IMIDAZO-CONDENSED BICYCLES AS INHIBITORS OF DISCOIDIN DOMAIN RECEPTORS (DDRS)

RELATED APPLICATIONS

This application is related to United States patent application number 61/844,990 filed 11 July 2013, the contents of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

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.). Sequence motifs have been identified that generally correspond to each of these kinase families (e.g., Hanks, S.K., Hunter, T., FASEB J., 9:576-596 (1995); Knighton, et ai, Science, 253:407-414 (1991); Hiles, et ai, Cell, 70:419-429 (1992); Kunz, et ai, Cell, 73:585-596 (1993); Garcia-Bustos, et ai, EMBO J., 13:2352-2361 (1994)).

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

transcription factor. 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. 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). In addition to reports of association with increased expression and activity of wild-type DDRs in tumour cells and tumour progression, Meyerson and co-workers reported that 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).

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.

Mutated Kinases

Mutations arise in kinases causing abherant cellular processing. As described above a number of mutations have been identified in DDRs isolated from a number of cancer types. In addition, drug resistant kinase mutations arise in patient populations being treated with kinase inhibitors. These occur, in part, in the regions of the protein that bind to or interact with the particular inhibitor used in therapy. Such mutations reduce the capacity of the inhibitor to bind to and inhibit the kinase in question. This can occur at any of the amino acid residues which interact with the inhibitor or are important for supporting the binding of said inhibitor to the target. 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).

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. For example, 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.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of formula (I):

or a tautomeric form, stereochemical^ isomeric form, /V-oxide, pharmaceutically acceptable salt or solvate thereof, wherein:

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 . ₆ cycloalkyl, -0-CH ₂ -CHOH-CH ₂ OH, - C(=0)NHC ₃ - ₆ cycloalkyl, -0-(CH ₂ )p-OCH ₃ , -0-(CH ₂ ) _p -OH, 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 cyclic groups is optionally substituted with one or more R ⁷ groups;

R ³ is hydrogen, Ci _-4 alkyl, C ₃ . ₆ cycloalkyl, haloCi_ ₄ alkyl, hydroxyCi_ ₄ alkyl or

methoxymethyl;

R ⁴ is -C(=0)-R ⁵ , -C(=0)-NH-R ⁵ or R ⁶ ;

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 groups;

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; and

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:

In further aspects of the invention there is provided a compound of formula (I) for use in the propylaxis or treatment of a disease or condition as described herein, pharmaceutical compositions comprising a compound of fomula (I) and processes for the synthesis of a compound of formula (I).

DEFINITIONS Unless the context indicates otherwise, references to formula (I) in all sections of this document (including the uses, methods and other aspects of the invention) include references to all other sub-formula, sub-groups, preferences, embodiments and examples as defined herein.

By "DDRs" we mean any of the DDR family members, in particular DDR1 (e.g.

DDR1 a-e) or DDR2, or any isoforms or mutants or splice variants thereof, most particularly DDR2. In particular, we mean the kinase domains of DDR, in particular the kinase domains of DDR1 a-e, or DDR2.

By "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.

The term "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. Thus, modulation encompasses physiological changes which effect an increase or decrease in the relevant protein kinase activity. In the latter case, 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. Thus, 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). The terms "modulated", "modulating" and "modulate" are to be interpreted accordingly. The term "mediated", as used e.g. in conjunction with the kinase as described herein (and applied for example to various physiological processes, diseases, states, conditions, therapies, treatments or interventions) is intended to operate limitatively so that the various processes, diseases, states, conditions, treatments and interventions to which the term is applied are those in which the kinase plays a biological role. In cases where the term is applied to a disease, state or condition, the biological role played by a kinase may be direct or indirect and may be necessary and/or sufficient for the manifestation of the symptoms of the disease, state or condition (or its aetiology or progression). Thus, 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. In cases where the term is applied to treatment, prophylaxis or intervention, 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. Thus, a disease state or condition mediated by a kinase includes the development of resistance to any particular cancer drug or treatment.

The term "treatment" as used herein 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. For example, treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.

The term "prophylaxis" (i.e. use of a compound as prophylactic measure) as used herein in the context of treating a condition i.e. state, disorder or disease, pertains generally to the 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.

The term Optionally substituted' as used herein refers to a group which may be unsubstituted or substituted by a substituent as herein defined.

The prefix "C _x . _y " (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a Ci_ ₆ alkyl group contains from 1 to 6 carbon atoms, a C ₃ . ₆ cycloalkyl group contains from 3 to 6 carbon atoms, a Ci_ ₄ alkoxy group contains from 1 to 4 carbon atoms, and so on.

The term 'halo' or 'halogen' as used herein refers to fluorine, chlorine, bromine or iodine.

The term 'Ci. ₄ alkyl' as used herein as a group or part of a group 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.

The term '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.

The term 'C ₃ . ₆ cycloalkyr as used herein refers to a saturated monocyclic

hydrocarbon ring of 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.

The term 'hydroxyCi. ₄ alkyl' as used herein as a group or part of a group 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.

The term 'haloCi. ₄ alkyl' as used herein as a group or part of a group 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.

The term 'haloCi. ₄ alkoxy' as used herein as a group or part of a group 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.

The term "heterocyclyl group having from 4 to 6 ring members" as used herein shall, unless the context indicates otherwise, include both aromatic and non-aromatic ring systems. Thus, for example, the term "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. Where reference is made herein to a heterocyclyl group, 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

embodiment, 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.

Examples of 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.

Examples of 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 .

The term "non-aromatic" embraces, unless the context indicates otherwise, unsaturated ring systems without aromatic character, partially saturated and fully saturated heterocyclyl ring systems. The terms "unsaturated" and "partially saturated" refer to rings wherein the ring structure(s) contains atoms sharing more than one valence bond i.e. the ring contains at least one multiple bond e.g. a C=C, C≡C or N=C bond. The term "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.

Examples of 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. as in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (e.g. as in imidazolidin-2-one) cyclic ester moieties (e.g. as in

butyrolactone), cyclic sulfones (e.g. as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and combinations thereof (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,

tetrahydrofuranyl, tetrahydrothienyl, dioxanyl, tetrahydropyranyl (e.g.

tetrahydropyran-4-yl), imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, pyrazolin- 2-yl, pyrazolidinyl, piperazinonyl, piperazinyl, and N-alkyl piperazines such as N- methyl piperazinyl. In general, preferred non-aromatic heterocyclyl groups include saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl and N-alkyl piperazines such as N-methyl piperazinyl.

In 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,

[1 ,2]thiazinanyl 1 , 1 -dioxide or [1 ,2]thiazepanyl 1 , 1 -dioxide) and combinations thereof.

Particular examples of 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. pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl), pyrrolidonyl, dihydrothiazolyl, imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, 6H-1 ,2,5-thiadiazinyl, pyrazolin-2-yl, pyrazolin-3-yl,

pyrazolidinyl, piperazinyl, and N-alkyl piperazines such as N-methyl piperazinyl.

The heterocyclyl group can each be unsubstituted or substituted by one or more substituent groups. For example, heterocyclyl or carbocyclyl groups can be unsubstituted or substituted by 1 , 2, 3 or 4 substituents and typically it is

unsubstituted or has 1 , 2 or 3 substituents as defined herein. A combination of substituents is permissible only if such as combination results in a stable or chemically feasible compound (i.e. one that is not substantially altered when kept at 40°C or less for at least a week).

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.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a compound of formula (I):

or a tautomeric form, stereochemical^ isomeric form, /V-oxide, pharmaceutically acceptable salt or solvate thereof wherein W, X, R ² , R ³ , R ⁴ , R ^a and R ^b are as defined herein.

In one embodiment 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.

In one embodiment 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.

In one embodiment:

W is CH _S R ¹ or NH _S , and Y is CH _n ; and - n is 1 and s is 0, and both dotted bonds are double bonds; or

- n is 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.

In the situation where W is absent the dotted bond to W is also absent as required to satisfy valency.

Therefore, the bicyclic group is selected from the following:

(W is CR and Y is CH and both dotted bonds are double bonds);

(W is CHR and Y is CH ₂ and both dotted bonds are single

bonds);

(W is N and Y is CH and both dotted bonds are double bonds); NH and Y is CH ₂ and both dotted bonds are single bonds);

(W is CR ¹ and Y is N and both dotted bonds are double bonds);

(W is CHR ¹ and Y is NH and both dotted bonds are single bonds); and

(W is absent and Y is S, and the dotted bond is a double bond).

In one embodiment, the bicyclic group is selected from:

In one embodiment, the bicyclic group is imidazopyridine. In another embodiment, the bicyclic group is:

In some circumstances, for example in buffer of the appropriate pH, the ring nitrogens may be protonated. This may result in quartenary N carrying a positive charge.

R ¹ and R ² are independently selected from the group consisting of hydrogen, halogen, -CN, d- ₄ alkyl, d. ₄ alkoxy, C ₃ - ₆ cycloalkyl, -O-CH ₂ -CHOH-CH ₂ OH, - C(=0)NHd. ₄ alkyl, -C(=0)N(d- ₄ alkyl) ₂ , -C(=0)NHC ₃ - ₆ cycloalkyl, -0-(CH ₂ ) _P -OCH ₃ , -O- (CH ₂ ) _p -OH, a heterocyclic group having from 4 to 6 ring members, -(CH ₂ ) _P - (heterocyclic group having from 4 to 6 ring members) and -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 cyclic groups is optionally substituted with one or more (e.g. one or two, in particular one) R ⁷ groups.

In one embodiment, 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. In one embodiment, 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. In one embodiment the 4 to 6 membered heterocyclic groups are non-aromatic. In one embodiment the 4 to 6 membered heterocyclic groups are aromatic. In one embodiment, 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.

In one embodiment, R ¹ and R ² are independently hydrogen, halogen, -CN, Ci _-4 alkyl, Ci. ₄ alkoxy, cyclopropyl, -0-CH ₂ -CHOH-CH ₂ OH, ₄ alkyl) ₂ , -C(=0)NHcyclopropyl, N-methyl-pyrazolyl, 4-methylpiperazin-1-yl, morpholin- 4-yl, -0-(CH ₂ )p-OCH ₃ , -0-(CH ₂ ) _P -OH, -0-(CH ₂ ) _P -(methylpiperazin-1-yl), wherein in each case p is 1 or 2.

In one embodiment, R ¹ is selected from the group consisting of hydrogen, halogen, Ci_ ₄ alkyl and Ci_ ₄ alkoxy.

In one embodiment, R ¹ is selected from hydrogen, CI, Br, -CN, methyl, methoxy, ethoxy, cyclopropyl, -0-CH ₂ -CH ₂ -OMe, -0-CH ₂ -CH ₂ -OH, -0-CH ₂ -CHOH-CH ₂ OH, - C(=0)NHMe, -C(=0)N(Me) ₂ , -C(=0)NHcyclopropyl, pyrazolyl, morpholinyl, piperazin- 1-yl, and -0-(CH ₂ ) ₂ -(piperazin-1-yl) wherein each of the cyclic groups is optionally substituted with one or more (e.g. 1 or 2) R ⁷ .

In one embodiment, R ¹ is selected from hydrogen, CI, Br, -CN, methyl, methoxy, ethoxy, cyclopropyl, -0-CH ₂ -CH ₂ -OMe, -0-CH ₂ -CH ₂ -OH, -0-CH ₂ -CHOH-CH ₂ OH, - C(=0)NHMe, -C(=0)N(Me) ₂ , -C(=0)NHcyclopropyl, N-methyl-pyrazol-4-yl, morpholin-4-yl, 4-methylpiperazin-1-yl, and -0-(CH ₂ ) ₂ -(4-methylpiperazin-1-yl).

In one embodiment, R ¹ is hydrogen.

In another embodiment, R ² is selected from the group consisting of hydrogen, halogen, Ci_ ₄ alkyl and Ci_ ₄ alkoxy. In another embodiment, R ² is selected from the group consisting of hydrogen, CI, -C(=0)NHMe, and Ci_ ₄ alkoxy. In one embodiment, R ² is hydrogen.

When present, 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). In one embodiment, 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 . In one embodiment, R ⁷ is Ci_ ₄ alkyl, in particular methyl.

In another embodiment, R ⁷ is not present i.e. the cyclic groups, if present, in R ¹ and R ² are unsubstituted.

In one embodiment R ⁴ is -C(=0)-R ⁵ or -C(=0)-NH-R ⁵ . In another embodiment R ⁴ is - C(=0)-R ⁵ , and in another embodiment R ⁴ is -C(=0)-NH-R ⁵ . 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.

In one embodiment, 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.

In one embodiment, 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.

When present, 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:

In one embodiment, 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:

In one embodiment, 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).

In one embodiment, two R ⁸ groups on adjacent ring atoms join to form: In one embodiment, R is halogen or haloCi. ₄ alkyl. In one embodiment, R is fluorine or -CF ₃ .

In one embodiment 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.

In one embodiment, 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.

When present, 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).

In one embodiment, 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

embodiment, 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.

In one embodiment, R ³ is selected from hydrogen, methyl, ethyl, iso-propyl, cyclopropyl, -CF ₃ , -CH ₂ OH and methoxymethyl.

In one embodiment, R ³ is hydrogen or Ci_ ₄ alkyl e.g. methyl or ethyl. In one

embodiment, R ³ is hydrogen or methyl.

In one embodiment of the invention, 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. In one embodiment, 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.

Alternatively, 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.

In one embodiment, the compound of formula (I) is a compound of formula (la):

or a tautomeric form, stereochemically isomeric form, /V-oxide, pharmaceutically acceptable salt or solvate thereof wherein W, X, R ² , R ³ , R ⁴ , R ^a and R ^b are as defined in any of the embodiments herein.

In one embodiment, 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%.

In one embodiment, 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.

Subformulae

In one embodiment, the compound of formula (I) is a compound of formula (lb):

or a tautomeric form, stereochemical^ isomeric form, /V-oxide, pharmaceutically acceptable salt or solvate thereof wherein W, X, R ³ and R ⁵ are as defined in any of the embodiments herein.

In one embodiment, W is CR ¹ or NH.

In one embodiment, 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.

In one embodiment, the compound of formula (I) is a compound of formula (Ic):

or a tautomeric form, stereochemical^ isomeric form, /V-oxide, pharmaceutically acceptable salt or solvate thereof wherein W, X, R ³ and R ⁵ are as defined in any of the embodiments herein,

In one embodiment, W is CR ¹ or NH.

In one embodiment, 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.

In one embodiment, the compound of formula (I) is a compound of formula (Id):

or a tautomeric form, stereochemical^ isomeric form, /V-oxide, pharmaceutically acceptable salt or solvate thereof wherein W, X, R ³ and R ⁵ are as defined in any of the embodiments herein.

In one embodiment, W is CR ¹ or NH.

In one embodiment, 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).

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 ⁹ is fluorine.

In one embodiment of formula (lb), of formula (Ic) or formula (Id) R ¹ is hydrogen.

In one embodiment of formula (lb), of formula (Ic) or formula (Id) R ³ is hydrogen or methyl.

In one embodiment, the compound of formula (I) is a compound of formula (le):

or a tautomeric form, stereochemically isomeric form, /V-oxide, pharmaceutically acceptable salt or solvate thereof wherein W, Y, R ² , R ³ and R ⁴ are as defined in any of the embodiments herein.

In one embodiment 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; or

W is CR ¹ and Y is NH; and both dotted bonds are double bonds;

X is CH or N;

R ¹ is hydrogen, halogen, -CN, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, cyclopropyl, -0-CH ₂ -CHOH- CH ₂ OH, -C(=0)NHcyclopropyl, 1-methyl-1 H- pyrazol-4-yl, 4-methylpiperazin-1-yl, morpholin-4-yl, -0-(CH ₂ )p-OCH ₃ , -0-(CH ₂ ) _p -OH, or -0-(CH ₂ )p-(methylpiperazin-1-yl), wherein in each case p is 1 or 2;

R ² is hydrogen, halogen, Ci_ ₄ alkoxy, or R ³ is hydrogen, Ci _-4 alkyl, cyclopropyl, -CF ₃ , hydroxyCi_ ₄ alkyl or methoxymethy; R ⁴ is -C(=0)-R ⁵ , -C(=0)-NH-R ⁵ or R ⁶ ;

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.

