WO2015004481A1 - Bicycles imidazo-condensés comme inhibiteurs de récepteurs à domaine discoïdine (ddr) - Google Patents

Bicycles imidazo-condensés comme inhibiteurs de récepteurs à domaine discoïdine (ddr) Download PDF

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WO2015004481A1
WO2015004481A1 PCT/GB2014/052129 GB2014052129W WO2015004481A1 WO 2015004481 A1 WO2015004481 A1 WO 2015004481A1 GB 2014052129 W GB2014052129 W GB 2014052129W WO 2015004481 A1 WO2015004481 A1 WO 2015004481A1
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methyl
pyridine
phenyl
imidazo
carboxamide
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PCT/GB2014/052129
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English (en)
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Gordon Saxty
Christopher William Murray
Valerio Berdini
Lee William Page
Susan Roomans
Emiliano TAMANINI
Ildiko Maria Buck
James Edward Harvey DAY
Maria Grazia Carr
Lydia Yuen Wah LEE
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Astex Therapeutics Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to new bicyclic compounds, to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes within the cell (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA).
  • the kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).
  • Protein kinases may be characterized by their regulation mechanisms. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein- polynucleotide interactions. An individual protein kinase may be regulated by more than one mechanism.
  • kinases regulate many different cell processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signalling processes, by adding phosphate groups to target proteins. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc.
  • the appropriate protein kinase functions in signalling pathways to activate or inactivate (either directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or
  • Uncontrolled signalling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system, and angiogenesis.
  • the discoidin domain receptors (DDRs) DDR1 and DDR2 are type I transmembrane Receptor Tyrosine Kinases (RTKs) that function as collagen receptors (Vogel et al., Mol Cell 1997).
  • the DDRs are characterised by the presence of collagen-binding discoidin homology domains in the N-terminal extra-cellular domain. These domains are followed by an extracellular juxtamembrane domain, a single transmembrane domain, a large cytosolic juxtamembrane domain, a catalytic kinase domain and a short C-terminal tail.
  • DDR1 There are five isoforms of DDR1 identified to date DDR1 a-e, all of which are generated by alternative splicing of the cytoplasmic region. In contrast no isoforms of DDR2 have been identified yet.
  • the DDRs bind and are activated by collagen in its native triple helical conformation.
  • the DDRs have broad collagen specificity but display distinct preferences for certain collagen types of which there are many. Following activation with collagen, DDRs are known to regulate cell adhesion, proliferation, and extracellular matrix remodelling.
  • DDR1 and DDR2 have been shown to have mutually exclusive expression profiles in epithelial and stromal cells respectively although recent data indicate that this may be more complex than previously thought. DDRs have also been associated with a number of other therapeutic areas including cancer, atherosclerosis, fibrosis, and inflammation (Vogel Cell. Signalling 2006). It is clear that DDRs are upregulated in response to many forms of cellular transformation and tissue injury.
  • DDRs have been linked to a number of cancers summarised recently in a review (Valiathan Ca. Met Rev 2012).
  • DDR1 and DDR2 mutations have been identified in several cancers, including 4 DDR1 mutations (W385C, A496S, F866Y and F824W) and 2 DDR2 mutatyions in lung cancer (R105S and N456S).
  • DDR2 was mutated in 3.8% of lung squamous cell carcinomas (SCC) and identified 11 different mutations (L63V, I 120M, D125Y, L239R, G253C, G505S, C580Y, I638F, T765P, G774E, G774V).
  • DDR2 mutants were transforming in Ba/F3 cells and knockdown of DDR2 by RNA interference selectively reduced proliferation in lung SCC cell lines.
  • Dasatinib is a non-selective inhibitor of DDR2 and it was shown to inhibit DDR2- mutant cell lines; dasatinib also inhibited a xenograft derived from a DDR2-mutant lung SCC cell line.
  • a patient with lung SCC that responded to dasatinib (and eriotinib) treatment was shown to harbour a DDR2 kinase mutation (and no evidence of EGFR mutation).
  • No selective DDR inhibitors are known from the literature but a number of approved or experimental drugs such as dasatnib, nilotinib and ponatinib are DDR inhibitors.
  • a selective DDR2/DDR1 inhibitor may avoid dose limiting toxicities associated with the inhibition of off-target kinases (e.g. PDGFR and src).
  • DDRs have been shown to have an involvement in the progression of atherosclerosis and vascular injury with studies in knock-out mice (Franco Circ Res 2008) identified DDR1 as an early positive regulator of plaque development that when inhibited, can limit disease progression.
  • Studies investigating tissue injury leading to fibrosis in the kidney, liver, lung and skin show upregulation of DDR expression (often associated with collagen upregulation) in relevant tissues and may be critically involved in the mediation of fibrotic responses and contribute to disease progression.
  • Studies in knockout mice suggest potential benefit of inhibiting DDR1 and DDR2 signalling and that DDRs may represent a potential target to prevent the progression to end-stage diseases. (Vogel Cell. Signalling 2006).
  • DDR2 Collagens and other ECM molecules derived from the stromal microenvironment initiate renewal and differentiation of haematopoietic stem cells and this area has indicated a potential role for DDRs in pro-inflammatory responses and immune cell maturation.
  • Increased expression of DDR2 was found in knee joints of aged mice in a mouse-model of arthritis (Xu JBC 2005) and in synovial cells of an adjuvant- induced rat model for rheumatoid arthritis (Li Chin Med Sci 2005) whilst increased DDR2 expression has also been documented in patients with rheumatoid arthritis or osteoarthritis in cells from isolated synovial fluid (Islam Osteoarthr. Cartil. 2001 , Wang Autoimmun. 2002). Inhibitors of DDRs may therefore have potential benefit in chronic inflammatory diseases.
  • Another inhibitor that binds to a target kinase without requiring the interaction with the mutated amino acid residue will likely be unaffected by the mutation and will remain an effective inhibitor of the enzyme (Carter et al, PNAS, 2005, 102, 31 , 1 1011-1101 16).
  • gate keeper residue One common site at which drug resistant mutations occur is the so-called gate keeper residue. This particular residue forms a key site of interaction for several kinase inhibitors and their respective targets.
  • imatinib (Gleevec) binds in part to threonine 315 the gate keeper residue in the abl kinase domain.
  • T315I mutations are one of the major forms of drug resistance arising in imatinib treated CML patients and may also be seen in patients with acute lymphoblastic leukemia.
  • the invention provides a compound of formula (I):
  • W is CH S R 1 and Y is CH n or NH S , or W is NH S and Y is CH n , or W is absent and Y is S, wherein the dotted bonds are either both single bond or both double bonds, n is 1 or 2 and s is 0 or 1 as appropriate to satisfy valency;
  • X is CH or N
  • R a is Ci -2 alkyl, haloCi. 2 alkyl or halogen; and t is 0 or 1 ;
  • R b is methyl or chlorine;
  • R 1 and R 2 are independently hydrogen, halogen, -CN, Ci -4 alkyl, d_ 4 alkoxy, C 3 .
  • R 3 is hydrogen, Ci -4 alkyl, C 3 . 6 cycloalkyl, haloCi_ 4 alkyl, hydroxyCi_ 4 alkyl or
  • R 5 is phenyl, benzyl, C 4 . 6 cycloalkyl, -CH 2 -C 3 . 6 cycloalkyl, -CH 2 -piperidin-1-yl or pyridinyl wherein each of the cyclic groups is optionally substituted with one or more
  • R is benzoxazol-2-yl, 5-azabenzoxazol-2-yl, benzimidazol-2-yl, benzothiazol-2-yl, or quinazolin-2-yl, wherein R 6 is optionally substituted by one or more R 9 groups;
  • R 7 , R 8 and R 9 are independently halogen, Ci -4 alkyl, d_ 4 alkoxy, haloCi_ 4 alkyl, haloCi. 4 alkoxy, hydroxyCi. 4 alkyl, -Ci. 4 alkyl-CN, -NH 2 , -N(CH 3 ) 2 , -CH 2 -N(CH 3 ) 2 , -CH 2 -CH 2 - N(CH 3 ) 2 , -CH 2 -(4-methyl)piperazine, -CH 2 -(morpholinyl) or two R 8 groups on adjacent ring atoms join to form:
  • compositions comprising a compound of fomula (I) and processes for the synthesis of a compound of formula (I).
  • references to formula (I) in all sections of this document include references to all other sub-formula, sub-groups, preferences, embodiments and examples as defined herein.
  • DDRs we mean any of the DDR family members, in particular DDR1 (e.g.
  • DDR1 a-e DDR1 a-e
  • DDR2 DDR2 a-e
  • DDR2 a-e DDR2 a-e
  • DDR2 a-e DDR2 a-e domains of DDR1 a-e
  • DDR2 a-e DDR2 a-e domains of DDR1 a-e
  • DDR2 a-e DDR2 a-e domains thereof
  • one or more DDR family members we mean any of the DDR family members or isoforms or mutants or splice variants thereof in particular DDR1 (e.g. DDR1a-e) and/or DDR2, more particularly DDR2.
  • “Potency” is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations. Potency is proportional to affinity and efficacy. Affinity is the ability of the drug to bind to a receptor. Efficacy is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level.
  • modulation as applied to the activity of a kinase, is intended to define a change in the level of biological activity of the protein kinase.
  • modulation encompasses physiological changes which effect an increase or decrease in the relevant protein kinase activity.
  • the modulation may be described as "inhibition”.
  • the modulation may arise directly or indirectly, and may be mediated by any mechanism and at any physiological level, including for example at the level of gene expression (including for example transcription, translation and/or post- translational modification), at the level of expression of genes encoding regulatory elements which act directly or indirectly on the levels of kinase activity.
  • modulation may imply elevated/suppressed expression or over- or under-expression of a kinase, including gene amplification (i.e. multiple gene copies) and/or increased or decreased expression by a transcriptional effect, as well as hyper- (or hypo- )activity and (de)activation of the protein kinase(s) (including (de)activation) for example by mutation(s).
  • gene amplification i.e. multiple gene copies
  • hyper- (or hypo- )activity i.e. multiple gene copies
  • de deactivation of the protein kinase(s) (including (de)activation) for example by mutation(s).
  • modulated modulating
  • modulate are to be interpreted accordingly.
  • kinase activity (and in particular aberrant levels of kinase activity, e.g.
  • kinase over-expression need not necessarily be the proximal cause of the disease, state or condition: rather, it is contemplated that the kinase mediated diseases, states or conditions include those having multifactorial aetiologies and complex progressions in which the kinase in question is only partially involved.
  • the role played by the kinase may be direct or indirect and may be necessary and/or sufficient for the operation of the treatment, prophylaxis or outcome of the intervention.
  • a disease state or condition mediated by a kinase includes the development of resistance to any particular cancer drug or treatment.
  • treatment in the context of treating a condition i.e. state, disorder or disease, pertains generally to treatment and therapy, whether for a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, diminishment or alleviation of at least one symptom associated or caused by the condition being treated and cure of the condition.
  • treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.
  • prophylaxis i.e. use of a compound as prophylactic measure
  • a condition i.e. state, disorder or disease
  • prophylaxis or prevention whether for a human or an animal (e.g. in veterinary applications), in which some desired preventative effect is achieved, for example, in preventing occurance of a disease or guarding from a disease.
  • Prophylaxis includes complete and total blocking of all symptoms of a disorder for an indefinite period of time, the mere slowing of the onset of one or several symptoms of the disease, or making the disease less likely to occur.
  • References to the prophylaxis or treatment of a disease state or condition such as cancer include within their scope alleviating or reducing the incidence e.g. of cancer.
  • Optionally substituted refers to a group which may be unsubstituted or substituted by a substituent as herein defined.
  • Ci_ 6 alkyl group contains from 1 to 6 carbon atoms
  • C 3 . 6 cycloalkyl group contains from 3 to 6 carbon atoms
  • Ci_ 4 alkoxy group contains from 1 to 4 carbon atoms, and so on.
  • 'halo' or 'halogen' refers to fluorine, chlorine, bromine or iodine.
  • 'Ci. 4 alkyl' refers to a linear or branched saturated hydrocarbon group containing from 1 to 4 carbon atoms respectively.
  • examples of such groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert butyl and the like.
  • Ci_ 4 alkoxy' as used herein as a group or part of a group refers to an -O-C1. 4 alkyl group wherein Ci_ 4 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and the like.
