WO2013005041A1 - Tricyclic heterocyclic compounds as kinase inhibitors - Google Patents

Tricyclic heterocyclic compounds as kinase inhibitors Download PDF

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Publication number
WO2013005041A1
WO2013005041A1 PCT/GB2012/051576 GB2012051576W WO2013005041A1 WO 2013005041 A1 WO2013005041 A1 WO 2013005041A1 GB 2012051576 W GB2012051576 W GB 2012051576W WO 2013005041 A1 WO2013005041 A1 WO 2013005041A1
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optionally substituted
compound
group
formula
groups
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PCT/GB2012/051576
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French (fr)
Inventor
Joaquín PASTOR FERNANDEZ
Sonia MARTÍNEZ GONZÁLEZ
Carmen BLANCO-APARICIO
Milagros LORENZO GARCÍA
Francisco Javier Ramos Lima
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Centro Nacional De Investigaciones Oncológicas (Cnio)
SNODIN, Michael D
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Publication of WO2013005041A1 publication Critical patent/WO2013005041A1/en

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of protein or lipid kinases (such as inhibitors of 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., ⁇ /ood 2003, 102, 1833-184].
  • the strong linkage between reported overexpression data and the occurrence of PI -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- bjpyridazines, but none in which such a bicycle is a sub-component of a fused tricyclic compound. Nor does this document disclose that the compounds therein may be useful as kinase inhibitors.
  • US patent application US 2003/0078277 discloses tricyclic compounds that may be useful as a corticotrophin, and therefore of use in the treatment of e.g. depression. However, this document does not primiarly relate to [1 ⁇ triazolo ⁇ .S-bJpyridazines, 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 tricycles substituted with an amino moiety and an aromatic group. Further, this document does not mention that the compounds disclosed therein may be useful as kinase inhibitors.
  • International patent application WO 99/06404 discloses various fused tricyclic compounds, for use as phosphodiesterase 4 inhibitors. However, this document only relates to fused tricyclic compounds in which each of the three rings is aromatic.
  • R 1 , R 2 and X-containing ring is non-aromatic in which: R and R 2 are independently selected from -0-, -S-, -S(O)-, -S(0) 2 -, -C(R 6 )(R 6a )- and -N(R 6 )-; and
  • X represents C 1-3 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 d2 and R d3 independently represent C 1-12 (e.g. C 1-6 ) alkyl optionally substituted by one or more substituents selected from E 1 ;
  • R 3 represents aryl or heteroaryl, both of which are optionally substituted by one or more substituents selected from E 3 ;
  • R 4 represents a fragment of formula IA
  • (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 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:
  • R 60 , R 61 and 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 we include salts of pharmaceutically acceptable esters or amides, and solvates of pharmaceutically acceptable esters, amides or salts.
  • pharmaceutically acceptable esters and amides such as those defined herein may be mentioned, as well as pharmaceutically acceptable solvates or salts.
  • HCOOH HCOOH
  • HCI salts HCOOH and HCI salts.
  • Oxide salts such as N-oxides (e.g. in which there is a " ⁇ + -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- 0 aryl and/or C 5- 0 aryl-C 1-6 alkyl- esters.
  • amides of carboxylic acids of compounds of the invention
  • pharmaceutically acceptable amides include those of the formula -C ⁇ N R ⁇ R 22 , in which R z1 and R 22 independently represent optionally substituted C 1-6 alkyl, C 5 . 0 aryl, or C 5- 0 aryl-C 1-6 alkylene-.
  • C 1-6 alkyl groups that may be mentioned in the context of such pharmaceutically acceptable esters and amides are not cyclic, e.g. linear and/or branched.
  • Further compounds of the invention that may be mentioned include carbamate, carboxamido or ureido derivatives, e.g. such derivatives of existing amino functional groups.
  • prodrugs of compounds of the invention are also included within the scope of the invention.
  • 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- annich 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 £ (ent ought) and Z (zusammen) geometric isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g.
  • tautomer or tautomeric form
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganisation of some of the bonding electrons.
  • Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
  • a 'chiral pool' method by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
  • derivatisation i.e. a resolution, including a dynamic resolution
  • stereoisomers including but not limited to diastereoisomers, enantiomers and atropisomers
  • mixtures thereof e.g. racemic mixtures
  • stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid 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, C, 13 C, 4 C ,
  • Positron emitting isotopes such as 5 0, 13 N, 11 C and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • 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 Cs-q-cycloalkyl group).
  • Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic.
  • Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C 2-q alkenyl or a C 2-q alkynyl group).
  • C -q alkylene (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number of carbon atoms, be saturated or unsaturated (so forming, for example, an alkenylene or alkynylene linker group). Unless otherwise specified, such C -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, this alkylene group is straight-chained.
  • C 3 .q cycloalkyl groups may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups).
  • Such cycloalkyl groups may be saturated or unsaturated containing one or more double bonds (forming for example a cycloalkenyl group).
  • Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic.
  • halo when used herein, preferably includes fluoro, chloro, bromo and iodo.
  • Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is from 3 to 20 (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.
  • such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2 .
  • C 2- q heterocycloalkenyl (where q is the upper limit of the range) group.
  • C 2- q heterocycloalkyi 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-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl
  • heterocycloalkyi groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heterocycloalkyi 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.
  • Heterocycloalkyi groups may also be in the N- or S- oxidised form. Heterocycloalkyi 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 heterocycloalkyi groups refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).
  • Aryl groups that may be mentioned include C 6-2 o, such as C 6 .i 2 (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- io 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.
  • aryl group when the aryl group is polycyclic the point of attachment may be via atom including an atom of a non- aromatic ring.
  • aryl groups 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).
  • the point of attachment may be via any atom including an atom of a non-aromatic ring.
  • 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. 3,4-dihydro-1 - - isoquinolin-2-yl, 1 ,3-dihydroisoindol-2-yl, 1 ,3-dihydroisoindol-2-yl; i.e.
  • heteroaryl groups that are linked via a non-aromatic ring or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3- benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1,3- benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1 ,3- benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imi
  • heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • the heteroaryl group is monocyclic or bicyclic.
  • the heteroaryl may consist of a five-, six- or seven-mem bered 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 Ci -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 ).
  • compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.
  • X represents optionally substituted Ci to C 3 alkylene.
  • alkylene groups are straight-chained and hence X may represent -CH 2 -, -CH 2 CH 2 - or -CH 2 -CH 2 -CH 2 -, all of which moieties are optionally substituted by one or more substituents selected from E 2 , and hence may represent either one of the compounds of formula IA, IB or IC:
  • E 2 alkylene moieties between the R 1 and R 2 groups are optionally substituted by one or more substituents selected from E 2 (and the integers R 1 , R 2 , R 3 and R 4 are as hereinbefore defined).
  • One or more E 2 substituents may be attached to the relevant alkylene moieties (i.e. the substituent may replace a hydrogen atom).
  • the E 2 substituent may be a non-aromatic cyclic group (e.g. optionally substituted C 3-12 cycloalkyl or heterocycloalkyl), which may be attached to a single carbon atom of the relevant -CH 2 -, -CH 2 -CH 2 or -CH 2 -CH 2 -CH 2 - moiety.
  • Preferred compounds of the invention include those in which:
  • R 3 represents a substituted aryl (e.g. phenyl) group (i.e. substituted by one or more E 3 substituents), then that/those E 3 substituent(s) are preferably not located at the position ortho to the point of attachment of the R 3 group (to the requisite triazolopyridazine bicycle of formula I).
  • aryl e.g. phenyl
  • E 3 substituent(s) are preferably not located at the position ortho to the point of attachment of the R 3 group (to the requisite triazolopyridazine bicycle of formula I).
  • Preferred aryl groups and bicyclic heteroaryl groups that R 3 may represent include optionally substituted phenyl, naphthyl, indazolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1 ,3- benzodioxolyl, 1 ,3-dihydroisoindolyl, 3,4-dihydro-1H-isoquinolinyl, 1 ,3- dihydroisoindolyl, benzothiazolyl, and/or benzodioxanyl.
  • Particularly preferred groups include optionally substituted aryl (e.g. naphthyl or, preferably, phenyl) or bicyclic heteroaryl (e.g. a bicyclic 9- or 10-membered group, in which one ring of the bicycle is benzene and the other ring preferably contains one, two, three or four (e.g. one or two) heteroatoms preferably selected from nitrogen, oxygen and sulfur), in which the point of attachment of the bicyclic heteroaryl group to the requisite triazolopyridazine core of the compound of formula I is via a benzene or, preferably heteroaromatic ring of the bicyclic heteroaryl group.
  • aryl e.g. naphthyl or, preferably, phenyl
  • bicyclic heteroaryl e.g. a bicyclic 9- or 10-membered group, in which one ring of the bicycle is benzene and the other ring preferably contains one, two, three or four (e.g.
  • Preferred monocyclic heteroaryl groups that R a or R b or Q , Q 2 , Q 4 or Q 5 may independently represent include 5- or 6-membered rings, containing one to three (e.g. one or two) heteroatoms selected from sulfur, oxygen and nitrogen.
  • Preferred bicyclic heteroaryl groups that R 3 , R a or R b , or Q , 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).
  • bicyclic rings may consist of benzene rings fused with a monocyclic heteroaryl group (as hereinbefore defined), e.g. a 6- or, preferably 5-membered monocyclic heteroaryl group optionally containing two, or, preferably, one heteroatom selected from sulfur, oxygen and nitrogen.
  • a monocyclic heteroaryl group as hereinbefore defined
  • a 6- or, preferably 5-membered monocyclic heteroaryl group optionally containing two, or, preferably, one heteroatom selected from sulfur, oxygen and nitrogen.
  • Preferred heterocycloalkyi groups that R a or R b or Q 1 , Q 2 , Q 4 or Q 5 may independently represent include 4- to 8-membered (e.g. 5- or 6-membered) heterocycloalkyi groups, which groups preferably contain one or two heteroatoms (e.g. sulfur or, preferably, nitrogen and/or oxygen heteroatoms), so forming for example, an optionally substituted pyrrolidinyl, piperidinyl, morpholinyl or tetrahydropyranyl group.
  • 4- to 8-membered (e.g. 5- or 6-membered) heterocycloalkyi 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 pyrrolidinyl, piperidinyl, morpholinyl or tetrahydropyranyl group.
  • 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 C 3 . 8 (e.g. C 3 . 6 ) cycloalkyl groups, such as cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.
  • C 3 . 8 e.g. C 3 . 6
  • Further preferred compounds of the invention include those in which:
  • R 10a , R 11a and R 12a may be linked together as defined herein (although they are preferably not linked);
  • any two E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , E 7 , E 8 and/or E 9 groups may be linked together (e.g. any two E 3 substituents may also be linked 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;
  • aryl e.g. phenyl; preferably unsubstituted, but which may be substituted by one to three J 5 groups
  • Ci -6 e.g. C 1-3 alky
  • halo e.g. fluoro
  • each R 50 , R 51 , R 52 and R 53 substituent independently represents, on each occasion when used herein, hydrogen or 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 1-3 (e.g. C 1-2 ) alkyl optionally substituted by one or more fluoro atoms.
  • R 3 , R 4 and the R 1 , R 2 and X-containing ring include:
  • halo e.g. fluoro, chloro or bromo
  • C 1-6 e.g. C 1 -4) alkyl, which alkyl group may be cyclic, part-cyclic, unsaturated or, preferably, linear or branched (e.g. C 1-4 alkyl (such as ethyl, A?-propyl, isopropyl, t- butyl or, preferably, n-butyl or methyl), all of which are optionally substituted with one or more halo (e.g.
  • fluoro groups (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl) or substituted with an aryl, heteroaryl or heterocycloalkyi group (which themselves may be substituted with one or more -OR z1 , -C ⁇ R 22 , -C(0)OR 23 , -N(R z )R 25 , -S ⁇ R 26 , -S(0) 2 N(R z7 )R z8 ; -N ⁇ -C ⁇ -R 210 , -C(0)-N(R z11 )R z12 and/or -N(R z9 )-C(0)-N(R z10 ) substituents; aryl (e.g. phenyl) (e.g. which substitutent may also be present on an alkyl group, thereby forming e.g. a benzyl group);
  • aryl e.g. phenyl
  • each R z to R z12 independently represents, on each occasion when used herein, H or C 1-4 alkyl (e.g. ethyl, n-propyl, f-butyl or, preferably, n-butyl, methyl, isopropyl or cyclopropylmethyl (i.e. a part cyclic alkyl group)) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a trifluoromethyl group).
  • any two R z groups e.g. R z4 and R z5 ), when attached to the same nitrogen heteroatom may also be linked together to form a ring such as one hereinbefore defined in respect of corresponding linkage of R 0a and R 1a groups.
  • Preferred compounds of the invention include those in which:
  • each J 1 , J 2 , J 3 , J 4 , J 5 and J 6 independently represent C 1-6 alkyl (e.g. C 1-4 acyclic alkyl or C 3-5 cycloalkyl) optionally substituted by one or more substituents selected from Q 8 , or, J 1 to J 6 more preferably represent a substituent selected from Q 7 ;
  • each R 50 , R 51 , R 52 and R 53 independently represents hydrogen or C 1-6 (e.g. C 1-4 ) alkyl optionally substituted by one or more fluoro atoms;
  • each R 60 , R 6 and R 62 independently represents hydrogen or C -2 alkyl (e.g. methyl).
  • More preferred compounds of the invention include those in which:
  • R d1 , R d2 and R d3 independently represent C 1-6 (e.g. C 1-3 ) alkyl optionally substituted by one or more substituents selected from E 1 , but which is preferably unsubstituted;
  • R a and R b when linked together, they may represent a 3- to 6-membered ring (e.g. a 5- or, preferably, 6-membered ring), optionally containing one further heteroatom selected from nitrogen and oxygen, which ring may be: (a) fused to another saturated 5- or 6-membered carbocyclic or heterocyclic ring, in which the latter contains one to four heteroatoms preferably selected from nitrogen and oxygen; (b) comprises a linker group linking any two non-adjacent atoms; or (c) comprises a further 4- to 6-membered saturated carbocyclic or heterocyclic ring, in which the latter contains one or two heteroatoms preferably selected from nitrogen and oxygen, which second ring is linked to the first via a single atom; Q 4 and Q 5 independently represent halo (e.g.
  • R 22 represents C -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 C 1-6 alkyl (e.g. C 1-4 alkyl);
  • halo e.g. fluoro
  • each R 50 , R 51 , R 52 and R 53 independently represents H or C 1-4 alkyl.
  • Preferred compounds of the invention include those in which:
  • R 1 and R 2 independently represent -C(R 6 )(R 6a )-, preferably, -S(O)- -S(0) 2 -, and, more preferably, -0-, -S- or -N(R 6 )-;
  • each R 6 and R 6a independently represents, on each occasion when used herein, H or R d3 ;
  • R d3 represents C 1-6 (e.g. C 1-4 ) alkyl; X represents optionally substituted (i.e. by E 2 ) C 2 or C 3 alkylene;
  • R 3 represents aryl (e.g. phenyl) or heteroaryl, both of which are optionally substituted by one or more (e.g. one to three) substituent(s) selected from E 3 ;
  • R a and R b independently represents H, C 1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more (one to three) substituent(s) selected from Q 1 ); or
  • R a and R b may be linked together to form a 3- to 6- membered ring (e.g. a 5- or, preferably, 6-membered ring), preferably containing no further heteroatoms, which ring may be linked to a further 4- to 6-membered ring (e.g. 4-membered ring) via a single atom (i.e. forming a spiro cycle), all of which cyclic groups are optionally substituted by one or more substituents selected from E 4 ;
  • E 1 to E 9 independently represent Q 4 or C-,.6 (e g- C 1-3 , such as methyl) alkyl optionally substituted by one or more Q 5 substituents; or
  • R 20 and R 21 independently represent hydrogen, C 1-4 alkyl, which latter group is optionally substituted by one or more (e.g. one) substituent(s) selected from J 4 ; when there is a -N(R )R moiety present, then one of R and R represents hydrogen, and the other represents hydrogen or C 1-4 alkyl (e.g. methyl, ethyl or isopropyl), which latter group is optionally substituted by one or more (e.g. one) substituent(s) selected from J 4 ;
  • R 22 represents hydrogen and C 1-3 alkyl (e.g. methyl);
  • J 3 represents Q 7 ;
  • J 4 represents Q 7 or C 1-6 (e.g. C 1-3 ) alkyl, which is preferably unsubstituted;
  • Q 7 represents halo (e.g. fluoro). More preferred compounds of the invention include those in which:
  • R and R 2 independently represent -N(R 6 )-, -O- or -C(R 6 )(R 6a )-;
  • R 6 and R 6a independently represent H or R d3 ;
  • R d3 represents C 1-3 alkyl (e.g. methyl or ethyl);
  • R a and R b represents H or C 1-3 alkyl (e.g. methyl) and the other represents a substituent other than hydrogen (e.g. as hereinbefore defined).
  • Preferred compounds of the invention include those in which:
  • R 3 represents (i) phenyl optionally substituted by one or two (e.g. one) substituent(s) selected from E 3 or (ii) heteroaryl (e.g. a 5- or 6-membered monocyclic or, preferably, a 9- or 10-membered bicyclic heteroaryl group) optionally substituted by one or two (e.g. one) substituent(s) selected from E 3 ; when R 3 represents aryl (e.g. phenyl), it is preferably substituted by at least one (e.g. one) substituent selected from E 3 (in which that substituent is preferably located at the meta position when R 3 is phenyl);
  • heteroaryl e.g. a 5- or 6-membered monocyclic or, preferably, a 9- or 10-membered bicyclic heteroaryl group
  • R 3 when R 3 represents a bicyclic heteroaryl group, it preferably represents a 5- or 6- membered monocyclic heteroaryl group (e.g. containing one heteroatom, e.g. pyridyl, furanyl or thienyl) fused to a benzene ring;
  • R 3 represents a bicyclic heteroaryl group, it is preferably unsubstituted or substituted with at least one (e.g. one) substituent on the benzene ring of the bicyclic group (preferably located ortho relative to the point of fusion between the benzene ring and monocyclic heteroaryl group);
  • E 3 represents Q 4 or C 1-3 alkyl (e.g. methyl) optionally substituted by Q 5 (e.g. fluoro, so forming e.g. a perfluoro alkyl group such as -CF 3 );
  • Q 5 represents halo (e.g. fluoro);
  • R 20 represents hydrogen or preferably C 1-4 (e.g. C 1-2 ) alkyl (e.g. methyl) optionally (and preferably) substituted by one or more substituents selected from J 4 (e.g. fluoro, so forming a trifluoromethyl group);
  • J 4 represents Q 7 ;
  • Q 7 represents halo (e.g. fluoro).
  • R 3 groups of the compounds of the invention include optionally substituted aryl (e.g. phenyl) and hetereoaryl (e.g. a 5- or 6-membered monocyclic heteroaryl group, containing one or two heteroatoms, preferably selected from nitrogen, so forming e.g. a pyridyl group).
