| Title of Invention | "A MORPHOLINOMETHYL-BENZIMIDAZOL-2-YLPYRAZOLE COMPOUND OF THE FORMULA(VII)" |
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| Abstract | A MORPHOLINOMETHYL-BENZIMIDAZOL-2-YLPYRAZOLE COMPOUND OF THE FORMULA(VII): (FORMULA REMOVED) OR A SALT,N-OXIDE OR SOLVATE THEREOF |
| Full Text | The present invention relates to a morpholinomethyl-benzimidazol-2-ylpyrazole compound of the formula (VII). This invention relates to pyrazole compounds that inhibit or modulate the activity of Cyclin Dependent Kinases (CDK), Glycogen Synthase Kinases (GSK) and Aurora kinases to the use of the compounds in the treatment or prophylaxis of disease states or conditions mediated by the kinases, and to novel compounds having kinase inhibitory or modulating activity. Also provided are pharmaceutical compositions containing the compounds and novel chemical intermediates. 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., FASEBJ., 9:576-596 (1995); Knighton, et al., Science, 253:407-414 (1991); Hiles, etal, Cell, 70:419-429 (1992); Kunz, etal, Cell, 73:585-596 (1993); Garcia-Bustos, etal, 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. Cyclin Dependent Kinases The process of eukaryotic cell division may be broadly divided into a series of sequential phases termed Gl, S, G2 and M. Correct progression through the various phases of the cell cycle has been shown to be critically dependent upon the spatial and temporal regulation of a family of proteins known as cyclin dependent kinases (cdks) and a diverse set of their cognate protein partners termed cyclins. Cdks are cdc2 (also known as cdkl) homologous serine-threonine kinase proteins that are able to utilise ATP as a substrate in the phosphorylation of diverse polypeptides in a sequence dependent context. Cyclins are a family of proteins characterised by a homology region, containing approximately 100 amino acids, termed the "cyclin box" which is used in binding to, and defining selectivity for, specific cdk partner proteins. Modulation of the expression levels, degradation rates, and activation levels of various cdks and cyclins throughout the cell cycle leads to the cyclical formation of a series of cdk/cyclin complexes, in which the cdks are enzymatically active. The formation of these complexes controls passage through discrete cell cycle checkpoints and thereby enables the process of cell division to continue. Failure to satisfy the pre-requisite biochemical criteria at a given cell cycle checkpoint, i.e. failure to form a required cdk/cyclin complex, can lead to cell cycle arrest and/or cellular apoptosis. Aberrant cellular proliferation, as manifested in cancer, can often be attributed to loss of correct cell cycle control. Inhibition of cdk enzymatic activity therefore provides a means by which abnormally dividing cells can have their division arrested and/or be killed. The diversity of cdks, and cdk complexes, and their critical roles in mediating the cell cycle, provides a broad spectrum of potential therapeutic targets selected on the basis of a defined biochemical rationale. Progression from the Gl phase to the S phase of the cell cycle is primarily regulated by cdk2, cdk3, cdk4 and cdk6 via association with members of the D and E type cyclins. The D-type cyclins appear instrumental in enabling passage beyond the Gl restriction point, where as the cdk2/cyclin E complex is key to the transition from the Gl to S phase. Subsequent progression through S phase and entry into G2 is thought to require the cdk2/cyclin A complex. Both mitosis, and the G2 to M phase transition which triggers it, are regulated by complexes of cdkl and the A and B type cyclins. During Gl phase Retinoblastoma protein (Rb), and related pocket proteins such as pl30, are substrates for cdk(2,4, & 6)/cyclin complexes. Progression through Gl is in part facilitated by hyperphosphorylation, and thus inactivation, of Rb and p130 by the cdk(4/6)/cyclin-D complexes. Hyperphosphorylation of Rb and p130 causes the release of transcription factors, such as E2F, and thus the expression of genes necessary for progression through Gl and for entry into S-phase, such as the gene for cyclin E. Expression of cyclin E facilitates formation of the cdk2/cyclin E complex which amplifies, or maintains, E2F levels via further phosphorylation of Rb. The cdk2/cyclin E complex also phosphorylates other proteins necessary for DNA replication, such as NPAT, which has been implicated in histone biosynthesis. Gl progression and the Gl/S transition are also regulated via the mitogen stimulated Myc pathway, which feeds into the cdk2/cyclin E pathway. Cdk2 is also connected to the p53 mediated DNA damage response pathway via p53 regulation of p21 levels. p21 is a protein inhibitor of cdk2/cyclin E and is thus capable of blocking, or delaying, the Gl/S transition. The cdk2/cyclin E complex may thus represent a point at which biochemical stimuli from the Rb, Myc and p53 pathways are to some degree integrated. Cdk2 and/or the cdk2/cyclin E complex therefore represent good targets for therapeutics designed at arresting, or recovering control of, the cell cycle in aberrantly dividing cells. The exact role of cdk3 in the cell cycle is not clear. As yet no cognate cyclin partner has been identified, but a dominant negative form of cdk3 delayed cells in Gl, thereby suggesting that cdk3 has a role in regulating the Gl/S transition. Although most cdks have been implicated in regulation of the cell cycle there is evidence that certain members of the cdk family are involved in other biochemical processes. This is exemplified by cdk5 which is necessary for correct neuronal development and which has also been implicated in the phosphorylation of several neuronal proteins such as Tau, NUDE-1, synapsinl, DARPP32 and the Muncl8/SyntaxinlA complex. Neuronal cdk5 is conventionally activated by binding to the p35/p39 proteins. Cdk5 activity can, however, be deregulated by the binding of p25, a truncated version of p35. Conversion of p35 to p25, and subsequent deregulation of cdk5 activity, can be induced by ischemia, excitotoxicity, and P-amyloid peptide. Consequently p25 has been implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's, and is therefore of interest as a target for therapeutics directed against these diseases. Cdk7 is a nuclear protein that has cdc2 CAK activity and binds to cyclin H. Cdk7 has been identified as component of the TFIIH transcriptional complex which has RNA polymerase II C-terminal domain (CTD) activity. This has been associated with the regulation of HIV-1 transcription via a Tat-mediated biochemical pathway. Cdk8 binds cyclin C and has been implicated in the phosphorylation of the CTD of RNA polymerase II. Similarly the cdk9/cyclin-Tl complex (P-TEFb complex) has been implicated in elongation control of RNA polymerase II. PTEF-b is also required for activation of transcription of the HIV-1 genome by the viral transactivator Tat through its interaction with cyclin Tl. Cdk7, cdk8, cdk9 and the P-TEFb complex are therefore potential targets for anti-viral therapeutics. At a molecular level mediation of cdk/cyclin complex activity requires a series of stimulatory and inhibitory phosphorylation, or dephosphorylation, events. Cdk phosphorylation is performed by a group of cdk activating kinases (CAKs) and/or kinases such as weel, Mytl and Mikl. Dephosphorylation is performed by phosphatases such as cdc25(a & c), pp2a, or KAP. Cdk/cyclin complex activity may be further regulated by two families of endogenous cellular proteinaceous inhibitors: the Kip/Cip family, or the INK family. The INK proteins specifically bind cdk4 and cdk6. pl6ink4 (also known as MTS1) is a potential tumour suppressor gene that is mutated, or deleted, in a large number of primary cancers. The Kip/Cip family contains proteins such as p21cipi,wafl} p27KiPi and p57kiP2 As discussed previously p21 is induced by p53 and is able to inactivate the cdk2/cyclin(E/A) and cdk4/cyclin(Dl/D2/D3) complexes. Atypically low levels of p27 expression have been observed in breast, colon and prostate cancers. Conversely over expression of cyclin E in solid tumours has been shown to correlate with poor patient prognosis. Over expression of cyclin Dl has been associated with oesophageal, breast, squamous, and non-small cell lung carcinomas. The pivotal roles of cdks, and their associated proteins, in co-ordinating and driving the cell cycle in proliferating cells have been outlined above. Some of the biochemical pathways in which cdks play a key role have also been described. The development of monotherapies for the treatment of proliferative disorders, such as cancers, using therapeutics targeted generically at cdks, or at specific cdks, is therefore potentially highly desirable. Cdk inhibitors could conceivably also be used to treat other conditions such as viral infections, autoimmune diseases and neuro-degenerative diseases, amongst others. Cdk targeted therapeutics may also provide clinical benefits in the treatment of the previously described diseases when used in combination therapy with either existing, or new, therapeutic agents. Cdk targeted anticancer therapies could potentially have advantages over many current antitumour agents as they would not directly interact with DNA and should therefore reduce the risk of secondary tumour development. Aurora Kinases Relatively recently, a new family of serine/threonine kinases known as the Aurora kinases has been discovered that are involved in the G2 and M phases of the cell cycle, and which are important regulators of mitosis. The precise role of Aurora kinases has yet to be elucidated but that they play a part in mitotic checkpoint control, chromosome dynamics and cytokinesis (Adams et al., Trends Cell Biol, 11: 49-54 (2001). Aurora kinases are located at the centrosomes of interphase cells, at the poles of the bipolar spindle and in the mid-body of the mitotic apparatus. Three members of the Aurora kinase family have been found in mammals so far (E. A. Nigg, Nat. Rev. Mol. Cell Biol. 2: 21-32, (2001)). These are: Aurora A (also referred to in the literature as Aurora 2); Aurora B (also referred to in the literature as Aurora 1); and Aurora C (also referred to in the literature as Aurora 3). The Aurora kinases have highly homologous catalytic domains but differ considerably in their N-terminal portions (Katayama H, Brinkley WR, Sen S.; The Aurora kinases: role in cell transformation and tumorigenesis; Cancer Metastasis Rev. 2003 Dec;22(4):451-64). The substrates of the Aurora kinases A and B have been identified as including a kinesin-like motor protein, spindle apparatus proteins, histone H3 protein, kinetochore protein and the tumour suppressor protein p53. Aurora A kinases are believed to be involved in spindle formation and become localised on the centrosome during the early G2 phase where they phosphorylate spindle-associated proteins (Prigent et al, Cell, 114: 531-535 (2003). Hirota et al, Cell, 114:585-598, (2003) found that cells depleted of Aurora A protein kinase were unable to enter mitosis. Furthermore, it has been found (Adams, 2001) that mutation or disruption of the Aurora A gene in various species leads to mitotic abnormalities, including centrosome separation and maturation defects, spindle aberrations and chromosome segregation defects. The Aurora kinases are generally expressed at a low level in the majority of normal tissues, the exceptions being tissues with a high proportion of dividing cells such as the thymus and testis. However, elevated levels of Aurora kinases have been found in many human cancers (Giet et al.,J. Cell. SC1- 112: 3591-361, (1999) and Katayama (2003). Furthermore, Aurora A kinase maps to the chromosome 20ql3 region that has frequently been found to be amplified in many human cancers. Thus, for example, significant Aurora A over-expression has been detected in human breast, ovarian and pancreatic cancers (see Zhou et al.,Nat. Genet. 20: 189-193, (1998), Tanaka et al, Cancer Res., 59: 2041-2044, (1999) and Han et al, cancer Res., 62: 2890-2896, (2002). Moreover, Isola, American Journal of Pathology 147,905-911 (1995) has reported that amplification of the Aurora A locus (20ql3) correlates with poor prognosis for patients with node-negative breast cancer. Amplification and/or over-expression of Aurora-A is observed in human bladder cancers and amplification of Aurora-A is associated with aneuploidy and aggressive clinical behaviour, see Sen et al,J. Natl.Cancer Inst, 94: 1320-1329 (2002). Elevated expression of Aurora-A has been detected in over 50% of colorectal cancers, (see Bischoff et al., EMBOJ., 17: 3052-3065, (1998) and Takahashi et al., Jpn. J. Cancer Res. , 91: 1007-1014 (2000)) ovarian cancers (see Gritsko et al. Clin. Cancer Res., 9: 1420-1426 (2003), and gastric tumours Sakakura et al., British Journal of Cancer, 84: 824-831 (2001). Tanaka et al. Cancer Research, 59: 2041-2044 (1999) found evidence of over-expression of Aurora A in 94% of invasive duct adenocarcinomas of the breast. High levels of Aurora A kinase have also been found in renal, cervical, neuroblastoma, melanoma, lymphoma, pancreatic and prostate tumour cell lines Bischoff et al. (1998), EMBO J., 17: 3052-3065 (1998); Kimura et al. J. Biol. Chem., 274: 7334-7340 (1999); Zhou et al., Nature Genetics, 20: 189-193 (1998); Li et al., Clin Cancer Res. 9 (3): 991-7 (2003) ]. Aurora-B is highly expressed in multiple human tumour cell lines, including leukemic cells [Katayama et al., Gene 244: 1-7) ]. Levels of this enzyme increase as a function of Duke's stage in primary colorectal cancers [Katayama et al., J. Natl Cancer Inst, 91: 1160-1162(1999)]. High levels of Aurora-3 (Aurora-C) have been detected in several tumour cell lines, even though this kinase tends to be restricted to germ cells in normal tissues (see Kimura et al. Journal of Biological Chemistry, 21 A: 7334-7340 (1999)). Over-expression of Aurora-3 in approximately 50% of colorectal cancers has also been reported in the article by Takahashi et al., Jpn J. Cancer Res. 91: 1007-1014 (2001)]. Other reports of the role of Aurora kinases in proliferative disorders may be found in Bischoff et al, Trends in Cell Biology 9: 454-459 (1999); Giet et al. Journal of Cell Science, 112: 3591-3601 (1999) and Dutertre, etal. Oncogene, 21: 6175-6183 (2002). Royce et al report that the expression of the Aurora 2 gene (known as STK15 or BTAK) has been noted in approximately one-fourth of primary breast tumours. (Royce ME, Xia W, Sahin AA, Katayama H, Johnston DA, Hortobagyi G, Sen S, Hung MC; STK15/Aurora-A expression in primary breast tumours is correlated with nuclear grade but not with prognosis; Cancer. 2004 Jan l;100(l):12-9). Endometrial carcinoma (EC) comprises at least two types of cancer: endometrioid carcinomas (EECs) are estrogen-related tumours, which are frequently euploid and have a good prognosis. Nonendometrioid carcinomas (NEECs; serous and clear cell forms) are not estrogen related, are frequently aneuploid, and are clinically aggressive. It has also been found that Aurora was amplified in 55.5% of NEECs but not in any EECs (P Results by Hamada et al {Br. J. Haematol. 2003 May;121(3):439-47) also suggest that Aurora 2 is an effective candidate to indicate not only disease activity but also tumourigenesis of non-Hodgkin's lymphoma. Retardation of tumour cell growth resulting from the restriction of this gene's functions could be a therapeutic approach for non-Hodgkin's lymphoma. In a study by Gritsko et al {Clin Cancer Res. 2003 Apr; 9(4): 1420-6)), the kinase activity and protein levels of Aurora A were examined in 92 patients with primary ovarian tumours. In vitro kinase analyses revealed elevated Aurora A kinase activity in 44 cases (48%). Increased Aurora A protein levels were detected in 52 (57%) specimens. High protein levels of Aurora A correlated well with elevated kinase activity. Results obtained by Li et al {Clin. Cancer Res. 2003 Mar; 9(3):991-7) showed that the Aurora A gene is overexpressed in pancreatic tumours and carcinoma cell lines and suggest that overexpression of Aurora A may play a role in pancreatic carcinogenesis. Similarly, it has been shown that Aurora A gene amplification and associated increased expression of the mitotic kinase it encodes are associated with aneuploidy and aggressive clinical behaviour in human bladder cancer. {J. Natl. Cancer Inst. 2002 Sep 4; 94(17): 1320-9). Investigation by several groups (Dutertre S, Prigent C.,Aurora-A overexpression leads to override of the microtubule-kinetochore attachment checkpoint; Mol. Interv. 2003 May; 3(3): 127-30 and Anand S, Penrhyn-Lowe S, Venkitaraman AR., Aurora-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol, Cancer Cell. 2003 Jan;3(l):51-62) suggests that overexpression of Aurora kinase activity is associated with resistance to some current cancer therapies. For example overexpression of Aurora A in mouse embryo fibroblasts can reduce the sensitivity of these cells to the cytotoxic effects of taxane derivatives. Therefore Aurora kinase inhibitors may find particular use in patients who have developed reistance to existing therapies. On the basis of work carried out to date, it is envisaged that inhibition of Aurora kinases, particularly Aurora kinase A and Aurora kinase B, will prove an effective means of arresting tumour development. Harrington et al (Nat Med. 2004 Mar;10(3):262-7) have demonstrated that an inhibitor of the Aurora kinases suppresses tumour growth and induces tumour regression in vivo. In the study, the Aurora kinase inhibitor blocked cancer cell proliferation, and also triggered cell death in a range of cancer cell lines including leukaemic, colorectal and breast cell lines. Cancers which may be particularly amenable to Aurora inhibitors include breast, bladder, colorectal, pancreatic, ovarian, non-Hodgkin's lymphoma, gliomas and nonendometrioid endometrial carcinomas. Glycogen Synthase Kinase Glycogen Synthase Kinase-3 (GSK3) is a serine-threonine kinase that occurs as two ubiquitously expressed isoforms in humans (GSK3α & beta GSK3ß). GSK3 has been implicated as having roles in embryonic development, protein synthesis, cell proliferation, cell differentiation, microtubule dynamics, cell motility and cellular apoptosis. As such GSK3 has been implicated in the progression of disease states such as diabetes, cancer, Alzheimer's disease, stroke, epilepsy, motor neuron disease and/or head trauma. Phylogenetically GSK3 is most closely related to the cyclin dependent kinases (CDKs). The consensus peptide substrate sequence recognised by GSK3 is (Ser/Thr)-X-X-X-(pSer/pThr), where X is any amino acid (at positions (n+1), (n+2), (n+3)) and pSer and pThr are phospho-serine and phospho-threonine respectively (n+4). GSK3 phosphorylates the first serine, or threonine, at position (n). Phospho-serine, or phospho-threonine, at the (n+4) position appear necessary for priming GSK3 to give maximal substrate turnover. Phosphorylation of GSK3α at Ser21, or GSK3ß at Ser9, leads to inhibition of GSK3. Mutagenesis and peptide competition studies have led to the model that the phosphorylated N-terminus of GSK3 is able to compete with phospho-peptide substrate (S/TXXXpS/pT) via an autoinhibitory mechanism. There are also data suggesting that GSK3α and GSKP may be subtly regulated by phosphorylation of tyrosines 279 and 216 respectively. Mutation of these residues to a Phe caused a reduction in in vivo kinase activity. The X-ray crystallographic structure of GSK3(3 has helped to shed light on all aspects of GSK3 activation and regulation. GSK3 forms part of the mammalian insulin response pathway and is able to phosphorylate, and thereby inactivate, glycogen synthase. Upregulation of glycogen synthase activity, and thereby glycogen synthesis, through inhibition of GSK3, has thus been considered a potential means of combating type II, or non-insulin-dependent diabetes mellitus (NIDDM): a condition in which body tissues become resistant to insulin stimulation. The cellular insulin response in liver, adipose, or muscle tissues, is triggered by insulin binding to an extracellular insulin receptor. This causes the phosphorylation, and subsequent recruitment to the plasma membrane, of the insulin receptor substrate (IRS) proteins. Further phosphorylation of the IRS proteins initiates recruitment of phosphoinositide-3 kinase (PI3K) to the plasma membrane where it is able to liberate the second messenger phosphatidylinosityl 3,4,5-trisphosphate (PIP3). This facilitates co-localisation of 3-phosphoinositide-dedependent protein kinase 1 (PDKl) and protein kinase B (PKB or Akt) to the membrane, where PDKl activates PKB. PKB is able to phosphorylate, and thereby inhibit, GSK3α and/or GSKP through phosphorylation of Ser9, or ser21, respectively. The inhibition of GSK3 then triggers upregulation of glycogen synthase activity. Therapeutic agents able to inhibit GSK3 may thus be able to induce cellular responses akin to those seen on insulin stimulation. A further in vivo substrate of GSK3 is the eukaryotic protein synthesis initiation factor 2B (eIF2B). eIF2B is inactivated via phosphorylation and is thus able to suppress protein biosynthesis. Inhibition of GSK3, e.g. by inactivation of the "mammalian target of rapamycin" protein (mTOR), can thus upregulate protein biosynthesis. Finally there is some evidence for regulation of GSK3 activity via the mitogen activated protein kinase (MAPK) pathway through phosphorylation of GSK3 by kinases such as mitogen activated protein kinase activated protein kinase 1 (MAPKAP-K1 or RSK). These data suggest that GSK3 activity may be modulated by mitogenic, insulin and/or amino acid stimulii. It has also been shown that GSK3ß is a key component in the vertebrate Wnt signalling pathway. This biochemical pathway has been shown to be critical for normal embryonic development and regulates cell proliferation in normal tissues. GSK3 becomes inhibited in response to Wnt stimulii. This can lead to the de-phosphorylation of GSK3 substrates such as Axin, the adenomatous polyposis coli (APC) gene product and (3-catenin. Aberrant regulation of the Wnt pathway has been associated with many cancers. Mutations in APC, and/or (3-catenin, are common in colorectal cancer and other tumours. P-catenin has also been shown to be of importance in cell adhesion. Thus GSK3 may also modulate cellular adhesion processes to some degree. Apart from the biochemical pathways already described there are also data implicating GSK3 in the regulation of cell division via phosphorylation of cyclin-Dl, in the phosphorylation of transcription factors such as c-Jun, CCAAT/enhancer binding protein a (C/EBPa), c-Myc and/or other substrates such as Nuclear Factor of Activated T-cells (NFATc), Heat Shock Factor-1 (HSF-1) and the c-AMP response element binding protein (CREB). GSK3 also appears to play a role, albeit tissue specific, in regulating cellular apoptosis. The role of GSK3 in modulating cellular apoptosis, via a pro-apoptotic mechanism, may be of particular relevance to medical conditions in which neuronal apoptosis can occur. Examples of these are head trauma, stroke, epilepsy, Alzheimer's and motor neuron diseases, progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. In vitro it has been shown that GSK3 is able to hyper-phosphorylate the microtubule associated protein Tau. Hyperphosphorylation of Tau disrupts its normal binding to microtubules and may also lead to the formation of intra-cellular Tau filaments. It is believed that the progressive accumulation of these filaments leads to eventual neuronal dysfunction and degeneration. Inhbition of Tau phosphorylation, through inhibition of GSK3, may thus provide a means of limiting and/or preventing neurodegenerative effects. WO 02/34721 from Du Pont discloses a class of indeno [l,2-c]pyrazol-4-ones as inhibitors of cyclin dependent kinases. WO 01/81348 from Bristol Myers Squibb describes the use of 5-thio-, sulphinyl-and sulphonylpyrazolo[3,4-b]-pyridines as cyclin dependent kinase inhibitors. WO 00/62778 also from Bristol Myers Squibb discloses a class of protein tyrosine kinase inhibitors. WO 01/72745A1 from Cyclacel describes 2-substituted 4-heteroaryl-pyrimidines and their preparation, pharmaceutical compositions containing them and their use as inhibitors of cyclin-dependant kinases (cdks) and hence their use in the treatment of proliferative disorders such as cancer, leukaemia, psoriasis and the like. WO 99/21845 from Agouron describes 4-aminothiazole derivatives for inhibiting cyclin-dependent kinases (cdks), such as CDK1, CDK2, CDK4, and CDK6. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds and to methods of treating malignancies and other disorders by administering effective amounts of such compounds. WO 01/53274 from Agouron discloses as CDK kinase inhibitors a class of compounds which can comprise an amide-substituted benzene ring linked to an N-containing heterocyclic group. Although indazole compounds are not mentioned generically, one of the exemplified compounds comprises an indazole 3-carboxylic acid anilide moiety linked via a methylsulphanyl group to a pyrazolopyrimidine. WO 01/98290 (Pharmacia & Upjohn) discloses a class of 3-aminocarbonyl-2-carboxamido thiophene derivatives as protein kinase inhibitors. The compounds are stated to have multiple protein kinase activity. WO 01/53268 and WO 01/02369 from Agouron disclose compounds that mediate or inhibit cell proliferation through the inhibition of protein kinases such as cyclin dependent kinase or tyrosine kinase. The Agouron compounds have an aryl or heteroaryl ring attached directly or though a CH=CH or CH=N group to the 3-position of an indazole ring. WO 00/39108 and WO 02/00651 (both to Du Pont Pharmaceuticals) describe broad classes of heterocyclic compounds that are inhibitors of trypsin-like serine protease enzymes, especially factor Xa and thrombin. The compounds are stated to be useful as anticoagulants or for the prevention of thromboembolic disorders. Heterocyclic compounds that have activity against factor Xa are also disclosed in WO 01/1978 Cor Therapeutics) and US 2002/0091116 (Zhu et al). WO 03/035065 (Aventis) discloses a broad class of benzimidazole derivatives as protein kinase inhibitors but does not disclose activity against CDK kinases or GSK kinases. WO 97/36585 and US 5,874,452 (both to Merck) disclose biheteroaryl compounds that are inhibitors of farnesyl transferase. WO 03/066629 (Vertex) discloses benzimidazolylpyrazole amines as GSK-3 inhibitors. WO 97/12615 (Warner Lambert) discloses benzimidazoles as 15-lipoxygenase inhibitors. Summary of the Invention The invention provides compounds that have cyclin dependent kinase inhibiting or modulating activity and glycogen synthase kinase-3 (GSK3) inhibiting or modulating activity, and/or Aurora kinase inhibiting or modulating activity, and which it is envisaged will be useful in preventing or treating disease states or conditions mediated by the kinases. Thus, for example, it is envisaged that the compounds of the invention will be useful in alleviating or reducing the incidence of cancer. Accordingly, the invention provides a compound of the formula (VII): (Formula Removed) or a salt, N-oxide or solvate thereof; wherein A is NH(C=O), O(C=O) or C=O; and R is a group R where R1 is hydrogen, an optionally substituted carbocyclic or heterocyclic group having from 3 to 12 ring members, or an optionally substituted C1-8 hydrocarbyl group. In one embodiment, R is a carbocyclic or heterocyclic group having from 3 to 12 ring members which is unsubstituted or substituted by one or more substituent groups R10 selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group Ra-Rb wherein Ra is a bond, O, CO, X1C(X2), C(X2)X1, x1C(X2)X1, S, SO, SO2, NRC, SO2NRc or NRcSO2; and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C1-g hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRC, X1C(X2), C(X2)X1 or X1C(X2)X1; or two adjacent groups R10, together with the carbon atoms or heteroatoms to which they are attached may form a 5-membered heteroaryl ring or a 5- or 6-membered non-aromatic carbocyclic or heterocyclic ring, wherein the said heteroaryl and heterocyclic groups contain up to 3 heteroatom ring members selected from N, O and S; Rc is selected from hydrogen and C1-4 hydrocarbyl; and X1 is O, S or NRC and X2 is =O, =S or =NRC; and provided that where the substituent group R10 comprises or includes a carbocyclic or heterocyclic group, the said carbocyclic or heterocyclic group may be unsubstituted or may itself be substituted with one or more further substituent groups R10 and wherein (a) such further substituent groups R10 include carbocyclic or heterocyclic groups, which are not themselves further substituted; or (b) the said further substituents do not include carbocyclic or heterocyclic groups but are otherwise selected from the groups listed above in the definition of R1 . In another embodiment, the substituents for the optionally substitutedC1-8 hydrocarbyl group within the definition of R1 are selected from hydroxy, oxo, alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C1-4 hydrocarbylamino, and monocyclic or bicyclic carbocyclic and heterocyclic groups having from 3 to 12 ring members In a further embodiment, Rld is selected from: o 6-membered monocyclic aryl groups substituted by one to three substituents R10c provided that when the aryl group is substituted by a methyl group, at least one substituent other than methyl is present; o 6-membered monocyclic heteroaryl groups containing a single heteroatom ring member which is nitrogen, the heteroaryl groups being substituted by one to three substituents R10c; o 5-membered monocyclic heteroaryl groups containing up to three heteroatom ring members selected from nitrogen and sulphur, and being optionally substituted by one to three substituents RIOc; o 5-membered monocyclic heteroaryl groups containing a single oxygen heteroatom ring member and optionally a nitrogen heteroatom ring member, and being substituted by one to three substituents R10c provided that when the heteroaryl group contains a nitrogen ring member and is substituted by a methyl group, at least one substituent other than methyl is present; o bicyclic aryl and heteroaryl groups having up to four heteroatom ring members and wherein either one ring is aromatic and the other ring is non-aromatic, or wherein both rings are aromatic, the bicyclic groups being optionally substituted by one to three substituents R10c; o four-membered, six-membered and seven-membered monocyclic C-linked saturated heterocyclic groups containing up to three heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic groups being optionally substituted by one to three substituents R10c provided that when the heterocyclic group has six ring members and contains only one heteroatom which is oxygen, at least one substituent R10c is present; o five membered monocyclic C-linked saturated heterocyclic groups containing up to three heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic groups being optionally substituted by one to three substituents R10c provided that when the heterocyclic group has five ring members and contains only one heteroatom which is nitrogen, at least one substituent R1 c other than hydroxy is present; o four and six membered cycloalkyl groups optionally substituted by one to three substituents R10c; o three and five membered cycloalkyl groups substituted by one to three substituents R10c; and o a group Ph'CR17R18 - where Ph' is a phenyl group substituted by one to three substituents R10c; R17 and R18 are the same or different and each is selected from hydrogen and methyl; or R17 and R18 together with the carbon atom to which they are attached form a cyclopropyl group; or one of R and R is hydrogen and the other is selected from amino, methylamino, C1-4 acylamino, and C1-4 alkoxycarbonylamino; o unsubstituted phenyl and phenyl substituted with one or more methyl groups; o unsubstituted 6-membered monocyclic heteroaryl groups containing a single heteroatom ring member which is nitrogen; o unsubstituted furyl; o 5-membered monocyclic heteroaryl groups containing a single oxygen heteroatom ring member and a nitrogen heteroatom ring member, and being unsubstituted or substituted by one or more methyl groups; o unsubstituted six membered monocyclic C-linked saturated heterocyclic groups containing only one heteroatom which is oxygen; and o unsubstituted three and five membered cycloalkyl groups; and R10c is selected from: o halogen; o hydroxyl; o C1-4 hydrocarbyloxy optionally substituted by one or more substituents selected from hydroxyl and halogen; o C1-4 hydrocarbyl substituted by one or more substituents selected from hydroxyl, halogen and five and six-membered saturated heterocyclic rings containing one or two heteroatom ring members selected from nitrogen, oxygen and sulphur; o S-CM hydrocarbyl; o phenyl optionally substituted with one to three substituents selected from C1-4 alkyl, trifluoromethyl, fluoro and chloro; o heteroaryl groups having 5 or 6 ring members and containing up to 3 heteroatoms selected from N, O and S, the heteroaryl groups being optionally substituted with one to three substituents selected from C1-4 alkyl, trifluoromethyl, fluoro and chloro; o 5- and 6-membered non-aromatic heterocyclic groups containing up to 3 heteroatoms selected from N, O and S and being optionally substituted with one to three substituents selected from C1-4 alkyl, trifluoromethyl, fluoro and chloro; o cyano, nitro, amino, C1-4 alkylamino, di-C1-4alkylamino, C1-4 acylamino, C1-4 alkoxycarbonylamino; o a group R19-S(O)n- where n is 0,1 or 2 and R19 is selected from amino; C1-4 alkylamino; di-C1-4alkylamino; C1-4 hydrocarbyl; phenyl optionally substituted with one to three substituents selected from C1-4 alkyl, trifluoromethyl, fluoro and chloro; and 5- and 6-membered non-aromatic heterocyclic groups containing up to 3 heteroatoms selected from N, O and S and being optionally substituted with one to three C1-. 4 alkyl group substituents; and 90 90 o a group R -Q- where R is phenyl optionally substituted with one to three substituents selected from C1-4 alkyl, trifluoromethyl, fluoro and chloro; and Q is a linker group selected from OCH2, CH2O, NH, CH2NH, NCH2, CH2, NHCO and CONH. In another embodiment, A is NH(C=O) or (C=O), and Rld is a substituted phenyl group having from 1 to 4 substituents whereby: (Formula Removed) (i) when Rld bears a single substituent it is selected from halogen, hydroxyl, C1-4 hydrocarbyloxy optionally substituted by one or more substituents selected from hydroxyl and halogen; C1-4 hydrocarbyl substituted by one or more substituents selected from hydroxyl and halogen; heteroaryl groups having 5 ring members; and 5- and 6-membered non-aromatic heterocyclic groups, wherein the heteroaryl and heterocyclic groups contain up to 3 heteroatoms selected from N, O and S; and (ii) when R bears 2, 3 or 4 substituents, each is selected from halogen, hydroxyl, C1-4 hydrocarbyloxy optionally substituted by one or more substituents selected from hydroxyl and halogen; C1-4 hydrocarbyl optionally substituted by one or more substituents selected from hydroxyl and halogen; heteroaryl groups having 5 ring members; amino; and 5- and 6-membered non-aromatic heterocyclic groups; or two adjacent substituents together with the carbon atoms to which they are attached form a 5-membered heteroaryl ring or a 5- or 6-membered non-aromatic heterocyclic ring; wherein the said heteroaryl and heterocyclic groups contain up to 3 heteroatoms selected from N, O and S. In another embodiment, Rld is selected from: (a) a mono-substituted phenyl group wherein the substituent is selected from o-amino, o-methoxy; o-chloro;p-chloro; o-difluoromethoxy; o-trifluoromethoxy; o-tert-butyloxy; m-methylsulphonyl and p-fluoro; (b) a 2,4- or 2,6-disubstituted phenyl group wherein one substituent is selected from o-methoxy, o-ethoxy, o-fluoro, P-morpholino and the other substituent is selected from o-fluoro, o-chloro,P-chloro, and p-amino; (c) a 2,5-disubstituted phenyl group wherein one substituent is selected from o-fluoro and o-methoxy and the other substituent is selected from m-methoxy, m-isopropyl; m-fluoro, m-trifluoromethoxy, m-trifiuoromethyl, m-methylsulphanyl, m-pyrrolidinosulphonyl, m-(4-methylpiperazin-l -yl)sulphonyl, m-morpholinosulphonyl, m-methyl, m-chloro and m-aminosulphonyl; (d) a 2,4,6-tri-substituted phenyl group where the substituents are the same or different and are each selected from o-methoxy, o-fluoro,p-fluoro,p-methoxy provided that no more than one methoxy substituent is present; (e) a 2,4,5-tri-substituted phenyl group where the substituents are the same or different and are each selected from o-methoxy, m-chloro and p-amino; (f) unsubstituted benzyl; 2,6-difluorobenzyl; α,α-dimethylbenzyl; 1-phenylcycloprop-1-yl; and a-tert-butoxycarbonylaminobenzyl; (g) an unsubstituted 2-furyl group or a 2-furyl group bearing a single substituent selected from 4-(morpholin-4-ylmethyl), piperidinylmethyl; and optionally a further substituent selected from methyl; (h) an unsubstituted pyrazolo[l,5-a]pyridin-3-yl group; (i) isoxazolyl substituted by one or two C1-4 alkyl groups; (j)4,5,6,7-tetrahydro-benz[d]isoxazol-3-yl; (k) 3-tert-butyl-phenyl-1 H-pyrazol-5-yl; (1) quioxalinyl; (m) benz[c]isoxazol-3-yl; (n)2-methyl-4-trifluoromethyl-thiazol-5-yl; (o) 3-phenylamino-2-pyridyl; (p) l-toluenesulphonylpyrrol-3-yl; (q) 2,4-dimethoxy-3-pyridyl; and 6-chloro-2-methoxy-4-methyl-3-pyridyl; (r) imidazo[2,l-b]thiazol-6-yl; (s) δ-chloro-2-methylsulphanyl-pyrimidin-4-yl; (t) 3-methoxy-naphth-2-yl; (u) 2,3-dihydro-benz[l,4]dioxin-5-yl; (v) 2,3-dihydro-benzfuranyl group optionally substituted in the five membered ring by one or two methyl groups; (w) 2-methyl-benzoxazol-7-yl; (x) 4-aminocyclohex-l-yl; (y) 1,2,3,4-tetrahydro-quinolin-6-yl; (z) 2-methyl-4,5,6,7-tetrahydro-benzfuran3 -yl; (k) 2-pyrimidinyl-lpiperidin-4-yl; and l-(5-trifluoromethyl-2-pyridyl)-piperidin-4-yl and l-methylsulphonylpiperidin-4-yl; (l) 1-cyanocyclopropyl; (m) N-benzylmorpholin-2-yl; and when A is NH(C=O), Rlc is additionally selected from: (ad) unsubstituted phenyl. General Preferences and Definitions The following general preferences and definitions shall apply to each of the moieties R1d to R10, and their various sub-groups, sub-definitions, examples and embodiments unless the context indicates otherwise. Any references to formula (VII) herein shall also be taken to refer to formula (VIIa) and any other sub-group of compounds within formula (VII) unless the context requires otherwise. The term upregulation of Aurora kinase as used herein is defined as including elevated expression or over-expression of Aurora kinase, including gene amplification (i.e. multiple gene copies) and increased expression by a transcriptional effect, and hyperactivity and activation of Aurora kinase, including activation by mutations. References to "carbocyclic" and "heterocyclic" groups as used herein shall, unless the context indicates otherwise, include both aromatic and non-aromatic ring systems. Thus, for example, the term "carbocyclic and heterocyclic groups" includes within its scope aromatic, non-aromatic, unsaturated, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. In general, such groups may be monocyclic or bicyclic and may contain, for example, 3 to 12 ring members, more usually 5 to 10 ring members. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7, and 8 ring members, more usually 3 to 7, and preferably 5 or 6 ring members. Examples of bicyclic groups are those containing 8, 9, 10, 11 and 12 ring members, and more usually 9 or 10 ring members. The carbocyclic or heterocyclic groups can be aryl or heteroaryl groups having from 5 to 12 ring members, more usually from 5 to 10 ring members. The term "aryl" as used herein refers to a carbocyclic group having aromatic character and the term "heteroaryl" is used herein to denote a heterocyclic group having aromatic character. The terms "aryl" and "heteroaryl" embrace polycyclic (e.g. bicyclic) ring systems wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the group may be attached by the aromatic ring, or by a non-aromatic ring. The aryl or heteroaryl groups can be monocyclic or bicyclic groups and can be unsubstituted or substituted with one or more substituents, for example one or more groups R as defined herein. The term "non-aromatic group" embraces unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic 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 carbocyclic groups include cycloalkyl groups as defined below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings, or two fused five membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl 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 heteroaryl ring contains at least one ring nitrogen atom. 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 five membered heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine. A bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; g) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; h) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; j) an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; 1) a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; m) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; n) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; o) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and p) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms. Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,l-b]thiazole) and imidazoimidazole (e.g. imidazo[l,2-a]imidazole). Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g. pyrazolo[l,5-a]pyrimidine), triazolopyrimidine (e.g. [l,2,4]triazolo[l,5-a]pyrimidine), benzodioxole and pyrazolopyridine (e.g. pyrazolo[l,5-a]pyridine) groups. Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups. Examples of polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiene, dihydrobenzfuran, 2,3-dihydro-benzo[l,4]dioxine, benzo[l,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoline and indane groups. Examples of carbocyclic aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl groups. Examples of non-aromatic heterocyclic groups are groups having from 3 to 12 ring members, more usually 5 to 10 ring members. Such groups can be monocyclic or bicyclic, for example, and typically have from 1 to 5 heteroatom ring members (more usually 1, 2, 3 or 4 heteroatom ring members), usually selected from nitrogen, oxygen and sulphur. The heterocylic 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 sulphones (e.g. as in sulpholane and sulpholene), cyclic sulphoxides, cyclic sulphonamides and combinations thereof (e.g. thiomorpholine). Particular examples include morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), piperidone, pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazone, piperazine, and N-alkyl piperazines such as N-methyl piperazine. In general, preferred non-aromatic heterocyclic groups include saturated groups such as piperidine, pyrrolidine, azetidine, morpholine, piperazine and N-alkyl piperazines. Examples of non-aromatic carbocyclic groups include cycloalkane groups such as cyclohexyl and cyclopentyl, cycloalkenyl groups such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well as cyclohexadienyl, cyclooctatetraene, tetrahydronaphthenyl and decalinyl. Where reference is made herein to carbocyclic and heterocyclic groups, the carbocyclic or heterocyclic ring can, unless the context indicates otherwise, be unsubstituted or substituted by one or more substituent groups R selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group Ra-Rb wherein Ra is a bond, O, CO, X!C(X2), C(X2)X\ X'CCX^X1, S, SO, SO2, NR°, SO2NRc or NRcSO2; and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di- C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRC, XlC(X2), C(X2)X1 or X1C(X2)X1; or two adjacent groups R10, together with the carbon atoms or heteroatoms to which they are attached may form a 5-membered heteroaryl ring or a 5- or 6-membered non-aromatic carbocyclic or heterocyclic ring, wherein the said heteroaryl and heterocyclic groups contain up to 3 heteroatom ring members selected from N, O and S; Rc is selected from hydrogen and C1-4 hydrocarbyl; and X1 is O, S or NRC and X2 is =O, =S or =NRC. Where the substituent group R10 comprises or includes a carbocyclic or heterocyclic group, the said carbocyclic or heterocyclic group may be unsubstituted or may itself be substituted with one or more further substituent groups R10. In one sub-group of compounds of the formula (VII), such further substituent groups R10may include carbocyclic or heterocyclic groups, which are typically not themselves further substituted. In another sub-group of compounds of the formula (VII), the said further substituents do not include carbocyclic or heterocyclic groups but are otherwise selected from the groups listed above in the definition of R . The substituents R10 may be selected such that they contain no more than 20 non-hydrogen atoms, for example, no more than 15 non-hydrogen atoms, e.g. no more than 12, or 11, or 10, or 9, or 8, or 7, or 6, or 5 non-hydrogen atoms. Where the carbocyclic and heterocyclic groups have a pair of substituents on adjacent ring atoms, the two substituents may be linked so as to form a cyclic group. For example, an adjacent pair of substituents on adjacent carbon atoms of a ring may be linked via one or more heteroatoms and optionally substituted alkylene groups to form a fused oxa-, dioxa-3 aza-, diaza- or oxa-aza-cycloalkyl group, Examples of such linked substituent groups include: (Formula Removed) Examples of halogen substituents include fluorine, chlorine, bromine and iodine. Fluorine and chlorine are particularly preferred. In the definition of the compounds of the formula (VII) above and as used hereinafter, the term "hydrocarbyl" is a generic term encompassing aliphatic, alicyclic and aromatic groups having an all-carbon backbone, except where otherwise stated. In certain cases, as defined herein, one or more of the carbon atoms making up the carbon backbone may be replaced by a specified atom or group of atoms. Examples of hydrocarbyl groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups. Such groups can be unsubstituted or, where stated, substituted by one or more substituents as defined herein. The examples and preferences expressed below apply to each of the hydrocarbyl substituent groups or hydrocarbyl-containing substituent groups referred to in the various definitions of substituents for compounds of the formula (VII) unless the context indicates otherwise. Preferred non-aromatic hydrocarbyl groups are saturated groups such as alkyl and cycloalkyl groups. Generally by way of example, the hydrocarbyl groups can have up to eight carbon atoms, unless the context requires otherwise. Within the sub-set of hydrocarbyl groups having 1 to 8 carbon atoms, particular examples areC1-6 hydrocarbyl groups, such as C1-4 hydrocarbyl groups (e.g. C1.3 hydrocarbyl groups or C1.2 hydrocarbyl groups), specific examples being any individual value or combination of values selected from Ci, C2, C3, C4, C5, C&, C7 and Cs hydrocarbyl groups. The term "alkyl" covers both straight chain and branched chain alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl butyl, 3-methyl butyl, and n-hexyl and its isomers. Within the sub-set of alkyl groups having 1 to 8 carbon atoms, particular examples are C1-6 alkyl groups, such as C1-4 alkyl groups (e.g. C1.3 alkyl groups or C1-2 alkyl groups). Examples of cycloalkyl groups are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. Within the sub-set of cycloalkyl groups the cycloalkyl group will have from 3 to 8 carbon atoms, particular examples being C3.6 cycloalkyl groups. Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-l,4-dienyl, pentenyl, and hexenyl. Within the sub-set of alkenyl groups the alkenyl group will have 2 to 8 carbon atoms, particular examples being C2-6 alkenyl groups, such as C2-4 alkenyl groups. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. Within the subset of cycloalkenyl groups the cycloalkenyl groups have from 3 to 8 carbon atoms, and particular examples are C3-6 cycloalkenyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl (propargyl) groups. Within the sub-set of alkynyl groups having 2 to 8 carbon atoms, particular examples are C2-6 alkynyl groups, such as C2-4 alkynyl groups. Examples of carbocyclic aryl groups include substituted and unsubstituted phenyl groups. Examples of cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, aralkenyl and aralkynyl groups include phenethyl, benzyl, styryl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl and cyclopentenylmethyl groups. When present, and where stated, a hydrocarbyl group can be optionally substituted by one or more substituents selected from hydroxy, oxo, alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C1-4 hydrocarbylamino, and monocyclic or bicyclic carbocyclic and heterocyclic groups having from 3 to 12 (typically 3 to 10 and more usually 5 to 10) ring members. Preferred substituents include halogen such as fluorine. Thus, for example, the substituted hydrocarbyl group can be a partially fluorinated or perfluorinated group such as difluoromethyl or trifluoromethyl. In one embodiment preferred substituents include monocyclic carbocyclic and heterocyclic groups having 3-7 ring members, more usually 3, 4, 5 or 6 ring members. Where stated, one or more carbon atoms of a hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRC, X1C(X2), C(X2)X1 or X1C(X2)X1 wherein X1 and X2 are as hereinbefore defined, provided that at least one carbon atom of the hydrocarbyl group remains. For example, 1, 2, 3 or 4 carbon atoms of the hydrocarbyl group may be replaced by one of the atoms or groups listed, and the replacing atoms or groups may be the same or different. In general, the number of linear or backbone carbon atoms replaced will correspond to the number of linear or backbone atoms in the group replacing them. Examples of groups in which one or more carbon atom of the hydrocarbyl group have been replaced by a replacement atom or group as defined above include ethers and thioethers (C replaced by O or S), amides, esters, thioamides and thioesters (C-C replaced by X C(X ) or C(X )X ), sulphones and sulphoxides (C replaced by SO or SO2), amines (C replaced by NR°), and ureas, carbonates and carbamates (C-C-C replaced by X1C(X2)X1). Where an amino group has two hydrocarbyl substituents, they may, together with the nitrogen atom to which they are attached, and optionally with another heteroatom such as nitrogen, sulphur, or oxygen, link to form a ring structure of 4 to 7 ring members. The definition "Ra-Rb" as used herein, either with regard to substituents present on a carbocyclic or heterocyclic moiety, or with regard to other substituents present at other locations on the compounds of the formula (VII), includes inter alia compounds wherein Ra is selected from a bond, O, CO, OC(O), SC(O), NR°C(O), OC(S), SC(S), NRCC(S), OC(NRc), SC(NRC), NRCC(NRC), C(O)O, C(O)S, C(O)NRc, C(S)O, C(S)S, C(S) NRc, C(NRc)O, C(NRC)S, C(NRc)NRc, OC(O)O, SC(O)O, NRcC(O)O, OC(S)O, SC(S)O, NRcC(S)O, OC(NRc)O, SC(NRc)O, NRcC(NRc)O, OC(O)S, SC(O)S, NRcC(O)S, OC(S)S, SC(S)S, NRCC(S)S, OC(NRc)S, SC(NRC)S, NRCC(NRC)S, OC(O)NRc, SC(O)NRc, NRcC(O) NRc, OC(S)NRc, SC(S) NRC, NRCC(S)NRC, OC(NRc)NRc, SC(NRC)NRC, NRCC(NRCNRC, S, SO, SO2 ,NRC, SO2NRc and NRcSO2 wherein Rc is as hereinbefore defined. The moiety R can be hydrogen or it can be a group selected from carbocyclic and heterocyclic groups having from 3 to 12 ring members (typically 3 to 10 and more usually from 5 to 10), and a C1-g hydrocarbyl group optionally substituted as hereinbefore defined. Examples of hydrocarbyl, carbocyclic and heterocyclic groups are as set out above. When Ra is O and Rb is a C1-g hydrocarbyl group, Ra and Rb together form a hydrocarbyloxy group. Preferred hydrocarbyloxy groups include saturated hydrocarbyloxy such as alkoxy (e.g. C1-6 alkoxy, more usually C1-4 alkoxy such as ethoxy and methoxy, particularly methoxy), cycloalkoxy (e.g. C3-6 cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy) and cycloalkyalkoxy (e.g. C3-6 cycloalkyl-C1-2 alkoxy such as cyclopropylmethoxy). The hydrocarbyloxy groups can be substituted by various substituents as defined herein. For example, the alkoxy groups can be substituted by halogen (e.g. as in difiuoromethoxy and trifluoromethoxy), hydroxy (e.g. as in hydroxyethoxy), C1-2 alkoxy (e.g. as in methoxyethoxy), hydroxy-C1-2 alkyl (as in hydroxyethoxyethoxy) or a cyclic group (e.g. a cycloalkyl group or non-aromatic heterocyclic group as hereinbefore defined). Examples of alkoxy groups bearing a non-aromatic heterocyclic group as a substituent are those in which the heterocyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C1-4-alkyl-piperazines, C3-7-cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran and the alkoxy group is a C1-4 alkoxy group, more typically a C1-3 alkoxy group such as methoxy, ethoxy or n-propoxy. Alkoxy groups substituted by a monocyclic group such as pyrrolidine, piperidine, morpholine and piperazine and N-substituted derivatives thereof such as N-benzyl, N-C1-4 acyl and N-C1-4 alkoxycarbonyl. Particular examples include pyrrolidinoethoxy, piperidinoethoxy and piperazinoethoxy. When Ra is a bond and Rb is a C1-8 hydrocarbyl group, examples of hydrocarbyl groups Ra-Rb are as hereinbefore defined. The hydrocarbyl groups may be saturated groups such as cycloalkyl and alkyl and particular examples of such groups include methyl, ethyl and cyclopropyl. The hydrocarbyl (e.g. alkyl) groups can be substituted by various groups and atoms as defined herein. Examples of substituted alkyl groups include alkyl groups substituted by one or more halogen atoms such as fluorine and chlorine (particular examples including bromoethyl, chloroethyl and trifiuoromethyl), or hydroxy (e.g. hydroxymethyl and hydroxyethyl), C1-8 acyloxy (e.g. acetoxymethyl and benzyloxymethyl), amino and mono- and dialkylamino (e.g. aminoethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl and tert-butylaminomethyl), alkoxy (e.g. C1-2 alkoxy such as methoxy - as in methoxyethyl), and cyclic groups such as cycloalkyl groups, aryl groups, heteroaryl groups and non-aromatic heterocyclic groups as hereinbefore defined). Particular examples of alkyl groups substituted by a cyclic group are those wherein the cyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C1-4-alkyl-piperazines, C3-7-cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran and the alkyl group is a C1-4 alkyl group, more typically a C1-3 alkyl group such as methyl, ethyl or n-propyl. Specific examples of alkyl groups substituted by a cyclic group include pyrrolidinomethyl, pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, piperidinylmethyl, piperazinomethyl and N-substituted forms thereof as defined herein. Particular examples of alkyl groups substituted by aryl groups and heteroaryl groups include benzyl and pyridylmethyl groups. When Ra is SO2NR0, Rb can be, for example, hydrogen or an optionally substituted C1-4 hydrocarbyl group, or a carbocyclic or heterocyclic group. Examples of Ra-R where Ra is SO2NR0 include aminosulphonyl, C1-4 alkylaminosulphonyl and di-C1-4 alkylaminosulphonyl groups, and sulphonamides formed from a cyclic amino group such as piperidine, morpholine, pyrrolidine, or an optionally N-substituted piperazine such as N-methyl piperazine. Examples of groups Ra-Rb where Ra is SO2 include alkylsulphonyl, heteroarylsulphonyl and arylsulphonyl groups, particularly monocyclic aryl and heteroaryl sulphonyl groups. Particular examples include methylsulphonyl, phenylsulphonyl and toluenesulphonyl. WhenRaisNRc,Rb can be, for example, hydrogen or an optionally substituted C1-8 hydrocarbyl group, or a carbocyclic or heterocyclic group. Examples of Ra-R where Ra is NRC include amino, C1-4 alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino), di-C1-4 alkylamino (e.g. dimethylamino and diethylamino) and cycloalkylamino (e.g. cyclopropylamino, cyclopentylamino and cyclohexylamino). Specific Embodiments of and Preferences for Rld to R10 A is C=O, NH(C=O) or O(C=O) In one preferred group of compounds of the invention A is C=O or NRg(C=O), preferably C=O. More preferably, m is 0, n is 1 and B is C=O. Thus the moiety Rld-A-NH linked to the 4-position of the pyrazole ring can take the form of an amide Rld-C(=O)NH, a urea Rld-NHC(=O)NH or a carbamate Rld-OC(=O)NH. R is hydrogen, a carbocyclic or heterocyclic group having from 3 to 12 ring members, or an optionally substituted C1-8 hydrocarbyl group as hereinbefore defined. Examples of carbocyclic and heterocyclic, and optionally substituted hydrocarbyl groups are as set out above. For example, Rld can be a monocyclic or bicyclic group having from 3 to 10 ring members. Where Rld is a monocyclic group, typically it has 3 to 7 ring members, more usually 3 to 6 ring members, for example, 3,4, 5 or 6. When the monocyclic group Rld is an aryl group, it will have 6 ring members and will be an unsubstituted or substituted phenyl ring. When the monocyclic group Rld is a non-aromatic carbocyclic group, it can have from 3 to 7 ring members, more usually 3 to 6 ring members, for example, 3, or 4, or 5, or 6 ring members. The non-aromatic carbocyclic group may be saturated or partially unsaturated but preferably it is saturated, i.e. R1 is a cycloalkyl group. When the monocyclic group Rld is a heteroaryl group, it will have 5 or 6 ring members. Examples of heteroaryl groups having 5 and 6 ring members are set out above, and particular examples are described below. In one sub-group of compounds, the heteroaryl group has 5 ring members. In another sub-group of compounds, the heteroaryl group has 6 ring members. The monocyclic heteroaryl groups Rld typically have up to 4 ring heteroatoms selected from N, O and S, and more typically up to 3 ring heteroatoms, for example 1, or 2, or 3 ring heteroatoms. When Rld is a non-aromatic monocyclic heterocyclic group, it may be any one of the groups listed hereinabove or hereinafter. Such groups typically have from 4 to 7 ring members and more preferably 5 or 6 ring members. The non-aromatic monocyclic heterocyclic groups typically contain up to 3 ring heteroatoms, more usually 1 or 2 ring heteroatoms, selected from N, S and O. The heterocyclic group may be saturated or partially unsaturated, but preferably it is saturated. Particular examples of non-aromatic monocyclic heterocyclic groups are the particular and preferred examples defined in the "General Preferences and Definitions" section above, and as set out in the tables and examples below. Where Rld is a bicyclic group, typically it has 8 to 10 ring members, for example 8, or 9, or 10 ring members. The bicyclic group can be an aryl or heteroaryl group and examples of such groups include groups comprising a 5-membered ring fused to another 5-membered ring; a 5-membered ring fused to a 6-membered ring; and a 6-membered ring fused to another 6-membered ring. Examples of groups in each of these categories are set out above in the "General Preferences and Definitions" section. A bicyclic aryl or heteroaryl group can comprise two aromatic or unsaturated rings, or one aromatic and one non-aromatic (e.g. partially saturated) ring. Bicyclic heteroaryl groups typically contain up to 4 heteroatom ring members selected from N, S and O. Thus, for example, they may contain 1, or 2, or 3, or 4 heteroatom ring members. In the monocyclic and bicyclic heterocyclic groups Rld, examples of combinations of heteroatom ring members include N; NN; NNN; NNNN; NO; NNO; NS, NNS, O, S, 00 and SS. Particular examples of RId include optionally substituted or unsubstituted heteroaryl groups selected from pyrazolo[l,5-a]pyridinyl (e.g. pyrazolo[l,5-a]pyridin-3-yl), furanyl (e.g. 2-furanyl and 3-furanyl), indolyl (e.g. 3-indolyl, 4-indolyl and 7-indolyl), oxazolyl, thiazolyl (e.g. thiazol-2-yl and thiazol-5-yl), isoxazolyl (e.g. isoxazol-3-yl and isoxazol-4-yl), pyrrolyl (e.g. 3-pyrrolyl), pyridyl (e.g. 2-pyridyl), quinolinyl (e.g. quinolin-8-yl), 2,3-dihydro-benzo[l,4]dioxine (e.g. 2,3-dihydro-benzo[l,4]dioxin-5-yl), benzo[l,3]dioxole (e.g. benzo[l,3]dioxol-4-yl), 2,3-dihydrobenzofuranyl (e.g. 2,3-dihydrobenzofuran-7-yl), imidazolyl and thiophenyl (e.g. 3-thiophenyl). Other examples of R include substituted or unsubsituted heteroaryl groups selected frompyrazolo[l,5-a]pyrimidine, isobenzofuran, [l,2,4]triazolo[l,5-a]pyrimidine, tetrazolyl, tetrahydroisoqumolinyl (e.g. 1,2,3,4-tetrahydroisoquinolin-7-yl), pyrimidinyl, pyrazolyl, triazolyl, 4,5,6,7-tetrahydro-benzo[d]isoxazole, phthalazine, 2H-phthalazin-l-one, benzoxazole, cinnoline, quinoxaline, naphthalene, benzo[c]isoxazole, imidazo[2,l-b]thiazole, pyridone, tetrahydroquinolinyl (e.g. l,2,3,4-tetrahydroquinolin-6-yl), and 4,5,6,7-tetrahydro-benzofuran groups. Preferred Rldheteroaryl groups include pyrazoIo[l,5-a]pyridinyl, furanyl, 2,3-dihydrobenzofuranyl, thiophenyl, indolyl, thiazolyl, isoxazolyl and 2,3-dihydro-benzo [ 1,4] dioxine groups. Preferred aryl groups Rld are optionally substituted phenyl groups. Examples of non-aromatic groups Rld include monocyclic cycloalkyl and azacycloalkyl groups such as cyclohexyl, cyclopentyl and piperidinyl, particularly cyclohexyl and 4-piperidinyl groups. Other examples of non-aromatic groups R1 include monocyclic oxacycloalkyl groups such as tetrahydropyranyl and aza-oxa cycloalkyl groups such as morpholino (e.g. 2-morpholino and 4-morpholino). Preferred substituted and unsubstituted C1-8 hydrocarbyl groups include trifiuoromethyl and tertiary butyl groups. One sub-set of preferred R1 groups includes phenyl, pyrazolo[l,5-a]pyridinyl and 2,3-dihydro-benzo [ 1,4]dioxine groups. Another sub-set of preferred R groups includes unsubstituted and substituted phenyl, pyrazolo[l,5-a]pyridinyl, 2,3-dihydro-benzo[l,4]dioxine, indol-4-yl, 2,3-dihydrobenzofuranyl, tert-butyl, furanyl, pyrazolo[l,5-a]pyridin-3-yl, pyrazolo[l,5-a]pyrimidin-3-yl, oxazolyl, isoxazolyl, benzoxazol-2-yl, 2H-tetrazol-5-yl, pyrazin-2-yl, pyrazolyl, benzyl, a,a-dimethylbenzyl, a-aminobenzyl, a-methylaminobenzyl, 4,5,6,7-tetrahydro-benzo[d]isoxazol-3-yl, 2H-phthalazin-l-one-4-yl, benzoxazol-7-yl, quinazolinyl, 2-naphthyl, cyclopropyl, benzo[c]isoxazol-3-yl, 4-piperidinyl, 5- thiazolyl, 2-pyridyl, 3-pyridyl, 3-pyrrolyl, isoxazolyl, imidazo[2,l-b]thiazolyl, 4-pyrimidinyl, cyclohexyl, tetrahydropyran-4-yl, tetrahydroquinolinyl, 4,5,6,7-tetrahydro-benzofuranyl and morpholinyl groups. The group Rld can be an unsubstituted or substituted carbocyclic or heterocyclic group in which one or more substituents can be selected from the group R10 as hereinbefore defined. In one embodiment, the substituents on Rld may be selected from the group R10a consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, heterocyclic groups having 5 or 6 ring members and up to 2 heteroatoms selected from O, N and S, a group Ra-Rb wherein Ra is a bond, O, CO, X3C(X4), C(X4)X3, X3C(X4)X3, S, SO, or SO2, and Rb is selected from hydrogen, heterocyclic groups having 5 or 6 ring members and up to 2 heteroatoms selected from O, N and S, and a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having 5 or 6 ring members and up to 2 heteroatoms selected from O, N and S; wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, X3C(X4), C(X4)X3 or X3C(X4)X3; X3 is O or S; and X4 is =O or =S. In a further embodiment, the substituents on R1 may be selected from the group R10b consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, a group Ra-Rb wherein Ra is a bond, O, CO, X3C(X4), C(X4)X3, X3C(X4)X3, S, SO, or SO2, and R is selected from hydrogen and a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy; wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, X3C(X4), C(X4)X3 or X3C(X4)X3; X3 is O or S; and X4 is =O or =S. In another embodiment, the substituents on Rld may be selected from halogen, hydroxy, trifluoromethyl, a group Ra-Rb wherein Ra is a bond or O, and Rb is selected from hydrogen and a C1-4 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxyl and halogen. One sub-set of substituents that may be present on a group R (e.g. an aryl or heteroaryl group Rld) includes fluorine, chlorine, methoxy, methyl, oxazolyl, morpholino, trifluoromethyl, bromomethyl, chloroethyl, pyrrolidino, pyrrolidinylethoxy, pyrrolidinylmethyl, difluoromethoxy and morpholinomethyl. Another sub-set of substituents that may be present on a group R1 includes fluorine, chlorine, methoxy, ethoxy, methyl, ethyl, isopropyl, tert-butyl, amino, oxazolyl, morpholino, trifluoromethyl, bromomethyl, chloroethyl, pyrrolidino, pyrrolidinylethoxy, pyrrolidinylmethyl, difluoromethoxy, trifluoromethoxy, morpholino, N-methylpiperazino, piperazine, piperidino, pyrrolidino, and morpholinomethyl. The moiety Rld may be substituted by more than one substituent. Thus, for example, there may be 1 or 2 or 3 or 4 substituents, more typically 1, 2 or 3 substituents. In one embodiment, where Rld is a six membered ring (e.g. a carbocyclic ring such as a phenyl ring), there may be a single substituent which may be located at any one of the 2-, 3- and 4-positions on the ring. In another embodiment, there may be two or three substituents and these may be located at the 2-, 3-, 4- or 6-positions around the ring. By way of example, a phenyl group Rld may be 2,6-disubstituted, 2,3-disubstituted, 2,4-disubstituted 2,5-disubstituted, 2,3,6-trisubstituted or 2,4,6-trisubstituted. In one embodiment, a phenyl group Rld may be disubstituted at positions 2- and 6-with substituents selected from fluorine, chlorine and Ra-Rb, where Ra is O and Rb is C1-4 alkyl, with fluorine being a particular substituent. In one subgroup of compounds, the group Rld is a five membered heteroaryl group containing 1 or 2 ring heteroatoms selected from O, N and S. Particular heteroaryl groups include furan, thiophene, pyrrole, oxazole, isoxazole and thiazole groups. The heteroaryl groups may be unsubstituted or substituted by one or more substituent groups as hereinbefore defined. One preferred group of five membered heteroaryl groups consists of optionally substituted isoxazole and thiazole groups. In another sub-group of compounds, R1 is a pyrazolopyridine group, for example, a pyrazolo[l,5-a]pyridine group, such as a 3-pyrazolo[l,5-a]pyridinyl group. Particular examples of groups Rld include the groups Al to A183 (e.g. Al to A60) set out in Table 1 below. Table 1 (Table Removed) One preferred sub-set of compounds of the invention is the sub-set wherein R is a group selected from Al to A34. Another preferred sub-set of compounds of the invention is the sub-set wherein R ' is a group selected from Al to A24, A26 to A34, A38 to A46, A48 to A57, A59 to A64, A66 to A114, Al 16 to A165, A167 to A168 and A170 to A183. One particularly preferred sub-set of groups Rld includes 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2-fiuoro-6-methoxyphenyl, 2,6-dichlorophenyl, 2,4,6- trifluorophenyl, 2-chloro-6-methyl, 2,3-dihydro-benzo[l,4]dioxin-5-yl and pyrazolo[l,5-a]pyridin-3-yl. Compounds containing groups Rld selected from this sub-set have particularly good cdk inhibitory activity. Another particularly preferred sub-set of groups Rld includes 2,6-difluorophenyl, 2-methoxyphenyl, 2,6-difiuoro-4-methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2,6-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2-chloro-6-fluorophenyl, 2,6-dichlorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methyl, 2,3-dihydro-benzo[l,4]dioxin-5-yl and pyrazolo[l,5-a]pyridin-3-yl. In the context of the inhibition of cdk kinases, one currently most preferred group Rld is 2,6-difluorophenyl. In one preferred sub-group of compounds, Rld is selected from heteroaryl groups having 5 or 6 ring members (e.g. oxazole, thiazole, pyridyl, pyrimidinyl) and containing up to 3 heteroatoms selected from N, O and S, the heteroaryl groups being optionally substituted with one to three substituents selected from C1-4 alkyl, trifluoromethyl, fluoro and chloro. A substituted thiazole group, for example, 2-methyl-4-trifluoromethyl-2-thiazolyl, represents one preferred embodiment. In another preferred sub-group of compounds, Rld is selected from 5-membered monocyclic heteroaryl groups containing a single oxygen heteroatom ring member and optionally a nitrogen heteroatom ring member, and being substituted by one to three substituents R10c provided that when the heteroaryl group contains a nitrogen ring member and is substituted by a methyl group, at least one substituent other than methyl is present. One such group is isoxazole substituted by a C2-4 alkyl group such as a propyl or butyl group, e.g. isobutyl. In another preferred sub-group of compounds, Rld is selected from three and five membered cycloalkyl groups substituted by one to three substituents R10c. Substituted cyclopropyl groups are particularly preferred, for example cyclopropyl group substituted by phenyl or cyano, e.g. 1-cyanocyclopropyl and 1-phenylcy clopropyl. In a further sub-group of compounds, R is selected from a group Ph'CR17R18-where Ph' is a phenyl group substituted by one to three substituents R10c; R17 and 1 O 1 -J R are the same or different and each is selected from hydrogen and methyl; or R 1 ft and R together with the carbon atom to which they are attached form a 17 1R cyclopropyl group; or one of R andR is hydrogen and the other is selected from amino, methylamino, C1-4 acylamino, and C1-4 alkoxycarbonylamino. The group Rld-A-NH or Rld-A-NH linked to the 4-position of the pyrazole ring can take the form of an amide Rld-C(=O)NH, urea RId-NHC(=O) or carbamate Rld-OC(=O). Amides and ureas are preferred. In one embodiment, the compound is an