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WO2013005057A1 - Nouveaux composés - Google Patents

Nouveaux composés Download PDF

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Publication number
WO2013005057A1
WO2013005057A1 PCT/GB2012/051606 GB2012051606W WO2013005057A1 WO 2013005057 A1 WO2013005057 A1 WO 2013005057A1 GB 2012051606 W GB2012051606 W GB 2012051606W WO 2013005057 A1 WO2013005057 A1 WO 2013005057A1
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Prior art keywords
optionally substituted
alkyl
formula
compound
substituents selected
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PCT/GB2012/051606
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English (en)
Inventor
Joaquín PASTOR FERNÁNDEZ
Sonia MARTÍNEZ GONZÁLEZ
Carmen BLANCO-APARICIO
Sonsóles RODRÍGUEZ-ARÍSTEGUI
Cristina Ana GÓMEZ DE LA OLIVA
Ana Isabel HERNÁNDEZ HIGUERAS
Esther GONZÁLEZ CANTALAPIEDRA
Nuria AJENJO DÍEZ
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Centro Nacional De Investigaciones Oncológicas (Cnio)
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Publication of WO2013005057A1 publication Critical patent/WO2013005057A1/fr

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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
    • A61P35/00—Antineoplastic agents

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, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.
  • PIM-1 is the protooncogene activated by murine leucemia virus (Provirus Integration site for Moloney murine leucemia virus - MoMuLV) that induces T-cell lymphoma [Cuypers, H.T., et. al. Cell, 1984, 37, 141-150].
  • the expression of the protooncogene produces a non-transmembrane serine/threonine kinase of 313 residues, including a kinase domain consisting of 253 amino acid residues.
  • Two isoforms are known through alternative initiation (p44 and p33) [Saris, C.J.M. et al. EMBO J. 1991, 10, 655-664].
  • PIM-1 , PIM-2 and PIM-3 phosphorylate protein substrates that are important in cancer neogenesis and progression.
  • PIM-1 phosphorylates inter alia p21, Bad, c-myb, Cdc 25A and elF4B (see e.g. Quian, K. C. et al, J. Biol. Chem. 2005, 280(7), 6130-6137, and references cited therein).
  • 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 PIM-1 can promote STAT3-mediated cell cycle progression and antiapoptosis [Shirogane, T. et si., 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.
  • chromosomal translocation of PIM-1 leads to overexpression of PIM-1 in diffuse large cell lymphoma.
  • a number of missense mutations in PIM-1 have been reported in lymphomas of the nervous system and AIDS-induced non-Hodgkins' lymphomas that probably affect PIM-1 kinase activity or stability [Pasqualucci, L. et al, Nature 2001, 412, 341-346; Montesinos-Rongen, M. et al., Blood 2004, 103, 1869-1875; Gaidano, G. et al., Blood 2003, 102, 1833-184].
  • the strong linkage between reported overexpression data and the occurrence of PIM-1 mutations in cancer suggests a dominant role of PIM-1 in tumorigenesis.
  • PIM-1 has a role in pulmonary artery hypertension (PAH), see the journal article by Paulin et al, "Singal transducers and activators of transcription-3/PIM-1 axis plays a critical role in the pathogenesis of human pulmonary arterial hypertension”.
  • targeted therapies are becoming more important. That is, therapy that has the effect of interfering with specific target molecules that are linked to tumor growth and/or carcinogenesis. Such therapy may be more effective than current treatments (e.g. chemotherapy) and less harmful to normal cells (e.g. because chemotherapy has the potential to kill normal cells as well as cancerous cells).
  • current treatments e.g. chemotherapy
  • targeted therapies may be selective (i.e. it may inhibit a certain targeted molecule more selectively as compared to other molecular targets, e.g. as described hereinafter), may have the benefit of reducing side effects and may also have the benefit that certain specific cancers can be treated (also selectively). The latter may in turn also reduce side effects.
  • International patent application WO 2005/041971 discloses inter alia fused tricyclic compounds that may bind to of ⁇ 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 0 548 923 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- b]pyridazines, 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. depression. However, 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. However, this document does not specifically relate to [1,2,4]triazolo[4,3-b]pyridazines substituted with an amino moiety and an aromatic group.
  • R 5 represents hydrogen, halo or C 1-3 alkyl optionally substituted by one or more substituents selected from fluoro and -CN;
  • X represents C -3 alkylene 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 and R independently represent C -12 (e.g. C 1-6 ) alkyl optionally substituted by one or more substituents selected from E 1 ; R 3 represents hydrogen or a substituent selected from -CI, -CN, -OH, -OCH 3 and C1-3 alkyl optionally substituted by one or more fluoro atoms;
  • R 4 represents: -0-C 1-6 alkyl-OCH 3 ; -0-C 1-6 alkyl-NH 2 ; -0-C 1-6 alkyl-N(H)(CH 3 ); -[0]o-i-(CH 2 ) n i-heterocycloalkyl (in which n1 is 0, 1 , 2 or 3; and heterocycloalkyl is optionally substituted by one or more substituents selected from Q 1 ); -C(0)-[fragment IA]; -N(R 4a )-C(0)-R b ; -(CH 2 ) m -[fragment IA] (in which m represents 1 or 2); -(CH 2 ) n 2-OR 4c (in which n2 represents 0, 1 or 2); aryl (optionally substituted by one or more substitutents selected from E 3 ); heteroaryl (optionally substituted by one or more substitutents selected from E 3 ); or a fragment of formula IA;
  • R 4a represents hydrogen or C 1-6 alkyl optionally substituted by one or more substituents selected from halo;
  • R 4b represents C 1-6 alkyl, heterocycloalkyl, aryl or heteroaryl (which latter four groups are optionally substituted by one or more substitutents selected from halo, C -3 alkyl and -OC -3 alkyl);
  • R 4c represents hydrogen, C 1-6 alkyl, heterocycloalkyl, aryl or heteroaryl (which latter four groups are optionally substituted by one or more substitutents selected from halo, C 1-3 alkyl and -OC 1-3 alkyl); each fragment of formula IA independently represents:
  • (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);
  • (b) 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 x 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. forming a bridged structure); or
  • (c) 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:
  • two E 3 groups may be attached to adjacent carbon atoms of an aryl group, so forming a fused bicycle), may be linked together to form a 3- to 12-membered ring (in which each of the atoms of the ring may be a carbon atom or a heteroatom), optionally containing one or more (e.g. one to three) unsaturations (e.g.
  • R 6o R 6i anc R 62 independently represent hydrogen or C 1-6 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.
  • esters or amides such as those defined herein may be mentioned, as well as pharmaceutically acceptable solvates or salts.
  • Specific salts that may be mentioned include HCOOH and HCI salts.
  • Oxide salts, such as N-oxides (e.g. in which there is a "N + -0 " moiety present) may also be mentioned (for instance, when the nitrogen atom is an integral part of the compound of the invention).
  • 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 5-10 aryl and/or C 5- io aryl-C 1-6 alkyl- esters.
