Title of Invention	"A SUBSTITUTED PYRIMIDINE COMPOUND"
Abstract	The invention provides compounds of formula (I) which R1, R2, R3 and R4 have the meanings defined in the specification; processes for their preparation; pharmaceutical compositions containing them; a process for preparing the pharmaceutical compositions; and their use in therapy.

Full Text

The present invention relates to pyrimidine derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy. The insulin-like growth factor (IGF) axis consists of ligands, receptors, binding proteins' and proteases. The two ligands, IGF-I and IGF-II, are mitogenic peptides that signal through interaction with the type 1 insulin-like growth factor receptor (IGF-1R), a hetero-tetrameric cell surface receptor. Binding of either ligand stimulates activation of a tyrosine kinase domain in the intracellular region of the p-chain and results in phosphorylation of several tyrosine residues resulting in the recruitment and activation of various signaling molecules. The intracellular domain has been shown to transmit signals for mitogenesis, survival, transformation, and differentiation in cells. The structure and function of the IGF-1R has been reviewed by Adams et al {Cellular and Molecular Life Sciences, 57, 1050-1093, 2000). The IGF-IIR (also known as mannose 6-phosphate receptor) has no such kinase domain and does not signal mitogenesis bur may act to regulate ligand availability at the cell surface, counteracting the effect of the IGF-1R. The IGF binding proteins (IGFBP) control availability of circulating IGF and release of IGF from these can be mediated by proteolytic cleavage. These other components of the IGF axis have been reviewed by Collett-Solberg and Cohen {Endocrine, 12, 121-136, 2000). There is considerable evidence linking IGF signaling with cellular transformation and the onset and progression of tumours. IGF has been identified as the major survival factor that protects from oncogene induced cell death (Harrington et al, EMBO J, 13, 3286-3295, 1994). Cells lacking IGF-1R have been shown to be refractory to transformation by several different oncogenes (including SV40T antigen and ras) that efficiently transform corresponding wild-type cells (Sell et al, Mol. Cell Biol., 14, 3604-12,1994). Upregulaiion of components of the IGF axis has been described in various tumour cell lines and tissues, particularly tumours of the breast (Surmacz, Journal of Mammary Gland Biology & Neoplasia, 5, 95-105, 2000), prostate (Djavan et al, World J. Urol., 19, 225-233, 2001, and O'Brien et al, Urology, 58, 1-7, 2001) and colon (Guo et al, Gastroenterology, 102, 1101-1108, 1992). Conversely, IGF-IIR has been implicated as a tumour suppressor and is deleted in some cancers (DaCosta et al, Journal of Mammary Gland Biology & Neoplasia, 5, 85-94, 2000). There is a growing number of epidemiological studies linking increased circulating IGF (or increased ratio of IGF-1 to IGFBP3) with cancer risk (Yu and Rohan, J. NatlCancer Inst. , 92, 1472-1489, 2000). Transgenic mouse models also implicate IGF signaling in the onset of tumour cell proliferation (Lamm and Christofori, Cancer Res. 58, 801-807, 1998, Foster et al, Cancer Metas. Rev., 17, 317-324, 1998, and DiGiovanni et al, Proc. Natl. Acad. Sci., 91, 3455-3460, 2000). Several in vitro and in vivo strategies have provided the proof of principal that inhibition of IGF-1 R signaling reverses the transformed phenotype and inhibits tumour cell growth. These include neutralizing antibodies (Kalebic et al Cancer Res., 54, 5531-5534, 1994), antisense oligonucleotides (Resnicoff et al, Cancer Res., 54, 2218-2222, 1994), triple-helix forming oligonucleotides (Rinninsland et al, Proc. Natl. Acad. Sci., 94, 5854-5859, 1997), antisense mRNA (Nakamura et al, Cancer Res., 60, 760-765, 2000) and dominant negative receptors (D'Ambrosio et al., Cancer Res., 56, 4013-4020, 1996). Antisense oligonucleotides have shown that inhibition of IGF-1 R expression results in induction of apoptosis in cells in vivo (Resnicoff et al, Cancer Res., 55, 2463-2469, 1995) and have been taken into man (Resnicoff et al, Proc. Amer. Assoc. Cancer Res., 40 Abs 4816, 1999). However, none of these approaches is particularly attractive for the treatmenl of major solid tumour disease. Since increased IGF signaling is implicated in the growth and survival of tumour cells, and bloking IGF-1R function can reverse this, inhibition of the IGF-1R tyrosine kinase domain is an appropriate therapy by which to treat cancer. In vitro and in vivo studies with the use of dominant-negative 1GF-1R variants support this. In particular, a point mutation in the ATP binding site which blocks receptor tyrosine kinase activity has proved effective in preventing tumour cell growth (Kulik et al, Mol. Cell. Biol., 17, 1595-1606, 1997). Several pieces of evidence imply that normal cells are less susceptible to apoptosis caused by inhibition of IGF signaling, indicating that a therapeutic margin is possible with such treatment (Baserga, Trends BiotechnoL, 14, 150-2,1996). There are few reports of selective IGF-1R tyrosine kinase inhibitors. Parrizas et al. described tyrphostins that had some efficacy in vitro and in vivo (Parrizas et al, Endocrinology, 138:1427-33 (1997)). These compounds were of modest potency and selectivity over the insulin receptor. Telik Inc. have described heteroaryl-aryl ureas which have selectivity over insulin receptors but potency against tumour cells in vitro is still modest (Published PCT Patent Application No. WO 00/35455). In accordance with the present invention, there is provided a compound of formula (I): (Formula Removed) wherein R1 represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen, amino (-NH2), hydroxy) and trifiuoromethyl), halogen, nitro, cyano, -NR5R , carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6alkylcarbonylamino, phenylcarbonyl, -S(0)mC1-C6alkyl, -C(0)NR7R8, -S02NR7aR8a, and an unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected fromC1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen, amino (-NH2), hydroxyl and trifiuoromethyl), halogen, nitro, cyano, -NR9R10, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6alkylcarbonylamino, phenylcarbonyl, -S(0)nC1-C6alkyl, -C(0)NR"R12 and -S02NRllnRUa; m is 0, 1 or 2; n is 0, 1 or 2; R2 represents a C1-C4alkyl group optionally substituted by at least one substituent selected from halogen, hydroxyl and C1-C3alkoxy; R represents hydrogen, halogen or trifiuoromethyl; R represents a 5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen, amino (-NH2), hydroxyl and trifiuoromethyl), halogen, nitro, cyano, -NR!3R14, carboxyl, hydroxy], C2-C6alkenyl, C3-C6cycloalkyI, C1-C4alkoxycarbonyI, C1-C4alkylcarbonyl, C1-C4alkylcarbonylamino, phenylcarbonyl, -S(0)pC1-C4alkyl, -C(0)NRI5R16 and -S02NR15aR16a; p is 0, 1 or 2; R5 and R each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R7 and R8 each independently represent hydrogen, C1-C4alkyl or C3-C6cycIoalkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R7a and R8a each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R7a and R8a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R9 and R10 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R11 and R12 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R11 and R12 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; RUa and R12a each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R1'" and Rl2a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R13 and R14 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R13 and R14 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R15 and R16 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R15 and R16 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; and R15a and R16a each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R,5a and Rl6a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; or a pharmaceutically acceptable salt or solvate thereof. In the context of the present specification, unless otherwise indicated, an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched. When R5 and R6, or R7 and R8, or R7a and R8a, or R9 and R10, or R11 and R12, or Rlla and R12a, or R13 and R14, or R15 and R16, or Rl5a and R16a represent a saturated heterocycle, it should be understood that the only heteroatom present is the nitrogen atom to which R5 and R6, or R7 and R8, or R7° and R8a, or R9 and R10, or R1' and R12, or R1 la and Rl2a, or R13 and RM, or R15 and R16, or R15a and R16a are attached. In the definition of R1, it should be noted that the unsaturated 5- to 6-membered ring may have alicyclic or aromatic properties. Examples of "C1-C6alkyl" and "C1-C4alkyl" include methyl, ethyi, isopropyl and /-butyl. Examples of "C1-C6alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n-and f-butoxycarbonyl. Examples of "C1.C6alkoxy" and "C1-C3alkoxy" include methoxy, ethoxy and propoxy. Examples of "C1-C6alkylcarbonylamino" include formamido, acetamido and propionylamino. Examples of "S(0)mC1-C6alkyl" wherein m is 0 to 2 include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of "C1-C6alkylcaibonyl" include propionyl and acetyl. Examples of "C2-C6alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C3.C6cycloalkyl" are cyclopropyl, cyclopentyl and cyclohexyl. A "5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur" is a fully unsaturated, aromatic monocyclic ring containing 5 or 6 atoms of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, which may, unless otherwise specified, be carbon or nitrogen linked. Suitably a "5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur" is pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl or thienyl. An "unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur" is a fully or partially unsaturated, monocyclic ring containing 5 or 6 atoms optionally of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, and which may, unless otherwise specified, be carbon or nitrogen linked. Suitably an "unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur" is'phenyl or pyridyl. A "5- membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur" is a fully unsaturated, aromatic monocyclic ring containing 5 atoms of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, which may, unless otherwise specified, be carbon or nitrogen linked. Suitably a "5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur" is pyrazolyl. R represents an optionally substituted 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur. Examples of heteroaromatic rings include thienyl (e.g. 3-thienyl), pyrazolyl (e.g. 4-pyrazolyl), isoxazolyl (e.g. 5-isoxazolyl), thiadiazolyl, pyrrolyl (e.g. 2-pyrrolyl), furanyl (2-or 3-furanyl), thiazolyl, triazoiyl, tetrazolyl, imidazolyl (e.g. 4-imidazolyl), pyrazinyl (e.g. 2-pyrazinyl), pyridazinyl (e.g. 3-pyridazinyl), pyrimidinyl (e.g. 4- or 5-pyrimidiny!) and pyridyl (2-, 3- or 4-pyridyl). In R1, the 5- or 6-membered heteroaromatic ring is optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from C1-C6, particularly