  • Preferred R 3 groups include trifluoromethoxyphenyl (e.g. 3-OCF 3 -phenyl) and trifluoromethylpyridyl (e.g. 2-trifluoromethyl-4-pyridyl).
  • Particularly preferred E 3 substituents include trifluoromethyl and trifluoromethoxy.
  • Most preferred compounds of the invention include those in which the R , R 2 and X-containing ring
  • R may represent -O- or -N(R 6 )-;
  • R 2 may represent -0-, -N(R 6 )- or -C(R 6 )(R 6a )-;
  • R 1 and R 2 may represent -O- and the other represents -O- or, preferably, -C(R 6 )(R 6a )- or -N(R 6 )-;
  • each R 6 (e.g. on -N(R 6 )- moieties) represents hydrogen or, preferably, C 1-3 alkyl (preferably unsubstituted methyl);
  • E 2 (e.g. when present on a 7-membered ring) represents Q 4 ;
  • Q 4 when E 2 represents Q 4 , Q 4 preferably represents halo (e.g. fluoro), C -6 alkyl (e.g. unsubstituted C 1-2 alkyl, such as methyl, or cycloalkyl, e.g. cyclopropyl, cyclobutyl or cyclopentyl, which groups are preferably unsubstituted and linked via a single carbon atom of the alkylene group, so forming a spiro-cycle) or heterocycloalkyl (e.g. a 3- to 6-membered heterocycloalkyl group preferably containing one heteroatom (e.g. oxygen) so forming e.g.
  • halo e.g. fluoro
  • C -6 alkyl e.g. unsubstituted C 1-2 alkyl, such as methyl, or cycloalkyl, e.g. cyclopropyl, cyclobutyl or cyclopenty
  • R 376 represents R a or R b
  • the other integers e.g. E 4 , E 5 , Q 1 and J 2 ; 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 5 /Q 1 /E 4 substituents
  • the depiction of a substituent in brackets signifies that that substituent is optionally present, and may therefore be absent (i.e. N-(E 5 ) may signify N-E 5 or N-H).
  • R 4 in compounds of the invention represents one of the following gro
  • R a and R represents H or C 1-3 alkyl (e.g. methyl) and the other represents a substituent other than hydrogen (or the following groups);
  • R a and R b when either of R a and R b represents a substituent (see above), then it may be:
  • C 1-6 alkyl e.g. C 1-3 acyclic alkyl or C 3-6 cycloalkyl
  • C 1-6 alkyl e.g. C 1-3 acyclic alkyl or C 3-6 cycloalkyl
  • substituents e.g. methyl, ethyl, n-propyl, cyclobutyl or cyclohexyl
  • Q 1 e.g. one substituent
  • heterocycloalkyi e.g. a 5- or, preferably 6-membered heterocycloalkyi group containing one or two (e.g. one) heteroatom(s) in which one is preferably nitrogen or oxygen, so forming e.g. piperidinyl or tetrahydropyranyl, such as 4-piperidinyl or 4-tetrahydropyranyl) and which heterocycloalkyi group is optionally substituted by one or more substituents (e.g. one; which substituent(s) may be attached to a nitrogen heteroatom) selected from Q 1 ; or
  • substituents e.g. one; which substituent(s) may be attached to a nitrogen heteroatom
  • R a and R b may be linked together to form a 3- to 7-membered ring (e.g. a 5- or, preferably, a 6-membered ring), preferably containing no further heteroatoms, which ring may be linked to a further 4- to 6-membered ring (e.g. a 4- or 6- membered ring) via a single atom (i.e. forming a spiro cycle, which is preferably a [3.5], [5.3] or [5.5] spiro-cycle), all of which cyclic groups are optionally substituted by one or more substituents selected from E 4 ;
  • Q 1 may represent -N(R 0a )R 11a or heterocycloalkyl (e.g.
  • E 4 represents Q 4 or C 1-3 alkyl (e.g. methyl) optionally substituted by one or more (e.g. one) substituent(s) selected from Q 5 ;
  • E 5 represents C -3 alkyl (e.g. methyl) or Q 4 ;
  • Q 4 may represent heterocycloalkyl, e.g. a 5- or preferably 6-membered heterocycloalkyl group (e.g. containing two or preferably one heteroatom (e.g. nitrogen), so forming e.g. a 4-piperidinyl group; and which group when present as a substituent on a cyclic group (e.g. cycioalkyi), may be attached via a single atom, so forming a spiro-cycle e.g. a 4-piperidinyl group linked to a cyclobutyl group via a single atom);
  • heterocycloalkyl e.g. a 5- or preferably 6-membered heterocycloalkyl group (e.g. containing two or preferably one heteroatom (e.g. nitrogen), so forming e.g. a 4-piperidinyl group; and which group when present as a substituent on a cyclic group (e.g. cycio
  • Q 5 represents -N(R 20 )R 21 ;
  • R 20 and R 21 independently represent hydrogen or C 1-6 (e.g. C 1-3 ) alkyl optionally substituted by one or more fluoro atoms.
  • Particular compounds of the invention include compounds of formula I,
  • R 1 , R 2 and X-containing ring is non-aromatic in which:
  • R represents O;
  • R 2 represents -C(R 6 )(R 6a )- or -N(R 6 )-;
  • X represents C 1-2 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 or R d3 ;
  • R d3 represent C -4 alkyl (e.g. methyl) optionally substituted by one or more substituents selected from E 1 ;
  • R 3 represents (i) phenyl optionally substituted by one or two (e.g. one) substituent(s) selected from E 3 or (ii) a 5- or 6-membered monocyclic heteroaryl (e.g. pyridyl) optionally substituted by one or two (e.g. one) substituent(s) selected from E 3 ;
  • 4 represents one of the following groups:
  • E 4 , E 5 and Q 1 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 5 /Q 1 /E 4 substituents;
  • R 3 * represents H or C 1-2 alkyl (e.g. methyl) optionally substituted by one or more substituents selected from Q 1 ; each Q independently represents, on each occasion when used herein: halo, -CN, -N0 2 , -N(R 10a )R 11a , -OR 10a ; each R 10a and R 11a independently represent, on each occasion when used herein, hydrogen or alkyl (e.g. methyl); each E 1 , E 3 , E 4 and E 5 , independently represents, on each occasion when used herein:
  • C 1-4 alkyl e.g. methyl
  • Particular compounds of the invention include those described above but in which X represents a -CH 2 -CH 2 - linker.
  • Particularly preferred compounds of the invention include those of the examples described hereinafter.
  • L 1 represents a suitable leaving group, such as iodo, bromo, chloro or a sulfonate group (e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 or -OS(0) 2 Ph e), and R , R 2 , R 3 and X are as hereinbefore defined, with a compound of formula III,
  • R -H III wherein R 4 is as hereinbefore defined, under standard conditions, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc) 2 , Cul (or Cul/diamine complex), copper tris(triphenyl-phosphine)bromide, Pd(OAc) 2l tris(dibenzylideneacetone)- dipalladium(O) (Pd 2 (dba) 3 ) or NiCI 2 and an optional additive such as Ph 3 P, 2,2'- bis(diphenylphosphino)-1 ,1'-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et 3 N, pyridine, A/ ⁇ -dimethylethylenediamine, Na 2 C0 3 , K 2 C0 3 , K 3 P0 4 , Cs 2 C0 3
  • 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 iert-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 1 , R 2 , X and R 4 are as hereinbefore defined, with a compound of formula V,
  • L 4 represents a suitable group, such as -B(OH) 2 , -B(OR wx ) 2 or -SniR ⁇ , in which each R"* independently represents a C 1-6 alkyl group, or, in the case of -B(OR wx ) 2 , the respective R w 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 3 is as hereinbefore defined.
  • the reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2 , Pd(Ph 3 P) 4 (i.e.
  • a suitable catalyst system e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2 , Pd(Ph 3 P) 4 (i.e.
  • PdCI 2 (dppf).DCM palladium
  • a ligand such as PdCI 2 (dppf).DCM, f-Bu 3 P, (CeHn ⁇ P, Ph 3 P, AsPh 3 , P(o-Tol) 3 , 1 ,2-bis(diphenylphosphino)ethane, 2,2'-bis(di-terf-butyl- phosphino)-1 , 1 '-biphenyl, 2,2'-bis(diphenylphosphino)-1 , 1 '-bi-naphthyl, 1,1'- bis(diphenyl-phosphino-ferrocene), 1,3-bis(diphenylphosphino)propane, xantphos, or a mixture thereof
  • PdCI 2 (dppf).DCM PdCI 2 (dppf).DCM
  • f-Bu 3 P CeHn ⁇ P, Ph 3 P, AsPh 3
  • reaction may be carried out for example at room temperature or above (e.g. at a high temperature such as at about the reflux temperature of the solvent system).
  • Alternative reaction conditions include microwave irradiation conditions, for example at elevated temperature of about 130°C; (iii) reaction of a compound of formula VI,
  • R 4 L 1 represents either L 1 or R 4
  • R 1 , R 2 , R 4 , X and L 1 are as hereinbefore defined, with a compound of formula VII,
  • base such as an organic base (e.g. triethylamine or the like)
  • an acid such as an organic acid (e.g. para-toluenesulfonic acid or the like)
  • the base and acid are preferably in a ratio of about 1 :1.
  • the reaction may also take place in the presence of a suitable solvent, such as a polar solvent (e.g.
  • reaction may be heated at room termperature, or, preferably, above room temperature, e.g. above 50°C, such as at about 100°C.
  • room temperature e.g. above 50°C
  • the 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 one of R 1 and R 2 represents -0-, intramolecular reaction of a compound of formula VIII,
  • T 1a represents -R 1 -X-OH
  • T 2a represents -R 2 -X-OH
  • the other represents a suitable leaving group such as one defined hereinbefore by L 1 (e.g. chloro or -OH, which latter group may if necessary be converted to a leaving group) and R 3 and R 4 are as hereinbefore defined, under standard reaction conditions e.g. in the presence of base (e.g. a metal alkyl oxide, such as potassium terf-butoxide) in a suitable solvent (e.g. a polar aprotic solvent such as THF) under reflux reaction conditions;
  • base e.g. a metal alkyl oxide, such as potassium terf-butoxide
  • a suitable solvent e.g. a polar aprotic solvent such as THF
  • L a and L 2a each independently represent a suitable leaving group such as one defined hereinbefore by L 1 (e.g. chloro) and R 3 and R 4 are as hereinbefore defined, with a compound of formula X,
  • 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);
  • 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);
  • R 1a and R 2a independently represent -0-, -S- and -NR 6 -, and R 3 and R 4 are as hereinbefore defined, with a compound of formula XIII,
  • L 5 and L 6 independently represent a suitable leaving group, such as one hereinbefore defined in respect of L 1 (e.g. halo, such as chloro), and X is as hereinbefore defined, under standard reaction conditions (to promote the nucleophilic substitution reactions), for example in the presence of a suitable base, such as Na 2 C0 3 , K 3 P0 4 , Cs 2 C0 3 , NaOH, KOH, 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, te f-butanol, dimethylformamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N- methylpyrrolidinone, tetrahydrofuran or mixtures thereof.
  • a suitable base such as Na 2 C0 3
  • Compounds of formula II may be prepared by reaction of a compound of formula VI as hereinbefore defined but in which R 4 L 1 represents L 1 and a compound of formula VII as hereinbefore defined, for example under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (iii)).
  • Compounds of formula II may alternatively be prepared by reaction of a compound of formula XIV,
  • L 1 , L 3 , R 1 , R 2 and X are as hereinbefore defined, with a compound of formula V as hereinbefore defined, under reaction conditions such as those described in respect of preparation of compounds of formula I (process step (ii) above).
  • Compounds of formula IV may be prepared by reaction of a compound of formula XVI as hereinbefore defined with a compound of formula III as hereinbefore defiend, for example under reaction conditions such as those described in respect of preparation of compounds of formula I (process step (i) above).
  • Compounds of formula IV and compounds of formula XIV (in which L 3 represents halo, e.g. bromo) may be prepared by reaction of a compound of formula XV,
  • R 4 L 1 , 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 or chloride) ions, for instance an electrophile that provides a source of iodide ions includes iodine, diiodoethane, diiodotetrachloroethane or, preferably, /V-iodosuccinimide, a source of bromide ions includes V-bromosuccinimide and bromine, and a source of chloride ions includes /V-chlorosuccinimide, chlorine and iodine monochloride, for instance in the presence of a suitable solvent, such as an alcohol (e.g.
  • methanol 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 4 L 1 , L 1 are as hereinbefore defined, with a compound of formula XVII,
  • 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 1 b group (in which R 10 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 1a (in which R 10a and R 11a are as hereinbefore defined), under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere);
  • acyl halide e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like
  • 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 1b 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)C1, 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 1a (in which R 0a and R 11a are as hereinbefore defined), under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere);
  • nucleophilic substitution reactions where any nucleophile replaces a leaving group, e.g. methylsulfonylpiperazine may replace a chloro leaving group;
  • alkylation, acylation or sulfonylation reactions which may be performed in the presence of base and solvent (such as those described hereinbefore in respect of preparation of compounds of formula I, process step (iv) above, for instance, a -N(H)- or -OH or -NH 2 (or a protected version of the latter) moiety may be alkylated, acylated or sulfonylated by employing a reactant that is an alkyl, acyl or sulfonyl moiety attached to a leaving group (e.g. C 1-6 alkyl-halide (e.g. ethylbromide), C 1-6 alkyl-C(0)-halide (e.g.
  • a leaving group e.g. C 1-6 alkyl-halide (e.g. ethylbromide), C 1-6 alkyl-C(0)-halide (e.g.
  • H 3 C-C(0)CI an anhydride (e.g. H 3 C- C(0)-0-C(0)-CH 3 , i.e. "-0-C(0)-CH 3 " is the leaving group), dimethylformamide (i.e. -N(CH 3 ) 2 is the leaving group) or a sulfonyl halide (e.g. H 3 C-S(0) 2 CI) and the like); (x) specific deprotection steps, such as deprotection of an /V-Boc protecting group by reaction in the presence of an acid, or, a hydroxy group protected as a silyl ether (e.g.
  • a ferf-butyl-dimethylsilyl protecting group may be deprotected by reaction with a source of fluoride ions, e.g. by employing the reagent tetrabutylammonium fluoride (TBAF).
  • TBAF reagent tetrabutylammonium fluoride
  • Wiley &Sons Ltd Chichester, UK, 2002, and references cited therein;
  • the substituents R 1 , R 2 , R 3 , R 4 and X in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations or nitrations. Such reactions may result in the formation of a symmetric or asymmetric final compound of the invention or intermediate.
  • the precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.
  • transformation steps include: the reduction of a nitro or azido group to an amino group; the hydrolysis of a nitrile group to a carboxylic acid group; and standard nucleophilic aromatic substitution reactions, for example in which an iodo-, preferably, fluoro- or bromo-phenyl group is converted into a cyanophenyl group by employing a source of cyanide ions (e.g. by reaction with a compound which is a source of cyano anions, e.g. sodium, copper (I), zinc or potassium cyanide, optionally in the presence of a palladium catalyst) as a reagent (alternatively, in this case, palladium catalysed cyanation reaction conditions may also be employed).
  • a source of cyanide ions e.g. by reaction with a compound which is a source of cyano anions, e.g. sodium, copper (I), zinc or potassium cyanide, optionally in the presence of a palladium catalyst
  • transformations 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)OH to a -NH 2 group, under Schmidt reaction conditions, or variants thereof, for example in the presence of HN 3 (which may be formed in by contacting NaN 3 with a strong acid such as H 2 S0 4 ), or, for variants, by reaction with diphenyl phosphoryl azide ((PhO) 2 P(0)N 3 ) in the presence of an alcohol, such as te/if-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
  • Compounds of the invention bearing a carboxyester functional group may be converted into a variety of derivatives according to methods well known in the art to convert carboxyester groups into carboxamides, N-substituted carboxamides, ⁇ , ⁇ -disubstituted carboxamides, carboxylic acids, and the like.
  • the operative conditions are those widely known in the art and may comprise, for instance in the conversion of a carboxyester group into a carboxamide group, the reaction with ammonia or ammonium hydroxide in the presence of a suitable solvent such as a lower alcohol, dimethylformamide or a mixture thereof; preferably the reaction is carried out with ammonium hydroxide in a methanol/dimethyl- formamide mixture, at a temperature ranging from about 50°C to about 100°C.
  • Analogous operative conditions apply in the preparation of N-substituted or N,N- disubstituted carboxamides wherein a suitable primary or secondary amine is used in place of ammonia or ammonium hydroxide.
  • carboxyester groups may be converted into carboxylic acid derivatives through basic or acidic hydrolysis conditions, widely known in the art.
  • amino derivatives of compounds of the invention may easily be converted into the corresponding carbamate, carboxamido or ureido derivatives.
  • Compounds of the invention may be isolated from their reaction mixtures using conventional techniques (e.g. recrystallisations).
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenylmethyleneoxycarbonyl (Fmoc) and 2,4,4-trimethylpentan-2-yl (which may be deprotected by reaction in the presence of an acid, e.g. HCI in water/alcohol (e.g. MeOH)) or the like.
  • an acid e.g. HCI in water/alcohol (e.g. MeOH)
  • protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter.
  • protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
  • the type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.
  • Compounds of the invention may inhibit protein or lipid kinases, such as a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3, for example as may be shown in the tests described below and/or in tests known to the skilled person.
  • the compounds of the invention may be useful in the treatment of those disorders in an individual in which the inhibition of such protein or lipid kinases (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) is desired and/or required.
  • the term "inhibit” may refer to any measurable reduction and/or prevention of catalytic kinase (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) activity.
  • the reduction and/or prevention of kinase activity may be measured by comparing the kinase activity in a sample containing a compound of the invention and an equivalent sample of kinase (e.g. a PIM family kinase such as PIM-1, PIM-2 and/or PIM-3) in the absence of a compound of the invention, as would be apparent to those skilled in the art.
  • the measurable change may be objective (e.g.
  • test or marker for example in an in vitro or in vivo assay or test, such as one described hereinafter, or otherwise another suitable assay or test known to those skilled in the art) or subjective (e.g. the subject gives an indication of or feels an effect).
  • Compounds of the invention may be found to exhibit 50% inhibition of a protein or lipid kinase (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) at a concentration of 100 ⁇ or below (for example at a concentration of below 50 ⁇ , or even below 10 ⁇ , such as below 1 ⁇ ), when tested in an assay (or other test), for example as described hereinafter, or otherwise another suitable assay or test known to the skilled person.
  • a protein or lipid kinase e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3
  • a concentration of 100 ⁇ or below for example at a concentration of below 50 ⁇ , or even below 10 ⁇ , such as below 1 ⁇
  • an assay or other test
  • Compounds of the invention are thus expected to be useful in the treatment of a disorder in which a protein or lipid kinase (e.g. a PIM family kinase such as PIM- 1 , PIM-2 and/or PIM-3) is known to play a role and which are characterised by or associated with an overall elevated activity of that protein kinase (due to, for example, increased amount of the kinase or increased catalytic activity of the kinase).
