I, dans laquelle R1, R2, R3 et R4 (et la fraction -CH2-CH2) ont les significations données dans la description, et des esters, amides, solvates ou sels pharmaceutiquement acceptables de ceux-ci, les composés étant utiles dans le traitement de maladies dans lesquelles l'inhibition d'une protéine ou d'une lipide kinase (par exemple une kinase de la famille PIM, telle que PIM-1, PIM-2 et/ou PIM-3) est souhaitée et/ou nécessaire, et en particulier dans le traitement du cancer ou d'une maladie proliférative.
PCT/GB2012/050091 2011-01-18 2012-01-17 Dérivés de triazolo[4,3-b]pyridazines au cycle 6,7 fusionné utilisés en tant qu'inhibiteurs de pim WO2012098387A1 (fr)

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WO2016180833A1 (fr) 2015-05-11 2016-11-17 Basf Se Procédé de préparation de 4-amino-pyridazines
WO2018082964A1 (fr) 2016-11-04 2018-05-11 Basf Se Procédé de production de pyridazinyle-amides dans une synthèse one pot
US10513498B2 (en) 2014-07-31 2019-12-24 Basf Se Process for preparing pyrazoles
WO2021233861A1 (fr) 2020-05-19 2021-11-25 Bayer Aktiengesellschaft (thio)amides azabicycliques en tant que composés fongicides
WO2021249995A1 (fr) 2020-06-10 2021-12-16 Bayer Aktiengesellschaft Hétérocycles à substitution azabicyclyle utilisés comme fongicides

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