  • 'C 3 . 6 cycloalkyr refers to a saturated monocyclic
  • hydrocarbon ring of 3 to 6 carbon atoms examples include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
  • 'hydroxyCi. 4 alkyl' refers to a Ci_ 4 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a hydroxyl group.
  • the term 'hydroxyCi_ 4 alkyl' therefore includes monohydroxyCi- 4 alkyl, and also polyhydroxyCi_ 4 alkyl. There may be one, two, three or more hydrogen atoms replaced with a hydroxyl group, so the hydroxyCi_ 4 alkyl may have one, two, three or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.
  • 'haloCi. 4 alkyl' refers to a Ci. 4 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen.
  • the term 'haloCi. 4 alkyl' therefore include monohaloCi_ 4 alkyl and also polyhaloCi_ 4 alkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi_ 4 alkyl may have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and the like.
  • 'haloCi. 4 alkoxy' refers to a -O- Ci_ 4 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen.
  • the terms 'haloCi_ 4 alkoxy' therefore include monohaloCi. 4 alkoxy, and also polyhaloCi_ 4 alkoxy. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi_ 4 alkoxy may have one, two, three or more halogens. Examples of such groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.
  • heterocyclyl group having from 4 to 6 ring members shall, unless the context indicates otherwise, include both aromatic and non-aromatic ring systems.
  • heterocyclyl group include within their scope aromatic, non-aromatic, unsaturated, partially saturated and fully saturated heterocyclyl ring systems.
  • the reference to 4 to 6 ring members include 4, 5, or 6 atoms in the ring, in particular 5 or 6 ring members.
  • the heterocyclyl ring can, unless the context indicates otherwise, be optionally substituted i.e. unsubstituted or substituted, by one or more (e.g. 1 , 2, 3, or 4 in particular one or two) substituents as defined herein.
  • the heterocyclyl group can be, for example, a five membered or six membered monocyclic ring. Each ring may contain up to five heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heterocyclyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heterocyclyl ring will contain one or two heteroatoms selected from N, O, S and oxidised forms of N or S. In one
  • the heterocyclyl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heterocyclyl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heterocyclyl group, including any amino group substituents of the ring, will be less than five.
  • the heterocyclyl groups can be attached via a carbon atom or a heteroatom (e.g. nitrogen). Equally the heterocyclyl groups can be substituted on a carbon atom or on a heteroatom (e.g. nitrogen).
  • Examples of five membered aromatic heterocyclyl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • six membered aromatic heterocyclic groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • a nitrogen-containing aromatic heterocyclic ring must contain at least one ring nitrogen atom.
  • the nitrogen-containing heteroaryl ring can be N-linked or C-linked. Each ring may, in addition, contain up to about four other heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, for example 1 , 2 or 3, more usually up to 2 nitrogens, for example a single nitrogen.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • nitrogen-containing aromatic heterocyclic groups include, but are not limited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g., 1 ,2,3-triazolyl, 1 ,2,4-triazolyl) and tetrazolyl .
  • non-aromatic embraces, unless the context indicates otherwise, unsaturated ring systems without aromatic character, partially saturated and fully saturated heterocyclyl ring systems.
  • fully saturated refers to rings where there are no multiple bonds between ring atoms.
  • Saturated heterocyclyl groups include piperidinyl, morpholinyl, and thiomorpholinyl.
  • Partially saturated heterocyclyl groups include pyrazolinyl, for example pyrazolin-2-yl and pyrazolin-3-yl.
  • non-aromatic heterocyclyl groups are groups having from 4 to 6 ring members. Such groups typically have from 1 to 4 heteroatom ring members (more usually 1 , 2, or 3heteroatom ring members), usually selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl groups can contain, for example, cyclic ether moieties (e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. as in pyrrolidine), cyclic amide moieties (e.g.
  • cyclic thioamides as in pyrrolidone
  • cyclic thioesters as in imidazolidin-2-one
  • cyclic ureas e.g. as in imidazolidin-2-one
  • cyclic ester moieties e.g. as in
  • cyclic sulfones e.g. as in sulfolane and sulfolene
  • cyclic sulfoxides e.g. thiomorpholine
  • Particular examples include morpholinyl, piperidinyl (e.g. piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl), piperidinonyl, pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl), pyrrolidonyl, azetidinyl, pyranyl (2H-pyran or 4H- pyran), dihydrothienyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl,
  • piperidinyl e.g. piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl
  • piperidinonyl e.g. pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl and pyr
  • preferred non-aromatic heterocyclyl groups include saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl and N-alkyl piperazines such as N-methyl piperazinyl.
  • a nitrogen-containing non-aromatic heterocyclyl ring the ring must contain at least one ring nitrogen atom.
  • the nitrogen-containing heterocyclyl ring can be N-linked or C-linked.
  • the heterocylic groups can contain, for example, cyclic amine moieties (e.g. as in pyrrolidinyl), cyclic amides (such as a pyrrolidinonyl, piperidinonyl or caprolactamyl), cyclic sulfonamides (such as an isothiazolidinyl 1 , 1 -dioxide,
  • nitrogen-containing non-aromatic heterocyclyl groups include aziridinyl, morpholinyl, thiomorpholinyl, piperidinyl (e.g. piperidin-1-yl, piperidiny-2-l, piperidin-3-yl and piperidin-4-yl), pyrrolidinyl; (e.g.
  • heterocyclyl group can each be unsubstituted or substituted by one or more substituent groups.
  • heterocyclyl or carbocyclyl groups can be unsubstituted or substituted by 1 , 2, 3 or 4 substituents and typically it is
  • the various functional groups and substituents making up the compounds of the invention are typically chosen such that the molecular weight of the compound of the invention does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. In particular, the molecular weight is less than 525 and, for example, is 500 or less.
  • the invention provides a compound of formula (I):
  • W is CH S R 1 and Y is CH n or NH S , or W is NH S and Y is CH n , or W is absent and Y is S, wherein the dotted bonds are either both single bond or both double bonds, n is 1 or 2 and s is 0 or 1 as appropriate to satisfy valency, except where W is absent in which case one dotted bond is a double bond and the other (which is connected to the absent W) is absent.
  • W is CH S R 1 and Y is CH n or NH S , or W is NH S and Y is CH n , or W is absent and Y is S, wherein the dotted bonds are either both single bond or both double bonds, n is 1 or 2 and s is 0 or 1 as appropriate to satisfy valency, except where W is absent in which case the one dotted bond connected to the absent W is also absent and the remaining one dotted bond is a double bond.
  • W is CH S R 1 or NH S
  • Y is CH n
  • - n is 1 and s is 0, and both dotted bonds are double bonds
  • - n 2 and s is 1 , and both dotted bonds are single bonds; or W is CH S R 1 and Y is NH S ; wherein either both s are 0 and both dotted bonds are double bonds or both s are 1 and both dotted bonds are single bonds; or W is absent and Y is S, and the dotted bond is a double bond.
  • the bicyclic group is selected from the following:
  • the bicyclic group is selected from:
  • the bicyclic group is imidazopyridine. In another embodiment, the bicyclic group is:
  • the ring nitrogens may be protonated. This may result in quartenary N carrying a positive charge.
  • R 1 is a heterocyclic group having from 4 to 6 ring members, - (CH 2 )p-(heterocyclic group having from 4 to 6 ring members) or -0-(CH 2 ) p - (heterocyclic group having from 4 to 6 ring members), wherein in each case p is 1 or 2, and wherein each of the heterocyclic groups is optionally substituted with one or more (e.g. one or two, in particular one) R 7 groups.
  • R 1 is a nitrogen-containing heterocyclic group having from 4 to 6 ring members, -(CH 2 ) P - (nitrogen-containing heterocyclic group having from 4 to 6 ring members) or -O- (CH 2 ) p -(nitrogen-containing heterocyclic group having from 4 to 6 ring members), wherein in each case p is 1 or 2, and wherein each of the heterocyclic groups is optionally substituted with one or more (e.g. one or two, in particular one) R 7 groups.
  • the 4 to 6 membered heterocyclic groups are non-aromatic.
  • the 4 to 6 membered heterocyclic groups are aromatic.
  • R 1 is a heterocyclic group having from 4 to 6 ring members or -O- (CH 2 )p-(heterocyclic group having from 4 to 6 ring members), wherein in each case p is 1 or 2, and wherein each of the heterocyclic groups is optionally substituted with one or more (e.g. one or two, in particular one) R 7 groups.
  • R 1 is selected from the group consisting of hydrogen, halogen, Ci_ 4 alkyl and Ci_ 4 alkoxy.
  • R 7 is selected from hydrogen, CI, Br, -CN, methyl, methoxy, ethoxy, cyclopropyl, -0-CH 2 -CH 2 -OMe, -0-CH 2 -CH 2 -OH, -
  • R 1 is hydrogen
  • R 7 is selected from the group consisting of halogen, Ci_ 4 alkyl, Ci. 4 alkoxy, haloCi_ 4 alkyl, haloCi_ 4 alkoxy, hydroxyCi_ 4 alkyl, -Ci_ 4 alkyl-CN, -NH 2 , -N(CH 3 ) 2 , -CH 2 -N(CH 3 ) 2 , -CH 2 -CH 2 -N(CH 3 ) 2 , -CH 2 -(4-methyl)piperazine, and -CH 2 - (morpholinyl).
  • R 7 is selected from the group consisting of halogen, Ci_ 4 alkyl, Ci_ 4 alkoxy, haloCi_ 4 alkyl, haloCi_ 4 alkoxy, hydroxyCi_ 4 alkyl, -Ci_ 4 alkyl-CN, and -NH 2 .
  • R 7 is Ci_ 4 alkyl, in particular methyl.
  • R 7 is not present i.e. the cyclic groups, if present, in R 1 and R 2 are unsubstituted.
  • R 5 is selected from the group consisting of phenyl, benzyl, C 4 . 6 cycloalkyl, -CH 2 -C3.6 cycloalkyl, -CH 2 -piperidin-1-yl and pyridinyl wherein each of the cyclic groups is optionally substituted with one or more (e.g. one or two, in particular one) R 8 groups.
  • R 5 is selected from phenyl, benzyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclohexyl, -CH 2 -piperidin-1-yl and pyridinyl wherein each of the cyclic groups is optionally substituted with one or more (e.g. 1 or 2) R 8 groups.
  • R 5 is selected from phenyl and benzyl optionally substituted with one or more (e.g. one or two, in particular one) R 8 groups.
  • R 8 is selected from the group consisting of halogen, Ci_ 4 alkoxy, haloC ⁇ alkyl, haloC ⁇ alkoxy, hydroxyd. 4 alkyl, -C ⁇ alkyl-CN, -NH 2 , -N(CH 3 ) 2 , -CH 2 - N(CH 3 ) 2 , -CH 2 -CH 2 -N(CH 3 ) 2 , -CH 2 -(4-methyl)piperazine and -CH 2 -(morpholinyl) or two R 8 groups on adjacent ring atoms join to form:
  • R is selected from the group consisting of halogen, Ci_ 4 alkoxy, haloC ⁇ alkyl, haloC ⁇ alkoxy, hydroxyd. 4 alkyl, -C ⁇ alkyl-CN, -N(CH 3 ) 2 , -CH 2 -N(CH 3 ) 2 , -CH 2 -CH 2 -N(CH 3 ) 2 , -CH 2 -(4-methyl)piperazine and -CH 2 -(morpholinyl), or two R 8 groups on adjacent ring atoms join to form:
  • R is independently selected from F, CI, -CF 3 , and -OCHF 2 , -OCH 2 CHF 2 , -OC(CH3) 2 , -C(CH 3 ) 2 CN, -C(CH 3 ) 2 OH, -N(CH 3 ) 2 , -CH 2 -N(CH 3 ) 2 , -CH 2 - CH 2 -N(CH 3 ) 2 , -CH 2 -(4-methyl)piperazinyl and -CH 2 -(morpholinyl).
  • R 8 groups on adjacent ring atoms join to form:
  • R is halogen or haloCi. 4 alkyl.
  • R is fluorine or -CF 3 .
  • R 4 is R 6 , wherein R 6 is selected from the group consisting of benzoxazol-2-yl, 5-azabenzoxazol-2-yl, benzimidazol-2-yl, benzothiazol-2-yl and quinazolin-2-yl, wherein R 6 is optionally substituted by one or more (e.g. one or two, in particular one) R 9 groups.