C1-C4alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, lert-butyl, n-pentyl or n-hexyl), C1-C6particularly C1-C4alkoxy (such as methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, n-pentoxy or n-hexoxy) (each of the C1-C6alkyl and C1-C6alkoxy substituent groups being optionally substituted by at least one substituent, e.g. one, two, three or four substituents independently, selected from halogen (such as fluorine, chlorine bromine or iodine), amino, hydroxyl and trifluoromethyl), halogen (such as fluorine, chlorine, bromine or iodine), nitro, cyano, -NR5R6, carboxyl, hydroxy], C2-C6, particularly C2-C4alkenyl (such as ethenyl), C3-C6cycloalkyI (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C1-C6, particularly C1-C4alkoxycarbonyI (such as methoxycarbonyl or ethoxycarbonyl), C1-C6, particularly C1-C4alkylcarbonyl (such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C1-C6, particularly C1-C4alkylcarbonylamino (such as methylcarbonylamino or ethylcarbonylamino), phenylcarbonyl, -S(0)mC1-C6, particularly C1-C4alkyl, -C(0)NR7R8, -S02NR7aR8a, and an optionally substituted unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur. Examples of the unsaturated 5- to 6-membered ring include phenyl, cylopentenyl, cyclohexenyl, thienyl (e.g. 3-thienyl), pyrazolyl (e.g. 4-pyrazolyl), isoxazolyl (e.g. 5-isoxazolyl), thiadiazolyl, pyrrolyl (e.g. 2-pyrrolyl), furanyl (2-or 3-furanyl), thiazolyl, triazoiyl, tetrazolyl, imidazolyl (e.g. 4-imidazolyl), pyrazinyl (e.g. 2-pyrazinyl), pyridazinyl (e.g. 3-pyridazinyl), pyrimidinyl (e.g. 4- or 5-pyrimidinyl) and pyridyl (2-, 3-or 4-pyridyl). The ring may itself be optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected fromC1-C6 particularly C1-C4alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, rert-butyl, n-pentyl or n-hexyl), C1-C6, particularly C1-C4alkoxy (such as methoxy, ethoxy, n-propoxy, n-butoxy, ferr-butoxy, n-pentoxy or n-hexoxy) (each of the C1-C6alkyl and C1-C6alkoxy substituent groups being optionally substituted by at least one substituent, e.g. one, two, three or four substituents independently, selected from halogen (such as fluorine, chlorine bromine or iodine), amino, hydroxyl and trifluoromethyl), halogen (such as fluorine, chlorine, bromine or iodine), nitro, cyano, -NR9R10, carboxyl, hydroxyl, C2-C6, particularly C2-C4alkenyl (such as ethenyl), C3-Q,cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C1-C6, particularly C1-C4alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl), C1-C6, particularly C1-C4alkylcarbonyl (such as methylcarbony], ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C1-C6, particularly C1-C4alkylcarbonylamino (such as methylcarbonylamino or ethylcarbonylamino), phenylcarbonyl, -S(0)nC1-C6, particularly Cl-C4alkyl, -C(0)NRnR12 and -SC^NR1"^12*. Particular values of variable groups are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter. In one embodiment of the invention, R1 represents a 5- or 6-membered heteroaromatic ring comprising one or two ring heteroatoms selected from nitrogen and oxygen, the ring being optionally substituted by at least one substituent selected from C1-C66alkyl, C1-C6alkoxy, halogen, nitro, cyano, -NR5R6, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6alkylcarbonylamino, phenylcarbonyl, -S(0)mC1-C6alkyl, -C(0)NR7R8, -S02NR7aREa, and an unsaturated 6-membered ring which may comprise one ring nitrogen atom, the ring itself being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy, halogen, nitro, cyano, -NR9R10, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxycarbony], C1-C6alkylcarbonyl, C1-C6alkylcarbonylamino, phenylcarbonyl, -S(0)nC1-C6alkyl, -C(0)NR"R12 and -S02NRllaR12a. In a further embodiment of the invention, R1 represents a 5- or 6-membered heteroaromatic ring comprising one or two ring heteroatoms selected from nitrogen and oxygen, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy, halogen, phenyl and pyridyl, each of the phenyl and pyridyl substituent groups itself being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy and halogen. In an additional aspect R represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from hydroxyl), halogen, -C(0)NR7R8, C1-C6alkoxycarbonyl, and an unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen and oxygen, the ring itself being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen), halogen and cyano; wherein R7 and R8 are both hydrogen or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle. In a further additional aspect R1 represents pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl orthienyl; said pyridyl, imidazolyl, isoxazolyl, pyrazoJyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl and thienyl being optionally substituted by at least one substituent selected from methyl, isopropyl, hydroxymethyl, methoxy, chloro, bromo, carbamoyl, methoxycarbonyl, pyrrolidin-1-ylcarbonyl, phenyl and pyridyl; said phenyl or pyridyl being optionally substituted by at least one substituent selected from methyl, trifluoromethyl, methoxy, ethoxy, trifluoromelhoxy, fluoro, chloro, bromo and cyano. In a further additional aspect R1 represents pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-methoxypyrid-5-yl, 2-cyanopyrid-5-yl, 3-bromopyrid-5-yl, 3-(pyrid-2-yl)pyrid-5-y!, 4-(pyrid-2-yl)pyrid-2-yl, 3-chloropyrid-2-yl, 3-methylpyrid-2-yl, 6-methylpyrid-2-yl, 5,6-dimethylpyrid-2-yl, imidazol-4-yl, imidazol-5-yl, 3-mefhylisoxazol-5-yl, 5-methylisoxazol-3-yl, 3-isopropylisoxazol-5-yl, 3-methoxycarbonylisoxazol-5-yJ, 3-(hydroxymethyl)isoxazol-5-yl, 3-carbamoylisoxazol-5-yl, 3-(pyrrolidin-l-ylcarbonyl)isoxazol-5-yl, 3-phenylisoxazol-5-yI, 3-(pyrid-2-yl)isoxazol-5-yl, 3-(2-methoxypyrid-3-yl)isoxazol-5-yl, 3-(2-methoxyphenyl)isoxazol-5-yl, 3-(3-methoxyphenyl)isoxazol-5-yl, 3-(2-ethoxyphenyl)isoxazol-5-yl, 3-(2-trifluoromethy]phenyl)isoxazol-5-yl, 3~(2-trifluoromethoxyphenyl)isoxazoI-5-yl, 3-(2-chlorophenyl)isoxazol-5-yl, 3-(2-bromophenyl)isoxazol-5-yl, 3-(2-methylphenyl)isoxazol-5-yl, 3-(2-fluorophenyl)isoxazol-5-yl, 3-(2-cyanophenyl)isoxazol-5-yI, 5-methylpyrazol-4-yl, fur-2-yl, fur-3-yl, 5-methylfur-2-yl, pyrazin-2-yl, 2-methylpyrazin-5-yl, pyridazin-3-yl, pyrimidin-4-yl, l-methylpyrrol-2-yl and thien-3-yl. R2 represents a C1-C4alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl and C1-C3alkoxy (e.g. methoxy, ethoxy and n-propoxy). In one embodiment of the.invention, R2 represents CH2 or (CH2)2- In a further embodiment R2 represents a C1-C4alkyl group. In an additional embodiment R2 represents methyl, ethyl and propyl. R3 represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine) or trifluoromethyl. In one embodiment of the invention, R3 represents chlorine or bromine. In a further embodiment R3 represents hydrogen or halogen. In an additional embodiment R3 represents hydrogen, chloro or bromo. R4 represents an optionally substituted 5-membered heteroaromatic ring comprising at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur. Examples of rings include thienyl (e.g. 3-thienyl), pyrazolyl (e.g. 4-pyrazolyl), isoxazolyl (e.g. 5-isoxazolyl), thiadiazolyl, pyrrolyl (e.g. 2-pyrrolyl), furanyl (2- or 3-furanyl), thiazolyl, triazolyl, tetrazolyl, imidazolyl (e.g. 4-imidazolyl). The 5-membered heteroaromatic ring in R4 is optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from C1-C6 particularly C1-C4alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C1-C6, particularly C1-C4alkoxy (such as methoxy, ethoxy, n-propoxy, n-butoxy, rert-butoxy, n-pentoxy or n-hexoxy) (each of the C1-C6alkyl and C1-C6alkoxy substituent groups being optionally substituted by at least one substituent, e.g. one, two, three or four substituents independently, selected from halogen (such as fluorine, chlorine bromine or iodine), amino, hydroxyl and trifluoromethyl), halogen (such as fluorine, chlorine, bromine or iodine), nitro, cyano, -NRI3R14, carboxyl, hydroxy], C2-C6 particularly C2-C4alkenyl (such as ethenyl), C3-C6cycloalkyl (cyclopropyl, cyclobutyl^ cyclopentyl and cyclohexyl), C1-C4, particularly C1-C3alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl), C1-C4, particularly C1-C3alkylcarbonyl (such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl or n-butylcarbonyl), C1-C4, particularly C1-C3alkylcarbonylamino (such as methylcarbonylamino or ethylcarbonylamino), phenylcarbonyl, -S(0)pC,-C4, particularly C,-C2alkyl, -C(0)NRl5R16 and -S02NR15!1R16a. In one embodiment of the invention, R4 represents a 5-membered heteroaromatic ring comprising one or two ring heteroatoms selected from nitrogen and oxygen, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy, halogen, nitro, cyano, -NRI3R14, carboxyl, hydroxy!, C2-C6alkenyl, C3-C6cycloalkyl, C1-C4alkoxycarbonyl, C1-C4alkylcarbonyl, C1-C4alkylcarbonylamino, phenylcarbonyl, -S(0)pC1-C4alkyl, -C(0)NR15R16 and -S02NRl5aRl6a. In a further embodiment of the invention, R represents a 5-membered heteroaromatic ring comprising two ring nitrogen atoms, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy, halogen and C3-C6cycloalkyl. In an additional embodiment R4 represents a 5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl and C3-C6cycloalkyl. In an additional further embodiment R4 represents pyrazolyl, the ring being optionally substituted by at least one substituent selected from methyl, ethyl, isopropyl, propyl, /-butyl and cyclopropyl. In another further embodiment R4 represents 5-methylpyrazol-3-yl, 5-ethylpyrazol-3-yl, 5-isopropylpyrazol-3-yl, 5-propylpyrazol-3-yl, 5-t-butylpyrazol-3-yl and 5-cyclopropylpyrazol-3-yl. R5 and R6 each independently represent hydrogen, C1-C4t, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or rer/-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyfrolidinyl or piperidinyl). R7 and Rs each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl). R7a and R8a each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or rerr-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R7a and R8a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl). R9 and R10 each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyi and cyclohexyl), or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl). R11 and R12 each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or /erf-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyi and cyclohexyl), or R11 and R12 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl). Rlla and Rl2a each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyi and cyclohexyl), or Rlla and R12a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl). R13 and RM each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyi and cyclohexyl), or R13 and R14 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl). R15 and R16 each independently represent hydrogen, C1-C4, particularly C|-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-buty\) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyi and cyclohexyl), or R15 and R16 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl). R15" and R16a each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyi and cyclohexyl), or Rl5a and R1 a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl). In an embodiment of the invention, there is provided a subset of compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, in which: R1 represents a 5- or 6-membered heteroaromatic ring comprising one or two ring heteroatoms selected from nitrogen and oxygen, the ring being optionally substituted by at least one substituent selected from C1-C3alky], pyridyl, and phenyl optionally substituted by methoxy; R2 represents a C1-C2alkyl group; R3 represents chlorine or bromine; and R4 represents pyrazolyl substituted by at least one substituent selected from C1-C4alkyl and cyclopropyl. In a further aspect of the invention, there is provided a compound of formula (I) (as depicted above) wherein: R1 represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from hydroxy]), halogen, -C(0)NR7R8, C1-C6alkoxycarbonyl, and an unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen and oxygen, the ring itself being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen), halogen and cyano; wherein R7 and R8 are both hydrogen or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R represents a C1-C4alkyl group; R3 represents hydrogen or halogen; and R4 represents a 5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl and C3-C6cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. In an additional aspect of the invention, there is provided a compound of formula (I) (as depicted above) wherein: R1 represents pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-methoxypyrid-5-yl, 2-cyanopyrid-5-yl, 3-bromopyrid-5-yl, 3-(pyrid-2-yl)pyrid-5-yl, 4-(pyrid-2-yl)pyrid-2-yl, 3-chloropyrid-2-yl, 3-methylpyrid-2-y], 6-methylpyrid-2-yI, 5,6-dimethylpyrid-2-yl, imidazol-4-yI, imidazoI-5-yl, 3-methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 3-isopropylisoxazol-5-yl, 3-methoxycarbonylisoxazol-5-yl, 3-(hydroxymethyl)isoxazol-5-yl, 3-carbamoylisoxazol-5-yI, 3-(pyrroIidin-l-yIcarbonyl)isoxazol-5-yl, 3-phenylisoxazol-5-yl, 3-(pyrid-2-y])isoxazol-5-y], 3-(2-methoxypyrid-3-yl)isoxazo]-5-yl, 3-(2-methoxyphenyl)isoxazol-5-y], 3-(3-methoxyphenyl)isoxazol-5-yl, 3-(2-ethoxyphenyl)isoxazol-5-yl, 3-(2-trifluoromethylphenyl)isoxazol-5-yl, 3-(2-trif]uoromethoxypheny])isoxazol-5-yI, 3-(2-chlorophenyl)isoxazol-5-yl, 3-(2-bromophenyl)isoxazol-5-yl, 3-(2-methylphenyl)isoxazol-5-yl, 3-(2-fluorophenyl)isoxazol-5-yl, 3-(2-cyanophenyl)isoxazol-5-y], 5-methylpyrazol-4-y], fur-2-yl, fur-3-yl, 5-methylfur-2-yl, pyrazin-2-yl, 2-methylpyrazin-5-yl, pyridazin-3-yl, pyrimidin-4-yl, 1-methylpyrrol-2-yl and thien-3-yl; R2 represents methyl, ethyl and propyl; R represents hydrogen, chloro or bromo; and R4 represents 5-methylpyrazol-3-yl, 5-ethylpyrazol-3-yl, 5-isopropylpyrazol-3-yl, 5-propylpyrazol-3-yl, 5-t-butylpyrazol-3-yl and 5-cyclopropylpyrazol-3-yl; or a pharmaceutically acceptable salt or solvate thereof. Examples of compounds of the invention include: 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-rnethyl-lH-pyrazo]-3-ylamino)pyrimidhie, 5-Chloro-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-y]amino)pyrimidine, 5-Bromo-2-(3-methylisoxazol-5-y]methylamino)-4-(5-cyc]opropy]-1H-pyrazol-3-ylamino)pyrimidine, 5-Chloro-2-(3-isopropylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-y 1 ami no)pyrimidi ne, 5-Chloro-2-(3-phenylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine, 5-Bromo-2-[3-(2-methoxyphenyl)isoxazol-5-ylmethyIamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine, 5-Chloro-2-[3-(2-methoxyphenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine, 5-Chloro-2-(3-pyrid-2-ylisoxazol-5-ylmethylamino)-4-(5-methyl-lH-pyrazol-3-ylamino)pyrimidine, 5-Bromo-2-(3-pyrid-2-ylisoxazoI-5-ylmethy]amino)-4-(5-methyI-1H-pyrazol-3-ylamino)pyrimidine, 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3- ylarnino)pyrimidine, 5-Chloro-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3- ylamino)pyrimidine, 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-ethyl-1H-pyrazol-3-yIamino)pyrimidine, 5-Bromo-2-(2-fur-2-ylethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine, 5-Bromo-2-(pyrid-3-ylmethy]amino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine, 5-Chloro-2-(pyrid-3-ylmethylamino)-4-(5-terr-butyl-lH-pyrazol-3-ylamino)pyrimidine, 5-Chloro-2-(pyrid-2-ylmethylamino)-4-(5-tert-butyl-lH-pyrazol-3-ylamino)pyrimidine, 5-Bromo-2-(pyrid-3-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine, 5-Bromo-2-[2-(imidazol-4-ylethyl)amino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine, 5-Bromo-2-(pyrid-2-ylmethylamino)-4-(5-methyl-lH-pyrazol-3-ylamino)pyrimidine, 5-Chloro-2-[2-(pyrid-2-yl)ethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine, 5-Brorno-2-[2-(pyrid-3-yl)ethylamino]-4-(5-methyl-lH-pyrazol-3-yamino)pyrimidine, 5-Bromo-2-(5-methylpyrazin-2-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-yIamino)pyrimidine, 5-Bromo-2-(pyrid-3-ylmethylamino)-4-(5-cyc]opropyl-1H-pyrazol-3-ylamino)pyrimidine, and pharmaceutically acceptable salts and solvates of any one thereof. In a furlher aspect of the invention, particular compounds of the invention are any one of Examples 3,5, 8, 9, II, 12,34, 39,40,41,47,48, 68, 70 and 79 or pharmaceutically acceptable salts and solvates of any one thereof. In another aspect of the invention, particular compounds of the invention are any one of the Examples or pharmaceutically acceptable salts and solvates of any one thereof. The present invention further provides a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, which comprises: (i) reacting a compound of formula (Formula Removed) wherein L1 represents a leaving group (e.g. halogen or sulphonyloxy such as methanesulphonyloxy or toluene-4-sulphonyloxy) and R3 and R4 are as defined in formula (I), with a compound of formula (III), H2N-R2-R1 wherein R1 and R2 are as defined in formula (I); or (ii) reacting a compound of formula (Formula Removed) wherein L2 represents a leaving group (e.g. halogen or sulphonyloxy such as methanesulphonyloxy or toluene-4-sulphonyloxy) and R1, R2 and R3 are as defined in formula (I), with a compound of formula (V), H2N-R4, wherein R4 is as defined in formula (I); or (iii) reacting a compound of formula (Formula Removed) wherein R1 and R2 are as defined in formula (I), with a compound of formula (Formula Removed) wherein X represents an oxygen atom and q is 1 or X represents a nitrogen atom and q is 2, each R20 independently represents a C1-C6alkyl group and R3 and R4 are as defined in formula (I); or (iv) when R4 represents a substituted pyrazolyl, reacting a compound of formula (Formula Removed) wherein R21 lepresents a C1-C6alkyl or C3-C6cycloalkyl group and R , R2 and R are as defined in formula (I) with hydrazine; and optionally after (i), (ii), (iii) or (iv) carrying out one or more of the following: • converting the compound obtained to a further compound of the invention • forming a pharmaceutically acceptable salt or solvate of the compound. Processes (i) and (ii) may conveniently be carried out as follows: a) in the presence of a suitable solvent for example a ketone such as acetone or an alcohol such as ethanol or butanol or an aromatic hydrocarbon such as toluene or N-methyl pyrrolid-2-one, optionally in the presence of a suitable acid for example an inorganic acid such as hydrochloric acid or sulphuric acid, or an organic acid such as acetic acid or formic acid (or a suitable Lewis acid) and at a temperature in the range from 0°C to reflux, particularly reflux; or b) under standard Buchwald conditions (for example see /. Am. Chem. Soc, 118, 7215; J Am. Chem. Soc, 119, 8451; J. Org. Chem., 62, 1568 and 6066) for example in the presence of palladium acetate, in a suitable solvent for example an aromatic solvent such as toluene, benzene or xylene, with a suitable base for example an inorganic base such as caesium carbonate or an organic base such as potassiurrw-butoxide, in the presence of a suitable ligand such as 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and at a temperature in the range from 25 to 80°C. Process (iii) may conveniently be carried out in a suitable solvent such as N-methylpyrrolidinone or butanol at a temperature in the range from 100-200°C, in particular in the range fiom 150-170°C. The reaction is preferably conducted in the presence of a suitable base such as, for example, sodium methoxide or potassium carbonate. Process (iv) may be carried out in a suitable solvent, for example, an alcohol such as ethanol or butanol at a temperature in the range from 50-120°C, in particular in the range from 70-100°C. Compounds of formulae (II), (III), (IV), (V), (VI), (VII) and (VIII) are either commercially available, are known in the literature or may be prepared using known techniques. Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures. Examples of the types of conversion reactions that may be used include introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid; the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of reduction reactions include the reduction of a nitro group to an amino group by catalytic hydrogenation with a nickel catalyst or by treatment with iron in the presence of hydrochloric acid with heating; and particular examples of oxidation reactions include oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl. It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at various stages, the addition and removal of one or more protecting groups. The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991). The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. For example where R4 is pyrazolyl; pyrazolyl-5-yl and pyrazolyl-3-yl are tautomers of the same compound. The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators or inhibitors of insulin-like growth factor-1 receptor (IGF-1R) activity, and may be used in the treatment of proliferative and hyperproliferative diseases/conditions, examples of which include the following cancers: (1) carcinoma;including that of the bladder, brain, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, thyroid and skin; (2) hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukaemia, B-cell lymphoma and Burketts lymphoma; (3) hematopoietic tumours of myeloid lineage, including acute and chronic myelogenous leukaemias and promyelocytic leukaemia; (4) tumours of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and (5) other tumours, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma. The compounds of the invention are especially useful in the treatment of tumors of the breast and prostate. Thus, the present invention provides a compound of formula (I), or a pharmaceutical [y-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy. In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutical^ acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy. In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly. The invention also provides a method of treating cancer which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined. The invention still further provides a method of modulating insulin-like growth factor-1 receptor (IGF-IR) activity which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined. The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0 05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably fiom 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition. The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier. The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier. The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally. The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenie acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenz.oate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonale, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcelluiose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame). Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters wi;h ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art. Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30u. or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate. Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient. For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansen; Chairman of Editorial Board), Pergamon Press 1990. The size of the dose for therapeutic purposes of a compound of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. In general, a compound of the invention will be administered so that a daily dose in the range, for example, from 0.5 mg to 75 mg active ingredient per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, from 0.5 mg to 30 mg active ingredient per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, from 0.5 mg to 25 mg active ingredient per kg body weight will generally be used. Oral administration is however preferred. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. Examples The invention will now be further described with reference to the following illustrative examples in which, unless stated otherwise: (i) temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C; (ii) organic solutions were dried over anhydrous magnesium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30mmHg) with a bath temperature of up to 60°C; (iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; (iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only; (v) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data; (vi) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz, in DMSO-d6 +CD3COOD unless otherwise indicated; (viii) chemical symbols have their usual meanings; SI units and symbols are used; (ix) solvent ratios are given in volume:volume (v/v) terms; and (x) mass spectra were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is (MH)+; (xi) the following abbreviations have been used: THF tetrahydrofuran; DMF N,N,-dimethylformamide; EtOAc ethyl acetate; DCM dichloromethane; and DMSO dimethylsulphoxide. Example 1 5-Bromo-2-(3-methv]isoxazol-5-ylmethylamino)-4-(5-methvl-1H-pyrazol-3-ylamino) pyrimidine A mixture of 5-aminomethyl-3-methylisoxazole hydrochloride (890mg, 6.0mmol), 5-bromo-2-chloro-4-(5-methyl-1H-pyrazo]-3-ylamino)pyrimidine (Method 1; 578mg, 2.0mmol) and N.A'-diisopropylethylamine (].4ml, 8.0mmol) in 1-butanol (10ml) was heated at 120°C for 18 hours. The mixture was allowed to cool to ambient temperature and volatiles removed by evaporation. The residue was triturated with ether and the product collected by filtration to give the titled compound (225mg, 31%). 1H NMR (DMSO): δ 2.15 (s, 3H), 2.2 (s, 3H),4.5(m,2H),6.1 (br s, 2H), 7.6 (br s, 1H), 8.0 (br s, 2H), 12.05(brs, 1H); MS: m/z 366. Examples 2 -12 Following a similar procedure to Example 1, the following compounds were synthesised after replacement with a suitable pyrimidine (SMI) and amine (SM2) (the NMR was recorded in DMSO-d6). Where a starting material is not indicated, this compound is commercially available. (Table Removed) Required aqueous work-up. 2 Purified by column chromatography on silica gel eluting with DCM/methanol (95:5). Example 13 5-Bromo-2-(2-fur-2-ylethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine A mixture of 5-bromo-2-ch!oro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 1; 290mg, l.0mmol), 2-(2-aminoeyhyl)furan (330mg, 3.0mmol) and 1-butanol (5ml) was heated at 120°C for 5 hours. The mixture was allowed to cool to ambient temperature and the volatiles removed by evaporation. The residue was dissolved in DCM and washed with water followed by brine. The organics were separated, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether, the solid product collected and purified by column chromatography on silica gel eluting with DCM /methanol (95:5) to give the titled compound (80mg, 22%). 1H NMR (DMSO): δ 2.1 (s, 3H), 2.85 (m, 2H), 3.45 (m 2H), 6.10 (m, 1H), 6.35 (m, 1H), 6.4 (br s, 1H), 7.15 (br s, 1H), 7.5 (s, 1H), 8.0 (br s, 2H), 12.05 (brs, lH);MS:m/z363. Examples 14 - 106 Following a similar procedure to Example 13, the following compounds were synthesised after replacement with appropriate pyrimidine (SM1) arid amine (SM2) starting materials. Where a starting material is not indicated, this compound is commercially available (Table Removed) Heated for 12 hours. 2 Heated for 24 hours. 3 Reaction treated with 2M NH3/MeOH to pH 9. Precipitate was filtered and washed with distilled water and diethyl ether. 4 No aqueous work-up, product precipitates from DCM. 5 No chromatography necessary. 6 500MHz (393K). 7 NMR run with no d4 acetic acid. 8 NMR run at 373K/400MHz. 9 NMR run with no d4 acetic acid at 343K. 10 NMR: Trifluorodeuterated acetic acid-di use in place of acetic aicd-d4. 11 NMR run in CD3OD. 12 Compound could be prepared by the procedure described in this paper. 13 Ester exchange with the methanol used in the chromatography occurred. Example 107 5-Bromo-2-(3-carbamoylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 5-Bromo-2-[3-(methoxycarbonyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 104; 50mg, 0.1 Immol) was suspended in 7N methanolic ammonia (5ml) and stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue was triturated with DCM/diethyl ether (50:50) and the product collected by filtration to give the title compound (35mg, 76%). NMR (DMSO): 2.18 (s, 3H), 4.57 (d, 2H), 6.28 (br s, 1H), 6.50 (s, 1H), 7.72 (s, 2H), 8.01 (s, 1H), 8.05 (s, 1H), 12.06 (s, lH);m/z393(MH)+. Preparation of Starting Materials :- The starting materials for the examples above are either commercially available or are readily prepared by standard methods from known materials. For example, the following reactions are an illustration, but not a limitation, of some of the starting materials used in the above reactions. Method 1 5-Bromo-2-chloro-4-(5-methyl-l#-pyrazol-3-ylamino)pvrimidine A solution of 5-bromo-2,4-dichloropyrimidine (l0.0g, 44mmol), 3-amino-5-methyl-1H-pyrazole (6.0g, 62mmol) and N,N-diisopropylethylamine (9.20ml, 53mmol) in I-butanol (80ml) was heated at 85°C for 12 hours. The mixture was allowed to cool to ambient temperature and the resulting precipitate collected by filtration. The solid product was washed with ethanol and dried to give the sub-titled compound (10.8g, 85%). 1H NMR (DMSO): δ 2.23 (s, 3H), 6.23 (s, 1H), 8.39 (s, 1H), 9.21 (s, 1H), 12.27 (s, 1H); MS: m/z 290 (MH)+. Method 2 2-Qxobutvlnitrile Acetonitrile (13.7ml, 260mmol) was added to a suspension of sodium hydride (10.4g of a 60% suspension in mineral oil, 260mmol) in ethyl propionate (22.3g, 220mmol) and anhydrous 1,4-dioxane (200ml) at ambient temperature. The mixture was heated at 100°C for 12 hours and then allowed to cool. Water was added, the mixture adjusted to pH 2.0 with concentrated hydrochloric acid and extracted with DCM. The extracts were combined dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with DCM to give the title compound (20g, 94%) as an oil. NMR (CDC13): 1.10 (t, 3H), 2.65 (q, 2H), 3.50 (s, 2H). Methods 3 - 5 The following compounds were prepared by the procedure of Method 2 using the appropriate starting materials. (Table Removed) Method 6 3-Amino-5-ethyl-l#-pvrazole Hydrazine monohydrate (11.3g, 230mmol) was added to a solution of 3-oxobutyronitrile (Method 2; 20.0g, 210mmol) in ethanol (50ml) and the mixture heated at 70°C for 12 hours. The volatiles were removed by evaporation and the residue was purified by column chromatography on silica gel eluting with DCM/methanol (90:10) to give the title compound as an oil (10 2g,44%) NMR (DMSO) 1 10 (t, 3H), 2 40 (q, 2H), 5 15 (s, IH), m/z 112 (MH)+ Methods 7 - 9 The following compounds were prepared by the procedure of Method 6 using the appropriate starting materials (Table Removed) Method 10 2.5-Dichloro-4-(5-methyI-l#-pyrrazol-3-ylamino)pvrimidine A solution of 2,4,5-tnchloropynmidine (6 Og, 32 6mmol), 3-amino-5-methyl-lH-pyrrazole (3 18g, 32 7mmol) and N,N-dnsopropylethylamine (6 30ml, 36 2mmoI) in 1-butanol (50ml) was heated at 100°C for 2 hours The volatiles were removed by evaporation and the residue was tntuiated with DCM to afford the title compound (5 7g, 72%) as a white solid NMR (DMSO) 2 23 (s, 3H), 6 23 (s, IH), 8 39 (s, IH), 9 21 (s, IH), 12 27 (s, IH), m/z 290 (MH)+ Methods 11-21 The following compounds were prepared by the procedure of Method 10 using the appropriate starting materials (Table Removed) Method 22 α-Chlorobenzaldehyde oxime N-chlorosuccinimide (5.50g, 41.3mmo]) was added in portions to a solution of benzaldehyde oxime (5.0g, 41.3mmol) in DMF (34ml) such that the temperature did not rise above 35°C. The mixture was stirred at ambient temperature for 2 hours and then cooled with an ice bath. Water was added and the aqueous mixture extracted with ether. The organics were combined, washed with water and brine, dried (MgSO4}) and the solvent removed by evaporation to give the title compound (6.43g, 100%) as an oil. NMR (CDC13): 7.4 (m, 3H), 7.8 (d, 2H), 8.9 (bs, 1H). Methods 23 - 33 The following compounds were prepared by the procedure of Method 22 using the appropriate starting materials. (Table Removed) Method 34 α-Chloro-pyrid-3-ylcarbaldehyde oxime was prepared according to the method described in Tetrahedron 2000, 56, 1057-1064. Method 35 3-Methoxvbenzaldehyde oxime A solution of hydroxylamine hydrochloride (l0g, 0.144mol) in distilled water (20ml) was added to 20%(w/v) aqueous sodium hydroxide solution (28ml). 