  • amides of carboxylic acids of compounds of the invention
  • Pharmaceutically acceptable amides include those of the formula -CiOJNfR ⁇ R 22 , in which R z1 and R 22 independently represent optionally substituted C -6 alkyl, C ⁇ o aryl, or C 5-10 aryl-C 1-6 alkylene-.
  • Ci-e 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).
  • Compounds of the invention may contain double bonds and may thus exist as E (entussi) and Z (zusammen) geometric isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g. if a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention).
  • tautomer or tautomeric form
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganisation of some of the bonding electrons.
  • Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e.
  • a resolution for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
  • stereoisomers including but not limited to diastereoisomers, enantiomers and atropisomers
  • mixtures thereof e.g. racemic mixtures
  • stereoisomers are included within the scope of the invention.
  • all stereoisomers are contemplated and included as the compounds of the invention.
  • stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 1 C, 13 C, 1 C , 13 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 8 F, 36 CI, 123 l, and 125 l.
  • Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and 14 C
  • Tritiated ( 3 H) and carbon-14 ( 1 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 1-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.
  • 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. In the case of the C -3 alkylene groups that X may represent, these alkylene groups are 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.
  • 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 (such as 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.
  • heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2-q heterocycloalkenyl (where q is the upper limit of the range) group.
  • C 2-q heterocycloalkyl groups that may be mentioned include 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-dihydropyrrolyl), dioxolanyl (including 1 ,3-dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4- dioxanyl), dithianyl (including 1,4-dithiany
  • 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 ⁇ o, such as (e.g. C 6- io) 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 10)) ring carbon atoms, in which at least one ring is aromatic.
  • C 6- i 0 aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl.
  • the point of attachment of aryl groups may be via any atom of the ring system. For example, when the aryl group is polycyclic the point of attachment may be via atom including an atom of a non- aromatic ring. However, when aryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring.
  • heteroaryl when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S.
  • Heteroaryl groups include those which have 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).
  • heteroaryl groups that may be mentioned are preferably monocyclic.
  • heteroaryl group When the heteroaryl group is polycyclic the point of attachment may be via any atom including an atom of a non-aromatic ring. However, when heteroaryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. Heteroaryl groups that may be mentioned include 3,4-dihydro-1/-/-isoquinolinyl, 1 ,3-dihydroisoindolyl, 1 ,3-dihydroisoindolyl (e.g.
  • 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-2H-1 ,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazoly
  • 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.
  • Heteroaryl groups may also be in the N- or S- oxidised form. Heteroaryl groups mentioned herein may be stated to be specifically monocyclic or bicyclic.
  • the heteroaryl group is monocyclic or bicyclic (although for the purposes of this invention, heteroaryl groups are preferably monocyclic).
  • the heteroaryl is bicyclic, then it may 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 , R 2 and X- containing ring may represent a 5-, 6- or 7-membered ring and hence a compound of one of the following formulae:
  • the squiggly lines represent the point of attachment to the remainder of the compound of formula I and R 1 , R 2 , R 3 , X 1 and X 2 are as hereinbefore defined.
  • the most preferred compunds are those in which the R 1 and R 2 -containing ring is 5-, 6- or 7-membered, particularly those that are 6-membered.
  • the -CH 2 -, -CH 2 CH 2 - and -CH 2 CH 2 CH 2 - moieities linking R 1 and R 2 are optionally substituted as defined herein (by one or more substituents selected from E 2 ).
  • preferred compounds of the invention include those in which: R 1 may 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 )-.
  • 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 a or R b , or Q 1 , Q 2 , Q 4 or Q 5 may represent include 8- to 12- (e.g. 9- or 10-) membered rings containing one to four (e.g. one to three, or, preferably, one or two) heteroatoms selected from sulfur, oxygen and nitrogen (e.g. an indolyl group).
  • Preferred heterocycloalkyl groups that R a or R b or Q 1 , Q 2 , Q 4 or Q 5 may independently represent include 4- to 8-membered (e.g. 5- or 6-membered) heterocycloalkyl groups, which groups preferably contain one or two heteroatoms (e.g. sulfur or, preferably, nitrogen and/or oxygen heteroatoms), so forming for example, an optionally substituted azetidinyl, azepinyl, piperazinyl or tetrahydropyridinyl group or, particularly, an optionally substituted pyrrolidinyl, piperidinyl, morpholinyl or tetrahydropyranyl group.
  • 4- to 8-membered (e.g. 5- or 6-membered) heterocycloalkyl groups which groups preferably contain one or two heteroatoms (e.g. sulfur or, preferably, nitrogen and/or oxygen heteroatoms), so forming for example, an optionally substituted azetidin
  • C 3-6 cycloalkyl groups that R a or R b or Q 1 , Q 2 , Q 4 or Q 5 may independently represent include optionally substituted C3-8 (e.g. C ⁇ ) cycloalkyl groups, such as cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.
  • C3-8 e.g. C ⁇
  • Further preferred compounds of the invention include those in which:
  • R 10a , R 1 a 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 together as defined herein, for example when attached to the same or, preferably, adjacent carbon atoms), but (e.g. any two E 1 , E 2 , E 4 , E 5 , E 6 , E 7 , E 8 and/or E 9 ) are preferably not linked together;
  • each R 50 , R 51 , R 52 and R 53 substituent independently represents, on each occasion when used herein, hydrogen or C 1-6 (e.g. C-1.3) alkyl optionally substituted by one or more substituents selected from fluoro;
  • R 60 , R 61 and R 62 independently represent hydrogen or C -3 (e.g. C 1-2 ) alkyl optionally substituted by one or more fluoro atoms.
  • Preferred compounds of the invention include those in which:
  • each J 1 , J 2 , J 3 , J 4 , J 5 and J 6 independently represent heterocycloalkyl or C 1-6 alkyl (which latter two groups are 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 (e.g. C M ) alkyl optionally substituted by one or more fluoro atoms;
  • each R 60 , R 61 and R 62 independently represents hydrogen or C 1-2 alkyl (e.g. methyl).
  • More preferred compounds of the invention include those in which:
  • R d , R d2 and R d3 independently represent Ci_ 6 (e.g. C 1-4 or, particularly, C 1-3 ) alkyl optionally substituted by one or more substituents selected from E ;
  • halo e.g. fluoro
  • R 22 represents C 1-3 alkyl or hydrogen
  • 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 represents alkyl (e.g. C -4 alkyl) or a 4- to 8-membered heterocycloalkyl group;
  • each R 50 , R 51 , R 52 and R 53 independently represents H or C 1-4 alkyl.