  • R 6 is benzoxazol-2-yl, benzimidazol-2-yl or benzothiazol-2-yl optionally substituted by one or more (e.g. one or two, in particular one) R 9 groups. In one embodiment, R 6 is benzoxazol-2-yl optionally substituted by one or more (e.g. one or two, in particular one) R 9 groups. In one embodiment R 6 is benzoxazol-2-yl optionally substituted by fluorine.
  • R 9 is selected from halogen, Ci_ 4 alkyl, Ci_ 4 alkoxy, haloCi_ 4 alkyl, halod. 4 alkoxy, hydroxyd. 4 alkyl, -d. 4 alkyl-CN, -NH 2 , -N(CH 3 ) 2 , -CH 2 -N(CH 3 )2, -CH 2 - CH 2 -N(CH 3 )2, -CH 2 -(4-methyl)piperazine, and -CH 2 -(morpholinyl).
  • R 9 is selected from the group consisting of halogen, Ci_ 4 alkyl and Ci_ 4 alkoxy. In another embodiment, R 9 is halogen or Ci_ 4 alkoxy. In one
  • R 9 is fluorine or methoxy. In one embodiment, R 9 is fluorine. In one embodiment, t is 0.
  • R b is selected from the group consisting of methyl and chlorine. In one embodiment, R b is methyl.
  • R 3 is selected from the group consisting of hydrogen, Ci_ 4 alkyl, C 3 . 6 cycloalkyl, haloCi- 4 alkyl, hydroxyCi_ 4 alkyl and methoxymethyl.
  • R 3 is selected from hydrogen, methyl, ethyl, iso-propyl, cyclopropyl, -CF 3 , -CH 2 OH and methoxymethyl.
  • R 3 is hydrogen or Ci_ 4 alkyl e.g. methyl or ethyl. In one
  • R 3 is hydrogen or methyl.
  • R 3 is other than hydrogen i.e. R 3 is selected from the group consisting of Ci_ 4 alkyl, C 3 . 6 cycloalkyl, haloCi_ 4 alkyl, hydroxyCi_ 4 alkyl or methoxymethyl.
  • the enantiomers (assuming no other sterocentres are present in the compounds) are present in a ratio of essentially 1 :1 i.e. a racemic mixture.
  • the compounds are present in a ratio of other than 1 :1 , so that one enantiomer is present in an amount greater than the other enantiomer.
  • the compound of formula (I) is a compound of formula (la):
  • the compounds of the invention are at least 75% in the enantiomeric form of formula l(e), for example at least 80%, at least 85%, or at least 90%, or at least 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5%.
  • the compounds of the invention have an enantiomeric excess of at least 50% for example at least 75%, at least 85%, or at least 90%, or at least 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5%, such that the enantiomeric form of formula l(a) predominates.
  • the compound of formula (I) is a compound of formula (lb):
  • W is CR 1 or NH.
  • the compound of formula (I) is a compound of formula (lb) wherein:
  • W is CR 1 ; X is CH;
  • R 1 is hydrogen, halogen, Ci -4 alkyl and Ci_ 4 alkoxy;
  • R 3 is hydrogen or Ci_ 4 alkyl;
  • R 5 is phenyl or benzyl optionally substituted with one or more (e.g. one or two, in particular one) R 8 groups; and R 8 is halogen or haloCi_ 4 alkyl.
  • the compound of formula (I) is a compound of formula (Ic):
  • W is CR 1 or NH.
  • the compound of formula (I) is a compound of formula (Ic) wherein:
  • W is CR 1 ; X is CH;
  • R 1 is hydrogen, halogen, Ci -4 alkyl and Ci_ 4 alkoxy;
  • R 3 is hydrogen or Ci_ 4 alkyl;
  • R 5 is phenyl or benzyl optionally substituted with one or more (e.g. one or two, in particular one) R 8 groups; and R 8 is halogen or haloCi_ 4 alkyl.
  • the compound of formula (I) is a compound of formula (Id):
  • W is CR 1 or NH.
  • the compound of formula (I) is a compound of formula (Id) wherein:
  • W is CR 1 ; X is CH;
  • R 1 is hydrogen, halogen, Ci -4 alkyl and Ci_ 4 alkoxy (in particular hydrogen);
  • R 3 is hydrogen or Ci -4 alkyl (in particular methyl);
  • R 6 is benzoxazol-2-yl, benzimidazol-2-yl or benzothiazol-2-yl (in particular benzoxazol-2-yl) optionally substituted by one or more (e.g. one or two, in particular one) R 9 groups; and R is selected from the group consisting of halogen, Ci -4 alkyl and Ci_ 4 alkoxy e.g. halogen or Ci_ 4 alkoxy (in particular fluorine).
  • R 6 is benzoxazol-2-yl optionally substituted by one or more (e.g. one or two, in particular one) R 9 groups.
  • R 9 is fluorine.
  • R 1 is hydrogen
  • R 3 is hydrogen or methyl.
  • the compound of formula (I) is a compound of formula (le):
  • the compound of formula (I) is a compound of formula (le) wherein:
  • W is CR 1 or N and Y is CH; and both dotted bonds are double bonds; or
  • W is CHR 1 and Y is CH 2 or NH; and both dotted bonds are single bonds; or
  • W is absent and Y is S, and the dotted bond is a double bond
  • W is CR 1 and Y is NH; and both dotted bonds are double bonds;
  • X is CH or N
  • R 5 is phenyl, benzyl, C 4 . 6 cycloalkyl, -CH 2 -C3. 6 cycloalkyl, -CH 2 -piperidin-1-yl or pyridinyl wherein each of the cyclic groups is optionally substituted with one or more (e.g. one or two, in particular one) R 8 groups;
  • R 6 is benzoxazol-2-yl, 5-azabenzoxazol-2-yl, benzimidazol-2-yl, benzothiazol-2-yl or quinazolin-2-yl, wherein R 6 is optionally substituted by one or more (e.g. one or two, in particular one) R 9 groups;
  • R 8 is halogen, Ci_ 4 alkoxy, haloC ⁇ alkyl, haloCi_ 4 alkoxy, hydroxyCi_ 4 alkyl, -Ci_ 4 alkyl-CN, -N(CH 3 ) 2 , -CH 2 -N(CH 3 ) 2 , -CH 2 -CH 2 -N(CH 3 ) 2 , -CH 2 -(4-methyl)piperazine, -CH 2 - (morpholinyl), or two R 8 groups on adjacent ring atoms join to form: and R is halogen or Ci_ 4 alkoxy.
  • the compound of formula (I) is a compound of formula (le) wherein R 2 is hydrogen.
  • the invention provides a compound of formula (I) which is one of the Examples 1-120 or is selected from the Examples 1-120 or tautomeric or stereochemically isomeric forms, /V-oxides, pharmaceutically acceptable salts or the solvates thereof.
  • the invention provides a compound of formula (I) which is selected from the following compounds or is one of the following compounds:
  • the invention provides a compound of formula (I) which is selected from the following compounds or is one of the following compounds:
  • a reference to a compound of the formula (I) and sub-groups thereof also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed below; in particular, the salts or tautomers or isomers or N-oxides or solvates thereof; and for example, the salts or tautomers or N-oxides or solvates thereof, e.g. the salts or tautomers or solvates thereof.
  • salts can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (I) include the salt forms of the compounds.
  • the salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P.
  • salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g.
  • D-glucuronic D-glucuronic
  • glutamic e.g. L- glutamic
  • a-oxoglutaric glycolic, hippuric
  • hydrohalic acids e.g. hydrobromic, hydrochloric, hydriodic
  • isethionic lactic (e.g.
  • salts consist of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate),
  • ethanesulfonic naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
  • One particular salt is the hydrochloride salt.
  • a salt may be formed with an organic or inorganic base, generating a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Li + , Na + and K + , alkaline earth metal cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ or Zn + .
  • Suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R2 + , NHR 3 + , NR 4 + ).
  • Examples of some suitable substituted ammonium ions are those derived from: methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
  • the compounds of the invention may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed.
  • the salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19.
  • salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts.
  • Such non-pharmaceutically acceptable salt forms which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.
  • a pharmaceutical composition comprising a solution (e.g. an aqueous solution) containing a compound of the formula (I) and sub-groups and examples thereof as described herein in the form of a salt in a concentration of greater than 10 mg/ml, typically greater than 15 mg/ml and in particular greater than 20 mg/ml.
  • a solution e.g. an aqueous solution
  • a compound of the formula (I) and sub-groups and examples thereof as described herein in the form of a salt in a concentration of greater than 10 mg/ml, typically greater than 15 mg/ml and in particular greater than 20 mg/ml.
  • N-oxides may also form N-oxides.
  • a reference herein to a compound of the formula (I) that contains an amine function also includes the N-oxide.
  • nitrogen atom may be oxidised to form an N-oxide.
  • N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocyclylic group.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley
  • N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
  • MCPBA m-chloroperoxybenzoic acid
  • heteroaryl rings can exist in the two tautomeric forms such as A and B shown below.
  • a formula may illustrate one form but the formula is to be taken as embracing both tautomeric forms.
  • tautomeric forms include, for example, keto-, enol-, and enolate- forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/enediamines, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro
  • Stereocentres are illustrated in the usual fashion, using 'hashed' or 'wedged' lines, e.g.
  • references to compounds of the formula (I) include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise. Examples of chiral compounds of formula (I) are highlighted below:
  • optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and / isomers) or they may be characterised in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4 Edition, John Wiley & Sons, New York, 1992, pages 109-1 14, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.
  • Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.
  • optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)- pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, separating the diastereoisomers by preferential
  • enantiomeric separation can be achieved by covalently linking a enantiomerically pure chiral auxiliary onto the compound and then performing diastereisomer separation using conventional methods such as chromatography. This is then followed by cleavage of the aforementioned covalent linkage to generate the appropriate enantiomerically pure product.
  • one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity.
  • compositions containing a compound of the formula (I) having one or more chiral centres wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (I) is present as a single optical isomer (e.g. enantiomer or diastereoisomer).
  • at least 55% e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95
  • 99% or more (e.g. substantially all) of the total amount of the compound of the formula (I) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer).
  • the present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention, i.e. compounds of formula (I), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention comprise isotopes of hydrogen, such as 2 H (D) and 3 H (T), carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l, 125 l and 131 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • hydrogen such as 2 H (D) and 3 H (T)
  • carbon such as 11 C, 13 C and 14 C
  • chlorine such as 36 CI
  • fluorine such as 18 F
  • iodine such as 123 l, 125 l and 131 l
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P
  • sulfur such as 35 S.
  • the compounds of formula (I) can also have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors.
  • the detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc.
  • the radioactive isotopes tritium, i.e. 3 H (T), and carbon- 14, i.e. 14 C, are particularly useful for this purpose in view of their ease of
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H (D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • Esters such as carboxylic acid esters, acyloxy esters and phosphate esters of the compounds of formula (I) bearing a carboxylic acid group or a hydroxyl group are also embraced by Formula (I).
  • phosphate esters are those derived from phosphoric acid.
  • formula (I) includes within its scope esters of compounds of the formula (I) bearing a carboxylic acid group or a hydroxyl group. In another embodiment of the invention, formula (I) does not include within its scope esters of compounds of the formula (I) bearing a carboxylic acid group or a hydroxyl group.
  • solvates such as hydrates, alcoholates and the like.
  • the compounds of the invention may form solvates, for example with water (i.e., hydrates) or common organic solvents.
  • solvate means a physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are
  • solvate is intended to encompass both solution-phase and isolatable solvates.
  • suitable solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine and the like.
  • the compounds of the invention may exert their biological effects whilst they are in solution.
  • Solvates are well known in pharmaceutical chemistry. They can be important to the processes for the preparation of a substance (e.g. in relation to their purification, the storage of the substance (e.g. its stability) and the ease of handling of the substance and are often formed as part of the isolation or purification stages of a chemical synthesis.
  • a person skilled in the art can determine by means of standard and long used techniques whether a hydrate or other solvate has formed by the isolation conditions or purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g.
  • the skilled person can deliberately form a solvate using crystallisation conditions that include an amount of the solvent required for the particular solvate. Thereafter the standard methods described above, can be used to establish whether solvates had formed.