  • a protein or lipid kinase e.g. a PIM family kinase such as PIM- 1 , PIM-2 and/or PIM-3
  • Compounds of the invention (alone or in combination with another active) may be shown to be active e.g. in the biochemical assays described herein, may be shown to have predictive activity based on e.g.
  • the phosphorylation assay described herein may reduce the rate of cell proliferation e.g. as may be shown in the cell proliferation assays described herein (for instance using cancer cell lines (e.g. known commercially available ones), such as those described herein).
  • cancer cell lines e.g. known commercially available ones
  • compounds of the invention are expected to be useful in the treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with the protein or lipid kinase (e.g. a PIM family kinase such as PIM- 1, PIM-2 and/or PIM-3).
  • a disease/disorder arising from abnormal cell growth, function or behaviour associated with the protein or lipid kinase (e.g. a PIM family kinase such as PIM- 1, PIM-2 and/or PIM-3).
  • 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, 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.
  • cardiovascular disease stroke, 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.
  • 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, gall- bladder, 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 passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells
  • 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.
  • a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3
  • PIM-1 a PIM family kinase
  • PIM-2 a PIM family kinase
  • 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.
  • 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.
  • a pharmaceutically acceptable adjuvant, diluent and/or carrier Depending on e.g. potency and physical characteristics of the compound of the invention (i.e.
  • compositions 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.
  • 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-KB).
  • an agent that modulates the Ras/Raf/Mek pathway e.g. an inhibitor of MEK
  • the Jak/Stat pathway e.g. an inhibitor of Jak
  • the PI3K/Akt pathway e.g. an inhibitor of Akt
  • the DNA damage response mechanism e.g. an inhibitor of ATM or ATR
  • the stress signaling pathway an inhibitor of p38 or NF-KB
  • RTK receptor tyrosine kinase
  • an Akt or PI3-K inhibitor such as GDC-0941;
  • a therapeutic monoclonal antibody such as the HER2 inhibitor trastuzumab
  • a MEK inhibitor such as PD-0325901
  • a 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
  • 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-KB.
  • a combination product comprising:
  • A a compound of the invention, as hereinbefore defined; and (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 hyperprol iferative 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 A/-[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.
  • PIM-1 biochemical assay The biochemical assay to measure PIM-1 activity relies on the ADP Hunter assay kit (DiscoveRx Corp., Cat. # 90-0077), that determines the amount of ADP as direct product of the kinase enzyme activity.
  • the enzyme has been expressed and purified in-house as a recombinant human protein with a C-terminal histidine tag.
  • the protein is active and stable.
  • Assay conditions were as indicated by the kit manufacturers with the following adaptations for the kinase activity step: ⁇ 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)
  • 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.
  • 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).
  • Millipore # 14-738
  • the protein is active and stable. Assay conditions were as indicated by the kit manufacturers with the following adaptations for the kinase activity step:
  • PIM-1 substrate peptide PIMtide (ARKRRRHPSGPPTA)
  • H1299 cells overexpressing Pim1 H1299Pim1
  • DMSO Plates 96-well- Polystyrene, Untreated, Round-Bottom plates from Costar (Cat #3797)
  • Cell Plates 96-Flat bottom biocoated with Poly-D-Lysin plates with lid from Becton Dickinson (Cat#354651)
  • 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 may be tested.
  • a combination index score is calculated by the Chou and Talalay method (CalcuSyn software, Biosoft). The strength of synergy is scored using the ranking system Chou and Talalay: CI less than 0.8 indicates synergy, CI between 0.8 and 1.2 indicates additivity and CI greater than 1.2 indicates antagonism.
  • the EC50 values of representative combinations are also calculated.
  • the individually measured EC50 values of the chemotherapeutic agent and the example compounds are compared to the EC50 value of the combination.
  • the cell lines are characterised by tumor type.
  • DCM dichloromethane
  • DMF dimethylformamide
  • MeOH methanol
  • THF tetrahydrofuran
  • EtOAc ethyl acetate
  • DIPEA diisopropylethylamine
  • TEA triethylamine
  • BINAP 2,2'-bis(diphenylphosphino)-1 ,1'-binaphtyl
  • eq means equivalents
  • Et 2 0 means diethyl ether
  • BINAP means 2,2'-bis(diphenylphosphino)-1 ,1'-binaphtyl
  • eq means equivalents
  • Et 2 0 means diethyl ether
  • ""BuOH means n-butanol
  • PdCI 2 (PPh 3 ) 2 means dichlorobis(triphenylphosphine)palladium(ll)
  • Pd 2 (dba) 3 means tris(dibenzylidene
  • 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- S.
  • R t means retention time (in minutes)
  • [M+Hf means the protonated mass of the compound
  • method refers to the method used for (LC)MS.
  • Biological activity in PIM1 , PIM2 & PI 3 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 than the one described for one or some examples.
  • the compound may be in the free base form or, where specified, salt form (e.g. HCOOH salt), sometimes this depends on the purification method in HPLC.

Abstract

There is provided compounds of formula (I), wherein R1, R2, X, R3 and R4 have meanings given in the description (and which compounds are optionally substituted as indicated in the description), and pharmaceutically-acceptable esters, amides, solvates or salts thereof, which compounds are useful in the treatment of diseases in which inhibition of a 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, and particularly in the treatment of cancer or a proliferative disease. There is also provided combinations comprising the compounds of formula I.

Description

TRICYCLIC HETEROCYCLIC COMPOUNDS AS KINASE INHIBITORS
Field of the Invention
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.
Background of the Invention
The malfunctioning of protein kinases (PKs) is the hallmark of numerous diseases. 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.
For a general reference to PKs malfunctioning or disregulation see, for instance, Current Opinion in Chemical Biology 1999, 3, 459 - 465. 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. For example, PIM-1 phosphorylates inter alia p21 , Bad, c-myb, Cdc 25A and elF4B (see e.g. Quian, K. C. et al, J. Biol. Chem. 2005, 280(7), 6130-6137, and references cited therein).
Two PIM-1 homologs have been described [Baytel, D. Biochem. Biophys. Acta 1998, 1442, 274-285; Feldman, J. et al. J. Biol. Chem. 1998, 273, 16535.16543]. PIM-2 and PIM-3 are respectively 58% and 69% identical to PIM-1 at the amino acid level. PIM-1 is mainly expressed in thymus, testis, and cells of the hematopoietic system [Mikkers, H.; Nawijn, M.; Allen, J.; Brouwers, C; Verhoeven, E.; Jonkers, J.; Berns, Mol. Cell. Biol. 2004, 24, 6104; Bachmann, M.; Moroy, T. Int. J. Biochem. Cell Biol. 2005, 37, 726-730. 6115]. 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 γ-interferon, erythropoietin, and prolactin [Wang, Z et al.. J. Vet. Sci. 2001 , 2, 167-179].
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]. Signalling through 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].
Additionally, control of cell proliferation and survival by PIM-1 may be effected by means of its phosphorylation of the well-established cell cycle regulators cdc25 [Mochizuki, T. et al., J. Biol. Chem. 1999, 274, 18659-18666] and/or p21(Cip1/WAF1) [Wang Z. et al. Biochim. 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. In particular, it was shown that PIM function is required for efficient cell cycle induction of T cells in response to synergistic T-cell receptor and IL-2 signalling. A large number of interaction partners and substrates of PIM-1 have been identified, suggesting a pivotal role for PIM-1 in cell cycle control, proliferation, as well as in cell survival. The oncogenic potential of this kinase has been first demonstrated in E μ PIM-1 transgenic mice in which PIM-1 over-expression is targeted to the B-cell lineage which leads to formation of B-cell tumors [van Lohuizen, M.et al.; Cell 1989, 56, 673-682. Subsequently PIM-1 has been reported to be over-expressed in a number of prostate cancers, erythroleukemias, and several other types of human leukemias [Roh, M.et al.;. Cancer Res. 2003, 63, 8079-8084; Valdman, A. et al; Prostate 2004, 60, 367-371 ;
For example, chromosomal translocation of PIM-1 leads to overexpression of PIM-1 in diffuse large cell lymphoma. [Akasaka, H.et al.; Cancer Res. 2000, 60, 2335-2341]. Furthermore, 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., β/ood 2003, 102, 1833-184]. Thus, the strong linkage between reported overexpression data and the occurrence of PI -1 mutations in cancer suggests a dominant role of PIM-1 in tumorigenesis.
Several other protein kinases have been described in the literature, in which the activity and/or elevated activity of such protein kinases have been implicated in diseases such as cancer, in a similar manner to PIM-1 , PIM-2 and PIM-3.
It has also been reported that 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".
There is a constant need to provide alternative and/or more efficacious inhibitors of protein kinases, and particularly inhibitors of PIM-1, PIM-2 and/or PIM-3. Such modulators are expected to offer alternative and/or improved approaches for the management of medical conditions associated with activity and/or elevated activity of PIM-1, PIM-2 and/or PIM-3 protein kinases.
For the treatment of cancer, 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). This, and also the fact that 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.
Hence, it is a clear goal of current oncologists to develop targeted therapies (e.g. ones that are selective). In this respect, it should be pointed out that several different molecular targets may exist that are linked to certain diseases (e.g. cancer). However, one simply cannot predict if a therapy (e.g. a small molecule as a therapeutic) that interferes with or inhibits one target molecule could inhibit a different molecular target (be it one that will ultimately have the effect of treating the same disease or a different one).
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Journal articles J. Med. Chem. 2005, 48, 1367-1383 by Russell et al and J. Med. Chem. 2005, Vol 48, No. 23, 7089 by Carling et al both disclose inter alia triazolophthalazine compounds of potential use as GABAA receptor agonists, which may be useful therefore as inter alia hypnotics (and therefore for treating sleep disorders) and muscle relaxants. However, these documents only relate to fused tricyclic compounds in which one of the cyclic moieties is bridged. Further, there is no mention that the compounds disclosed therein may be useful as kinase inhibitors.
International patent application WO 2005/041971 discloses inter alia fused tricyclic compounds that may bind to of α2δ-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 GABAA receptors, WO 98/04560 discloses those that may act as inverse agonists of GABAA receptors, UK patent GB 2345443 discloses inter alia tricyclic compounds, which may be of use in treating premenstrual syndrome, and international patent application WO 2005/041971 discloses various tricyclic compounds for use in the treatment of bipolar diseases and the like. All of these documents only disclose fused tricyclic compounds that necessarily have oxy substituents, and do not disclose the use of those compounds as kinase inhibitors. US patent application US 5,011 ,835 discloses inter alia fused tricyclic compounds that may be useful as bronchodilators and antiallergic agents, but does not disclose tricyclic compounds that are substituted with an aromatic substituent, nor does it mention that the compounds may be useful as kinase inhibitors. European patents EP 0 104 506 and EP 0 029 130 both disclose inter alia tricyclic compounds that may be useful as bronchodilators, but does not disclose any that bear an aromatic substituent, nor does it disclose the potential use of those compounds as kinase inhibitors.
Journal article J. Het. Chew. 1988, 25(2), 393-8 by Branko et al discloses various tricyclic compounds, including those that contain an aromatic triazolopyridazine bicycle as an integral part of the tricycle. However, this journal article does not disclose that those compounds have a medical use, and further only discloses tricycles in which the 'third' ring fused to the triazolopyridazine bicycle contains an unsaturation (double bond).
European patent applications EP 0 548 923 and EP 0 562 439 disclose inter alia tricyclic compounds containing an aromatic imidazopyridazine bicyclic core or a [1 ,2,4]triazolo[1 ,5-b]pyridazine core. However, it does not disclose any tricyclic compounds containing a [1 ,2,4]triazolo[4,3-b]pyridazine core, nor does it mention that any of the compounds disclosed therein may be useful as kinase inhibitors.
European patent application EP 0 620 224 discloses inter alia [1 ,2,4]triazolo[4,3- bjpyridazines, but none in which such a bicycle is a sub-component of a fused tricyclic compound. Nor does this document disclose that the compounds therein may be useful as kinase inhibitors.
US patent application US 2003/0078277 discloses tricyclic compounds that may be useful as a corticotrophin, and therefore of use in the treatment of e.g. depression. However, this document does not primiarly relate to [1 ^^triazolo^.S-bJpyridazines, 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 tricycles substituted with an amino moiety and an aromatic group. Further, this document does not mention that the compounds disclosed therein may be useful as kinase inhibitors. International patent application WO 99/06404 discloses various fused tricyclic compounds, for use as phosphodiesterase 4 inhibitors. However, this document only relates to fused tricyclic compounds in which each of the three rings is aromatic.
International patent application WO 2008/109104 discloses various triazolopyridazines for use as Akt kinase inhibitors, but this document does not disclose any fused tricyclic compounds. International patent applications WO 2009/060197 and WO 2009/040552 disclose various imidazopyridazine-based and imidazolothiadiazolo-based compounds, for use as certain protein kinase inhibitors. However, these documents do not mention fused tricyclic compounds containing a bicyclic aromatic triazolopyridazine core fused to a non-aromatic ring.
Unpublished international patent application PCT/GB2010/002348 and unpublished European patent application EP 11382011.2 both disclose various tricyclic compounds for use as certain kinase inhibitors. However, these documents only disclose triazolopyridazine-based tricycles.
Disclosure of the Invention
According to the invention, there is now provided a compound of formula I,
Figure imgf000008_0001
wherein: the R1, R2 and X-containing ring is non-aromatic in which: R and R2 are independently selected from -0-, -S-, -S(O)-, -S(0)2-, -C(R6)(R6a)- and -N(R6)-; and
X represents C1-3 alkylene optionally substituted by one or more substituents selected from E2; each R6 and R6a independently represents, on each occasion when used herein, H, -C(0)NHRd1, -C(0)Rd2 or Rd3; Rd1, Rd2 and Rd3 independently represent C1-12 (e.g. C1-6) alkyl optionally substituted by one or more substituents selected from E1;
R3 represents aryl or heteroaryl, both of which are optionally substituted by one or more substituents selected from E3;
R4 represents a fragment of formula IA,
Figure imgf000009_0001
Ra and Rb independently represent H, C - 2 (e.g. C1-8) alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =NOR7a and Q ), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Q2); or Ra and Rb are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a (first) 3- to 7-membered cyclic group, optionally containing one further heteroatom selected from nitrogen, sulfur and oxygen, and which ring optionally:
(a) is fused to a second ring that is either a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen, sulfur and nitrogen (preferably oxygen and nitrogen), a 3- to 12- membered saturated carbocyclic ring, or an unsaturated 5- to 12- membered carbocyclic or heterocyclic ring (in which the heteroatoms are preferably selected from sulfur and, especially, nitrogen and oxygen);
(b) comprises a linker group -(C(RX)2)P- and/or -(C(Rx)2)r-0-(C(Rx)2)s- (wherein p is 1 or 2; r is 0 or 1 ; s is 0 or 1 ; and each Rx independently represents hydrogen or C1-6 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 or a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen and nitrogen, and which second ring is linked together with the first ring via a single carbon atom common to both rings (i.e. forming a spiro-cycle), all of which cyclic groups, defined by the linkage of Ra and Rb, are optionally substituted by one or more substituents selected from =0, =NOR7b and E4; each Q1 and Q2 independently represents, on each occasion when used herein: halo, -CN, -N02, -N(R10a)R11a, -OR 0a, -C(=Y)-R10a, -C(=Y)-OR 0a, -C(=Y)N(R10a)R11a, -C(=Y)N(R 0a)-OR11c, -OC(=Y)-R10a, -OC(=Y)-OR10a, -OC(=Y)N(R10a)R11a, -OS(O)2OR 0a, -OP(=Y)(OR10a)(OR11a), -OP(OR10a)(OR1 a), -N(R12a)C(=Y)R 1a, -N(R12a)C(=Y)OR11a, -N(R12a)C(=Y)N(R 0a)R a,
-NR12aS(O)2R 0a, -NR 2aS(O)2N(R10a)R11a, -S(O)2N(R10a)R11a, -SC(=Y)R10a, -S(O)2R10a, -SR10a, -S(O)R10a, C1-12 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R10a) and E5), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E6);
R7a and R7b independently represent hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms; each R11c independently represents, on each occasion when used herein, d.i2 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E7), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E8); each R 0a, R11a and R12a independently represent, on each occasion when used herein, hydrogen, alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E7), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E8); or any relevant pair of R 0a, R 1a and R12a (for example, when attached to the same atom, adjacent atom (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. double bonds), and which ring is optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E9; each E1, E2, E3, E4, E5, E6, E7, E8 and E9 independently represents, on each occasion when used herein:
(i) Q4;
(ii) Ci-12 alkyl optionally substituted by one or more substituents selected from =0 and Q5; or any two E , E2, E3, E4, E5, E6, E7, E8 or E9 groups, for example on Ci-12 alkyl groups or on aryl groups, e.g. when they are attached to the same or adjacent carbon atoms (e.g. two E3 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. double bonds), and which ring is optionally substituted by one or more substituents selected from =0 and J1; each Q4 and Q5 independently represent, on each occasion when used herein: halo, -CN, -N02, -N(R20)R21, -OR20, -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -C(=Y)N(R20)-O-R21a, -OC(=Y)-R20, -OC(=Y)-OR20, -OC(=Y)N(R20)R21, -OS(0)2OR20, -OP(=Y)(OR20)(OR21), -OPiOR^XOR21), -N(R22)C(=Y)R21, -N(R22)C(=Y)OR21, -N(R22)C(=Y)N(R20)R21, -NR22S(0)2R20, -NR22S(O)2N(R20)R21, -S(O)2N(R20)R21, -SC(=Y)R20, -S(0)2R20, -SR20, -S(0)R20, C -6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and J2), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from
J3); each Y independently represents, on each occasion when used herein, =0, =S, =NR23 or =N-CN; each R21a independently represents, on each occasion when used herein, C1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J4 and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J5); each R20, R2 , R22 and R23 independently represent, on each occasion when used herein, hydrogen, Ci-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J4 and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J5); or any relevant pair of R20, R21 and R22, may (for example, when attached to the same atom, adjacent atom (i.e. 1 ,2-relationship) or to atoms that are two atoms apart, i.e. in a 1 ,3-relationship) 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. double bonds), and which ring is optionally substituted by one or more substituents selected from J6 and =0; each J1, J2, J3, J4, J5 and J6 independently represents, on each occasion when used herein:
CO Q7;
(ii) C1-6 alkyl or heterocycloalkyl, both of which are optionally substituted by one or more substituents selected from =0 and Q8; each Q7 and Q8 independently represents, on each occasion when used herein: halo, -N(R50)R51, -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R50)R51, -N(R52)C(=Ya)R51, -NR52S(0)2R50, -S(0)2R50, -SR50, -S(0)R50 or C1-6 alkyl optionally substituted by one or more fluoro atoms; each Ya independently represents, on each occasion when used herein, =0, =S, =NR53 or =N-CN; each R50, R51, R52 and R53 independently represents, on each occasion when used herein, hydrogen or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, -OR60 and -N(R61)R62; or
any relevant pair of R50, R5 and R52 may (for example when attached to the same or adjacent atoms) be linked together to form, a 3- to 8-membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, heteroatoms selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (e.g. double bonds), and which ring is optionally substituted by one or more substituents selected from =0 and Ci_3 alkyl;
R60, R61 and R62 independently represent hydrogen or C1-6 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".