3-Methoxybenzaldehyde (14ml, 0.12mol) was added in one portion and the mixture was stirred for 2 hours at 0-5°C The mixture was adjusted to pH7 and extracted with dichloromethane. The extracts were combined, dried (MgS04) and the solvent removed by evaporation to give the title compound (18 7g, 100%) as a colourless oil. NMR (CDC1,): 3.8 (s, 3H), 6.9 (m, 1H), 7 1 (m, 2H), 7 15 (m, 1H), 8.1 (s, lH),8 6(brs, 1H). Methods 36 - 42 The following compounds were prepared by the procedure of Method 35 using the appropriate starting materials (Table Removed) 5-(tert-Butoxycarbonylaminomethyl)-3-phenylisoxazole A solution of α-chlorobenzaldehyde oxime (Method 22, lg, 6 4mmol) in THF (13ml) was added dropwise to a solution of N-tert-butoxycarbonyl-propargylamine (0 5g, 3 2mmol) and triethylamine (0 9ml, 6 4mmol) in THF (25ml) cooled with an ice bath. The mixture was allowed to warm to ambient temperature and stirred for 2 days The volatiles were removed by evaporation and the residue dissolved in DCM The solution was washed with water and brine, dried (MgSO4) and the solvent removed by evaporation The residue was triturated with isohexane/ether (9:1) and collected by filtration to give the title compound (473mg, 54%). NMR (CDCl3) 1.45 (s, 9H),4.45 (d, 2H), 5.10 (bs, IH), 6.5 (s, IH), 7.42 (m, 3H), 7.8 (m, 2H). Methods 44 - 55 The following compounds were prepared by the procedure of Method 43 using the appropriate starting materials. (Table Removed) Method 56 5-Aminomethvl-3-phenylisoxazole Trifluoroacetic acid (1.7ml, 2.6mmol) was added dropwise to a solution of 5-{tert-butoxycarbonylaminomethyl)-3-pheny]isoxazole (Method 43; 473mg, 1.73mmol) in DCM (8ml) cooled in an ice bath. The mixture was warmed to ambient temperature and stirred for 18 hours and the volatiles removed by evaporation. The residue was triturated with ether to give the title compound (427mg, 86%). NMR (DMSO) 4.33 (s, 2H), 7.1 (s, IH), 7.5 (m, 3H), 7.8 (m, 2H), 8.6 (br s, 3H). Methods 57 - 68 The following compounds were prepared by the procedure of Method 56 using the appropriate starting materials (Table Removed) Method 69 5-(tert-Butoxycarbonylaminomethyl)-3-(pyrid-2-yl)isoxazole Sodium hypochlorite (16ml of a 14%w/v aqueous solution, 29 5mmol) was added dropwise to a solution of 2-pyndinealdoxime (2g, 16 4mmol) and /v'-rerf-butoxycarbonyl-piopargylamine (5 6g, 36 lmmol) in DCM (30ml) cooled in an ice bath The mixture was stined vigorously and allowed to warm to ambient temperature and stirred for 18 hours The aqueous layer was separated and extracted with DCM The combined organic extracts were combined, dried (MgSO4) and the solvent removed by evaporation The residue was purified by column chromatography on silica gel elutmg with diethyl ether/isohexane ( 11) to give the title compound (1 93g, 43%) NMR (CDC13) 1 45 (s, 9H), 4 5 (m, 2H), 5 03 (bs, 1H), 6 8 (s, 1H), 7 35 (m, 1H), 7 8 (m, 1H), 8 05 (d, 1H), 8 67 (m, 1H) Method 70 5-Aminomethyl-3-(pyrid-2-yl)isoxazole 5-(tert-Butoxycarbonylaminomethyl)-3-(pyrid~2-yl)isoxazole (Method 69) was treated as described in Method 56 to give 5-aminomethyl-3-(2-pyndyl)isoxazole NMR (DMSO) 4 38 (s, 2H), 7 1 (s, 1H), 7 5 (m, 1H), 7 95 (m, 2H), 8 65 (br s, 3H), 8 7 (m, 1H) Method 71 3-Methyl-5-( 1 -phthalamidoethyl)isoxazole A solution of triethylamine (0.35ml, 2.5mmol) in toluene (15ml) was added dropwise to a solution of phenylisocyanate (5.43ml, 50mmol), nitroethane (2.15ml, 30mmol) and N-(but-l-yn-3-yl)phthalamide (5.0g, 25mmol) in toluene (65ml) at ambient temperature. The mixture was stirred for 18 hours, filtered and the volatiles removed by evaporation. The residue was triturated with ether and the product collected by filtration to give the title compound (5.35g, 89%). NMR (CDCI3): 1.88 (d, 3H), 2.27 (s, 3H), 5.60 (q, H), 6.11 (s, H), 7.69-7.75 (m, 2H), 7.79-7.85 (m, 2H); m/z 257 (MH)+. Method 72 5-(l-aminoethyl)-3-methylisoxazo]e A mixture of the 3-methyl-5-(l-phthalamidoethyl)isoxazole (Method 71; 3.55g, 13.9m.mol), hydrazine monohydrate (0.75ml, 15.3mmol) and ethanol (50ml) was heated at reflux for 4 hours. The mixture was allowed to cool to ambient temperature and glacial acetic acid (8.8ml, 153mmol) added, the mixture then heated at reflux for 2 hours. The mixture was allowed to cool to ambient temperature and the mixture neutralized with 50% aqueous sodium hydroxide solution, diluted with water and extracted with DCM, and the combined extracts washed with water followed by brine. The organics were separated, dried (MgSO4) and the solvent removed by evaporation. The residue was dissolved in ethanol and treated with an excess of IN ethereal hydrogen chloride, the volatiles removed by evaporation to give the title compound (1.52g, 87%). NMR (DMSO): 1.46 (dd, 3H), 2.20 (m, 3H), 4.39 (q H), 6.38 (s, 1H), 6.60 (br s, 3H); m/z 127 (MH)+. Method 73 3-Ethoxvcarbonvl-5-rN-(tert-butyloxycarbonyl)aminomethyl]isoxazole A solution of ethyl chlorooximidoacetate (l0g, 66mmol) in THF (200ml) was added dropwise over 3 hours to a mixture of N-(tert-butyloxycarbonyl)propargylamine (20.5g, 131mmol) and triethylamine (11.2ml, 80mmol) in tetrahyrofuran (100ml). The mixture was stirred at ambient temperature for 18 hours and then the volatiles were removed by evaporation. The residue was dissolved in DCM and washed with water followed by brine. The organics were separated, dried (MgSO4) and the solvent removed by evaporation The residue was purified by column chromatography on silica gel eluting with isohexane/diethyl ether (80:20 then 50:50) to give the title compound (10.6g, 60%). NMR (DMSO): 1.3 (t, 3H), 1.38 (s, 9H), 4.35 (m, 2H), 6.62 (s, 1H), 7.55 (s, 1H); m/z 269 (M-H)Method 74 3-Ethoxycarbonyl-5-aminomethylisoxazole Trifluoroacetic acid (2.1ml, 29mmol) was added to a solution of 3-ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethy!]isoxazole (Method 73; 790mg, 2.9mmol) in DCM (]5ml). The mixture was stirred at ambient temperature for 4 hours then the volatiles removed by evaporation. The residue was triturated with diethyl ether to give the title compound (763g, 93%). NMR (DMSO): 1.31 (t, 3H), 4.37 (m, 2H), 6.97 (s, 1H), 8.64 (s, 3H); m/z 171 (MH)+. Method 75 3-Hydroxymethyl-54N-(tert-butyloxycarbonyl)aminomethyl]isoxazole Sodium borohydride (610mg, 16mmol) was added in portions to a solution of 3-ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 73; 1.62g, 6mrnol) in ethanol (15ml) at 0°C under a nitrogen atmosphere. The mixture was stirred at ambient temperature for 4 hours then quenched with saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with EtOAc and the organics washed with brine then dried (MgSO4). The solvent was removed by evaporation to give the title compound (1.25g, 91%). NMR (DMSO): 1.38 (s, 9H), 4.21 (d, 2H), 4.44 (s, 2H), 5.40 (br s, 1H), 6.21 (s, 1H), 7.49 (br s, 1H); m/z 229 (MH)+ Method 76 3-Hydroxymethyl-5-aminomethylisoxazole Trifluoroacetic acid (4ml, 54mmol) was added to a solution of 3-hydroxymethyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 75; 1.25g, 5.4mmol) in DCM (40ml). The mixture was stirred at ambient temperature for 18 hours then the volatiles removed by evaporation. The residue was purified by chromatography on a SCX-2 column (50g) eluting with methanol then 7N ammonia in methanol to give the title compound (676mg, 96%). NMR (DMSO): 1.97 (br s, 2H), 3.76 (s, 2H), 4.44 (s, 2H), 5.38 (s, 1H), 6.26 (s, 1H). Method 77 3-(Pyrrolidin-l-ylcaibonyl)-5-[N-(tert-butyloxycarbony])aminomethyllisoxazole 3-Ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 73; 500mg, 1.85mmol) was dissolved in pyrrolidine (4ml) and the mixture healed for 3 hours at 85°C. The volatiles were removed by evaporation and the residue was triturated with diethyl ether to give the title compound (432mg, 79%) as a white solid. NMR (DMSO): 1.38 (s, 9H), 1.85 (m, 4H), 3.50 (t, 2H), 3.62 (t, 2H), 4.29 (d, 2H), 6.47 (1H), 7.53 (s, 1H); m/z 240 (M-C4H8)+. Method 78 3-(Pyrrolidin-1 -ylcarbonyl)-5-aminomethvnisoxazole 3-(Pyrrolidin-1 -ylcarbonyl)-5-[N-(tert-butyloxycarbonyl)aminomelhyl]isoxazole (Method 77) was deprotected as described in Method 74 to give the title compound as its trifluoroacetate salt (428mg, 95%). NMR (DMSO): 1.88 (m, 4H), 3.49 (t, 2H), 3.63 (t, 2H), 4.35 (s, 2H), 6.83 (s, 1H), 8.58 (s, 3H); m/z 196 (MH)+. Method 79 5-rN-(tert-Butoxvcarbonvl)aminomethvn-3-(2-iodoophenvl)isoxazole 2-Iodobenzaldehyde oxime (Method 42) was treated as described in Methods 22 and 43 to give the title compound. Method 80 5-[N-(tert-Butoxycarbonyl)aminomethyl1-3-(2-cyanophentyl)isoxazole Copper (I) cyanide (2.49g, 27.8mmol), tefra-n-butylammoniumcyanide (1.87g, 6.95mmol), tris(dibenzylideneacetone)dipalladium(0) (0.247g, 0.28mrnol) and diphenylphosphinoferrocene (0.619g, 1.12mmol) were added to a degassed solution of 5-[N-(ferf-butoxycarbonyl)aminomethyl]-3-(2-iodoophenyl)isoxazole (Method 79; 2.78g, 6.95mmol) in 1,4-dioxan (35ml) under nitrogen. The mixture was heated at reflux for 3 hours, cooled to ambient temperature, diluted with EtOAc and filtered through diatomaceous earth. The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel eluting with EtOAc/isohexanes (15:85 increasing in polarity to 25:75) to give the title compound (1.29g, 62%). NMR (CDC13): 1.49 (s, 9H), 4.52 (d, 2H), 5.09 (br s, H), 6.81 (s, H), 7.55 (t, H), 7.70 (t, H), 7.79 (d, H), 7.95 (d, H); m/z 300 (MH)+. Method 81 5-Aminomethvl-3-(2-cyanophenvl)isoxazole 5-[N-(tert-Butoxycarbonyl)aminomethyl]-3-(2-cyanophenyl)isoxazole (Method 80; 1.28g, 4.28mmol) was treated as described in Method 56 to give the title compound (1.34g, 100%). NMR (DMSO): 4.45 (s, 2H), 7.17 (s, H), 7.73 (dd, H), 7.85-7.95 (m, 2H), 8.62 (br s, 3H); m/z 200 (MH)+. Method 82 3-Methyl-5-(2-[bis-(N-tert-butoxycarbonyl)amino]ethyllisoxazole Bis-N-tert-butoxycarbonyl-3-butyne as synthesised in J. Am. Chem. Soc. 1987 (109), 2765 (2.2g, 8.2mmol), was treated as described in Method 71 to give the title compound (0.59g, 22%). NMR (CDC13): 1.49 (s, 18H), 2.24 (s, 3H), 3.00 (t, 2H), 3.88 (t, 2H), 5.85 (s, H). Method 83 3-Methyl-5-(2-aminoethyl)isoxazole Trifluoroacetic acid (2.5ml, 3.8mmol) was added dropwise to a solution of 3-methyl-5-{2-[bis-(N-(err-butoxycarbonyl)amino]ethyl]isoxazole (Method 82; 0.589g, 1.8mmol) in DCM (10ml) cooled at 0°C. The mixture was allowed to warm to ambient temperature and stirred for 48 hours. The volatiles were removed by evaporation and the residue was purified by chromatography on a SCX-2 ion exchange column eluting with methanol and then 7 N ammonia in methanol. The purified product was treated with an excess of 1.0M ethereal hydrogen chloride (3.5ml) to give the title compound as its hydrochloride salt (0.24g, 82%). NMR (DMSO) freebase: 2.18 (s, 3H), 2.71-2.79 (m, 2H), 2.80-2.88 (m, 2H), 6.10 (s, H). Method 84 3-Azidomethyl-5-methylisoxazole 3-Chloromethyl-5-methylisoxazole (500mg, 3.8mmol) and sodium azide (494mg, 7.6mmol) were heated in DMF (10ml) at 60°C for 6 hours. The reaction mixture was diluted with water then extracted with EtOAc. The organic extracts were dried (MgS04) and the volatiles removed by evaporation to give the title compound (387mg, 73%) as an oil. NMR (DMSO): 2.40 (s, 3H), 4.48 (s, 2H), 6.28 (s, IH). Method 85 3-Aminomethyl-5-methylisoxazole 3-Azidomethyl-5-methylisoxazole (Method 84; 384mg, 2.8mmol) and polystyrene polymer supported triphenylphosphine (4.2g, 4.2mmol) were stirred together in a mixture of THF (17ml) and distilled water (0.58ml) for 24 hours. The reaction mixture was filtered, the resin washed with diethyl ether and then DCM. The combined filtrates were evaporated and the residue purified on a SCX-2 column eluting with methanol followed by 7N methanolic ammonia to give the title compound (211mg, 67%) as an oil. NMR (DMSO): 1.93 (br s, 2H), 2.34 (s, 3H), 3.63 (s, 2H), 