In one embodiment, the compound of formula (I) is a compound of formula (le) wherein R ² is hydrogen.

In one embodiment, 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.

In one embodiment, the invention provides a compound of formula (I) which is selected from the following compounds or is one of the following compounds:

N-[5-({[(3-fluorophenyl)carbamoyl]amino}methyl)-2-methylp henyl]imidazo[1 ,2-a] pyridine-3-carboxamide;

N-{2-methyl-5-[(1S)-1-{[3-(trifluoromethyl)phenyl]formamido} ethyl]phenyl}imidazo[1 ,2- a]pyridine-3-carboxamide; and

N-{5-[(1 S)-1-[(5-fluoro-1 ,3-benzoxazol-2-yl)amino] ethyl]-2-methylphenyl}imidazo [1 ,2-a] pyridine-3-carboxamide; or tautomeric or stereochemical^ isomeric forms, /V-oxides, pharmaceutically acceptable salts or the solvates thereof.

In one embodiment, the invention provides a compound of formula (I) which is selected from the following compounds or is one of the following compounds:

N-[5-({[(3-fluorophenyl)carbamoyl]amino}methyl)-2-methylp henyl]imidazo[1 ,2-a] pyridine-3-carboxamide hydrochloride salt;

N-[5-({[(3-fluorophenyl)carbamoyl]amino}methyl)-2-methylphen yl]imidazo[1 ,2-a] pyridine-3-carboxamide;

N-{2-methyl-5-[(1S)-1-{[3-(trifluoromethyl)phenyl]formamido} ethyl]phenyl}imidazo[1 ,2- a]pyridine-3-carboxamide; and

N-{5-[(1 S)-1-[(5-fluoro-1 ,3-benzoxazol-2-yl)amino] ethyl]-2-methylphenyl}imidazo [1 ,2-a] pyridine-3-carboxamide.

For the avoidance of doubt, it is to be understood that each general and specific preference, embodiment and example for one substituent may be combined with each general and specific preference, embodiment and example for one or more, in particular all, other substituents as defined herein and that all such embodiments are embraced by this application.

SALTS, SOLVATES, TAUTOMERS, ISOMERS, N-OXIDES, ESTERS, PRODRUGS AND ISOTOPES

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

Many compounds of the formula (I) 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.

Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8,

Hardcover, 388 pages, August 2002. Generally, such 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 (mono- or di-salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of 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. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4- acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1 S)-camphor-10- sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane- 1 ,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L- glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2- sulfonic, naphthalene-1 ,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.

One particular group of salts consists 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.

If the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO ^" ), then a salt may be formed with an organic or inorganic base, generating a suitable cation. Examples of 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 ⁺ . Examples of 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 ⁺ .

Where the compounds of the formula (I) contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I).

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. However, 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.

In one embodiment of the invention, there is provided 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.

N-Oxides

Compounds of the formula (I) containing an amine function 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. Where a compound contains several amine functions one, or more than one, nitrogen atom may be oxidised to form an N-oxide. Particular examples of 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

Interscience, pages. More particularly, 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.

Geometric isomers and tautomers

Compounds of the formula (I) may exist in a number of different geometric isomeric, and tautomeric forms and references to compounds of the formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by formula (I).

For example, certain heteroaryl rings can exist in the two tautomeric forms such as A and B shown below. For simplicity, a formula may illustrate one form but the formula is to be taken as embracing both tautomeric forms.

A B or A B

Other examples of 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

H

I \ OH H ⁺

— c-c c=c

\ / / \

keto enol

Stereoisomers

Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms.

Stereocentres are illustrated in the usual fashion, using 'hashed' or 'wedged' lines, e.g.

Boc-N-methly-L-analine (S)-(+)-2-hydroxy-2-phenylpropionic acid methyl

Where a compound is described as a mixture of two diastereoisomers / epimers, the configuration of the stereocentre is not specified and is represented by straight lines.

Where compounds of the formula (I) contain one or more chiral centres, and can exist in the form of two or more optical isomers, 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:

The 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.

As an alternative to chiral chromatography, 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

crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.

Additionally 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.

Where compounds of the formula (I) exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain

circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereoisomers. Accordingly, the invention provides 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). In one general embodiment, 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).

Compounds encompassing double bonds can have an E (entgegen) or Z

(zusammen) stereochemistry at said double bond. Substituents on bivalent cyclic or (partially) saturated radicals may have either the cis- or frans-configuration. The terms cis and trans when used herein are in accordance with Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35 (9), 2849-2867), and refer to the position of the substituents on a ring moiety.

Of special interest are those compounds of formula (I) which are stereochemically pure. When a compound of formula (I) is for instance specified as R, this means that the compound is substantially free of the S isomer. If a compound of formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer. The terms cis, trans, R, S, E and Z are well known to a person skilled in the art.

Isotopic variations

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.

Examples of 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.

Certain isotopically-labelled compounds of formula (I), for example, those

incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. 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

incorporation and ready means of detection.

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.

Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ 0 and ¹³ N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.

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

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). Examples of esters are compounds containing the group -C(=0)OR, wherein R is an ester substituent, for example, a Ci _-7 alkyl group, a C ₃ -i ₂ heterocyclyl group, or a C ₅ .i ₂ aryl group, in particular a Ci _-6 alkyl group. Particular examples of ester groups include, but are not limited to, -C(=0)OCH ₃ , - C(=0)OCH ₂ CH ₃ , -C(=0)OC(CH ₃ ) ₃ , and -C(=0)OPh. Examples of acyloxy (reverse ester) groups are represented by -OC(=0)R, wherein R is an acyloxy substituent, for example, a Ci _-6 alkyl group, a C ₃ _i ₂ heterocyclyl group, or a C ₅ _i ₂ aryl group, in particular a Ci _-6 alkyl group. Particular examples of acyloxy groups include, but are not limited to, -OC(=0)CH ₃ (acetoxy), -OC(=0)CH ₂ CH ₃ , -OC(=0)C(CH ₃ ) ₃ ,

-OC(=0)Ph, and -OC(=0)CH ₂ Ph. Examples of phosphate esters are those derived from phosphoric acid.

In one embodiment of the invention, 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 and Crystalline forms

Also encompassed by formula (I) are any polymorphic forms of the compounds, and 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. As used herein, the term "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

incorporated in the crystal lattice of the crystalline solid. The term "solvate" is intended to encompass both solution-phase and isolatable solvates. Non-limiting examples of 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. single crystal X-ray crystallography or X-ray powder diffraction) and Solid State NMR (SS-NMR, also known as Magic Angle Spinning NMR or MAS-NMR). Such techniques are as much a part of the standard analytical toolkit of the skilled chemist as NMR, IR, HPLC and MS.

Alternatively 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.

Furthermore, 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. Inclusion complexes, clathrates and metal complexes can be formed by means of methods well known to the skilled person.

Prodrugs

Also encompassed by formula (I) are any pro-drugs of the compounds of the formula (I). By "prodrugs" is meant for example any compound that is converted in vivo into a biologically active compound of the formula (I).

For example, some prodrugs are esters of the active compound (e.g., a

physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=0)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=0)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

Examples of such metabolically labile esters include those of the formula -C(=0)OR wherein R is:

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); and 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).

Also, some 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.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. In one embodiment formula (I) does not include pro-drugs of the compounds of the formula (I) within its scope.

METHODS FOR THE PREPARATION OF COMPOUNDS OF FORMULA (I)

In this section, as in all other sections of this application unless the context indicates otherwise, 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.

Compounds of the formula (I) can be prepared in accordance with synthetic methods well known to the skilled person.

According to a further aspect of the invention there is provided a process which comprises:

(a) (i) reacting a compound of formula (II) with a compound of formula (III) to prepare a compound of formula (I):

where 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; or

(ii) reacting a compound of formula (IV) with a compound of formula (V) to prepare a compound of formula (I):

(iv) (V) where R ^a , R ^b , R ² , R ³ , R ⁴ , t, X, Y and W are as defined herein, wherein z is a leaving group; or (iii) reacting a compound of formula (IV) with an isocyanate of formula (X) to prepare a compound of formula (I):

where R ^a , R ^b , R ² , R ³ , R ⁵ , t, X, Y and W are as defined herein; or

(iv) reacting a compound of formula (VI) with a compound of formula (VII), either in the presence of or with subsequent addition of a reducing agent to prepare a compound of formula (I):

where R ^a , R°, R , R , R , t, X, Y and W are as defined herein; and/or

(b) interconversion of a compound of formula (I) or protected derivative thereof to a further compound of formula (I) or protected derivative thereof; and/or

(c) deprotection of a protected derivative of a compound of formula (I) to prepare a compound of formula (I); and/or

(d) providing a compound of formula (I) and forming a pharmaceutically acceptable salt of the compound.

Compounds of the formula (I) and the various subformulae thereof can be prepared in accordance with synthetic methods well known to the skilled person.

In one embodiment 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.

(III)

Scheme 1

This reaction involves a conventional coupling reaction between an amine and a carboxylic acid or an activated derivative thereof.

In one example, 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. Examples of such reagents 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). 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.

As an alternative, a reactive derivative of the carboxylic acid, e.g. an anhydride (z is - COOR) or acid chloride (z is - CI), may be used.

In another embodiment, 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:

Scheme 2

In one example useful in particular for preparing compounds of formula (lc) the compound of formula (V) is a compound of formula (V):

(V)

In this case, the 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.

In another example useful in particular for preparing compounds of formula (lb) the compound of formula (V) is a compound of the formula (V"):

(V)

The compounds of formula (V") can be prepared by reacting a compound of formula R ⁵ NH ₂ with a compound of the formula z(C=0)z, wherein z is a leaving group, for example CDI. In one example useful in particular for preparing compounds of formula (Id) the compound of formula (V) is a compound of formula (V"") wherein R ⁴ is R ⁶ and z is a leaving group :

R ⁶ — z

(V"")

In this case, 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).

In another example useful in preparing compounds of formula (lb) the compound of formula (IV) is reacted with an isocyanate of formula (X) i.e.:

N=C=0

R ^5/

(X)

Compounds of formula (IV) can be synthesised using the amide coupling described in Scheme 1 wherein R ⁴ is H or a protecting group such as -Boc.

In another embodiment 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:

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

Advanced Organic Chemistry by Jerry March, 4 ^th Edition, John Wiley & Sons, 1992, pp898-900). For example, 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.

Compounds of formulae (II), (III), (IV), (V), (VI), and (VII) are either commercially available, known in the literature or can be prepared by methods analogous to those described in the literature or by methods similar to that described in the example experimental procedures below.

In particular the 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

disubstituted ring. 4-Chloro-pyridin-2-ylamine or 4-bromo-pyridin-2-ylamine in an appropriate solvent and base can be cyclised under reflux with chloroacetaldehyde or an enolate to give the imidazopyridine ring. Appropriate functionality at the R ¹ and R ² positions can be added by use of appropriate starting materials. Alternatively at 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. 37, 2046-2067), the Suzuki reaction (see review by Rossi et al (2004) Synthesis, 15, 2419) or transformations as presented in 'Palladium Reagents and Catalysts' [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1 , Edited by Ei-ichi Negishi, Wiley, ISBN 0-471-31506-0].

In a further embodiment the invention provides a novel intermediate as described herein. In one embodiment the invention provides a novel intermediate of formula (IV) or (VI).

A wide range of well known functional group interconversions are known by a person skilled in the art for converting a precursor compound to a compound of formula I and are described in Advanced Organic Chemistry by Jerry March, 4 ^th Edition, John Wley & Sons, 1992. For example possible metal catalysed functionalisations such as using organo-tin reagents (the Stille reaction), Grignard reagents and reactions with nitrogen nucleophiles are described in 'Palladium Reagents and Catalysts' [Jiro Tsuji, Wley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1 , Edited by Ei-ichi Negishi, Wiley, ISBN 0-471-31506-0].

If appropriate, the reactions previously described in Schemes 1 to 3 are followed or preceded by one or more reactions known to the skilled of the art and are performed in an appropriate order to achieve the requisite substitutions defined above to afford other compounds of formula (I). Non-limiting examples of such reactions whose conditions can be found in the literature include: protection of reactive functions,

deprotection of reactive functions,

halogenation,

dehalogenation,

dealkylation,

alkylation or arylation of amine, aniline, alcohol and phenol,

Mitsunobu reaction on hydroxyl groups, cycloaddition reactions on appropriate groups,

reduction of nitro, esters, cyano, aldehydes,

transition metal-catalyzed coupling reactions,

acylation,

sulfonylation/introduction of sulfonyl groups,

saponification/hydrolysis of ester groups,

amidification or transesterification of ester groups,

esterification or amidification of carboxylic groups,

halogen exchange,

nucleophilic substitution with amine, thiol or alcohol,

reductive amination,

oxime formation on carbonyl and hydroxylamine groups,

S-oxidation,

N-oxidation,

salification.

Protecting Groups

In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction from taking place at an undesirable location on the molecule. Examples of protecting groups, and methods of protecting and

deprotecting functional groups, can be found in Protective Groups in Organic

Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

A hydroxy group may be protected, for example, as an ether (-OR) or an ester (- OC(=0)R), for example, as: a t-butyl ether; a tetrahydropyranyl (THP) ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=0)CH ₃ ).

An aldehyde or ketone group may be protected, for example, as an acetal (R- CH(OR) ₂ ) or ketal (R ₂ C(OR) ₂ ), respectively, in which the carbonyl group (>C=0) is treated with, for example, a primary alcohol. 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

(-NHCO-OC(CH ₃ ) ₃ , -NH-Boc); a 2-biphenyl-2-propyl carbamate (-NHCO- OC(CH ₃ )2C ₆ H ₄ C ₆ H5, -NH-Bpoc), as a 9-fluorenylmethyl carbamate (-NH-Fmoc), as a 6-nitroveratryl carbamate (-NH-Nvoc), as a 2-trimethylsilylethyl carbamate (-NH- Teoc), as a 2,2,2-trichloroethyl carbamate (-NH-Troc), as an allyl carbamate

(-NH-Alloc), or as a 2(-phenylsulfonyl)ethyl carbamate (-NH-Psec).

Other protecting groups for amines, such as cyclic amines and heterocyclic N-H groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.

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. A thiol group may be protected, for example, as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH ₂ NHC(=0)CH ₃ ).

Isolation and purification of the compounds of the invention

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. 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. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC/MS; J Comb Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C, Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5(3); 322-9.An example of such a system for purifying compounds via preparative LC-MS is described below in the Examples section of this application (under the heading "Mass Directed Purification LC-MS System").

Methods of recrystallisation of compounds of formula (I) and salt thereof can be carried out by methods well known to the skilled person - see for example (P.

Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8,

Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Chapter 8, Publisher Wiley-VCH). Products obtained from an organic reaction are seldom pure when isolated directly from the reaction mixture. If the compound (or a salt thereof) is solid, it may be purified and/or crystallized by recrystallisation from a suitable solvent. A good recrystallisation solvent should dissolve a moderate quantity of the substance to be purified at elevated temperatures but only a small quantity of the substance at lower temperature. It should dissolve impurities readily at low temperatures or not at all. Finally, the solvent should be readily removed from the purified product. This usually means that it has a relatively low boiling point and a person skilled in the art will know recrystallising solvents for a particular substance, or if that information is not available, test several solvents. To get a good yield of purified material, 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. If it is not, 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. In this case, 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).