Pharmaceutically-acceptable 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.
By "pharmaceutically acceptable ester, amide, solvate or salt thereof, we include salts of pharmaceutically acceptable esters or amides, and solvates of pharmaceutically acceptable esters, amides or salts. For instance, pharmaceutically acceptable esters and 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 "Ν+-0'" moiety present) may also be mentioned (for instance, when the nitrogen atom is an integral part of the compound of the invention).
Pharmaceutically acceptable 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. For example, pharmaceutically acceptable esters (of carboxylic acids of compounds of the invention) that may be mentioned include optionally substituted C1-6 alkyl, C5- 0 aryl and/or C5- 0 aryl-C1-6 alkyl- esters. Pharmaceutically acceptable amides (of carboxylic acids of compounds of the invention) that may be mentioned include those of the formula -C^N R^R22, in which Rz1 and R22 independently represent optionally substituted C1-6 alkyl, C5. 0 aryl, or C5- 0 aryl-C1-6 alkylene-. Preferably, C1-6 alkyl groups that may be mentioned in the context of such pharmaceutically acceptable esters and amides are not cyclic, e.g. linear and/or branched. Further compounds of the invention that may be mentioned include carbamate, carboxamido or ureido derivatives, e.g. such derivatives of existing amino functional groups. For the purposes of this invention, therefore, prodrugs of compounds of the invention are also included within the scope of the invention.
The term "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)). For the avoidance of doubt, the term "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.
Examples of 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- annich 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 £ (entgegen) 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).
Compounds of the invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerisations. 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. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
All stereoisomers (including but not limited to diastereoisomers, enantiomers and atropisomers) and mixtures thereof (e.g. racemic mixtures) are included within the scope of the invention.
In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid 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 2H, 3H, C, 13C, 4C ,
13N 150 1 0 180 32p 33p SSg 18p 36^ 123, ^ 125, jsotopjCa||y.|abe,ec| compounds of the present invention (e.g., those labeled with 3H and 14C) are useful in compound and for substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 50, 13N, 11C and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. 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.
Unless otherwise specified, C1-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 Cs-q-cycloalkyl group). Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C2-q alkenyl or a C2-q alkynyl group).
Unless otherwise stated, the term C -q alkylene (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number of carbon atoms, be saturated or unsaturated (so forming, for example, an alkenylene or alkynylene linker group). Unless otherwise specified, such C -q alkylene groups may be branched (if sufficient number of atoms), but are preferably straight-chained. In the case of the C3 alkylene groups that X may represent, this alkylene group is straight-chained.
C3.q cycloalkyl groups (where q is the upper limit of the range) that may be specifically mentioned 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. The term "halo", when used herein, preferably includes fluoro, chloro, bromo and iodo.
Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is from 3 to 20 (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. Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C2.q heterocycloalkenyl (where q is the upper limit of the range) group. C2-q heterocycloalkyi 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-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6- oxabicyclo-[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, non-aromatic pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1 ,2,3,4-tetrahydropyridyl and 1 ,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1 ,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyi groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heterocycloalkyi 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. Heterocycloalkyi groups may also be in the N- or S- oxidised form. Heterocycloalkyi mentioned herein may be stated to be specifically monocyclic or bicyclic.
For the avoidance of doubt, the term "bicyclic" (e.g. when employed in the context of heterocycloalkyi groups) refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring. The term "bridged" (e.g. when employed in the context of cycloalkyl or heterocycloalkyi 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 C6-2o, such as C6.i2 (e.g. C6-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. C6-io 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.
Unless otherwise specified, the term "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). 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. 3,4-dihydro-1 - - isoquinolin-2-yl, 1 ,3-dihydroisoindol-2-yl, 1 ,3-dihydroisoindol-2-yl; i.e. heteroaryl groups that are linked via a non-aromatic ring), or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3- benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1,3- benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1 ,3- benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1 ,6-naphthyridinyl or, preferably, 1 ,5-naphthyridinyl and 1 ,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1 ,2,3,4- tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl and 1 ,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1 ,2,3-triazolyl, 1 ,2,4-triazolyl and 1 ,3,4-triazolyl) and the like. Substituents on 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. When heteroaryl groups are polycyclic in which there is a non- aromatic ring present, then that non-aromatic ring may be substituted by one or more =0 group.
It may be specifically stated that the heteroaryl group is monocyclic or bicyclic. In the case where it is specified that the heteroaryl is bicyclic, then it may consist of a five-, six- or seven-mem bered 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.
For the avoidance of doubt, where it is stated herein that a group (e.g. a Ci-12 alkyl group) may be substituted by one or more substituents (e.g. selected from E5), then those substituents (e.g. defined by E5) are independent of one another. That is, such groups may be substituted with the same substituent (e.g. defined by E5) or different substituents (defined by E5).
For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which there is more than one e.g. Q1 or Q2, or, E1 to E9 (such as E6) substituent present, then those Q1 or Q2, or, E1 to E9 (e.g. E6) substituents may be the same or different. Further, in the case where there are e.g. Q1 or Q2, or, E to E9 (such as E6) substituents present, in which one represents -OR10a (or e.g. -OR20, as appropriate) and the other represents -C(O)2R10a (or e.g. -C(0)2R2°, as appropriate), then those R10a or R20 groups are not to be regarded as being interdependent. Also, when e.g. there are two -OR substituents present, then those -OR10a groups may be the same or different (i.e. each R 0a group may be the same or different). For the avoidance of doubt, when a term such as UE1 to E9" is employed herein, this will be understood by the skilled person to mean E1, E2, E3, E4, E5, E6, E7, E8 and E9, inclusively.
All individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).
The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.
It is stated herein that X represents optionally substituted Ci to C3 alkylene. Such alkylene groups are straight-chained and hence X may represent -CH2-, -CH2CH2- or -CH2-CH2-CH2-, all of which moieties are optionally substituted by one or more substituents selected from E2, and hence may represent either one of the compounds of formula IA, IB or IC:
Figure imgf000022_0001
IA IB IC in which the alkylene moieties between the R1 and R2 groups are optionally substituted by one or more substituents selected from E2 (and the integers R1, R2, R3 and R4 are as hereinbefore defined). One or more E2 substituents may be attached to the relevant alkylene moieties (i.e. the substituent may replace a hydrogen atom). The E2 substituent may be a non-aromatic cyclic group (e.g. optionally substituted C3-12 cycloalkyl or heterocycloalkyl), which may be attached to a single carbon atom of the relevant -CH2-, -CH2-CH2 or -CH2-CH2-CH2- moiety.
Preferred compounds of the invention include those in which:
when R3 represents a substituted aryl (e.g. phenyl) group (i.e. substituted by one or more E3 substituents), then that/those E3 substituent(s) are preferably not located at the position ortho to the point of attachment of the R3 group (to the requisite triazolopyridazine bicycle of formula I).
Preferred aryl groups and bicyclic heteroaryl groups that R3 may represent include optionally substituted phenyl, naphthyl, indazolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1 ,3- benzodioxolyl, 1 ,3-dihydroisoindolyl, 3,4-dihydro-1H-isoquinolinyl, 1 ,3- dihydroisoindolyl, benzothiazolyl, and/or benzodioxanyl. Particularly preferred groups include optionally substituted aryl (e.g. naphthyl or, preferably, phenyl) or bicyclic heteroaryl (e.g. a bicyclic 9- or 10-membered group, in which one ring of the bicycle is benzene and the other ring preferably contains one, two, three or four (e.g. one or two) heteroatoms preferably selected from nitrogen, oxygen and sulfur), in which the point of attachment of the bicyclic heteroaryl group to the requisite triazolopyridazine core of the compound of formula I is via a benzene or, preferably heteroaromatic ring of the bicyclic heteroaryl group.
Preferred monocyclic heteroaryl groups that Ra or Rb or Q , Q2, Q4 or Q5 (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 R3, Ra or Rb, or Q , Q2, Q4 or Q5 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). Further, bicyclic rings may consist of benzene rings fused with a monocyclic heteroaryl group (as hereinbefore defined), e.g. a 6- or, preferably 5-membered monocyclic heteroaryl group optionally containing two, or, preferably, one heteroatom selected from sulfur, oxygen and nitrogen.
Preferred heterocycloalkyi groups that Ra or Rb or Q1, Q2, Q4 or Q5 may independently represent include 4- to 8-membered (e.g. 5- or 6-membered) heterocycloalkyi groups, which groups preferably contain one or two heteroatoms (e.g. sulfur or, preferably, nitrogen and/or oxygen heteroatoms), so forming for example, an optionally substituted pyrrolidinyl, piperidinyl, morpholinyl or tetrahydropyranyl group.
Preferred C3-6 cycloalkyl groups that Ra or Rb or Q1, Q2, Q4 or Q5 may independently represent include optionally substituted C3.8 (e.g. C3.6) cycloalkyl groups, such as cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl. Further preferred compounds of the invention include those in which:
each R10a, R11a and R12a independently represent, on each occasion when used herein, hydrogen or C - 2 (e.g. d-6) alkyl (which latter group is optionally substituted by one or more substituents selected from =0 and E7); or
any relevant pair of R10a, R11a and R12a may be linked together as defined herein (although they are preferably not linked);
each of E1, E2, E3, E4, E5, E6, E7, E8 and E9 independently represent, on each occasion when used herein, Q4 or C -6 alkyl (e.g. C -3) alkyl optionally substituted by one or more substituents selected from =0 and Q5;
each Q4 and Q5 independently represent halo, -CN, -N02, -N(R20)R21, -OR20, -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -N(R22)C(=Y)R21, -N(R22)C(=Y)OR21, -N(R22)C(=Y)N(R20)R21, -NR22S(0)2R20, -NR22S(O)2N(R20)R21, -S(O)2N(R20)R21, -S(0)2R20, -SR20, -S(0)R20 or C1-6 alkyl optionally substituted by one or more fluoro atoms (and each Q5 more preferably represents halo, such as fluoro);
any two E1, E2, E3, E4, E5, E6, E7, E8 and/or E9 groups may be linked together (e.g. any two E3 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 E1, E2, E4, E5, E6, E7, E8 and/or E9) are preferably not linked together;
each R20, R21, R22 and R23 independently represent, on each occasion when used herein, aryl (e.g. phenyl; preferably unsubstituted, but which may be substituted by one to three J5 groups) or, more preferably, hydrogen or Ci-6 (e.g. C1-3) alkyl optionally substituted by one or more substituents selected from =0 and J4; or any pair of R20 and R2 , may, when attached to the same nitrogen atom, be linked together to form a 4- to 8-membered (e.g. 5- or 6-membered) ring, optionally containing one further heteroatom selected from nitrogen and oxygen, optionally containing one double bond, and which ring is optionally substituted by one or more substituents selected from J6 and =0;
each J1, J2, J3, J4, J5 and J6 independently represents C -6 alkyl (e.g. acyclic C1-4 alkyl or C3-6 cycloalkyl) optionally substituted by one or more substituents selected from =0 and Q8, or, such groups independently represent a substituent selected from Q7;
each Q7 and Q8 independently represents a substituent selected from halo (e.g. fluoro), -N(R50)R51, -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R50)R51, -N(R52)C(=Ya)R51, -NR52S(0)2R50, -S(0)2R50 or CM alkyl optionally substituted by one or more fluoro atoms;
each R50, R51, R52 and R53 substituent independently represents, on each occasion when used herein, hydrogen or C1-6 (e.g. C1-3) alkyl optionally substituted by one or more substituents selected from fluoro;
when any relevant pair of R50, R51 and R52 are linked together, then those pairs that are attached to the same nitrogen atom may be linked together (i.e. any pair of R50 and R51), and the ring so formed is preferably a 5- or 6-membered ring, optionally containing one further nitrogen or oxygen heteroatom, and which ring is optionally substituted by one or more substituents selected from =0 and C1-3 alkyl (e.g. methyl);
R60, R61 and R62 independently represent hydrogen or C1-3 (e.g. C1-2) alkyl optionally substituted by one or more fluoro atoms.
Preferred optional substituents on R3, R4 and the R1, R2 and X-containing ring (if applicable) include:
=0 (unless the group is aromatic);
-CN;
halo (e.g. fluoro, chloro or bromo);
C1-6 (e.g. C1-4) alkyl, which alkyl group may be cyclic, part-cyclic, unsaturated or, preferably, linear or branched (e.g. C1-4 alkyl (such as ethyl, A?-propyl, isopropyl, t- butyl or, preferably, n-butyl or methyl), all of which are optionally substituted with one or more halo (e.g. fluoro) groups (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl) or substituted with an aryl, heteroaryl or heterocycloalkyi group (which themselves may be substituted with one or more -ORz1, -C^R22, -C(0)OR23, -N(Rz )R25, -S^R26, -S(0)2N(Rz7)Rz8; -N^-C^-R210, -C(0)-N(Rz11)Rz12 and/or -N(Rz9)-C(0)-N(Rz10) substituents; aryl (e.g. phenyl) (e.g. which substitutent may also be present on an alkyl group, thereby forming e.g. a benzyl group);
-ORz1;
-CiOJR22;
-C(0)ORz3;
-N(Rz4)Rz5;
-S(0)2RZ6;
-S(0)2N(Rz7)Rz8;
-N(Rz9)-C(0)-Rz1°;
-C(0)-N(Rz11)Rz12;
-N(Rz9)-C(0)-N(Rz10);
wherein each Rz to Rz12 independently represents, on each occasion when used herein, H or C1-4 alkyl (e.g. ethyl, n-propyl, f-butyl or, preferably, n-butyl, methyl, isopropyl or cyclopropylmethyl (i.e. a part cyclic alkyl group)) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a trifluoromethyl group). Further, any two Rz groups (e.g. Rz4 and Rz5), when attached to the same nitrogen heteroatom may also be linked together to form a ring such as one hereinbefore defined in respect of corresponding linkage of R 0a and R 1a groups.
Preferred compounds of the invention include those in which:
each R10a, R 1a and R12a independently represent phenyl (optionally substituted by one or more E8 substituents), preferably, heterocycloalkyi (optionally substituted by one or more =0 and/or E7 substituents) and, more preferably, hydrogen or C1-12 (e.g. C1-6) alkyl (optionally substituted by one or more =0 and/or E7 substituents), or any pair of R 0a, R a and R12a (e.g. any pair of R10a and R11a when attached to the same nitrogen atom) may be linked together to form a 4- to 10-membered (e.g. a 4- to 6-membered monocyclic) ring, optionally substituted by one or more substituents selected from =0 and E9; each E , E2, E3, E4, E5, E6, E7, E8 and E9 independently represents C1-12 alkyl optionally substituted by one or more substituents selected from =0 and Q5, or, each E1 to E9 independently represent Q4; or, any two E1 to E9 substituents (e.g. when attached to the same or adjacent atoms) may be linked together to form a 3- to 8-membered ring, optionally containing one to three double bonds, one to three heteroatoms, and which ring may be substituted by one or more substituents selected from =0 and J1;
each R20, R21, R22 and R23 (e.g. each R20 and R21) independently represents heteroaryl, preferably, aryl (e.g. phenyl) (which latter two groups are optionally substituted by one or more substituents selected from J5), or, more preferably, hydrogen or C1-6 (e.g. C1-4) alkyl optionally substituted by one or more substituents selected from =0 and J4; or
any relevant pair of R20, R21 and R22 (e.g. R20 and R2 ) may (e.g. when both are attached to the same nitrogen atom) be linked together to form a 3- to 8- (e.g. 4- to 8-) membered ring, optionally containing a further heteroatom, and optionally substituted by one or more substituents selected from =0 and J6;
each J1, J2, J3, J4, J5 and J6 independently represent C1-6 alkyl (e.g. C1-4 acyclic alkyl or C3-5 cycloalkyl) optionally substituted by one or more substituents selected from Q8, or, J1 to J6 more preferably represent a substituent selected from Q7;
each R50, R51, R52 and R53 independently represents hydrogen or C1-6 (e.g. C1-4) alkyl optionally substituted by one or more fluoro atoms;
each R60, R6 and R62 independently represents hydrogen or C -2 alkyl (e.g. methyl).