  • the compounds of the present invention may have one or more polymorph or amorphous crystalline forms and as such are intended to be included in the scope of the invention.
  • Complexes Formula (I) also includes within its scope complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds.
  • complexes e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals
  • Inclusion complexes, clathrates and metal complexes can be formed by means of methods well known to the skilled person.
  • pro-drugs of the compounds of the formula (I).
  • prodrugs is meant for example any compound that is converted in vivo into a biologically active compound of the formula (I).
  • some prodrugs are esters of the active compound (e.g., a
  • Ci -7 alkyl e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu;
  • Ci- 7 aminoalkyl e.g., aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl
  • acyloxy-Ci_ 7 alkyl e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl
  • acetoxy methyl ; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl; 1- (benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy- carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; 1-(4-tetrahydropyranyloxy)carbonyloxyethyl; (4- tetrahydropyranyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonyloxyethyl).
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in antigen-directed enzyme pro-drug therapy (ADEPT), gene-directed enzyme pro-drug therapy (GDEPT), and ligand-directed enzyme pro-drug therapy (LIDEPT), etc.).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • formula (I) does not include pro-drugs of the compounds of the formula (I) within its scope.
  • references to formula (I) also include all other subformula e.g. formulae (la), (lb), (lc), (Id) and (le), and examples thereof as defined herein, unless the context indicates otherwise.
  • R a , R b , R 2 , R 3 , R 4 , t, X, Y and W are as defined herein and z is a leaving group;
  • R a , R b , R 2 , R 3 , R 5 , t, X, Y and W are as defined herein;
  • R a , R°, R , R , R , t, X, Y and W are as defined herein;
  • compounds of the formula (I) can be prepared by reacting a compound of formula (II) with a compound of formula (III) as shown in Scheme 1.
  • This reaction involves a conventional coupling reaction between an amine and a carboxylic acid or an activated derivative thereof.
  • the leaving group z is -OH and the compound of formula (III) is a carboxylic acid.
  • the coupling reaction between the carboxylic acid and the amine is typically carried out in the presence of a reagent of the type commonly used in the formation of peptide linkages.
  • reagents examples include 1 ,3- dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (referred to herein either as EDC or EDAC, uronium-based coupling agents such as 0-(7-azabenzotriazol-1-yl)-/ ⁇ /,A/,/ ⁇ /',A/ -tetramethyluronium hexafluorophosphate (HATU) and phosphonium-based coupling agents such as 1-benzo-triazolyloxytris- (pyrrolidino)phosphonium hexafluorophosphate (PyBOP).
  • DCC dicyclohexylcarbodiimide
  • EDAC 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide
  • uronium-based coupling agents such as 0-(7-azabenzotriazol-1-y
  • Carbodiimide-based coupling agents are advantageously used in combination with 1-hydroxy-7- azabenzotriazole (HOAt) or 1-hydroxybenzotriazole (HOBt).
  • Preferred coupling reagents include EDC (EDAC) and DCC in combination with HOAt or HOBt.
  • a reactive derivative of the carboxylic acid e.g. an anhydride (z is - COOR) or acid chloride (z is - CI), may be used.
  • the compounds of formula (I) can be prepared by reacting a compound of formula (IV) with a compound of formula (V) wherein z is a leaving group as shown in Scheme 2:
  • the compound of formula (V) is a compound of formula (V):
  • reaction involves a conventional coupling reaction between an amine and a carboxylic acid or an activated derivative thereof, and the same comments, explanations and embodiments discussed above in relation to the Scheme 1 apply.
  • the compound of formula (V) is a compound of the formula (V"):
  • the compound of formula (V) is a compound of formula (V"") wherein R 4 is R 6 and z is a leaving group :
  • the reaction involves a nucleophilic aromatic substitution reaction between an aromatic leaving group (wherein z is for example CI) and an amine nucleophile created by the prescence of base (e.g. diisopropylethylamine).
  • an aromatic leaving group wherein z is for example CI
  • an amine nucleophile created by the prescence of base e.g. diisopropylethylamine
  • the compound of formula (I), in particular a compound of formula (Id), may be synthesised by reacting a compound of formula (VI) with a compound of formula (VII), either in the presence of a reducing agent or with subsequent addition of a reducing agent to prepare a compound of formula (I) as shown in Scheme 3:
  • Reductive amination with an appropriate aldehyde (R 3 is H) or ketone (R 3 is other than H) can be carried out in the presence of variety of reducing agents (see
  • reductive amination can be carried out in the presence of sodium triacetoxyborohydride in the presence of an aprotic solvent such as dichloromethane at or near ambient temperatures.
  • imidazo[1 ,2-a]pyridine core can be synthesised from commercially available starting materials to give a 3,7 disubstituted ring or to give a 3,6
  • halogenated positions for example introduced by iodination using N-iodosuccinimide at room temperature, can be converted to a boronic acid or ester, or pseudohalides (for example triflates), and used to synthesise alternative motifs, for example these can then be used directly in any of the well-known metal catalysed reactions such as Buchwald-Hartwig type reaction (see Review: Hartwig, J. F. (1998) Angew. Chem. Int. Ed.
  • the invention provides a novel intermediate as described herein. In one embodiment the invention provides a novel intermediate of formula (IV) or (VI).
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • An amine group may be protected, for example, as an amide (-NRCO-R) or a carbamate (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a benzyl carbamate (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz or NH-Z); as a t-butyl carbamate
  • protecting groups for amines include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.
  • tosyl toluenesulfonyl
  • methanesulfonyl methanesulfonyl
  • benzyl groups such as a para-methoxybenzyl (PMB) group
  • TTP tetrahydropyranyl
  • a carboxylic acid group may be protected as an ester for example, as: an Ci -7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci_ 7 haloalkyl ester (e.g., a Ci -7 trihaloalkyl ester); a triCi. 7 alkylsilyl-Ci_ 7 alkyl ester; or a C 5 . 2 o aryl-Ci. 7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester; para-methoxybenzyl ester.
  • an Ci -7 alkyl ester e.g., a methyl ester; a t-butyl ester
  • a Ci_ 7 haloalkyl ester e.g., a Ci -7 trihaloalkyl ester
  • the compounds of the invention can be isolated and purified according to standard techniques well known to the person skilled in the art and examples of such methods include chromatographic techniques such as column chromatography (e.g. flash chromatography) and HPLC.
  • chromatographic techniques such as column chromatography (e.g. flash chromatography) and HPLC.
  • One technique of particular usefulness in purifying the compounds is preparative liquid chromatography using mass spectrometry as a means of detecting the purified compounds emerging from the chromatography column.
  • Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein.
  • the methods for the liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of the crude materials and improved detection of the samples by MS.
  • Optimisation of the preparative gradient LC method will involve varying columns, volatile eluents and modifiers, and gradients. Methods are well known in the art for optimising preparative LC-MS methods and then using them to purify compounds.
  • the minimum amount of hot solvent to dissolve all the impure material is used. In practice, 3-5% more solvent than necessary is used so the solution is not saturated. If the impure compound contains an impurity which is insoluble in the solvent it may then be removed by filtration and then allowing the solution to crystallize. In addition, if the impure compound contains traces of coloured material that are not native to the compound, it may be removed by adding a small amount of decolorizing agent e.g. activating charcoal to the hot solution, filtering it and then allowing it to crystallize. Usually crystallization spontaneously occurs upon cooling the solution.
  • decolorizing agent e.g. activating charcoal
  • crystallization may be induced by cooling the solution below room temperature or by adding a single crystal of pure material (a seed crystal). Recrystallisation can also be carried out and/or the yield optimized by the use of an anti-solvent or co-solvent.
  • the compound is dissolved in a suitable solvent at elevated temperature, filtered and then an additional solvent in which the required compound has low solubility is added to aid
  • crystallization The crystals are then typically isolated using vacuum filtration, washed and then dried, for example, in an oven or via desiccation.
  • Other examples of methods for purification include sublimation, which includes an heating step under vacuum for example using a cold finger, and crystallization from melt (Crystallization Technology Handbook 2nd Edition, edited by A. Mersmann, 2001).
  • the compounds of the invention, subgroups and examples thereof, are modulators e.g. inhibitors of DDRs, and which may be useful in preventing or treating disease states or conditions described herein.
  • modulators e.g. inhibitors of DDRs
  • the compounds of the invention, and subgroups thereof, will be useful in preventing or treating diseases or condition mediated by one or more DDR.
  • the compounds of the invention will be useful in alleviating or reducing the incidence of cancer.
  • the compounds of the present invention may be useful for the treatment of the adult population.
  • the compounds of the present invention may be useful for the treatment of the pediatric population.
  • the compounds of the formula (I) and sub-groups thereof are inhibitors of DDRs.
  • compounds of the invention have affinity against DDR1 and/or DDR2, and in particular DDR2.
  • Preferred compounds are compounds that have affinity for one or more DDR selected from DDR1 and/or DDR2.
  • Preferred compounds of the invention are those having IC 50 values of less than 0.1 ⁇ .
  • compounds of the invention exhibit selectivity for the DDR1 and/or DDR2 compared to other kinases in particular c-kit, PDGFR (such as PDGFR- beta), B-raf, Abl and/or c-Src, and such compounds represent one embodiment of the invention.
  • compounds of the invention may have at least 10 times greater affinity against one or more DDR family member in particular DDR1 and/or DDR2 than for other kinases such as c-kit, PDGFR (such as PDGFR-beta), B-raf, Abl and/or c-Src. This can be determined using the methods described herein.
  • DDRs in their role as collagen receptors are associated with a number of diseases linked to cellular transformation, tissue injury cell adhesion, proliferation, and extracellular matrix remodelling. Inhibitors of DDRs may therefore have potential benefit in therapeutic areas including cancer, atherosclerosis, vascular injury, fibrosis, and inflammation such as chronic inflammatory diseases including rheutamoid arthritis.
  • the compounds of the invention may be useful in treating non-oncological such as inflammation, fibrosis, atherosclerosis, and vascular injury.
  • disease or condition to be treated is inflammation, fibrosis, atherosclerosis, or vascular injury, in particular rheutamoid arthritis or fibrosis.
  • the compounds may prove useful in treating or preventing proliferative disorders such as cancers.
  • cancers and their benign counterparts which may be treated (or inhibited) include, but are not limited to tumours of epithelial origin (adenomas and carcinomas of various types including adenocarcinomas, squamous carcinomas, transitional cell carcinomas and other carcinomas) such as carcinomas of the bladder and urinary tract, breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, colon, rectum and anus), liver (hepatocellular carcinoma), gall bladder and biliary system, exocrine pancreas, kidney, lung (for example adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas and mesotheliomas), head and neck (for example cancers of the tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsil, salivary glands, nasal cavity and paranasal sinuses), ovary, fallopian
  • lymphoid lineage for example acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, T-cell lymphomas and leukaemias, natural killer [NK] cell lymphomas, Hodgkin's lymphomas, hairy cell leukaemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorders), and haematological malignancies and related conditions of myeloid lineage (for example acute myelogenous leukemia [AML], chronic myelogenous leukemia [CML], chronic myelomonoc
  • tumours of the central or peripheral nervous system for example astrocytomas, gliomas and glioblastomas, meningiomas, ependymomas, pineal tumours and schwannomas
  • endocrine tumours for example pituitary tumours, adrenal tumours, islet cell tumours, parathyroid tumours, carcinoid tumours and medullary carcinoma of the thyroid
  • ocular and adnexal tumours for example retinoblastoma
  • neuroblastoma neuroblastoma, Wilms tumour, and primitive neuroectodermal tumours
  • syndromes congenital or otherwise, which leave the patient susceptible to malignancy (for example Xeroderma Pigmentosum).
  • the disease or condition comprising abnormal cell growth in one embodiment is a cancer.
  • Metastasis or metastatic disease is the spread of a disease from one organ or part to another non-adjacent organ or part.
  • the cancers which can be treated by the compounds of the invention include primary tumours (i.e. cancer cells at the originating site), local invasion (cancer cells which penetrate and infiltrate
  • metastatic tumours ie. tumours that have formed from malignant cells which have circulated through the bloodstream (haematogenous spread) or via lymphatics or across body cavities (trans-coelomic) to other sites and tissues in the body.
  • the compounds of the invention may be useful in the treatment of metastasis and metastatic cancers.
