Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors.
The present invention relates to a series of substituted heteroaromatic compounds, methods for their preparation, pharmaceutical compositions containing them and their use in medicine. In particular, the invention relates to bioisosteres of quinoline and quinazoline derivatives which exhibit protein tyrosine kinase inhibition. Protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth and differentiation (A.F. Wilks, Progress in Growth Factor Research, 1990, 2, 97-111; S.A. Courtneidge, Dev. Supp.l, 1993, 57-64; J.A. Cooper, Semin. Cell Biol., 1994, 5(6), 377-387; R.F. Paulson, Semin. Immunol., 1995, 7(4), 267-277; A.C. Chan, Curr. Opin. Immunol., 1996, 8(3), 394-401). Protein tyrosine kinases can be broadly classified as receptor (e.g. EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-receptor (e.g. c-src, Ick, Zap70) kinases. Inappropriate or uncontrolled activation of many of these kinase, i.e. aberrant protein tyrosine kinase activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Aberrant activity of protein tyrosine kinases, such as c-erbB-2, c-src, c-met, EGFr and PDGFr have been implicated in human malignancies. Elevated EGFr activity has, for example, been implicated in non-small cell lung, bladder and head and neck cancers, and increased c-erbB-2 activity in breast, ovarian, gastric and pancreatic cancers. Inhibition of protein tyrosine kinases should therefore provide a treatment for tumours such as those outlined above. Aberrant protein tyrosine kinase activity has also been implicated in a variety of other disorders: psoriasis, (Dvir et al, J.Cell.Biol; 1991, 113, 857-865), fibrosis, atherosclerosis, restenosis, (Buchdunger et al, Proc.Natl.Acad.Sci. USA; 1991, 92, 2258-2262), auto-immune disease, allergy, asthma, transplantation rejection (Klausner and Samelson, Cell; 1991, 64, 875-878), inflammation (Berkois, Blood; 1992, 79(9), 2446-2454), thrombosis (Salari et al, FEBS; 1990, 263(1), 104-108) and nervous system diseases (Ohmichi et al, Biochemistry, 1992, 31, 4034-4039). Inhibitors of the specific protein tyrosine kinases involved in these diseases eg PDGF-R in restenosis and EGF-R in psoriasis, should lead to novel therapies for such disorders. P56lck and zap 70 are indicated in disease conditions in which T cells are hyperactive e.g. rheumatoid arthritis, autoimmune disease, allergy, asthma and graft rejection. The process of angiogenesis has been associated with a number of disease states (e.g. tumourogenesis, psoriasis, rheumatoid arthritis) and this has been shown to be controlled through the action of a number of receptor tyrosine kinases (L.K. Shawver, DDT, 1997, 2(2), 50-63). EP0635507 discloses a class of tricyclic quinazoline derivatives of the formula: wherein R1 and R2 together form specified optionally substituted groups containing at least one heteroatom so as to form a 5 or 6-membered ring, in which there is a N atom at the 6 position of the quinazoline ring; R3 includes independently hydrogen, hydroxy, halogeno, (1-4C)alkyl, (1-4C) alkoxy di-[(1-4C)alkyl]amino, or (2-4C)alkanoylamino. The above citation notes that receptor tyrosine kinases in general, which are important in the transmission of biochemical signals initiating cell replication, are frequently present at increased levels or with higher activities in common human cancers such as breast cancer (Sainsbury et al, Brit. J. Cancer, 1988, 58, 458). It is suggested that inhibitors of receptor tyrosine kinase should be of value as inhibitors of the growth of mammalian cancer cells (Yaish WO 95/15758 discloses aryl and heteroaryl quinazoline derivatives of formula wherein X includes a bond, O, S, SO, SO2, C≡C, C=C, CH2 and NH; Ar includes phenyl, naphthyl, naphthalenyl, indolyl, pyridyl, piperidinyl, piperazinyl, dihydroquinolinyl, tetrahydroquinolinyl, thienyl, indanyl, pyrazolyl and 1,4-benzodioxanyl; and R5, R6 and R7 independently include hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; as inhibitors of CSF-1 R and/or p56lck receptor tyrosine kinase activity. WO 95/19774 discloses bicyclic derivatives of formula: in which A to E are nitrogen or carbon and at least one of A to E is nitrogen; or two adjacent atoms together are N, O or S; R1 is H or alkyl and n is 0, 1 or 2; m is 0 to 3 and R2 includes optionally substituted alkyl, alkoxy, cycloalkoxy, cycloalkoxy, or two R2 groups together form a carbocycle or heterocycle. The compounds are said to inhibit epidermal growth factor receptor tyrosine kinase and suggested uses include the treatment of cancer, psoriasis, kidney disease, pancreatitis and contraception. WO 96/07657 discloses pyrimido[5,4-d]pyrimidine derivatives of formula wherein Ra includes hydrogen or alkyl; Rb includes optionally substituted phenyl; and Rc includes hydrogen, halo, alkyl, cycloalkyl, cycloalkylalkylaryl, aralkyl, OH, optionally substituted alkoxy, cycloalkoxy, aryloxy, aralkoxy, mercapto, optionally substituted alkyl- or arylsulfenyl, -sulfinyl, or -sulfonyl and substituted alkyleneimino; as EGF-R inhibitors. WO 96/09294 discloses quinoline and quinazoline derivatives of formula wherein X is N or CH; Y includes O, S, CH2O and NH; R6 includes phenoxy, benzyloxy, benzylmercapto, benzylamino, benzyl, anilino, benzoyl, anilinocarbonyl, anilinomethyl, phenylethynyl, phenylethenyl, phenylethyl, phenylthio, phenylsulphonyl, benzylthio, benzylsulphonyl, phenylthiomethyl, phenylsulphonylmethyl, phenoxymethyl, thienylmethoxy, furanylmethoxy, cyclohexyl, and cyclohexylmethoxy; and R1, R2, R3 and R3' include a range of possible substituents, predominantly not including heterocyclic ring systems; as protein receptor tyrosine kinase inhibitors, in particular as c-erbB-2 and/or p56lck inhibitors. WO 96/15118 discloses quinazoline derivatives of formula wherein X includes O, S, SO, SO2, CH2, OCH2, CH2O and CO; Q includes a phenyl or naphthyl group and various 5- or 6-membered heteroaryl moieties; n is 0, 1, 2 or 3 and each R2 is independently