6.17 (s, IH). Method 86 a-Methyl-pyridin-3-vlcarbaldehvde oxime Hydroxylamine hydrochloride (9.46g, 136.2mmol) was added to a solution of 3-acelylpyridine (11.02g, 90.7mmol) in methanol (100ml) and the reaction mixture heated at reflux for 30 minutes. The volatiles were removed by evaporation and the residue dissolved in water. The solution was cooled to 0°C and basified with 2N aqueous sodium hydroxide solution to pH 12 and the mixture then extracted with EtOAc. The extracts were combined, washed with saturated brine and dried (Na2SO4). The solvent was removed by evaporation to give the title product (11.6g, 94%) as a solid. NMR (DMSO): 2.20 (s, 3H), 7.40 (m, IH), 8.00 (m, lH),8.55(d, IH), 8.85 (s, IH) 11.43 (s, IH). m/z: 137 (MH)+. Methods 87 - 89 The following compounds were prepared by the procedure of Method 86 using the appropriate starling materials (Table Removed) Method 90 3-(l-Aminoethyl)pyridine A 50% suspension of rainey nickel in water (1 Ig) was added to a solution of a methyl-pyndin-3-ylcarbaldehyde oxime (Method 86, 10 6g, 77 9mmol) and 20% ethanolic ammonia (500ml) and the reaction mixture hydrogenated with gaseous hydrogen at 40 psi and 40°C until the theoretical volume of gas was consumed The reaction mixture was filtered through a layer of diatomaceous earth and the filter pad washed with water and ethanol The filtrate was removed by evaporation of give the title product (8 05g, 85%) as an oil NMR (DMSO) 1 28 (d, 3H), 4 05 (m, 1H), 7 33 (t, 1H), 7 75 (d, 1H), 8 40 (d, 1H), 8 55 (s, 1H) m/z 123 (MH)+ Methods 91 - 93 The following compounds were prepared by the procedure of Method 90 using the appropriate starting materials (Table Removed) Method 94 2-Aminomethyl-6-chloropyridine A 1M solution of lithium aluminium hydride in THF (2 88ml, 2 88mmol) was added dropwise to a solution of 6-chloro-2-cyanopyndine (532mg, 3 84mmol) in THF (10ml) at -5°C under an atmosphere of nitrogen The mixture was stirred at -5°C for two hours and the reaction quenched by careful, sequential addition of water (0 1ml), 15% aqueous sodium hydroxide solution (0.1ml) and then water (0.3ml). The mixture was stirred for one hour at 0°C, the insolubles removed by filtration and the filter pad washed thoroughly with methanol. The resulting solution was evaporated and the residue purified by column chromatography on silica gel eluting with DCM/methanol/arnmonia (95:5:0 increasing in polarity to 90:10:1) to give the title compound. (215mg, 40%) as an oil. NMR (DMSO): 2.10 (br s, 2H), 3.75 (s, 2H), 7.30 (d, 1H), 7.55 (d, 1H), 7.80 (t, 1H). Methods 95 - 97 The following compounds were prepared by the procedure of Method 94 using the appropriate starting materials. (Table Removed) ' SM Bioorg. Med. Chem. Lett. 1998, 453-8 Method 98 2-(Af-Oxopyridin-4-yl)pyridine 3-Chloroperbenzoic acid (57%-86% active strength) (7.5g, 43mmoI) was added in portions to a solution of 2-(pyridin-4-yl)pyridine (4.78g, 30.6mmol) in DCM (50ml) at 0°C. After stirring for 2 hours sodium metabisulfite was added in portions until all excess peroxide was destroyed. The solids were removed by filtration and the filtrate was basified with solid potassium carbonate. The mixture was filtered, the filtrate evaporated and the residue purified by column chromatography on silica gel eluting with methanol/acetone (10:90) to give the title compound (4.2g, 80%) as a white solid. NMR (DMSO): 7.41 (t, 1H), 7.92 (t, 1H), 8.10 (m, 3H), 8.30 (d, 2H), 8.70 (d, 1H); m/z 173 (MH)+. Method 99 2-(2-Cyanopyiidin-4-yl)pyridine Trimethylsilylcyanide (1.9ml, 14.5mmol) was added dropwise to a suspension of 2-(/V-oxopyridin-4-yl)pyridine (Method 98; lg, 5.8mmol) and triethylamine (1.2ml, 8.7mmol) in acetonitrile (5ml). The mixture was heated at 110°C for 18 hours, cooled to ambient temperature then diluted with aqueous saturated sodium hydrogen carbonate solution. The mixture was extracted with DCM, the extracts dried (MgSCU) and the volatiles removed by evaporation. The residue was pre-adsorbed onto silica and purified by column chromatography on silica gel eluting with hexane:EtOAc (1:1). The purified product was triturated with diethyl ether to give the title compound (627mg, 60%) as a white solid. NMR (DMSO): 7.54 (t, IH), 8.01 (t, IH), 8.25 (d, IH), 3.40 (d, IH), 8.66 (s, IH), 8.77 (d, IH), 8.87 (d, IH). Method 100 2-(2-Aminomethv]pyridin-4-y])pyridine 2-(2-Cyanopyridin-4-yl)pyridine (Method 99; 563mg, 3.1 lmmol) was dissolved in anhydrous THF (10ml) under a nitrogen atmosphere and was cooled to 0°C. LiAlH4 (2.3ml of a IM solution in THF, 2.3mmol) was added dropwise and the reaction was stirred at 0°C for 3 hours. The reaction was quenched with water (0.1ml) followed by 15% sodium hydroxide solution (0.1ml) then water (0.3ml). The mixture was filtered and the filter pad was washed with methanol. The volatiles were removed from the filtrate by evaporation to give the title compound (570mg, 99%) as a gum. m/z 186 (MH)+ Method 101 2-(3-Cyanopyridin-5-yl)pyridine 2-(3-Bromopyridin-5-yl)pyridine (2g, 10.9mmol) in THF (10ml) was added dropwise to a solution of 2-pyridylzincbromide (22ml of a0.5M solution in THF, 1 lmmol) in THF (10ml) under a nitrogen atmosphere. Tetrakis (triphenylphosphine)palladium(0) (630mg, 0.54rnmol) was added and the reaction stirred at ambient temperature for 18 hours. The reaction was quenched with saturated aqueous ammonium chloride solution then the volatiles were removed by evaporation. The residue was suspended in water then extracted with DCM. The organic extracts were combined, washed with water then filtered through phase separating paper and the volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with hexane:EtOAc (2:1). The purified product was triturated with diethyl ether to give the title compound (0.98g, 50%) as a white solid. NMR (DMSO): 7.47 (t, lH),7.97(t, IH), 8.15 (d, IH), 8.75 (d, lH),8.90(d, lH),9.07(s, IH), 9.53 (s, IH); m/z 182(MH)+. Method 102 2-(3-Aminomethy]pyridin-5-yl)pyridine 2-(3-Cyanopyridin-5-yl)pyridine (Method 101; 0.98g, 5.4mmol) was dissolved in a mixture of ethanol (45ml) and methanol (30ml). Concentrated hydrochloric acid (1.2ml) and 10% palladium on carbon catalyst (575mg) were added and the mixture stirred under an atmosphere of hydrogen for 4 hours. The mixture was filtered through diatomaceous earth, the filter pad washed with ethanol and the volatiles removed from the filtrate by evaporation. The crude solid was suspended in a small volume of methanol and filtered to give the title compound (794mg, 66%) as an orange solid. NMR (DMSO): 4.31 (m, 2H) 7.58 (t, 1H), 8.09 (t, 1H), 8.24 (d, 1H), 8.78 (d, 1H), 8.89 (bs, 2H), 9.03 (s, 1H), 9.26 (s, 1H), 9.43 (s, 1H); m/z 186(MH)+. Pharmacological Analysis Methods For Detecting Inhibition Of Igf-lr Kinase Activity And Downstream Signalling And Selectivity Over Insulin Receptor Kinase And Egfr Signalling Abbreviations used PBS (PBS/T) is Phosphate buffered saline, pH7.4 (with 0.05% Tween 20) HEPES is N-[2-Hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid] DTT is dithiothreitol TMB is tetramethyl benzidine DMSO is dimethyl sulphoxide BSA is bovine serum albumin ATP is adenosine tri-phosphate DMEM is Dulbecco's modified Eagle's Medium FBS/FCS is foetal bovine/calf serum HBSS is Hanks Balanced Salts Solution HRP is horse-radish peroxidase SDS is sodium dodecyl sulphate IGF-I (IGF-1R) is insulin-like growth factor-I (IGF-1 receptor) EGF is Epidermal growth factor IGF-1R Kinase Assay a) Protein cloning, expression and purification A DNA molecule encoding a fusion protein containing glutathione-S-transferase (GST), thrombin cleavage site and IGF-1R intracellular domain (amino-acids 930-1367) and subsequently referred to as GST-IGFR, was constructed and cloned into pFastBacl (Life Technologies Ltd, UK) using standard molecular biology techniques (Molecular Cloning - A Laboratory Manual, Second Edition 1989; Sambrook, Fritsch and Maniatis; Cold Spring Harbour Laboratory Press). Production of recombinant virus was performed following the manufacturer's protocol. Briefly, the pFastBac-1 vector containing GST-ldFR was transformed into E. coli DHlOBac cells containing the baculovirus genome (bacmid DNA) and via a transposition event in the cells, a region of the pFastBac vector containing gentamycin resistance gene and the GST-IGFR expression cassette including the baculovirus polyhedrin promoter was transposed directly into the bacmid DNA. By selection on gentamycin, kanamycin, tetracycline and X-gal, resultant white colonies should contain recombinant bacmid DNA encoding GST-IGFR. Bacmid DNA was extracted from a small scale culture of several BHlOBac white colonies and transfected into Spodoptera frugiperda Sf21 cells grown in TCI00 medium (Life Technologies Ltd, UK) containing 10% serum using CellFECTIN reagent (Life Technologies Ltd, UK) following the manufacturer's instructions. Virus particles were harvested by collecting cell culture medium 72 hrs post transfection. 0.5 mis of medium was used to infect 100 ml suspension culture of Sf21s containing 1 x 107 cells/ml. Cell culture medium was harvested 48 hrs post infection and virus titre determined using a standard plaque assay procedure. Virus stocks were used to infect Sf9 and "High 5" cells at a multiplicity of infection (MOI) of 3 to ascertain expression of recombinant GST-IGFR . The GST-IGFR protein was purified by affinity chromatography on Glutathione-Sepharose followed by elution with glutathione. Briefly, cells were lysed in 50mM HEPES pH 7.5 (Sigma, H3375), 200mM NaCl (Sigma, S7653), Complete Protease Inhibitor cocktail (Roche, 1 873 580) and ImM DTT (Sigma, D9779), hereinafter referred to as lysis buffer. Clarified lysate supernatant was loaded through a chromatography column packed with Glutathione Sepharose (Amersham Pharmacia Biotech UK Ltd.). Contaminants were washed from the matrix with lysis buffer until the UV absorbance at 280nm returned to the baseline. Elution was carried out with lysis buffer containing 20mM reduced glutathione (Sigma, D2804) and fractions containing the GST fusion protein were pooled and dialysed into a glycerol-containing buffer comprising 50 mM HEPES, pH 7.5, 200 mM NaCl, 10% glycerol (v/v), 3 mM reduced glutathione and 1 mM DTT. b) Kinase activity assay The activity of the purified enzyme was measured by phosphorylation of a synthetic poly GluAlaTyr (EAY) 6:3:1 peptide (Sigma-Aldrich Company Ltd, UK, P3899) using an ELISA detection system in a96-well format b.i) Reagents used Stock solutions 200mM HEPES,pH7.4 stored at 4°C (Sigma, H3375) 1M DTT stored at -20°C (Sigma, D9779) l00mM Na3VO, stored at 4°C (Sigma, S6508) 1M MnCl2 stored at 4°C (Sigma, M3634) ImM ATP stored at -20°C (Sigma, A3377) Neat Triton X-100 stored at room temperature (Sigma, T9284) l0mg/ml BSA stored at 4°C (Sigma, A7888) Enzyme solution GST-IGF-1R fusion protein at 75ng/ml in l00mM HEPES, pH 7.4, 5mM DTT, 0.25mM Na3V04, 0.25% Triton X-100, 0.25mg/ml BSA, freshly prepared. Co-factor solution l00mM HEPES, pH 7.4, 60mM MnCl2, 5mM ATP Poly EAY substrate Sigma substrate poly (Glu, Ala, Tyr) 6.3:1 (P3899) Made up to 1 mg/ml in PBS and stored at -20°C Assay plates Nunc Maxisorp 96 well immunoplates (Life Technologies Ltd, UK) Antibodies Anti-phosphotyrosine antibody, monoclonal from Upstate Biotechnology Inc., NY, USA (UBI05-321). Dilute 3(il in 11ml PBS/T + 0.5% BSA per assay plate. Sheep- anti-mouse IgG HRP-conjugated secondary antibody from Amersham Pharmacia Biotech UK Ltd (NXA931). Dilute 20u.l of stock, into 11ml PBS/T + 0.5% BSA per assay plate. TMB solution Dissolve ling TMB tablet (Sigma T5525) into 1ml DMSO (Sigma, D8779) in the dark for 1 hour at room temperature Add this solution to 9m! of freshly prepared 50mM phosphate-citrate buffer pH 5.0 + 0.03% sodium perborate [1 buffer capsule (Sigma P4922) per 100ml distilled water]. Stop solution is 1M H2S04 (Fisher Scientific UK. Cat. No. S/9200/PB08). Test compound Dissolve in DMSO to l0mM then dilutions in distilled water to give a range from 200 to 0.0026U.M in 1-2% DMSO final concentration in assay well. b.ii) Assay protocol The poly EAY substrate was diluted to 1 1µg/ml in PBS and then dispensed in an amount of l00µ1 per well into a 96-well plate. The plate was sealed and incubated overnight at 4°C. Excess poly EAY solution was discarded and the plate was washed (2x PBS/T; 250µl PBS per well), blotting dry between washes. The plate was then washed again (lx 50mM HEPES, pH 7.4; 250µl per well) and blotted dry (this is important in order to remove background phosphate levels). 