  • cancers include, lung, brain, ovarian, endometrial, head and neck, liver, pancreatic, prostate, thyroid, mesenchymal, lymphoma and leukemia.
  • haematological malignancies is leukaemia.
  • the leukemia is AML.
  • the haematological malignancies is lymphoma.
  • the lymphoma is selected from DLBCL, Hodgkin's lymphoma, non- Hodgkin's lymphoma, and anaplastic large cell lymphoma.
  • cancers include breast (e.g. primary tumour, metastasis-containing lymph nodes, invasive ductal carcinoma), lung (e.g. NSCLC, SCC), brain (e.g. gliomas, glioblastoma multiforme, atrocytoma, ependymoma, meningeal sarcoma), head and neck (e.g. squamous cell carcinoma), liver (e.g. cholangiocarcimona), pancreatic (e.g. pancreatic endocrine), thyroid (e.g. aneuploid papillary thyroid cancer), and mesenchymal (e.g. fibrous tumours).
  • breast e.g. primary tumour, metastasis-containing lymph nodes, invasive ductal carcinoma
  • lung e.g. NSCLC, SCC
  • brain e.g. gliomas, glioblastoma multiforme, atrocytoma, ependymoma, men
  • the cancer is non-small-cell lung cancer.
  • cancers include epithelial or squamous cell carcinomas.
  • the cancer is lung squamous cell carcinoma.
  • leukemaia such as acute and chronic leukaemias, acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL). and chronic lymphocytic leukaemia (CLL).
  • references to SCC includes SCC with resistance towards platinums, in particular cisplatin-resistant SCC.
  • references to multiple myeloma includes bortezomib-insensitive multiple myeloma or refractory multiple myeloma and references to chronic myelogenous leukemia includes imitanib-insensitive chronic myelogenous leukemia and refractory chronic myelogenous leukemia.
  • the cancers may be cancers which are sensitive to inhibition of any one or more DDR selected from DDR1 (e.g. DDR1a, DDR1 b, DDR1 c, DDR1 d, and/or DDR1e), and/or DDR2, in particular DDR2.
  • DDR1 e.g. DDR1a, DDR1 b, DDR1 c, DDR1 d, and/or DDR1e
  • DDR2 in particular DDR2.
  • the compounds of the invention will be particularly useful in the treatment or prevention of cancers of a type associated with or characterised by the presence of elevated levels of DDR, or mutants of DDR, or splice variants of DDR for example the cancers referred to in this context herein.
  • Whether a particular cancer is one which is sensitive to DDR inhibition may be determined by a method as set out in the section headed "Methods of Diagnosis”.
  • the invention provides a compound for use in the treatment of a disease or condition which is mediated by DDRs (e.g. DDR1 and/or DDR2). In a further embodiment the invention provides a compound for use in the treatment of a disease or condition which overexpresses DDRs (e.g. DDR1 and/or DDR2). In a further embodiment the invention provides a compound for use in the treatment of a disease or condition which is mediated by a mutated DDR (e.g. DDR1 and/or DDR2).
  • the compounds may also be useful in the treatment of tumour growth, pathogenesis, resistance to chemo- and radio-therapy by sensitising cells to chemotherapy and as an anti-metastatic agent.
  • Inhibitors of DDRs represent a class of chemotherapeutics with the potential for: (i) sensitizing malignant cells to anticancer drugs and/or treatments; (ii) alleviating or reducing the incidence of resistance to anticancer drugs and/or treatments; (iii) reversing resistance to anticancer drugs and/or treatments; (iv) potentiating the activity of anticancer drugs and/or treatments; (v) delaying or preventing the onset of resistance to anticancer drugs and/or treatments.
  • the affinity of the compounds of the invention as inhibitors of DDRs can be measured using the biological and biophysical assays set forth in the examples herein and the level of affinity exhibited by a given compound can be defined in terms of the IC 50 value.
  • Preferred compounds of the present invention are compounds having an IC 50 value of less than 1 ⁇ , in particular less than 0.1 ⁇ .
  • the invention provides a compound for use in the treatment of a disease or condition which is mediated by DDR, in particular the DDR is DDR1 and/or DDR2.
  • the disease or condition which is mediated by DDR is a cancer which is characterised by overexpression of at least one DDR and/or mutation of atleast one DDR.
  • the invention provides a compound of the formula (I) for use in the treatment of a cancer in which the cancer cells thereof contain a drug resistant kinase mutation which is:
  • a further aspect provides the use of a compound for the manufacture of a medicament for the treatment of a disease or condition as decribed herein, in particular cancer.
  • a patient Prior to administration of a compound of the formula (I), a patient may be screened to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against DDRs.
  • the term 'patient' includes human and veterinary subjects.
  • a biological sample taken from a patient may be analysed to determine whether a condition or disease, such as cancer, that the patient is or may be suffering from is one which is characterised by a genetic abnormality (e.g. contains a mutated form of a kinase as described herein) or abnormal protein expression which leads to over-activation of a kinase, to up-regulation of the levels or activity of DDR, to sensitisation of a pathway to normal DDR activity or to upregulation of a biochemical pathway downstream of DDR activation.
  • a genetic abnormality e.g. contains a mutated form of a kinase as described herein
  • abnormal protein expression which leads to over-activation of a kinase, to up-regulation of the levels or activity of DDR, to sensitisation of a pathway to normal DDR activity or to upregulation of a biochemical pathway downstream of DDR activation.
  • Tumours with mutations of DDR1 and/or DDR or up- regulation of DDR in particular over-expression of DDR, or gain-of-function mutants of DDR1 or DDR2, may be particularly sensitive to DDR inhibitors.
  • overexpression and mutations of DDR1 and DDR2 has been identified in a range of cancers as discussion in the Background section.
  • up-regulation includes elevated expression or over-expression, including gene amplification (i.e. multiple gene copies), cytogenetic aberration and increased expression by a transcriptional effect, and hyperactivity and activation, including activation by mutations.
  • diagnosis includes screening.
  • marker we include genetic markers including, for example, the measurement of DNA composition to identify presence of mutations of DDR or genetic amplification.
  • marker also includes markers which are characteristic of up regulation of DDR, including protein levels, protein state and mRNA levels of the aforementioned proteins.
  • the diagnostic tests and screens are typically conducted on a biological sample (i.e. body tissue or body fluids) selected from tumour biopsy samples, blood samples (isolation and enrichment of shed tumour cells), cerebrospinal fluid, plasma, serum, saliva, stool biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, buccal spears, skin biopsy or urine.
  • a biological sample i.e. body tissue or body fluids
  • Screening methods could include, but are not limited to, standard methods such as reverse-transcriptase polymerase chain reaction (RT-PCR) or in-situ hybridization such as fluorescence in situ hybridization (FISH).
  • RT-PCR reverse-transcriptase polymerase chain reaction
  • FISH fluorescence in situ hybridization
  • telomere amplification is assessed by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR.
  • Methods of PCR amplification, the selection of primers, and conditions for amplification are known to a person skilled in the art. Nucleic acid manipulations and PCR are carried out by standard methods, as described for example in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M.A. et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego.
  • in situ hybridization comprises the following major steps: (1) fixation of tissue to be analyzed; (2) prehybridization treatment of the sample to increase accessibility of target nucleic acid, and to reduce nonspecific binding; (3)
  • probes used in such applications are typically labelled, for example, with radioisotopes or fluorescent reporters.
  • Preferred probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to enable specific hybridization with the target nucleic acid(s) under stringent conditions. Standard methods for carrying out FISH are described in Ausubel, F.M. et al., eds.
  • double-stranded cDNA is synthesized from total RNA using a (dT)24 oligomer for priming first-strand cDNA synthesis, followed by second strand cDNA synthesis with random hexamer primers.
  • the double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides.
  • cRNA is chemically fragmented according to protocols described by Affymetrix (Santa Clara, CA, USA), and then hybridized overnight on Human Genome Arrays.
  • the protein products expressed from the mRNAs may be assayed by immunohistochemistry of tumour samples, solid phase immunoassay with microtitre plates, Western blotting, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and other methods known in the art for detection of specific proteins. Detection methods would include the use of site specific antibodies. The skilled person will recognize that all such well-known techniques for detection of upregulation of DDR, detection of DDR splice variants or DDR mutations,.
  • Abnormal levels of proteins such as DDR can be measured using standard protein assays, for example, those assays described herein. Elevated levels or
  • overexpression could also be detected in a tissue sample, for example, a tumour tissue by measuring the protein levels with an assay such as that from Chemicon International.
  • the protein of interest would be immunoprecipitated from the sample lysate and its levels measured.
  • Alternative methods for the measurement of the over expression or elevation of DDRs including the isoforms thereof include the measurement of microvessel density. This can for example be measured using methods described by Orre and Rogers (Int J Cancer (1999), 84(2), 101-8). Assay methods also include the use of markers.
  • a further aspect of the invention includes use of a compound according to the invention for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition in a patient who has been screened and has been determined as suffering from, or being at risk of suffering from, a disease or condition which would be susceptible to treatment with a compound having activity against one or more DDR family member (e.g. DDR1 and/or DDR2).
  • DDR family member e.g. DDR1 and/or DDR2
  • Another aspect of the invention includes a compound of the invention for use in the prophylaxis or treatment of cancer in a patient selected from a sub-population possessing overexpression of one or more of the DDR family members (e.g. DDR1 and/or DDR2).
  • DDR family members e.g. DDR1 and/or DDR2.
  • Another aspect of the invention includes a compound of the invention for use in the prophylaxis or treatment of cancer in a patient selected as possessing a cytogenetic abherration that results in overexpression of one or more DDR family members (e.g. DDR1 and/or DDR2).
  • DDR family members e.g. DDR1 and/or DDR2.
  • DDR1 e.g. W385C, A496S, F866Y and F824W
  • DDR2 e.g. L63V, I 120M, D125Y, L239R, G253C, G505S, C580Y, I638F, T765P, G774E, G774V
  • SCC identiy squamous cell carcinomas
  • DDR2 Further mutations identified in DDR2 include R105S and N456S in lung cancer, T654I and T685S in endometrial and T692N in Colorectal cancer.
  • another aspect of the invention includes a compound of the invention for use in the prophylaxis or treatment of cancer in a patient selected as possessing a mutation in one or more DDR family members (e.g. DDR1 and/or DDR2).
  • MRI determination of vessel normalization e.g. using MRI gradient echo, spin echo, and contrast enhancement to measure blood volume, relative vessel size, and vascular permeability
  • circulating biomarkers may also be used to identify for treatment with a compound of the invention.
  • a further aspect of the invention is a method for the diagnosis and treatment of a disease state or condition mediated by a DDR, which method comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against one or more DDR family members ((e.g. DDR1 and/or DDR2); and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a compound of formula 1 and sub-groups or examples thereof as defined herein.
  • DDR family members e.g. DDR1 and/or DDR2
  • composition e.g. formulation
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising (e.g admixing) at least one compound of formula (I) (and sub-groups thereof as defined herein), together with one or more pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents as described herein.
  • the pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents, fillers or bulking agents, granulating agents, coating agents, release-controlling agents, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavouring agents, sweeteners, taste masking agents, stabilisers or any other excipients conventionally used in
  • compositions examples of excipients for various types of pharmaceutical compositions are set out in more detail below.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g. a human subject
  • Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • compositions containing compounds of the formula (I) can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
  • compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.
  • compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.
  • the delivery can be by bolus injection, short term infusion or longer term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump or syringe driver.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, surface active agents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient.
  • aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, surface active agents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for
  • compositions for parenteral administration may also take the form of aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21 (2) 2004, p 201-230).
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules, vials and prefilled syringes, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections
  • the pharmaceutical formulation can be prepared by lyophilising a compound of formula (I), or sub-groups thereof. Lyophilisation refers to the procedure of freeze- drying a composition. Freeze-drying and lyophilisation are therefore used herein as synonyms. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • compositions of the present invention for parenteral injection can also comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil, safflower oil, corn oil or olive oil), and injectable organic esters such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • carboxymethylcellulose and suitable mixtures thereof examples include vegetable oils (such as sunflower oil, safflower oil, corn oil or olive oil), and injectable organic esters such as ethyl oleate.
  • vegetable oils such as sunflower oil, safflower oil, corn oil or olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of thickening materials such as lecithin,
  • compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include agents to adjust tonicity such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion.