halogeno, trifluoromethyl, hydroxy, amino, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, diC1-4 alkyl amino or C2-4 alkanoylamino; m is 1, 2 or 3 and R1 includes a range of possible substituents, predominantly not including heterocyclic ring systems; as receptor tyrosine kinase inhibitors, in particular as EGF-R inhibitors. WO 96/15128 discloses pyrido[2,3-d]pyrimidine and naphthyridine derivatives of formula wherein X is CH or N; B is halo, hydroxy or NR3R4; Ar includes unsubstituted and substituted phenyl or pyridyl; and R1, R2, R3 and R4 independently include hydrogen, amino, C1-8alkylamino, di-C1-8alkylamino, unsubstituted and substituted aromatic or heteroaromatic groups, and unsubstituted and substituted C1-8alkyl, C2-8alkenyl or C2-8alkynyl groups. WO 96/16960 discloses quinazoline derivatives of formula wherein m is 1 or 2; each R1 independently includes hydrogen and C1-4alkoxy; n is 1, 2 or 3; each R2 independently includes hydrogen, halogeno and C1-4alkyl, or R2 is an aryl- or heteroaryl-containing group, including pyridylmethoxy and benzoyl; and Ar includes a substituted or unsubstituted 5- or 9-membered nitrogen-linked heteroaryl moiety containing up to four nitrogen atoms, in particular imidazol-1-yl, imidazolin-1-yl, benzimidazol-1-yl, pyrazol-1-yl and 1,2,4-triazol-1-yl; as receptor tyrosine kinase inhibitors, in particular as EGF-R inhibitors. It is therefore a general object of the present invention to provide compounds suitable for the treatment of disorders mediated by protein tyrosine kinase activity, and in particular treatment of the above mentioned disorders. In addition to the treatment of tumours, the present invention envisages that other disorders mediated by protein tyrosine kinase activity may be treated effectively by inhibition, including preferential inhibition, of the appropriate protein tyrosine kinase activity. Broad spectrum inhibition of protein tyrosine kinase may not always provide optimal treatment of, for example tumours, and could in certain cases even be detrimental to subjects since protein tyrosine kinases provide an essential role in the normal regulation of cell growth. It is another object of the present invention to provide compounds which preferentially inhibit protein tyrosine kinases, such as EGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr, c-src, Ick, Zap70, and fyn. There is also perceived to be a benefit in the preferential inhibition involving small groups of protein tyrosine kinases, for example c-erbB-2 and c-erbB-4 or c-erbB-2, c-erbB-4 and EGF-R. A further object of the present invention is to provide compounds useful in the treatment of protein tyrosine kinase related diseases which minimise undesirable side-effects in the recipient. The present invention relates to heterocyclic compounds which may be used to treat disorders mediated by protein tyrosine kinases and in particular have anti-cancer properties. More particularly, the compounds of the present invention are potent inhibitors of protein tyrosine kinases such as such as EGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr, c-src, Ick, Zap70, and fyn, thereby allowing clinical management of particular diseased tissues. The present invention envisages, in particular, the treatment of human malignancies, for example breast, non-small cell lung, ovary, stomach, and pancreatic tumours, especially those driven by EGFr or erbB-2, using the compounds of the present invention. For example, the invention includes compounds which are highly active against the c-erbB-2 protein tyrosine kinase often in preference to the EGF receptor kinase hence allowing treatment of c-erbB-2 driven tumours. However, the invention also includes compounds which are highly active against both c-erbB-2 and EGF-R receptor kinases hence allowing treatment of a broader range of tumours. More particularly, the present invention envisages that disorders mediated by protein tyrosine kinase activity may be treated effectively by inhibition of the appropriate protein tyrosine kinase activity in a relatively selective manner, thereby minimising potential side effects. Accordingly, the present invention provides a compound of formula (I): or a salt thereof; A represents a fused 5, 6 or 7-membered heterocyclic ring containing 1 to 5 heteroatoms which may be the same or different and which are selected from N, O or S(O)m, wherein m is as defined above, the heterocyclic ring containing a total of 1, 2 or 3 double bonds inclusive of the bond in the pyridine or pyrimidine ring to which it is fused, with the provisos that the heterocyclic ring does not form part of a purine and that the fused heterocyclic ring does not contain two adjacent O or S(O)m atoms. Solvates of the compounds of formula (I) are also included within the scope of the present invention. Heterocyclic groups comprise one or more rings which may be saturated, unsaturated, or aromatic and which may independently contain one or more heteroatoms in each ring. Carbocyclic groups comprise one or more rings which may be independently saturated, unsaturated, or aromatic and which contain only carbon and hydrogen. Suitably the 5, 6, 7, 8, 9 or 10-membered heterocyclic moiety is selected from the group comprising: furan, dioxolane, thiophene, pyrrole, imidazole, pyrrolidine, pyran, pyridine, pyrimidine, morpholine, piperidine, oxazole, isoxazole, oxazoline, oxazolidine, thiazole, isothiazole, thiadiazole, benzofuran, indole, isoindole, quinazoline, quinoline, isoquinoline and ketal. Suitably the 5, 6, 7, 8, 9 or 10-membered carbocyclic moiety is selected from the group comprising: phenyl, benzyl, indene, naphthalene, tetralin, decalin, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. By halo is meant fluoro, chloro, bromo or iodo. Alkyl groups containing three or more carbon atoms may be straight, branched or cyclised. In an embodiment R1 is as defined above with the exception of wherein any substituent containing a heterocyclic ring bears one or two oxo