More preferred compounds of the invention include those in which:
Rd1, Rd2 and Rd3 independently represent C1-6 (e.g. C1-3) alkyl optionally substituted by one or more substituents selected from E1, but which is preferably unsubstituted;
when Ra and Rb are linked together, they may represent a 3- to 6-membered ring (e.g. a 5- or, preferably, 6-membered ring), optionally containing one further heteroatom selected from nitrogen and oxygen, which ring may be: (a) fused to another saturated 5- or 6-membered carbocyclic or heterocyclic ring, in which the latter contains one to four heteroatoms preferably selected from nitrogen and oxygen; (b) comprises a linker group linking any two non-adjacent atoms; or (c) comprises a further 4- to 6-membered saturated carbocyclic or heterocyclic ring, in which the latter contains one or two heteroatoms preferably selected from nitrogen and oxygen, which second ring is linked to the first via a single atom; Q4 and Q5 independently represent halo (e.g. fluoro), -OR20, -N(R20)R21, -C(=Y)R20, -C(=Y)OR20, -C(=Y)N(R20)R21, -N(R22)C(=Y)R21, -NR^SiO^R20, heterocycloalkyi, aryl, heteroaryl (which latter three groups are optionally substituted with one or more substitutents selected from J2 or J3, as appropriate) and/or d-e alkyl (e.g. C1-3 alkyl) optionally substituted by one or more fluoro atoms;
each Y represents, on each occasion when used herein, =S, or preferably =0; each R20, R21, R22 and R23 (e.g. each R20 and R21) independently represents hydrogen or 01-4 (e.g. C1-3) alkyl (e.g. C -4 acyclic alkyl group or a part cyclic C4 group) optionally substituted (but preferably unsubstituted) by one or more (e.g. one) J4 substituent(s); or
any relevant pair of R20, R21 and R22 (e.g. R20 and R21) may (e.g. when both are attached to the same nitrogen atom) may be linked together to form a 5- or, preferably, a 6-membered ring, optionally containing a further heteroatom (preferably selected from nitrogen and oxygen), which ring is preferably saturated, and optionally substituted by one or more substituents selected from =0 and J6;
R22 represents C -3 alkyl or hydrogen;
each J1, J2, J3, J4, J5 and J6 independently represent a substituent selected from Q7, or J1 to J6 represents C1-6 alkyl (e.g. C1-4 alkyl);
each Q7 and Q8 independently represent halo (e.g. fluoro), -N(R50)R51, -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R 0)R51, -N(R52)C(=Ya)R51 or C1-6 alkyl optionally substituted by one or more fluoro atoms;
each Ya independently represents =S or, preferably, =0;
each R50, R51, R52 and R53 independently represents H or C1-4 alkyl. Preferred compounds of the invention include those in which:
R1 and R2 independently represent -C(R6)(R6a)-, preferably, -S(O)- -S(0)2-, and, more preferably, -0-, -S- or -N(R6)-;
each R6 and R6a independently represents, on each occasion when used herein, H or Rd3;
Rd3 represents C1-6 (e.g. C1-4) alkyl; X represents optionally substituted (i.e. by E2) C2 or C3 alkylene;
R3 represents aryl (e.g. phenyl) or heteroaryl, both of which are optionally substituted by one or more (e.g. one to three) substituent(s) selected from E3; Ra and Rb independently represents H, C1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more (one to three) substituent(s) selected from Q1); or Ra and Rb may be linked together to form a 3- to 6- membered ring (e.g. a 5- or, preferably, 6-membered ring), preferably containing no further heteroatoms, which ring may be linked to a further 4- to 6-membered ring (e.g. 4-membered ring) via a single atom (i.e. forming a spiro cycle), all of which cyclic groups are optionally substituted by one or more substituents selected from E4;
Q1 and Q2 independently represent halo, -N(R10a)R11a, -OR 0a, -C(=Y)-R 0a, -C(=Y)-OR10a, -C(=Y)N(R 0a)R11a, -N(R 2a)C(=Y)R11a, -N(R 2a)C(=Y)OR11a, -N(R12a)C(=Y)N(R10a)R a, -NR12aS(O)2R10a, -NR12aS(O)2N(R10a)R11a, -S(O)2N(R 0a)R1 a, -S(O)2R 0a, -SR10a, -S(O)R10a, C1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R10a) and E5), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E6); pioa piia ancj pi2a independently represent H or C1-6 (e.g. C-M) alkyl optionally substituted by one or more groups selected from =0 and E7;
E1 to E9 independently represent Q4 or C-,.6 (e g- C1-3, such as methyl) alkyl optionally substituted by one or more Q5 substituents; or
any two E to E9 substituents (e.g. two E3 substituents) when attached to adjacent carbon atoms may be linked together to form a 3- to 8-membered (e.g. 5- or 6- membered) ring (preferably containing one to three double bonds, e.g. forming an aromatic ring), preferably containing one to three (e.g. one) heteroatom(s), and which ring is optionally substituted by one or more substituents selected from =0 and, preferably, J1 (when the ring is aromatic, then it may only be substituted by one or more J1 substituents);
Q4 and Q5 independently represent C1-6 alkyl (optionally substituted by one or more =0 and/or J2 substituents, but preferably, unsubstituted) or, preferably, halo, -CN, -OR20, -N(R20)R21, -C(=Y)R20, -C(=Y)OR20 or -N(R22)C(=Y)R21;
Y represents =S or, preferably, =0;
R20 and R21 independently represent hydrogen, C1-4 alkyl, which latter group is optionally substituted by one or more (e.g. one) substituent(s) selected from J4; when there is a -N(R )R moiety present, then one of R and R represents hydrogen, and the other represents hydrogen or C1-4 alkyl (e.g. methyl, ethyl or isopropyl), which latter group is optionally substituted by one or more (e.g. one) substituent(s) selected from J4;
R22 represents hydrogen and C1-3 alkyl (e.g. methyl);
J3 represents Q7;
J4 represents Q7 or C1-6 (e.g. C1-3) alkyl, which is preferably unsubstituted;
Q7 represents halo (e.g. fluoro). More preferred compounds of the invention include those in which:
R and R2 independently represent -N(R6)-, -O- or -C(R6)(R6a)-;
R6 and R6a independently represent H or Rd3;
Rd3 represents C1-3 alkyl (e.g. methyl or ethyl);
one of Ra and Rb represents H or C1-3 alkyl (e.g. methyl) and the other represents a substituent other than hydrogen (e.g. as hereinbefore defined).
Preferred compounds of the invention include those in which:
R3 represents (i) phenyl optionally substituted by one or two (e.g. one) substituent(s) selected from E3 or (ii) heteroaryl (e.g. a 5- or 6-membered monocyclic or, preferably, a 9- or 10-membered bicyclic heteroaryl group) optionally substituted by one or two (e.g. one) substituent(s) selected from E3; when R3 represents aryl (e.g. phenyl), it is preferably substituted by at least one (e.g. one) substituent selected from E3 (in which that substituent is preferably located at the meta position when R3 is phenyl);
when R3 represents a bicyclic heteroaryl group, it preferably represents a 5- or 6- membered monocyclic heteroaryl group (e.g. containing one heteroatom, e.g. pyridyl, furanyl or thienyl) fused to a benzene ring;
when R3 represents a bicyclic heteroaryl group, it is preferably unsubstituted or substituted with at least one (e.g. one) substituent on the benzene ring of the bicyclic group (preferably located ortho relative to the point of fusion between the benzene ring and monocyclic heteroaryl group);
E3 represents Q4 or C1-3 alkyl (e.g. methyl) optionally substituted by Q5 (e.g. fluoro, so forming e.g. a perfluoro alkyl group such as -CF3);
when E3 represents Q4, then Q4 represents -OR20;
Q5 represents halo (e.g. fluoro); R20 represents hydrogen or preferably C1-4 (e.g. C1-2) alkyl (e.g. methyl) optionally (and preferably) substituted by one or more substituents selected from J4 (e.g. fluoro, so forming a trifluoromethyl group);
J4 represents Q7;
Q7 represents halo (e.g. fluoro).
Particularly preferred R3 groups of the compounds of the invention include optionally substituted aryl (e.g. phenyl) and hetereoaryl (e.g. a 5- or 6-membered monocyclic heteroaryl group, containing one or two heteroatoms, preferably selected from nitrogen, so forming e.g. a pyridyl group). Preferred R3 groups include trifluoromethoxyphenyl (e.g. 3-OCF3-phenyl) and trifluoromethylpyridyl (e.g. 2-trifluoromethyl-4-pyridyl). Particularly preferred E3 substituents include trifluoromethyl and trifluoromethoxy. Most preferred compounds of the invention include those in which the R , R2 and X-containing ring
Figure imgf000031_0001
wherein the squiggly lines represent the point of attachment to the requisite bicycle of the compound of formula I, and the atoms of the ring may be substituted by one or more substituents selected from E2, in which E2 is as defined herein. The most preferred rings are:
Figure imgf000031_0002
Most preferred compounds of the invention include those in which:
R may represent -O- or -N(R6)-;
R2 may represent -0-, -N(R6)- or -C(R6)(R6a)-;
one of R1 and R2 may represent -O- and the other represents -O- or, preferably, -C(R6)(R6a)- or -N(R6)-;
each R6 (e.g. on -N(R6)- moieties) represents hydrogen or, preferably, C1-3 alkyl (preferably unsubstituted methyl);
E2 (e.g. when present on a 7-membered ring) represents Q4;
when E2 represents Q4, Q4 preferably represents halo (e.g. fluoro), C -6 alkyl (e.g. unsubstituted C1-2 alkyl, such as methyl, or cycloalkyl, e.g. cyclopropyl, cyclobutyl or cyclopentyl, which groups are preferably unsubstituted and linked via a single carbon atom of the alkylene group, so forming a spiro-cycle) or heterocycloalkyl (e.g. a 3- to 6-membered heterocycloalkyl group preferably containing one heteroatom (e.g. oxygen) so forming e.g. an oxetanyl group; and in which the heterocycloalkyl group is preferably linked via a single carbon atom of the alkylene group, so forming a spiro-cycle). unds of the invention include those in which R4 represents:
Figure imgf000032_0001
Figure imgf000032_0002
in which the squiggly line represents the point of attachment to the requisite triazolopyridazine of the compound of formula I, R376 represents Ra or Rb, and the other integers (e.g. E4, E5, Q1 and J2; 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 E5/Q1/E4 substituents) are as defined herein. The depiction of a substituent in brackets signifies that that substituent is optionally present, and may therefore be absent (i.e. N-(E5) may signify N-E5 or N-H). More preferably, R4 in compounds of the invention, represents one of the following gro
Figure imgf000033_0001
Most preferred compounds of the invention include those in which:
one of Ra and R represents H or C1-3 alkyl (e.g. methyl) and the other represents a substituent other than hydrogen (or the following groups);
when either of Ra and Rb represents a substituent (see above), then it may be:
(i) C1-6 alkyl (e.g. C1-3 acyclic alkyl or C3-6 cycloalkyl) (e.g. methyl, ethyl, n-propyl, cyclobutyl or cyclohexyl) optionally substituted by one or more substituents (and preferably substituted by at least one (e.g. one) substituent) selected from Q1;
(ii) heterocycloalkyi (e.g. a 5- or, preferably 6-membered heterocycloalkyi group containing one or two (e.g. one) heteroatom(s) in which one is preferably nitrogen or oxygen, so forming e.g. piperidinyl or tetrahydropyranyl, such as 4-piperidinyl or 4-tetrahydropyranyl) and which heterocycloalkyi group is optionally substituted by one or more substituents (e.g. one; which substituent(s) may be attached to a nitrogen heteroatom) selected from Q1; or
Ra and Rb may be linked together to form a 3- to 7-membered ring (e.g. a 5- or, preferably, a 6-membered ring), preferably containing no further heteroatoms, which ring may be linked to a further 4- to 6-membered ring (e.g. a 4- or 6- membered ring) via a single atom (i.e. forming a spiro cycle, which is preferably a [3.5], [5.3] or [5.5] spiro-cycle), all of which cyclic groups are optionally substituted by one or more substituents selected from E4; Q1 may represent -N(R 0a)R11a or heterocycloalkyl (e.g. a 5- or, preferably, 6- membered heterocycloalkyl group containing one or two (e.g. one) heteroarom preferably selected from nitrogen or oxygen; e.g. 4-piperidinyl or 4- tetrahydropyranyl) optionally substituted by one or more substituents selected from E5 (and which heterocycloalkyl group may be linked to a cycioalkyi group via a single carbon atom, so forming a spiro-cyclic group, which is preferably a [3.5] or [5.3] spiro-cycle, e.g. a 4-piperidinyl group may be linked to a cyclobutyl group via a single atom);
E4 represents Q4 or C1-3 alkyl (e.g. methyl) optionally substituted by one or more (e.g. one) substituent(s) selected from Q5;
E5 represents C -3 alkyl (e.g. methyl) or Q4;
when E4 represents Q4, then Q4 represents -N(R20)R21;
when E5 represents Q4, then Q4 may represent heterocycloalkyl, e.g. a 5- or preferably 6-membered heterocycloalkyl group (e.g. containing two or preferably one heteroatom (e.g. nitrogen), so forming e.g. a 4-piperidinyl group; and which group when present as a substituent on a cyclic group (e.g. cycioalkyi), may be attached via a single atom, so forming a spiro-cycle e.g. a 4-piperidinyl group linked to a cyclobutyl group via a single atom);
Q5 represents -N(R20)R21;
R20 and R21 independently represent hydrogen or C1-6 (e.g. C1-3) alkyl optionally substituted by one or more fluoro atoms.
Particular compounds of the invention include compounds of formula I,
Figure imgf000034_0001
wherein: the R1, R2 and X-containing ring is non-aromatic in which:
R represents O; R2 represents -C(R6)(R6a)- or -N(R6)-;
X represents C1-2 alkylene optionally substituted by one or more substituents selected from E2; each R6 and R6a independently represents, on each occasion when used herein, H or Rd3;
Rd3 represent C -4 alkyl (e.g. methyl) optionally substituted by one or more substituents selected from E1;
R3 represents (i) phenyl optionally substituted by one or two (e.g. one) substituent(s) selected from E3 or (ii) a 5- or 6-membered monocyclic heteroaryl (e.g. pyridyl) optionally substituted by one or two (e.g. one) substituent(s) selected from E3; 4 represents one of the following groups:
Figure imgf000035_0001
in which the squiggly line represents the point of attachment to the requisite triazolopyridazine of the compound of formula I, and E4, E5 and Q1 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 E5/Q1/E4 substituents;
R3* represents H or C1-2 alkyl (e.g. methyl) optionally substituted by one or more substituents selected from Q1; each Q independently represents, on each occasion when used herein: halo, -CN, -N02, -N(R10a)R11a, -OR10a; each R10a and R11a independently represent, on each occasion when used herein, hydrogen or alkyl (e.g. methyl); each E1, E3, E4 and E5, independently represents, on each occasion when used herein:
(i) Q4;
(ii) C1-4 alkyl (e.g. methyl) optionally substituted by one or more substituents selected from =0 and Q5; or each Q4 and Q5 independently represent, on each occasion when used herein: halo, -N(R20)R21 or -OR20; each R20 and R21 independently represent, on each occasion when used herein, hydrogen or C1-4 alkyl (e.g. methyl) optionally substituted by one or more halo substituents; or a pharmaceutically acceptable ester, amide, solvate or salt thereof.
Particular compounds of the invention include those described above but in which X represents a -CH2-CH2- linker.
Further particular compounds of the invention include those described above but in which X represents a -CH2-CH2- linker, and R3 represents phenyl optionally substituted by one or two (e.g. one) substituent(s) selected from E3.
Particularly preferred compounds of the invention include those of the examples described hereinafter.
Compounds of the invention may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I which process comprises: (i) reaction of a compound of formula II,
Figure imgf000037_0001
wherein L1 represents a suitable leaving group, such as iodo, bromo, chloro or a sulfonate group (e.g. -OS(0)2CF3, -OS(0)2CH3 or -OS(0)2Ph e), and R , R2, R3 and X are as hereinbefore defined, with a compound of formula III,
R -H III wherein R4 is as hereinbefore defined, under standard conditions, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc)2, Cul (or Cul/diamine complex), copper tris(triphenyl-phosphine)bromide, Pd(OAc)2l tris(dibenzylideneacetone)- dipalladium(O) (Pd2(dba)3) or NiCI2 and an optional additive such as Ph3P, 2,2'- bis(diphenylphosphino)-1 ,1'-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et3N, pyridine, A/^-dimethylethylenediamine, Na2C03, K2C03, K3P04, Cs2C03, f-BuONa or f-BuOK (or a mixture thereof, optionally in the presence of 4A molecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, /V-methylpyrrolidinone, tetrahydrofuran or a mixture thereof). 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 iert-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 R4 represents 1-aza-bicyclo[2.2.1]hept-4-ylmethyl-amino;
(ii) reaction of a compound of formula IV,
Figure imgf000038_0001
wherein L3 represents a suitable leaving group such as one hereinbefore defined in respect of L1 (e.g. halo, such as chloro or, preferably, bromo), and R1, R2, X and R4 are as hereinbefore defined, with a compound of formula V,
R3-L4 V wherein L4 represents a suitable group, such as -B(OH)2, -B(ORwx)2 or -SniR^, in which each R"* independently represents a C1-6 alkyl group, or, in the case of -B(ORwx)2, the respective Rw 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 L4 may represent iodo, bromo or chloro, provided that L3 and L4 are mutually compatible) and R3 is as hereinbefore defined. The reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI2, Pd(OAc)2, Pd(Ph3P)2CI2, Pd(Ph3P)4 (i.e. palladium tetrakistriphenylphosphine), Pd2(dba)3 and/or NiCI2 (preferred catalysts include palladium) and a ligand such as PdCI2(dppf).DCM, f-Bu3P, (CeHn^P, Ph3P, AsPh3, P(o-Tol)3, 1 ,2-bis(diphenylphosphino)ethane, 2,2'-bis(di-terf-butyl- phosphino)-1 , 1 '-biphenyl, 2,2'-bis(diphenylphosphino)-1 , 1 '-bi-naphthyl, 1,1'- bis(diphenyl-phosphino-ferrocene), 1,3-bis(diphenylphosphino)propane, xantphos, or a mixture thereof (preferred ligands include PdCI2(dppf).DCM), together with a suitable base such as, Na2C03l K3P04, Cs2C03, NaOH, KOH, K2C03, CsF, Et3N, (/-Pr)2NEt, i-BuONa or f-BuOK (or mixtures thereof; preferred bases include Na2C03 and K2C03) in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, dimethoxyethane, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, /V-methylpyrrolidinone, tetrahydrofuran or mixtures thereof (preferred solvents include dimethylformamide and dimethoxyethane). The reaction may be carried out for example at room temperature or above (e.g. at a high temperature such as at about the reflux temperature of the solvent system). Alternative reaction conditions include microwave irradiation conditions, for example at elevated temperature of about 130°C; (iii) reaction of a compound of formula VI,
Figure imgf000039_0001
wherein R4L1 represents either L1 or R4, and R1, R2, R4, X and L1 are as hereinbefore defined, with a compound of formula VII,
H-C(0)-C(H)(R3)(CI) VII wherein R3 is 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. The reaction may also take place in the presence of a suitable solvent, such as a polar solvent (e.g. 1 ,4-dioxane and the like), which may be heated at room termperature, or, preferably, above room temperature, e.g. above 50°C, such as at about 100°C. In the case where reaction takes place with a compound of formula VI in which R4L1 represents either L1, then the 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 one of R1 and R2 represents -0-, intramolecular reaction of a compound of formula VIII,
Figure imgf000040_0001
wherein either T1a represents -R1-X-OH or T2a represents -R2-X-OH and the other represents a suitable leaving group such as one defined hereinbefore by L1 (e.g. chloro or -OH, which latter group may if necessary be converted to a leaving group) and R3 and R4 are as hereinbefore defined, under standard reaction conditions e.g. in the presence of base (e.g. a metal alkyl oxide, such as potassium terf-butoxide) in a suitable solvent (e.g. a polar aprotic solvent such as THF) under reflux reaction conditions;
(v) for compounds of formula I in which R1 and R2 both represent -O- (and preferably X represents C3 alkylene), reaction of a compound of formula IX,
Figure imgf000040_0002
wherein L a and L2a each independently represent a suitable leaving group such as one defined hereinbefore by L1 (e.g. chloro) and R3 and R4 are as hereinbefore defined, with a compound of formula X,
HO-X-OH X wherein X is as hereinbefore defined (preferably C3 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);
(vi) for compounds of formula I in which X represents C1 alkylene substituted by a methyl group, an intramolecular addition reaction of a compound of formula XI,
Figure imgf000041_0001
wherein either Q a or Q2a represents -CH2-CH2=CH2 and the other represents -OH, under addition reaction conditions, for instance in the presence of an organic acid (e.g. para-toluene sulfonic acid), in an appropriate solvent (e.g. an aromatic solvent, such as toluene) for instance under reflux reaction conditions;
(vii) for compounds of formula I in which R and R2 are independently selected from -0-, -S- and -NR6-, reaction of a compound of formula XII,
Figure imgf000041_0002
wherein R1a and R2a independently represent -0-, -S- and -NR6-, and R3 and R4 are as hereinbefore defined, with a compound of formula XIII,
L5-X-L6 XIII wherein L5 and L6 independently represent a suitable leaving group, such as one hereinbefore defined in respect of L1 (e.g. halo, such as chloro), and X is as hereinbefore defined, under standard reaction conditions (to promote the nucleophilic substitution reactions), for example in the presence of a suitable base, such as Na2C03, K3P04, Cs2C03, NaOH, KOH, K2C03, CsF, Et3N, ( - Pr)2NEt, f-BuONa or f-BuOK (or mixtures thereof) in a suitable solvent such as dioxane, toluene, ethanol, te f-butanol, dimethylformamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N- methylpyrrolidinone, tetrahydrofuran or mixtures thereof. Preferred bases include i-BuOK.