  • the solution can be dosed as is, or can be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% dextrose), before administration.
  • the pharmaceutical composition is in a form suitable for sub-cutaneous (s.c.) administration.
  • Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.
  • tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch.
  • Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked
  • carboxymethylcellulose e.g. carboxymethylcellulose
  • lubricating agents e.g. stearates
  • preservatives e.g. parabens
  • antioxidants e.g. BHT
  • buffering agents for example phosphate or citrate buffers
  • effervescent agents such as citrate/bicarbonate mixtures.
  • Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the Gl tract.
  • Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form.
  • Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.
  • the solid dosage forms can be coated or un-coated. Coatings may act either as a protective film (e.g. a polymer, wax or varnish) or as a mechanism for controlling drug release or for aesthetic or identification purposes.
  • the coating e.g. a EudragitTM type polymer
  • the coating can be designed to release the active component at a desired location within the gastro-intestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the
  • the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to release the compound in a controlled manner in the
  • the drug can be presented in a polymer coating e.g. a polymethacrylate polymer coating, which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
  • the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the
  • the coating can be designed to disintegrate under microbial action in the gut.
  • the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations (for example formulations based on ion exchange resins) may be prepared in accordance with methods well known to those skilled in the art.
  • the compound of formula (I) may be formulated with a carrier and administered in the form of nanoparticles, the increased surface area of the nanoparticles assisting their absorption.
  • nanoparticles offer the possibility of direct penetration into the cell.
  • Nanoparticle drug delivery systems are described in "Nanoparticle Technology for Drug Delivery", edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published 13 th March 2006.
  • Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1-2), 167-172, and in Sinha et ai, Mol. Cancer Ther. August 1 , (2006) 5, 1909.
  • the pharmaceutical compositions typically comprise from approximately 1 % (w/w) to approximately 95% active ingredient and from 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient or combination of excipients.
  • the compositions comprise from approximately 20% (w/w) to approximately 90%,% (w/w) active ingredient and from 80% (w/w) to 10% of a pharmaceutically acceptable excipient or combination of excipients.
  • the pharmaceutical compositions comprise from approximately 1 % to approximately 95%, in particular from approximately 20% to approximately 90%, active ingredient.
  • Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, tablets or capsules.
  • the pharmaceutically acceptable excipient(s) can be selected according to the desired physical form of the formulation and can, for example, be selected from diluents (e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), disintegrants, buffering agents, lubricants, flow aids, release controlling (e.g. release retarding or delaying polymers or waxes) agents, binders, granulating agents, pigments, plasticizers, antioxidants, preservatives, flavouring agents, taste masking agents, tonicity adjusting agents and coating agents.
  • diluents e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents
  • disintegrants e.g solid diluents such as fillers or bulking agents
  • lubricants such as solvents and co-solvents
  • flow aids e.g
  • tablets and capsules typically contain 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/ or bulking agents (depending on drug dose). They may also contain 0-10% (w/w) polymer binders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow release tablets would in addition contain 0-99% (w/w) polymers (depending on dose).
  • the film coats of the tablet or capsule typically contain 0-10% (w/w) release-controlling (e.g. delaying) polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.
  • Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50% (w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI) (depending on dose and if freeze dried).
  • WFI Water for Injection
  • Formulations for intramuscular depots may also contain 0-99% (w/w) oils.
  • compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be incorporated into a polymer or waxy matrix that allow the active ingredients to diffuse or be released in measured amounts.
  • the compounds of the invention can also be formulated as solid dispersions.
  • Solid dispersions are homogeneous extremely fine disperse phases of two or more solids.
  • Solid solutions molecularly disperse systems
  • one type of solid dispersion are well known for use in pharmaceutical technology (see (Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300 (1971)) and are useful in increasing dissolution rates and increasing the bioavailability of poorly water-soluble drugs.
  • Solid dosage forms include tablets, capsules, chewable tablets and dispersible or effervescent tablets.
  • Known excipients can be blended with the solid solution to provide the desired dosage form.
  • a capsule can contain the solid solution blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant.
  • a capsule can contain a bulking agent, such as lactose or microcrystalline cellulose.
  • a tablet can contain the solid solution blended with at least one disintegrant, a lubricant, a surfactant, a bulking agent and a glidant.
  • a chewable tablet can contain the solid solution blended with a bulking agent, a lubricant, and if desired an additional sweetening agent (such as an artificial sweetener), and suitable flavours.
  • Solid solutions may also be formed by spraying solutions of drug and a suitable polymer onto the surface of inert carriers such as sugar beads ('non-pareils'). These beads can subsequently be filled into capsules or compressed into tablets.
  • the pharmaceutical formulations may be presented to a patient in "patient packs" containing an entire course of treatment in a single package, usually a blister pack.
  • Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions.
  • the inclusion of a package insert has been shown to improve patient compliance with the physician's instructions.
  • compositions for topical use and nasal delivery include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.
  • formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound. Solutions of the active compound may also be used for rectal administration.
  • compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known.
  • the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.
  • a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).
  • a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 miligrams to 1 gram, of active compound.
  • the active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.
  • the compounds of the formula (I) and sub-groups as defined herein may be useful in the prophylaxis or treatment of a range of disease states or conditions mediated by one or more DDR family members. Examples of such disease states and conditions are set out above.
  • the compounds are generally administered to a subject in need of such
  • administration for example a human or animal patient, in particular a human.
  • the compounds will typically be administered in amounts that are therapeutically or prophylactically useful and which generally are non-toxic.
  • the benefits of administering a compound of the formula (I) may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer compounds in amounts that are associated with a degree of toxicity.
  • the compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively they may be administered in a continuous manner or in a manner that provides intermittent dosing (e.g. a pulsatile manner).
  • a typical daily dose of the compound of formula (I) can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of bodyweight, and more usually 10 nanograms to 15 milligrams per kilogram (e.g. 10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for example 1 microgram to 10 milligrams per kilogram) per kilogram of bodyweight although higher or lower doses may be administered where required.
  • the compound of the formula (I) can be administered on a daily basis or on a repeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21 , or 28 days for example.
  • the compounds of the invention may be administered orally in a range of doses, for example 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, e.g. 2 to 200 mg or 10 to 1000 mg, particular examples of doses including 10, 20, 50 and 80 mg.
  • the compound may be administered once or more than once each day.
  • the compound can be administered continuously (i.e. taken every day without a break for the duration of the treatment regimen).
  • the compound can be administered intermittently (i.e. taken continuously for a given period such as a week, then discontinued for a period such as a week and then taken continuously for another period such as a week and so on throughout the duration of the treatment regimen).
  • treatment regimens involving intermittent administration include regimens wherein administration is in cycles of one week on, one week off; or two weeks on, one week off; or three weeks on, one week off; or two weeks on, two weeks off; or four weeks on two weeks off; or one week on three weeks off - for one or more cycles, e.g. 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cycles.
  • a patient will be given an infusion of a compound of the formula (I) for periods of one hour daily for up to ten days in particular up to five days for one week, and the treatment repeated at a desired interval such as two to four weeks, in particular every three weeks.
  • a patient may be given an infusion of a compound of the formula (I) for periods of one hour daily for 5 days and the treatment repeated every three weeks.
  • a patient is given an infusion over 30 minutes to 1 hour followed by maintenance infusions of variable duration, for example 1 to 5 hours, e.g. 3 hours.
  • a patient is given a continuous infusion for a period of 12 hours to 5 days, an in particular a continuous infusion of 24 hours to 72 hours.
  • a compund of the invention may be beneficial to use as a single agent or to combine the compound of the invention with another agent which acts via a different mechanism to regulate cell growth thus treating two of the characteristic features of cancer development.
  • Combination experiments can be performed, for example, as described in Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regulat 1984;22: 27-55.
  • the compounds as defined herein can be administered as the sole therapeutic agent or they can be administered in combination therapy with one of more other compounds (or therapies) for treatment of a particular disease state, for example a neoplastic disease such as a cancer as hereinbefore defined.
  • the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents or adjuvants (supporting agents in the therapy) in cancer therapy.
  • Examples of other therapeutic agents or treatments that may be administered together (whether concurrently or at different time intervals) with the compounds of the formula (I) include but are not limited to:
  • anti-cancer agents or adjuvants include but are not limited to any of the agents selected from groups (i)-(xlvi), and optionally group (xlvii), below:
  • Taxane compounds for example paclitaxel, paclitaxel protein bound particles (AbraxaneTM), docetaxel, cabazitaxel or larotaxel;
  • Topoisomerase I inhibitors for example camptothecin compounds, for example camptothecin, irinotecan(CPT11), SN-38, or topotecan;
  • Topoisomerase II inhibitors for example anti-tumour epipodophyllotoxins or podophyllotoxin derivatives for example etoposide, or teniposide;
  • Vinca alkaloids for example vinblastine, vincristine, liposomal vincristine (Onco-TCS), vinorelbine, vindesine, vinflunine or vinvesir;
  • Nucleoside derivatives for example 5-fluorouracil (5-FU, optionally in combination with leucovorin), gemcitabine, capecitabine, tegafur, UFT, S1 , cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, or nelarabine;
  • Antimetabolites for example clofarabine, aminopterin, or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine, thiopurine, 6- mercaptopurine, or hydroxyurea (hydroxycarbamide);
  • Alkylating agents such as nitrogen mustards or nitrosourea, for example cyclophosphamide, chlorambucil, carmustine (BCNU), bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), altretamine, busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine,
  • nitrogen mustards or nitrosourea for example cyclophosphamide, chlorambucil, carmustine (BCNU), bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), altretamine, busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (
  • nimustine ACNU
  • Anthracyclines, anthracenediones and related drugs for example daunorubicin, doxorubicin (optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (eg. CaelyxTM, MyocetTM, DoxilTM), idarubicin, mitoxantrone, epirubicin, amsacrine, or valrubicin;
  • Epothilones for example ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO, epothilone A, epothilone B, desoxyepothilone B (also known as epothilone D or KOS-862), aza-epothilone B (also known as BMS- 247550), aulimalide, isolaulimalide, or luetherobin;
  • DNA methyl transferase inhibitors for example temozolomide, azacytidine or decitabine;
  • Antifolates for example methotrexate, pemetrexed disodium, or raltitrexed; Cytotoxic antibiotics, for example antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, or mithramycin; (xiv) Tubulin-binding agents, for example combrestatin, colchicines or nocodazole;
  • VEGFR vascular endothelial growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • MTKI multi target kinase inhibitors
  • Raf inhibitors mTOR inhibitors
  • imatinib mesylate erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, , temsirolimus, everolimus (RAD 001), or PLX4032 (RG7204);
  • Aurora kinase inhibitors for example AT9283, barasertib (AZD1152), TAK- 901 , MK0457 (VX680), cenisertib (R-763), danusertib (PHA-739358), alisertib (MLN-8237), or MP-470;