  • More preferred compounds of the invention include those in which:
  • R 1 and R 2 independently represent -N(R 6 )-, -O- or -C(R 6 )(R 6a )- (and more preferably, R and R 2 independently represent -N(R 6 )- or -0-);
  • R 6 and R 6a independently represent H or R d3 ;
  • R d3 represents Ci -3 alkyl (e.g. methyl or ethyl) optionally substituted by one or two (e.g. one) substituent selected from E 1 ;
  • R a represents hydrogen or C -4 alkyl (optionally substituted by one or more halo atoms);
  • R 4b represents C -4 alkyl or a heterocycloalkyl group (which latter two groups are optionally substituted by one or more substituents selected from halo and C 1-2 alkyl);
  • R c represents hydrogen, C 1-4 alkyl or a heterocycloalkyl group (which latter two groups are optionally substituted by one or more substituents selected from halo and C 1-2 alkyl) and, more preferably, R 4c represents hydrogen or C 1-4 alkyl;
  • X represents C 2- 3 alkylene optionally substituted by one or more (e.g. one or two) substituents selected from E 2 ;
  • E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , E 7 , E 8 and E 9 independently represent Q 4 or C 1-6 (e.g. C M ) alkyl optionally substituted by one or more (e.g. two or, preferably, one) substituent(s) selected from Q 5 ;
  • E 7 , E 8 and E 9 independently represent Q 4 ;
  • R 10a and R 11a independently represent H or, preferably, C 1-3 alkyl (e.g. methyl);
  • R 20 represents H, C 1-4 alkyl (optionally substituted by one or more J 4 substituents), heterocycloalkyl (e.g. a 4- to 8-membered or preferably 5- or 6- membered heterocycloalkyl group; optionally substituted by one or more J 4 substituents) or aryl (e.g. phenyl; optionally substituted by one or more J 5 substituents);
  • heterocycloalkyl e.g. a 4- to 8-membered or preferably 5- or 6- membered heterocycloalkyl group; optionally substituted by one or more J 4 substituents
  • aryl e.g. phenyl; optionally substituted by one or more J 5 substituents
  • R 21 represents hydrogen or C 1-4 (e.g. C 1-3 ) alkyl
  • R 22 represents hydrogen
  • J 1 , J 2 , J 3 , J 4 , J 5 and J 6 independently represent Q 7 or a heterocycloalkyl group (e.g. a 4- to 8-membered such as a 5- or 6-membered heterocycloalkyl group); J 1 , J 2 , J 3 , J 5 and J 6 more preferably represent Q 7 (e.g. in which Q 7 represents halo);
  • Q 7 represents halo, -N(R 50 )R 51 , -OR 50 or -S(0) 2 R 5 °;
  • Q 8 represents halo (e.g. fluoro);
  • R 50 and R 51 independently represent hydrogen or C -2 alkyl
  • R 60 , R 61 and R 62 independently represent hydrogen or C -2 alkyl.
  • the X 1 and X 2 -containing bicycles contain at least three nitrogen atoms.
  • the bicycles (at the X 1 position) are optionally substituted, i.e. R 5 represents hydrogen or a substituent.
  • R 5 represents hydrogen, halo or unsubstituted Ci -2 alkyl. Most preferably R 5 represents hydrogen.
  • Most preferred bicycles are the following:
  • each R 7 preferably represents hydrogen or a substituent selected from -F, -CI, -Br, -CN, methyl, ethyl, methoxy, trifluoromethyl and triflouromethoxy (most preferably, each R 7 represents hydrogen; and hence the X a to X 9 - containing bicycle is only substituted with one substituent (the R 4 substituent)).
  • Preferred compounds of the invention include those in which R 4 represents:
  • n1 represents 0 or 1 ;
  • the ring so forming is preferably not fused to another ring (to form a bicycle) and preferably does not comprise a linker group (to form a bridged structure), nor does it comprise a second ring attached via a common carbon atom (to form a spiro cycle);
  • R 4 when R 4 represents aryl, it is preferably monocyclic e.g. phenyl, preferably substituted by one substituent (e.g. located at the meta or para-position) selected from E 3 ;
  • R 4 when R 4 represents heteroaryl, it is preferably a monocyclic 5- or 6-membered ring (e.g. containing one or two heteroatom(s) preferably selected from nitrogen and oxygen; so forming e.g. a pyridyl, furanyl, pyrazolyl or pyrimidinyl group, such as 4-pyridyl, 2-furanyl, 4-pyrazolyl or 5-pyrimidinyl);
  • heterocycloalkyi group is preferably 4- to 8-membered (e.g. 5- or, preferably 6-membered), preferably containing one or two (e.g. one) heteroatom(s) (e.g. nitrogen) so forming a piperidinyl (e.g. 4-piperidinyl) group;
  • R 4 when R 4 represents heterocycloalkyi, it preferably represents a 5- or 6-membered group optionally containing one or two (e.g. one) double bond(s) and preferably containing one or two (e.g. one) heteroatom, preferably selected from nitrogen, so forming e.g. piperidinyl containing an optional double bond;
  • R a and R b independently represent hydrogen, C 1-4 alkyl (e.g. ethyl) (preferably at least one of R a and R b represents hydrogen) or a substituent selected from R aby (as defined hereinafter);
  • R 4 represents a fragment of formula IA or -CH 2 -[fragment IA]
  • one of R a and R b represents hydrogen or d -3 alkyl and the other represents hydrogen or a substituent selected from R abx (as defined hereinafter); or R a and R b are linked together to form a 4- to 8-membered ring (e.g. a 5- or preferably 6-membered group containing one or two heteroatoms; e.g. a piperidinyl or piperazinyl group) optionally substituted by one or more substituents selected from E 4 .
  • a 4- to 8-membered ring e.g. a 5- or preferably 6-membered group containing one or two heteroatoms; e.g. a piperidinyl or piperazinyl group
  • Preferred compounds of the invention include those in which:
  • R 4a represents Ci. 3 alkyl or, preferably, hydrogen
  • R 4b represents C 1-4 alkyl (e.g. d -2 alkyl, such as methyl) or a 5- or 6-membered heterocycloalkyi group (e.g. in which there is one or two (e.g. one) heteroatom (s), preferably a nitrogen heteroatom; so forming e.g. piperidinyl, such as 4- piperidinyl);
  • R aby and R a x independently represent: acyclic C 1-4 alkyl (e.g. methyl or ethyl) optionally (and preferably) substituted by one or more (e.g. one) substituent(s) selected from Q 1 ; cycloalkyl (e.g. a 3- to 7-membered group, e.g. cyclohexyl) optionally (and preferably) substituted by one or more (e.g. one) substituent(s) selected from Q 1 ; or heterocycloalkyi (e.g. a 5-, 6- or 7-membered heterocycloalkyi group, containing one or two (e.g.