Compounds of formula II may be prepared by reaction of a compound of formula VI as hereinbefore defined but in which R4L1 represents L1 and a compound of formula VII as hereinbefore defined, for example under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (iii)). Compounds of formula II may alternatively be prepared by reaction of a compound of formula XIV,
Figure imgf000042_0001
wherein L1, L3, R1, R2 and X are as hereinbefore defined, with a compound of formula V as hereinbefore defined, under reaction conditions such as those described in respect of preparation of compounds of formula I (process step (ii) above). Compounds of formula IV may be prepared by reaction of a compound of formula XVI as hereinbefore defined with a compound of formula III as hereinbefore defiend, for example under reaction conditions such as those described in respect of preparation of compounds of formula I (process step (i) above). Compounds of formula IV and compounds of formula XIV (in which L3 represents halo, e.g. bromo) may be prepared by reaction of a compound of formula XV,
XV
Figure imgf000042_0002
wherein R4L1, R1, R2 and X are as hereinbefore defined, for example by reaction in the presence of a source of halide (e.g. bromide or chloride) ions, for instance an electrophile that provides a source of iodide ions includes iodine, diiodoethane, diiodotetrachloroethane or, preferably, /V-iodosuccinimide, a source of bromide ions includes V-bromosuccinimide and bromine, and a source of chloride ions includes /V-chlorosuccinimide, chlorine and iodine monochloride, for instance in the presence of a suitable solvent, such as an alcohol (e.g. methanol) 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.
Compounds of formula VI may be prepared by reaction of a compound of formula XVI,
Figure imgf000043_0001
wherein L4 and L5 independently represent a suitable leaving group (e.g. chloro), and R4L1, L1 are as hereinbefore defined, with a compound of formula XVII,
H-R1a-X-R2a-H XVII wherein R1a, R2a 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 (viii) 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. Other specific transformation steps (including those that may be employed in order to form compounds of formula I) that may be mentioned include: (i) reductions, for example of a carboxylic acid (or ester) to either an aldehyde or an alcohol, using appropriate reducing conditions (e.g. -C(0)OH (or an ester thereof), may be converted to a -C(0)H or -CH2-OH group, using DIBAL and LiAIH4, respectively (or similar chemoselective reducing agents));
(ii) reductions of an aldehyde (-C(O)H) group to an alcohol group (-CH2OH), using appropriate reduction conditions such as those mentioned at point (i) above;
(iii) oxidations, for example of a moiety containing an alcohol group (e.g. -CH2OH) to an aldehyde (e.g. -C(O)H), for example in the presence of a suitable oxidising agent, e.g. Mn02 or the like;
(iv) reductive amination of an aldehyde and an amine, under appropriate reaction conditions, for example in "one-pot" procedure in the presence of an appropriate reducing agent, such as a chemoselective reducing agent such as sodium cyanoborohydride or, preferably, sodium triacetoxyborohydride, or the like. Alternatively, such reactions may be performed in two steps, for example a condensation step (in the presence of e.g. a dehydrating agent such as trimethyl orthoformate or MgS04 or molecular sieves, etc) followed by a reduction step (e.g. by reaction in the presence of a reducing agent such as a chemoselective one mentioned above or NaBH4, AIH4, or the like), for instance the conversion of -NH2 to -N(H)-isopropyl by condensation in the presence of acetone (H3C-C(0)-CH3) followed by reduction in the presence of a reducing agent such as sodium cyanaoborohydride (i.e. overall a reductive amination);
(iv) amide coupling reactions, i.e. the formation of an amide from a carboxylic acid (or ester thereof), for example when R2 represents -C(0)OH (or an ester thereof), it may be converted to a -C(O)N(R10b)R1 b group (in which R10 and R1 b are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g. when R2 represents -C(O)OH) be performed in the presence of a suitable coupling reagent (e.g. 1 ,1'-carbonyldiimidazole, Λ/,Λ - dicyclohexylcarbodiimide, or the like) or, in the case when R2 represents an ester (e.g. -C(0)OCH3 or -C(0)OCH2CH3), in the presence of e.g. trimethylaluminium, or, alternatively 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(R10a)R 1a (in which R10a and R11a 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);
(v) amide coupling reactions, i.e. the formation of an amide from a carboxylic acid (or ester thereof), for example when R2 represents -C(0)OH (or an ester thereof), it may be converted to a -C(O)N(R10b)R11b group (in which R10b and R 1b are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g. when R2 represents -C(O)OH) be performed in the presence of a suitable coupling reagent (e.g. 1,1'-carbonyldiimidazole, Λ/,Λ - dicyclohexylcarbodiimide, or the like) or, in the case when R2 represents an ester (e.g. -C(0)OCH3 or -C(0)OCH2CH3), in the presence of e.g. trimethylaluminium, or, alternatively the -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)C1, 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(R10a)R 1a (in which R 0a and R11a 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);
(vi) conversion of a primary amide to a nitrile functional group, for example under dehydration reaction conditions, e.g. in the presence of POCI3, or the like;
(vii) nucleophilic substitution reactions, where any nucleophile replaces a leaving group, e.g. methylsulfonylpiperazine may replace a chloro leaving group;
(viii) transformation of a methoxy group to a hydroxy group, by reaction in the presence of an appropriate reagent, such as boron fluoride-dimethyl sulfide complex or BBr3 (e.g. in the presence of a suitable solvent such as dichloromethane);
(ix) 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 -NH2 (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. C1-6 alkyl-halide (e.g. ethylbromide), C1-6 alkyl-C(0)-halide (e.g. H3C-C(0)CI), an anhydride (e.g. H3C- C(0)-0-C(0)-CH3, i.e. "-0-C(0)-CH3" is the leaving group), dimethylformamide (i.e. -N(CH3)2 is the leaving group) or a sulfonyl halide (e.g. H3C-S(0)2CI) and the like); (x) specific deprotection steps, such as deprotection of an /V-Boc protecting group by reaction in the presence of an acid, or, a hydroxy group protected as a silyl ether (e.g. a ferf-butyl-dimethylsilyl protecting group) may be deprotected by reaction with a source of fluoride ions, e.g. by employing the reagent tetrabutylammonium fluoride (TBAF).
Intermediate compounds described herein are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. Further, processes to prepare compounds of formula I may be described in the literature, for example in:
Werber,G. et al.; J. Heterocycl. Chem.; EN; 14; 1977; 823-827;
Andanappa K. Gadad et al. Bioorg. Med. Chem. 2004, 12, 5651-5659;
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M. Kuwahara et al., Chem. Pharm Bull., 1996, 44, 122;
A.F. Abdel-Magid and C.A Maryanoff. Synthesis, 1990, 537;
M. Schlosser et al. Organometallics in Synthesis. A Manual, (M. Schlosser, Ed.),
Wiley &Sons Ltd: Chichester, UK, 2002, and references cited therein;
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M. Plotkin et al. Tetrahedron Lett, 2000, 41, 2269; Seyden-Penne, J. Reductions by the Alumino and Borohydrides, VCH, NY, 1991;
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T. Ikemoto and M. Wakimasu, Heterocycles, 2001 , 55, 99;
E. Abignente et ai, II Farmaco, 1990, 45, 1075;
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J. A. H. Lainton et al., J. Comb. Chem., 2003, 5, 400; or
Wiggins, J. M. Synth. Commun., 1988, 18, 741.
The substituents R1, R2, R3, R4 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.
For example, when substituents in the compounds of the invention such as C02Et, CHO, CN and/or CH2CI, are present, these groups can be further derivatized to other fragments described (e.g. by those integers mentioned above) in compounds of the invention, following synthetic protocols very well know to the person skilled in the art and/or according to the experimental part described in the patent. Other specific transformation steps that may be mentioned 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).
Other transformations that may be mentioned include: the conversion of a halo group (preferably iodo or bromo) to a 1-alkynyl group (e.g. by reaction with a 1- alkyne), which latter reaction may be performed in the presence of a suitable coupling catalyst (e.g. a palladium and/or a copper based catalyst) and a suitable base (e.g. a tri-(C1-6 alkyl)amine such as triethylamine, tributylamine or ethyldiisopropylamine); the 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 NaN02 and a strong acid, such as HCI or H2S04, 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. 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 NaN3 or NaCN; the conversion of -C(0)OH to a -NH2 group, under Schmidt reaction conditions, or variants thereof, for example in the presence of HN3 (which may be formed in by contacting NaN3 with a strong acid such as H2S04), or, for variants, by reaction with diphenyl phosphoryl azide ((PhO)2P(0)N3) in the presence of an alcohol, such as te/if-butanol, which may result in the formation of a carbamate intermediate; the conversion of -C(0)NH2 to -NH2, for example under Hofmann rearrangement reaction conditions, for example in the presence of NaOBr (which may be formed by contacting NaOH and Br2) which may result in the formation of a carbamate intermediate; the conversion of -C(0)N3 (which compound itself may be prepared from the corresponding acyl hydrazide under standard diazotisation reaction conditions, e.g. in the presence of NaN02 and a strong acid such as H2S04 or HCI) to -NH2> for example under Curtius rearrangement reaction conditions, which may result in the formation of an intermediate isocyanate (or a carbamate if treated with an alcohol); the conversion of an alkyl carbamate to -NH2, by hydrolysis, for example in the presence of water and base or under acidic conditions, or, when a benzyl carbamate intermediate is formed, under hydrogenation reaction conditions (e.g. catalytic hydrogenation reaction conditions in the presence of a precious metal catalyst such as Pd); halogenation of an aromatic ring, for example by an electrophilic aromatic substitution reaction in the presence of halogen atoms (e.g. chlorine, bromine, etc, or an equivalent source thereof) and, if necessary an appropriate catalyst/Lewis acid (e.g. AICI3 or FeCIs).
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, Ν,Ν-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. Likewise, carboxyester groups may be converted into carboxylic acid derivatives through basic or acidic hydrolysis conditions, widely known in the art. Further, 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. The need for such protection is readily determined by one skilled in the art.
The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes. Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.
The use of protecting groups is fully described in "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999).
Medical and Pharmaceutical Uses
Compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined, for use as a pharmaceutical.
Compounds of the invention may inhibit protein or lipid kinases, such as a PIM 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. Thus, the compounds of the invention may be useful in the treatment of those disorders in an individual in which the inhibition of such protein or lipid kinases (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) is desired and/or required.
The term "inhibit" may refer to any measurable reduction and/or prevention of catalytic kinase (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) activity. The reduction and/or prevention of kinase activity may be measured by comparing the kinase activity in a sample containing a compound of the invention and an equivalent sample of kinase (e.g. a PIM family kinase such as PIM-1, PIM-2 and/or PIM-3) in the absence of a compound of the invention, as would be apparent to those skilled in the art. The measurable change may be objective (e.g. measurable by some 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 μΜ or below (for example at a concentration of below 50 μΜ, or even below 10 μΜ, such as below 1 μΜ), 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.
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 (alone or in combination with another active) may be shown to be active e.g. in the biochemical assays described herein, may be shown to have predictive activity based on e.g. the phosphorylation assay described herein, 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).
Hence, 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). Such conditions/disorders include cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders and neurological disorders. Compounds of the invention (particular PIM-1 inhibitors) may also be useful in the treatment of pulmonary artery hypertension (PAH). 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. 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. Other disease states that may be mentioned include cardiovascular disease, stroke, 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. As stated above, 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, gall- bladder, 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 passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukaemia; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma.
Further, the protein or lipid kinases (e.g. a PI family kinase such as PIM-1 , PIM- 2 and/or PIM-3) 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.
Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
According to a further aspect of the present invention, there is provided a method of treatment of a disease (e.g. cancer or another disease as mentioned herein) which is associated with the inhibition of protein or lipid kinase (e.g. a PIM family kinase such as PIM-1, PIM-2 and/or PIM-3) is desired and/or required (for example, a method of treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with protein or lipid kinases, e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3), which method comprises administration of a therapeutically effective amount of a compound of the invention, as hereinbefore defined, to a patient suffering from, or susceptible to, such a condition. "Patients" include mammalian (including human) patients. Hence, 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. According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier. Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), 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).
For instance, 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-KB).
For instance, compounds of the invention may be combined with:
(i) a targeted kinase inhibitor;
(ii) a receptor tyrosine kinase (RTK) inhibitor;
(iii) an Akt or PI3-K inhibitor, such as GDC-0941;
(iv) an Flt-3 inhibitor;
(v) an EGFR or HER2 inhibitor, such as lapatanib;
(vi) a therapeutic monoclonal antibody, such as the HER2 inhibitor trastuzumab;
(vii) a MEK inhibitor, such as PD-0325901;
(vii) a BRaf inhibitor, such as GDC-0879;
(viii) an anthracyclin, such as doxorubicin;
(ix) a taxane, such as paclitaxel or, particularly, docetaxel (Taxotere);
(x) a platin, such as carboplatin or, particularly, cisplatin;
(xi) a nucleotide analog, such as 5-fluorouracil (5-FU) or gemcitabine);
(xii) an alkylating agent, such as temozolomide;
(xiii) a hormone therapeutic agent, such as an estrogen receptor antagonist e.g. tamoxifen;
(xiv) an anti-tumour compound that has potential radiosensitising and/or chemosensitising effects, such as chloroquine;
(xv) an mTOR inhibitor, such as rapamycin;
(xvi) a JAK inhibitor;
(xvii) a cyclin dependent kinase inhibitor (e.g. a CDK6 or CDK4 inhibitor, such as PD-0332991); and/or
(xviii) an agent that modulates the DNA damage response mechanism and/or the stress signaling pathway, e.g. an inhibitor of ATM or ATR, an inhibitor of p38 and/or NF-KB.
According to a further aspect of the invention, there is provided a combination product comprising:
(A) a compound of the invention, as hereinbefore defined; and (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),
wherein 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). Thus, there is further provided:
(1) 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
(2) a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(b) 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.
In a particularly preferred aspect of the invention, 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 hyperprol iferative disorders such as cancer (e.g. specific cancers that may be mentioned herein, e.g. in the examples) in mammals, especially humans). Such active ingredients in combinations may act in synergy.
In particular, 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:
(i) a PI3K inhibitor, such as GDC-0941 ;
(ii) an EGFR inhibitor, such as Lapatinib;
(iii) a BRaf inhibitor such as GDC-0879;
(iv) docetaxel (Taxotere®, Sanofi-Aventis);
(v) a MEK inhibitor, such as PD-0325901 ; and/or
(vi) 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:
Figure imgf000058_0001
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. 114977-28-5) (or named as 1,73,^-trihydroxy-9-oxo- 5p,20-epoxytax-11-ene-2a,4,13a-triyl 4-acetate 2-benzoate 13-{(2R,3S)-3-[(ferf- butoxycarbonyl)amino -2-hydroxy-3-phenylpropanoate}) and has the structure:
Figure imgf000059_0001
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. 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 A/-[3-chloro-4-[(3- fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl] quinazolin-4-amine), and has the structure:
Figure imgf000059_0002
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. By "bringing into association", we mean that the two components are rendered suitable for administration in conjunction with each other.
Thus, in relation to the process for the preparation of a kit 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:
(i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or
(ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.
Depending on the disorder, and the patient, to be treated, as well as the route of administration, compounds of the invention may be administered at varying therapeutically effective doses to a patient in need thereof. However, 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. One skilled in the art will recognize that 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. In any event, 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). 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.
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).
Furthermore, 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
PIM-1 biochemical assay The biochemical assay to measure PIM-1 activity relies on the ADP Hunter assay kit (DiscoveRx Corp., Cat. # 90-0077), that determines the amount of ADP as direct product of the kinase enzyme activity.
The enzyme has been expressed and purified in-house as a recombinant human protein with a C-terminal histidine tag. The protein is active and stable.
Assay conditions were as indicated by the kit manufacturers with the following adaptations for the kinase activity step: · 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 MgCI2 and 0.1 mg/ml bovine y-globulins/75 μΙ assay volume)
• Incubation time and temperature: 60 min at 30°C
• PIM-1 concentration: 50 pg/μΙ
· ATP concentration: 100 μΜ
• PIM-1 substrate peptide: PIMtide (ARKRRRHPSGPPTA)
• Peptide concentration: 60 μΜ
• Positive control for kinase activity inhibition: 1-10 μΜ Staurosporine
• DMSO concentration have to stay below 2% during the kinase reaction
Assays were performed in either 96 or 384-well plates. The final outcome of the coupled reactions provided by the kit is the release of the fluorescent product Resorufin and has been measured with a multilabel HTS counter VICTOR V (PerkinElmer) using an excitation filter at 544 nm and an emission filter at 580 nm. PIM-2 biochemical assay
The biochemical assay to measure PIM-2 activity relies on the ADP Hunter assay kit (DiscoveRx Corp., Cat. # 90-0077), that determines the amount of ADP as direct product of the kinase enzyme activity.
The enzyme has been expressed and purified in-house as a recombinant human protein with a N-terminal histidine tag. The protein is active and stable.
Assay conditions were as indicated by the kit manufacturers with the following adaptations for the kinase activity step:
• 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
MgCI2 and 0.1 mg/ml bovine y-globulins/20 μΙ assay volume)
• Incubation time and temperature: 30 min at 30°C
• PIM-2 concentration: 350 pg/μΙ
• ATP concentration: 100 μΜ
· PIM-1 substrate peptide: PIMtide (ARKRRRHPSGPPTA)
• Peptide concentration: 100 μΜ
• Positive control for kinase activity inhibition: 1-10 μΜ Staurosporine
• DMSO concentration have to stay below 2% during the kinase reaction Assays were performed in either 96 or 384-well plates. The final outcome of the coupled reactions provided by the kit is the release of the fluorescent product Resorufin and has been measured with a multilabel HTS counter VICTOR V (PerkinElmer) using an excitation filter at 544 nm and an emission filter at 580 nm.
PIM-3 biochemical assay
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. Assay conditions were as indicated by the kit manufacturers with the following adaptations for the kinase activity step:
• 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 MgCI2 and 0.1 mg/ml bovine y-globulins/20 μΙ assay volume)
• Incubation time and temperature: 30 min at 30°C
• PIM-3 concentration: 250 pg/μΙ
• ATP concentration: 100 μΜ
• PIM-1 substrate peptide: PIMtide (ARKRRRHPSGPPTA)
· Peptide concentration: 60 μΜ
• Positive control for kinase activity inhibition: 1-10 μΜ Staurosporine
• DMSO concentration have to stay below 2% during the kinase reaction
Assays were performed in either 96 or 384-well plates. The final outcome of the coupled reactions provided by the kit is the release of the fluorescent product Resorufin and has been measured with a multilabel HTS counter VICTOR V (PerkinElmer) using an excitation filter at 544 nm and an emission filter at 580 nm. BAD S112 Phosphorylation inhibition assay
Efficacy of compounds of the invention on the inhibition of Bad phosphorylation was measured by an In Cell ELISA. EC50 values were established for the tested compounds.