or thioxo substituents on said ring; and R14 and R15 are as defined above with the exception of wherein they together with the nitrogen atom to which they are attached represent a 5- or 6-membered ring and said ring bears one or two oxo or thioxo substituents; save that R1 may represent 4-pyridon-1-yl, 4-pyridon-1-yl-C1-4 alkyl, 4-pyridon-1-yl-C2-4 alkoxy, 4-pyridon-1-yl-C2-4 alkylamino, 2-oxopyrrolidin-1-yl or 2,5-dioxopyrrolidin-1-yl. In an embodiment, X is N. In a further embodiment, Y is NRb, NRb(CH2), or (CH2)NRb, preferably Y is NRb and Rb is preferably hydrogen or methyl. In a further embodiment R" is a 5- or 6-membered heterocyclic ring as defined above, optionally substituted by one or more R1 groups selected from the group comprising amino, hydrogen, halogen, hydroxy, formyl, carboxy, cyano, nitro, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio, C1-8 alkylsulphinyl, C1-8 alkylsulphonyl, C1-4 alkylamino, C1-4 dialkylamino, dioxolanyl, hydroxy-C1-4 alkyl or hydroxy-C1-4 alkanoyl-(C1-4 alkyl)-amino. In a further embodiment, n is 0 and each R1 is selected from the group comprising amino, hydrogen, halogen, hydroxy, formyl, carboxy, cyano, nitro, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio, C1-8 alkylsulphinyl, C1-8 alkylsulphonyl, C1-4 alkylamino, C1-4 dialkylamino, dioxolanyl, benzyloxy or hydroxy-C1-4 alkanoyl-(C1-4 alkyl)-amino. In a preferred embodiment, n is 0, p is 1 and R1 is selected from the group comprising amino, C1-4 alkylamino, diC1-4 alkylamino, especially diC1-4 alkylamino, most especially dimethylamino or methylethylamino. In a further embodiment, n is 0 and R1 is selected from M1-M2-M3-M4, M1-M5 or M1-M2-M3'-M6 as defined above; and p = 1. In a further embodiment R" is a 5- or 6-membered heterocyclic ring as defined above substituted with an R1 group selected from M1-M2-M3-M4, M1-M5 or M1-M2-M3'-M6 as defined above; and p = 0. In a further embodiment the group M2-M3-M4 represents an α-, β- or γ-amino carboxylic, sulphinic or sulphonic acid or a C1-4 alkyl ester, an amide or a C1-4 alkyl- or di-(C1-4 alkyl)-amide thereof. Preferably M1 represents CH2, CO, CH2CH2 or CH2CO, more preferably CH2. Preferably M2 represents NR12 in which R12 is as defined above; more preferably R12 represents H or methyl. Preferably M3 represents CH2, CH2CH2 or propyl. Preferably M3' represents CH2, ethyl, propyl, isopropyl or is absent. Preferably M4 represents SOR13, SO2R13, NR12SO2R13, CO2R13 or CONR14R15 in which R12 and R13 are defined above and R14 and R15 each independently represent H or C1-4 alkyl; more preferably R12, R13, R14 and R15 each independently represent H or methyl. Preferably M5 represents a group NR14R15 in which R14 and R15 together with the nitrogen atom to which they are attached represent a 6-membered ring optionally containing an additional heteroatom selected from N or O, in which ring any nitrogen atom present may optionally be substituted with a C1-4 alkyl group, preferably a methyl group; or M5 represents a group in which t represents 2 or 3 and R16 represents OH, NH2, N(C1-4 alkyl)2 or OC1-4 alkyl; more preferably R16 represents NH2 or N(CH3)2. M5 also preferably represents a group NR14R15 in which R14 and R15 each independently represent hydrogen or C1-4 alkyl, more preferably hydrogen, methyl, ethyl or isopropyl. Preferably M6 represents a group NR14R15 in which R14 and R15 each independently represent C1-4 alkyl, more preferably methyl, or R14 and R15 together with the nitrogen atom to which they are attached represent a 5- or 6-membered ring optionally containing an additional heteroatom selected from N or O, in which ring any nitrogen atom present may optionally be substituted with a C1-4 alkyl group, preferably a methyl group; or M6 represents a 5- or 6-membered heterocyclic ring system containing 1 or 2 heteroatoms selected from N or O. In a further preferred embodiment M2-M3-M4 represents an α-amino carboxylic acid or a methyl ester or amide thereof. In a further preferred embodiment M2-M3-M4 represents an α-, β- or γ-amino sulphinic or sulphonic acid, more preferably a β- or γ-amino sulphinic or sulphonic acid, most preferably a β-aminosulphonic acid, or a methyl ester thereof. In an especially preferred embodiment M2-M3-M4 represents a methylsulphonylethylamino, methylsulphinylethylamino, methylsulphonylpropylamino, methylsulphinylpropylamino, methylsulphonamidoethylamino, sarcosinamide, glycine, glycinamide, glycine methyl ester or acetylaminoethylamino group. In a further especially preferred embodiment M5 represents a piperazinyl, methylpiperazinyl, piperidinyl, prolinamido or In a further especially preferred embodiment M5 represents an isopropylamino or N-morpholinyl group. In a further especially preferred embodiment M1-M5 represents an isopropylacetamido or N-morpholinoacetamido group. In a further especially preferred embodiment M2-M3'-M6 represents a pyridylamino, cyclopropylamino, N-(piperidin-4-yl)-N-methylamino, N,N-dimethylaminoprop-2-ylamino, N-(2-dimethylaminoethyl)-N-ethylamino or tetrahydrofuranomethylamino group, preferably a pyridylamino group. In an embodiment R" may be selected from the group comprising phenyl, furan, thiophene, pyridine, pyrimidine, pyrazine, pyrrole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, triazole, tetrazole and imidazole or a hydrogenated derivative of any of the aforementioned. In a further preferred embodiment R" may be selected from the group comprising phenyl, furan, imidazole, tetrazole, triazole, pyrrolidine, piperazine, piperidine and oxadiazole. In a further embodiment each R1 is independently selected from the group comprising amino, hydrogen, halogen, hydroxy, formyl, carboxy, cyano, nitro, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio, C1-8 alkylsulphinyl, C1-8 alkylsulphonyl, C1-4 alkylamino, C1-4 dialkylamino, benzyloxy, hydroxy-C1-4 alkyl, hydroxy-C1-4 alkanoyl-(C1-4 alkyl)-amino. In an embodiment R2 is hydrogen, C1-4 alkyl, C1-4 alkoxy or halogen, preferably methyl or hydrogen, more