BIOLOGICAL EFFECTS

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. In addition the compounds of the invention, and subgroups thereof, will be useful in preventing or treating diseases or condition mediated by one or more DDR.

Thus, for example, it is envisaged that 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.

More particularly, the compounds of the formula (I) and sub-groups thereof are inhibitors of DDRs. For example, 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 μΜ.

In addition many of the 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. In particular 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.

Thus, the compounds of the invention may be useful in treating non-oncological such as inflammation, fibrosis, atherosclerosis, and vascular injury. In one embodiment disease or condition to be treated is inflammation, fibrosis, atherosclerosis, or vascular injury, in particular rheutamoid arthritis or fibrosis.

As a consequence of their activity against DDR it is anticipated that the compounds may prove useful in treating or preventing proliferative disorders such as cancers.

Examples of 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 tubes, peritoneum, vagina, vulva, penis, cervix, myometrium, endometrium, thyroid (for example thyroid follicular carcinoma), adrenal, prostate, skin and adnexae (for example melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic naevus); haematological malignancies (i.e. leukemias, lymphomas) and premalignant haematological disorders and disorders of borderline malignancy including haematological malignancies and related conditions of 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 myelomonocytic leukemia [CMML], hypereosinophilic syndrome, myeloproliferative disorders such as polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplasia syndrome, and promyelocytic leukemia); tumours of mesenchymal origin, for example sarcomas of soft tissue, bone or cartilage such as osteosarcomas, fibrosarcomas,

chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas, liposarcomas, angiosarcomas, Kaposi's sarcoma, Ewing's sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumours, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; 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); germ cell and trophoblastic tumours (for example teratomas, seminomas, dysgerminomas, hydatidiform moles and choriocarcinomas); and paediatric and embryonal tumours (for example medulloblastoma,

neuroblastoma, Wilms tumour, and primitive neuroectodermal tumours); or syndromes, congenital or otherwise, which leave the patient susceptible to malignancy (for example Xeroderma Pigmentosum).

Thus, in the pharmaceutical compositions, uses or methods of this invention for treating a disease or condition comprising abnormal cell growth (i.e. uncontrolled and/or rapid cell growth), 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

surrounding normal tissues in the local area), and metastatic (or secondary) 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. In particular, the compounds of the invention may be useful in the treatment of metastasis and metastatic cancers.

Particular cancers include, lung, brain, ovarian, endometrial, head and neck, liver, pancreatic, prostate, thyroid, mesenchymal, lymphoma and leukemia. In one embodiment the haematological malignancies is leukaemia. In one

embodiment the leukemia is AML.

In another embodiment the haematological malignancies is lymphoma. In one embodiment the lymphoma is selected from DLBCL, Hodgkin's lymphoma, non- Hodgkin's lymphoma, and anaplastic large cell lymphoma.

Particular 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).

In one particular embodiment the cancer is non-small-cell lung cancer.

Particular cancers include epithelial or squamous cell carcinomas. In one

embodiment the cancer is lung squamous cell carcinoma.

In one embodiment leukemaia, such as acute and chronic leukaemias, acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL). and chronic lymphocytic leukaemia (CLL).

Certain cancers are resistant to treatment with particular drugs. This can be due to the type of the tumour (most common epithelial malignancies are inherently chemoresistant and SCC is relatively resistant to currently available regimens of chemotherapy or radiation therapy) or resistance can arise spontaneously as the disease progresses or as a result of treatment. In this regard, references to SCC includes SCC with resistance towards platinums, in particular cisplatin-resistant SCC. Similarly 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.

It is further envisaged that 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".

In one embodiment 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.

Therapeutic anticancer interventions of all types necessarily increase the stresses imposed on the target tumour cells. 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 μΜ, in particular less than 0.1 μΜ.

In one embodiment 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. In a further embodiment 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. In a further embodiment 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) a threonine gatekeeper mutation; or

(b) a drug-resistant gatekeeper mutation.

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.

METHODS OF DIAGNOSIS

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.

For example, 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.

Examples of such abnormalities that result in activation or sensitisation of the kinase signal, loss of, or inhibition of apoptotic pathways, up-regulation of the receptors or ligands, cytogenetic aberrations or presence of mutant variants of the receptors or ligands e.g. RTK variants. 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. For example, overexpression and mutations of DDR1 and DDR2 has been identified in a range of cancers as discussion in the Background section.

The term 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. Thus, the patient may be subjected to a diagnostic test to detect a marker characteristic of up-regulation of DDR. The term diagnosis includes screening. By marker we include genetic markers including, for example, the measurement of DNA composition to identify presence of mutations of DDR or genetic amplification. The term 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.

Methods of identification and analysis of cytogenetic aberration, genetic amplification, mutations and up-regulation of proteins are known to a person skilled in the art.

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).

In screening by RT-PCR, the level of mRNA in the tumour 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. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., (2001), 3 ^rd Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively a commercially available kit for RT-PCR (for example Roche Molecular Biochemicals) may be used, or methodology as set forth in United States patents 4,666,828; 4,683,202; 4,801 ,531 ; 5, 192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated herein by reference. An example of an in-situ hybridisation technique for assessing mRNA expression would be fluorescence in-situ hybridisation (FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).

Generally, 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)

hybridization of the mixture of nucleic acids to the nucleic acid in the biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments not bound in the hybridization, and (5) detection of the hybridized nucleic acid fragments. The 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. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760- 2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

Methods for gene expression profiling are described by (DePrimo et al. (2003), BMC Cancer, 3:3). Briefly, the protocol is as follows: 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.

Alternatively, 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.

Therefore all of these techniques could also be used to identify tumours particularly suitable for treatment with the compounds of the invention.

Therefore in 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).

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).

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).

The methods described herein could be used to diagnose patients have a cancer possessing a mutation of DDR1 (e.g. W385C, A496S, F866Y and F824W), or a mutation of DDR2 (e.g. L63V, I 120M, D125Y, L239R, G253C, G505S, C580Y, I638F, T765P, G774E, G774V). In particular, these methods canbe used to identiy squamous cell carcinomas (SCC) patients with DDR2 mutations (e.g. I638F and L239R).

Further mutations identified in DDR2 include R105S and N456S in lung cancer, T654I and T685S in endometrial and T692N in Colorectal cancer.

Therefore 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) in combination with circulating biomarkers may also be used to identify for treatment with a compound of the invention.

Thus 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.

PHARMACEUTICAL FORMULATIONS

While it is possible for the active compound to be administered alone, generally it is presented as a pharmaceutical composition (e.g. formulation).

Thus, 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

pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are set out in more detail below.

The term "pharmaceutically acceptable" as used herein pertains 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. Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

Pharmaceutical 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.

The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the 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.

Pharmaceutical formulations 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. Pharmaceutical formulations 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.

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.

Pharmaceutical 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.

Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles 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. Proper fluidity can be maintained, for example, by the use of thickening materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

The 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.

In one preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion. For intravenous administration, 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.

In another preferred embodiment, 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. Thus, 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), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.

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 (eg; tablets, capsules etc.) 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 Eudragit™ type polymer) 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

gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum, duodenum, jejenum or colon.

Instead of, or in addition to, a coating, 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

gastrointestinal tract. Alternatively 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. Alternatively, 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

gastrointestinal tract. In another alternative, the coating can be designed to disintegrate under microbial action in the gut. As a further alternative, 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. In addition, 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. In particular, 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. The skilled person will have the expertise to select the appropriate amounts of ingredients for use in the formulations. For example 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). Formulations for intramuscular depots may also contain 0-99% (w/w) oils.

Pharmaceutical 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.

This invention also provides solid dosage forms comprising the solid solution described above. 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. For example, a capsule can contain the solid solution blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. In addition 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.

Examples of 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. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.

The compounds of the formula (I) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, 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). For oral compositions, 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.

METHODS OF TREATMENT

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. However, in certain situations (for example in the case of life threatening diseases), 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). Alternatively, 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). Examples of 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.

In one particular dosing schedule, 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.

More particularly, 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.

In another particular dosing schedule, 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.

In a further particular dosing schedule, 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.

Ultimately, however, the quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or

physiological condition being treated and will be at the discretion of the physician.

It may be beneficial to use a compund of the invention 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. For the treatment of the above conditions, 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:

Topoisomerase I inhibitors

Antimetabolites

Tubulin targeting agents

DNA binder and topoisomerase II inhibitors

Alkylating Agents

Monoclonal Antibodies.

Anti-Hormones

Signal Transduction Inhibitors

Proteasome Inhibitors

DNA methyl transferases

Cytokines and retinoids

Chromatin targeted therapies

Radiotherapy, and,

Other therapeutic or prophylactic agents.

Particular examples of anti-cancer agents or adjuvants (or salts thereof), include but are not limited to any of the agents selected from groups (i)-(xlvi), and optionally group (xlvii), below:

(i) Platinum compounds, for example cisplatin (optionally combined with

amifostine), carboplatin or oxaliplatin; Taxane compounds, for example paclitaxel, paclitaxel protein bound particles (Abraxane™), 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,

methylcyclohexylchloroethylnitrosurea, or nimustine (ACNU);

Anthracyclines, anthracenediones and related drugs, for example daunorubicin, doxorubicin (optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (eg. Caelyx™, Myocet™, Doxil™), 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;

(xv) Signal Transduction inhibitors such as Kinase inhibitors (e.g. EGFR

(epithelial growth factor receptor) inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MTKI (multi target kinase inhibitors), Raf inhibitors, mTOR inhibitors) for example imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, , temsirolimus, everolimus (RAD 001), or PLX4032 (RG7204);

(xvi) Aurora kinase inhibitors for example AT9283, barasertib (AZD1152), TAK- 901 , MK0457 (VX680), cenisertib (R-763), danusertib (PHA-739358), alisertib (MLN-8237), or MP-470;

(xvii) CDK inhibitors for example AT7519, roscovitine, seliciclib, alvocidib

(flavopiridol), dinaciclib (SCH-727965), 7-hydroxy-staurosporine (UCN-01), JNJ-7706621 , BMS-387032 (a.k.a. SNS-032), PHA533533, PD332991 , ZK- 304709, or AZD-5438;

(xviii) 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);

(xix) 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;

(xx) 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),

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 (CTLA4), catumaxumab (EpCAM and CD3), abagovomab (CA125), farletuzumab (folate receptor), elotuzumab (CS1), denosumab (RANK ligand), figitumumab (IGF1 R), CP751.871 (IGF1 R), mapatumumab (TRAIL receptor), metMAB (met), mitumomab (GD3 ganglioside), naptumomab estafenatox (5T4), or siltuximab (IL6);

(xxi) Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or inhibitors of estrogen synthesis, for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, or raloxifene;

(xxii) Aromatase inhibitors and related drugs, such as exemestane, anastrozole, letrazole, testolactone aminoglutethimide, mitotane or vorozole;

(xxiii) Antiandrogens (i.e. androgen receptor antagonists) and related agents for example bicalutamide, nilutamide, flutamide, cyproterone, or ketoconazole;

(xxiv) Hormones and analogues thereof such as medroxyprogesterone,

d i ethyl sti I bestrol (a.k.a. diethylstilboestrol) or octreotide;

(xxv) Steroids for example dromostanolone propionate, megestrol acetate,

nandrolone (decanoate, phenpropionate), fluoxymestrone or gossypol,

(xxvi) Steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor

(CYP17), e.g. abiraterone;

(xxvii) Gonadotropin releasing hormone agonists or antagonists (GnRAs) for

example abarelix, goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, or deslorelin;

(xxviii) Glucocorticoids, for example prednisone, prednisolone, dexamethasone;

(xxix) 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;

(xxx) Farnesyltransferase inhibitors for example tipifarnib;

(xxxi) 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;

(xxxii) Proteasome Inhibitors for example bortezomib, carfilzomib, CEP-18770, MLN-9708, or ONX-0912;

(xxxiii) Photodynamic drugs for example porfimer sodium or temoporfin;

(xxxiv) Marine organism-derived anticancer agents such as trabectidin; (xxxv) Radiolabeled drugs for radioimmunotherapy for example with a beta particle-emitting isotope (e.g. , Iodine -131 , Yittrium -90) or an alpha particle- emitting isotope (e.g., Bismuth-213 or Actinium-225) for example

ibritumomab or Iodine tositumomab;

(xxxvi) Telomerase inhibitors for example telomestatin;

(xxxvii) Matrix metalloproteinase inhibitors for example batimastat, marimastat, prinostat or metastat;

(xxxviii) Recombinant interferons (such as interferon-γ and interferon a) and

interleukins (e.g. interleukin 2), for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, or peginterferon alfa 2b;

(xxxix) Selective immunoresponse modulators for example thalidomide, or

lenalidomide;

(xl) Therapeutic Vaccines such as sipuleucel-T (Provenge) or OncoVex;

(xli) Cytokine-activating agents include Picibanil, Romurtide, Sizofiran, Virulizin, or Thymosin;

(xlii) Arsenic trioxide;

(xliii) Inhibitors of G-protein coupled receptors (GPCR) for example atrasentan ; (xliv) Enzymes such as L-asparaginase, pegaspargase, rasburicase, or

pegademase;

(xlv) DNA repair inhibitors such as PARP inhibitors for example, olaparib,

velaparib, iniparib, INO-1001 , AG-014699, or ONO-2231 ;

(xlvi) Agonists of Death receptor (e.g. TNF-related apoptosis inducing ligand

(TRAIL) receptor), such as 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;

(xlvii) Prophylactic agents (adjuncts); i.e. agents that reduce or alleviate some of the side effects associated with chemotherapy agents, for example

- anti-emetic agents,

- agents that prevent or decrease the duration of chemotherapy-associated neutropenia and prevent complications that arise from reduced levels of platelets, red blood cells or white blood cells, for example interleukin-1 1 (e.g. oprelvekin), erythropoietin (EPO) and 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 that suppress inflammatory responses such as dexamethasone, prednisone, and prednisolone,

- 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.

octreotide acetate,

- antidote to drugs that decrease levels of folic acid such as leucovorin, or folinic acid,

- agents for pain e.g. opiates such as morphine, diamorphine and fentanyl,

- non-steroidal anti-inflammatory drugs (NSAID) such as COX-2 inhibitors for example celecoxib, etoricoxib and lumiracoxib,

- agents for mucositis e.g. palifermin,

- agents for the treatment of side-effects including anorexia, cachexia,

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. As such, 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. For example, 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

2500 mg/m ² per course of treatment.

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.

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

administered orally in a dosage of about 60mg once a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. 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.

Where the compound of the formula (I) is administered in combination therapy with one, two, three, four or more other therapeutic agents (in particular one or two, e.g. one), the compounds can be administered simultaneously or sequentially. In the latter case, 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. When administered sequentially, 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.

It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.

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.

The compounds of the present invention also have therapeutic applications in sensitising tumour cells for radiotherapy and chemotherapy. Hence 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". In one embodiment the compound of the invention is for use as chemosensitiser.

The term "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.

The term "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

chemotherapeutics.

Many cancer treatment protocols currently employ radiosensitizers in conjunction with radiation of x-rays. Examples of x-ray activated 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. Examples of 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.

For use in combination therapy with another chemotherapeutic agent, 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. In an alternative, the individual therapeutic agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.

In one embodiment the pharmaceutical composition comprises a compound of formula I together with a pharmaceutically acceptable carrier and optionally one or more therapeutic agent(s)

In another embodiment 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.

In a further embodiment 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.

EXAMPLES

The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples. Compounds are named using an automated naming package such as AutoNom (MDL) or are as named by the chemical supplier. In the examples, the following abbreviations are used.