Assay conditions:
Cells: H1299 cells overexpressing Pim1 (H1299Pim1)
DMSO Plates: 96-well- Polystyrene, Untreated, Round-Bottom plates from Costar (Cat #3797) Cell Plates: 96-Flat bottom biocoated with Poly-D-Lysin plates with lid from Becton Dickinson (Cat#354651)
Cell Culture Medium: 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)
Reagent: SuperSignal ELISA femto from Pierce (cat.#1001110)
Procedure:
Cells were seeded in 15000 cells per 200 μΙ per well into 96-well plates and incubated for 16 h at 37°C, 5% C02. On day two, nine serial 1 :2 compound dilutions were made in DMSO in a 96-well plate. The compounds were added to duplicate wells in 96-well cell plates using a FX BECKMAN robot (Beckman Coulter) and were incubated at 37°C under C02 atmosphere in medium without FBS. After 4 hours, relative levels of Bad S112 phosphorylation were measured in Cell ELISA using SuperSignal ELISA Femto substrate (Pierce) and read on VICTOR (Perkin Elmer). EC50 values were calculated using ActivityBase from IDBS. MTT in vitro cell proliferation assay
Proliferation assays (MTT) are performed as described in:
"Chemical interrogation of FOX03a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases", W. Link, J. Oyarzabal, B.G. Serelde, M.I. Albarran, O. Rabal, A. Cebria.P. Alfonso, J. Fominaya, O. Renner, S. Peregrina, D. Soilan, P.A. Ceballos, A.I. Hernandez, M. Lorenzo, P. Pevarello, T.G. Granda, G. Kurz, A. Carnero, J.R. Bischoff, J. Biol. Chem. 284 (2009) 28392-28400. Combination assay
The combination index (CI) of combinations of certain example compounds and various chemotherapeutic agents in the MTT in vitro cell proliferarion assays may be tested. A combination index score is calculated by the Chou and Talalay method (CalcuSyn software, Biosoft). The strength of synergy is scored using the ranking system Chou and Talalay: CI less than 0.8 indicates synergy, CI between 0.8 and 1.2 indicates additivity and CI greater than 1.2 indicates antagonism.
The EC50 values of representative combinations are also calculated. The individually measured EC50 values of the chemotherapeutic agent and the example compounds are compared to the EC50 value of the combination. The cell lines are characterised by tumor type.
Combination assays are performed as described in:
"Pirn 1 kinase inhibitor ETP-45299 suppresses cellular proliferation and synergizes with PI3K inhibition". Blanco-Aparicio, Carmen; Collazo, Ana Maria
Garcia; Oyarzabal, Julen; Leal, Juan F.; Albaran, Maria Isabel; Lima, Francisco
Ramos; Pequeno, Belen; Ajenjo, Nuria; Becerra, Mercedes; Alfonso, Patricia;
Reymundo, Maria Isabel; Palacios, Irene; Mateos, Genoveva; Quinones, Helena; Corrionero, Ana; Carnero, Amancio; Pevarello, Paolo; Lopez, Ana Rodriguez;
Fominaya, Jesus; Pastor, Joaquin; Bischoff, James R. Cancer Letters (Shannon,
Ireland) 2011, 300(2), 145-153.
The invention is illustrated by way of the following examples.
Experimental part:
The compound names given herein were generated with MDL ISIS/DRAW 2.5 SP 2, Autonom 2000.
Herein after, the term "DCM" means dichloromethane, "DMF" means dimethylformamide, "MeOH" means methanol, "THF" means tetrahydrofuran, "EtOAc" means ethyl acetate, "DIPEA" means diisopropylethylamine, "TEA" means triethylamine, "BINAP" means 2,2'-bis(diphenylphosphino)-1 ,1'-binaphtyl, "eq" means equivalents, "Et20" means diethyl ether, ""BuOH " means n-butanol, "PdCI2(PPh3)2 " means dichlorobis(triphenylphosphine)palladium(ll), "Pd2(dba)3" means tris(dibenzylideneacetone)dipalladium(0), "Pd(dppf)CI2.DCM" means 1 ,1'- bis(diphenylphosphino)ferrocenepalladium(ll) dichloride, dichloromethane, "NCS" means N-chlorosuccinimide, "NBS" means N-bromosuccinimide, "NIS" means N- iodosuccinimide, "rt" means room temperature, "min" means minutes, "h" means hours. General Procedure
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.
The 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.
Method 1
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.
Method 2
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.
Method 3
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.
Method 4
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.
Method 5
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- S.
SYNTHESIS OF INTERMEDIATES
intermediate 1-01
Figure imgf000068_0001
1-01
To a solution of 3,4,5-trichloropyridazine (1.0 eq) in MeOH (1 mL/mmol) was added dropwise a solution of 2-methylamino-ethanol (3.0 eq) in MeOH (1 mL/mmol) for 1 h at rt. The solvent was removed in vacuum to give a brown oil which was purified by Biotage flash column chromatography (eluent: 70% EtOAc in cyclohexane to 100% EtOAc) to give Intermediate 1-01 (85%).
HPLC-MS (method 4): Rt =2.5 min, [M+H]+ 222.1, 224.0.
1H NMR (300 MHz, CDCI3) δ 8.60 (s, 1H), 3.90 (t, J = 5.4 Hz, 2H), 3.72 (m, 2H), 3.20 (s, 3H).
Intermediate 1-02
Figure imgf000068_0002
Intermediate 1-01 (1.0 eq) was dissolved in THF (20 mUmmol). When the solution reached reflux, 'BuOK (1.2 eq) was added portionwise. The reaction mixture was refluxed for 2 h. On cooling, a saturated aqueous solution of NH CI was added and the layers were separated. The aqueous phase was extracted twice with EtOAc. The combined organic layers were dried (Na2S04), filtered and evaporated. The residue was triturated with Et20-DCM 9:1 and filtered off to afford Intermediate I-02 (90%).
HPLC-MS (method 4): Rt =0.98 min, [M+H]+ 186.1.
1H NMR (300 MHz, CDCI3) δ 8.47 (s, 1 H), 4.42 (m, 2H), 3.46 (m, 2H), 3.06 (s, 3H). Intermediate 1-03
Figure imgf000069_0001
1-02 1-03 A mixture of Intermediate 1-02 (1.0 eq) in acetonitrile (5 mUmmol) was heated at 50°C. Then, NCS (1.2 eq) was added and the reaction mixture was heated at 50°C for 3h. The solvent was removed in vacuum. The residue was taken up into DCM and washed with a saturated solution of NaHC03. The organic layer was dried (Na2S04), filtered and evaporated to give an orange solid which was purified by column chromatography (Biotage, DCM/EtOAc 20%) to Intermediate 1-03 (60%).
HPLC-MS (method 4): Rt =3.1 min, [M+H]+ 220.0, 222.0.
1H NMR (300 MHz, CDCI3) δ 4.36 (m, 2H), 3.31 (m, 2H), 3.14 (s, 3H).
Intermediates 1-04 and 1-05
Figure imgf000069_0002
1-03 1-04 1-05
A mixture of Intermediate 1-03 (5.7 g, 25.9 mmol), copper (82 mg, 1.29 mmol) and liquid ammonia (100 ml_) was heated in a Parr reactor at 170 °C for 24 h. After the mixture was cooled, excess of ammonia was vented off and the residual solid was dissolved in MeOH. The solvent was removed in vacuum and the residue was purified by column chromatography (Biotage, EtOAc:DCM, 30:70 to 90:10) to afford a mixture of Intermediates 1-04 and 1-05 (2.45 g, 47%). Intermediates 1-06 and 1-07
Figure imgf000070_0001
1-04 1-05
1-06 1-07
A mixture of Intermediates 1-04 and 1-05 (2.0 g, 9.97 mmol) was suspended in water (100 mL) and heated at 95°C. Then, chloroacetaldehyde (50% water solution, 25.0 mmol) was added. The reaction mixture was heated at 100°C overnight. On cooling, the mixture was poured onto sat. solution of NaHC03 (100 mL) and extracted with DCM. The combined organic layers were dried, filtered and concentrated. The residue was purified by flash chromatography (Biotage, EtOAc:DCM 20:80 to 100:0) to give Intermediate I-06 (1.468 g, 66%) and Intermediate 1-07 (558 mg, 25%) as white solids.
1-06: 1H NMR (300 MHz, CDCI3) δ 7.67 (d, J= 0.9 Hz, 1H), 7.49 (s, H), 4.43-4.32 (m, 2H), 3.23-3.08 (m, 2H), 2.80 (s, 3H).
I-07: 1H NMR (300 MHz, CDCI3) δ 7.65 (d, J= 1.2 Hz, 1H), 7.46 (d, J= 1.1 Hz, 1H), 4.35-4.25 (m, 2H), 3.81 (s, 3H), 3.56-3.45 (m, 2H).
Intermediate I-08
Figure imgf000070_0002
1-06 1-08
To a solution of Intermediate I-06 (1.47 g, 6.54 mmol) in chloroform (65 mL) was added NBS (1.28 g, 7.19 mmol). The reaction mixture was stirred at rt for 4 h. The mixture was washed with sat. sol. NaHC03. The organic layer was dried, filtered and evaporated. The residue was purified by flash chromatography (Biotage, EtOAc:DCM 0:100 to 50:50) to give Intermediate I-08 (1.54 g, 78%) as a yellow solid. 1H NMR (300 MHz, CDCI3) δ 7.53 (s, 1H), 4.55-4.26 (m, 2H), 3.30-3.08 (m, 2H), 2.85 (s, 3H).
Intermediate I-09
Figure imgf000071_0001
A mixture of Intermediate 1-08 (100 mg, 0.33 mmol), 3- (trifluoromethoxy)phenylboronic acid (75 mg, 0.36 mmol), Pd(dppf)CI2 DCM (20 mg, 0.02 mmol) and Cs2C03 (215 mg, 0.66 mmol) in dioxane:H20 (1.9:0.4 mL) was heated at 100 °C for 2 h. On cooling, H20 was added, and the aqueous phase was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (Isolute 5g, EtOAc:DCM 0:100 to 100:0) to give Intermediate I- 09 (101 mg, 75%) as a yellow oil.
1H NMR (300 MHz, CDCI3) δ 7.95 (m, 2H), 7.88 (m, 1H), 7.48 (dd, J= 12.9, 4.7 Hz, 1H), 7.24-7.13 (m, 1H), 4.56-4.38 (m, 2H), 3.25 (m, 2H), 2.91 (s, 3H).
The following Intermediates were prepared following the same procedure:
Intermediate 1-10
Figure imgf000071_0002
1-10
H NMR (300 MHz, CDCI3) δ 8.77 (d, J= 5.2 Hz, 1 H), 8.34 (d, J= 0.9 Hz, 1H), 8.24 (dd, J= 5.2, 1.4 Hz, 1H), 8.12 (s, 1H), 4.48 (m, 2H), 3.20 (m, 2H), 2.93 (s, 3H). Intermediate 1-11
Figure imgf000072_0001
1-11
To a mixture of 3-amino-6-chloropyridazine (5 g, 38.59 mmol) and NaHC03 (6.48 g, 77.19 mmol) in MeOH (70 mL) was added dropwise a solution of bromine (1.98 mL, 38.59 mmol) in MeOH (10 mL) at 0°C. The reaction mixture was stirred at rt overnight. More NaHC03 (3.3 g) and Br2 (1 mL) were added and the mixture was stirred at rt for 2 days. The mixture was concentrated and the residue was taken up in water and extracted with EtOAc. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (EtOAc Hex 80:20) to afford Intermediate 1-11 (1.58 g, 20%).
HPLC-MS (method 4): Rt =1.7 min, [M+H]+ 210.
1H NMR (300 MHz, CDCI3) δ 7.54 (s, 1H), 5.57 (s, 2H).
Intermediate 1-12
Figure imgf000072_0002
1 2
To a suspension of Intermediate 1-11 (1.6 g, 7.67 mmol) in water (50 mL) heated to 95 °C was added chloroacetaldehyde (50% in water, 1.5 mL, 11.5 mmol). The reaction mixture was stirred at 95°C overnight. On cooling, NaHC03 was added until pH=7. The suspension was filtered off and washed with cold water to afford Intermediate 1-12 (1.28 g) as an orange solid. The filtrate was extracted with
DCM. The organic layer was dried, filtered and evaporated to give Intermediate I-
12 (310 mg) as a reddish oil. Total yield: 1.59 g, 72%.
1H NMR (300 MHz, DMSO) δ 8.45 (s, 1H), 7.90 (d, J = 13.4 Hz, 2H). Intermediate 1-13
Figure imgf000073_0001
1-12 M3
To a suspension of Intermediate 1-12 (950 mg, 4.08 mmol) and Cs2C03 (1.6 g, 4.9 mmol) in acetonitrile (20 mL) was added allyl alcohol (0.3 mL, 4.5 mmol). The reaction mixture was heated at 65°C for 6 h. More Cs2C03 (1.0 g) and allyl alcohol (0.25 mL) were added and the mixture was stirred at rt overnight. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried, filtered and concentrated. The residue was purified by column chromatography (cHex:EtOAc 2:1 to 1 :1.5) to give Intermediate 1-13 (690 mg, 80%).
HPLC-MS (method 4): Rt =3.32 min, [M+Hf 210.
H NMR (300 MHz, CDCI3) δ 7.87 (d, J = 0.9 Hz, 1H), 7.68 (s, 1H), 6.43 (s, 1 H), 6.13 (ddd, J = 22.7, 10.8, 5.5 Hz, 1H), 5.54 (d, J = 16.3 Hz, 1H), 5.44 (d, J = 10.4 Hz, 1H), 4.89 (d, J = 5.5 Hz, 2H).
Intermediate 1-14
Figure imgf000073_0002
A solution of Intermediate 1-13 (280 mg, 1.33 mmol) in 'BuOH (5 mL) was heated in a sealed tube at 180 °C for 16 h. On cooling, Et20 was added, and the mixture was filtered to give Intermediate 1-14 (247 mg, 88%).
H NMR (300 MHz, DMSO) δ 8.11 (d, J = 1.9 Hz, 1H), 7.88 (d, J = 1.9 Hz, 1 H), 5.84 (ddt, J = 16.1, 10.1, 6.0 Hz, 1H), 5.00 (dd, J = 12.4, 1.8 Hz, 1H), 4.98 - 4.88 (m, 1H), 3.36 (d, J = 6.0 Hz, 2H). Intermediates 1-15 and 1-16
Figure imgf000074_0001
1-14 1-15 1-16
To a suspension of Intermediate 1-14 (209 mg, 0.99 mmol) in THF (10 mL) was added borane-methyl sulfide complex (2M in THF, 2.0 mL, 3.97 mmol) at 0°C. The reaction mixture was stirred overnight. The mixture was cooled to 0°C and carefully quenched with water. Sodium perborate tetrahydrate (763 mg, 4.96 mmol) was added and the mixture was stirred at rt for 2 h. The mixture was acidified with 1 M aq HCI and extracted with 'PrOH/CHCI3 1 :1. The organic layers were dried, filtered and evaporated. The residue was purified by column chromatography (DCM/MeOH 95:5 to 85:15) to give a mixture of Intermediates I-
15 and 1-16 (130 mg, 58%).
Intermediates 1-17 and 1-18
Figure imgf000074_0002
1-15 1-16 1-17 I-
To a mixture of Intermediates 1-15 and 1-16 (145 mg, 0.64 mmol) in DCM (5 mL) was added Vilsmayer's reagent (90 mg, 0.70 mmol). The mixture was stirred at rt for 10 min and ΤΕΞΑ (0.35 mL, 2.55 mmol) was added. The reaction mixture was stirred at rt for 2 h. Water was added and the mixture was extracted with DCM and with CHCI3:'PrOH 1 :1. The combined organic layers were dried, filtered and evaporated. The residue was purified by column chromatography (DCM/MeOH 100:0 to 9:1) to give a mixture of Intermediates 1-17 and 1-18 (62 mg, 46%).
1-17: HPLC-MS (method 4): Rt =1.92 min, [M+H]+ 210.
1-18: HPLC-MS (method 4): Rt =3.37 min, [M+H]+ 210.
Figure imgf000075_0001
To a solution of Intermediates 1-17 and 1-18 (62 mg, 0.29 mmol) in DMF (1 mL) was added NIS (67 mg, 0.29 mmol). The reaction mixture was stirred at rt overnight. Water was added, and the mixture was filtered off and washed with water to give a mixture of Intermediates 1-19 and I-20 (100 mg, 100%).
1-19: HPLC-MS (method 4): Rt =4.18 min, [M+H]+ 336.
1-20: HPLC-MS (method 4): Rt =4.36 min, [M+H]+ 336.
Intermediates 1-21 and I-22
Figure imgf000075_0002
To mixture of Intermediates 1-19 and I-20 (125 mg, 0.37 mmol), 3- (trifluoromethoxy)phenylboronic acid (100 mg, 0.48 mmol) and 2M aq Na2C03 (1.5 mL) in 1 ,4-dioxane (5 mL) was added PdCI2(PPh3)2 (52 mg, 0.08 mmol). The reaction mixture was refluxed for 2 h. On cooling, the mixture was evaporated and the residue was taken up in water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic phases were dried, filtered and evaporated. The residue was purified by column chromatography (cHex/EtOAc 3:1 to 1 :1) to give Intermediate 1-22 (15 mg, 11%) and Intermediate 1-21 (60 mg, 44%).
1-21: HPLC-MS (method 1): Rt =6.22 min, [M+H]+ 370. H NMR (300 MHz, CDCI3) δ 7.94 (m, 3H), 7.51 (m, 1H), 7.24 (s, 1H), 4.52 (m,
2H), 2.82 (m, 2H), 2.22 (m, 2H).
I-22: HPLC-MS (method 1): Rt =6.51 min, [M+Hf 370.
1H NMR (300 MHz, CDCI3) δ 7.89 (m, 3H), 7.45 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 5.36 (dd, J = 15.7, 6.9 Hz, 1H), 3.48 (dd, J = 15.5, 9.5 Hz, 1H), 2.95 (dd, J = 15.5, 7.3 Hz, 1H), 1.59 (d, J = 6.3 Hz, 3H).