amide. In another embodiment, the compound is a urea. When Rld is a phenyl group, the phenyl group may be 2,6-disubstituted, 2,3-disubstituted, 2,4-disubstituted 2,5-disubstituted, 2,3,6-trisubstituted or 2,4,6-trisubstituted. In one group of preferred compounds, the phenyl group Rlb is 2,6-disubstituted, 2,3-disubstituted or 2,4,6-trisubstituted. More particularly, a phenyl group R1 may be disubstituted at positions 2- and 6- with substituents selected from fluorine, chlorine and Ra-Rb, where Ra is O and Rb is C1-4 alkyl, with fluorine being a particular substituent. Alternatively, two adjacent substituents (preferably in the 2- and 3-positions), together with the phenyl ring to which they are attached, may form a 2, 3-dihydro-benzo[l,4]dioxine group, or an indolyl group or a 2,3-dihydrobenzofuranyl group. In another group of preferred compounds, the phenyl group Rld is 2,4-disubstituted or 2,5-disubstituted. The 2-substituent may be, for example, a halogen (e.g. F or CI) or a methoxy group. In one particular group of compounds, the 2-substituent is methoxy. The 5-substituent, when present, can be selected from, for example, halogen (e.g. CI or F), C1-4 alkyl (e.g. tert-butyl or isopropyl), methoxy, trifluoromethoxy, trifluoromethyl, or a group HetN-SCh- where "HetN" is a nitrogen-containing saturated monocyclic heterocycle such as piperazino, N-CM alkylpiperazino, morpholino, piperidino or pyrrolidino. One preferred 5-subsitutent is CI, and a preferred 2,5-combination is 2-methoxy-5-chlorophenyl. In a further group of compounds, the phenyl group R has a single substituent at the 4-position of the phenyl ring. The substituent can be, for example, a halogen atom (preferably fluorine or chlorine, most preferably fluorine) or a trifluoromethyl group. In another group of compounds, the phenyl group Rld is 2,4-disubstituted. When two adjacent substituents together with the phenyl ring to which they are attached form an indolyl group or a 2,3-dihydrobenzofuranyl group, it is preferred that the said groups are the 4-indolyl and 7-(2,3-dihydrobenzofuranyl) groups respectively. Where R is mono-substituted, and the substituent is located at the 4-position of the phenyl ring, it is preferably other than a difluoromethoxy group or a 2-chloroethyl group. In one embodiment, where Rld is disubstituted, the substituted phenyl group may be other than a dimethoxyphenyl group, and may be other than a 2-fluoro-5-methoxyphenyl group. In another embodiment, the sub-group RIb may include the 2-fluoro-5-methoxyphenyl group. Such compounds have good activity against Aurora kinase. Where two adjacent substituents combine to form a ring so that R is an indole group, the indole group is preferably other than an indol-7-yl group. One preferred sub-group of compounds of the invention is the group wherein Rlb is selected from the groups Al to A8, A10, A12 and A14 to A24 set out in Table 1 above. Particularly preferred groups Rld include 2,6-difluorophenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-fluorophenyl, 2,6-dichlorophenyl, 2,4,6-trifluorophenyl and 2,3-dihydro-benzo[l,4]dioxine. One currently preferred group R is 2,6-difluorophenyl. Compounds of the formula (VII) show good CDK inhibitory activity and are also particularly active against Aurora kinases. A particularly preferred sub-group of compounds within formula (VII) is represented by formula (Vila): (Formula Removed) where Rld is as hereinbefore defined. For the avoidance of doubt, it is to be understood that each general and specific preference, embodiment and example of the groups R may be combined with each general and specific preference, embodiment and example of the group R and any sub-groups thereof and that all such combinations are embraced by this application. The various functional groups and substituents making up the compounds of the formula (VII) are typically chosen such that the molecular weight of the compound of the formula (VII) 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. More preferably, the molecular weight is less than 525 and, for example, is 500 or less. Particular and specific compounds of the invention are as illustrated in the examples below. Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate, and protected forms thereof, for example, as discussed below. Many compounds of the formula (VII) 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, sulphonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (VII) include the salt forms of the compounds. Acid addition salts may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic, ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. For example, 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 a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth metal cations such as Ca2+ and Mg2+, and other cations such as Al . Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH/) and substituted ammonium ions (e.g., NH3R , NH2R2 , NHR3 , NR4 ). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, 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(CH3)4+. Where the compounds of the formula (VII) 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 salts are within the scope of formula (VII). The salt forms of the compounds of theinvention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge etai, 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 salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention. Compounds of the formula (VII) containing an amine function may also form N-oxides. A reference herein to a compound of the formula (VII) 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 heterocycle. 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, 4th 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 zn-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane. Compounds of the formula may exist in a number of different geometric isomeric, and tautomeric forms and references to compounds of the formula (VII) 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 (VII). For example, in compounds of the formula (II) the benzimidazole group may take either of the following two tautomeric forms A and B (wherein in each case andR6 are hydrogen and R is morpholinylmethyl). For simplicity, the general formula (II) illustrates form A but the formula is to be taken as embracing both tautomeric forms. (Formula Removed) The pyrazole ring may also exhibit tautomerism and can exist in the two tautomeric forms C and D below. (Formula Removed) 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/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aC1-nitro. (Formula Removed) Where compounds of the formula (VII) contain one or more chiral centres, and can exist in the form of two or more optical isomers, references to compounds of the formula (VII) include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures or two or more optical isomers, unless the context requires otherwise. 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 109-114, 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. Where compounds of the formula (VII) 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 (VII) 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 (VII) 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 (VII) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer). The compounds of the invention include compounds with one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope H, H (D), and H (T). Similarly, references to carbon and oxygen include within their scope respectively I2C, I3C and I4C and I60 and 180. The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds contain no radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context. Esters such as carboxylic acid esters and acyloxy esters of the compounds of formula (VII) bearing a carboxylic acid group or a hydroxyl group are also embraced by Formula (VII). Examples of esters are compounds containing the group -C(=O)OR, wherein R is an ester substituent, for example, a C1-7 alkyl group, a C3.20 heterocyclyl group, or a C5.20 aryl group, preferably a C1-7 alkyl group. Particular examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh. Examples of acyloxy (reverse ester) groups are represented by -OC(=O)R, wherein R is an acyloxy substituent, for example, a C1.7 alkyl group, a C3-20 heterocyclyl group, or a C5.20 aryl group, preferably a C1.7 alkyl group. Particular examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, -OC(=O)Ph, and -OC(=O)CH2Ph. Also encompassed by formula (VII) are any polymorphic forms of the compounds, solvates (e.g. hydrates), complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds, and pro-drugs of the compounds. By "prodrugs" is meant for example any compound that is converted in vivo into a biologically active compound of the formula (VII). For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)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(=O)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(=O)OR wherein R is: C1-7alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu); C1-7aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C1-7alkyl (e.g., acyloxymethyl; acyloxy ethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1 -(1 -methoxy-1 -methyl)ethyl-carbonxyloxy ethyl; 1 -(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1 -isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1 -cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1 -cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy)carbonyloxymethyl; l-(4-tetrahydropyranyloxy)carbonyloxyethyl; (4-tetrahydropyranyl)carbonyloxymethyl; and 1 -(4-tetrahydropyranyl)carbonyloxy ethyl). 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 ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. Biological Activity The compounds of the formula (VII) are inhibitors of cyclin dependent kinases. For example, compounds of the invention have activity against CDK1, CDK2, CDK3, CDK5, CDK6 and CDK7 kinases. In addition, CDK4, CDK8 and/or CDK9 may be of interest. Compounds of the invention also have activity against glycogen synthase kinase-3 (GSK-3). Compounds of the invention also have activity against Aurora kinases. As a consequence of their activity in modulating or inhibiting CDK and Aurora kinases and glycogen synthase kinase, they are expected to be useful in providing a means of arresting, or recovering control of, the cell cycle in abnormally dividing cells. It is therefore anticipated that the compounds will prove useful in treating or preventing proliferative disorders such as cancers. It is also envisaged that the compounds of the invention will be useful in treating conditions such as viral infections, autoimmune diseases and neurodegenerative diseases for example. CDKs play a role in the regulation of the cell cycle, apoptosis, transcription, differentiation and CNS function. Therefore, CDK inhibitors could be useful in the treatment of diseases in which there is a disorder of proliferation, apoptosis or differentiation such as cancer. In particular RB+ve tumours may be particularly sensitive to CDK inhibitors. RB-ve tumours may also be sensitive to CDK inhibitors. Examples of cancers which may be inhibited include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermis, liver, lung, for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, oesophagus, gall bladder, ovary, pancreas e.g. exocrine pancreatic carcinoma, stomach, cervix, thyroid, prostate, or skin, for example squamous cell carcinoma; a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumour of myeloid lineage, for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocyte leukemia; thyroid follicular cancer; a tumour of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; a tumour of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentoum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma. CDKs are also known to play a role in apoptosis, proliferation, differentiation and transcription and therefore CDK inhibitors could also be useful in the treatment of the following diseases other than cancer; viral infections, for example herpes virus, pox virus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; prevention of AIDS development in HIV-infected individuals; chronic inflammatory diseases, for example systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus; cardiovascular diseases for example cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, for example Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotropic lateral sclerosis, retinitis pigmentosa, spinal muscular atropy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndromes, ischemic injury associated myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, haematological diseases, for example, chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, aspirin-senstive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain. It has also been discovered that some cyclin-dependent kinase inhibitors can be used in combination with other anticancer agents. For example, the cytotoxic activity of cyclin-dependent kinase inhibitor flavopiridol, has been used with other anticancer agents in combination therapy. Thus, in the pharmaceutical compositions, uses or methods of this invention for treating a disease or condition comprising abnormal cell growth, the disease or condition comprising abnormal cell growth in one embodiment is a cancer. Particular subsets of cancers include breast cancer, ovarian cancer, colon cancer, prostate cancer, oesophageal cancer, squamous cancer and non-small cell lung carcinomas. In the case of compounds having activity against Aurora kinase, particular examples of cancers where it is envisaged that the Aurora kinase inhibiting compounds of the invnention will be useful include: human breast cancers (e.g. primary breast tumours, node-negative breast cancer, invasive duct adenocarcinomas of the breast, non-endometrioid breast cancers); ovarian cancers (e.g. primary ovarian tumours); pancreatic cancers; human bladder cancers; colorectal cancers (e.g. primary colorectal cancers); gastric tumours; renal cancers; cervical cancers: neuroblastomas; melanomas; lymphomas; prostate cancers; leukemia; non-endometrioid endometrial carcinomas; gliomas; non-Hodgkin's lymphoma; Cancers which may be particularly amenable to Aurora inhibitors include breast, bladder, colorectal, pancreatic, ovarian, non-Hodgkin's lymphoma, gliomas and nonendometrioid endometrial carcinomas. The activity of the compounds of the invention as inhibitors of cyclin dependent kinases, Aurora kinases and glycogen synthase kinase-3 can be measured using the assays set forth in the examples below and the level of activity exhibited by a given compound can be defined in terms of the IC50 value. Preferred compounds of the present invention are compounds having an IC50 value of less than 1 micromole, more preferably less than 0.1 micromole. Methods for the Preparation of Compounds of the Formula (VII) Compounds of the formula (VII) can be prepared in accordance with synthetic methods well known to the skilled person. Unless stated otherwise Rld is as herein defined. Compounds of the formula (VII) wherein R1 -A- forms an acyl group can be prepared as illustrated in Scheme 1 below. In Scheme 1, R2 is hydrogen and the moieties R3 and R4 together with the carbon atoms to which they are attached form a benzene ring substituted with a morpholinylmethyl group. As shown in Scheme 1, an amine of the formula (X) can be reacted with with a carboxylic acid, or reactive derivative thereof, of the formula R -CO2H under standard amide formation conditions. Thus, for example, the coupling reaction between the carboxylic acid and the amine (X) can be 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) (Sheehan et al, J. Amer. ChemSoc. 1955,77, 1067), l-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (EDC) (Sheehan et al, J. Org. Chem., 1961, 26, 2525), uronium-based coupling agents such as 0-(7-azabenzotriazol-l-yl)-A^A^A^',A^'-tetramethyluronium hexafluorophosphate (HATU) (L. A. Carpino, J. Amer. Chem. Soc, 1993, 115, 4397) and phosphonium-based coupling agents such as 1-benzo-triazolyloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205). Carbodiimide-based coupling agents are advantageously used in combination with 1-hydroxyazabenzotriazole (HOAt) or 1-hydroxybenzotriazole (HOBt) (Konig et al, Chem. Ber., 103, 708, 2024-2034). Preferred coupling reagents include EDC and DCC in combination with HO At or HOBt. (Scheme Removed) Scheme 1 The coupling reaction is typically carried out in a non-aqueous, non-protic solvent such as acetonitrile, dioxan, dimethylsulphoxide, dichloromethane, dimethylformamide or N-methylpyrrolidine, or in an aqueous solvent optionally together with one or more miscible co-solvents. The reaction can be carried out at room temperature or, where the reactants are less reactive (for example in the case of electron-poor anilines bearing electron withdrawing groups such as sulphonamide groups) at an appropriately elevated temperature. The reaction may be carried out in the presence of a non-interfering base, for example a tertiary amine such as triethylamine or N, N-diisopropylethylamine. As an alternative, a reactive derivative of the carboxylic acid, e.g. an anhydride or acid chloride, may be used. Reaction with a reactive derivative such an anhydride is typically accomplished by stirring the amine and anhydride at room temperature in the presence of a base such as pyridine. Amines of the formula (X) can be prepared by reduction of the corresponding nitrocompound of the formula (XI) under standard conditions. The reduction may be effected, for example by catalytic hydrogenation in the presence of a catalyst such as palladium on carbon in a polar solvent such as ethanol or dimethylformamide at room temperature. The compounds of the formula (XI) can be prepared by reaction of a nitro-pyrazole carboxylic acid of the formula (XII) with a diamine of the formula (XII). The reaction between the diamine (XIII) and carboxylic acid (XII) can be carried out in the presence of a reagent such as DCC or EDC in the presence of HOBt as described above, under amide coupling conditions as described previously, to give an intermediate ort/zo-aminophenylamide (not shown) which is then cyclised to form the benzimidazole ring. The final cyclisation step is typically carried out by heating under reflux in the presence of acetic acid. Diamines of the formula (XIII) can be obtained commercially or can be prepared from appropriately substituted phenyl precursor compounds using standard chemistry and well known functional group interconversions, see for example, Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2), and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8), 1995. Examples of methods of preparing diamines of the formula (XIII) are provided in the examples below. The diamines of the formula (XIII) can also be reacted with carboxylic acids of the formula (XIV) to give compounds of the formula (VII). (Formula Removed) The reaction of the diamine (XIII) with the carboxylic acid (XIV) can be carried out under conditions analogous to those described above for preparing the nitrocompounds (XI). Carboxylic acids of the formula (XIV) can be prepared by the sequence of reactions shown in Scheme 2. As shown in Scheme 2, a substituted or unsubstituted 4-nitro-3-pyrazole carboxylic acid (XV) can be esterified by reaction with thionyl chloride to give the acid chloride intermediate followed by reaction with ethanol to form the ethyl ester (XVI). Alternatively, the esterification can be carried out by reacting the alcohol and carboxylic acid in the presence of an acidic catalyst, one example of which is thionyl chloride. The reaction is typically carried out at room temperature using the esterifying alcohol (e.g. ethanol) as the solvent. The nitro group can then be reduced using palladium on carbon according to standard methods to give the amine (XVII). The amine (XVII) is coupled with an appropriate carboxylic acid R'-CCbH under amide forming conditions the same as or analogous to those described above to give the amide (XVIII). The ester group of the amide (XVIII) can then be hydrolysed using an alkali metal hydroxide such as sodium hydroxide in a polar water miscible solvent such as methanol, typically at room temperature. (Scheme Removed) Scheme 2 Compounds of the formula (VII) in which A is NH(CO) can be prepared using standard methods for the synthesis of ureas. For example, such compounds can be prepared by reacting an aminopyrazole compound of the formula (X) with a suitably substituted phenylisocyanate in a polar solvent such as DMF. The reaction is conveniently carried out at room temperature. A further route to compounds of the formula (VII) is shown in Scheme 3 below. In Scheme 3, X is N and the moieties R3 and R4 together with the carbon atoms to which they are attached form a benzene ring substituted with a morpholinylmethyl group. (Scheme Removed) Scheme 3 As illustrated in Scheme 3, the ketone (XIX) can be reacted with dimethylformamide-dimethylacetal at elevated temperature to give an a,P-unsaturated ketone (XX) (Jachak et al, Montash. Chem., 1993,124(2), 199-207), which upon heating with hydrazine hydrate gives a pyrazole of formula (XXI). This can then be nitrated as discussed herein to give the nitropyrazole (XXII). The starting materials for the synthetic routes shown in the Schemes above, pyrazoles of Formula (XII) and (XV), can either be obtained commercially or can be prepared by methods known to those skilled in the art. They can be obtained using known methods e.g. from ketones, such as in a process described in EP308020 (Merck), or the methods discussed by Schmidt in Helv. Chim. Acta., 1956, 39, 986-991 and Helv. Chim. Acta., 1958, 41, 306-309. Alternatively they can be obtained by conversion of a commercially available pyrazole, for example those containing halogen, nitro, ester, or amide functionalities, to pyrazoles containing the desired functionality by standard methods known to a person skilled in the art. For example, in 3-carboxy-4-nitropyrazole, the nitro group can be reduced to an amine by standard methods. 4-Nitro-pyrazole-3-carboxylic acid (XII) can either be obtained commercially or can be prepared by nitration of the corresponding 4-unsubstituted pyrazole carboxy compound, and pyrazoles containing a halogen, may be utilized in coupling reactions with tin or palladium chemistry. A substituted or unsubstituted 4-nitro-3-pyrazole carboxylic acid can be esterified by reaction with thionyl chloride to give the acid chloride intermediate followed by reaction with an alcohol to form the ester of formula (XVI). Alternatively, the esterification can be carried out by reacting the alcohol and carboxylic acid in the presence of an acidic catalyst, one example of which is thionyl chloride. The reaction is typically carried out at room temperature using the esterifying alcohol (e.g. ethanol) as the solvent. 