Abbreviations

BINAP, 2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthalene; CDI, 1 ,1 '- carbonyldiimidazole; DCE, 1 ,2-dichloroethane; DCM, Dichloromethane; DMSO, dimethylsulfoxide; DMF, Ν,Ν-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 Spectroscopy; PyBOP, benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; Pd ₂ (dba) ₃ , tris(dibenzylidineacetone)palladium (0); Petrol, petroleum ether fraction with boiling point range 40 - 60 °C Sat., Saturated; TFA, trifluoroacetic acid; THF, Tetrahydrofuran.

NMR Data

Unless indicated, ¹ H NMR spectra were recorded at 25°C on a Bruker Avance I spectrometer operating at 400 MHz. The data were processed and analysed using Topspin 2.1 software. For NMR data, where the number of protons assigned is less than the theoretical number of protons in the molecule, it is assumed that the apparently missing signal(s) is/are obscured by solvent and/or water peaks. In addition, where spectra were obtained in protic NMR solvents, exchange of NH and/or OH protons with solvent occurs and hence such signals are normally not observed. Analytical and Preparative LC-MS systems Analytical LC-MS system and method description

In the following examples, compounds were characterised by mass spectroscopy using the systems and operating conditions set out below. Where atoms with different isotopes are present and a single mass quoted, the mass quoted for the compound is the monoisotopic mass (i.e. ³⁵ CI; ⁷⁹ Br etc.).

Waters Platform LC-MS system:

HPLC System: Waters 2795

Mass Spec Detector: Micromass Platform LC

PDA Detector: Waters 2996 PDA

• Platform MS conditions:

Capillary voltage: 3.6 kV (3.40 kV on ES negative)

Cone voltage: 30 V

Source Temperature: 120 °C

Scan Range: 125-800 amu

lonisation Mode: ElectroSpray Positive or

ElectroSpray Negative or

ElectroSpray Positive & Negative

Waters Fractionlynx LC-MS system:

HPLC System: 2767 autosampler - 2525 binary gradient pump

Mass Spec Detector: Waters ZQ

PDA Detector: Waters 2996 PDA

• Fractionlynx MS conditions:

Capillary voltage: 3.5 kV (3.25 kV on ES negative)

Cone voltage: 40 V (25 V on ES negative)

Source Temperature 120 °C

Scan Range: 125-800 amu

lonisation Mode: ElectroSpray Positive or

ElectroSpray Negative or

ElectroSpray Positive & Negative

Agilent 1200SL-6140 LC-MS system - RAPID: HPLC System: Agilent 1200 series SL

Mass Spec Detector: Agilent 6140 single quadrupole

Second Detector: Agilent 1200 MWD SL

• Agilent MS conditions:

Capillary voltage: 4000V on ES pos (3500V on ES Neg)

Fragmentor/Gain: 100

Gain: 1

Drying gas flow: 7.0 L/min

Gas Temperature: 345 °C

Nebuliser Pressure: 35 psig

Scan Range: 125-800 amu

lonisation Mode: ElectroSpray Positive-Negative switching

Preparation LC-MS system and method description

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. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC/MS; J Comb Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C, Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5(3); 322-9.

Several systems for purifying compounds via preparative LC-MS are described below although a person skilled in the art will appreciate that alternative systems and methods to those described could be used. From the information provided herein, or employing alternative chromatographic systems, a person skilled in the art could purify the compounds described herein by preparative LC-MS.

Waters Fractionlynx system:

• Hardware: 2767 Dual Loop Autosampler/Fraction Collector

2525 preparative pump

CFO (column fluidic organiser) for column selection

RMA (Waters reagent manager) as make up pump

Waters ZQ Mass Spectrometer

Waters 2996 Photo Diode Array detector

Waters ZQ Mass Spectrometer

• Waters MS running conditions:

Capillary voltage: 3.5 kV (3.2 kV on ES Negative)

Cone voltage: 25 V

Source Temperature: 120 °C

Scan Range: 125-800 amu

lonisation Mode: ElectroSpray Positive or

ElectroSpray Negative

Agilent 1 100 LC-MS preparative system:

• Hardware:

Autosampler: 1 100 series "prepALS"

Pump: 1 100 series "PrepPump" for preparative flow gradient and 1100

"QuatPump" for pumping modifier in prep flow

UV detector: 1100 series "MWD" Multi Wavelength Detector

MS detector: 1 100 series "LC-MSD VL"

Fraction Collector: 2 x "Prep-FC"

Make Up pump: "Waters RMA"

Agilent Active Splitter

• Agilent MS running conditions:

Capillary voltage: 4000 V (3500 V on ES Negative)

Fragmentor/Gain: 150/1

Drying gas flow: 12.0 L/min

Gas Temperature: 350 °C

Nebuliser Pressure: 50 psig

Scan Range: 125-800 amu

lonisation Mode: ElectroSpray Positive or

ElectroSpray Negative • Columns:

A range of commercially available columns - both achiral and chiral - may be used such that, in conjunction with the changes in mobile phase, organic modifier and pH, they enabled the greatest cover in terms of a broad range of selectivity. All columns were used in accordance with the manufacturers' recommended operating conditions. Typically 5 micron particle sized columns were used where available. For example, columns from Waters (including but not limited to

XBridge™ Prep OBD™ C18 and Phenyl, Atlantis® Prep T3 OBD™ and

Sunfire™ Prep OBD C18 5 μηι 19 x 100 mm), Phenomenex (including but not limited to Synergy MAX-RP and LUX™ Cellulose-2), Astec (Chirobiotic™ columns including but not limited to V, V2 and T2) and Diacel ^® (including but not limited to Chiralpak ^® AD-H) were available for screening.

• Eluents:

The mobile phase eluent was chosen in conjunction with column manufacturers' recommended stationary phase limitations in order to optimise a column's separation performance.

• Methods:

Achiral Preparative Chromatography

The compound examples described have undergone HPLC purification, where indicated, using methods developed following recommendations as described in Snyder L. R., Dolan J. W., High-Performance Gradient Elution The Practical Application of the Linear-Solvent-Strength Model, Wiley, Hoboken, 2007.

Chiral Preparative Chromatography

Preparative separations using Chiral Stationary Phases (CSPs) are the natural technique to apply to the resolution of enantiomeric mixtures. Equally, this technique can be applied to the separation of diastereomers and achiral molecules. Methods are well known in the art for optimising preparative chiral separations on CSPs and then using them to purify compounds. Such methods are described in Beesley T. E., Scott R.P.W.; Chiral Chromatography; Wiley, Chichester, 1998.

Synthetic Methods The following synthetic procedures are provided for illustration of the methods used; for a given preparation or step the precursor used may not necessarily derive from the individual batch synthesised according to the step in the description given.

Where a compound is described as a mixture of two diastereoisomers / epimers, the configuration of the stereocentre is not specified and is represented by straight lines.

As understood by a person skilled in the art, 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.

General Procedures

General Route to Compounds of Formula I (including sub formula lb, lc and Id)

C1 HATU

C2 ester condensation

H1 Acid chloride

H2 EDC/HOAt (if R=H) †

H3 Ester condensation I EDC/HOBt Step A: Synthesis of lmidazo[1 ,2-a]pyridine-3-carbonyl chloride

To imidazo[1 ,2-a]pyridine-3-carboxylic acid (1.0 eq) in DCM (0.2 M) at O °C was added oxalyl chloride (3.0 eq, 2.0 M solution in DCM) dropwise and then 1 drop of DMF. The mixture was slowly warmed to room temperature and stirred for 16 hours. LCMS analysis of the mixture showed >95% of the desired product (appeared as methyl ester on LCMS upon reaction with MeOH). The reaction was concentrated and azeotroped with toluene (x3). The acid chloride was obtained as a pale yellow amorphous solid which was used without further purification.

Step B: Synthesis of [(S)-1 -(3-Amino-4-methyl-phenyl)-ethyl]-carbamic acid ferf-butyl ester

To a solution of 5-((S)-1-Amino-ethyl)-2-methyl-phenylamine hydrochloride (9 g, 0.04 mmol) in DCM (900 ml) cooled to 0 °C was added Et ₃ N (11.71 ml, 2.1 eq) followed by (BOC) ₂ 0 (7.04 g, 0.8eq ). The reaction was followed by MS, with further BOC ₂ 0 (0.25eq) in (0.05eq) portions added over next 2.5 hours. The reaction was washed with water twice, and the combined aqueous layers were back washed with DCM. All of the organic layers were combined, washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure using a water bath maintained at 0 °C. To the residue was added petroleum ether, and the solid generated was filtered and then washed with fresh petroleum ether to give [(S)-1-(3-Amino-4-methyl- phenyl)-ethyl]-carbamic acid te/f-butyl ester (8.34 g), 2M+H = 501.

Step C1 :1 Synthesis of {3-[(lmidazo[1,2-a]pyridine-3-carbonyl)-amino]-4-methyl- benzyl}-carbamic acid ferf-butyl ester

(3-Amino-4-methyl-benzyl)-carbamic acid te/f-butyl ester (Monomer 19) (7.28 g, 30.9 mmol) and imidazo[l,2-a]pyridine-3-carboxylic acid (6.0 g, 37.0 mmol) were slurried in DMF (154 ml_) and DIPEA (16 ml_, 92.54 mmol) was added. HATU (20.5 g, 53.98 mmol) was added and the reaction was heated to 50 °C overnight. Water was then added and the resulting precipitate collected using vacuum filtration. The product was dried in a vacuum oven at 40 C. The crude brown solid product was slurried in ethyl acetate and 40-60 petroleum ether was added to form a precipitate. The solid was collected via vacuum filtration and dried in a vacuum oven at 40 °C, to give (8.5 g), (M+H) = 381.

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

To a stirred solution of [(S)-1-(3-amino-4-methyl-phenyl)-ethyl]-carbamic acid tert- butyl ester (250 mg, 1.0 mmol), 7-chloro-imidazo[1 ,2-a]pyridine-3-carboxylic acid (200 mg, 1.0 mmol) and N,N-diisopropylethylamine (350 μΙ_, 2.0 mmol) in DMF (6 ml_) was added HATU (570 mg, 1.5 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Saturated NaHC0 ₃ (15 ml_) was added and the product was extracted with ethyl acetate (2x15 ml_). The organic phase was washed with brine, dried and evaporated. The crude product was purified by column chromatography using silica gel with an eluting solvent of 0-5% MeOH in DCM to afford the product as a beige solid (360 mg, 84%), (M+H) ⁺ = 429.

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]-et hyl}-carbamic acid ferf-butyl ester

To a stirred solution of [(S)-1-(3-amino-4-methyl-phenyl)-ethyl]-carbamic acid tert- butyl ester (142 mg, 0.57 mmol) and 7-[2-(4-methyl-piperazin-1-yl)-ethoxy]- imidazo[1 ,2-a]pyridine-3-carboxylic acid ethyl ester (190 mg, 0.57 mmol) in THF (5 mL) was added lithium bis(trimethylsilyl)amide (0.9 M in methylcycloxexane, 1.6 ml, 1.42 mmol) at 0 °C. The reaction mixture was stirred at this temperature for 2 hours. Water (10 mL) was added and the product was extracted with EtOAc (2x10 mL). The crude product was purified by PREP HPLC to afford the title compound (81 mg, 27%), (M+H) ⁺ = 537.

Step D: Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid [5-((S)-1 -amino- ethyl)-2-methyl-phenyl]-amide

To a stirred solution of aniline (1.0 eq) in THF and pH 5 acetate buffer (1.0 M) was added portionwise the acid chloride (1.3 eq) and the mixture was stirred at rt for 1 hour. LCMS indicated predominantly one product (M+H+ 295.0). The THF and water were removed under reduced pressure. The residue dissolved in water and to the solution was added sufficient saturated aqueous NaHC0 ₃ to adjust the pH to 8-9. The free amine was then extracted with 3: 1 CH ₃ CI:IPA (x4), and the combined organic layers were washed with brine, dried (MgS0 ₄ ) and concentrated to yield the amine product as a pale yellow crystalline solid.

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. The white solid was washed with diethyl ether (100 mL x2), DCM (100 mL) and water (100 mL x2). The solid was dried in a vac-oven at 45 °C overnight to yield title compound as a white solid (770 mg, 1.7 mmol, 30% yield), MS: [M+H] ⁺ = 418.

Step E2: Synthesis of N-{2-methyl-5-[(1S)-1 -{[(2-methyl-1 , 2,3,4- tetrahydroisoquinolin-5-yl)carbamoyl]amino}ethyl]phenyl}imid azo[1 ,2- a]pyridine-3-carboxamide dihydrochloride

2-Methyl-1 ,2,3,4-tetrahydro-isoquinolin-5-ylamine (199 mg, 1 mmol) and carbonyl di- imidazole (165 mg, 1 mmol) were dissolved in DCM (5 mL) and DMF (2 mL) to this was added triethylamine (0.3 mL 2 mmol) and the sample was heated to 55 °C for 5 hours. After this time, lmidazo[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 the crude was purified by silica chromatography eluting 0-20% methanol in DCM. Clean product was collected and evaporated. The material was dissolved in methanol (2 mL) and 1 M HCI in ether (5 mL) was added then the sample was evaporated. The pale yellow solid was triturated with diethyl ether and dried in a vac-oven at 45 °C overnight to yield the title compound (75 mg, 0.16 mmol, 17% yield), MS: [M+H] ⁺ = 483.

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.

5-amino-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid te/f-butyl ester (248 mg, 1 mmol) and carbonyl di-imidazole (165 mg, 1 mmol) were dissolved in DCM (5 mL) and DMF (2 mL). To the resulting mixture was added triethylamine (0.3 mL 2 mmol) and the sample was heated to 55 °C for 5 hours. After this time, 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. The reaction was evaporated and purified by preparative HPLC to give a clean product from which the solvent was evaporated. The solid was evaporated in methanol (2 mL), and 1 M HCI in ether (5m L) was added then the solvent was evaporated from the sample. The pale yellow solid was triturated with diethyl ether and dried in a vac-oven at 45 °C overnight to yield the title compound (144 mg), MS: [M+H] ⁺ = 469.

Step F: Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid (2-methyl-5-{(S)- 1 -[(5-trifluoromethyl-pyridine-3-carbonyl)-amino]-ethyl}-phen yl)-amide

To a mixture of 5-trifluoromethyl-nicotinic acid (60 mg, 0.314 mmol, 1.0 eq), imidazo[1 ,2-a]pyridine-3-carboxylic acid [5-((S)-1-amino-ethyl)-2-methyl-phenyl]- amide hydrochloride (114 mg, 0.345 mmol, 1.1 eq) in DMF (0.1 M) was added HATU (1.1 eq) and DIPEA (2.2 eq), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude product was dissolved in MeOH and purified using Agilent HPLC to yield the desired amide product as a white solid (103 mg, 70%).

Step G: Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid [5-(benzooxazol- 2-ylaminomethyl)-2-methyl-phenyl]-amide

To imidazo[1 ,2-a]pyridine-3-carboxylic acid (5-aminomethyl-2-methyl-phenyl)-amide (75 mg, 0.27 mmol) and 2-chloro-benzoxazole (41 mg, 0.27 mmol) in NMP (0.134 ml_) was added N,N-diisopropylethylamine (103 μΙ_, 0.59 mmol) The reaction was heated to 150 °C for 30 min under microwave irradiation. The reaction was cooled and and the product was purified by preparative HPLC, to give the titled compound (23 mg).

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. The reaction was evaporated to dryness and a small portion of the residue (100 mg) was purified by preparative HPLC. This gave the title compound, imidazo[1 ,2-a]pyridine-3- carboxylic acid {2-methyl-5-[1-(3-phenyl-ureido)-ethyl]-phenyl}-amide, as a white solid (16 mg).