  • acyclic C 1-4 alkyl e.g. methyl or ethyl
  • R aby and R a x independently represent: acyclic C 1-4 alkyl (e.g. methyl or ethyl) optionally (and preferably) substituted by one or more (e
  • heteroatom(s) in which one is preferably selected from nitrogen and oxygen and hence may represent a piperidinyl group, e.g. 4-piperidinyl, a tetrahydropyranyl group, e.g. 4- tetrahydropyranyl or azepanyl, e.g. 4-azepanyl) optionally substituted by one or more subsitutents selected from Q ;
  • R aby and R ab independently represent acyclic C 1-4 alkyl (e.g. methyl) optionally substituted by one or more (e.g. one) substituent(s) selected from Q 1 ; 5- or 6-membered cycloalkyl (e.g. cyclohexyl) optionally (and preferably) substituted by one or more (e.g. one) substituent(s) selected from Q 1 ; or heterocycloalkyl (e.g. a 6-membered heterocycloalkyl group, containing one heteroatom preferably selected from nitrogen; and hence may represent a piperidinyl group, e.g. 4-piperidinyl) and which heterocycloalkyl group is unsubstituted or substituted with one Q 1 substituent on a nitrogen atom.
  • a piperidinyl group e.g. 4-piperidinyl
  • Q 1 (e.g. when present on an alkyl, e.g. acyclic alkyl, group) represents a heterocycloalkyl group or a heteroaryl group;
  • Q 1 when Q 1 represents a heterocycloalkyl group, it is preferably a 4-, 5- or 6- membered heterocycloalkyl group (containing one or two (e.g. one) heteroatom(s) in which one is preferably selected from nitrogen and oxygen; and hence may represent a piperidinyl group, e.g. 4-piperidinyl, tetrahydropyranyl, e.g. 4-tetrahydropyranyl, azetidinyl, e.g. 3-azetidinyl group, or piperazinyl, e.g. 1- piperazinyl) optionally substituted by one or more subsitutents selected from E 5 (although the heterocycloalkyl group is preferably unsubstituted);
  • a piperidinyl group e.g. 4-piperidinyl, tetrahydropyranyl, e.g. 4-tetrahydropyranyl, azetidinyl,
  • Q 1 when Q 1 represents a heteroaryl group, it is preferably a 5- or, especially, a 6- membered heteroaryl group, containing one or two (preferably one) heteroatom, preferably selected from nitrogen (so forming pyridyl, e.g. 4-pyridyl), which heteroaryl group is optionally substituted by one or more substituents selected from E 6 (but is preferably unsubsubstituted);
  • Q 1 (e.g. when present on a cycloalkyl group) represents -N(R 10a )R 1a (e.g. -NH 2 );
  • Q 1 (e.g. when present on the nitrogen atom of a heterocycloalkyl group) represents C 1-4 (e.g. C -3 ) alkyl (e.g. methyl, ethyl or cyclopropyl; which alkyl group is optionally substituted by E 5 , so forming e.g. -CH 2 CH 2 -OCH 3 ) or -S(O) 2 R 10a (e.g. -S(0) 2 CH 3 );
  • E 3 represents Q 4 or C 1-4 (e.g. C -2 ) alkyl (e.g. ethyl) optionally substituted by one or two (e.g. one) substituents selected from Q 5 ;
  • E 4 (which may be present on a nitrogen heteroatom) represents Q 4 or C -3 alkyl (e.g. methyl) optionally substituted by one or two (e.g. one) substituent(s) selected from Q 5 ;
  • E 5 (e.g. when present on a nitrogen heteroatom) represents C 1-2 alkyl (e.g. methyl) optionally substituted by one or two (e.g. one) Q 5 substituent;
  • E 5 (e.g. when present on an alkyl group) represents Q 4 ;
  • Q 5 represents -N(R 20 )R 21 , -OR 20 or aryl (e.g. unsubstituted phenyl);
  • R 10a and R 11a independently represent C -3 alkyl or, preferably, hydrogen;
  • R 20 and R 21 independently represent hydrogen, C 1-3 alkyl (e.g. methyl; which alkyl group is optionally substituted by one or more (e.g. one) substituent(s) selected from J 4 ), heterocycloalkyl (e.g. a 5- or preferably 6-membered heterocycloalkyl group; preferably containing one or two (e.g. one) heteroatom; so forming e.g. a piperidinyl group) or aryl (e.g. unsubstituted phenyl);
  • C 1-3 alkyl e.g. methyl; which alkyl group is optionally substituted by one or more (e.g. one) substituent(s) selected from J 4 ), heterocycloalkyl (e.g. a 5- or preferably 6-membered heterocycloalkyl group; preferably containing one or two (e.g. one) heteroatom; so forming e.g. a piperidinyl group) or aryl (
  • J 4 represents Q 7 or a 5- or 6-membered heterocycloalkyl group, e.g. containing one or two (e.g. one) heteroatom (s), preferably selected from nitrogen (so forming e.g. a piperidinyl, e.g. 4-piperidinyl group);
  • Q 7 represents -S(0) 2 R 50 ;
  • R 50 represents C 1-4 alkyl (e.g. C -2 alkyl, such as methyl);
  • E 3 substituents include amino (e.g. -NH 2 , -N(CH 3 ) 2 , -N(H)-[4-piperidinyl] and/or -N(H)-CH 2 -[4-piperidinyl]), hydroxy (-OH), alkoxy (e.g. -OCH 3 ), alkylalkoxy (e.g. -CH 2 CH 2 OCH 3 ), sulfonamido (e.g. -N(H)S(0) 2 CH 2 CH 3 ) and substituted alkylamino (e.g. -CH 2 -N(H)-CH 2 CH 2 -S(0) 2 CH 3 );
  • E 4 substituents on cyclic groups formed by the linkage of R a and R b ) include amino and alkylamino groups, e.g. -NH 2 and -CH 2 -NH 2 , alkylhydroxy groups (e.g. -CH 2 CH 2 OH) and alkylsulfonyl groups (e.g. -S(0) 2 CH 3 );
  • preferred E 5 substituents include methyl and benzyl.
  • R 4 groups of compounds of the invention include the following:
  • the squiggly line represents the point of attachment to the requisite X a to X 9 -containing bicycle of the compound of formula I
  • R 3 '" represents R a or R b
  • the other integers e.g. E 3 , E 4 , E 5 , E 6 and Q 1 ; which are optional substituents that may be attached to specific atoms, or, may be depicted as 'floating', in which case the relevant group is optionally substituted by one or more of those E 3 /E 4 /Q /E 5 /E 6 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).
  • R 1 , R 2 and X-containing rings of the compounds of the invention include:
  • R 3 groups in the compounds of the invention include those in which: R 3 represents hydrogen or a substituent selected from -CI, C 1-3 alkyl (preferably unsubstituted; e.g. methyl, cyclopropyl), -CN, -OH and -OCH 3 .