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(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc). An aldehyde or ketone group may be protected, for example, as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is converted to a diether (>C(OR)2), by reaction 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 urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OCCCHsfcCeliiCeHs, -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), or as a 2(-phenylsulphonyl)ethyloxy amide (-NH-Psec). Other protecting groups for amines, such as cyclic amines and heterocyclic N-H groups, include toluenesulphonyl (tosyl) and methanesulphonyl (mesyl) groups and benzyl groups such as a para-methoxybenzyl (PMB) group. A carboxylic acid group may be protected as an ester for example, as: an C1.7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a C1-7 haloalkyl ester (e.g., a C1-7 trihaloalkyl ester); a triC1-7alkylsilyl-C1-7alkyl ester; or a C5-20 aryl-C1-7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide. A thiol group may be protected, for example, as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3). Methods of Purification The compounds may be isolated and purified by a number of methods well known to those skilled in the art and examples of such methods include chromatographic techniques such as column chromatography (e.g. flash chromatography) and HPLC. 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. One such system for purifying compounds via preparative LC-MS is described in the experimental section below although a person skilled in the art will appreciate that alternative systems and methods to those described could be used. In particular, normal phase preparative LC based methods might be used in place of the reverse phase methods described here. Most preparative LC-MS systems utilise reverse phase LC and volatile acidic modifiers, since the approach is very effective for the purification of small molecules and because the eluents are compatible with positive ion electrospray mass spectrometry. Employing other chromatographic solutions e.g. normal phase LC, alternatively buffered mobile phase, basic modifiers etc as outlined in the analytical methods described above could alternatively be used to purify the compounds. Pharmaceutical Formulations While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation) comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents. Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other materials, as described herein. 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. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation. The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, 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. Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches. Pharmaceutical compositions containing compounds of the formula (VII) can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. 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 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. 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, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating. 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 or duodenum. 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 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. 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 may be prepared in accordance with methods well known to those skilled in the art. Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods. Compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection. 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. 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 inventions 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 intended for oral administration may contain from 0.1 milligrams to 2 grams of active ingredient, more usually from 10 milligrams to 1 gram, for example, 50 milligrams to 500 milligrams. 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 Diagnosis and Treatment It is envisaged that the compounds of the formula (VII) will useful in the prophylaxis or treatment of a range of disease states or conditions mediated by cyclin dependent kinases, glycogen synthase kinase-3 and Aurora kinases. Examples of such disease states and conditions are set out above. Compounds of the formula (VII) are generally administered to a subject in need of such administration, for example a human or animal patient, preferably 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 (VII) 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 pulsatile or continuous manner. A typical daily dose of the compound can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 10 nanograms to 10 milligrams per kilogram of bodyweight although higher or lower doses may be administered where required. Ultimately, 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. The compounds of the formula (VII) can be administered as the sole therapeutic agent or they can be administered in combination therapy with one of more other compounds for treatment of a particular disease state, for example a neoplastic disease such as a cancer as hereinbefore defined. Examples of other therapeutic agents that may be administered together (whether concurrently or at different time intervals) with the compounds of the formula (VII) include but are not limited to topoisomerase inhibitors, alkylating agents, antimetabolites, DNA binders and microtubule inhibitors (tubulin targeting agents), such as cisplatin, cyclophosphamide, doxorubicin, irinotecan, fludarabine, 5FU, taxanes, mitomycin C, or radiotherapy. For the case of CDK or Aurora inhibitors combined with other therapies, the two or more treatments may be given in individually varying dose schedules and via different routes. Where the compound of the formula (VII) is administered in combination therapy with one, two, three, four or more other therapeutic agents (preferably one or two, preferably one), the compounds can be administered simultaneously or sequentially. 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). 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. For use in combination therapy with another chemotherapeutic agent, the compound of the formula (VII) 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. 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. A person skilled in the art would know through their common general knowledge the dosing regimes and combination therapies to use. Prior to administration of a compound of the formula (VII), 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 Aurora kinases. 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 upregulation of Aurora kinase, this includes elevated expression or over-expression of Aurora kinase, including gene amplification (i.e. multiple gene copies) and increased expression by a transcriptional effect, and hyperactivity and activation of Aurora kinase, including activation by mutations.. Thus, the patient may be subjected to a diagnostic test to detect a marker characteristic of over-expression, up-regulation or activation of Aurora kinase. The term diagnosis includes screening. By marker we include genetic markers including, for example, the measurement of DNA composition to identify mutations of Aurora or CDC4. The term marker also includes markers which are characteristic of up regulation of Aurora or cyclin E, including enzyme activity, enzyme levels, enzyme state (e.g. phosphorylated or not) and mRNA levels of the aforementioned proteins. The diagnostic tests are typically conducted on a biological sample selected from tumour biopsy samples, blood samples (isolation and enrichment of shed tumour cells), stool biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, or urine. It has been found, see Ewart-Toland et al., (Nat Genet. 2003 Aug;34(4):403-12), that individuals forming part of the sub-population possessing the Ile31 variant of the STK gene (the gene for Aurora kinase A) may have an increased susceptibility to certain forms of cancer. It is envisaged therefore that such individuals suffering from cancer will benefit from the administration of compounds having Aurora kinase inhibiting activity. A patient suffering from, or suspected of suffering from, a cancer may therefore be screened to determine whether he or she forms part of the Ile31 variant sub-population. The screening process will typically involve direct sequencing, oligonucleotide microarray analysis, or a mutant specific antibody. Tumours with activating mutants of Aurora or up-regulation of Aurora including any of the isoforms thereof, may be particularly sensitive to Aurora inhibitors. Tumours may preferentially be screened for up-regulation of Aurora or for Aurora possessing the Ile31 variant prior to treatment (Ewart-Toland et al., Nat Genet. 2003 Aug;34(4):403-12). Ewart-Toland et al identified a common genetic variant in STK15 (resulting in the amino acid substitution F31I) that is preferentially amplified and associated with the degree of aneuploidy in human colon tumors. These results are consistent with an important role for the Ile31 variant of STK15 in human cancer susceptibility. The aurora A gene maps to the chromosome 20ql3 region that is frequently amplified in many cancers e.g. breast, bladder, colon, ovarian, pancreatic. Patients with a tumour that has this gene amplification might be particularly sensitive to reatments targeting aurora kinase inhibition Methods of identification and analysis of Aurora mutations and up-regulation of Aurora isoforms and chromosome 20ql3 amplification 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 hybridisation. In screening by RT-PCR, the level of Aurora 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. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc., or Innis, M.A. et-al., eds. PCR Protocols: a guide to methods and applications, 1990, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., 2001, 3rd 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 Aurora 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 labeled, 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. Current Protocols in Molecular Biology, 2004, 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. Alternatively, the protein products expressed from the mRNAs may be assayed by immunohistochemistry of tumour samples, solid phase immunoassay with microtiter 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 artisan will recognize that all such well-known techniques for detection of Aurora up-regulation and mutants of Aurora could be applicable in the present case. In addition, all of these techniques could also be used to identify tumours particularly suitable for treatment with CDK inhibitors. Tumours with mutants of CDC4 or up-regulation, in particular over-expression, of cyclin E or loss of p21 or p27 may be particularly sensitive to CDK inhibitors. Tumours may preferentially be screened for up-regulation, in particular over-expression, of cyclin E (Harwell RM, Mull BB, Porter DC, Keyomarsi K.; J Biol Chem. 2004 Mar 26;279(13):12695-705) or loss of p21 or p27 or for CDC4 variants prior to treatment (Rajagopalan H, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelstein B, Lengauer C; Nature. 2004 Mar 4;428(6978):77-81). Antifungal Use In a further aspect, the invention provides the use of the compounds of the formula (VII) as hereinbefore defined as antifungal agents. The compounds of the formula (VII) may be used in animal medicine (for example in the treatment of mammals such as humans), or in the treatment of plants (e.g. in agriculture and horticulture), or as general antifungal agents, for example as preservatives and disinfectants. In one embodiment, the invention provides a compound of the formula (VII) as hereinbefore defined for use in the prophylaxis or treatment of a fungal infection in a mammal such as a human. Also provided is the use of a compound of the formula (VII) for the manufacture of a medicament for use in the prophylaxis or treatment of a fungal infection in a mammal such as a human. For example, compounds of the invention may be administered to human patients suffering from, or at risk of infection by, topical fungal infections caused by among other organisms, species of Candida, Trichophyton, Microsporum or Epidermophyton, or in mucosal infections caused by Candida albicans (e.g. thrush and vaginal candidiasis). The compounds of the invention can also be administered for the treatment or prophylaxis of systemic fungal infections caused by, for example, Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, Coccidiodies, Paracoccidioides, Histoplasma or Blastomyces. In another aspect, the invention provides an antifungal composition for agricultural (including horticultural) use, comprising a compound of the formula (VII) together with an agriculturally acceptable diluent or carrier. The invention further provides a method of treating an animal (including a mammal such as a human), plant or seed having a fungal infection, which comprises treating said animal, plant or seed, or the locus of said plant or seed, with an effective amount of a compound of the formula (VII). The invention also provides a method of treating a fungal infection in a plant or seed which comprises treating the plant or seed with an antifungally effective amount of a fungicidal composition containing a compound of the formula (VII) as hereinbefore defined. Differential screening assays may be used to select for those compounds of the present invention with specificity for non-human CDK enzymes. Compounds which act specifically on the CDK enzymes of eukaryotic pathogens can be used as antifungal or anti-parasitic agents. Inhibitors of the Candida CDK kinase, CKSI, can be used in the treatment of candidiasis. Antifungal agents can be used against infections of the type hereinbefore defined, or opportunistic infections that commonly occur in debilitated and immunosuppressed patients such as patients with leukemias and lymphomas, people who are receiving immunosuppressive therapy, and patients with predisposing conditions such as diabetes mellitus or AIDS, as well as for non-immunosuppressed patients. Assays described in the art can be used to screen for agents which may be useful for inhibiting at least one fungus implicated in mycosis such as candidiasis, aspergillosis, mucormycosis, blastomycosis, geotrichosis, cryptococcosis, chromoblastomycosis, coccidiodomycosis, conidiosporosis, histoplasmosis, maduromycosis, rhinosporidosis, nocaidiosis, para-actinomycosis, penicilliosis, monoliasis, or sporotrichosis. The differential screening assays can be used to identify anti-fungal agents which may have therapeutic value in the treatment of aspergillosis by making use of the CDK genes cloned from yeast such as Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, or Aspergillus terreus, or where the mycotic infection is mucon-nycosis, the CDK assay can be derived from yeast such as Rhizopus arrhizus, Rhizopus oryzae, Absidia corymbifera, Absidia ramosa, or Mucorpusillus. Sources of other CDK enzymes include the pathogen Pneumocystis carinii. By way of example, in vitro evaluation of the antifungal activity of the compounds can be performed by determining the minimum inhibitory concentration (M.I.C.) which is the lowest concentration of the test compounds, in a suitable medium, at which growth of the particular microorganism fails to occur. In practice, a series of agar plates, each having the test compound incorporated at a particular concentration is inoculated with a standard culture of, for example, Candida albicans and each plate is then incubated for an appropriate period at 37 °C. The plates are then examined for the presence or absence of growth of the fungus and the appropriate M.I.C. value is noted. Alternatively, a turbidity assay in liquid cultures can be performed and a protocol outlining an example of this assay can be found in Example 314. The in vivo evaluation of the compounds can be carried out at a series of dose levels by intraperitoneal or intravenous injection or by oral administration, to mice that have been inoculated with a fungus, e.g., a strain of Candida albicans or Aspergillus flavus. The activity of the compounds can be assessed by monitoring the growth of the fungal infection in groups of treated and untreated mice (by histology or by retrieving fungi from the infection). The activity may be measured in terms of the dose level at which the compound provides 50% protection against the lethal effect of the infection (PD50). For human antifungal use, the compounds of the formula (VII) can be administered alone or in admixture with a pharmaceutical carrier selected in accordance with the intended route of administration and standard pharmaceutical practice. Thus, for example, they may be administered orally, parenterally, intravenously, intramuscularly or subcutaneously by means of the formulations described above in the section headed "Pharmaceutical Formulations". For oral and parenteral administration to human patients, the daily dosage level of the antifungal compounds of the formula (VII) can be from 0.01 to 10 mg/kg (in divided doses), depending on inter alia the potency of the compounds when administered by either the oral or parenteral route. Tablets or capsules of the compounds may contain, for example, from 5 mg to 0.5 g of active compound for administration singly or two or more at a time as appropriate. The physician in any event will determine the actual dosage (effective amount) which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. Alternatively, the antifungal compounds of formula (VII) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be incorporated, at a concentration between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required. In addition to the therapeutic uses described above, anti-fungal agents developed with such differential screening assays can be used, for example, as preservatives in foodstuff, feed supplement for promoting weight gain in livestock, or in disinfectant formulations for treatment of non-living matter, e.g., for decontaminating hospital equipment and rooms. In similar fashion, side by side comparison of inhibition of a mammalian CDK and an insect CDK, such as the Drosophilia CDK5 gene (Hellmich et al. (1994) FEBS Lett 356:317-21), will permit selection amongst the compounds herein of inhibitors which discriminate between the human/mammalian and insect enzymes. Accordingly, the present invention expressly contemplates the use and formulation of the compounds of the invention in insecticides, such as for use in management of insects like the fruit fly. In yet another embodiment, certain of the subject CDK inhibitors can be selected on the basis of inhibitory specificity for plant CDK's relative to the mammalian enzyme. For example, a plant CDK can be disposed in a differential screen with one or more of the human enzymes to select those compounds of greatest selectivity for inhibiting the plant enzyme. Thus, the present invention specifically contemplates formulations of the subject CDK inhibitors for agricultural applications, such as in the form of a defoliant or the like. For agricultural and horticultural purposes the compounds of the invention may be used in the form of a composition formulated as appropriate to the particular use and intended purpose. Thus the compounds may be applied in the form of dusting powders, or granules, seed dressings, aqueous solutions, dispersions or emulsions, dips, sprays, aerosols or smokes. Compositions may also be supplied in the form of dispersible powders, granules or grains, or concentrates for dilution prior to use. Such compositions may contain such conventional carriers, diluents or adjuvants as are known and acceptable in agriculture and horticulture and they can be manufactured in accordance with conventional procedures. The compositions may also incorporate other active ingredients, for example, compounds having herbicidal or insecticidal activity or a further fungicide. The compounds and compositions can be applied in a number of ways, for example they can be applied directly to the plant foliage, stems, branches, seeds or roots or to the soil or other growing medium, and they may be used not only to eradicate disease, but also prophylactically to protect the plants or seeds from attack. By way of example, the compositions may contain from 0.01 to 1 wt.% of the active ingredient. For field use, likely application rates of the active ingredient may be from 50 to 5000 g/hectare. The invention also contemplates the use of the compounds of the formula (VII) in the control of wood decaying fungi and in the treatment of soil where plants grow, paddy fields for seedlings, or water for perfusion. Also contemplated by the invention is the use of the compounds of the formula (VII) to protect stored grain and other non-plant loci from fungal infestation. EXAMPLES The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples. In the examples, the compounds prepared were characterised by liquid chromatography and mass spectroscopy using the systems and operating conditions set out below. Where chlorine is present, the mass quoted for the compound is for C1- Several systems were used, as described below, and these were equipped with were set up to run under closely similar operating conditions. The operating conditions used are also described below. Platform system 1 System: Waters 2790/Platform LC Mass Spec Detector: Micromass Platform LC PDA Detector: Waters 996 PDA Analytical conditions: Eluent A: 5% CH3CN in 95% H20 (0.1 % Formic Acid) Eluent B: CH3CN (0.1 % Formic Acid) Gradient: 10-95% eluent B Flow: 1.2 ml/min Column: Synergi 4um Max-RP Cn, 80A, 50 x 4.6 mm (Phenomenex) MS conditions: Capillary voltage: 3.5 kV Cone voltage: 30 V Source Temperature: 120 °C FractionLvnx system 1 System: Waters FractionLynx (dual analytical/prep) Mass Spec Detector: Waters-Micromass ZQ PDA Detector: Waters 2996 PDA Analytical conditions: Eluent A: H20 (0.1 % Formic Acid) Eluent B: CH3CN (0.1 % Formic Acid) Gradient: 5-95% eluent B Flow: 1.5 ml/min Column: Synergi 4um Max-RP Cn, 80A, 50 x 4.6 mm (Phenomenex) MS conditions: Capillary voltage: 3.5 kV Cone voltage: 30 V Source Temperature: 120 °C Desolvation Temperature: 300 °C Platform System 2 HPLC System: Waters 2795 Mass Spec Detector: Micromass Platform LC PDA Detector: Waters 2996 PDA Acidic Analytical conditions: Eluent A: H20 (0.1 % Formic Acid) Eluent B: CH3CN (0.1% Formic Acid) Gradient: 5-95% eluent B over 3.5 minutes Flow: 1.5 ml/min Column: Phenomenex Synergi 4µ Max-RP 80A, 50x4.6mm Basic Analytical conditions: Eluent A: H2O (10mM NH4HCO3 buffer adjusted to pH=9.5 with NH4OH) Eluent B: CH3CN Gradient: 05-95%) eluent B over 3.5 minutes Flow: 1.5 ml/min Column: Waters XTerra MS Cig 5um 4.6x50mm Polar Analytical conditions: Eluent A: H20 (0.1% Formic Acid) Eluent B: CH3CN (0.1 % Formic Acid) Gradient: 00-50% eluent B over 3 minutes Flow: 1.5 ml/min Column: Phenomenex Synergi 4u Hydro 80A, 50x4.6mm MS conditions: Capillary voltage: 3.5 kV Cone voltage: 30 V Source Temperature: 120 °C Scan Range: 165-700 amu Ionisation Mode: ElectroSpray Negative, Positive or Positive & Negative FractionLvnx System 2 System: Waters FractionLynx (dual analytical/prep) HPLC Pump: Waters 2525 Injector-Autosampler: Waters 2767 Mass Spec Detector: Waters-Micromass ZQ PDA Detector: Waters 2996 PDA Analytical conditions: Eluent A: H2O (0.1 % Formic Acid) Eluent B: CH3CN (0.1 % Formic Acid) Gradient: 5-95% eluent B over 5 minutes Flow: 2.0 ml/min Column: Phenomenex Synergi 4µ Max-RP 80A, 50x4.6mm Polar Analytical conditions: Eluent A: H20 (0.1 % Formic Acid) Eluent B: CH3CN (0.1 % Formic Acid) Gradient: 00-50% eluent B over 5 minutes Flow: 2.0 ml/min Column: Phenomenex Synergi 4µ Max-RP 80A, 50x4.6mm MS conditions: Capillary voltage: 3.5 kV Cone voltage: 25 V Source Temperature: 120 °C Scan Range: 125-800 amu Ionisation Mode: ElectroSpray Positive or ElectroSpray Positive & Negative Mass Directed Purification LC-MS System The following preparative chromatography systems can be used to purify the compounds of the invention. • Hardware: Waters Fractionlynx system: 2767 Dual 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 • Software: Masslynx 4.0 • Columns: 1. Low pH chromatography: Phenomenex Synergy MAX-RP, l0µ, 150 x 15mm (alternatively used same column type with 100 x 21.2mm dimensions). 