Step H2: Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid {2-methyl-5-[1 - (3-phenyl-ureido)-ethyl]-phenyl}-amide

1-[1-(3-Amino-4-methyl-phenyl)-ethyl]-3-phenyl-urea (1.1 eq, 86 mg, 0.34 mmol) was added to a solution of imidazo[1 ,2-a]pyridine-3-carboxylic acid (50 mg, 0.31 mmol), 3-dimethylamino-propyl)-ethyl-carbodiimide, EDC (1.1 eq, 65 mg, 0.34 mmol) and 1- hydroxy-7-azabenzotriazole, HOAt (1.1 eq, 46 mg, 0.34 mmol) in N,N- dimethylformamide, DMF (10 ml). The reaction was stirred at room temperature, in a nitrogen atmosphere, for 18 hours. It could be seen that starting material remained and a further portion (amounts used as above) of the acid, EDC and HOAt were added and stirring continued at room temperature, in a nitrogen atmosphere, for 18 hours. The reaction was evaporated to dryness and the residue was purified by preparative HPLC. This gave the title compound, imidazo[1 ,2-a]pyridine-3-carboxylic acid {2-methyl-5-[1-(3-phenyl-ureido)-ethyl]-phenyl}-amide, as a white solid (18 mg).

Step H3 Synthesis of 7-Methyl-imidazo[1,2-a]pyridine-3-carboxylic acid {2- methyl-5-[(3-phenyl-ureido)-methyl]-phenyl}-amide

To a stirred solution of 1-(3-amino-4-methyl-benzyl)-3-phenyl-urea (153 mg, 0.60 mmol) and 7-methyl-imidazo[1 ,2-a]pyridine-3-carboxylic acid ethyl ester (120 mg, 0.60 mmol) in THF (6 ml_) was added lithium bis(trimethylsilyl)amide (0.9 M in THF, 1.8 ml, 1.80 mmol) at 0 °C. The reaction mixture was stirred at this temperature for 1 hour. Water (10 ml_) was added and the product was extracted with EtOAc (2x10 ml_). The crude product was purified on silica, eluted with 0-10% MeOH in DCM to afford the title compound as an off white solid (78 mg, 31 %), (M+H) ⁺ = 414.

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

To a stirred solution of 1-[(S)-1-(3-amino-4-methyl-phenyl)-ethyl]-3-(3-fluoro-phenyl )- urea (143 mg, 0.5 mmol), 7-chloro-imidazo[1 ,2-a]pyridine-3-carboxylic acid (1 18 mg, 0.6 mmol) and N,N-diisopropylethylamine (170 μΙ_, 1.0 mmol) in DMF (3 ml_) was added HATU (285 mg, 0.75 mmol) and the reaction mixture was stirred at 50 °C for 3 hours. Saturated NaHC0 ₃ (15 ml_) was added and the product was extracted with ethyl acetate (2x15 ml_). The organic phase was washed with brine, dried, and evaporated. The crude product was purified on silica, eluted with -0-5% MeOH in DCM to afford the product as a beige solid (130 mg, 56%), (M+H) ⁺ = 466.

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.

N-[(R)-1-(3-Amino-4-methyl-phenyl)-2,2,2-trifluoro-ethyl]-3- trifluoromethyl-ben (269 mg, 0.715 mmol) was added to a solution of imidazo(1 ,2-a)pyridine-3-carboxylic acid (128 mg, 0.78 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

hydrochloride (164 mg, 0.86 mmol), 1-hydroxybenzotriazole hydrate (116 mg, 0.86 mmol) and N-ethyl-morpholine (0.3 ml_, 2.2 mmol) in DMF (20 ml_). The reaction was heated to 70 °C overnight (approx 18 hours). The reaction was cooled and then evaporated to dryness. The crude product was purified by silica chromatography eluting 0-15% methanol in DCM. The clean product was collected and the solvent was evaporated. The residue was further purified by preparative HPLC to yield the title compound as a white solid (10 mg), MS: [M+H] ⁺ = 521.

Step J: Reductive Amination (prophetic)

lmidazo[1 ,2-a]pyridine-3-carboxylic acid (5-formyl-2-methyl-phenyl)-amide could be reacted with a H ₂ N-R ⁶ group in NMP. Titanium isopropoxide is added and the reaction stirred for -1-2 hours. Sodium borohydride would be added for 40 min. Aqueous work up and purification by preparative HPLC to give the required compound.

General Route to Formula (IV)

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

Hydrochloric acid, cone. (13.5 drops) was added to a suspension of 1-(3-amino-4- methyl-phenyl)-ethanone oxime (1.11 g, 6.77 mmol) and 10% palladium on charcoal (203 mg) in methanol (34 ml). The reaction was subject to an atmosphere of hydrogen for 3 hours. The reaction was filtered and the filtrate evaporated to dryness to give the title compound, 5-(1-amino-ethyl)-2-methyl-phenylamine dihydrochloride, as a yellow solid (1.12 g).

General Route to 7-Methoxy-imidazo[1 ,2-a]pyridine-3-carboxylic acid

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

A mixture of ethyl 2-chloroacetate (9.6 mL, 89.8 mmol) and ethyl formate (8.0 mL, 98.7mmol) was added slowly to a suspension of potassium t-butoxide (1 1.1 g, 98.7 mmol) in THF (100 mL) at -5°C (maintaining the temperature <10°C) with stirring. The mixture was stirred at ambient temperature for 24 hours. The solids were collected by filtration and washed with THF (20 mL). The material was dried under vacuum to give the product (14.2 g, 84%) which was used without further purification. 1 H NMR (400 MHz, DMSO-d6): 8.96 (1 H, s), 3.93 (2H, q), 1.12 (3H, t). b) Synthesis of 7-Methyl-imidazo[1 ,2-a]pyridine-3-carboxylic acid ethyl ester

To a solution of concentrated sulfuric acid (1.2 mL, 24.0 mmol) in absolute ethanol (30 mL) was added potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (8.55 g, 45.0 mmol) and 4-methyi-pyridin-2-ylamine (1.62 g, 15 mmol) and the mixture was heated under nitrogen at reflux for 18 hours. The mixture was cooled to ambient temperature and the resulting suspension was evaporated to dryness under reduced pressure. Water (50 mL) was added to the residue and basified with 2N NaOH (pH=8.5). The product was extracted with EtOAc (2x30 mL). The organic phase was dried and then evaporated. The residue was purified on silica, eluted with 0-100% EtOAc in petroleum ether to afford the title compound (1.42 g, 46%), (M÷H) ⁺ =205. Step N2: Synthesis of 7-Methoxy-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (Monomer 3)

Potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (3.8 g, 20 mmol) was suspended (through vigorous magnetic stirring) in ether (50 mL) and 6N sulfuric acid (1.7 mL, 10.2 mmol) was added slowly. Additional water (10 mL) was added to promote phase separation. The ether phase was separated. The aqueous phase was further extracted with ether (20 mL). The combined ether phases were dried

( gS0 ₄ ). The solution was filtered and concentrated under reduced pressure, with the temperature not exceeding 20 °C. The residue was dissolved in absolute ethanol (20 mL). 4-Methoxy-pyridin-2-ylamine (1.24 g, 10 mmol) was added, and the mixture was heated under nitrogen at 65 °C for 18 hours. The mixture was cooled to ambient temperature and the resulting suspension was evaporated to dryness under reduced pressure. The residue was partitioned between saturated NaHC0 ₃ (50 mL) and EtOAc (50 mL). The precipitated yellow solid was filtered, washed with EtOAc and water and dried (1.15 g). The EtOAc phase was dried, evaporated to afford further product (0.74 g), ( ÷H) ⁺ = 221.

Step O: Synthesis of 7-Methoxy-imidazo[1,2-a]pyridine-3-carboxylic acid

A suspension of 7-methoxy-imidazo[1 ,2-a]pyridine-3-carboxylic acid ethyl ester (0.73 g, 3.3 mmol), lithium hydroxide (0.24 g, 9.9 mmol) in methanol (24 mL) and water (12 mL) was stirred for 18 hours. The resulting solution was acidified to pH=5 with 1 M HCI. The precipitate was filtered, washed with water, and dried to provide the titled compound (0.236 g, 37%), (M+H) ⁺ =193

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).

Alternative route to Formula (IV) [where R = HI

Step R: Synthesis of 5-Aminomethyl-2-methyl-phenylamine

Lithium aluminium hydride, 1 M in tetrahydrofuran (2 eq, 100 ml, 100 mmol) was added, dropwise, to a solution of 3-amino-4-methyl-benzamide (7.5 g, 50 mmol) in tetrahydrofuran (500 ml). The reaction was heated at reflux for 2 hours. The reaction was cooled and then water (4.5 ml), 15% sodium hydroxide (4.5 ml) and water (13.5 ml) were added cautiously. Stirring continued at room temperature for 30 mins. The solid that had formed was separated by filtration and washed thoroughly with diethylether. The filtrate was evaporated to dryness to give the title compound, 5- aminomethyl-2-methyl-phenylamine, as a brown solid (6.85 g).

Step S: Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid (5-aminomethyl- 2-methyl-phenyl)-amide hydrochloride (Boc deprotection)

{3-[(lmidazo[1 ,2-a]pyridine-3-carbonyl)-amino]-4-methyl-benzyl}-carbamic acid tert- butyl ester was dissolved in methanol (223 ml_) and 5M HCI (223 ml_) was added. The reaction was stirred for 2 hour at room temperature and then concentrated in vacuo and the residue dried in a vacuum at 40 °C. The resulting brown oil was dissolved in methanol and treated with decolourising charcoal. Filtered and concentrated. Dried in a vacuum over at 40 °C, to give the titled compound (5.9 g), (M+H) = 281

General Route to Monomers

Step T Synthesis of 5-Amino-2-chloro-6-methyl-nicotinonitrile

A filtered solution of tin (II) chloride (25 g, 131.85 mmol) in cone, hydrochloric acid (25 ml) was added to a suspension of 2-chloro-6-methyl-5-nitro-nicotinonitrile (1.5 g, 7.6 mmol) in diethylether (7.5 ml). The reaction was stirred at room temperature for 18 hours. The reaction was basified using sodium hydroxide (5N) and then extracted with dichloromethane. The organic layer was dried and then evaporated to dryness to give the title compound, 5-amino-2-chloro-6-methyl-nicotinonitrile, as a yellow solid (1.08 g).

Step U: Synthesis of 5-Aminomethyl-2-methyl-pyridin-3-ylamine

Hydrochloric acid, cone. (15 ml) and ethanol (85 ml) were added to 5-amino-2-chloro- 6-methyl-nicotinonitrile (500 mg, 2.98 mmol) and 10% palladium on charcoal (100 mg) under a nitrogen atmosphere. The reaction was subject to an atmosphere of hydrogen using the Parr hydrogenator at 30 psi for 2 hours. A fresh portion of catalyst (100 mg) was added and the hydrogenation continued at 30 psi for 18 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness to give the title compound, 5-aminomethyl-2-methyl-pyridin-3-ylamine, as a yellow solid (892 mg).

Step V: Synthesis of N-[(R)-1 -(3-Amino-4-methyl-phenyl)-2,2,2-trifluoro-ethyl]-3- trifluoromethyl-benzamide

3-Trifluoromethyl-benzoyl chloride (68 μΙ_, 0.46 mmol) was added dropwise to a stirred solution of 5-((R)-1-amino-2,2,2-trifluoro-ethyl)-2-methyl-phenylamine (220 mg, 0.92 mmol) and triethylamine (0.32 ml_, 2.3 mmol) in DCM (30 ml_) The reaction was stirred for 30 mins. After this time a further portion of 3-trifluoromethyl-benzoyl chloride (68 μΙ_, 0.46 mmol) was added and stirring continued for 1 hour. Water was added to the reaction mixture and the DCM layer was separated. The organic layer was washed with water (20 ml_ x2) and brine then dried (Na ₂ S0 ₄ ), filtered and evaporated to yield crude title compound as a yellow oil (269 mg), MS: [M+H] ⁺ = 377.

Alternative Route to Formula (la)

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

To a solution of 7-chloro-imidazo[1 ,2-a]pyridine-3-carboxylic acid {2-methyl-5-[(3- phenyl-ureido)-methyl]-phenyl}-amide (0.22 g, 0.5 mmol) in DMSO (2.5 ml_) were added potassium hydroxide (0.155 g, 2.76 mmol) and 2-methoxy-ethanol (0.08 ml_, 1.0 mmol) and the reaction mixture was heated at 95 °C for 16 hours. The reaction mixture was cooled, diluted with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried and the solvent was evaporated. The crude product was purified on silica, eluted with 0-10% MeOH in EtOAc (to afford the title compound (100 mg, 42%), (M+H) ⁺ =474.

Step X: General procedure for hydrochloride salt formation

To a solution of amine or basic heterocycle (1.0 mmol) in EtOAc (10 ml) was added 1 M HCI in dioxane (5 ml_) [THF can be added to aid solubility]. The resultant solution was stirred overnight to afford the final molecule as a mono-, di- or tri hydrochloride salt. If no precipitated is formed then the solvents are removed and triturated with a suitable solvent such as diethyl ether, petrol or EtOAc (or mixtures thereof)

Synthesis of Monomers and Intermediates

General Route 1 a: Synthesis of (3-Bromo-5-trifluoromethyl-benzyl)-dimethyl- amine

To a solution of 3-Bromo-5-(trifluoromethyl)benzaldehyde (1.50 g, 5.93 mmol, 1.0 eq) in DCM at rt was added dimethylamine (5.93 ml_, 1 1.9 mmol, 2.0 eq, 2.0 M solution in THF) and the mixture was stirred for 15 min. Sodium triacetoxyborohydride (3.77 g, 17.8 mmol, 3.0 eq) was added and the reaction was stirred over 60 hours. The reaction was quenched with saturated NaHC0 ₃ solution and the aqueous phase was extracted with EtOAc (x4). The combined organics were washed twice with water, brine, dried (Na ₂ S0 ₄ ), filtered and concentrated to give a pale yellow oil (ca. 1.5 g) which was used without further purification for next step (step 1 b).

General Route 1 b: Synthesis of 3-Dimethylaminomethyl-5-trifluoromethyl- benzoic acid (Intermediate 1 )

To a solution of (3-Bbromo-5-trifluoromethyl-benzyl)-dimethyl-amine (from Step 1 a, ca. 1.5 g, 5.32 mmol, 1.0 eq) in THF at -78 °C was added dropwise n-BuLi (2.34 mL, 5.85 mmol, 1.1 eq, 2.5 M solution in hexanes). The mixture was stirred for 20 min. Gaseous C0 ₂ was bubbled through the reaction while this was stirred for a further 1 hour. The reaction was quenched by addition of water (0.2 mL) and was then warmed to rt. The solvents were evaporated and the solid was dried overnight under vacuum to give the Li salt as a white solid. Aqueous HCI solution (1.0 eq, 1 N) was added and the solid dissolved. The resulting solution was then washed twice with EtOAc and then concentrated to give the acid as a pale yellow solid (1.21 g).

Intermediate 2: Synthesis of 3-(4-Methyl-piperazin-1 -ylmethyl)-5- trifluoromethyl-benzoic acid

General route 1 a (using 1-methylpiperazine), then 1 b to give Intermediate 2. Intermediate 3: Synthesis of 3-Dimethylaminomethyl-benzoic acid

General route 1 a (using 2-bromobenzaldehyde) then 1 b to give Intermediate 3.

Intermediate 4: Synthesis of (3-Trifluoromethyl-piperidin-1 -yl)-acetic acid (3- trifluoromethyl-piperidin-1 -yl)-acetic acid

To a solution of 3-(trifluoromethyl)piperidine (500 mg, 3.26 mmol, 1.0 eq) in DCM at rt was added DIPEA (1.25 mL, 7.18 mmol, 2.2 eq) followed by ethyl bromoacetate (600 mg, 3.59 mmol, 1.1 eq). The reaction was stirred for 30 min at rt and then quenched with sat. aqueous NaHC0 ₃ solution. The aqueous layer was extracted with DCM (x3) and the combined organics were dried (MgS0 ₄ ), filtered and concentrated. This crude ester was then dissolved in MeOH and 40% aqueous NaOH and stirred at rt for 4 hours. The solution was neutralised with dilute aqueous HCI (to pH 5) and concentrated to give a mixture of acid and NaCI. The product was extracted with hot ethanol, filtered, and the filtrated was concentrated to give an off-white oil (529 mg).