preferably hydrogen. In a further embodiment R4 is hydrogen, hydroxy, halogen, C1-4 alkyl, C1-4 alkoxy, di-[C1-4 alkyl]amino, nitro or trifluoromethyl, preferably hydrogen, halogen or methyl, more preferably hydrogen. In a preferred embodiment R7 is an optionally substituted phenyl, dioxolanyl, thienyl, cyclohexyl or pyridyl group. In a further embodiment, Z is absent or represents oxygen, CH2, NRb, NRb(CH2), (CH2)NRb, CH(CH3), O(CH2), (CH)CN, O(CF2), (CH2)O, (CF2)O, S(CH2), S(O)m, carbonyl or dicarbonyl, wherein Rb is hydrogen or C1-4 alkyl. In a preferred embodiment Z is oxygen, dicarbonyl, OCH2, CH2(CN), S(O)m or NRb, wherein Rb is hydrogen or C1-4 alkyl. In a further preferred embodiment R6 is benzyl, , halo-, dihalo- and trihalobenzyl, α-methylbenzyl, phenyl, halo-, dihalo- and trihalophenyl, pyridyl, pyridylmethyl, pyridyloxy, pyridylmethoxy, thienylmethoxy, dioxolanylmethoxy, cyclohexylmethoxy, phenoxy, halo-, dihalo- and trihalophenoxy, phenylthio, benzyloxy, halo-, dihalo- and trihalobenzyloxy, C1-4 alkoxybenzyloxy, phenyloxalyl or benzenesulphonyl, more preferably benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, pyridylmethyl, phenyl, benzenesulphonyl, phenoxy or fluorophenoxy. In a further embodiment R6 is in the para position with respect to Y. When the group Z is absent, R6 = R7. In a further embodiment A represents ; preferably more preferably One or both of the rings comprising the mono or bicyclic ring system U may be aromatic or non-aromatic. The R4 and R6 groups may be bound to the ring system by either a carbon atom or a heteroatom of the ring system. The ring system itself may be bound to the bridging group by a carbon atom or a heteroatom. The R4 and R6 groups may be bound to either ring when U represents a bicyclic ring system, but these groups are preferably bound to the ring which is not bound to the bridging group Y in such a case. Examples of suitable mono or bicyclic groups U include: isoindenyl, indenyl, indanyl, naphthyl, 1,2-dihydronaphthyl or 1,2,3,4-tetrahydronaphthyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, 2H-pyranyl, thiophenyl, 1H-azepinyl, oxepinyl, thiepinyl, azocinyl, 2H-oxocinyl, thieno[2,3-b] furanyl, thianaphthenyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indolizinyl, 1H-benzimidazolyl, 2,3-dihydro-1H-benzimidazolyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl, benzoxazolyl, 2,3-dihydrobenzoxazolyl, benzo[c]isoxazolyl, benzo[d]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, benzothiazoyl, 2,3-dihydrobenzothiazolyl, benzo[c]isothiazolyl, benzo[d]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 1H-benzotriazolyl, benzo[c]furanyl, benzo[c][1,2,3]thiadiazolyl, benzo[d][1,2,3]oxadiazolyl, benzo[d][1,2,3]thiadiazolyl, quinolyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolyl 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 4H-1,4-benzoxazinyl, 2,3-dihydro-4H-1,4-benzoxazinyl, 4H-1,4-benzothiazinyl or 2,3-dihydro-4H-1,4-benzothiazinyl. Suitably U represents an indolyl, isoindolyl, indolinyl, isoindolinyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl, 1H-benzimidazolyl, 2,3-dihydro-1H-benzimidazolyl or 1H-benzotriazolyl group. In an embodiment, the optional substitutents for the carbocyclic or heterocyclic moiety, which may be present at any available position of said moiety, are selected from the group comprising: (CH2)qS(O)m-C1-4alkyl, (CH2)qS(O)m-C3-6cycloalkyl, (CH2)qSO2NR8R9, (CH2)qNR8R9, (CH2)qCO2R8, (CH2)qOR8, (CH2)qCONR8R9, (CH2)qNR8COR9, (CH2)qCOR8, (CH2)qR8, NR8SO2R9 and S(O)mR8, wherein q is an integer from 0 to 4 inclusive; m is 0,1 or 2; R8 and R9 are independently selected from the group comprising hydrogen, C1-4 alkyl, C3-6 cycloalkyl, aryl, a 5- or 6-membered saturated or unsaturated heterocyclic ring which may be the same or different and which contains one or more heteroatoms which are selected from N, O or S(O)m, with the proviso that the heterocyclic ring does not contain two adjacent O or S(O)m atoms. In a further embodiment the optional substitutents for the carbocyclic or heterocyclic moiety are selected from the group comprising morpholine, piperazine, piperidine, pyrrolidine, tetrahydrofuran, dioxolane, oxothiolane and oxides thereof, dithiolane and oxides thereof, dioxane, pyridine, pyrimidine, pyrazine, pyridazine, furan, thiofuran, pyrrole, triazine, imidazole, triazole, tetrazole, pyrazole, oxazole, oxadiazole and thiadiazole. Other optional substituents for the carbocyclic or heterocyclic moiety and also for other optionally substituted groups include, but are not limited to, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, cyano, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkyl carbonyl, carboxylate and C1-4 alkoxy carboxyl. In a further embodiment X represents N; A represents a pyridine ring; p is 0; n is 1; and the group R" is in the 6-position of the pyridopyrimidine ring system. In a further embodiment X represents N; A represents a pyridine ring; n is 0; p is 1; and the group R1 is in the 6-position of the pyridopyrimidine ring system. In a preferred embodiment of the present invention there is provided a compound of formula (I) or a salt or solvate thereof wherein X represents N; Y represents NRa, wherein Ra is hydrogen or C1-4 alkyl; A represents a pyridine ring; R" represents furan, thiophene, pyrrole, pyridine, pyrimidine, pyrazine, imidazole, oxazole, isoxazole, oxadiazole, tetrazole, triazole, dioxolane or a partially or fully hydrogenated derivative of any of these groups, optionally substituted by one or more R1 groups selected from halo, C1-4 alkyl, carboxy, formyl, hydroxy-C1-4 alkyl, 1,3-dioxolan-2-yl, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy-C1-4 alkanoyl(C1-4 alkyl)amino, C1-4 alkylamino-C1-4 alkyl or di(C1-4 alkyl)amino-C1-4 alkyl; p is 0; R2 represents hydrogen; R4 represents hydrogen or methyl; U represents indolyl, benzimidazolyl or indazolyl, more preferably indazolyl; and R6 represents