2. High pH chromatography: Phenomenex Luna C18 (2), 10 µ, 100 x 21.2 mm (alternatively used Thermo Hypersil Keystone BetaBasic C18, 5 µ, 100 x 21.2 mm) • Eluents: 1. Low pH chromatography: Solvent A: H2O + 0.1% Formic Acid, pH 1.5 Solvent B: CH3CN + 0.1% Formic Acid 2. High pH chromatography: Solvent A: H2O + 10 mM NH4HCO3 + NH4OH, pH 9.5 Solvent B: CH3CN 3. Make up solvent: MeOH + 0.1% formic acid (for both chromatography type) • Methods: Prior to using preparative chromatography to isolate and purify the product compounds, analytical LC-MS can first be used to determine the most appropriate conditions for preparative chromatography. A typical routine is to run an analytical LC-MS using the type of chromatography (low or high pH) most suited for compound structure. Once the analytical trace shows good chromatography, a suitable preparative method of the same type can be chosen. Typical running condition for both low and high pH chromatography methods are: Flow rate: 24 ml/min Gradient: Generally all gradients have an initial 0.4 min step with 95% A + 5% B. Then according to analytical trace a 3.6 min gradient is chosen in order to achieve good separation (e.g. from 5% to 50% B for early retaining compounds; from 35% to 80% B for middle retaining compounds and so on) Wash: 1 minute wash step is performed at the end of the gradient Re-equilibration: A 2.1 minute re-equilibration step is carried out to prepare the system for the next run Make Up flow rate: 1 ml/min • Solvent: All compounds were usually dissolved in 100% MeOH or 100% DMSO • MS running conditions: Capillary voltage: 3.2 kV Cone voltage: 25 V Source Temperature: 120 °C Multiplier: 500 V Scan Range: 125-800 amu Ionisation Mode: ElectroSpray Positive Analytical LC-MS System HPLC System: Waters 2795 Mass Spec Detector: Micromass Platform LC PDA Detector: Waters 2996 PDA Acidic Analytical conditions : Eluent A: H20 (0.1 % Formic Acid) Eluent B: CH3CN (0.1% Formic Acid) Gradient: 5-95% eluent B over 3.5 minutes Flow: 0.8 ml/min Column: Phenomenex Synergi 4µ MAX-RP 80A, 2.0 x 50 mm Basic Analytical conditions: Eluent A: H2O (10mM NH4HCO3 buffer adjusted to pH=9.5 with NH4OH) Eluent B: CH3CN Gradient: 05-95% eluent B over 3.5 minutes Flow: 0.8 ml/min Column: Thermo Hypersil-Keystone BetaBasic-18 5µm 2.1 x 50 mm or Column: Phenomenex Luna C18(2) δum 2.0 x 50 mm Polar Analytical conditions: Eluent A: H2O (0.1 % Formic Acid) Eluent B: CH3CN (0.1% Formic Acid) Gradient: 00-50% eluent B over 3 minutes Flow: 0.8 ml/min Column: Thermo Hypersil-Keystone HyPurity Aquastar, 5µ, 2.1 x 50 mm or Column: Phenomenex Synergi 4µ MAX-RP 80A, 2.0 x 50 mm or Longer Analytical conditions: Eluent A: H2O (0.1 % Formic Acid) Eluent B: CH3CN (0.1 % Formic Acid) Gradient: 05-95% eluent B over 15 minutes Flow: 0.4 ml/min Column: Phenomenex Synergi 4µ MAX-RP 80A, 2.0 x 150 mm MS conditions: Capillary voltage: 3.6 kV Cone voltage: 30 V Source Temperature: 120 °C Scan Range: 165-700 amu Ionisation Mode: ElectroSpray Positive or ElectroSpray Negative or ElectroSpray Positive & Negative The starting materials for each of the Examples are commercially available unless otherwise specified. EXAMPLE 0 Synthesis of 2,6-Difluoro-N-[3-(4-morpholin-4-yl-methyl-lH-benzimidazol-2-yl)-1 H-pyrazol-4-yl]-benzamide 0A. 2-amino-3-nitrobenzoic acid A solution of methyl-2-(acetylamino)-3-nitrobenzoate (2.6 g) in EtOH (50 ml) was treated with concentrated hydrochloric acid (10 ml) then heated at reflux for 16 h. The reaction mixture was cooled, reduced in vacuo and azeotroped with toluene (2 x 50 ml) to give 2-amino-3-nitrobenzoic acid (1.83 g) as a bright yellow solid. 0B. 2-amino-3-nitrobenzvl alcohol To a solution of 2-amino-3-nitrobenzoic acid (1.82 g, 10.0 mmol) in anhydrous THF (50 ml) was added sodium borohydride (770 mg, 20.0 mmol) followed by boron trifluoride diethyl etherate (2.5 ml, 20 mmol) and the mixture stirred at ambient temperature under a nitrogen atmosphere for 2 h. MeOH was cautiously added until gas evolution had ceased and the mixture reduced in vacuo. The residue was partitioned between EtOAc and brine and the organic portion dried (MgSO4) and reduced in vacuo to give 2-amino-3-nitrobenzyl alcohol (1.42 g) as a yellow solid. PC. 2,3-diaminobenzyl alcohol A mixture of 2-amino-3-nitrobenzyl alcohol (1.4 g) and 10% Pd/C (140 mg) in EtOH (40 ml) and DMF (10 ml) was stirred under an atmosphere of hydrogen at ambient temperature for 18 h. The catalyst was removed by filtration through Celite, the filtrate reduced in vacuo and azeotroped with toluene (2 x 50 ml) to give 2,3-diaminobenzyl alcohol (1.15 g) as a dark brown solid. 0D. Synthesis of 4-(2.6-difluoro-benzoylamino)-lH-pyrazole-3-carboxylic acid (2-amino-3 -hydroxymethyl-phenyl(-amide (Formula Removed) A mixture of 4-(2,6-difluorobenzoylamino)-lH-pyrazole-3-carboxylic acid (1.0 g, 3.7 mmol) (Example ID), 2,3-diaminobenzylalcohol (560 mg, 4.1 mmol), EDC (870 mg, 4.5 mmol) and HOBt (610 mg, 4.5 mmol) in DMF (20 ml) was stirred at ambient temperature for 18 h and then reduced in vacuo. The residue was partitioned between EtOAc and brine and the organic portion dried (MgSO,*) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-hexane (1:1,2:1)] to give 4-(2,6-difluoro-benzoylamino)-lH-pyrazole-3-carboxylic acid (2-amino-3-hydroxymethyl-phenyl)-amide (860 mg). OE. Synthesis of 2.6-Difluoro-N- [3 -(4-hydroxymethyl-1 H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide and Acetic acid 2-[4-(2,6-difluoro-benzoylamino)-lH-pyrazol-3-yl]-1 H-benzimidazol-4-ylmethyl ester (Formula Removed) 4-(2,6-Difluoro-benzoylamino)-lH-pyrazole-3-carboxylicacid(2-amino-3-hydroxymethyl-phenyl)-amide (100 mg, 0.26 mmol) was dissolved in acetic acid (10 ml) then heated for 10 min at 150 °C (100 W) in a CEM discover microwave synthesiser. The reaction mixture was reduced then azeotroped with toluene (2 x 20 ml). The residue was purified by flash column chromatography [SiCh, EtOAc-hexane (1:1, 2:1, 3:1)] to give 2,6-difluoro-N-[3-(4-hydroxymethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-benzamide (25 mg) as an off white solid (LC/MS: Rt 2.70, [M+H]+370) and acetic acid 2-[4-(2,6-difluoro-benzoylamino)-lH-pyrazol-3-yl]-lH-benzimidazol-4-ylmethyl ester (20 mg) as an off white solid. (LC/MS: Rt 3.60, [M+H]+412). OF. 2.6-difluoro-N-[3-f4-formyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]- benzamide (Formula Removed) A mixture of 2,6-difluoro-N-[3-(4-hydroxymethyl-1 H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (200 mg, 0.54 mmol) and Mn02 (500 mg) in CH2C12/ MeOH (5:1, 12 ml) was stirred at ambient temperature for 18 h, then filtered through Celite and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-hexane (1:3,1:2)] to give 2,6-difluoro-N-[3-(4-formyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-benzamide (30 mg) as a cream solid. 0G. 2.6-Difluoro-N-[3-C4-morpholin-4-yl-methyl-1 H-benzimidazol-2-yl)-1H-pyrazol-4-yl] -benzamide (Formula Removed) To a solution of 2,6-difluoro-N-[3-(4-formyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-benzamide (30 mg, 0.08 mmol) and morpholine (14 mg, 0.16 mmol) in CH2CI2 (5 ml) and THF (2 ml) was added 3A molecular sieves (1 g) followed by sodium triacetoxyborohydride (50 mg, 0.24 mmol) and the mixture stirred at ambient temperature under a nitrogen atmosphere for 2 h. The reaction mixture was filtered through Celite, reduced in vacuo then purified by flash column chromatography [SiO2, EtOAc-hexane (1:1,1:0), then CH2Cl2-MeOH (95:5)] affording 2,6-difluoro-N- [3 -(4-morpholin-4-yl-methyl-1 H-benzimidazol-2-yl)-1 H-pyrazol-4-yl] -benzamide (13 mg) as a cream solid. (LC/MS: Rt 1.80, [M+H]+439). EXAMPLE 1 Synthesis of 2,6-Difluoro-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)--1 H-pyrazol-4- yl] -benzamide 1A. Synthesis of 4-Nitro-lH-pyrazole-3-carboxylic acid ethyl ester (Formula Removed) Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3-pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 h. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96%). (*H NMR (400 MHz, DMSO-d6) δ 14.4 (s, 1H), 9.0 (s, 1H), 4.4 (q, 2H), 1.3 (t, 3H)). IB. Synthesis of 4-Amino-lH-pyrazole-3-carboxylic acid ethyl ester (Formula Removed) A mixture of 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester (6.40 g, 34.6 mmol) and 10% Pd/C (650 mg) in EtOH (150ml) was stirred under an atmosphere of hydrogen for 20 h. The mixture was filtered through a plug of Celite, reduced in vacuo and dried through azeotrope with toluene to afford 4-amino-lH-pyrazole-3-carboxylic acid ethyl ester as a pink solid (5.28 g, 98%). (JH NMR (400 MHz, DMSO-d6) δ 12.7 (s, 1H), 7.1 (s, 1H), 4.8 (s, 2H), 4.3 (q, 2H), 1.3 (t, 3H)). 1C. Synthesis of 4-(2,6-Difluoro-benzoylamino)-lH-pyrazole-3-carboxylic acid ethyl ester (Formula Removed) A mixture of 2,6-difluorobenzoic acid (6.32 g, 40.0 mmol), 4-amino-lH-pyrazole-3-carboxylic acid ethyl ester (5.96 g, 38.4 mmol), EDC (8.83 g, 46.1 mmol) and HOBt (6.23 g, 46.1 mmol) in DMF (100 ml) was stirred at ambient temperature for 6 h. The mixture was reduced in vacuo, water added and the solid formed collected by filtration and air-dried to give 4-(2,6-difluoro-benzoylamino)-lH-pyrazole-3-carboxylic acid ethyl ester as the major component of a mixture (15.3 g). (LC/MS: Rt3.11,[M+H]+295.99). ID. Synthesis of 4-(2.6-Difluoro-benzoylamino)-lH-pyrazole-3-carboxylic acid (Formula Removed) A mixture of 4-(2,6-difluoro-benzoylamino)-lH-pyrazole-3-carboxylic acid ethyl ester (10.2 g) in 2 M aqueous NaOH/MeOH (1:1,250 ml) was stirred at ambient temperature for 14 h. Volatile materials were removed in vacuo, water (300 ml) added and the mixture taken to pH 5 using 1M aqueous HC1. The resultant precipitate was collected by filtration and dried through azeotrope with toluene to afford 4-(2,6-difluoro-benzoylamino)-lH-pyrazole-3-carboxylic acid as a pink solid (5.70 g). (LC/MS: Rt 2.33, [M+H]+267.96). 1E. Synthesis of 2,6-Difluoro-N-[3-(5-hydroxymethyl-1 H-benzimidazol-2-yl)-1H-pyrazol-4-yl] -benzamide (Formula Removed) A mixture of 4-(2,6-difiuoro-benzoylamino)-lH-pyrazole-3-carboxylic acid (584 mg, 2.19 mmol), (3,4-diamino-phenyl)-methanol (332 mg, 2.40 mmol), EDC (504 mg, 2.63 mmol) and HOBt (355 mg, 2.63 mmol) in DMF (15 ml) was stirred at ambient temperature for 20 h. The mixture was reduced in vacuo and the residue taken up in EtOAc, washed with water and brine and the organic portion dried (MgSO4) and reduced in vacuo to give the intermediate amide (591 mg) as a brown solid. (LC/MS: R, 2.34, [M+H]+ 388.00). A mixture of the amide (575 mg) in glacial AcOH (4 ml) was heated in the microwave (80 W) at 90 °C for 20 min. The mixture was poured into water and the solid formed collected by filtration. The residue was taken up in MeOH (10 ml) and stirred in the presence of NaOMe (320 mg, 5.90 mmol) for 30 min. The mixture was reduced in vacuo, taken up in EtOAc and washed with water and brine, dried (MgSO4) and reduced in vacuo. The residue was purified by column chromatography [SiO2, EtOAc] to give 2,6-difluoro-N-[3-(5-hydroxymethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-benzamide as a white solid (78 mg, 10% over two steps). (LC/MS: Rt 2.45, [M+H]+ 370.05). IF. Synthesis of 2,6-Difluoro-N-[3-(5-formyl-1 H-benzimidazol-2-yl) 1 H-pyrazol-4-yl"|-benzamide (Formula Removed) A mixture of 2,6-difluoro-N-[3-(5-hydroxymethyl-1 H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (800 mg, 2.17 mmol) and MnO2 (5.00 g, 57.5 mmol) in CH2Cla/MeOH (10:1,110 ml) was stirred at ambient temperature for 5 days. The mixture was filtered through a plug of Celite washing with MeOH and the filtrate reduced in vacuo to give 2,6-difluoro-N-[3-(5-formyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-benzamide (380 mg, 48%) as a yellow solid. (LC/MS: Rt 3.41, [M+H]+ 368.04). 1G. Synthesis of 2,6-Difluoro-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-ylMH-pyrazol-4-yl]-benzamide (Formula Removed) To a mixture of 2,6-difluoro-N-[3-(5-formyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-benzamide (75.0 mg, 0.20 mmol) in anhydrous THF (5 ml) stirring at ambient temperature was successively added 3 A molecular sieves, morpholine (35 uL, 0.40 mmol) and triacetoxy sodiumborohydride (127 mg, 0.60 mmol). The mixture was stirred for 4 h, MeOH (3 ml) added and then the mixture reduced in vacuo. The residue was taken up in EtOAc, washed with water and brine, dried (MgSO,*), reduced in vacuo and then purified through preparative LC/MS to give 2,6-difluoro-N-[3-(5-morpholin-4-ylmethyl-1 H-benzimidazol-2-yl)-1 H-pyrazol-4-yl]-benzamide (9 mg, 10%) as a white solid. (LC/MS: Rt 1.90, [M+H]+ 439.09). General Procedure A EXAMPLE 2 Synthesis of 2,6-Dichloro-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-1 H-pyrazol-4-yl]-benzamide 2A. Synthesis of (3,4-Dimtro-phenyl)-morpholm-4-yl-methanone (Formula Removed) A mixture of 3,4-dinitrobenzoic acid (10.0 g) and thionyl chloride (30 ml) was heated at reflux for 2 hours, cooled to ambient temperature and excess thionyl chloride removed through azeotrope with toluene. The residue was taken up in THF (100 ml) and morpholine (4.1 ml) and Et3N (7.2 ml) added concurrently to the mixture at 0 °C. The mixture was stirred for 3 hours, water (100 ml) added and then extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4) and reduced in vacuo. Recrystallisation of the residue from MeOH gave (3,4-dinitro-phenyl)-morpholin-4-yl-methanone (8.23 g) as a yellow solid. (1H NMR (300 MHz, DMSO-d6) δ 8.3 (d, 1H), 8.3 (s, 1H), 8.0 (d, 1H), 3.7-3.5 (m, 8H)). 2B. Synthesis of (3,4-Diamino-phenyl)-morpholin-4-yl-methanone (Formula Removed) A mixture of (3,4-dinitro-phenyl)-morpholin-4-yl-methanone (1.0 g) and 10% Pd/C (150 mg) in MeOH (30 ml) was shaken under a hydrogen atmosphere at ambient temperature for 10 hours, then filtered through a plug of Celite and reduced in vacuo to give (3,4-diamino-phenyl)-morpholin-4-yl-methanone (900 mg). (*H NMR (300 MHz, DMSO-d6) δ 6.6 (s, 1H), 6.5 (s, 2H), 4.8 (s, 1.5H), 4.6 (s, 1.5H), 4.1 (s, 1H), 3.6 (m, 4H), 3.4 (m, 4H)). 2C. Synthesis of 4-Morpholin-4-ylmethyl-benzene-l,2-diamine (Formula Removed) To a mixture of (3,4-dinitro-phenyl)-morpholin-4-yl-methanone (2.84 g) in dry THF (50 ml) was added NaBRt (954 mg) followed drop-wise by BF3.Et20 (3.2 ml). The mixture was stirred at ambient temperature for 3 hours and then quenched though addition of MeOH. The mixture was reduced in vacuo, partitioned between EtOAc and water and the organic portion washed with brine, dried (MgSO/i) and reduced in vacuo. The residue was purified via flash column chromatography eluting with EtOAc to give 4-(3,4-dinitro-benzyl)-morpholine (1.08 g). A mixture of 4-(3,4-dinitro-benzyl)-morpholine (550 mg) and 10% Pd/C (75 mg) in MeOH (10 ml) was shaken under a hydrogen atmosphere at ambient temperature for 4 hours, then filtered through a plug of Celite and reduced in vacuo to give 4-morpholin-4-ylmethyl-benzene-l,2-diamine (483 mg) as the major component of a mixture. 2D. Synthesis of 4-(2,6-Dichloro-benzoylamino)-lH-pyrazole-3-carboxylic acid (Formula Removed) Thionyl chloride (0.65 ml) was added to 2,6-dichlorobenzoic acid (825 mg) and the mixture heated at 70 °C for 2 hours. The mixture was allowed to cool and excess thionyl chloride removed through azeotrope with toluene. The residue was taken up in THF (30 ml) and 4-amino-lH-pyrazole-3-carboxylic acid methyl ester (609 mg) and Et3N (0.75 ml) added concurrently to the mixture at 0 °C. The mixture was stirred for 4 hours, water (100 ml) added and then extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4) and reduced in vacuo to give 4-(2,6-dichloro-benzoylamino)-lH-pyrazole-3-carboxylic acid methyl ester (1.23 g) as a red solid. (LC/MS: Rt 3.05, [M+H]+ 313.96). A mixture of 4-(2,6-dichloro-benzoylamino)-lH-pyrazole-3-carboxylic acid methyl ester (1.21 g) in 2 M aqueous NaOH/MeOH (1:1,50 ml) was stirred at ambient temperature for 14 hours. Volatile materials were removed in vacuo, water (100 ml) added and the mixture taken to pH 5 using 1M aqueous HC1. The resultant precipitate was collected by filtration and dried through azeotrope with toluene to afford 4-(2,6-dichloro-benzoylamino)-lH-pyrazole-3-carboxylic acid as a beige solid (790 mg). (LC/MS: Rt 2.53, [M+H]+ 299.95). 2E. Synthesis of 2,6-Dichloro-N- [3 -(5 -morpholin-4-ylmethyl-1 H-benzimidazol-2-yO-1 H-pyrazol-4-yl]-benzamide (Formula Removed) A mixture of 4-(2,6-dichloro-benzoylamino)-lH-pyrazole-3-carboxylic acid (75 mg, 0.25 mmol), 4-morpholin-4-ylmethyl-benzene-l,2-diamine (52 mg, 0.25 mmol), EDC (58 mg, 0.3 mmol) and HOBt (41 mg, 0.3 mmol) in DMF (4 ml) was stirred at ambient temperature for 48 hours. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3 and the organic portion washed with saturated aqueous NH4CI, dried (MgSO4) and reduced in vacuo. The residue was taken up in AcOH and heated at 100 °C for 14 hours, cooled to ambient temperature and reduced in vacuo. The residue was purified via flash column chromatography eluting with CH2Cl2-MeOH (20:1 - 10:1) to give 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-benzamide (30 mg) as a pink solid. (LC/MS: Rt 2.12, [M+H]+ 471.14). EXAMPLE 3 Synthesis of 2-Chloro-6-fluoro-N-[3-(5-morpholin-4-ylmethyl-1 H-benzimidazol-2-yl)-1 H-pyrazol-4-yl]-benzamide 3 A. Synthesis of 4-(2-Chloro-6-fluoro-benzoylamino)-1 H-pyrazole-3 -carboxylic acid (Formula Removed) The compound was prepared in a manner analogous to 4-(2,6-difiuoro-benzoylamino)-l H-pyrazole-3-carboxylic acid (Example ID), but using 2-chloro-6-fluorobenzoic acid as the starting acid to give 4-(2-chloro-6-fluoro-benzoylamino)-lH-pyrazole-3-carboxylic acid (4.42 g) as a pale blue solid. (LC/MS: Rt 2.35, [M+H]+ 283.94). 3B. Synthesis of 2-Chloro-6-fluoro-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl) 1 H-pyrazol-4-yl] -benzamide (Formula Removed) The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1 H-benzimidazol-2-yl)-1 H-pyrazol-4-yl]-benzamide (Example 2E), but using 4-(2-chloro-6-fluoro-benzoylamino)-l H-pyrazole-3-carboxylic acid, to give 2-chloro-6-fluoro-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-benzamide (37 mg) as a pink solid. (LC/MS: R, 2.04, [M+H]+455.18). EXAMPLE 4 Synthesis of 2.6-Difluoro-4-methoxv-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yD-1 H-pyrazol-4-yl] -benzamide 4A. Synthesis of 4-(2.6-Difluoro-4-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid (Formula Removed) The compound was prepared in a manner analogous to 4-(2,6-difluoro-benzoylamino)-lH-pyrazole-3-carboxylic acid (Example ID), but using 2,6-difluoro-4-methoxybenzoic acid as the starting acid, to give 4-(2,6-difluoro-4-methoxy-benzoylamino)-lH-pyrazole-3-carboxylic acid (1.58 g) as a white solid. (!HNMR (300 MHz, DMSO-cfe) δ 13.0 (s, 2H), 10.7 (s, 1H), 8.0 (s, 1H), 6.9 (s, 1H), 6.8 (s, 1H), 3.7 (s, 3H)). 4B. Synthesis of 2,6-Difluoro-4-methoxy-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1 H-pyrazol-4-yl] -benzamide (Formula Removed) The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-l H-pyrazol-4-yl]-benzamide (Example 2E), but using 4-(2,6-difluoro-4-methoxy-benzoylamino)-lH-pyrazole-3-carboxylic acid to give 2,6-difluoro-4-methoxy-N-[3-(5-morpholin-4-ylmethyl-lH- benzimidazol-2-yl)-lH-pyrazol-4-yl]-benzamide (32 mg) as a pink solid. (LC/MS: Rt 1.99, [M+H]+469.21). EXAMPLE 5 Synthesis of 2,3-Dihydro-benzo[l,4]dioxine-5-carboxylic acid [3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1 H-pyrazol-4-yl] -amide 5A. Synthesis of 4-[[(2,3-Dihydro-benzo[1.4]dioxme-5-carbonyl)-amino1-lH-pyrazole-3-carboxylic acid (Formula Removed) The compound was prepared in a manner analogous to 4-(2,6-difluoro-benzoylamino)-l H-pyrazole-3-carboxylic acid (Example ID), but using 2,3-dihydro-benzo[ 1,4] dioxine-5-carboxylic acid as the starting acid to give 4-[(2,3-dihydro-benzo [ 1,4] dioxine-5 -carbonyl)-amino] -1 H-pyrazole-3 -carboxylic acid (340 mg) as a white solid. (!H NMR (300 MHz, DMSO-rf6) δ 13.5 (s, 2H), 11.2 (s, IH), 8.4 (s, IH), 7.7 (d, IH), 7.1 (d, IH), 7.0 (t, IH), 4.5 (s, 2H), 4.4 (s, 2H)). 5B. Synthesis of 2,3-Dmydro-benzo[1,4]dioxine-5-carboxyric acid [3-(5-morpholin-4-ylmethyl-1 H-benzimidazol-2-yl)-1 H-pyrazol-4-yl] -amide (Formula Removed) The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1 H-benzimidazol-2-yl)-1 H-pyrazol-4-yl]-benzamide (Example 2E), but using 4-[(2,3-dihydro-benzo[l,4]dioxine-5-carbonyl)-amino]-lH-pyrazole-3-carboxylic acid to give 2,3-dihydro-benzo[l,4]dioxine-5-carboxylic acid [3 -(5 -morpholin-4-ylmethyl-1 H-benzimidazol-2-yl)-1 H-pyrazol-4-yl] -amide (39 mg) as a pink solid. (LC/MS: Rt 1.99, [M+H]+ 461.23). EXAMPLE 6 Synthesis of 2-fluoro-6-memoxy-N-[3-(5-morpholm-4-ylmemyl-lH-benzimidazol-2-yl)-1 H-pyrazol-4-yl]-benzamide 6A. Synthesis of 4-Nitro-lH-pyrazole-3-carboxylic acid ethyl ester (Formula Removed) Thionyl chloride (3.8 ml, 52.5 mmol) was added cautiously to a stirred, ice-cold mixture of 4-nitropyrazole-3-carboxylic acid (7.5 g, 47.7 mmol) in EtOH (150 ml), the mixture stirred at ambient temperature for 1 hour then heated at reflux for 3 hours. The reaction mixture was cooled, evaporated in vacuo then azeotroped with toluene to give 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester (8.8 g). 6B. Synthesis of l-(f4-methoxv-benzylV4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester (Formula Removed) To a solution of 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester (8.8 g, 47.5 mmol) in MeCN (100 ml) was added K2CO3 (7.9 g, 57.0 mmol) followed by 4-methoxybenzyl chloride (7.1 ml, 52.3 mmol) and the mixture stirred at ambient temperature for 20 hours. The mixture was evaporated in vacuo, the residue partitioned between EtO Ac and 2M aqueous hydrochloric acid and the organic portion washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-hexane (1:4)] to give l-(4-methoxy-benzyl)-4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester (11 g) as a colourless gum. 6C. Synthesis of l-(4-methoxy-benzyl)-4-nitro-lH-pyrazole-3-carboxylic acid A mixture of l-(4-methoxy-benzyl)-4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester (15.9 g, 52 mmol) in 2 M aqueous NaOH/MeOH (1:1,400 ml) was stirred at ambient temperature for 14 h. Volatile materials were removed in vacuo, the residue dissolved in EtOAc (200ml), water (100 ml) added and the mixture taken to pH 3 using 1M aqueous HC1. The layers were separated and the organic portion washed with saturated aqueous sodium hydrogen carbonate. EtOAc was added to the aqueous layer which was acidified to pH 3-4, and the combined organic portions dried (MgSQi) and reduced in vacuo to give l-(4-methoxy-benzyl)-4-nitro-lH-pyrazole-3-carboxylic acid (13 g, 86%) as a white solid. (LC/MS: Rt 2.63, [M+H]+ 292). 