  • Preferred compounds of the invention include those in which, in the R , R 2 and X- containing ring:
  • X preferably represents C 2 - 3 alkylene (e.g. -CH 2 -CH 2 - or -CH 2 CH 2 CH 2 -) optionally substituted by one or more (e.g. one or two) substituents selected from E 2 (for instance, one or two E 2 substituents may be located on the central carbon atom of a C 3 alkylene group so forming -CH 2 C(E )(E 2 )CH 2 -, e.g. -CH 2 C(CH 3 )2CH2-);
  • E 2 represents C1-4 (e.g. C1.2) alkyl (e.g. methyl, preferably unsubstituted);
  • R 6 and R 6a preferably represent hydrogen
  • R 6 represents hydrogen or, preferably, a substituent selected from alkoxyalkyl (e.g. -CH 2 CH 2 -OCH 3 , -(CH 2 ) 3 -OCH 3 ), aryloxyalkyl (e.g. -CH 2 CH 2 -0-phenyl), C 1-4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl) or benzyl;
  • alkoxyalkyl e.g. -CH 2 CH 2 -OCH 3 , -(CH 2 ) 3 -OCH 3
  • aryloxyalkyl e.g. -CH 2 CH 2 -0-phenyl
  • C 1-4 alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl
  • benzyl e.g.
  • R 6 represents R d3 ;
  • R d3 represents C 1-4 alkyl optionally substituted by one or more (e.g. one) substituent(s) selected from E 1 ;
  • E 1 represents Q 4 ;
  • Q 4 represents -OR 20 or aryl (e.g. phenyl);
  • R 20 represents C 1-4 alkyl (e.g. C 1-2 alkyl, such as methyl) or aryl (e.g. phenyl).
  • Particular compounds of the invention include compounds of formula Al,
  • X represents C 2-3 alkylene optionally substituted by one or more substituents selected from E 2 ;
  • R 6 represents C 1-4 alkyl optionally substituted by one or more substituents selected from E 1 ;
  • R 3 represents hydrogen or a substituent selected from -CI, -CN, -OH, -OCH 3 and C 1-3 alkyl;
  • R 4 represents -[0]o-i-(CH 2 ) 0 -i-heterocycloalkyl (which heterocycloalkyl is 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 substitutents selected from E 3 ); or R 4 represents -[C(O)] 0- i-N(R a )R b ;
  • 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 nitrogen atom, and which ring optionally comprises a second ring that is a 5- to 7-membered saturated heterocycloalkyl group containing one oxygen atom, 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), all of which cyclic groups, defined by the linkage of R a and R b , are optionally substituted by one or more substituents selected from E 4 ; each Q 1 independently represents, on each occasion when used herein:
  • each R 10a , R 11a and R 12a independently represent, on each occasion when used herein, hydrogen, C ⁇ 2 alkyl (which latter group is optionally substituted by one or more substituents selected from E 7 ); each E 1 , E 2 , E 3 , E 4 , E 5 , and E 7 independently represents, on each occasion when used herein:
  • each Q 7 independently represents, on each occasion when used herein:
  • heterocycloalkyi groups that may be mentioned with respect to compounds of formula Al include non-aromatic monocyclic and bicyclic heterocycloalkyi groups in which one or two of the atoms in the ring system is other than carbon (i.e. a heteroatom), the total number of atoms in the ring system is from 4 to 10, and which groups may be saturated or unsaturated (i.e. contain one or more double and/or triple bonds, forming for example a C 2-q heterocycloalkenyl (where q is the upper limit of the range)).
  • Particular compounds of the invention include compounds of formula All,
  • X represents C 2-3 alkylene optionally substituted by one or more substituents selected from E 2 ;
  • R 6 represents C 1-4 alkyl optionally substituted by one or more substituents selected from E 1 ;
  • R 3 represents hydrogen or a substituent selected from -CI, -CN, -OH, -OCH 3 and C -3 alkyl;
  • R 4 represents heterocycloalkyi (optionally substituted by one or more substituents selected from Q ), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substitutents selected from E 3 ); or R 4 represents
  • R a and R 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 nitrogen atom, and which ring optionally comprises a second ring that is a 5- to 7-membered saturated heterocycloalkyi group containing one oxygen atom, 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), all of which cyclic groups, defined by the linkage of R a and R b , are optionally substituted by one or more substituents selected from E 4 ; each Q independently represents, on each occasion when used herein:
  • each R 10a , R 11a and R 2a independently represent, on each occasion when used herein, hydrogen, C -12 alkyl (which latter group is optionally substituted by one or more substituents selected from E 7 ); each E 1 , E 2 , E 3 , E 4 , E 5 , and E 7 independently represents, on each occasion when used herein: (') Q 4 ;
  • each Q 7 independently represents, on each occasion when used herein:
  • each R 50 and R 51 independently represents, on each occasion when used herein, hydrogen or C -2 alkyl; or a pharmaceutically acceptable ester, amide, solvate or salt thereof.
  • heterocycloalkyi groups that may be mentioned with respect to compounds of formula All include non-aromatic monocyclic and bicyclic heterocycloalkyi groups in which one or two of the atoms in the ring system is other than carbon (i.e. a heteroatom), the total number of atoms in the ring system is from 4 to 10.
  • the heterocycloalkyi group may be a piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl or azepinyl group.
  • Particular compounds of the invention include compounds of formula AIM,
  • R a and R b independently represent H or ⁇ 1-4 alkyl, (which alkyl group is optionally substituted by one or more substituents selected from Q 1 ); each Q independently represents, on each occasion when used herein, C 1-2 alkyl or heterocycloalkyi (which two groups are optionally substituted by one or more E 5 substituents); and any two E 5 groups may be linked together to form a 6-membered ring (in which each of the atoms of the ring may be a carbon atom or a heteroatom); or a pharmaceutically acceptable ester, amide, solvate or salt thereof.
  • heterocycloalkyi groups that may be mentioned with respect to compounds of formula AMI include non-aromatic monocyclic and bicyclic heterocycloalkyi groups in which one or two of the atoms in the ring system is other than carbon (i.e. a heteroatom), the total number of atoms in the ring system is from 4 to 10.
  • the heterocycloalkyi group may be a piperidinyl group.
  • Particular compounds of the invention include compounds of formula AlV,
  • R 6 represents d-4 alkyl optionally substituted by one or more substituents selected from E 1 ;
  • R 3 represents hydrogen or a substituent selected from -CI and -CH 3 ;
  • R 4 represents -[C(O)] 0 - N(R a )R b ;
  • R a and R b independently represent H, -[C(O)] 0 -i-C 1-6 alkyl, or -[C(0)]o-i-heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from Q 1 ); or R a and R b are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a 6-membered cyclic group, optionally containing one further nitrogen atom, which cyclic groups, defined by the linkage of R a and R b , are optionally substituted by one or more substituents selected from
  • each Q independently represents, on each occasion when used herein: -NH 2 , -OH, C 1-2 alkyl, or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from E 5 ); each E 1 , E 4 , and E 5 independently represent, on each occasion when used herein:
  • heterocycloalkyl groups that may be mentioned with respect to compounds of formula AlV include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which one or two of the atoms in the ring system is other than carbon (i.e. a heteroatom), the total number of atoms in the ring system is from 4 to 10.
  • the heterocycloalkyl group may be a piperidinyl, piperazinyl, azetidinyl or azepinyl group.
  • Particularly preferred compounds of the invention include those of the examples described hereinafter.