10µl test compound solution was added with 40µl of kinase solution to each well. Then 50µl of co-factor solution were added to each well and the plate was incubated for 60 minutes at room temperature. The plate was emptied (i.e. the contents were discarded) and was washed twice with PBS/T (250µl per well), blotting dry between each wash. 100µl of diluted anti-phosphotyrosine antibody were added per well and the plate was incubated for 60 minutes at room temperature. The plate was again emptied and washed twice with PBS/T (250µ1 per well), blotting dry between each wash. 100µl of diluted sheep- anti-mouse IgG antibody were added per well and the plate was left for 60 minutes at room temperature. The contents were discarded and the plate washed twice with PBS/T (250µl per well), blotting dry between each wash. 100µl of TMB solution were added per well and the plate was incubated for 5-10 minutes at room temperature (solution turns blue in the presence horse radish peroxidase). Reaction was stopped with 50µl of H2SO4 per well (turns the blue solution yellow) and the plate was read at 450nm in Versamax plate reader (Molecular Devices Corporation, CA, USA) or similar. The compounds of the Examples were found to have an IC50 in the above test of less than 100µM. Inhibition of IGF-stimulated cell proliferation The construction of murine fibroblasts (NIH3T3) over-expressing human IGF-1 receptor has been described by Lammers et ai (EMBO J, 8, 1369-1375, 1989). These cells show a proliferative response to IGF-I which can be measured by BrdU incorporation into newly synthesised DNA. Compound potency was determined as causing inhibition of the IGF-stimulated proliferation in the following assay: a.i) Reagents used: Cell Proliferation ELISA, BrdU (colorimetric) [Boehringer Mannheim (Diagnostics and Biochemicals) Ltd, UK. Cat no. 1 647 229]. DMEM, FCS, Glutamine, HBSS (all from Life Technologies Ltd., UK). Charcoal/Dextran Stripped FBS (HyClone SH30068.02, Perbio Science UK Ltd). BSA (Sigma, A7888). Human recombinant IGF-1 Animal/media grade (GroPep Limited ABN 78 008 176 298, Australia. Cat No. IU 100). Preparation And Storage Of IGF 100µg of lyophilised IGF was reconstituted in l00µl of l0mM HC1. Add 400µl of lmg/ml BSA in PBS 25µ.1 aliquots @ 200µg/ml IGF-1 Stored at -20°C For Assay: 10 µl of stock IGF + 12.5ml growth medium to give 8X stock of 160ng/ml. Complete growth medium DMEM, 10% FCS, 2mM glutamine Starvation medium DMEM, 1% charcoal/dextran stripped FCS, 2mM glutamine Test Compound Compounds are initially dissolved in DMSO to l0mM, followed by dilutions in DMEM + 1% FCS + glutamine to give a range from 100 to 0.0.45µM in 1- 0.00045% DMSO final concentration in assay well a.ii) Assay protocol Day I Exponentially growing NIH3T3/IGFR cells were harvested and seeded in complete growth medium into a flat-bottomed 96 well tissue culture grade plate (Costar 3525) at 1,2x 104 cells per well in a volume of 100µl Day 2 Growth medium was carefully removed from each well using a multi-channel pipette. Wells were carefully rinsed three times with 200p:l with HBSS. 100µL of starvation medium was added to each well and the platewas re-incubated for 24 hours. Day 3 50u.l of a 4X concentrate of test compound was added to appropriate wells. Cells were incubated for 30 minutes with compound alone before the addition of IGF. For cells treated with IGF, an appropriate volume (ie. 25µl) of starvation medium was added to make a final volume per well up to 200µ1 followed by 25u.l of IGF-1 at 160ng/ml (to give a final concentration of 20ng/ml). Control cells unstimulated with IGF also had an appropriate volume (ie. 50µl) of starvation medium added to make final volume per well up to 200µl. The plate was re-incubated for 20 hours. Day 4 The incorporation of BrdU in the cells (after a 4h incorporation period) was assessed using the BrdU Cell Proliferation Elisa according to the manufacturer's protocol. The compounds of the Examples were found to have an IC50 in the above test of less than 50µM. Mechanism of Action Assay Inhibition of IGF-IR mediated signal transduction was determined by measuring changes in phosphorylation of IGF-IR, Akt and MAPK (ERK1 and 2) in response to IGF-I stimulation of MCF-7 cells (ATCC No. HTB-22). A measure of selectivity was provided by the effect on MAPK phosphorylation in response to EGF in the same cell line. a.i) Reagents used: RPMI 1640 medium, RPMI 1640 medium without Phenol Red, FCS, Glutamine (all from Life Technologies Ltd., UK) Charcoal/Dextran Stripped FBS (HyClone SH30068.02, Perbio Science UK Ltd) SDS (Sigma, L4390) 2-mercaptoethanol (Sigma, M6250) Bromophenol blue (Sigma, B5525) Ponceau S (Sigma, P3504) Tris base (TRIZMA™ base, Sigma, T1503) Glycine (Sigma, G7403) Methanol (Fisher Scientific UK. Cat. No M/3950/21) Dried milk powder (Marvel™, Premier Brands UK Ltd.) Human recombinant IGF-1 Animal/media grade (GroPep Limited ABN 78 008 176 298, Australia. Cat No. IU 100). Human recombinant EGF (Promega Corporation, WI, USA. Cat. No. G5021) Complete growth medium RPMI 1640, 10% FCS, 2mM glutamine Starvation medium RPMI1640 medium without Phenol Red, 1 % charcoal/dextran stripped FCS, 2mM glutamine Test Compound Compounds were initially dissolved in DMSO to l0mM, followed by dilutions in RPMI 1640 medium without Phenol Red + 1 % FCS + 2mM glutamine to give a range from 100 to 0.0.45µM in 1- 0.00045% DMSO final concentration in assay well. Western transfer buffer 50mM Tris base, 40mM glycine, 0.04% SDS, 20% methanol Laemmli buffer x2: l00mM Tris-HCl pH6.8, 20% glycerol, 4% SDS Sample buffer x4: 200mM 2-mercaptoethanol, 0.2% bromophenol blue in distilled water. Primary Antibodies Rabbit anti-human IGF-lRp1 (Santa Cruz Biotechnology Inc., USA, Cat. No .sc-713) Rabbit anti-insulin/IGF-lR [pYpY,152/m3] Dual Phosphospecific (BioSource International Inc. CA, USA. Cat No. 44-8041) Mouse anti-PKBα/Akt (Transduction Laboratories, KY, USA. Cat. No. P67220) Rabbit anti-Phospho-Akt (Ser473) (Cell Signalling Technology Inc, MA, USA. Cat. No#9271) Rabbit anti-p44/p42 MAP kinase (Cell Signalling Technology Inc, MA, USA. Cat. No.#9102) Rabbit anti-Phospho p44/p42 MAP kinase (Cell Signalling Technology Inc, MA, USA. Cat. No.#9101) Mouse anti-actin clone AC-40 (Sigma-Aldrich Company Ltd, UK, A4700) Antibody dilutions (Table Removed) Secondary antibodies Goat anti-rabbit, HRP linked (Cell Signalling Technology Inc, MA, USA. Cat. No.#7074) Sheep- anti-mouse IgG HRP-conjugated (Amersham Pharmacia Biotech UK Ltd. Cat. No.NXA931) Dilute anti-rabbit to 1:2000 in PBST + 5% milk Dilute anti-mouse to 1:5000 in PBST + 5% milk a.ii) Assay Protocol Cell treatment MCF-7 cells were plated out in a 24 well plate at lxl05 cells/well in 1ml complete growth medium. The plate was incubated for 24 hours to allow the cells to settle. The medium was removed and the plate was washed gently 3 times with PBS 2ml/well. 1ml of starvation medium was added to each well and the plate was incubated for 24 hours to serum starve the cells. Then 25U.I of each compound dilution was added and the cells and compound were incubated for 30 minutes at 37°C. After 30 minutes incubation of the compound, 25U.1 of IGF (for 20ng/ml final concentration) or EGF (for 0.1 ng/ml final concentration) was added to each well as appropriate and the cells incubated with the IGF or EGF for 5 minutes at 37°C. The medium was removed (by pipetting) and then 100µ1 of 2x Laemmli buffer was added. The plates were stored at 4°C until the cells were harvested. (Harvesting should occur within 2 hours following addition of Laemmli buffer to the cells.) To harvest the cells, a pipette was used to repeatedly draw up and expel the Laemmli buffer/cell mix and transfer into a 1.5m! Eppendorf tube. The harvested cell Iysates were kept at -20°C until required. The protein concentration of each lysate could be determined using the DC protein assay kit (Bio-Rad Laboratories, USA, according to manufacturer's instructions). Western blot technique Cell samples were made up with 4x sample buffer, syringed with a 21 gauge needle and boiled for 5 minutes. Samples were loaded at equal volumes and a molecular weight ladder on 4-12% Bis-Tris gels (Invitrogen BV, The Netherlands) and the gels were run in an Xcell SureLock™ Mini-Cell apparatus (Invitrogen) with the solutions provided and according to the manufacturer's instructions. The gels were blotted onto Hybond C Extra membrane (Amersham Pharmacia Biotech UK Ltd.) for 1 hour at 30 volts in the Xcell SureLock™ Mini-Cell apparatus, using Western transfer buffer. The blotted membranes were stained with 0.1% Ponceau S to visualise transferred proteins and then cut into strips horizontally for multiple antibody incubations according to the molecular weight standards. Separate strips were used for detection of IGF-1R, Akt, MAPK and actin control. The membranes were blocked for 1 hour at room temperature in PBST + 5% milk solution. The membranes were then placed into 3ml primary antibody solution in 4 well plates and the plates were incubated overnight at 4°C. The membranes were washed in 5ml PBST, 3 times for 5 minutes each wash. The HRP-conjugated secondary antibody solution was prepared and 5ml was added per membrane. The membranes were incubated for 1 hour at room temperature with agitation. The membranes were washed in 5ml PBST, 3 times for 5 minutes each wash. The ECL solution (SuperSignal ECL, Pierce, Perbio Science UK Ltd) was prepared and incubated with the membranes for 1 minute (according to manufacturer's instructions), followed by