  • CDK inhibitors for example AT7519, roscovitine, seliciclib, alvocidib
  • PKA/B inhibitors and PKB (akt) pathway inhibitors for example AT13148, AZ-5363, Semaphore, SF1126 and MTOR inhibitors such as rapamycin analogues, AP23841 and AP23573, calmodulin inhibitors (forkhead translocation inhibitors), API-2/TCN (triciribine), RX-0201 , enzastaurin HCI (LY317615), NL-71-101 , SR-13668, PX-316, or KRX-0401 (perifosine/ NSC 639966);
  • Hsp90 inhibitors for example AT13387, herbimycin, geldanamycin (GA), 17- allylamino-17-desmethoxygeldanamycin (17-AAG) e.g. NSC-330507, Kos- 953 and CNF-1010, 17-dimethylaminoethylamino-17- demethoxygeldanamycin hydrochloride (17-DMAG) e.g. NSC-707545 and Kos-1022, NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024 (BIIB-021 an oral purine), ganetespib (STA-9090), SNX-5422 (SC-1021 12) or IPI-504;
  • Monoclonal Antibodies (unconjugated or conjugated to radioisotopes, toxins or other agents), antibody derivatives and related agents, such as anti-CD, anti-VEGFR, anti-HER2 or anti-EGFR antibodies, for example rituximab (CD20), ofatumumab (CD20), ibritumomab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20), epratuzumab (CD22), lintuzumab (CD33),
  • CD20 rituximab
  • CD20 ofatumumab
  • ibritumomab tiuxetan CD20
  • GA101 CD20
  • tositumomab CD20
  • epratuzumab CD22
  • lintuzumab CD33
  • gemtuzumab ozogamicin CD33
  • alemtuzumab CD52
  • galiximab CD80
  • trastuzumab HER2 antibody
  • pertuzumab HER2
  • trastuzumab-DM1 HER2
  • ertumaxomab HER2 and CD3
  • cetuximab EGFR
  • panitumumab EGFR
  • necitumumab EGFR
  • nimotuzumab EGFR
  • bevacizumab VEGF
  • ipilimumab CLA4
  • catumaxumab EpCAM and CD3
  • abagovomab CA125
  • farletuzumab farletuzumab
  • elotuzumab CS1
  • denosumab R
  • CP751.871 IGF1 R
  • mapatumumab TRAIL receptor
  • metMAB metMAB
  • Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or inhibitors of estrogen synthesis for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, or raloxifene;
  • Aromatase inhibitors and related drugs such as exemestane, anastrozole, letrazole, testolactone aminoglutethimide, mitotane or vorozole;
  • Antiandrogens i.e. androgen receptor antagonists
  • related agents for example bicalutamide, nilutamide, flutamide, cyproterone, or ketoconazole;
  • nandrolone decanoate, phenpropionate
  • fluoxymestrone or gossypol
  • CYP17 e.g. abiraterone
  • abarelix goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, or deslorelin;
  • Glucocorticoids for example prednisone, prednisolone, dexamethasone;
  • Differentiating agents such as retinoids, rexinoids, vitamin D or retinoic acid and retinoic acid metabolism blocking agents (RAMBA) for example accutane, alitretinoin, bexarotene, or tretinoin;
  • RAMBA retinoic acid metabolism blocking agents
  • Chromatin targeted therapies such as histone deacetylase (HDAC) inhibitors for example sodium butyrate, suberoylanilide hydroxamide acid (SAHA), depsipeptide (FR 901228), dacinostat (NVP-LAQ824), R306465/ JNJ- 16241 199, JNJ-26481585, trichostatin A, vorinostat, chlamydocin, A-173, JNJ-MGCD-0103, PXD-101 , or apicidin;
  • HDAC histone deacetylase
  • a beta particle-emitting isotope e.g. , Iodine -131 , Yittrium -90
  • an alpha particle- emitting isotope e.g., Bismuth-213 or Actinium-225
  • interleukins e.g. interleukin 2
  • interleukins for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, or peginterferon alfa 2b;
  • Therapeutic Vaccines such as sipuleucel-T (Provenge) or OncoVex;
  • Cytokine-activating agents include Picibanil, Romurtide, Sizofiran, Virulizin, or Thymosin;
  • GPCR G-protein coupled receptors
  • Enzymes such as L-asparaginase, pegaspargase, rasburicase, or
  • DNA repair inhibitors such as PARP inhibitors for example, olaparib,
  • velaparib iniparib, INO-1001 , AG-014699, or ONO-2231 ;
  • Agonists of Death receptor e.g. TNF-related apoptosis inducing ligand
  • TRAIL TRAIL receptor
  • mapatumumab (formerly HGS-ETR1), conatumumab (formerly AMG 655), PRO95780, lexatumumab, dulanermin, CS-1008 , apomab or recombinant TRAIL ligands such as recombinant Human TRAIL/Apo2 Ligand;
  • interleukin-1 1 e.g. oprelvekin
  • EPO erythropoietin
  • analogues thereof e.g. darbepoetin alfa
  • colony-stimulating factor analogs such as granulocyte macrophage- colony stimulating factor (GM-CSF) (e.g. sargramostim), and granulocyte- colony stimulating factor (G-CSF) and analogues thereof (e.g. filgrastim, pegfilgrastim)
  • - agents that inhibit bone resorption such as denosumab or bisphosphonates e.g. zoledronate, zoledronic acid, pamidronate and ibandronate,
  • agents used to reduce blood levels of growth hormone and IGF-I (and other hormones) in patients with acromegaly or other rare hormone-producing tumours such as synthetic forms of the hormone somatostatin e.g.
  • agents for pain e.g. opiates such as morphine, diamorphine and fentanyl,
  • NSAID non-steroidal anti-inflammatory drugs
  • COX-2 inhibitors for example celecoxib, etoricoxib and lumiracoxib
  • agents for mucositis e.g. palifermin
  • oedema or thromoembolic episodes such as megestrol acetate.
  • each of the compounds present in the combinations of the invention may be given in individually varying dose schedules and via different routes.
  • the posology of each of the two or more agents may differ: each may be administered at the same time or at different times.
  • a person skilled in the art would know through his or her common general knowledge the dosing regimes and combination therapies to use.
  • the compound of the invention may be using in combination with one or more other agents which are administered according to their existing combination regimen. Examples of standard combination regimens are provided below.
  • the taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg/m 2 ) of body surface area, for example 75 to 250 mg/m 2 , particularly for paclitaxel in a dosage of about 175 to 250 mg/m 2 and for docetaxel in about 75 to 150 mg/m 2 per course of treatment.
  • the camptothecin compound is advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg/m 2 ) of body surface area, for example 1 to 300 mg/m 2 , particularly for irinotecan in a dosage of about 100 to 350 mg/m 2 and for topotecan in about 1 to 2 mg/m 2 per course of treatment.
  • the anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m 2 ) of body surface area, for example 50 to 250mg/m 2 , particularly for etoposide in a dosage of about 35 to 100 mg/m 2 and for teniposide in about 50 to 250 mg/m 2 per course of treatment.
  • the anti-tumour vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg/m 2 ) of body surface area, particularly for vinblastine in a dosage of about 3 to 12 mg/m 2 , for vincristine in a dosage of about 1 to 2 mg/m 2 , and for vinorelbine in dosage of about 10 to 30 mg/m 2 per course of treatment.
  • the anti-tumour nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg/m 2 ) of body surface area, for example 700 to 1500 mg/m 2 , particularly for 5-FU in a dosage of 200 to 500mg/m 2 , for gemcitabine in a dosage of about 800 to 1200 mg/m 2 and for capecitabine in about 1000 to
  • the alkylating agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg/m 2 ) of body surface area, for example 120 to 200 mg/m 2 , particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m 2 , for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustine in a dosage of about 150 to 200 mg/m 2 , and for lomustine in a dosage of about 100 to 150 mg/m 2 per course of treatment.
  • mg/m 2 body surface area
  • cyclophosphamide in a dosage of about 100 to 500 mg/m 2
  • chlorambucil in a dosage of about 0.1 to 0.2 mg/kg
  • carmustine in a dosage of about 150 to 200 mg/m 2
  • lomustine in a dosage of about 100 to 150 mg/m 2 per course of treatment.
  • the anti-tumour anthracycline derivative is advantageously administered in a dosage of 10 to 75 mg per square meter (mg/m 2 ) of body surface area, for example 15 to 60 mg/m 2 , particularly for doxorubicin in a dosage of about 40 to 75 mg/m 2 , for daunorubicin in a dosage of about 25 to 45mg/m 2 , and for idarubicin in a dosage of about 10 to 15 mg/m 2 per course of treatment.
  • the antiestrogen agent is advantageously administered in a dosage of about 1 to 100 mg daily depending on the particular agent and the condition being treated.
  • Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, in particular 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect.
  • Toremifene is advantageously
  • Anastrozole is advantageously administered orally in a dosage of about 1 mg once a day.
  • Droloxifene is advantageously administered orally in a dosage of about 20-1 OOmg once a day.
  • Raloxifene is advantageously administered orally in a dosage of about 60mg once a day.
  • Exemestane is advantageously administered orally in a dosage of about 25mg once a day.
  • Antibodies are advantageously administered in a dosage of about 1 to 5 mg per square meter (mg/m 2 ) of body surface area, or as known in the art, if different.
  • Trastuzumab is advantageously administered in a dosage of 1 to 5 mg per square meter (mg/m 2 ) of body surface area, particularly 2 to 4mg/m 2 per course of treatment.
  • the compounds can be administered simultaneously or sequentially.
  • the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved.
  • they can be administered at closely spaced intervals (for example over a period of 5-10 minutes) or at longer intervals (for example 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
  • These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days.
  • the weight ratio of the compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of formula (I) and another anticancer agent may range from 1/10 to 10/1 , more in particular from 1/5 to 5/1 , even more in particular from 1/3 to 3/1.
  • the compounds of the invention may also be administered in conjunction with non- chemotherapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy; surgery and controlled diets.
  • non- chemotherapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy; surgery and controlled diets.
  • the compounds of the present invention also have therapeutic applications in sensitising tumour cells for radiotherapy and chemotherapy.
  • the compounds of the present invention can be used as "radiosensitizer” and/or “chemosensitizer” or can be given in combination with another "radiosensitizer” and/or “chemosensitizer”.
  • the compound of the invention is for use as chemosensitiser.
  • radiosensitizer is defined as a molecule administered to patients in therapeutically effective amounts to increase the sensitivity of the cells to ionizing radiation and/or to promote the treatment of diseases which are treatable with ionizing radiation.
  • chemosensitizer is defined as a molecule administered to patients in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or promote the treatment of diseases which are treatable with
  • radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5- iododeoxyuridine (lUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives of the same.
  • Photodynamic therapy (PDT) of cancers employs visible light as the radiation activator of the sensitizing agent.
  • photodynamic radiosensitizers include the following, but are not limited to: hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tin etioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.
  • Radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of radiosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumour with or without additional radiation; or other therapeutically effective compounds for treating cancer or other diseases.
  • Chemosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of chemosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumour or other therapeutically effective compounds for treating cancer or other disease.
  • Calcium antagonists for example verapamil, are found useful in combination with antineoplastic agents to establish chemosensitivity in tumor cells resistant to accepted chemotherapeutic agents and to potentiate the efficacy of such compounds in drug-sensitive malignancies.
  • the compound of the formula (I) and one, two, three, four or more other therapeutic agents can be, for example, formulated together in a dosage form containing two, three, four or more therapeutic agents i.e. in a unitary pharmaceutical composition containing all components.
  • the individual therapeutic agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
  • the pharmaceutical composition comprises a compound of formula I together with a pharmaceutically acceptable carrier and optionally one or more therapeutic agent(s)
  • the invention relates to the use of a combination according to the invention in the manufacture of a pharmaceutical composition for inhibiting the growth of tumour cells.
  • the invention relates to a product containing a compound of formula I and one or more anticancer agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.
  • BINAP 2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthalene; CDI, 1 ,1 '- carbonyldiimidazole; DCE, 1 ,2-dichloroethane; DCM, Dichloromethane; DMSO, dimethylsulfoxide; DMF, ⁇ , ⁇ -dimethylformamide; DMAP, -(dimethylamino)pyridine; EtOAc, ethyl acetate; HATU, /V,/V,/ ⁇ /',/ ⁇ /-tetramethyl-0-(7-azabenzotriazol-1- yl)uronium hexafluorophosphate; HCI, Hydrochloric acid; HPLC, High pressure liquid chromatography; LiHMDS, lithium bis(trimethylsilyl)amide; mins., Minutes; MeCN, acetonitrile; MS, Mass Spectrometry; NMR, Nuclear Magnetic Resonance Spect
  • Nebuliser Pressure 35 psig
  • Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein.
  • the methods for the liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of the crude materials and improved detection of the samples by MS.
  • Optimisation of the preparative gradient LC method will involve varying columns, volatile eluents and modifiers, and gradients. Methods are well known in the art for optimising preparative LC-MS methods and then using them to purify compounds.
  • UV detector 1100 series "MWD” Multi Wavelength Detector
  • Nebuliser Pressure 50 psig
  • the mobile phase eluent was chosen in conjunction with column manufacturers' recommended stationary phase limitations in order to optimise a column's separation performance.
  • CSPs Chiral Stationary Phases
  • compounds synthesised using the protocols as indicated may exist as a solvate e.g. hydrate, and/or contain residual solvent or minor impurities.
  • Compounds isolated as a salt form may be integer stoichiometric i.e. mono- or di-salts, or of intermediate stoichiometry.