6D. Synthesis of 4-(3,4-dinitro-benzvl)-morpholine To a solution of 3,4-dinitro-phenyl)-morpholin-4-yl-methanone (Example 2A) (4.5 g, 16 mmol) in anhydrous THF (50 ml) at 0 °C was added sodium borohydride (1.2 g, 32 mmol) followed by dropwise addition of boron trifluoride diethyl etherate (4 ml, 32 mmol) and the mixture stirred at 0 °C under a nitrogen atmosphere for 2.5 h. Dry MeOH was cautiously added until gas evolution had ceased and the mixture reduced in vacuo. The residue was partitioned between EtOAc and brine and the organic portion dried (MgSO4) and reduced in vacuo to give a yellow-orange solid, which was recrystallised from MeOH to give 4-(3,4-dinitro-benzyl)-morpholine (3.5 g, 82%) as a yellow solid. (LC/MS: Rt 1.52, [M+H]+268). 6E. Synthesis of 4-morpholin-4-ylmethyl-benzene-l,2-diamine To a mixture of 4-(3,4-dinitro-benzyl)-morpholine (2.5 g, 9.3 mmol), Fe powder (5.2 g, 93 mmol) and FeSO4.7H2O (1.3 g, 4.6 mmol) was added 1,4-dioxane: water (5:1, 60ml). The mixture was refluxed for 3 h, filtered through celite, washing with MeOH, and reduced in vacuo azeotroping with toluene. EtOAc (100 ml) was added and insoluble material removed via filtration. The filtrate was reduced in vacuo to give 4-morpholin-4-ylmethyl-benzene-l,2-diamine as a dark brown solid (1.4 g, 73%). (LC/MS: Rt 0.40, no ionization). 6F. Synthesis of 2-[1-(4-methoxy-benzyl)-4-nitro-1H-pyrazol-3-yl]-5-morpholin-4-ylmethyl-1 H-benzimidazole A mixture of 4-morpholin-4-ylmethyl-benzene-l,2-diamine (2.5 g, 12 mmol), l-(4-methoxy-benzyl)-4-nitro-lH-pyrazole-3-carboxylic acid (2.91 g, 10 mmol), EDC (2.3 g, 12 mmol) and HOBt (1.62 g, 12 mmol) in dry DMF (40 ml) was stirred at ambient temperature for 24 h. The mixture was reduced in vacuo, the residue partitioned between EtOAc (100 ml) and water (50 ml) and the organic portion washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and reduced in vacuo. The residue was dissolved in AcOH (70 ml) and heated at reflux for 3 h. The solvent was removed in vacuo and the residue purified by flash column chromatography [SiCh, MeOH:DCM (5:95)] to give 2-[l-(4-methoxy-benzyl)-4-nitro-1 H-pyrazol-3-yl]-5-morpholin-4-ylmethyl-1 H-benzimidazole (2 g, 37%) as a yellow foam. (LC/MS: Rt 1.91, [M+H]+449). 6G. Synthesis of 1 -(4-methoxy-benzyl)-3 -(5 -morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1 H-pyrazol-4-ylamine To a mixture of 2-[l-(4-methoxy-benzyl)-4-nitro-lH-pyrazol-3-yl]-5-morpholin-4-ylmethyl-1 H-benzimidazole (1.6 g, 3.57 mmol), Fe powder (2 g, 35 mmol) and FeSO4.7H2O (0.496 g, 1.78 mmol) was added 1,4-dioxane:water (5:1,120 ml). The mixture was refluxed for 3 h, filtered through celite, washing with MeOH, and reduced in vacuo azeotroping with toluene. EtOAc (100 ml) was added and insoluble material removed via filtration. The filtrate was reduced in vacuo to give 1 -(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-1 H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine as a dark brown solid (1.4 g, 94%). (LC/MS: Rt 1.72, [M+H]+ 419). 6H. Synthesis of 2-fluoro-6-methoxy-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-1 H-pyrazol-4-yll-benzamide (Formula Removed) A mixture of 2-fluoro-6-methoxy-benzoic acid (20 mg, 0.12 mmol), l-(4-methoxy-benzyl)-3 -(5 -morpholin-4-ylmethyl-1 H-benzimidazol-2-yl)-1 H-pyrazol-4-ylamine (50 mg, 0.12 mmol), EDC (116 mg, 0.14 mmol) and HOBt (81 mg, 0.14 mmol) was stirred at room temperature in DMF (2 ml) for 20 h. The mixture was reduced in vacuo and the residue partitioned between EtO Ac (5 ml) and water (2 ml) and the organic portion washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtO Ac] to give 2-fluoro-6-methoxy-N-[l-(4-methoxy-benzyl)-3 -(5 -morpholin-4-ylmethyl-1 H-benzimidazol-2-yl)-1 H-pyrazol-4-yl]-benzamide as a white solid (80 mg, 61%). A mixture of 2-fiuoro-6-methoxy-N-[l-(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-benzamide (80 mg) and anisole (25 µl) in trifluoroacetic acid (1 ml) was heated at 140 °C (100W) for 20 min in a CEM Discover™ microwave synthesiser. The reaction mixture was evaporated and then azeotroped with toluene (2x10 ml). Diethyl ether (5 ml) was added to the crude material to give the trifluoroacetate salt of 2-fluoro-6-methoxy-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-benzamide (30 mg, 32%) as a white solid. (LC/MS: Rt 1.96, [M+H]+451). EXAMPLE 7 Synthesis of N-[3-(5-morpholin-4-ylmethyl-1 H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-trifluoromethoxy-benzamide (Formula Removed) The compound was prepared in a manner analogous to Example 6F, but using 2-trifluoromethoxy-benzoic acid instead of 2-fluoro-6-methoxy-benzoic acid and using the procedure below for the deprotection of the para-methoxy benzyl substituent of the pyrazole ring. A mixture of N-[l-(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-2-trifluoromethoxy-benzamide (50 mg) and anisole (25 ul) in trifluoroacetic acid (1 ml) was heated at 140 °C (100 W) for 20 min in a CEM Discover™ microwave synthesiser. The reaction mixture was evaporated and then azeotroped with toluene (2x10 ml). To the crude material was added EtOAc (5 ml) and the mixture neutralised with saturated aqueous sodium hydrogen carbonate. The organic portion was washed with water, dried (MgSO4) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, CH2Cl2-MeOH (100:0 - 95:5)] to give N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-2-trifluoromethoxy-benzamide (12 mg) as a white solid . (LC/MS: Rt2.06, [M+H]+487). EXAMPLE 8 Synthesis of benzo[c]isoxazole-3-carboxylic acid[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-1 -H-pyrazol-4-yl] -amide 8A. Synthesis of 5-morpholin-4-ylmethyl-2-(4-nitro-lH-pyrazol-3-yl)lH-benzimidazole A mixture of 4-morpholin-4-ylmethyl-benzene-l,2-diamine (2.30 g, 11.1 mmol), 4-nitro-lH-pyrazole-3-carboxylic acid (1.57 g, 10.0 mmol), EDC (2.13 g, 11.1 mmol) and HOBt (1.50 g, 11.1 mmol) in dry DMF (25 ml) was stirred at ambient temperature for 24 h. The mixture was reduced in vacuo and the crude residue dissolved in AcOH (40 ml) and heated at reflux for 3 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography eluting with 0-20% MeOH in EtOAc to give 5-morpholin-4-ylmethyl-2-(4-nitro-lH-pyrazol-3-yl)lH-benzimidazole as a yellow solid. (1.0 g, 61%). (LC/MS: Rt 1.83, [M+H]+ 329). 8B. Synthesis of 3 -(5 -morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-ylamine Palladium on carbon (10%, 0.08 g) was added to solution of 5-morpholin-4-ylmethyl-2-(4-nitro-lH-pyrazol-3-yl)lH-benzimidazole (0.82 g, 2.5 mmol) in DMF (30 ml) under an atmosphere of nitrogen. The mixture was shaken under a hydrogen atmosphere for 4 h then filtered through celite, washing with methanol. The filtrate was concentrated in vacuo to give 3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-ylamine as a brown solid (530 mg, 71%). (LC/MS: Rt 1.94, [M+H]+299). 8C. Synthesis of benzo[c]isoxazole-3-carboxylic acid[3-(5-morpholin-4-ylmethyl-1 H-benzimidazol-2-vD-1 -H-pyrazol-4-yl]-amide (Formula Removed) A mixture of benzo[c]isoxazole-3-carboxylic acid (46 mg, 0.28 mmol), 3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-ylamine (100 mg, 0.33 mmol), EDC (64 mg, 0.33 mmol) and HOBt (45 mg, 0.33 mmol) was stirred at room temperature in DMF (2.5 ml) for 20 h. The mixture was reduced in vacuo and the residue partitioned between EtOAc (5 ml) and water (2 ml), the organic portion washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-MeOH (100:0-90:10)] to give benzo[c]isoxazole-3-carboxylic acid[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-amide as a white solid (40 mg, 32%). (LC/MS: Rt 2.13, [M+H]+444). GENERAL PROCEDURE A General Procedure A describes the synthesis of N-[3-(5,6-dimethoxy-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-5-fluoro-2-methoxy-benzamide. The compound itself is not within the scope of the claims of this application but the general procedure is used to make some of the compounds described below in Table 3. A. Synthesis of 5,6-dimethoxy-2-(4-nitro-1 H-pyrazol-3 -yl)-1 H-benzimidazole To a solution of EDC (4.81 g, 25 mmol), HOBt (3.40 g, 25 mmol) and triethylamine (4.67 g, 46 mmol) in DMF (100 ml) was added 4-nitro-lH-pyrazole-3-carboxylic acid (3.63 g, 23.09 mmol) and 4,5-dimethoxy-benzene-l,2-diamine, dihydrochloride (5.06 g, 20.99 mmol) and the mixture stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid partitioned between ethyl acetate (50 ml) and sodium bicarbonate (50 ml). A precipitate was formed and removed by filtration. This was washed with water followed by diethyl ether and then azeotroped with methanol and toluene to yield 4-nitro-lH-pyrazole-3-carboxylic acid (2-amino-4,5-dimethoxy-phenyl)-amide (2.35 g, 36%). 4-Nitro-lH-pyrazole-3-carboxylic acid(2-amino-4,5-dimethoxy-phenyl)-amide (2.35 g, 7.65 mmol) was dissolved in acetic acid (150 ml) and refluxed at 140 °C for 5 hours. The solution was left to cool and the solvent removed in vacuo. The resulting solid was partitioned between ethyl acetate (25 ml) and brine (25 ml). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to yield 5,6-dimethoxy-2-(4-nitro-lH-pyrazol-3-yl)-lH-benzimidazole (2.08 g, 94%). B. Synthesis of 3-(5,6-dimethoxy-lH-benzimidazol-2-yl)-lH-pyrazol-4-ylamine A mixture of 5,6-dimethoxy-2-(4-nitro-lH-pyrazol-3-yl)-lH-benzimidazole (2.08 g, 7.2 mmol) and 10% palladium on carbon (200 mg) in ethanol (150 ml) and DMF (50 ml) was hydrogenated at room temperature and pressure overnight. The reaction mixture was filtered through celite and the solvent removed in vacuo. The resulting solid was azeotroped with methanol and toluene and the solvent removed in vacuo. The crude material was columned in DCM, methanol, acetic acid, water (120:18:3:2)[DMAW120] followed by dichloromethane 90ml, methanol 18ml, acetic acid 3ml, water 2ml (90:18:3:2) (DMAW90). Product fractions were combined and the solvent removed in vacuo to yield 3-(5,6-dimethoxy-lH-benzimidazol-2-yl)-lH-pyrazol-4-ylamine (~1 g, -53%). C. Synmesis of N-[3-(5,6-dimemoxy-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-5- fluoro-2-methoxy-benzamide (Formula Removed) To a solution of EDC (44 mg, 0.23 mmol) and HOBt (31 mg, 0.23 mmol) in DMF (5 ml) was added 3-(5,6-dimethoxy-lH-benzimidazol-2-yl)-lH-pyrazol-4-ylamine (50 mg, 0.19 mmol) and 5-fluoro-2-methoxy-benzoic acid (36 mg, 0.21 mmol) and the mixture stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid partitioned between DCM (20 ml) and saturated aqueous sodium bicarbonate (20 ml). A precipitate was formed which was removed by filtration and oven dried to yield N-[3-(5,6-dimethoxy-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-5-fluoro-2-methoxy-benzamide(64mg, 81%). (LC/MS: Rt 2.64, [M+H]+ 412). EXAMPLES 9-79 By following the procedures described in the foregoing examples, modified where necessary, the compounds set out in Table 3 were prepared. In the column headed "Method", the general procedure used to prepare the compound is given with reference to an earlier example or procedure. In the column headed "Differences" are listed the key differences between the general procedure described in the referenced example and the specific procedure used to prepare the compound in question. Table 3 (Table Removed) EXAMPLE 80 Synthesis of l-(2.6-Difluorophenyl)-N-[3-(5-Morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-1H-pyrazol-4-yl]-urea (Formula Removed) A mixture of 3-(5-morpholin-4-ylmethyl-1 H-benzimidazol-2-yl)-1 H-pyrazol-4-ylamine (50 mg, 0.16 mmol), 2,4 difluorophenyl isocyanate (26 mg, 0.16 mmol) and Et3N (0.024 ml) suspended in a mixture of toluene (2ml) and IPA (1 ml) was stirred at 80 °C for 1 h and then diluted with EtOAc. The reaction mixture was washed with water then brine, organics dried (MgSO4) and reduced in vacuo The residue was purified by flash column chromatography [SiO2, CH2Cl2-MeOH (90:10)] to give l-(2,6-Difluorophenyl)-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-urea as a colourless solid (30 mg, 39%). (LC/MS (acidic method): Rt 1.80, [M+H]+454). EXAMPLES 81 - 88 By following the procedure described in Example 80, the compounds set out in Table 4 were prepared. Table 4 (Table Removed) EXAMPLE 89 Synthesis of 4-Morpholinyl-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-1 -H-pyrazol-4-yl]-urea (Formula Removed) A mixture of 3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-ylamine (70 mg, 0.23 mmol), morpholine-4-carbonyl chloride (80 µl, 0.7 mmol) and diisopropylethylamine (170 ul, 0.92 mmol) in THF (2 ml) was stirred at 0 °C and then allowed to warm to room temperature over 16 h. The reaction was quenched by the addition of cone. aq. NH3 and then concentrated in vacuo. The residue was purified through preparative LC/MS to give 4-morpholinyl-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-l-H-pyrazol-4-yl]-urea as a white solid (35 mg). (LC/MS (basic method): Rt 2.28 min, [M-H+]" 415). EXAMPLE 90 Synthesis of 2-amino-N- [3 -(5 -morpholin-4-yl-methyl-1 H-benzimidazol-2-yl-V 1H-pyrazol-4-yl]-2-phenyl-acetamide (Formula Removed) {[3-(5-Morpholin-4-yl-methyl-1 H-benzimidazol-2-yl)-1 H-pyrazol-4-yl-carbamoyl]-phenyl-methyl}-carbamic acid tert-butyl ester (Example 54) (30mg) was dissolved in 4M HCl/dioxane, and 3ml of methanol and stirred at room temperature overnight. The solvent solvent was removed in vacuo and residue triturated with diethylether to give 2-amino-N-[3-(5-morpholin-4-yl-methyl-lH-benzimidazol-2-yl-)-lH-pyrazol-4-yl]-2-phenyl-acetamide (AT8162) as a white solid (20mg, 83%). (LC/MS (acidic method): Rt 2.39 min, [M+H]+ 432). EXAMPLE 91 By following the procedure described in Example 90, the compound set out in Table 5 was prepared. Table 5 (Table Removed) GENERAL PROCEDURE B Synthesis of 4-(5-tert-butyl-2-memoxy-benzoylamino)-1 H-pyrazole-3 -carboxylic acid methyl ester (Intermediate compound) A: Synthesis of 4-nitro-l H-pyrazole-3-carboxylic acid methyl ester The compound was prepared in a manner analogous to 4-nitro-l H-pyrazole-3 -carboxylic acid ethyl ester (Example 16A) using 4-nitro-lH-pyrazole-3-carboxylic acid (100g, 636mmol), thionyl chloride (55.5ml, 764ml) and MeOH (750ml), instead of EtOH. 4-Nitro-lH-pyrazole-3-carboxylic acid methyl ester was obtained as an off-white solid (109g, 100%). (LC/MS (acidic method): Rt 1.82 min, [M+H]+ 172). B: Synthesis of 4-amino-lH-pyrazole-3-carboxylic acid methyl ester A mixture of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (10g, 58mmol) and 10% palladium on carbon (500mg) in ethanol (150ml) and DMF (30ml) stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through celite reduced in vacuo and dried through azeotrope with toluene and methanol to afford 4-amino-lH-pyrazole-3-carboxylic acid methyl ester as a dark amber tar (9.35g). (LC/MS (acidic): Rt 0.39 min, [M+H]+142). C: Synthesis of 4-(5-tert-butyl-2-methoxv-benzoylamino)-lH-pyrazole-3-carboxylic acid methyl ester To a solution of EDC (11.59g, 60.7mmol), HOBt (8.19g, 60.7mmol) and 4-amino-lH-pyrazole-3-carboxylic acid methyl ester (7.84g, 55.6mmol) in DMF (100ml) was added 5-tert-butyl-2-methoxy-benzoic acid (10.52g, 50.6mmol) and the mixture stirred at room temperature overnight. The mixture was reduced in vacuo and the residue partitioned between EtOAc (500ml) and brine (200ml), the organic portion was washed with saturated aqueous sodium hydrogen carbonate (200ml), dried (MgSO4) and reduced in vacuo to yield 4-(5-tert-butyl-2-methoxy-benzoylamino)-lH-pyrazole-3-carboxylic acid methyl ester as a pale yellow solid (17.07g, 93 %). (LC/MS (acidic method): Rt 3.12 min, [M+H]+332). EXAMPLE 92 Synthesis of 4-(2-chloro-5-(methylthio)-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide 92A: Synthesis of 4-(2-chloro-5-(methylthio)-benzoylamino)-lH-pyrazole-3-carboxylic acid methyl ester The title compound was prepared in a manner analogous to General Procedure B, but using 2-chloro-5-(methylthio)benzoic acid (15.34 g, 72.7 mmol) instead of 5-ter?-butyl-2-methoxy-benzoic acid. The product was obtained as a beige solid containing 4-(2-chloro-5-(methylthio)-benzoylamino)-lH-pyrazole-3-carboxylic acid methyl ester as the major component (25 g). (LC/MS (acidic method): Rt 2.78, [M+H]+325.94). 92B: Synthesis of 4-(2-chloro-5-(methylthioVbenzoylaminoVlH-pyrazole-3-carboxylic acid The compound was prepared in a manner analogous to Example ID, but using 4-(2-chloro-5-(methylthio)-benzoylamino)-lH-pyrazole-3-carboxylic acid methyl ester (11.8 g) as the starting ester. This afforded 4-(2-chloro-5-(methylthio)-benzoylamino)-lH-pyrazole-3-carboxylic acid as a beige solid (5.82 g). (LC/MS(acidic method): Rt 2.46, [M+H]+ 311.99). 92C: Synthesis of 4-(2-chloro-5-rmethylthioVN-r3-r5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl) 1 H-pyrazol-4-yl]-benzamide (Formula Removed) A mixture of 4-(2-chloro-5-(methylthio)-benzoylamino)-1 H-pyrazole-3 -carboxylic acid (2 g, 6.43 mmol), 4-morpholin-4-ylmethyl-benzene-l,2-diamine (1.33 g, 6.43 mmol) (Example 6E), EDC (1.36 g, 7.07 mmol) and HOBt (0.96 g, 7.07 mmol) in DMF (20 ml) was stirred at ambient temperature for 18 h. The residue was reduced in vacuo and then partitioned between saturated NaHCO3 solution (150 ml) and EtOAc (3x150 ml). The combined organics were dried (Na2SO4), filtered and evaporated in vacuo to give a crude oil. This was purified by flash chromatography [SiO2; eluting with CH2C12 : MeOH (100:0-95:5)] to afford the product as a beige solid (1.23g). (LC/MS(acidic method): Rt 2.10, [M+H]+ 501.09). A mixture of this product (1.23 g, 2.46 mmol) in glacial AcOH (20 ml) was heated at 120 °C for 1.5 h. The mixture was reduced in vacuo and partitioned between saturated NaHCO3 solution (150 ml) and EtOAc (2x150 ml). The combined organics were dried (Na2SO4), filtered and evaporated in vacuo to give a crude oil. This was purified by flash chromatography [SiO2; eluting with CH2CI2: MeOH (100:0-95:5)] to afford 4-(2-chloro-5-(methylthio)-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-benzamide as a beige solid (0.9 g, 29%). (LC/MS(acidic method): Rt 2.14, [M+H]+ 483.13). EXAMPLE 93 Synthesis of: [3 -f 5-Morpholin-4-yrmethyl-1 H-benzimidazol-2-yl) 1 H-pyrazol-4-yl]-carbamic acid. 4-fluoro-phenvl ester (Formula Removed) A mixture of 3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-ylamine (50 mg, 0.16 mmol) and pyridine (0.02ml, 0.24mmol) dissolved in a mixture of CH2Cl2 (1ml) and THF (1 ml) was stirred at 0 °C and then treated with 4-fluorophenylchloroformate (30.7mgs, 0.168mmol). The reaction mixture was stirred at RT until complete and then diluted with CH2Cl2. The CH2Cl2 fraction was washed with sat. bicarbonate, brine, dried (MgSO4) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, CH2Cl2-MeOH (90:10)] to give [3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-lH-pyrazol-4-yl]-carbamic acid 4-fluoro-phenyl ester as a colourless solid (5 mg, 7%). (LC/MS (acidic method): Rt 2.08, [M+H]+437). EXAMPLES 94-100 The compounds of Examples 94 to 100 were prepared by the methods of the preceding Examples. EXAMPLE 94 5-Methyl-2-trifluoromethyl-furan-3-carboxylic acid [3-(5-morpholin-4-ylmethyl-1 H-benzimidazol-2-yl) 1 H-pyrazol-4-yl] -amide (Formula Removed) EXAMPLE 95 Isobenzofuran-1 -carboxylic acid [3-(5-morpholin-4-ylmemyl-lH-benzimidazol-2-yl)-1H-pyrazol-4-yl] -amide (Formula Removed) EXAMPLE 96 Biphenyl-2-carboxylic acid [3 -(5 -morpholin-4-ylmethyl-1 H-benzimidazol-2-yl) 1 H-pyrazol-4-yl] –amide (Formula Removed) EXAMPLE 97 4.6-Dimethyl-2-oxo-l,2-dihydro-pyridine-3-carboxylic acid [3-(5-morpholin-4-ylmethyl-1 H-benzimidazol-2-yl) 1 H-pyrazol-4-yl] -amide (Formula Removed) EXAMPLE 98 2-Oxo-1.2-dihydro-pyridine-3-carboxylic acid [3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1 H-pyrazol-4-yl] –amide (Formula Removed) EXAMPLE 99 3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid [3-(5-morpholin-4-ylmethyl-1 H-benzimidazol-2-yl) 1 H-pyrazol-4-yl] -amide (Formula Removed) EXAMPLE 100 2-(4-Chloro-phenvlsulphanyl)-N-[3-(5-morpholin-4-ylmethyl-lH-benzimidazol-2-yl)-1 H-pyrazol-4-yl] -nicotinamide (Formula Removed) BIOLOGICAL ACTIVITY EXAMPLE 101 Measurement of CDK2 Kinase Inhibitory Activity (IC 50) Compounds of the invention were tested for kinase inhibitory activity using either Protocol A or Protocol B. Protocol A 1.7 ul of active CDK2/CyclinA (Upstate Biotechnology, 10U/µl) is diluted in assay buffer (250ul of 10X strength assay buffer (200mM MOPS pH 7.2,250mM p-glycerophosphate, 50mM EDTA, 150mM MgCl2), 11.27 µl l0mM ATP, 2.5 µl IM DTT, 25 µl l00mM sodium orthovanadate, 708.53 µl H2O), and 10 µl mixed with 10 µl of histone substrate mix (60 µl bovine histone H1 (Upstate Biotechnology, 5 mg/ml), 940 µl H2O, 35 µCi 33P-ATP) and added to 96 well plates along with 5 µl of various dilutions of the test compound in DMSO (up to 2.5%). The reaction is allowed to proceed for 5 hours before being stopped with an excess of ortho-phosphoric acid (30 ul at 2%). 33P-ATP which remains unincorporated into the histone H1 is separated from phosphorylated histone H1 on a Millipore MAPH filter plate. The wells of the MAPH plate are wetted with 0.5% orthophosphoric acid, and then the results of the reaction are filtered with a Millipore vacuum filtration unit through the wells. Following filtration, the residue is washed twice with 200 µl of 0.5% orthophosphoric acid. Once the filters have dried, 25 ul of Microscint 20 scintillant is added, and then counted on a Packard Topcount for 30 seconds. The % inhibition of the CDK2 activity is calculated and plotted in order to determine the concentration of test compound required to inhibit 50% of the CDK2 activity (IC50). The compounds of Examples 0 to 5 each have IC50 values of less than 20uM or provide at least 50% inhibition of the CDK2 activity at a concentration of l0µM. Preferred compounds have IC50 values of less than 1 µM. ProtocolB Activated CDK2/CyclinA (Brown et al, Nat. Cell Biol., 1, pp438-443,1999; Lowe, E.D., et al Biochemistry, 41, ppl5625-15634, 2002) is diluted to 125pM in 2.5X strength assay buffer (50mM MOPS pH 7.2, 62.5 mM ß-glycerophosphate, 12.5mM EDTA, 37.5mM MgCl2,112.5 mM ATP, 2.5 mM DTT, 2.5 mM sodium orthovanadate, 0.25 mg/ml bovine serum albumin), and 10 µl mixed with 10 µl of histone substrate mix (60 µl bovine histone H1 (Upstate Biotechnology, 5 mg/ml), 940 µl H2O, 35 µCi 33P-ATP) and added to 96 well plates along with 5 ul of various dilutions of the test compound in DMSO (up to 2.5%). The reaction is allowed to proceed for 2 to 4 hours before being stopped with an excess of orthophosphoric acid (5 µl at 2%). 