GENERAL SYNTHETIC PROCEDURE FOR THE SYNTHESIS OF FINAL PRODUCTS BOC deprotection of amino group was carried out using standard protocols, very well known for a person skilled in the art, such us acidic media, by using hydrochloric acid or trifluoroacetic acid, in the presence of an appropriate solvent or using an acid resin such as amberlyst. General Synthetic Procedure A
Example: Synthesis of final products 1 and 2
Figure imgf000076_0001
1-10
A mixture of Intermediate 1-10 (74 mg, 0.2 mmol), 4- [(methylamino)methyl]piperidine-1-carboxylic acid te/f-butyl ester (183 mg, 0.8 mmol) and DIPEA (0.21 mL, 1.2 mmol) in "BuOH (2 mL) was heated at 170°C for 3 days. More amine (92 mg, 0.4 mmol) and DIPEA (0.07 mL, 0.4 mmol) were added and the reaction mixture was heated at 170°C for 2 days. On cooling, the mixture was evaporated. The residue was purified by column chromatography (Isolute Flash-NH2 10g; MeOH:DCM 0:100 to 50:50) and by HPLC to give Final Product 2 (16 mg, 16%) and Final Product 1 (4.2 mg, 4%) as yellow solids. General Synthetic Procedure B
Figure imgf000077_0001
1-21 10
To a suspension of Intermediate 1-21 (30 mg, 0.08 mmol), (1-methyl-4- piperidinyl)methanamine (21 mg, 0.16 mmol), Na'BuO (23 mg, 0.24 mmol) and rac-BINAP (10 mg, 0.02 mmol) in dioxane (1.5 mL) was added Pd2(dba)3 (7 mg, 0.008 mmol). The reaction mixture was refluxed for 5 h. On cooling, sat. aq. sol. NaHC03 was added and the mixture was extracted with CHCI/PrOH (1:1). The organic layers were dried, filtered and evaporated. The residue was purified by column chromatography (DCM/ eOH 100:0 to 90:10 and DC /1M NH3 in MeOH 4:1) to give Final Product 10 (15 mg, 40%).
Table 1 : Compounds, Analytical data, PIM activity, Synthetic methodology -
Rt means retention time (in minutes), [M+Hf means the protonated mass of the compound, method refers to the method used for (LC)MS. Biological activity in PIM1 , PIM2 & PI 3 for certain examples is represented by quantitative results, IC50 in nM and for certain examples is represented by semi-quantative results: IC50 >1μΜ (.), IC50 <100 nM (-), 100 nM<IC50<1 μΜ («). Synthetic method column refers to the general synthetic method used to generate the compounds following a similar protocol than the one described for one or some examples. The compound may be in the free base form or, where specified, salt form (e.g. HCOOH salt), sometimes this depends on the purification method in HPLC.
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Cpd PIM1 PIM2 PIM3 Synth.
Structure *H-NMR (300 MHz) LC/MS Salt Nr. IC50 IC50 IC50 Method
MeOD δ 8.38 (s, 1H),
8.01 (d, J = 7.9 Hz,
1H), 7.82 (s, 1H),
method
7.53 (m, 1H), 7.24 (m,
1, RT =
1H), 5.36 (m, 1H),
3.11 min,
11 3.34 (m, 5H), 2.81 *** >1000 ** B No
[M+Hf
(dd, J = 15.3, 7.2 Hz,
m/z
1H), 2.62 (m, 5H),
462.2
2.05 (m, 3H), 1.58 (d,
J = 6.2 Hz, 3H), 1.47
(m, 2H).
MeOD δ 8.37 (s, 1 H),
8.24 (s, 1H), 7.97 (d,
J = 7.8 Hz, 1H), 7.83 method
(s, 1H), 7.51 (m, 1H), 1, RT =
7.21 (d, J = 7.6 Hz, 3.01 min,
12 1H), 4.37 (m, 2H), [M+Hf 4 *** 32 A HCOOH
3.60 (m, 2H), 3.44 (m, m/z
2H), 3.29 (m, 2H), 503.3
3.12 (m, 4H), 2.94 (s,
3H), 1.79 (m, 8H).
MeOD δ 8.40 (broad
s, 1H), 8.35 (s, 1H),
method
7.96 (d, J = 7.9 Hz,
1 , RT =
1H), 7.88 (s, 1H),
3.27 min,
7.53 (m, 1H), 7.23 (m,
13 [M+H]+ 1 *** *** A HCOOH
1H), 4.41 (m, 2H),
m/z
3.44 (m, 2H), 3.32 (m,
503.3
4H), 3.22 (m, 4H),
2.91 (s, 3H), 1.86 (m,
6H), 1.69 (m, 2H).
Efficacy of compounds of the examples to inhibit the Bad phosphorylation is represented in Table 2 by quantative results. Assay was performed in absence of FBS. Table 2: BAD phosphorylation inhibition data
Figure imgf000082_0001

Claims

Claims
1. A compound of formula I,
Figure imgf000083_0001
wherein:
R2 and X-containing ring is non-aromatic in which:
R1 and R2 are independently selected from -0-, -S-, -S(O)-, -S(0)2-, -C(R6)(R6a)- and -N(R6)-; and
X represents d-3 alkylene optionally substituted by one or more substituents selected from E2; each R6 and R6a independently represents, on each occasion when used herein, H, -C(0)NHRd1, -C(0)Rd2 or Rd3; Rd1, Rd2 and Rd3 independently represent C1-12 (e.g. C -6) alkyl optionally substituted by one or more substituents selected from E ;
R3 represents aryl or heteroaryl, both of which are optionally substituted by one or more substituents selected from E3;
R4 represents a fragment of formula IA,
Figure imgf000083_0002
Ra and Rb independently represent H, C1-12 (e.g. C1-8) alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =NOR7a and Q1), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Q2); or
Ra 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 heteroatom selected from nitrogen, sulfur and oxygen, and which ring optionally:
(a) is fused to a second ring that is either a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen, sulfur and nitrogen (preferably oxygen and nitrogen), a 3- to 12- membered saturated carbocyclic ring, or an unsaturated 5- to 12- membered carbocyclic or heterocyclic ring (in which the heteroatoms are preferably selected from sulfur and, especially, nitrogen and oxygen);
(b) comprises a linker group -(C(RX)2)P- and/or -(C(R )2)r-0-(C(Rx)2)s- (wherein p is 1 or 2; r is 0 or 1 ; s is 0 or 1 ; and each Rx independently represents hydrogen or C1-6 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 or a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen and nitrogen, and which second ring is linked together with the first ring via a single carbon atom common to both rings (i.e. forming a spiro-cycle), all of which cyclic groups, defined by the linkage of Ra and Rb, are optionally substituted by one or more substituents selected from =0, =NOR7b and E4; each Q1 and Q2 independently represents, on each occasion when used herein: halo, -CN, -N02l -N(R10a)R11a, -OR10a, -C(=Y)-R10a, -C(=Y)-OR 0a, -C(=Y)N(R10a)R a, -C(=Y)N(R 0a)-OR 1c, -OC(=Y)-R10a, -OC(=Y)-OR10a, -OC(=Y)N(R10a)R11a, -OS(O)2OR10a, -OP(=Y)(OR10a)(OR 1a), -OP(OR10a)(OR11a), -N(R12a)C(=Y)R 1a, -N(R12a)C(=Y)OR11a, -N(R12a)C(=Y)N(R10a)R11a, -NR 2aS(O)2R10a, -NR12aS(O)2N(R10a)R11a, -S(O)2N(R 0a)R 1a, -SC(=Y)R 0a, -S(O)2R 0a, -SR10a, -S(O)R10a, C1-12 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R10a) and E5), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E6);
R7a and R7b independently represent hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms; each R11c independently represents, on each occasion when used herein, C1-12 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E7), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E8); each R10a, R11a and R12a independently represent, on each occasion when used herein, hydrogen, C - 2 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E7), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E8); or any relevant pair of R10a, R a and R 2a (for example, when attached to the same atom, adjacent atom (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. double bonds), and which ring is optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E9; each E1, E2, E3, E4, E5, E6, E7, E8 and E9 independently represents, on each occasion when used herein:
(') Q4; (ii) Ci- 2 alkyl optionally substituted by one or more substituents selected from =0 and Q5; or any two E\ E2, E3, E4, E5, E6, E7, E8 or E9 groups, for example on Ci-12 alkyl groups or on aryl groups, e.g. when they are attached to the same or adjacent carbon atoms (e.g. two E3 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. double bonds), and which ring is optionally substituted by one or more substituents selected from =0 and J1; each Q4 and Q5 independently represent, on each occasion when used herein: halo, -CN, -N02, -N(R20)R21, -OR20, -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -C(=Y)N(R20)-O-R21a, -OC(=Y)-R20, -OC(=Y)-OR20, -OC(=Y)N(R20)R21, -OS(0)2OR20, -OP(=Y)(OR20)(OR21), -OP(OR20)(OR21), -N(R22)C(=Y)R21, -N(R22)C(=Y)OR21, -N(R22)C(=Y)N(R20)R21, -NR22S(0)2R2°, -NR 2S(O)2N(R20)R21, -S(O)2N(R20)R21, -SC(=Y)R20, -S(0)2R20, -SR20, -S(0)R20, C1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and J2), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from
J3); each Y independently represents, on each occasion when used herein, =0, =S, =NR23 or =N-CN; each R 1a independently represents, on each occasion when used herein, C1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J4 and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J5); each R20, R21, R22 and R23 independently represent, on each occasion when used herein, hydrogen, C -6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J4 and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J5); or any relevant pair of R20, R21 and R22, may (for example, when attached to the same atom, adjacent atom (i.e. 1 ,2-relationship) or to atoms that are two atoms apart, i.e. in a 1,3-relationship) 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. double bonds), and which ring is optionally substituted by one or more substituents selected from J6 and =0; each J1, J2, J3, J4, J5 and J6 independently represents, on each occasion when used herein:
(0 Q7;
(ii) C1-6 alkyl or heterocycloalkyl, both of which are optionally substituted by one or more substituents selected from =0 and Q8; each Q7 and Q8 independently represents, on each occasion when used herein: halo, -N(R50)R51, -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R50)R51, -N(R52)C(=Ya)R51, -NR52S(0)2R50, -S(0)2R5°, -SR50, -S(0)R50 or C1-6 alkyl optionally substituted by one or more fluoro atoms; each Ya independently represents, on each occasion when used herein, =0, =S, =NR53 or =N-CN; each R50, R5 , R52 and R53 independently represents, on each occasion when used herein, hydrogen or C -6 alkyl optionally substituted by one or more substituents selected from fluoro, -OR60 and -N(R61)R62; or
any relevant pair of R50, R51 and R52 may (for example when attached to the same or adjacent atoms) be linked together to form, a 3- to 8-membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, heteroatoms selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (e.g. double bonds), and which ring is optionally substituted by one or more substituents selected from =0 and Ci-3 alkyl;
R6o R6i and R62 independen ly represent hydrogen or C^ alkyl optionally substituted by one or more fluoro atoms, or a pharmaceutically acceptable ester, amide, solvate or salt thereof.
2. A compound as claimed in Claim 1 , wherein:
the R , R2 and X-containing rings of the compounds represents a group the following formula
Figure imgf000088_0001
in which the rings are optionally substituted with one or more substituents selected from E2 and R6 is as defined in Claim 1 (and wherein the squiggly lines represent the point of attachment to the requisite triazolopyridazine of the compound of formula I);
R4 represents a group of the following formulae:
Figure imgf000088_0002
in which the squiggly line represents the point of attachment to the requisite triazolopyridazine of the compound of formula I, Ra/b represents Ra or Rb, and the other integers (e.g. E4, E5, Q1 and J2; 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 E5/Q1/E4 substituents) are as defined in Claim I (and the depiction of a substituent in brackets signifies that that substituent is optionally present, and may therefore be absent).
3. A compound as claimed in Claim 1 or Claim 2, wherein:
one of Ra and Rb represents H or C1-3 alkyl (e.g. methyl) and the other represents a substituent other than hydrogen;
when either of Ra and Rb represents a substituent (see above), then it may be: (i) C1-6 alkyl (e.g. C1-3 acyclic alkyl or C3-6 cycloalkyl) (e.g. methyl, ethyl, n-propyl, cyclobutyl or cyclohexyl) optionally substituted by one or more substituents (and preferably substituted by at least one (e.g. one) substituent) selected from Q1; (ii) heterocycloalkyl (e.g. a 5- or, preferably 6-membered heterocycloalkyl group containing one or two (e.g. one) heteroatom(s) in which one is preferably nitrogen or oxygen, so forming e.g. piperidinyl or tetrahydropyranyl, such as 4-piperidinyl or 4-tetrahydropyranyl) and which heterocycloalkyl group is optionally substituted by one or more substituents (e.g. one; which substituent(s) may be attached to a nitrogen heteroatom) selected from Q ; or
Ra and Rb may be linked together to form a 3- to 7-membered ring (e.g. a 5- or, preferably, a 6-membered ring), preferably containing no further heteroatoms, which ring may be linked to a further 4- to 6-membered ring (e.g. a 4- or 6- membered ring) via a single atom (i.e. forming a spiro cycle, which is preferably a [3.5], [5.3] or [5.5] spiro-cycle), all of which cyclic groups are optionally substituted by one or more substituents selected from E4;
Q1 may represent -N(R10a)R11a or heterocycloalkyl (e.g. a 5- or, preferably, 6- membered heterocycloalkyl group containing one or two (e.g. one) heteroarom preferably selected from nitrogen or oxygen; e.g. 4-piperidinyl or 4- tetrahydropyranyl) optionally substituted by one or more substituents selected from E5 (and which heterocycloalkyl group may be linked to a cycloalkyl group via a single carbon atom, so forming a spiro-cyclic group, which is preferably a [3.5] or [5.3] spiro-cycle, e.g. a 4-piperidinyl group may be linked to a cyclobutyl group via a single atom);
E4 represents Q4;
E5 represents C1-3 alkyl (e.g. methyl) or Q4;
when E4 represents Q4, then Q4 represents -N(R20)R21; and/or when E5 represents Q4, then Q4 may represent heterocycloalkyi, e.g. a 5- or preferably 6-membered heterocycloalkyi group (e.g. containing two or preferably one heteroatom (e.g. nitrogen), so forming e.g. a 4-piperidinyl group; and which group when present as a substituent on a cyclic group (e.g. cycloalkyi), may be attached via a single atom, so forming a spiro-cycle e.g. a 4-piperidinyl group linked to a cyclobutyl group via a single atom).
4. A compound as claimed in any one of the preceding claims, wherein: R3 represents trifluoromethoxyphenyl (e.g. 3-OCF3-phenyl) or trifluoromethylpyridyl (e.g. 2-trifluoromethyl-4-pyridyl).
5. A compound of formula I as defined in any one of Claims 1 to 4, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, for use as a pharmaceutical.
6. A pharmaceutical formulation including a compound of formula I, as defined in any one of Claims 1 to 4, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
7. A compound, as defined in any one of Claims 1 to 4, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, for use in the treatment of a disease in which inhibition of PIM-1, PIM-2 and/or PIM-3 is desired and/or required.
8. Use of a compound of formula I, as defined in any one of Claims 1 to 4, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, for the manufacture of a medicament for the treatment of a disease in which inhibition of PIM-1 , PIM-2 and/or PIM-3 is desired and/or required.
9. A compound as claimed in Claim 7 or a use as claimed in Claim 8, wherein the disease is cancer, an immune disorder, a cardiovascular disease, a viral infection, inflammation, a metabolism/endocrine function disorder, a neurological disorder, an obstructive airways disease, an allergic disease, an inflammatory disease, immunosuppression, a disorder commonly connected with organ transplantation, an AIDS-related disease, benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, a bone disorder, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis, restenosis, stroke, diabetes, hepatomegaly, Alzheimer's disease, cystic fibrosis, a hormone-related disease, an immunodeficiency disorder, a destructive bone disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukaemia, liver disease, a pathologic immune condition involving T cell activation, CNS disorders, pulmonary artery hypertension (PAH), and other associated diseases.
10. A method of treatment of a disease in which inhibition of PIM-1 , PIM-2 and/or PI -3 is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound of formula I as defined in any one of Claims 1 to 4, or a pharmaceutically-acceptable ester, amide, solvate or salt thereof, to a patient suffering from, or susceptible to, such a condition.
11. A combination product comprising:
(A) a compound of formula I as defined in any one of Claims 1 to 4, or a pharmaceutically-acceptable ester, amide, solvate or salt thereof; and
(B) another therapeutic agent that is useful in the treatment of in the treatment of cancer and/or a proliferative disease,
wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
12. A process for the preparation of a compound of formula I as defined in Claim 1 , which process comprises:
(i) reaction of a c
Figure imgf000091_0001
wherein L1 represents a suitable leaving group, and R1, R2, R3 and X are as defined in Claim 1, with a compound of formula III, R -H III
wherein R4 is as defined in Claim 1 ;
(ii) reaction of a compound of formula IV,
Figure imgf000092_0001
wherein L3 represents a suitable leaving group, and R1, R2, X and R4 are as defined in Claim 1 , with a compound of formula V,
R3-L4 V
wherein L4 represents a suitable group, and R3 is as defined in Claim 1 ;
(iii) reaction of a compound of formula VI,
wherein R L1 represents either L1 or R4, and R1, R2, R4, X and L are as defined in Claim 1/above, with a compound of formula VII,
H-C(0)-C(H)(R3)(CI) VII wherein R3 is as defined in Claim 1 ;
(iv) for compounds of formula I in which one of R1 and R2 represents -0-, intramolecular reaction of a compound of formula VIII,
Figure imgf000092_0003
wherein either T1a represents -R1-X-OH or T2a represents -R2-X-OH and the other represents a suitable leaving group and R3 and R4 are as defined in Claim 1 ; (v) for compounds of formula I in which R1 and R2 both represent -O- (and preferably X represents C3 alkylene), reaction of a compound of formula IX,
Figure imgf000093_0001
wherein L1a and L2a each independently represent a suitable leaving group and R3 and R4 are as defined in Claim 1 , with a compound of formula X,
HO-X-OH X
wherein X is as defined in Claim 1 ;
(vi) for compounds of formula I in which X represents Ολ alkylene substituted by a methyl group, an intramolecular addition reaction of a compound of formula XI,
Figure imgf000093_0002
wherein either Q a or Q2a represents -CH2-CH2=CH2 and the other represents -OH;
(vii) for compounds of formula I in which R1 and R2 are independently selected from -0-, -S- and -NR6-, reaction of a compound of formula XII,
Figure imgf000093_0003
wherein R1a and R2a independently represent -0-, -S- and -NR6-, and R3 and R4 are as defined in Claim 1 , with a compound of formula XIII,
L5-X-L6 XIII
wherein L5 and L6 independently represent a suitable leaving group, and X is as defined in Claim 1.
13. A process for the preparation of a pharmaceutical formulation as defined in Claim 6, which process comprises bringing into association a compound of formula I, as defined in any one of one of Claims 1 to 4, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with a pharmaceutically- acceptable adjuvant, diluent or carrier.
14. A process for the preparation of a combination product as defined in Claim 11 , which process comprises bringing into association a compound of formula I, as defined in any one of Claims 1 to 4, 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.
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