  • Step B Synthesis of [(S)-1 -(3-Amino-4-methyl-phenyl)-ethyl]-carbamic acid ferf-butyl ester
  • Step C1 1 Synthesis of ⁇ 3-[(lmidazo[1,2-a]pyridine-3-carbonyl)-amino]-4-methyl- benzyl ⁇ -carbamic acid ferf-butyl ester
  • Step C1.2 Synthesis of ((S)-1 - ⁇ 3-[(7-chloro-imidazo[1,2-a]pyridine-3-carbonyl)- amino]-4-methyl-phenyl ⁇ -ethyl)-carbamic acid ferf-butyl ester
  • Step C2 Synthesis of ⁇ (S)-1 -[4-methyl-3-( ⁇ 7-[2-(4-methyl-piperazin-1 -yl)- ethoxy]-imidazo[1,2-a]pyridine-3-carbonyl ⁇ -amino)-phenyl]-ethyl ⁇ -carbamic acid ferf-butyl ester
  • Step D Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid [5-((S)-1 -amino- ethyl)-2-methyl-phenyl]-amide
  • Step E1 Synthesis of N-[5-( ⁇ [(3-fluorophenyl)carbamoyl]amino ⁇ methyl)-2- methylphenyl]imidazo[1 ,2-a]pyridine-3-carboxamide hydrochloride.
  • 3-fluorophenyl-isocyanate (0.8 mL, 6.85 mmol) was added slowly to a solution of imidazo[1 ,2-a]pyridine-3-carboxylic acid (5-aminomethyl-2-methyl-phenyl)-amide (1.8 g, 5.7 mmol) and triethylamine (1.8 mL, 12.6 mmol) in DCM (100 mL).
  • the reaction was stirred at room temperature overnight.
  • the solvents were evaporated from the reaction mixture d and the crude product was purified by chromatography using silica gel eluting 0-15% methanol in DCM. 1 M HCI in ether (10 mL) was added to the clean combined fractions and the solution was evaporated.
  • Step E2 Synthesis of N- ⁇ 2-methyl-5-[(1S)-1 - ⁇ [(2-methyl-1 , 2,3,4- tetrahydroisoquinolin-5-yl)carbamoyl]amino ⁇ ethyl]phenyl ⁇ imidazo[1 ,2- a]pyridine-3-carboxamide dihydrochloride
  • Step E3 Synthesis of N- ⁇ 2-methyl-5-[(1S)-1 - ⁇ [(1 ,2,3,4 tetrahydroisoquinolin-5- yl)carbamoyl]amino ⁇ ethyl]phenyl ⁇ imidazo[1 ,2-a]pyridine-3-carboxamide dihydrochloride.
  • imidazo[1 ,2- a]pyridine-3-carboxylic acid [5-((S)-1-amino-ethyl) 2-methyl-phenyl]-amide hydrochloride 300 mg, 0.91 mmol was added and the reaction heated at 55 °C overnight. The reaction was cooled and then evaporated to dryness, and the crude product was purified by silica chromatography with an eluting solvent of 0-15% methanol in DCM. The clean product eluted at approximately 8-10% methanol in DCM, which was collected and evaporated. The product was suspended in 4 M HCI in 1 ,4-dioxane (8 mL) and stirred overnight.
  • Step F Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid (2-methyl-5- ⁇ (S)- 1 -[(5-trifluoromethyl-pyridine-3-carbonyl)-amino]-ethyl ⁇ -phenyl)-amide
  • Step G Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid [5-(benzooxazol- 2-ylaminomethyl)-2-methyl-phenyl]-amide
  • Step H1 Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid ⁇ 2-methyl-5-[1 - (3-phenyl-ureido)-ethyl]-phenyl ⁇ -amide lmidazo[1 ,2-a]pyridine-3-carbonyl chloride (1.2 eqs, 484 mg, 2.7 mmol) in dichloromethane (10 ml) was added to a solution of 1-[1-(3-amino-4-methyl-phenyl)- ethyl]-3-phenyl-urea (600 mg, 2.23 mmol) in dichloromethane (100 ml). The reaction was stirred at room temperature, in a nitrogen atmosphere, for 18 hours.
  • Step H2 Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid ⁇ 2-methyl-5-[1 - (3-phenyl-ureido)-ethyl]-phenyl ⁇ -amide
  • Step H4 Synthesis of 7-Chloro-imidazo[1,2-a]pyridine-3-carboxylic acid (5- ⁇ (S)- 1 -[3-(3-fluoro-phenyl)-ureido]-ethyl ⁇ -2-methyl-phenyl)-amide
  • Step I Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid ⁇ 2-methyl-5-[(R)- 2,2,2-trifluoro-1 -(3-trifluoromethyl-benzoylamino)-ethyl]-phenyl ⁇ -amide.
  • Step K Synthesis of 1 -(3-Amino-4-methyl-phenyl)-ethanone
  • Tin (II) chloride (3 eqs, 15.9 g, 83.7 mmol) was added to a solution of 1-(4-methyl-3- nitro-phenyl)-ethanone (5 g, 27.9 mmol) in ethanol (200 ml). The reaction was heated at reflux for 60 min. The reaction was cooled and brought to pH 7-8 using saturated NaHC0 3 . The solid that formed was removed by filtration and discarded. The filtrate was concentrated and then partitioned between EtOAc and water. The organic layer was dried and then evaporated to dryness to give the title compound, 1-(3-amino-4- methyl-phenyl)-ethanone, as a yellow oil (3.85 g).
  • Step L Synthesis of 1 -(3-Amino-4-methyl-phenyl)-ethanone oxime
  • Triethylamine (1.5 eqs, 1.4 ml, 10.07 mmol) was added to a solution of 1-(3-amino-4- methyl-phenyl)-ethanone (1 g, 6.71 mmol) and hydroxylamine hydrochloride (1.5 eqs, 700 mg, 10.07 mmol) in ethanol (10 ml).
  • the reaction was heated to 120 °C for 20 min under microwave irradiation. The reaction was cooled and then concentrated. The residue was partitioned between EtOAc and water. The organic layer was dried and then evaporated to dryness to give the title compound, 1-(3-amino-4-methyl- phenyl)-ethanone oxime, as a yellow solid (1.11 g).
  • Step M Synthesis of 5-(1 -Amino-ethyl)-2-methyl-phenylamine
  • Step N1 Synthesis of 7-Methyl-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (Monomer 2) a) Synthesis of potassium 2-chloro-3-ethox -3-oxoprop-1-en-1-olate
  • Step Q Synthesis of 1 -[1 -(3-Amino-4-methyl-phenyl)-ethyl]-3-phenyl-urea
  • Phenylisocyanate (0.5 eq, 0.123 ml, 1.13 mmol) was added, dropwise, to a solution of 5-(1-Amino-ethyl)-2-methyl-phenylamine hydrochloride (500 mg, 2.3 mmol) and triethylamine (2 eq, 0.631 ml, 4.5 mmol) in dichloromethane (40 ml). The reaction was stirred at room temperature, in a nitrogen atmosphere, for 30 min. The reaction was evaporated to dryness to give the title compound, 1-[1-(3-amino-4-methyl- phenyl)-ethyl]-3-phenyl-urea, as a yellow gum (600 mg).
  • Step S Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid (5-aminomethyl- 2-methyl-phenyl)-amide hydrochloride (Boc deprotection)
  • Step V Synthesis of N-[(R)-1 -(3-Amino-4-methyl-phenyl)-2,2,2-trifluoro-ethyl]-3- trifluoromethyl-benzamide
  • Step W Synthesis of 7-(2-Methoxy-ethoxy)-imidazo[1,2-a]pyridine-3-carboxylic acid ⁇ 2-methyl-5-[(3-phenyl-ureido)-methyl]-phenyl ⁇ -amide
  • Step X General procedure for hydrochloride salt formation
  • Dimethylamine hydrochloride (684 mg, 8.4 mmol) was added to a solution of 2- amino-4-fluoro-benzoic acid (1 g, 6.45 mmol), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (1.48 g, 7.74 mmol), 1- hydroxybenzotriazole hydrate (1.05 g, 7.74 mmol) and N-ethyl-morpholine (3.2 mL, 25.8 mmol) in acetonitrile (20 mL). The reaction was stirred at room temperature overnight (approx 18 hours).
  • Dimethylamine hydrochloride (616 mg, 7.6 mmol) was added to a solution of 2- amino-4-chloro-benzoic acid (1 g, 5.8 mmol), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (1.34 g, 6.96 mmol), 1- hydroxybenzotriazole hydrate (940 mg, 6.96 mmol) and N-ethyl-morpholine (2.93 mL, 23.2 mmol) in acetonitrile (20 mL). The reaction was stirred at room temperature overnight (approx 18 hours).
  • Dimethylamine hydrochloride (1.4 g, 16.8 mmol) was added to a solution of 3-amino- 4-fluoro-benzoic acid (2 g, 12.9 mmol), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (3 g, 15.5 mmol), 1- hydroxybenzotriazole hydrate (2.1 g, 15.5 mmol) and N-ethyl-morpholine (6.6 mL, 51.6 mmol) in acetonitrile (25 mL). The reaction was stirred at room temperature overnight (approx 18 hours).
  • lmidazo[1 ,2-a]pyridine-3,6-dicarboxylic acid 3-ethyl ester was prepared using essentially the same procedure as in step N1 starting from 6-amino-nicotinic acid. After evaporation of the solvent, the product was isolated by partition between water and EtOAc. To a solution of imidazo[1 ,2-a]pyridine-3,6-dicarboxylic acid 3-ethyl ester (100 mg, 0.43 mmol), methylamine hydrochloride (43 mg, 0.64 mmol) and DIPEA (190 ⁇ _, 1.07 mmol) in D F was added HATU (245 mg, 0.64 mmol) and the reaction mixture was stirred for 1 hour.
  • Monomer 8 Synthesis of 7-(4-methyf-piperazin-1-yi)-imidazo[1,2-a]pyridine-3- carboxylic acid ethyl ester
  • Monomer 15 Synthesis of 7-[2-(4-Methyi-piperazin-1 -yl)-ethoxy]-imidazo[1,2- a]pyridine-3-carboxylic acid ethyl ester

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Abstract

L'invention concerne un composé de formule (I) (formule (I)) ou une forme tautomère, une forme de stéréochimiquement isomère, un N-oxyde, un sel ou un solvate pharmaceutiquement acceptables correspondants, R2, R3, R4, Ra, Rb, X, W, Y et t étant tels que définis dans les revendications. Les composés de formule (I) sont des inhibiteurs de DDR et donc utiles dans le traitement de maladies tels qu'un cancer. Des utilisations des composés de formule (I) et des procédés pour leur préparation sont également décrits.
PCT/GB2014/052129 2013-07-11 2014-07-11 Bicycles imidazo-condensés comme inhibiteurs de récepteurs à domaine discoïdine (ddr) WO2015004481A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2021239643A1 (fr) 2020-05-25 2021-12-02 Chiesi Farmaceutici S.P.A. Dérivés de benzylamine en tant qu'inhibiteurs de ddr
EP4032896A1 (fr) * 2021-01-20 2022-07-27 Fundación del Sector Público Estatal Centro Nacional de Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Thiazolopyrimidinones en tant qu'inhibiteurs de ddr1/2 et leurs utilisations thérapeutiques
WO2024076155A1 (fr) * 2022-10-04 2024-04-11 노보렉스 주식회사 Nouveau composé utilisé en tant qu'inhibiteur du domaine yeats

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QIAO L ET AL: "Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 19, no. 21, 1 November 2009 (2009-11-01), pages 6122 - 6126, XP026673792, ISSN: 0960-894X, [retrieved on 20090909], DOI: 10.1016/J.BMCL.2009.09.010 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021239643A1 (fr) 2020-05-25 2021-12-02 Chiesi Farmaceutici S.P.A. Dérivés de benzylamine en tant qu'inhibiteurs de ddr
EP4032896A1 (fr) * 2021-01-20 2022-07-27 Fundación del Sector Público Estatal Centro Nacional de Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Thiazolopyrimidinones en tant qu'inhibiteurs de ddr1/2 et leurs utilisations thérapeutiques
WO2022157166A1 (fr) * 2021-01-20 2022-07-28 Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Thiazolopyrimidones en tant qu'inhibiteurs de ddr1/2 et leurs utilisations thérapeutiques
WO2024076155A1 (fr) * 2022-10-04 2024-04-11 노보렉스 주식회사 Nouveau composé utilisé en tant qu'inhibiteur du domaine yeats

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