Intermediate 5: Synthesis of 3-(2-Dimethylamino-ethyl)-phenylamine.

2-(3-Amino-phenyl)-N,N-dimethyl-acetamide (1 g, 5.62 mmol) was added to a stirred suspension of lithium aluminium hydride (1.3 g, 33.7 mmol) in ether (30 mL) and THF (20 mL). The reaction was heated to 50 °C for 4 hours and then cooled. The reaction was cooled to 0 ° C with an external ice/water bath and quenched with the dropwise addition of water (10 mL) followed by 2 N (aq) sodium hydroxide (10 mL) and finally water (20 mL).

The reaction mixture was filtered and the liquor extracted with ether (50 mL). The collected separated organic layer was dried (Na ₂ S0 ₄ ), filtered and evaporated to give title compound as an orange oil (889 mg, 96%), MS: [M+H] ⁺ = 165.

Intermediate 6: Synthesis of 4-Morpholin-4-ylmethyl-phenylamine.

To morpholine (3.83 g, 44 mmol) in toluene (60ml_) was added 1-chloromethyl-4- nitro-benzene (6.86 g, 40 mmol) then potassium carbonate (6.07 g, 44 mmol) and the reaction was reacted at reflux overnight. The reaction was cooled, filtered and evaporated. The orange oil was diluted with ether and 1 M HCI in diethyl ether (-30 ml_) was added. The pale yellow solid was collected by filtration and washed with more ether (8.03 g, 78%).

4-(4-Nitro-benzyl)-morpholine hydrochloride (4.75 g, 21.4 mmol) was dissolved in ethanol (100 ml_). To this was added water (50 ml_), sodium dithionite (18.6 g, 107 mmol) and the mixture was heated at reflux for 3 hours. The reaction was cooled and evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic layer was dried (Na ₂ S0 ₄ ), filtered and evaporated. The solid was triturated with ether and then dried in a vac-oven to give the title compound as an off white solid (820 mg, 20%), 1 H NMR (400 MHz, DMSO-d6): 6.92 (2H, d), 6.50 (2H, d), 4.93 (2H, s), 3.56-3.51 (4H, m), 3.26 (2H, s), 2.29 (4H, s)

Intermediate 7: 3-Morpholin-4-ylmethyl-phenylamine.

1-Bromomethyl-3-nitro-benzene (2 g, 9.26 mmol) in acetonitrile (20 ml_) was stirred under a nitrogen atmosphere. Triethylamine (4 ml_, 27.8 mmol) and morpholine (2.5 ml_, 27.8 mmol) were added and the reaction stirred overnight. The mixture was diluted with ethyl acetate (30 ml_) and washed with (aq) NaHC0 ₃ (50 ml_ x2) and brine (30 ml_). The separated organic layer was dried (MgS0 ₄ ), filtered and evaporated to afford 4-(3-nitro-benzyl)-morpholine as an orange oil which crystallised on standing (1.85 g, 91 %) MS: [M+H] ⁺ = 223. 4-(3-Nitro-benzyl)-morpholine (1.85 g, 9.26m mol) was dissolved in ethanol (100 mL). To this was added Pt/C (10 wt%) (300 mg cat) and the sample stirred at room temperature at a pressure of 1 atm under an excess of hydrogen overnight. The reaction was filtered through cellite and the liquor evaporated to afford title compound (1.57 g, 98%) MS: [M+H] ⁺ = 193.

Intermediate 8: 2-Dimethylaminomethyl-5-trifluoromethyl-phenylamine.

1-Bromomethyl-2-nitro-4-trifluoromethyl-benzene (1 g, 3.5 mmol) in acetonitrile (10 mL) was stirred under a nitrogen atmosphere. Triethylamine (2 mL, 14.1 mmol) and dimethylamine hydrogen chloride (864 mg, 10.6 mmol) were added and the reaction stirred overnight. The mixture was diluted with ethyl acetate (50 mL) and washed with (aq) NaHC0 ₃ (50 mL x2) and brine (50 mL). The separated organic layers were dried (Na ₂ S0 ₄ ), filtered and evaporated to afford dimethyl-(2-nitro-4-trifluoromethyl-benzyl)- amine as an orange oil which crystallised on standing (962 mg), MS: [M+H] ⁺ = 249.

Dimethyl-(2-nitro-4-trifluoromethyl-benzyl)-amine (962 mg, 3.9 mmol) was dissolved in Ethanol (50 mL). To this was added Pt/C (10wt%) (150 mg cat) and the sample stirred at room temperature at a pressure of 1 atm under an excess of hydrogen overnight. The reaction was filtered through cellite and the liquor evaporated to afford the title compound as a yellow oil (731 mg), MS: [M+H] ⁺ = 219.

Intermediate 9: 2-Dimethylaminomethyl-5-fluoro-phenylamine.

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). The reaction was evaporated to dryness and the crude product was partitioned between water (30 mL) and ethyl acetate (50 mL). The organic layer was collected and washed with water (50 mL), sat (aq) sodium bicarbonate (50 mL x2) and brine (30 mL). The organic layer was dried (Na ₂ S0 ₄ ) filtered and evaporated to afford 2-amino-4-fluoro-N,N-dimethyl-benzamide as a yellow oil (1.1 1 g, 94%), MS: [M+H] ⁺ = 183.

2-Amino-4-fluoro-N,N-dimethyl-benzamide (1.1 1 g, 6.1 mmol) was added to a stirred suspension of lithium aluminium hydride (1.5 g, 36.6 mmol) in ether (50 mL) and THF (30 mL). The reaction was heated to 50 °C for 4 hours and then cooled. The reaction was cooled to 0 ° C with an external ice/water bath and quenched with the dropwise addition of water (20mL) followed by 2N (aq) sodium hydroxide (20 mL) and finally water (40 mL). The reaction mixture was filtered and the liquor extracted with ether (50 mL). The collected separated organic layer was dried (Na ₂ S0 ₄ ), filtered and evaporated to give title compound as a pale yellow oil (721 mg, 71 %), MS: [M+H] ⁺ = 169.

Intermediate 10: 2-Dimethylaminomethyl-5-chloro-phenylamine.

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). The reaction was evaporated to dryness and the crude partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was collected and washed with water (50 mL), sat (aq) sodium bicarbonate (50 mL x2) and brine (30 mL). The organic layer was dried (Na ₂ S0 ₄ ) filtered and evaporated to afford 2-amino-4-chloro-N,N-dimethyl-benzamide as a yellow oil (1.05 g, 91 %), MS: [M+H] ⁺ = 199.

2-Amino-4-chloro-N,N-dimethyl-benzamide (1.05 g, 5.4mmol) was added to a stirred suspension of lithium aluminium hydride (1.3 g, 32.1 mmol) in ether (50 mL) and THF (30 mL). The reaction was heated to 50 °C for 4 hours and then cooled. The reaction was cooled to 0 ° C with an external ice/water bath and quenched with the dropwise addition of water (20 mL) followed by 2N (aq) sodium hydroxide (20 mL) and finally water (40 mL).

The reaction mixture was filtered and the liquor extracted with ether (50 mL). The collected separated organic layer was dried (Na ₂ S0 ₄ ), filtered and evaporated to give title compound as a pale yellow oil (783 mg, 78%), MS: [M+H] ⁺ = 185.

Intermediate 11 : 5-Dimethylaminomethyl-2-fluoro-phenylamine.

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). The reaction was evaporated to dryness and the crude extracted between water (30 mL) and ethyl acetate (50 mL). The organic layer was collected and washed with water (50 mL), sat (aq) sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried (Na ₂ S0 ₄ ), filtered and evaporated to afford 3-amino-4-fluoro-N,N-dimethyl-benzamide as a yellow oil (2.28 g, 97%), MS: [M+H] ⁺ = 183.

3-Amino-4-fluoro-N,N-dimethyl-benzamide (2.28g, 12.5mmol) was added to a stirred suspension of lithium aluminium hydride (2.85 g, 75 mmol) in ether (50 mL) and THF (30 mL). The reaction was heated to 50 ° C for 4hours and then cooled. The reaction was cooled to 0 °C with an external ice/water bath and quenched with the dropwise addition of water (20 mL) followed by 2N (aq) sodium hydroxide (20 mL) and finally water (40 mL). The reaction mixture was filtered and the liquor extracted with ether (50 mL). The collected separated organic layer was dried (Na ₂ S0 ₄ ), filtered and evaporated to give title compound as a pale yellow oil (1.79 g, 85%), MS: [M+H] ⁺ = 169.

Monomer 4: Synthesis of 7-chloro-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester

Potassium 2-chioro-3-ethoxy-3-oxoprop-1-en-1-oiate (6.0 g, 31.6 mmo!) was suspended in acetonitrile (16 mL) and 12 M aqueous HCI (0.64 mL, 7.8 mmol) was added s!owiy. The mixture was stirred at ambient temperature for 15 mins. 4- Chioropyridin-2-amine (2.0 g, 15.5 mmol) was added to the mixture and the mixture was heated at 35°C for 20 hours. The mixture was cooled to ambient temperature and water (50 mL) was added. The pH of the mixture was adjusted to 8,0-8.5 with 2.0 N aqueous NaOH to precipitate the product. The solids were collected by filtration, washed with water, and dried to afford brown solid. (3.08 g, 89%) ( ÷H) ⁺ =225

Monomer 5: Synthesis of 6-methyfcarbamoyl-smidazo[1 ,2-a]pyridine-3- carboxyfsc acid ethyl ester

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 μΙ_, 1.07 mmol) in D F was added HATU (245 mg, 0.64 mmol) and the reaction mixture was stirred for 1 hour. Water was added and the product was extracted with EtOAc. The organic phase was dried and evaporated. The crude product was purified on silica, eluted with 0-10% MeOH in DC to afford the product (70 mg, 66%). ( +H) ⁺ =248

Monomer 6: Synthesis of 7-ethoxy-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester

The title compound was prepared using essentially the same procedure as in step N2 starting from 4-ethoxy-pyridine-2-yiamine, (M+H) ⁺ =235.

Monomer 7: Synthesis of 7-methylcarbamoyl-imidazo[1,2-a]pyridine-3- carboxylic acid ethyl ester

The title compound was prepared using similar procedure as for the preparation of monomer 5 starting from 2-amino-isonicotinic acid, ( +H) ⁺ =248.

Monomer 8: Synthesis of 7-(4-methyf-piperazin-1-yi)-imidazo[1,2-a]pyridine-3- carboxylic acid ethyl ester

A mixture of 4-chloro-pyridin-2-ylamine (1.65 g, 12.9 mmol) and 1-methyl-piperazine (4.2 ml, 37.9 mmol) in NMP (15 ml) was heated under microwave irradiation at 225 °C for 25 mins. The solvent was evaporated, the residue was dissolved in water (40 ml_) and 4M NaOH (15 ml_) was added. The precipitate was filtered, washed with diethyl ether and dried to afford 4-(4-methyl-piperazin-1-yl)-pyridin-2-ylamine as a white solid (2.09 g, 85%), (M+H) ⁺ =193. 4-(4-Methyl-piperazin-1-yl)-pyridin-2-ylamine was converted to the title compound using essentially similar procudure as in step N2, (M+H) ⁺ =289. Monomer 9: Synthesis of 7-morphoiine-4-yS-imidazo[1,2-a]pyrsdine-3-carboxySsc acid ethyl ester

The title compound was prepared using similar procedure as for the preparation of Monomer S using morpholine instead of 1-methyl-piperazine, (M+H) ⁺ =276.

Monomer 10: Synthesis of 7-cyc!opropyicarbamoyl-imsdazo[1,2-a]pyridine-3- carboxyiic acid ethyl ester

The title compound was prepared using similar procedure as for the preparation of Monomer 5 starting from 2-amino-isonicotinic acid and using cyclopropylamine instead of methylamine hydrochloride, (M÷H) ⁺ =274.

Monomer 11 : Synthesis of imidazo[1,2-a]pyrazine-3-carboxylic acid ethyl ester

The title compound was prepared using essentially the same procedure as in step N1 starting from pyrazin-2-ylamine, (M+H) ⁺ =192.

Monomer 12: Synthesis of 7-Cyano-imidazo[1,2-a]pyrazine-3-carboxylic acid ethyl ester

The title compound was prepared using essentially the same procedure as in step N2 starting from 2-amino-isonicotinitri!e, ( +H) ⁺ =216.

Monomer 13: Synthesis of 7-methylcarbamoyi-imidazo[1,2-a]pyridine-3- carboxyfic acid ethyl ester

Preparation of 2-chioro-4-(2-methoxy-ethoxY)-pyridine: A mixture of 2-chioro-4-nitro- pyridine (4.36 g, 27.5 mmoi) and 2-methoxyethanoi (32. 8 mi, 42.5 mmoi) was cooled to 0 °C. Potassium 2-methylpropan-2-o!ate (3.57 g, 30.2 mmoi) was added and the resulting mixture was stirred while warming to ambient temperature over 2 hours. The reaction mixture was concentrated under reduced pressure followed by dilution with 50 ml of water. The resulting mixture was extracted twice with 25 mi of dichloromethane. The combined organic layers were dried over gS0 ₄ and concentrated under reduced pressure to produce the desired compound as a golden oil (5.0 g, 97 %), (M+H) =188

Preparation of 4-(2-methoxy-ethoxy)-pyridin-2-yiamine: A steady stream of nitrogen was passed through a mixture of 2-chloro-4-(2-methoxy-ethoxy)-pyridine (5.0. g, 26.7 mmoi), Pd ₂ dba ₃ (0.5 g, 0.5 mmoi), XPHOS (0.5 g, 1.0 mmoi) and tetrahydrofuran (50 mL) for 10 minutes. To the resulting degassed mixture was added lithium

bis(trimethylsilyl)amide (56 mL, 56.0 mmoi). After addition, the resulting mixture was heated to 60 °C for 18 hours. The reaction was cooled to ambient temperature and diluted with 1 N hydrochloric acid (20 mL). The resulting solution was washed twice with 50 mL of diethyl ether. The pH of the aqueous layer was taken to 1 1 with 6 N NaOH and was extracted with dich!oromethane (3 x 50 ml). The combined organic layers were dried over gS0 ₄ and concentrated under reduced pressure to afford 0.3 g of product. The diethyl ether extract contained the bulk of the material, it was extracted with 2.5 N hydrochloric acid (3x20 mL), basified to pH 1 1 with 8 N NaOH and was extracted with dichloromethane (3 x 50 ml). The combined organic layers were dried over gS0 ₄ and concentrated under reduced pressure to afford the product as a tan solid (2.35 g, 52%), (M+H) =169.

The title compound was prepared using similar procedure as in step N1 of monomer 5 starting from 4-(2-methoxy-ethoxy)-pyridin-2-yiamine, ( +H) ⁺ =265.

Monomer 14: Synthesis of 7-dimethy!carbamoyMmidazo[1,2-a]pyridine-3- carboxylic acid ethyl ester

The title compound was prepared using similar procedure as for the preparation of monomer 5 starting from 2-amino-isonicotinic acid and using dimethyiamine hydrochloride instead of methylamine hydrochloride. (M+H) ⁺ =262

Monomer 15: Synthesis of 7-[2-(4-Methyi-piperazin-1 -yl)-ethoxy]-imidazo[1,2- a]pyridine-3-carboxylic acid ethyl ester

Sodium hydride (60%, 0.87 g, 21.80 mmol) was added to diglyme (10 mL). A solution of 2-(4-methyl-piperazin-1-yl)-ethanol (3.14 g, 21.80 mmol) in diglyme (10 mL) was added slowly. The reaction mixture was heated at 40 °C for I hour, 4-chloro-pyridin-2- ylamine (1.40 g, 10.9 mmol) was added and the reaction mixture was heated at 80 ° C for 1 hour, then at 157 ° C for 16 hours. The reaction mixture was cooled, diluted with water (20 mL), and then THF (20 mL) and NaCI were added. The organic phase was separated and the aqueous phase was extracted with THF. The combined organic phase was dried, and then the solvent was evaporated. Diethyl ether was added to the residue. The resulting solid was filtered, washed with ether, and dried to afford white solid (1.86 g, 72%), (M+H) ⁺ =237.