phenyl, benzyl, α-methylbenzyl, fluorobenzyl, benzenesulphonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy. In further preferred embodiment of the present invention there is provided a compound of formula (I) or a salt or solvate thereof wherein X represents N; Y represents NRa, wherein Ra is hydrogen or C1-4 alkyl; A represents a pyridine ring, R" represents furan, thiophene, pyrrole, pyridine, pyrimidine, pyrazine, imidazole, oxazole, isoxazole, oxadiazole, tetrazole, triazole, dioxolane or a partially or fully hydrogenated derivative of any of these groups, optionally substituted with an R1 group selected from methylsulphonylethylaminomethyl, methylsulphonylethylamino-carbonyl, methylsulphinylethylamino-methyl, methylsulphinylethylamino-carbonyl, methylsulphonylpropylamino-methyl, methylsulphinylpropylamino-methyl, methylsulphonylpropyamino-carbonyl, methylsulphinylpropylamino-carbonyl, methylsulphonylethyl-(methylamino)-methyl, methylsulphonylethyl-(methylamino)-carbonyl, methylsulphinylethyl-(methylamino)-methyl, methylsulphinylethyl-(methylamino)-carbonyl, methylsulphonylpropyl-(methylamino)-methyl, methylsulphinylpropyl-(methylamino)-methyl, methylsulphonylpropyl-(methylamino)-carbonyl, methylsulphinylpropyl-(methylamino)-carbonyl, methylsulphonamidoethylamino-methyl, methylsulphonamidopropylamino-methyl, sarcosinamidomethyl, glycinylmethyl, glycinamidomethyl, glycinylmethyl methyl ester, acetylaminoethylaminomethyl, piperazinylmethyl, methylpiperazinylmethyl, piperidinylmethyl, N-(prolinamido)methyl, (N,N-dimethyl-prolinamido)methyl, pyridylaminomethyl, cyclopropylaminomethyl, N-(piperidin-4-yl)-N-methylaminomethyl, N,N-dimethylaminoprop-2-ylaminomethyl, N-(2-dimethylaminoethyl)-N-ethylaminomethyl, isopropylacetamido, N-morpholinylacetamido or tetrahydrofuranomethylaminomethyl and optionally further substituted by one or more C1-4 alkyl groups; p is 0; R2 represents hydrogen; R4 represents hydrogen or methyl; U represents indolyl, benzimidazolyl or indazolyl, more preferably indazolyl; and R6 represents phenyl, benzyl, α-methylbenzyl, fluorobenzyl, benzenesulphonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy. In a further preferred embodiment of the present invention there is provided a compound of formula (I) or a salt or solvate thereof, wherein X represents N; Y represents NRa wherein Ra is hydrogen or C1-4 alkyl; A represents a pyridine ring; n is 0; each R1 group is selected from hydrogen, halo, C1-4 alkyl, carboxy, formyl, hydroxy-C1-4 alkyl, 1,3-dioxolan-2-yl, benzyloxy, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy-C1-4 alkanoyl(C1-4 alkyl)amino, C1-4 alkylamino-C1-4 alkyl, di(C1-4 alkyl)amino-C1-4 alkyl, methylsulphonylethylaminomethyl, methylsulphonylethylamino-carbonyl, methylsulphinylethylamino-methyl, methylsulphinylethylamino-carbonyl, methylsulphonylpropylamino-methyl, methylsulphinylpropylamino-methyl, methylsulphonylpropyamino-carbonyl, methylsulphinylpropylamino-carbonyl, methylsulphonylethyl-(methylamino)-methyl, methylsulphonylethyl-(methylamino)-carbonyl, methylsulphinylethyl-(methylamino)-methyl, methylsulphinylethyl-(methylamino)-carbonyl, methylsulphonylpropyl-(methylamino)-methyl, methylsulphinylpropyl-(methylamino)-methyl, methylsulphonylpropyl-(methylamino)-carbonyl, methylsulphinylpropyl-(methylamino)-carbonyl, methylsulphonamidoethylamino-methyl, methylsulphonamidopropylamino-methyl, sarcosinamidomethyl, glycinylmethyl, glycinamidomethyl, glycinylmethyl methyl ester, acetylaminoethylaminomethyl, piperazinylmethyl, methylpiperazinylmethyl, piperidinylmethyl, N-(prolinamido)methyl, (N,N-dimethyl-prolinamido)methyl, pyridylaminomethyl, cyclopropylaminomethyl, N-(piperidin-4-yl)-N-methylaminomethyl, N,N-dimethylaminoprop-2-ylaminomethyl, N-(2-dimethylaminoethyl)-N-ethylaminomethyl, isopropylacetamido, N-morpholinylacetamido or tetrahydrofuranomethylaminomethyl; R2 represents hydrogen; R4 represents hydrogen or methyl; U represents indolyl, benzimidazolyl or indazolyl, more preferably indazolyl; and R6 represents phenyl, benzyl, α-methylbenzyl, fluorobenzyl, benzenesulphonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy. In an especially preferred embodiment of the present invention there is provided a compound of formula (I) or a salt or solvate thereof wherein X represents N; Y represents NRa, wherein Ra is hydrogen or C1-4 alkyl; A represents a pyridine ring; R" represents a furan, imidazole, triazole, oxadiazole, pyrrolidine, piperidine or piperazine ring, optionally substituted by one or more R1 groups selected from 1,3-dioxolan-2-yl, formyl, carboxy, C1-4-alkyl, prolinamidomethyl, isopropylacetamido, N-morpholinylacetamido, methylsulphonylethylaminomethyl or methylsulphonylethylaminocarbonyl; p is 0; R2 represents hydrogen; R4 represents hydrogen or methyl; U represents indazolyl, indolyl or benzimidazolyl, more preferably indazolyl; and R6 represents benzyl, fluorobenzyl, pyridylmethyl or benzenesulphonyl. In a further especially preferred embodiment of the present invention there is provided a compound of formula (I) or a salt or solvate thereof wherein X represents N; Y represents NRa, wherein Ra is hydrogen or C1-4 alkyl; A represents a pyridine ring; n is 0; each R1 group is selected from hydrogen, halo, benzyloxy, amino, C1-4 alkylamino, di(C1-4 alkyl)amino or hydroxy-C1-4 alkanoyl(C1-4 alkyl)amino, more preferably dimethylamino; R2 represents hydrogen; R4 represents hydrogen or methyl; U represents indazolyl, indolyl or benzimidazolyl, more preferably indazolyl; and R6 represents benzyl, fluorobenzyl, pyridylmethyl or benzenesulphonyl. Preferred compounds of the present invention include: Other preferred compounds of the present invention include: Particularly preferred compounds of the present invention include: Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen in the compound of formula (I). The therapeutic activity resides in the moiety derived from the compound of the invention as defined herein and the identity of the other component is of less importance although for