exposure to light sensitive film and,development. The compounds of the Examples were found to have an IC50 in the above test of less than 20µM. WE CLAIM: 1. A substituted pyrimidine compound of formula (I): wherein (Formula Removed) R1 represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR5R6, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxycarbonyl, C1-C6alkylcarbonyl, C1- C6alkylcarbonylamino, phenylcarbonyl, -S(O) mC1-C6alkyl, C(0)NR7R8, -S02N R7aR8a . and an unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which maybe optionally substituted by at least one substituent selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano,-NR9R10, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxycarbonyl, C1 C6alkylcarbonyl, C1-C6alkylcarbonylamino, phenylcarbonyl, S(0)nC1 -C6alkyl,-C(0)NR11R12 and -S02N R11aR12a, m is 0 1 or 2; n is 0 1 or 2; R2 represents a C1-C4alkyl group optionally substituted by at least one substituent selected from halogen, hydroxyl and C1-C3alkoxy; R3 represents hydrogen, halogen or trifluoromethyl; R4 represents a 5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR13R14, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C4alkoxycarbonyl, C1-C4alkylcarbonyl,C1- C4alkylcarbonylamino, phenylcarbonyl, -S(0)p-C1-C4alkyl, C(0)NR15R16 and -S02NR15aR16a; p is 0, 1 or 2;» R5 and R6 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R7 and R8 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R7a and R8a each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R7a and R8a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R9 and R10 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R9 and R10 together with the nitrogen atom to which they arc attached form a 4- to 6-membered saturated heterocycle; R11 and R12 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R11 and R12 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; Rlla and R12a each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R11a- and R12a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R13 and R14 each independently represent hydrogen, C1-C4alkyl or C3-C6Cycloalkyl, or R13 and R14 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R15 and R16 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R15 and R16 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; and R15a and R16a each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R15a and R16a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; or a pharmaceutically acceptable salt or solvate thereof 2. A compound as claimed in claim 1, wherein, R1 represents a 5-or 6- membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent of hydroxyl), halogen, -C(0)NR7R8, C1-C6alkoxycarbonyl, and an unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen and oxygen, the ring itself being optionally substituted by at least one substituent selected from Ci-C6alkyl, Ci-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen), halogen and cyano; wherein R7 and R8 are both hydrogen or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; or a pharmaceutically acceptable salt or solvate thereof. 3. A compound as claimed in claim 1, wherein, in R1, the 5-or 6- membered heteroaromatic ring is selected from thienyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyridyl; or a pharmaceutically acceptable salt or solvate thereof. 4. A compound as claimed in claim 3, wherein, in R1, the 5- or 6-membered heteroaromatic ring is selected from thienyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl and pyridyl; or a pharmaceutically acceptable salt or solvate thereof. 5. A compound as claimed in claim 1 or claim 2, wherein in R1 the 5- or 6-membered heteroaromatic ring is selected from pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl and thienyl; said pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl and thienyl being optionally substituted by at least one substituent selected from methyl, isopropyl, hydroxymethyl, methoxy, chloro, bromo, carbamoyl, methoxycarbonyl, pyrrolidin-1 -ylcarbonyl, phenyl and pyridyl; said phenyl or pyridyl being optionally substituted by at least one substituent selected from methyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, fluoro, chloro, bromo and cyano; or a pharmaceutically acceptable salt or solvate thereof. 6. A compound as claimed in claim 1 ,wherein, in R1, the unsaturated 5- to 6-membered ring is selected from phenyl, cyclopentenyl, cyclohexenyl, thienyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyridyl; or a pharmaceutically acceptable salt or solvate thereof. 7. A compound as claimed in claim 6, wherein, in R1, the unsaturated 5- to 6-membered ring is selected from phenyl, cyclopentenyl, cyclohexenyl, thienyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl and pyridyl; or a pharmaceutically acceptable salt or solvate thereof. 8. A compound as claimed in any one of claims 1 to 7, wherein R2 represents a C1-C4alkyl group; or a pharmaceutically acceptable salt or solvate thereof. 9. A compound as claimed in any one of claims 1 to 8, wherein R3 represents hydrogen or halogen; or a pharmaceutically • acceptable salt or solvate thereof. 10. A compound as claimed in claim 1, wherein R3 represents a halogen atom; or a pharmaceutically acceptable salt or solvate thereof. 11. A compound as claimed in any one of claims 1 to 9, wherein, R4 represents a 5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl and C3-C6cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. 12. A compound as claimed in claim 1, wherein, in R4, the 5-membered heteroaromatic ring is selected from thienyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, triazolyl, tetrazolyl and imidazolyl; or a pharmaceutically acceptable salt or solvate thereof. 13. A compound as claimed in claim 11, wherein, in R4, the 5-membered heteroaromatic ring is pyrazolyl, the ring being optionally substituted by at least one substituent selected from methyl, ethyl, isopropyl, propyl, t-butyl and cyclopropyl; or a pharmaceutically acceptable salt or solvate thereof. 14. A compound as claimed in claim 12, wherein, in R4, the 5-membered heteroaromatic ring is pyrazolyl; or a pharmaceutically acceptable salt or solvate thereof. 15. A compound as claimed in claim 1, wherein R1 represents pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-methoxypyrid~ 5-yl, 2-cyanopyrid-5-yl, 3~bromopyrid-5-yl, 3-(pyrid-2-yl)pyrid-5-yl, 4-(pyrid-2-yl)pyrid-2-yl, 3-chloropyrid-2-yl, 3-methylpyrid-2-yl, 6-methylpyrid-2-yl, 5, 6-dimethylpyrid-2-yl, imidazol-4-yl, imidazol-5-yl, 3- methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 3-isopropylisoxazol-5-yl, 3- methoxycarbonylisoxazol-5-yl, 3-(hydroxymethyl)isoxazol-5-yl, 3 -carbamoylisoxazol-5-yl, 3-(-pyrrolidin-1 -ylcarbonyl)isoxazol-5-yl, 3-phenylisoxazol-5-yl, 3-(pyrid-2-yl)isoxazol-5-yl,3-(2-methoxypyrid-3-yl)isoxazol-5-yl, 3-(2-methoxyphenyl)isoxazol-5-yl, 3-(3-methoxyphenyl)iso- xazol-5-yl, 3-(2-ethoxyphenyl)isoxazol-5-yl, 3-(2-trifluoromethylphenyl) isoxazol-5-yl, 3-(2-trifiuoromethoxyphenyl)isoxazol-5-yl, 3-(2-chlorophenyl) isoxazol-5-yl, 3-(2-bromophenyl)isoxazol-5-yl, 3-(2-methylphenyl)isoxazol-5- yi, 3-(2-fluorophenyl)isoxazol-5yl, 3 -(2-cyanophenyl)isoxazol-5-yl, 5-methylpyrazol-4-yl, fur-2-yl, fur-3-yl, 5-methylfur-2-yl, pyrazin-2-yl, 2-methylpyrazin-5-yl, pyridazin-3-yl, pyrimidin-4-yl, 1 methylpyrrol-2-yl and thien-3-yl; R2 represents methyl, ethyl and propyl; R3 represents hydrogen, chloro or bromo; and R4 represents 5-methylpyrazol-3-yI, 5-ethylpyrazol-3-yl, 5- isopropylpyrazol-3-yl, 5-propylpyrazol-3-yl, 5-t-butylpyrazol-3- yl and 5-cyclopropylpyrazol-3-yl; or a pharmaceutically acceptable salt or solvate thereof. 16. A compound as claimed in any of the preceding claims, wherein it is selected from: 5-Bromo-2- (3-methylisoxazol-5-ylmethylamino) -4- (5-cyclopropyl- 1 H-pyrazol-3 -ylamino)pyrimidine, 5-Chloro-2-(3 -phenylisoxazol-5-ylmethylamino)-4-(5-methyl- 1 H-pyrazol- 3 -ylamino) pyrimidine, 5-Chloro-2-(3-pyrid-2-ylisoxazol-5-ylmethylamino)-4-(5-methyl- lH-pyrazol-3-ylamino)pyrimidine, 5-Brorno-2-(3-pyrid-2-ylisoxzol-sylmethylamino)-4-(5-rnethyl- 1 H-pyrazol-3-ylamino)pyrimidine, 5-Chloro-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-tert-butyl- 1 H-pyra2ol-3-ylamino)pyrimidine, 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-ethyl-lH- pyrazol-3-ylaxnino)pyrimidine, 5-Chloro-2-[3-(2-fluorophenyl)isoxazol-5-ylmethylamino)-4~(5- methyl-1 Hpyrazol-3-ylamino)pyrimidine, 5-Bromo-2-[3-(2-fluorophenyl)isoxazol-5-ylmethylamino)-4-(5- methyl-lH-pyrazol-3-ylamino)pyrimidine, 5-Chloro-2-[3-(2-fluorophenyl)isoxazol-5-ylmethylamino) - 4-(5- tert-butyl-lH-pyrazol-3-ylamino)pyrimidine, 5-Bromo-4-(5-isopropyl-IH-pyrazol-3-ylamino)-2-(pyrid-2-ylmethylamino) pyrimidine, 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-propyl - 1H- pyrazol-3-y] amino) pyrimidine, 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-isopropyl- 1 H-pyrazol- 3 -ylamino) pyrimidine, 5-Chloro-2-[3-(pyrid-2-yl)isoxazol-5-ylmethylamino-4-(5-tert- butyl-lH-pyrazol-3-ylamino)pyrimidine, 5-Bromo-2-[3-(pyrid-2-yl)isoxazol-5-ylmethylamino-4-(5-tert- butyl- lH-pyrazol-3-ylamino)pyrimidine, and 5-Bromo-2-(3-bromopyrid-5-ylmethylamino)-4-(5-tert-butyl-lH- pyrazol-3-ylamino)pyrimidine, and pharmaceutically acceptable salts and solvates of any one thereof. 17. A process for the preparation of a compound as claimed in claim 1, which comprises: (i) reacting a compound of formula (Formula Removed) wherein L1 represents a leaving group such as herein described and R3 and R4 are as defined in formula (I), with a compound of formula (III), H2N-R2-R1, wherein R1 and R2 are as defined in formula (I); and optionally: • forming a pharmaceutically acceptable salt or solvate of the compound. 18. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof from 0.05 to 99% (percent by weight), as claimed in any one of claims 1 to 16 in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 19. A process for the preparation of a pharmaceutical composition as claimed in claim 18 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 16 with a pharmaceutically acceptable adjuvant, diluent or carrier. 20. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 16 for use in the treatment of cancer.

Documents:

1377-delnp-2004-abstract.pdf

1377-delnp-2004-claims.pdf

1377-delnp-2004-complete specification (as,files).pdf

1377-delnp-2004-complete specifiction (granted).pdf

1377-delnp-2004-Correspondence Others-(30-04-2012).pdf

1377-delnp-2004-correspondence-others.pdf

1377-delnp-2004-correspondence-po.pdf

1377-delnp-2004-description (complete).pdf

1377-delnp-2004-form-1.pdf

1377-delnp-2004-form-19.pdf

1377-delnp-2004-form-2.pdf

1377-delnp-2004-Form-27-(30-04-2012).pdf

1377-delnp-2004-form-3.pdf

1377-delnp-2004-form-5.pdf

1377-delnp-2004-gpa.pdf

1377-delnp-2004-pct-210.pdf

1377-delnp-2004-pct-220.pdf

1377-delnp-2004-pct-304.pdf

1377-delnp-2004-pct-409.pdf

1377-delnp-2004-pct-416.pdf

1377-delnp-2004-Petition-137-(30-04-2012).pdf

1377-delnp-2004-petition-137.pdf

abstract.jpg