4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-pyridin-2-ylamine was converted to the title compound using essentially similar procudure as in step N2, (M+H) ⁺ =333.

Monomer 18: Synthesis of 5,6,7,8-Tetrahydro-imidazo[1,2-a]pyridine-3- carboxylic acid

To imidazo[1 ,2-a]pyridine-3-carboxylic acid (0.5 g, 3.08 mmol) suspended in EtOH (30 ml ) was added c. HCI (2. 7ml ) and Pt0 ₂ ( 120mg) and the mixture was hydrogenated for 2 hours. A solid precipitated out of the reaction mixture and water (3 ml) was added and the hydrogenation continued for a further 2 hours. The catalyst was removed by filtration and the solvent was evaporated to dryness to give 5,6,7,8- tetrahydro-imidazo[1 ,2-a]pyridine-3-carboxylic acid (0.5 g) (the product used without further purification). 1 H NMR (400 MHz, DMSO-d6): 8.24 (1 H, s), 4.32 (2H, t), 3.01 (2H, t), 1.99 (2H, d), 1.94-1.79 (2H, m).

Monomer 17: Synthesis of 5,6,7,8-Tetrahydro-imidazo[1,2-a]pyrimidine-3- carboxylic acid

To imidazo[1 ,2-a]pyrimidine-3-carboxylic acid (0.5 g, 3 mmol) suspended in EtOH (30ml) was added c. HCI (2.7 m) and PtO ₂ (120mg) and the mixture was

hydrogenated for 2 hours. A solid precipitated and water (5ml) was added and hydrogenation continued for a further 2 hours. The catalyst was removed by filtration and the solvent was evaporated to dryness to give 5,6,7,8-tetrahydro-imidazo[1 ,2- a]pyrimidine-3-carboxylic acid (0.4 g) (the product used without further purification). 1 H NMR (400 MHz, DMSO-d6): 8.58 (1 H, s), 7.72 (1 H, s), 4.18 (2H, t), 3.34 (2H, s), 2.06-1.94 (2H, m).

Monomer 18: Synthesis of 4-[2-(4-Methyl-piperazin-1 -yl)-ethoxy]-pyridin-2- ylamine

Sodium hydride (60%, 0.87 g, 21.80 mmol) was added to diglyme (10 mL). A solution of 2-(4-methyl-piperazin-1-yl)-ethanol (3.14 g, 21.80 mmol) in diglyme (10 mL) was added slowly. The reaction mixture was heated at 40 °C for 1 hour, 4-chloro-pyridin- 2-ylamine (1.40 g, 10.9 mmol) was added and the reaction mixture was heated at 80 °C for 1 hour, then at 157 ° C for 16 hours. The reaction mixture was cooled, diluted with water (20 mL), and THF (20 mL) was added, then NaCI. The organic phase was separated, and the aqueous phase was extracted with THF. The combined organic phase was dried, and the solvent was evaporated. Diethyl ether was added to the residue. The resulting solid was filtered, washed with ether, and dried to afford a white solid (1.86 g, 72%), (M+H) ⁺ =237.

Monomer 19: Synthesis of (3-Amino-4-methyl-benzyl)-carbamic acid ferf-butyl ester

5-Aminomethyl-2-methyl-phenylamine (11.7 g, 86.10 mmol) was dissolved in dichloromethane (430 mL), filtered and di-te/f-butyl carbonate (16.9 g, 77.5 mmol) in DCM (5 mL) was added over 20 min. The reaction was monitored with a temperature probe and the temperature rose from 20 to 25 °C. Stirred for 2 hours and the reaction was concentrated in vacuo. The crude oil slowly crystallised over time in diethyl ether. 40-60 Petroleum ether was added and the resulting precipitate filtered washing with 40-60 petroleum ether. The solid was dried in a vacuum oven. The solid was triturated with diethyl ether and filtered washing with 40-60 petroleum ether. The solid was dried in a vacuum oven at 40 °C to give the titled compound (7.28 g) as a beige solid. The filtrate which slowly gave a precipitate which was collected by vacuum filtration washing with 40-60 petroleum ether. The solid was dried in a vacuum oven at 40 °C to give the titled compound (5.38 g). 1 H NMR (400 MHz, DMSO-d6): 7.18 (1 H, d), 6.83 (1 H, d), 6.47 (1 H, s), 6.34 (1 H, d), 4.82-4.68 (2H, m), 3.95 (2H, d), 2.01 (3H, s), 1.39 (9H, s).

Examples 1 -120

By following methods similar and/or analogous to those described above, the compounds set out in Table 8 were prepared from the corresponding N-Boc protected derivatives, with any significant variations indicated below except where otherwise stated. The title compounds were either isolated directly as the free base or appropriate salt without further purification, or purified for example using mass- directed preparative HPLC, crystallization or trituration. ¹ H NMR Data is recorded at 400 MHz in DMSO-d6 as solvent unless indicated. MS Data is m/z.

Ex. Structure Name Route Used Salt ¹ H NMR Data MS

N-{2-methyl-5- 9.90 (1 H, s), 9.44 (1 H, d), 9.06 (1 H, t), 8.53 (1 H,

General route R, B,

[(phenylformamido)methyl]p s), 7.94-7.86 (2H, m), 7.76 (1 H, d), 7.55-7.44 (4H,

4 C1 S then F using 385 henyl}imidazo[1 ,2- m), 7.34-7.23 (2H, m), 7.16 (2H, d), 4.48 (2H, d), benzoic acid

a]pyridine-3-carboxamide 2.23 (3H, s).

^I - N-{2-methyl-5-[(2-

General route R, B, 9.86 (1 H, s), 9.46 (1 H, d), 8.60-8.52 (2H, m), 7.78 phenylacetamido)methyl]ph

5 C1 S then F using - (1 H, d), 7.55-7.48 (1 H, m), 7.32-7.12 (8H, m), 7.06 399 enyl}imidazo[1 ,2-a]pyridine-

1 ^H 11 /r phenylacetic acid (1 H, d), 4.27 (2H, d), 3.48 (2H, s), 2.23 (3H, s).

3-carboxamide

Ex. Structure Name Route Used Salt ¹ H NMR Data MS

N-(5-

9.90 (1H, s), 9.46 (1H, d), 8.56 (1H, s), 7.77 (1H,

{[(benzylcarbamoyl)amino]m General route R, B,

d), 7.54-7.47 (1H, m), 7.28-7.22 (6H, m), 7.19-7.12

14 ethyl}-2-methyl C1, S then E1 using - 414

(2H, m), 7.11-7.04 (1H, m), 6.44 (2H, d), 4.24 (4H, phenyl)imidazo[1 ,2-a] benzyl-isocyanate

d), 2.24 (3H, s).

H /r pyridine-3-carboxamide

N-[2-methyl-5-({[3-

General route R, B, 9.90 (1H, s), 9.44 (1H, d), 9.33 (1H, t), 8.54 (1H, (trifluoromethyl)phenyl]form

C1 S then F using 3- s), 8.29-8.17 (2H, m), 7.92 (1H, d), 7.81-7.69 (2H,

15 amido}methyl)phenyl]imidaz - 453

(trifluoromethyl) m), 7.55-7.45 (1H, m), 7.34 (1H, s), 7.26 (1H, d), o[1,2-a] pyridine-3- benzoic acid 7.22-7.10 (2H, m), 4.51 (2H, d), 2.24 (3H, s).

carboxamide

N-{2-methyl-5-[({[3-

General route R, B, 9.93 (1H, s), 9.46 (1H, d), 8.97 (1H, s), 8.57 (1H, (trifluoromethyl)phenyl]carba

C1 S then E1 using 3- s), 7.99 (1H, s), 7.78 (1H, d), 7.53 (2H, t), 7.45

16 moyl}amino)methyl]phenyl}i - 468

(trifluoromethyl)phenyl (1H, t), 7.34-7.11 (5H, m), 6.85-6.72 (1H, m), 4.31 midazo[1 ,2-a]pyridine-3- isocyanate (2H, d), 2.24 (3H, s).

carbox amide

Ex. Structure Name Route Used Salt ¹ H NMR Data MS

General route Q then

7-cyano-N-(2-methyl-5- H3 using 7-cyano-

10.16 (1 H, s), 9.53 (1 H, d), 8.73 (1 H, s), 8.55 (2H, {[(phenylcarbamoyl)amino]m imidazo[1 ,2-a]

62 - s), 7.50-7.35 (3H, m), 7.33-7.1 1 (5H, m), 6.89 (1 H, 425 ethyl}phenyl)imidazo[1 ,2- pyridine-3-carboxylic

t), 6.62 (1 H, t), 4.31 (2H, d), 2.24 (3H, s).

a]pyridine-3-carboxamide acid ethyl ester

(Monomer 12)

N-(2-methyl-5-{[({3-[(4- General route R, B,

9.92 (1 H, s), 9.45 (1 H, d), 8.64-8.52 (2H, m), 7.76 methylpiperazin-1- C1 , S then E2 using

(1 H, d), 7.55-7.45 (1 H, m), 7.39-7.24 (4H, m), yl)methyl]phenyl}carbamoyl) 3-(4-methyl-

63 - 7.17-7.12 (3H, m), 6.86-6.76 (1 H, m), 6.62 (1 H, t), 512 amino]methyl}phenyl)imidaz piperazine-1-yl- 4.30 (2H, d), 3.37 (2H, s), 3.33 (2H, s), 2.32 (6H, o [1 ,2-a]pyridine-3- methyl)phenylamine.2

s), 2.24 (3H, s), 2.14 (3H, s).

carboxamide HCI

N-(5-{[({3-[2- 9.95-9.87 (1 H, m), 9.45 (1 H, d), 8.59-8.52 (1 H, m), (dimethylamino)ethyl]phenyl General route R, B, 8.49 (1 H, s), 7.76 (1 H, d), 7.55-7.45 (1 H, m), 7.36-

64 }carbamoyl)amino]methyl}- C1 , S then E2 using - 7.05 (7H, m), 6.75 (1 H, d), 6.66-6.55 (1 H, m), 4.30 471

2-methylphenyl)imidazo[1 ,2- Intermediate 5 (2H, d), 2.72-2.58 (2H, m), 2.42 (2H, t), 2.24 (3H, a]pyridine-3-carboxamide s), 2.16 (6H, s).

Ex. Structure Name Route Used Salt ¹ H NMR Data MS

N-{2-methyl-5-[(1S)-1-({3- Intermediate 2. B, C1,

[(4-methyl piperazin-1- S then F (with (Me-d3-OD): 9.50 (1H, d), 8.45 (1H, s), 8.08 (2H, yl)methyl]-5- EDC/HOAt replacing s), 7.83 (1H, s), 7.73 (1H, d), 7.60-7.54 (1H, m),

68 (trifluoromethyl)phenyl}form HATU; DIPEA - 7.49 (1H, s), 7.34-7.27 (2H, m), 7.19-7.11 (1H, m), 579 amido)ethyl]phenyl}imidazo[ replacing Et ₃ N; 5.30 (1H, q), 3.66 (2H, s), 2.52 (8H, s), 2.33 (3H, 1,2-a]pyridine-3- reaction carried out at s), 2.26 (3H, s), 1.63 (3H, d).

carboxamide 60 °C over 16 h).

General route Q then

9.81 (1H, s), 9.28 (1H, d), 8.53 (1H, s), 8.46 (1H,

7-cyclopropyl-N-(2-methyl-5- H4 using 7- s), 7.47 (1H, s), 7.40 (2H, d), 7.33-7.16 (4H, m), {[(phenylcarbamoyl)amino]m cyclopropyl-

69 - 7.12 (1H, d), 6.94-6.82 (2H, m), 6.60 (1H, t), 4.30 440 ethyl}phenyl)imidazo[1 ,2-a] imidazo[1,2- (2H, d), 2.23 (3H, s), 2.13-2.02 (1H, m), 1.12-1.01 pyridine-3-carbox amide a]pyridine-3- (2H, m), 0.91-0.80 (2H, m).

carboxylic acid

N-{5-[(1S)-1-(2H-1,3- (Me-d3-OD): 9.51 (1H, d), 8.44 (1H, s), 7.73 (1H, benzodioxol-5- General route B, C1, d), 7.62-7.51 (1H, m), 7.49-7.40 (2H, m), 7.34 (1H,

70 ylformamido)ethyl]-2- S then F using - d), 7.33-7.23 (2H, m), 7.16 (1H, t), 6.87 (1H, d), 443 methylphenyl}imidazo [1,2- piperonylic acid. 6.03 (2H, s), 5.24 (1H, q), 2.32 (3H, s), 1.59 (3H, a] pyridine-3-carboxamide d).

Ex. Structure Name Route Used Salt ¹ H NMR Data MS

N-[5-({[(3- General route Q then

10.19 (1H, s), 9.35-9.23 (2H, m), 8.85 (1H, s), 8.69 fluorophenyl)carbamoyl]ami H3 using imidazo

(1H, s), 8.14 (1H, d), 7.52-7.41 (1H, m), 7.34-7.19

71 no}methyl)-2- [1,2-a]pyrazine-3- - 419

(3H, m), 7.16 (1H, d), 7.05 (1H, d), 6.81-6.64 (2H, methylphenyl]imidazo [1,2- carboxylic acid ethyl

m), 4.31 (2H, d), 2.25 (3H, s).

a] pyrazine-3-carboxamide ester (Monomer 11)

/

N-{5-[(1S)-1-[(5-methoxy- 9.92 (1H, s), 9.45 (1H, d), 8.53 (1H, s), 8.44 (1H, ft 1 ,3-benzoxazol-2-yl)amino] General route D, G d), 7.76 (1H, d), 7.55-7.45 (1H, m), 7.38 (1H, s),

72 ethyl]-2- using 2-chloro-5- - 7.30-7.10 (4H, m), 6.81 (1H, d), 6.51 (1H, dd), 442 methylphenyl}imidazo [1,2- methoxy-benzoxazole 4.97-4.86 (1H, m), 3.71 (3H, s), 2.22 (3H, s), 1.50 a] pyridine-3-carbox amide (3H, d).

N-{5-[(1S)-1-[(5-fluoro-1,3- 9.92 (1H, s), 9.44 (1H, d), 8.67 (1H, d), 8.54 (1H, benzoxazol-2-yl)amino] General route D, G s), 7.77 (1H, d), 7.56-7.45 (1H, m), 7.39 (1H, s),

73 ethyl]-2- using 2-chloro-5- - 7.32 (1H, dd), 7.30-7.21 (2H, m), 7.21-7.11 (1H, 430 methylphenyl}imidazo [1,2- fluoro-benzoxazole m), 7.05 (1H, dd), 6.82-6.70 (1H, m), 4.99-4.89 a] pyridine-3-carboxamide (1H, m), 2.22 (3H, s), 1.51 (3H, d).