  • compounds of formula I in which R 4 represents -0-C 1-6 alkyl-OCH 3 , -O-Cvealkyl-NHz, -0-C ⁇ alkyl-N(H)(CH 3 ), -0-(CH 2 ) n -heterocycloalkyl, -OR 4c or a fragment of formula IA may be prepared by reaction of a compound of formula II, wherein L 1 represents a suitable leaving group, such as iodo, bromo, chloro or a sulfonate group (e.g.
  • R 4x -H III wherein R 4x represents represents -0-C 1-6 alkyl-OCH 3 , -0-C 1-6 alkyl-NH 2 , -0-(CH 2 ) n i-heterocycloalkyl, -OR c or a fragment of formula IA, 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(0) (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-benz
  • This reaction may be carried out under microwave irradiation reaction conditions or, alternatively, the reaction may be performed in the absence of other reagents such as catalyst, base and even solvent.
  • Such a reaction may be accompanied by a rearrangement reaction, for instance if the compound of formula III is 2,7-diaza- spiro[3.5]nonane (or the 7-protected derivative thereof, e.g. the corresponding 7- carboxylic acid 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. a bridged amine) so forming a corresponding compound of formula I in which R 4 represents 1-aza-bicyclo[2.2.1]hept-4-ylmethyl-amino;
  • L 3 represents a suitable leaving group such as one hereinbefore defined in respect of L 1 (e.g. halo, such as chloro or, preferably, bromo), and R , R 2 , X, X 1 , X 2 and R 3 are as hereinbefore defined, with a compound of formula V,
  • L 4 represents a suitable group, such as -B(OH) 2 , -BiOR ⁇ or -SniR ⁇ , in which each RTM* independently represents a C 1-6 alkyl group, or, in the case of -BiOR ⁇ , the respective R"* 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 pinacolato boronate ester group (or L 4 may represent iodo, bromo or chloro, provided that L 3 and L 4 are mutually compatible) and R 4 , X a , X b , X c , X d , X f and X 9 are as hereinbefore defined.
  • the reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2l Pd(Ph 3 P) 4 (i.e.
  • PdCI 2 (dppf).DCM palladium
  • a ligand such as PdCI 2 (dppf).DCM, f-Bu 3 P, (CeHnfeP, Ph 3 P, AsPh 3 , P(o-Tol) 3 , 1 ,2- bis(diphenylphosphino)ethane, 2,2'-bis(di-feAf-butylphosphino)-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
  • PdCI 2 (dppf).DCM f-Bu 3 P
  • CeHnfeP Ph 3 P, AsPh 3 , P(o-Tol)
  • L 1 represents a suitable leaving group as hereinbefore defined
  • X 1 , R 1 , R 2 , R 3 and X are as hereinbefore defined, with a compound of formula VII,
  • R 4 , X a , X b , X°, X d , X f and X 9 are as hereinbefore defined, under standard reaction conditions to promote the formation of the requisite triazolopyridazine bicyclic core, for example, in the presence of base, such as an organic base (e.g. triethylamine or the like), and/or an acid, such as an organic acid (e.g. para- toluenesulfonic acid or the like), and the base and acid are preferably in a ratio of about 1 :1.
  • 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 proceeded by reaction with a compound of formula III, for example as defined in respect of process step (i) above; (iv) for compounds of formula I in which R and R 2 are independently selected from -0-, -S- and -NR 6 -, reaction of a compound of formula VIII,
  • R a and R 2a independently represent -0-, -S- and -NR 6 -, and R 3 , X 1 , X 2 , X a , X b , X c , X d , X f , X 9 and R 4 are as hereinbefore defined, with a compound of formula IX, L 5 -X-L 6 IX wherein 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
  • 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, K 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, terf-butanol, dimethylformamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N- methylpyrrolidinone, tetrahydrofuran or mixtures thereof.
  • Preferred bases include f-BuOK;
  • R X1 -L 4 wherein L 4 represents a suitable leaving group, as hereinbefore defined and R 4 1 represents optionally substituted aryl or heteroaryl (which R 4 may represent) under reaction conditions such as those hereinbefore described in respect of process step (ii) above;
  • a metal alkyl oxide such as potassium terf-butoxide
  • a suitable solvent e.g. a polar aprotic solvent such as THF
  • reaction of a compound of formula XII for compounds of formula I in which R 1 and R 2 both represent -O- (and preferably X represents C 2 or, especially, C 3 alkylene), reaction of a compound of formula XII,
  • L 1a and L 2a each independently represent a suitable leaving group such as one defined hereinbefore by L 1 (e.g. chloro) and R 3 , X 1 , X 2 , X a , X b , X°, X d , X f , X 9 and R 4 are as hereinbefore defined, with a compound of formula XIII,
  • X is as hereinbefore defined (preferably C 3 alkylene), under reaction conditions such as basic conditions, e.g. in the presence of an inorganic base (such as NaH or the like) in a suitable solvent (such as a polar aprotic solvent, e.g. DMF);
  • a suitable solvent such as a polar aprotic solvent, e.g. DMF
  • an organic acid e.g. para-toluene sulfonic acid
  • an appropriate solvent e.g. an aromatic solvent, such as toluene
  • R 1 , R 2 , X, R 3 and X 1 are as hereinbefore defined, with a compound of formula XIVB, wherein X a , X b , X c , X d , X f , X 9 and R 4 are as hereinbefore defined, in the presence of appropriate reaction conditions, such as reaction in the presence of a suitable solvent (e.g. an alcoholic solvent such as ethanol) for instance at elevated temperature (e.g. at reflux), which reaction mixture may then be concentrated and taken up in another solvent (e.g. dichloromethane) in the presence of a suitable reagent (e.g. iodobenzene diacetate) to allow reaction to continue.
  • a suitable solvent e.g. an alcoholic solvent such as ethanol
  • a suitable reagent e.g. iodobenzene diacetate
  • L 1 , L 4 , X a , X b , X c , X d , X f and X 9 are as hereinbefore defined under reaction conditions such as those hereinbefore described in respect of process step (ii) above.
  • R 3 , X 1 , X 2 , R 1 , R 2 and X are as hereinbefore defined, for example by reaction in the presence of a source of halide (e.g. 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 N-chlorosuccinimide, chlorine and iodine monochloride, for instance in the presence of a suitable solvent, such as an alcohol (e.g.
  • methanol or, preferably a halogenated solvent (e.g. chloroform), and which reaction may take place under microwave irradiation conditions (e.g. at above 100°C, such as at about 120°C) or may alternatively take place in the presence of a suitable base, such as a weak inorganic base, e.g. sodium bicarbonate.
  • a suitable base such as a weak inorganic base, e.g. sodium bicarbonate.
  • L 4 and L 5 independently represent a suitable leaving group (e.g. chloro), and R 3 , L 1 are as hereinbefore defined, with a compound of formula XVIII,
  • 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. NaOf-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. NaOf-Bu in the presence of a solvent such as acetonitrile
  • reaction conditions such as those described in respect of process step (ii) above.