therapeutic and prophylactic purposes it is, preferably, pharmaceutically acceptable to the patient. Examples of pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and methanesulphonic and arylsulphonic, for example p-toluenesulphonic, acids. According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula (I) as defined above which comprises the steps: (a) the reaction of a compound of formula (II) wherein A, X, n, p and R2 are as defined above and L, L' and L" are suitable leaving groups, with a compound of formula (III)UYH wherein U and Y are as defined above, to prepare a compound of formula (IV) and subsequently (b) where n is 1, reaction with an appropriate reagent to substitute the group R" onto the ring A by replacement of the leaving group L'; and (c) where p is other than 0, reaction with appropriate reagent(s) to substitute the group(s) R1 onto the ring A by replacement of the leaving group(s) L"; and, if desired, (d) subsequently converting the compound of formula (I) thereby obtained into another compound of formula (I) by means of appropriate reagents. Alternatively, the compound of formula (II) as defined above is reacted with the appropriate reagents to substitute the groups R" and R1 onto the ring A by replacement of the respective leaving groups and then the product thereby obtained (of formula (V) below) is reacted with the compound of formula (III) as defined above, followed, if desired, by conversion of the compound of formula (I) thereby obtained into another compound of formula (I). In a variant of this alternative the compound of formula (V) may be prepared by the reaction of a compound of formula (VI) with appropriate reagents to substitute the group(s) R1 and the group R" onto the ring A to prepare a compound of formula (VII) and subsequent reaction to incorporate the leaving group L. For example, a chloro leaving group can be incorporated by reaction of a corresponding 3,4-dihydropyrimidone with carbon tetrachlorlde/triphenylphosphine in an appropriate solvent. Simplified versions of these general processes will apply where either (i) p is 0 and n is 1 or (ii) where n is 0 and p is other than 0. The group R" may, therefore, be substituted onto the ring A by replacement of a suitable leaving group. This is especially suitable for preparing compounds where R" is a substituted or unsubstituted phenyl or heterocyclic ring system; such compounds may, for example, be prepared by reaction of the corresponding aryl or heteroaryl stannane derivative with the corresponding compound of formula (IV) carrying the leaving group L' in the appropriate position on the ring. The group(s) R1 may, therefore, also be substituted onto the ring A by replacement of suitable leaving group(s). This is especially suitable for preparing compounds of formula (I) wherein an R1 group is linked to the ring A by a nitrogen atom; such compounds may, for example, be obtained by reaction of the amine corresponding to the group R1 with the corresponding compound carrying a halo substituent in the appropriate position on the ring A. The reagents used to effect the substitution of the groups R" and R1 onto the ring A may, in certain circumstances, include appropriate protecting group(s) well known to the person skilled in the art for particular functionalities. This may, for example, be suitable where either of the groups R" or R1 contain a free amino functionality. Such protecting group(s) would be removed by standard methods after the substitution onto the ring A has been effected. For a description of protecting groups and their use see T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2nd edn., John Wiley & Sons, New York, 1991. According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula (I) as defined above which comprises the steps: Such processes are particularly suitable for the preparation of compounds of formula (I) wherein either R" carries or R1 represents a substituent selected from M1-M2-M3-M4, M1-M5 or M1-M2-M3'-M6 as defined above in which M2 represents NR12. In such cases preferably the group Z carries a terminal formyl group (CHO). Such processes are especially suitable for the preparation of compounds of formula (I) wherein either (i) p is 0, n is 1 and R" carries a substituent selected from M1-M2-M3-M4, M1-M5 or M1-M2-M3'-M6 as defined above in which M2 represents NR12, or (ii) p is 1, n is 0 and R1 is selected from M1-M2-M3-M4, M1-M5 or M1-M2-M3'-M6 as defined above in which M2 represents NR12. Where Z carries a formyl group the compound may be suitably prepared from the corresponding dioxolanyl substituted compound, for example by acid hydrolysis. The dioxolanyl substituted compound may be prepared by reaction of a compound of formula (IV) with an appropriate reagent to substitute the relevant leaving group with the substituent carrying the dioxolanyl ring. This reagent could, for example, be an appropriate heteroaryl stannane derivative. Where Z carries a terminal formyl group the compound could suitably be prepared by reaction of a compound of formula (IV) with an appropriate heteroaryl stannane derivative. This derivative is either readily available or can be readily synthesised by those skilled in the art using conventional methods of organic synthesis. Suitable possibilities for preparation of compounds where R" carries the aforementioned substituents include the following schematic examples:- The resulting compounds would, for example, then be converted into the respective stannane derivative. Analogous methods could be used for phenyl and other heterocyclic ring systems and also for the preparation of compounds where R1 represents one of the aforementioned substituents. Therefore a suitable process may comprise reaction of the compound in which the group Z carries a terminal formyl group (i.e. a -CHO or -(C1-3 alkylene)-CHO group) with a compound of formula HM2-M3-M4, a compound of formula HM2-M3'-M6 or a compound of formula HM5, wherein M2 represents NR12. The reaction preferably