Ex. Structure Name Route Used Salt ¹ H NMR Data MS

N-{5-[(1 S)-1 -{[3-(1 -cyano-1 - (Me-d3-OD): 9.51 (1H, d), 8.45 (1H, s), 8.00 (1H,

General route A, D

methylethyl)phenyl]formami t), 7.83 (1H, d), 7.78-7.68 (2H, m), 7.63-7.56 (1H, then F using 3-(2-

102 do}ethyl]-2- - m), 7.56-7.45 (2H, m), 7.36-7.27 (2H, m), 7.17 466 cyanopropan-2-yl)

methylphenyl}imidazo [1,2- (1H, t), 5.30 (1H, q), 2.34 (3H, s), 1.77 (6H, s),

benzoic acid.

a] pyridine-3-carboxamide 1.63 (3H, d).

N-{5-[(1S)-1-{[3-(2-

General route A, D (Me-d3-OD): 9.60 (1H, d), 8.73 (1H, d), 8.55 (1H, hydroxypropan-2- For

then F using 3-(1- s), 7.98 (1H, t), 7.84 (1H, d), 7.80-7.64 (3H, m), yl)phenyl]formamido}ethyl]- mat

103 hydroxy-1- 7.48 (1H, s), 7.42 (1H, t), 7.38-7.27 (3H, m), 5.35- 457

2-methylphenyl}imidazo e

methylethyl)benzoic 5.25 (1H, m), 2.34 (3H, s), 1.62 (3H, d), 1.56 (6H, [1,2-a] pyridine-3- (3:1)

acid. s).

carboxamide

N-{5-[(1S)-1-{[3- (Me-d3-OD): 9.50 (1H, d), 8.65 (1H, d), 8.44 (1H,

General route A, D

(dimethylamino)phenyl]form s), 7.73 (1H, d), 7.62-7.51 (1H, m), 7.47 (1H, s),

then F using 3-

104 HNy» amido}ethyl]-2- - 7.31-7.28 (2H, m), 7.26 (1H, d), 7.22 (1H, t), 7.19- 442 dimethylaminobenzoic

methylphenyl}imidazo[1 ,2-a] 7.10 (2H, m), 6.91 (1H, dd), 5.34-5.23 (1H, m),

acid.

H H / pyridine-3-carboxamide 2.97 (6H, s), 2.33 (3H, s), 1.60 (3H, d).

Example 13

Synthesis of 7-(1 -methyl-1 H-pyrazol-4-yl)-N-(2-methyl-5-

{[(phenylcarbamoyl)amino]methyl}phenyl)imidazo[1,2-a]pyri dine-3- carboxamide

A degassed mixture of 7-chloro-imidazo[1 ,2-a]pyridine-3-carboxylic acid {2-methyl-5- [(3-phenyl-ureido)-methyl]-phenyl}-amide (430 mg, 1.0 mmol), 1-methyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (416 mg, 2.0 mmol), Pd ₂ dba ₃ (23 mg, 0.025 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos) (20 mg, 0.05 mmol) and 1 M K ₃ P0 ₄ (3 mL, 3.0 mmol) in 1 ,4-dioxane (6 mL) was heated under nitrogen at 70 °C for 16 hours. The reaction mixture was cooled, diluted with water and the product extracted with EtOAc. The product precipitated during extraction, and was separated by filtration, washed with water and EtOAc, to afford an off-white solid (248 mg, 52%), (M+H) ⁺ =480.

Example 19

Synthesis of lmidazo[1 ,2-a]pyridine-3-carboxylic acid {2-methyl-5-[1 -(3-phenyl- ureido)-propyl]-phenyl}-amide

Step 1 : 1 -(4-Methyl-3-nitro-phenyl)-propan-1 -one To mechanically stirred cone. H ₂ S0 ₄ (20 ml_) at -15 °C was slowly added 1-p-tolyl- propan-1-one (5.0 g, 33.8 mmol). After stirring the mixture for 5 min, cone. HN0 ₃ (3 ml_) was slowly added maintaining the temperature below -10 °C. The resulting solution was stirred for 10 mi at the same temperature and then it was poured into ice. The product was extracted with EtOAc (3x). The organic phases were dried over MgS0 ₄ , filtered and concentrated in vacuo to give 6.9 g of the desired product as a pale yellow oil that solidifies by standing at room temperature. 1 H NMR (400 MHz, CDCIs): 8.54 (1 H, d), 8.10 (1 H, dd), 7.48 (1 H, d), 3.04 (2H, q), 2.68 (3H, s), 1.27 (3H, t).

Step 2: 1 -(3-Amino-4-methyl-phenyl)-propan-1 -one

The title compound was prepared form 1-(4-methyl-3-nitro-phenyl)-propan-1-one (4.5 g, 23.2 mmol) and SnCI ₂ (13.2 g, 69.9 mmol) following similar methods to those described in general procedure K to give 1-(3-amino-4-methyl-phenyl)-propan-1-one (2.9 g) as an oil. LCMS: [M+H]+ = 164.

Step 3: 1 -(3-Amino-4-methyl-phenyl)-propan-1 -one oxime

The title compound was prepared form 1-(3-amino-4-methyl-phenyl)-propan-1-one (3.5 g, 25.7 mmol), hydroxylamine hydrochloride (2.7 g, 38.6 mmol) and triethylamine (5.5 ml_, 38.6 mmol) following a similar procedure to those described in general procedure L. 1-(3-Amino-4-methyl-phenyl)-propan-1-one oxime was obtained as an orange solid (3.2 g). LCMS: [M+H]+ = 179.

Step 4: 5-(1 -Amino-propyl)-2-methyl-phenylamine hydrochloride salt

Reduction of 1-(3-Amino-4-methyl-phenyl)-propan-1-one oxime (3.0 g, 16.8 mmol) with Pd/C (1.8 g, 10 mol%) following general procedure M afforded the desired product 5-(1-amino-propyl)-2-methyl-phenylamine hydrochloride salt (3.1 g) as a yellow solid. LCMS: [M+H]+ = 165.

Step 5: 1 -[1 -(3-Amino-4-methyl-phenyl)-propyl]-3-phenyl-urea

The title compound was prepared from 5-(1-amino-propyl)-2-methyl-phenylamine hydrochloride salt (1.0 g, 6.1 mmol), phenyl isocyanate (382 μί, 3.2 mmol) and triethylamine (1.7 mL, 12 mmol) following similar methods to those described in general procedure E to give 1.2 g of 1-[1-(3-amino-4-methyl-phenyl)-propyl]-3- phenyl-urea as a yellow solid. LCMS: [M+H]+ = 284. Step 6: lmidazo[1 ,2-a]pyridine-3-carboxylic acid {2-methyl-5-[1 -(3-phenyl- ureido)-propyl]-phenyl}-amide

The final compound was prepared following general procedure H starting form 1-[1- (3-amino-4-methyl-phenyl)-propyl]-3-phenyl-urea (283 mg, 1.0 mmol), imidazo[1 ,2- a]pyridine-3-carbonyl chloride (216 mg, 1.0 mmol) and triethylamine (288 μΙ_, 2.0 mmol). The final compound was purified by flash chromatography on silica gel (10% MeOH in dichloromethane) to afford imidazo[1 ,2-a]pyridine-3-carboxylic acid {2- methyl-5-[1-(3-phenyl-ureido)-propyl]-phenyl}-amide (100 mg) as a white solid.

LCMS: [M+H]+ = 428.

Example 23 & 24

Enanthiomers of imidazo[1 ,2-a]pyridine-3-carboxylic acid {2-methyl-5-[1-(3-phenyl- ureido)-propyl]-phenyl}-amide were separated by chiral HPLC using a Chirapak AD-H (250x21.2 mm) column, isocratic elution heptane/EtOH 25/75.

Example 41

Synthesis of 7-(2,3-dihydroxypropoxy)-N-(2-methyl-5- {[(phenylcarbamoyl)amino]methyl} phenyl)imidazo[1 ,2-a] pyridine-3-carbox- amide

A solution of 7-(2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-imidazo[1 ,2-a]pyridine-3- carboxylic acid {2-methyl-5-[(3-phenyl-ureido)-methyl]-phenyl}-amide (prepared by General route W using (2,2-Dimethyl-[1 ,3]dioxolan-4-yl)-methanol (17 mg, 0.03 mmol) in TFA (1 mL), water (1 mL) and 1 ,4-dioxane (0.25 mL) was stirred for 1 hour at room temperature. The solvent was evaporated and the residue was purified by preparative HPLC (4.5 mg, 31 %), (M+H) ⁺ =490.

Example 88

Synthesis of N-{5-[(1S)-1 -{[(3-fluorophenyl)carbamoyl]amino}ethyl]-2- methylphenyl}-7-(2-hydroxyethoxy)imidazo[1,2-a]pyridine-3-ca rboxamide

To a solution of N-{5-[(1 S)-1-{[(3-fluorophenyl)carbamoyl]amino}ethyl]-2- methylphenyl}-7-(2-methoxyethoxy)imidazo[1 ,2-a]pyridine-3-carboxamide (127 mg, 0.2 mmol) in DCM (15 mL) was added a solution of BBr ₃ (1 M in hexanes, 0.5 mL, 0.5 mmol) and the reaction mixture was stirred for 2 hours. The mixture was diluted with DCM, washed with saturated NaHC0 ₃ . The precipitate which formed was filtered and dried. The organic phase was dried and evaporated and combined with the precipitate and purified on silica, eluted with 0-5 % MeOH in DCM. The fractions were evaporated and the residue was triturated with Et ₂ 0 to afford off-white solid (57 mg, 58%), (M+H) ⁺ = 492.

Example 107

Step 1 : Synthesis of imidazo[1 ,2-a]pyridine-3-carboxylic acid [5-((R)-1 -amino-2- methoxy-ethyl)-2-methyl-phenyl]-amide

5-((R)-1-Amino-2-methoxy-ethyl)-2-methyl-phenylamine hydrochloride (400 mg, 1.59 mmol) was dissolved in acetate buffer (pH5, 1.0M, 10.65 mL) and THF (6.1 mL) was added followed by imidazo[1 ,2-a]pyridine-3-carbonyl chloride (430 mg, 2.38 mmol). The reaction was stirred for 20 min at room temperature. Saturated sodium carbonate was added and the reaction was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo, to give the titled compound (370 mg) M+H = 325

Step 2: Synthesis of imidazo[1 ,2-a]pyridine-3-carboxylic acid (5-{(R)-2- methoxy-1 -[3-(3-trifluoromethyl-phenyl)-ureido]-ethyl}-2-methyl-pheny l)-amide

lmidazo[1 ,2-a]pyridine-3-carboxylic acid [5-((R)-1-amino-2-methoxy-ethyl)-2-methyl- phenyl]-amide (185 mg, 0.57 mmol) was dissolved in toluene (2.2 ml_) and 3- (fluorophenyl)isocyanate added (1 18 mg, 0.63 mmol). The reaction was stirred at RT for 48 hours. The reaction was concentrated in vacuo and the residue was purified by prep HPLC to give the titled compound (127 mg).

In vitro Binding Assay for DDR1 & DDR2

DDR1 and DDR2 assays were performed using Invitrogen's LanthaScreen™

Europium Kinase binding assay. Compounds were incubated with 0.5 nM DDR1 (Invitrogen) or 0.25nM DDR2 (Invitrogen) for 1 hour at room temperature in low volume black 384 well assay plates (Corning) containing 5 nM or 10 nM Kinase Tracer 178 respectively and 2 nM Europium labelled anti-GST antibody (Invitrogen) in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCI ₂ , 1 mM EGTA and 0.01 % BRIJ35). The ratio of fluorescence emission 665 nm/ 615 nm after excitation at 340 nm was obtained using the BMG Pherastar FS plate reader. IC ₅₀ values were determined from dose-response plots using nonlinear least-squares analysis.

The compounds of Examples 1-120 have IC ₅₀ values of less than 10 μΜ or provide at least 50% inhibition of the activity at a concentration of 10 μΜ in the assay whereas the compounds of Examples 1-19, 21-23, 25-73 and 75-120 have IC ₅₀ values of less than 1 μΜ or provide at least 50% inhibition of the activity at a concentration of 1 μΜ. The compounds of Examples 1-8, 9-19, 21-23, 25, 27-37, 38-64, 67-73, 75-79, and 81-120 have IC ₅₀ values of 0.1 μΜ or less than against DDR1 and/or DDR2 or provide at least 50% inhibition of the activity at a concentration of 0.1 μΜ. Data for the compounds of the invention in the above assays are provided in the table below. 104 0.033 113 0.023

105 0.037 114 0.064

106 0.0065 0.02 115 0.037

107 0.013 116 0.0041 0.012

108 0.014 117 0.045

109 0.0067 0.029 118 35%@0.0015 0.0087

110 0.07 119 33%@0.0015 0.009

11 1 0.0073 0.017 120 0.014

112 0.041

Where more than one data point has been obtained, the table above shows an average (e.g. geometric mean) of these data points (to two significant figures).

Pharmaceutical Formulations

(i) Tablet Formulation

A tablet composition containing a compound of the formula (1) is prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as a lubricant and compressing to form a tablet in known manner.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of a compound of the formula (1) with 100 mg lactose and optionally 1 % by weight of magnesium stearate and filling the resulting mixture into standard opaque hard gelatin capsules.

(iii) Injectable Formulation I

A parenteral composition for administration by injection can be prepared by dissolving a compound of the formula (1) (e.g. in a salt form) in water containing 10% propylene glycol to give a concentration of active compound of 1.5 % by weight. The solution is then sterilised by filtration, filled into an ampoule and sealed.

(iv) Injectable Formulation II

A parenteral composition for injection is prepared by dissolving in water a compound of the formula (1) (e.g. in salt form) (2 mg/ml) and mannitol (50 mg/ml), sterile filtering the solution and filling into sealable 1 ml vials or ampoules.

(v) Injectable formulation III A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (1) (e.g. in a salt form) in water at 20 mg/ml. The vial is then sealed and sterilised by autoclaving.

(vi) Injectable formulation IV

A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (1) (e.g. in a salt form) in water containing a buffer (e.g. 0.2 M acetate pH 4.6) at 20mg/ml. The vial is then sealed and sterilised by autoclaving.

(vii) Subcutaneous Injection Formulation

A composition for sub-cutaneous administration is prepared by mixing a compound of the formula (1) with pharmaceutical grade corn oil to give a concentration of 5 mg/ml. The composition is sterilised and filled into a suitable container.

(viii) Lvophilised formulation

Aliquots of formulated compound of formula (I) or a salt thereof as defined herein are put into 50 ml_ vials and lyophilized. During lyophilisation, the compositions are frozen using a one-step freezing protocol at (-45 °C). The temperature is raised to - 10 °C for annealing, then lowered to freezing at -45 °C, followed by primary drying at +25 °C for approximately 3400 minutes, followed by a secondary drying with increased steps if temperature to 50 °C. The pressure during primary and secondary drying is set at 80 millitor.

(ix) Lvophilised Formulation for use in i.v. administration

An aqueous buffered solution is prepared by dissolving compound of formula (I) or a salt thereof as defined herein at a concentration of 10-20mg/ml in a buffer.

The buffered solution is filled, with filtration to remove particulate matter, into a container (such as class 1 glass vials) which is then partially sealed (e.g. by means of a Florotec stopper). If the compound and formulation are sufficiently stable, the formulation is sterilised by autoclaving at 121°C for a suitable period of time. If the formulation is not stable to autoclaving, it can be sterilised using a suitable filter and filled under sterile conditions into sterile vials. The solution is freeze dried using a suitable cycle: for example

Freezing - freeze to -40°C over 2 hours and hold at -40°C for 3 hours. Primary drying - ramp -40°C to -30°C over 8 hours and hold at -30°C for 7 hours.

Secondary drying - ramp to +30°C over 4 hours and hold at +30°C for 8-10 hours

On completion of the freeze drying cycle the vials are back filled with nitrogen to atmospheric pressure, stoppered and secured (e.g. with an aluminium crimp). For intravenous administration, the freeze dried solid can be reconstituted into a pharmaceutically acceptable excipient, such as 0.9% saline or 5% dextrose. 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.

Equivalents

The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.