  • Compounds of formula XVI may be prepared by reaction of a compound of formula VI as hereinbefore defined, with a compound of formula XIX, H-C(0)-N(H)-NH 2 XIX for example under reaction conditions described herein (e.g. process step (iii) above).
  • a reducing agent such as a chemoselective one mentioned above or NaBH 4 , AIH 4 , or the like
  • a reducing agent such as sodium cyanaoborohydride (i.e. overall a reductive amination)
  • amide coupling reactions i.e. the formation of an amide from a carboxylic acid (or ester thereof), for example when R 2 represents -C(0)OH (or an ester thereof), it may be converted to a -C(O)N(R 10b )R 11b group (in which R 10b and R 11b are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g. when R 2 represents -C(O)OH) be performed in the presence of a suitable coupling reagent (e.g.
  • R 2 represents an ester (e.g. -C(0)OCH 3 or -C(0)OCH 2 CH 3 ), in the presence of e.g.
  • the -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), and, in all cases, the relevant compound is reacted with a compound of formula HN(R 10a )R 11a (in which R 10a and R 1a 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
  • amide coupling reactions i.e. the formation of an amide from a carboxylic acid (or ester thereof), for example when R 2 represents -C(0)OH (or an ester thereof), it may be converted to a -C(O)N(R 10b )R 11b group (in which R 10b and R 1 b are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g. when R 2 represents -C(O)OH) be performed in the presence of a suitable coupling reagent (e.g.
  • R 2 represents an ester (e.g. -C(0)OCH 3 or -C(0)OCH 2 CH 3 ), in the presence of e.g.
  • the -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), and, in all cases, the relevant compound is reacted with a compound of formula HN(R 10a )R 11a (in which R 10a and R 11a are as hereinbefore defined), under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere);
  • acyl halide e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like
  • nucleophilic substitution reactions where any nucleophile replaces a leaving group, e.g. methylsulfonylpiperazine may replace a chloro leaving group;
  • alkylation, acylation or sulfonylation reactions which may be performed in the presence of base and solvent (such as those described hereinbefore in respect of preparation of compounds of formula I, process step (iv) above, for instance, a -N(H)- or -OH or -NH 2 (or a protected version of the latter) moiety may be alkylated, acylated or sulfonylated by employing a reactant that is an alkyl, acyl or sulfonyl moiety attached to a leaving group (e.g. d-s alkyl-halide (e.g. ethylbromide), alkyl-C(0)-halide (e.g.
  • H 3 C-C(0)CI an anhydride (e.g. H 3 C- C(0)-0-C(0)-CH 3 , i.e. "-0-C(0)-CH 3 " is the leaving group), dimethylformamide (i.e. -N(CH 3 ) 2 is the leaving group) or a sulfonyl halide (e.g. H 3 C-S(0) 2 CI) and the like);
  • anhydride e.g. H 3 C- C(0)-0-C(0)-CH 3 , i.e. "-0-C(0)-CH 3 " is the leaving group
  • dimethylformamide i.e. -N(CH 3 ) 2 is the leaving group
  • a sulfonyl halide e.g. H 3 C-S(0) 2 CI
  • deprotection steps such as deprotection of an ⁇ -Boc protecting group by reaction in the presence of an acid, or, a hydroxy group protected as a silyl ether (e.g. a terf-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
  • 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 that may be mentioned include: the conversion of a halo group (preferably iodo or bromo) to a 1-alkynyl group (e.g. by reaction with a 1- alkyne), which latter reaction may be performed in the presence of a suitable coupling catalyst (e.g. a palladium and/or a copper based catalyst) and a suitable base (e.g.
  • a suitable coupling catalyst e.g. a palladium and/or a copper based catalyst
  • a suitable base e.g.
  • a tri-(C 1-6 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
  • 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)0H 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 tert-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). It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods (and the need can be readily determined by one skilled in the art).
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenylmethyleneoxycarbonyl (Fmoc) and 2,4,4-trimethylpentan-2-yl (which may be deprotected by reaction in the presence of an acid, e.g. HCI in water/alcohol (e.g. MeOH)) or the like.
  • an acid e.g. HCI in water/alcohol (e.g. MeOH)
  • the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
  • 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 PI -3) is desired and/or required.
  • inhibitor 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 ⁇
  • 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).
  • Compounds of the invention 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, and/or 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).
  • 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).
  • Such conditions/disorders include cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders and neurological disorders.
  • Compounds of the invention may also be useful in the treatment of pulmonary artery hypertension (PAH).
  • PAH pulmonary artery hypertension
  • 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 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 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-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) 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).
  • compounds of the invention may be combined with one or more treatments independently selected from surgery, one or more anti-cancer/anti- neoplastic/anti-tumoral agent, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation. More specifically, compounds of the invention may be combined 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), the DNA damage response mechanism (e.g. an inhibitor of ATM or ATR) or the stress signaling pathway (an inhibitor of p38 or NF- B).
  • 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
  • the DNA damage response mechanism e
  • 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 BRaf inhibitor such as GDC-0879
  • an anthracyclin such as doxorubicin
  • a taxane such as paclitaxel or, particularly, docetaxel (Taxotere);
  • nucleotide analog such as 5-fluorouracil (5-FU) or gemcitabine
  • a hormone therapeutic agent such as an estrogen receptor antagonist e.g. tamoxifen;
  • a cyclin dependent kinase inhibitor e.g. a CDK6 or CDK4 inhibitor, such as PD-0332991
  • 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- B.
  • a combination product comprising:
  • (B) another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease e.g. another therapeutic agent as described herein, for instance in the examples
  • 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 with other therapeutic agents (e.g. chemotherapeutic agents) for use as medicaments (e.g. for use in the treatment of a disease or condition as mentioned herein, such as one in which the inhibition of growth of cancer cells are required and/or desired e.g. for treating hyperproliferative disorders such as cancer (e.g. specific cancers that may be mentioned herein, e.g. in the examples) in mammals, especially humans).
  • therapeutic agents e.g. chemotherapeutic agents
  • chemotherapeutic agents for use as medicaments
  • Such active ingredients in combinations may act in synergy.
  • compounds of the invention may be combined 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 proliferative in vitro), for instance:
  • a PI3K inhibitor such as GDC-0941 ;
  • an EGFR inhibitor such as Lapatinib
  • docetaxel (iv) docetaxel (Taxotere®, Sanofi-Aventis);
  • a MEK inhibitor such as PD-0325901 ;
  • a CDK4 inhibitor such as PD-0332991.
  • 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 (US6960614; US 6972298; US 2004/1147478; US 2005/085550). Phase II clinical trials have been conducted for the potential treatment of breast tumors, colon tumors, and melanoma.