involves a reductive amination by means of an appropriate reducing agent, for example sodium triacetoxyborohydride. A similar process would be involved where in M1 one CH2 group was replaced with a CO group and M2 was NR12. If necessary, in certain circumstances, the ketone could be protected by standard methods to ensure that the reductive amination involved the aldehyde functionality. For the preparation of those compounds wherein in M1 the CH2 group adjacent to M2 is replaced with a CO group a suitable process would comprise reaction of a compound in which the group Z carries a -(C0-3 alkylene)-CO2H group with a compound of formula HM2-M3-M4, a compound of formula HM2-M3'-M6 or a compound of formula HM5, wherein M2 represents NR12. Alternatively, an analogous scheme to those described above could be used wherein the substitution of the groups R" and R1 onto the ring A occurs prior to the coupling reaction with the compound of formula (III). According to a further alternative process the group Z is converted into the group R" by a For example, Z could suitably represent an alkyne group which when reacted with an appropriate nitrile oxide results in the formation of an isoxazole ring system; reaction with an azide would result in the formation of a triazole ring system. The group Z could also suitably represent an amidoxime group (derived from a cyano group) which when reacted with an activated carboxylic acid derivative (such as an acid chloride or an acid imidazolide) would result in the formation of a 1,2,4-oxadiazole ring system. The group Z could also suitably represent a bromomethylenecarbonyl group which would be reacted with an imidate to result in the formation of an oxazole ring system, with a guanidino group to result in the formation of an N-imidazole ring system or with an amidine group to result in the formation of a C-imidazole ring system. The group Z could also suitably represent an activated carboxylic acid group which would be reacted to form a hydrazinoketone which would subsequently be reacted with another activated carboxylic acid derivative to result in the preparation of a 1,3,4-oxadiazole ring system. Thus reaction of a compound carrying a relevant Z group with appropriate reagents carrying one of -C=N=O, -NH-C(NH2)=NH, -COX, -C(NH2)=NOH, -C(OMe)=NH, or -C(NH2)=NH as a terminal group would result in the formation of the ring systems indicated above. Alternatively, an analogous scheme to those described above could be used wherein the substitution of the group R" onto the ring A occurs prior to the coupling reaction with the compound of formula (III). The following scheme outlines, for example, the synthesis of derivatives carrying a substituted 1,3,4-oxadiazole ring as an R" substituent: Such processes are particularly suitable for the preparation of the compounds of formula (I) wherein R" carries a substituent selected from M1-M2-M3-M4, M1-M5 or M1-M2-M3'-M6 as defined above in which M2 represents CR12R13, including those in which in M1 one CH2 group is replaced by a CO group. Such processes are especially suitable for the preparation of compounds of formula (I) wherein either (i) p is 0, n is 1 and R" carries a substituent selected from M1-M2-M3-M4, M1-M5 or M1-M2-M3'-M6 as defined above in which M2 represents CR12R13, or (ii) p is 1, n is 0 and R1 is selected from M1-M2-M3-M4, M1-M5 or M1-M2-M3'-M6 as defined above in which M2 represents CR12R13. Suitable leaving groups for L, L' and L" will be well known to those skilled in the art and include, for example, halo such as chloro and bromo; sulphonyloxy groups such as methanesulphonyloxy and toluene-p-sulphonyloxy; alkoxy groups; and triflate. The coupling reaction referred to above with the compound of formula (III) is conveniently carried out in the presence of a suitable inert solvent, for example a C1-4 alkanol, such as isopropanol, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon or a dipolar aprotic solvent such as acetone or acetonitrile at a non-extreme temperature, for example from 0 to 150°, suitably 10 to 100°C, preferably 50 to 100°C. Optionally, the reaction is carried out in the presence of a base when Y = NH. Examples of suitable bases include an organic amine such as triethylamine, or an alkaline earth metal carbonate, hydride or hydroxide, such as sodium or potassium carbonate, hydride or hydroxide. When YH = OH or SH it is necessary to perform the reaction in the presence of a base, and in such a case the product is not obtained as the salt. The compound of formula (I) in the case in which Y = NRb may be obtained from this process in the form of a salt with the acid HL, wherein L is as hereinbefore defined, or as the free base by treating the salt with a base as hereinbefore defined. The compounds of formulae (II) and (III) as defined above, the reagents to substitute the group(s) R1 and the group R", and the reagent(s) to convert the group Z into the group R1 or R" are either readily available or can be readily synthesised by those skilled in the art using conventional methods of organic synthesis. As indicated above, the compound of formula (I) prepared may be converted to another compound of formula (I) by chemical transformation of the appropriate substituent or substituents using appropriate chemical methods (see for example, J.March "Advanced Organic Chemistry", Edition III, Wiley Interscience, 1985). For example, a group R1 may be substituted onto the ring A by replacement of another group R1 which is a suitable leaving group. This is especially suitable for preparing compounds of formula (I) wherein an R1 group is linked to the ring A by a nitrogen atom; such compounds may, for example, be obtained by reaction of the amine corresponding to the group R1 with the corresponding compound of formula (I) carrying a halo substituent in the appropriate position on the ring A. Similarly a group R" may be substituted onto the ring A by replacement of a group R1 which is a suitable leaving group. This is especially