33P-ATP which remains unincorporated into the histone H1 is separated from phosphorylated histone H1 on a Millipore MAPH filter plate. The wells of the MAPH plate are wetted with 0.5% orthophosphoric acid, and then the results of the reaction are filtered with a Millipore vacuum filtration unit through the wells. Following filtration, the residue is washed twice with 200 ul of 0.5% orthophosphoric acid. Once the filters have dried, 20 ul of Microscint 20 scintillant is added, and then counted on a Packard Topcount for 30 seconds. The % inhibition of the CDK2 activity is calculated and plotted in order to determine the concentration of test compound required to inhibit 50% of the CDK2 activity (IC50). CDKl/CyclinB Assay. CDKl/CyclinB assay, is identical to the CDK2/CyclinA above except that CDKl/CyclinB (Upstate Discovery) is used and the enzyme is diluted to 6.25nM. EXAMPLE 102 GSK3-B/Aurora Kinase Inhibitory Activity Assay AuroraA (Upstate Discovery) or GSK3-P (Upstate Discovery) are diluted to 10nM and 7.5nM respectively in 25mM MOPS, pH 7.00,25mg/ml BSA, 0.0025% Brij-35,1.25% glycerol, 0.5mM EDTA, 25mM MgCl2, 0.025% p-mercaptoethanol, 37.5mM ATP and and 10 ul mixed with 10 ul of substrate mix. The substrate mix for Aurora is 500µM Kemptide peptide (LRRASLG, Upstate Discovery) in 1ml of water with 35 µCi 33P-ATP. The substrate mix for GSK3-ß is 12.5 uM phospho-glycogen synthase peptide-2 (Upstate Discovery) in 1ml of water with 35 uCi y P-ATP. Enzyme and substrate are added to 96 well plates along with 5 ul of various dilutions of the test compound in DMSO (up to 2.5%). The reaction is allowed to proceed for 30 minutes (Aurora) or 3 hours (GSK3-P) before being stopped with an excess of ortho-phosphoric acid (5 µl at 2%). The filtration procedure is as for Activated CDK2/CyclinA assay above. EXAMPLE 103 CDK Selectivity Assays Compounds of the invention were tested for kinase inhibitory activity against a number of different kinases using the general protocol described in Example 129, but modified as set out below. Kinases are diluted to a 10x working stock in 20mM MOPS pH 7.0, ImM EDTA, 0.1% Y-mercaptoethanol, 0.01% Brij-35, 5% glycerol, lmg/ml BSA. One unit equals the incorporation of lnmol of phosphate per minute into 0. lmg/ml histone H1, or CDK7 substrate peptide at 30 °C with a final ATP concentration of l00µM. The substrate for all the CDK assays (except CDK7) is histone H1, diluted to 10X working stock in 20mM MOPS pH 7.4 prior to use. The substrate for CDK7 is a specific peptide diluted to 10X working stock in deionised water. Assay Procedure for CDKl/cYclinB. CDK2/cvclinA. CDK2/cvclinE. CDK3/cvclinE. CDK5/p35. CDK6/cYclinD3: In a final reaction volume of 25ul, the enzyme (5-10mU) is incubated with 8mM MOPS pH 7.0,0.2mM EDTA, 0.lmg/ml histone H1, l0mM MgAcetate and [-33P-ATP] (specific activity approx 500cpm/pmol, concentration as required). The reaction is initiated by the addition of Mg [y- P-ATP]. After incubation for 40 minutes at room temperature the reaction is stopped by the addition of 5µl of a 3% phosphoric acid solution. 10ml of the reaction is spotted onto a P30 filter mat and washed 3 times for 5 minutes in 75mM phosphoric acid and once in methanol prior to drying and counting. Assay procedure for CDK7/cyclinH/MATl In a final reaction volume of 25 µl, the enzyme (5-10mU) is incubated with 8mM MOPS pH 7.0,0.2mM EDTA, 500µM peptide, l0mM MgAcetate and [-33P-ATP] (specific activity approx 500cpm/pmol, concentration as required). The reaction is initiated by the addition of Mg2+[-33P-ATP]. After incubation for 40 minutes at room temperature the reaction is stopped by the addition of 5µl of a 3% phosphoric acid solution. 10ml of the reaction is spotted onto a P30 filtermat and washed 3 times for 5 minutes in 75mM phosphoric acid and once in methanol prior to drying and counting. EXAMPLE 104 Anti-proliferative Activity The anti-proliferative activities of compounds of the invention were determined by measuring the ability of the compounds to inhibition of cell growth in a number of cell lines. Inhibition of cell growth was measured using the Alamar Blue assay (Nociari, M. M, Shalev, A., Benias, P., Russo, C. Journal of Immunological Methods 1998,213,157-167). The method is based on the ability of viable cells to reduce resazurin to its fluorescent product resorufin. For each proliferation assay cells were plated onto 96 well plates and allowed to recover for 16 hours prior to the addition of inhibitor compounds for a further 72 hours. At the end of the incubation period 10% (v/v) Alamar Blue was added and incubated for a further 6 hours prior to determination of fluorescent product at 535nM ex / 590nM em. In the case of the non-proliferating cell assay cells were maintained at confluence for 96 hour prior to the addition of inhibitor compounds for a further 72 hours. The number of viable cells was determined by Alamar Blue assay as before. All cell lines were obtained from ECACC (European Collection of cell Cultures). By following the protocol set out above, compounds of the invention were found to inhibit cell growth in a number of cell lines. EXAMPLE 105 Measurement of inhibitory activity against Glycogen Synthase Kinase-3 (GSK-S) GSK3ß (human) is diluted to a 10x working stock in 50mM Tris pH 7.5, 0.1mM EGTA, O.lmM sodium vanadate, 0.1% P-mercaptoethanol, lmg/ml BSA. One unit equals the incorporation of lnmol of phosphate per minute phospho-glycogen synthase peptide 2 per minute. In a final reaction volume of 25µl, GSK3ß (5-10 mU) is incubated with 8mM MOPS 7.0, 0.2mM EDTA, 20µM YRRAAVPPSPSLSRHSSPHQS(p)EDEEE (phospho GS2 peptide), l0mM MgAcetate and [y- P-ATP] (specific activity approx 500cpm/pmol, concentration as required). The reaction is initiated by the addition of Mg2+[-33P-ATP]. After incubation for 40 minutes at room temperature the reaction is stopped by the addition of 5µl of a 3% phosphoric acid solution. 10µ1 of the reaction is spotted onto a P30 filter mat and washed 3 times for 5 minutes in 50mM phosphoric acid and once in methanol prior to drying and counting. PHARMACEUTICAL FORMULATIONS EXAMPLE 106 (T) Tablet Formulation A tablet composition containing a compound of the formula (VII) is prepared by mixing 50mg of the compound with 197mg of lactose (BP) as diluent, and 3mg magnesium stearate as a lubricant and compressing to form a tablet in known manner. (ii) Capsule Formulation A capsule formulation is prepared by mixing l00mg of a compound of the formula (VII) with l00mg lactose and filling the resulting mixture into standard opaque hard gelatin capsules. EXAMPLE 107 Determination of Antifungal Activity The antifungal activity of the compounds of the formula (VII) is determined using the following protocol. The compounds are tested against a panel of fungi including Candida parpsilosis, Candida tropicalis, Candida albicans-ATCC 36082 and Cryptococcus neoformans. The test organisms are maintained on Sabourahd Dextrose Agar slants at 4 °C. Singlet suspensions of each organism are prepared by growing the yeast overnight at 27 °C on a rotating drum in yeast-nitrogen base broth (YNB) with amino acids (Difco, Detroit, Mich.), pH 7.0 with 0.05 M morpholine propanesulphonic acid (MOPS). The suspension is then centrifuged and washed twice with 0.85% NaCl before sonicating the washed cell suspension for 4 seconds (Branson Sonifier, model 350, Danbury, Conn.). The singlet blastospores are counted in a haemocytometer and adjusted to the desired concentration in 0.85% NaCl. The activity of the test compounds is determined using a modification of a broth microdilution technique. Test compounds are diluted in DMSO to a 1.0 mg/ml ratio then diluted to 64 ug/ml in YNB broth, pH 7.0 with MOPS (Fluconazole is used as the control) to provide a working solution of each compound. Using a 96-well plate, wells 1 and 3 through 12 are prepared with YNB broth, ten fold dilutions of the compound solution are made in wells 2 to 11 (concentration ranges are 64 to 0.125 ug/ml). Well 1 serves as a sterility control and blank for the spectrophotometric assays. Well 12 serves as a growth control. The microtitre plates are inoculated with 10 µl in each of well 2 to 11 (final inoculum size is 104 organisms/ml). Inoculated plates are incubated for 48 hours at 35 °C. The IC50 values are determined spectrophotometrically by measuring the absorbance at 420 nm (Automatic Microplate Reader, DuPont Instruments, Wilmington, Del.) after agitation of the plates for 2 minutes with a vortex-mixer (Vorte-Genie 2 Mixer, Scientific Industries, Inc., Bolemia, N.Y.). The IC50 endpoint is defined as the lowest drug concentration exhibiting approximately 50% (or more) reduction of the growth compared with the control well. With the turbidity assay this is defined as the lowest drug concentration at which turbidity in the well is EXAMPLE 108 Protocol for the Biological Evaluation of Control of in vivo Whole Plant Fungal Infection Compounds of the formula (VII) are dissolved in acetone, with subsequent serial dilutions in acetone to obtain a range of desired concentrations. Final treatment volumes are obtained by adding 9 volumes of 0.05% aqueous Tween-20 ™ or 0.01% Triton X-100™, depending upon the pathogen. The compositions are then used to test the activity of the compounds of the invention against tomato blight (Phytophthora infestans) using the following protocol. Tomatoes (cultivar Rutgers) are grown from seed in a soil-less peat-based potting mixture until the seedlings are 10-20 C1-4 tall. The plants are then sprayed to run-off with the test compound at a rate of 100 ppm. After 24 hours the test plants are inoculated by spraying with an aqueous sporangia suspension of Phytophthora infestans, and kept in a dew chamber overnight. The plants are then transferred to the greenhouse until disease develops on the untreated control plants. Similar protocols are also used to test the activity of the compounds of the invention in combatting Brown Rust of Wheat (Puccinia), Powdery Mildew of Wheat (Ervsiphe vraminis), Wheat (cultivar Monon), Leaf Blotch of Wheat (Septoria tritici), and Glume Blotch of Wheat (Leptosphaeria nodorum). 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. WE CLAIM:- A morpholinomethyl-benzimidazol-2-ylpyrazole compound of the formula (VII): (Formula Removed) or a salt, N-oxide or solvate thereof; wherein A is NH(C=O), O(OO) or C=O; and Rld is hydrogen, an optionally substituted carbocyclic or heterocyclic group having from 3 to 12 ring members, or an optionally substituted C1-» hydrocarbyl group. A compound as claimed in claim 1 wherein Rld is a carbocyclic or heterocyclic group having from 3 to 12 ring members which is unsubstituted or substituted by one or more substituent groups R10 selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group Ra-Rb wherein Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NRC, SO2NRc or NRCSO2; and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group is optionally replaced by O, S, SO, SO2, NRC, X1C(X2), C(X2)X1 or X1C(X2)X1; or two adjacent groups R10, together with the carbon atoms or heteroatoms to which they are attached form a 5-membered heteroaryl ring or a 5- or 6-membered non-aromatic carbocyclic or heterocyclic ring, wherein the said heteroaryl and heterocyclic groups contain up to 3 heteroatom ring members selected from N, O and S; Rc is selected from hydrogen and C1-4 hydrocarbyl; and X1 is O, S or NRC and X2 is =O, =S or =NRC; and provided that where the substituent group R10 comprises or includes a carbocyclic or heterocyclic group, the said carbocyclic or heterocyclic group is unsubstituted or is itself substituted with one or more further substituent groups R10 and wherein (a) such further substituent groups R10 include unsubstituted carbocyclic or unsubstituted heterocyclic groups; or (b) the said further substituents are selected from the groups listed above in the definition of R10 other than carbocyclic or heterocyclic groups A compound as claimed in claim 1 wherein the substituents for the optionally substituted C1-8 hydrocarbyl group are selected from hydroxy, oxo, alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C1-4 hydrocarbylamino, and monocyclic or bicyclic carbocyclic and heterocyclic groups having from 3 to 12 ring members. A compound as claimed in claim 1 wherein Rld is selected from: o 6-membered monocyclic aryl groups substituted by one to three substituents R10c provided that when the aryl group is substituted by a methyl group, at least one substituent other than methyl is present; o 6-membered monocyclic heteroaryl groups containing a single heteroatom ring member which is nitrogen, the heteroaryl groups being substituted by one to three substituents R10c; o 5-membered monocyclic heteroaryl groups containing up to three heteroatom ring members selected from nitrogen and sulphur, and being optionally substituted by one to three substituents R10c; o 5-membered monocyclic heteroaryl groups containing a single oxygen heteroatom ring member and optionally a nitrogen heteroatom ring member, and being substituted by one to three substituents R10c provided that when the heteroaryl group contains a nitrogen ring member and is substituted by a methyl group, at least one substituent other than methyl is present; o bicyclic aryl and heteroaryl groups having up to four heteroatom ring members and wherein either one ring is aromatic and the other ring is non-aromatic, or wherein both rings are aromatic, the bicyclic groups being optionally substituted by one to three substituents R10c; o four-membered, six-membered and seven-membered monocyclic C-linked saturated heterocyclic groups containing up to three heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic groups being optionally substituted by one to three substituents R10c provided that when the heterocyclic group has six ring members and contains only one heteroatom which is oxygen, at least one substituent R10c is present; o five membered monocyclic C-linked saturated heterocyclic groups containing up to three heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic groups being optionally substituted by one to three substituents R10c provided that when the heterocyclic group has five ring members and contains only one heteroatom which is nitrogen, at least one substituent R10c other than hydroxy is present; o four and six membered cycloalkyl groups optionally substituted by one to three substituents R10c; o three and five membered cycloalkyl groups substituted by one to three substituents R10c; and o a group Ph'CR17R18- where Ph' is a phenyl group substituted by one to three substituents R10c; R17 and R18 are the same or different and each is selected from hydrogen and methyl; or R17 and R18 together with the carbon atom to which they are attached form a cyclopropyl group; or one of R17 and R18 is hydrogen and the other is selected from amino, methylamino, C1-4 acylamino, and C1-4 alkoxycarbonylamino; o unsubstituted phenyl and phenyl substituted with one or more methyl groups; o unsubstituted 6-membered monocyclic heteroaryl groups containing a single heteroatom ring member which is nitrogen; o unsubstituted furyl; o 5-membered monocyclic heteroaryl groups containing a single oxygen heteroatom ring member and a nitrogen heteroatom ring member, and being unsubstituted or substituted by one or more methyl groups; o unsubstituted six membered monocyclic C-linked saturated heterocyclic groups containing only one heteroatom which is oxygen; and o unsubstituted three and five membered cycloalkyl groups; and R10c is selected from: o halogen; o hydroxyl; o C1-4 hydrocarbyloxy optionally substituted by one or more substituents selected from hydroxyl and halogen; o C1-4 hydrocarbyl substituted by one or more substituents selected from hydroxyl, halogen and five and six-membered saturated heterocyclic rings containing one or two heteroatom ring members selected from nitrogen, oxygen and sulphur; o S-C1-4 hydrocarbyl; o phenyl optionally substituted with one to three substituents selected from C1-4 alkyl, trifiuoromethyl, fluoro and chloro; o heteroaryl groups having 5 or 6 ring members and containing up to 3 heteroatoms selected from N, O and S, the heteroaryl groups being optionally substituted with one to three substituents selected from C1-4 alkyl, trifiuoromethyl, fluoro and chloro; o 5- and 6-membered non-aromatic heterocyclic groups containing up to 3 heteroatoms selected from N, O and S and being optionally substituted with one to three substituents selected from C1-4 alkyl, trifiuoromethyl, fluoro and chloro; o cyano, nitro, amino, C1-4 alkylamino, di-C1-4alkylamino, C1-4 acylamino, C1-4 alkoxycarbonylamino; o a group R19-S(O)n- where n is 0, 1 or 2 and R19 is selected from amino; C1-4 alkylamino; di-C1-4alkylamino; C1-4 hydrocarbyl; phenyl optionally substituted with one to three substituents selected from C1-4 alkyl, trifiuoromethyl, fluoro and chloro; and 5- and 6-membered non-aromatic heterocyclic groups containing up to 3 heteroatoms selected from N, O and S and being optionally substituted with one to three C1-4 alkyl group substituents; and o a group R20-Q- where R20 is phenyl optionally substituted with one to three substituents selected from C1-4 alkyl, trifluoromethyl, fluoro and chloro; and Q is a linker group selected from OCH2, CH2O, NH, CH2NH, NCH2, CH2, NHCO and CONH. 5. A compound as claimed in claim 1 wherein A is NH(C=O) or (C=O), and Rld is a substituted phenyl group having from 1 to 4 substituents whereby: (i) when Rld bears a single substituent it is selected from halogen, hydroxyl, C1-4 hydrocarbyloxy optionally substituted by one or more substituents selected from hydroxyl and halogen; C1-4 hydrocarbyl substituted by one or more substituents selected from hydroxyl and halogen; heteroaryl groups having 5 ring members; and 5- and 6-membered non-aromatic heterocyclic groups, wherein the heteroaryl and heterocyclic groups contain up to 3 heteroatoms selected from N, O and S; and (ii) when Rld bears 2, 3 or 4 substituents, each is selected from halogen, hydroxyl, C1-4 hydrocarbyloxy optionally substituted by one or more substituents selected from hydroxyl and halogen; C1-4 hydrocarbyl optionally substituted by one or more substituents selected from hydroxyl and halogen; heteroaryl groups having 5 ring members; amino; and 5- and 6-membered non-aromatic heterocyclic groups; or two adjacent substituents together with the carbon atoms to which they are attached form a 5-membered heteroaryl ring or a 5- or 6-membered non-aromatic heterocyclic ring; wherein the said heteroaryl and heterocyclic groups contain up to 3 heteroatoms selected from N, O and S. 6. A compound as claimed in claim 1 wherein Rld is selected from: (a) a mono-substituted phenyl group wherein the substituent is selected from o-amino, o-methoxy; o-chloro; p-chloro; o-difluoromethoxy; o-trifluoromethoxy; o-tert-butyloxy; m-methylsulphonyl and p-fluoro; (b) a 2,4- or 2,6-disubstituted phenyl group wherein one substituent is selected from o-methoxy, o-ethoxy, o-fluoro, p-morpholino and the other substituent is selected from o-fluoro, o-chloro, p-chloro, and p-amino; (c) a 2,5-disubstituted phenyl group wherein one substituent is selected from o-fluoro and o-methoxy and the other substituent is selected from m-methoxy, m-isopropyl; m-fluoro, m-trifluoromethoxy, m-trifluoromethyl, m-methylsulphanyl, m-pyrrolidinosulphonyl, m-(4-methylpiperazin-1 -yl) sulphonyl, m-morpholinosulphonyl, m-methyl, m-chloro and m-aminosulphonyl; (d) a 2,4,6-tri-substituted phenyl group where the substituents are the same or different and are each selected from o-methoxy, o-fluoro, p-fluoro, p-methoxy provided that no more than one methoxy substituent is present; (e) a 2,4,5-tri-substituted phenyl group where the substituents are the same or different and are each selected from o-methoxy, m-chloro and p-amino; (f) unsubstituted benzyl; 2,6-difluorobenzyl; a,a-dimethylbenzyl; 1-phenylcycloprop-1-yl; and a-tert-butoxycarbonylaminobenzyl; (g) an unsubstituted 2-furyl group or a 2-furyl group bearing a single substituent selected from 4-(morpholin-4-ylmethyl), piperidinylmethyl; and optionally a further substituent selected from methyl; (h) an unsubstituted pyrazolo[l,5-a]pyridin-3-yl group; (i) isoxazolyl substituted by one or two C1-4 alkyl groups; (j) 4,5,6,7-tetrahydro-benz[d]isoxazol-3-yl; (k) 3-tert-butyl-phenyl- lH-pyrazol-5-yl; (1) quioxalinyl; (m) benz[c]isoxazol-3-yl; (n) 2-methyl-4-trifluoromethyl-thiazol-5-yl; (o) 3-phenylamino-2-pyridyl; (p) 1 -toluenesulphonylpyrrol-3-yl; (q) 2,4-dimethoxy-3-pyridyl; and 6-chloro-2-methoxy-4-methyl-3- pyridyl; (r) imidazo[2,l-b]thiazol-6-yl; (s) 5-chloro-2-methylsulphanyl-pyrimidin-4-yl; (t) 3-methoxy-naphth-2-yl; (u) 2,3-dihydro-benz[ 1,4]dioxin-5-yl; (v) 2,3-dihydro-benzfuranyl group optionally substituted in the five membered ring by one or two methyl groups; (w) 2-methyl-benzoxazol-7-yl; (x) 4-aminocyclohex-l-yl; (y) l,2,3,4-tetrahydro-quinolin-6-yl; (z) 2-methyl-4,5,6,7-tetrahydro-benzfuran3-yl; (aa) 2-pyrimidinyl-lpiperidin-4-yl; and l-(5-trifluoromethyl-2-pyridyl)- piperidin-4-yl and l-methylsulphonylpiperidin-4-yl; (l) 1-cyanocyclopropyl; (m) N-benzylmorpholin-2-yl; and when A is NH(C=Oj, Rld is additionally selected from: (ad) unsubstituted phenyl. A compound as claimed in claim 1 having the formula (Vila): (Formula Removed) where Rld and A are as defined in any one of claims 1 to 4. A compound as claimed in any one of claims 1 to 5 wherein A is NH(C=O). A compound as claimed in any one of claims 1 to 5 wherein A is C=O. A compound as claimed in any of the preceding claims as and when used along with a pharmaceutically acceptable carrier in a pharmaceutical composition. A process for the preparation of a compound as defined in any one of claims 1 to 9, which process comprises: (i) the reaction of a substituted 4-amino-pyrazol-3-ylcarboxylic acid compound of the formula: (Formula Removed) with a morpholinomethyl-phenylene diamine compound of the formula: (Formula Removed) wherein Rld and A are as defined in any one of the preceding claims. |
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60-DELNP-2006-Abstract-(17-03-2009).pdf
60-DELNP-2006-Abstract-(19-02-2009).pdf
60-DELNP-2006-Claims-(17-03-2009).pdf
60-DELNP-2006-Claims-(19-02-2009).pdf
60-delnp-2006-correspondence others 1..pdf
60-DELNP-2006-Correspondence-Others-(17-03-2009).pdf
60-DELNP-2006-Correspondence-Others-(19-02-2009).pdf
60-delnp-2006-correspondence-others.pdf
60-DELNP-2006-Description (Complete)-(17-03-2009).pdf
60-DELNP-2006-Description (Complete)-(19-02-2009).pdf
60-delnp-2006-description (complete).pdf
60-DELNP-2006-Form-1-(17-03-2009).pdf
60-DELNP-2006-Form-1-(19-02-2009).pdf
60-delnp-2006-form-13-(19-02-2009).pdf
60-DELNP-2006-Form-2-(17-03-2009).pdf
60-DELNP-2006-Form-2-(19-02-2009).pdf
60-DELNP-2006-GPA-(19-02-2009).pdf
60-DELNP-2006-Petition-137-(19-02-2009).pdf
| Patent Number | 232730 | ||||||||||||||||||||||||||||||||||||
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| Indian Patent Application Number | 60/DELNP/2006 | ||||||||||||||||||||||||||||||||||||
| PG Journal Number | 13/2009 | ||||||||||||||||||||||||||||||||||||
| Publication Date | 27-Mar-2009 | ||||||||||||||||||||||||||||||||||||
| Grant Date | 20-Mar-2009 | ||||||||||||||||||||||||||||||||||||
| Date of Filing | 03-Jan-2006 | ||||||||||||||||||||||||||||||||||||
| Name of Patentee | ASTEX THERAPEUTICS LIMITED | ||||||||||||||||||||||||||||||||||||
| Applicant Address | 436 CAMBRIDGE SCIENCE PARK, MILTON ROAD, CAMBRIDGE CB4 0QA, UK | ||||||||||||||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | A61K 31/00 | ||||||||||||||||||||||||||||||||||||
| PCT International Application Number | PCT/GB2004/002824 | ||||||||||||||||||||||||||||||||||||
| PCT International Filing date | 2004-07-05 | ||||||||||||||||||||||||||||||||||||
PCT Conventions:
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