  • PD-0325901 is named (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benz- amide, and has the structure:
  • Docetaxel (TAXOTERE®, Sanofi-Aventis) is used to treat breast, ovarian, and NSCLC cancers (US 4814470; US 5438072; US 5698582; US 5714512; US 5750561 ; Mangatal et al (1989) Tetrahedron 45:4177; Ringel et al (1991) J. Natl. Cancer Inst. 83:288; Bissery et al(1991) Cancer Res. 51 :4845; Herbst et al (2003) Cancer Treat. Rev. 29:407-415; Davies et al (2003) Expert. Opin. Pharmacother. 4:553-565).
  • Docetaxel is named as (2R,3S)-N-carboxy-3- phenylisoserine, N-tert-butyl ester, 13-ester with 5, 20-epoxy-1 , 2, 4, 7, 10, 13- hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate (US 4814470; EP 253738; CAS Reg. No.
  • Lapatinib (TYKERB®, 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 (ErbB2) and who have received prior therapy including an anthracycline, a taxane and trastuzumab.
  • Lapatinib is an ATP-competitive epidermal growth factor (EGFR) and HER2/neu (ErbB-2) dual tyrosine kinase inhibitor (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
  • ErbB-2 HER2/neu
  • Lapatinib is named as N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2-(methylsulfonyl)ethylamino)- methyl)furan-2-yl)quinazolin-4-amine (or alternatively named as /V-[3-chloro-4-[(3- fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl] quinazolin-4-amine), and has the structure:
  • 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.
  • Advantagouesly when compounds of the invention are employed in combination with known chemotherapeutic agents (such as those described herein), the components of the combinations may act in a synergistic manner.
  • Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above- stated indications or otherwise.
  • pharmacokinetic profile e.g. higher oral bioavailability and/or lower clearance
  • Compounds of the invention may be beneficial as they are medicaments with targeted therapy, i.e. which target a particular molecular entity by inferring or inhibiting it (e.g. in this case by inhibiting one or more protein or lipid kinases as hereinbefore described). Compounds of the invention may therefore also have the benefit that they have a new effect (for instance as compared to known compounds in the prior art), for instance, the new effect may be a particular mode of action or another effect resultant of the targeted therapy.
  • Targeted therapies may be beneficial as they may have the desired effect (e.g. reduce cancer, by reducing tumor growth or carcinogenisis) but may also have the advantage of reducing side effects (e.g. by preventing the killing of normal cells, as may occur using e.g. chemotherapy).
  • compounds of the invention may selectively target particular protein or lipid kinases (e.g. the ones described herein) compared to other known protein or lipid kinases (as may be shown experimentally hereinafter). Accordingly, compounds of the invention may have the advantage that certain, specific, cancers may be treated selectively, which selective treatment may also have the effect of reducing side effects. Examples/Biological Tests
  • 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.
  • Kinase assay buffer and assay volume stay as recommended (15 mM HEPES, pH 7.4, 20 mM NaCI, 1 mM EGTA, 0.02% Tween 20, 10 mM MgCI 2 and 0.1 mg/ml bovine y-globulins/75 ⁇ assay volume)
  • PIM-1 substrate peptide PIMtide (ARKRRRHPSGPPTA) • Peptide concentration: 60 ⁇
  • the biochemical assay to measure PIM-2 activity relies on the ADP Hunter assay kit (DiscoveRx Corp., Cat. # 90-0077), that determines the amount of ADP as direct product of the kinase enzyme activity.
  • the enzyme has been expressed and purified in-house as a recombinant human protein with a N-terminal histidine tag.
  • the protein is active and stable.
  • PIM-1 substrate peptide PIMtide (ARKRRRHPSGPPTA)
  • 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)
  • DMEM high glucose, 10% Fetal Bovine Serum, 2mM L- Glutamine, P/S
  • Antibodies phosphor Bad S112 antibody from Cell Signaling (cat. #9291S), anti rabbit conjugated with peroxidise from Amersham (cat.#3619)
  • MTT proliferation assays
  • the combination index (CI) of combinations of certain example compounds and various chemotherapeutic agents in the MTT in vitro cell proliferarion assays were tested.
  • a combination index score was calculated by the Chou and Talalay method (CalcuSyn software, Biosoft). The strength of synergy was 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 were compared to the EC50 value of the combination.
  • the cell lines were characterised by tumor type.
  • AIBN means 2,2'-azobis(2-methylpropionitrile)
  • BOP means (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
  • DCM means dichloromethane
  • DCE dichloroethane
  • MeOH means methanol
  • THF tetrahydrofuran
  • DMF means dimethylformamide
  • DME means 1 ,2-dimethoxyethane
  • EtOAc means ethyl acetate
  • DIPEA means diisopropylethylamine
  • TSA means triethylamine
  • BINAP means (R i+J ⁇ '-bisidiphenylphosphinoJ-l .l'-binaphtyl
  • eq means equivalents
  • EtOH means ethanol
  • nBuOH means n-butano
  • NMR spectra were recorded in a Bruker Avance II 300 spectrometer and Bruker Avance II 700 spectrometer fitted with 5 mm 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.
  • Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5um).
  • Solvent A water with 0.1% formic acid
  • Solvent B acetonitrile with 0.1% formic acid. Gradient: 0% 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 urn).
  • 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.
  • This methodology can be applied to synthesise analogues to I-5 with other amines instead of the piperazine fragment.
  • reaction mixture was partitioned between DCM (500 mL) and aq saturated Na 2 S 2 0 3 (400 mL). The organic layer was washed with brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash chromatography Biotage, with a gradient DCM/MeOH 100 to 80/20, to yield a yellow solid, 872 mg.
  • Table 1 Compounds, Analytical data, PIM activity, synthetic methodology -
  • R t means retention time (in minutes)
  • [M+H] + means the protonated mass of the compound
  • method refers to the method used for (LC)MS.
  • Biological activity in PIM1 , PIM2 and PIM3 for certain examples is represented by quantitative results
  • IC50 in nM and for certain examples is represented by semi-quantative results: IC50 >1 ⁇ ( ⁇ ), IC50 ⁇ 100 nM (-), 100 nM ⁇ IC50 ⁇ 1 ⁇ ( «).
  • Synthetic method column refers to the general synthetic method used to generate the compounds following a similar protocol to the one described for one or some examples. Column of salt indicates whether the compound is in the free base form or salt form, sometimes this depends on the purification method in HPLC.

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Abstract

La présente invention concerne des composés de formule I, dans laquelle R1 R2, X, R3, X1, X2, Xa, Xb, Xc, Xd, Xf, X9 et R4 ont les significations présentées dans la description (et lesdits composés sont facultativement substitués comme indiqué dans la description), et des esters, amides, solvates ou sels pharmaceutiquement acceptables de ceux-ci, lesdits composés étant utiles dans le traitement de maladies dans lesquelles l'inhibition d'une protéine ou lipide kinase (par exemple une kinase de la famille PIM, telle que PIM-1, PIM-2 et/ou PIM-3) est souhaitée et/ou requise, et particulièrement dans le traitement du cancer ou une maladie proliférative. La présente invention concerne en outre des combinaisons comprenant les composés de formule I.
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