suitable for preparing compounds where R" is a phenyl or heterocyclic ring system; such compounds may, for example, be prepared by reaction of the corresponding aryl or heteroaryl stannane derivative with the corresponding compound of formula (I) carrying a halo substituent in the appropriate position on the ring A. For example, a compound containing an alkyl or aryl mercapto group may be oxidised to the corresponding sulphinyl or sulphonyl compound by use of an organic peroxide (e.g. benzoyl peroxide) or suitable inorganic oxidant (eg OXONE ®). A compound containing a nitro substituent may be reduced to the corresponding amino-compound, e.g. by use of hydrogen and an appropriate catalyst (if there are no other susceptible groups) or by use of Raney Nickel and hydrazine hydrate. Amino or hydroxy substituents may be acylated by use of an acid chloride or an anhydride under appropriate conditions. Equally an acetate or amide group may be cleaved to the hydroxy or amino compound respectively by treatment with, for example, dilute aqueous base. In addition reaction of an amino substituent with triphosgene and another amine (eg aqueous ammonia, dimethylamine) gives the urea substituted product. An amino substituent may also be converted to a dimethylamino substituent by reaction with formic acid and sodium cyanoborohydride. A formyl substituent may be converted to a hydroxymethyl or a carboxy substituent by standard reduction or oxidation methods respectively. All of the above-mentioned chemical transformations may also be used to convert one compound of formula (II) to a further compound of formula (II) prior to any subsequent reaction; or to convert one compound of formula (II) to a further compound of formula (III) prior to any subsequent reaction. Various intermediate compounds used in the above-mentioned processes, including but not limited to certain of the compounds of formulae (II), (III), (IV), (V), (VI) and (VII) as illustrated above, are novel and thus represent a further aspect of the present invention. The compounds of formula (I) and salts thereof have anticancer activity as demonstrated hereinafter by their inhibition of the protein tyrosine kinase c-erbB-2, c-erbB-4 and/or EGF-r enzymes and their effect on selected cell lines whose growth is dependent on c-erbB-2 or EGF-r tyrosine kinase activity. The present invention thus also provides compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof for use in medical therapy, and particularly in the treatment of disorders mediated by aberrant protein tyrosine kinase activity such as human malignancies and the other disorders mentioned above. The compounds of the present invention are especially useful for the treatment of disorders caused by aberrant c-erbB-2 and/or EGF-r activity such as breast, ovarian, gastric, pancreatic, non-small cell lung, bladder, head and neck cancers, and psoriasis. A further aspect of the invention provides a method of treatment of a human or animal subject suffering from a disorder mediated by aberrant protein tyrosine kinase activity, including susceptible malignancies, which comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in therapy. A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of cancer and malignant tumours. A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of psoriasis. Whilst it is possible for the compounds, salts or solvates of the present invention to be administered as the new chemical, it is preferred to present them in the form of a pharmaceutical formulation. According to a further feature of the present invention there is provided a pharmaceutical formulation comprising at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients. Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain for example 0.5mg to 1g, preferably 70mg to 700mg, more preferably 5mg to 100mg of a compound of the formula (I) depending on the condition being treated, the route of administration and the age, weight and condition of the patient. Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986). Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For treatments of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes. Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas. Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient. Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators. Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations. Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. The animal requiring treatment with a compound, salt or solvate of the present invention is usually a mammal, such as a human being. A therapeutically effective amount of a compound, salt or solvate of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of the present invention for the treatment of neoplastic growth, for example colon or breast carcinoma will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70kg adult mammal, the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt or solvate of the present invention may be determined as a proportion of the effective amount of the compound perse. The compounds of the present invention and their salts and solvates may be employed alone or in combination with other therapeutic agents for the treatment of the above-mentioned conditions. In particular, in anti-cancer therapy, combination with other chemotherapeutic, hormonal or antibody agents is envisaged. Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other pharmaceutically active agent. The compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Certain embodiments of the present invention will now be illustrated by way of example only. The physical data given for the compounds exemplified is consistent with the assigned structure of those compounds. 1H NMR spectra were obtained at 500MHz on a Bruker AMX500 spectrophotometer, on a Bruker spectrophotometer at 300Mz, or on a Bruker AC250 or Bruker AM250 spectrophotometer at 250MHz. J values are given in Hz. Mass spectra were obtained on one of the following machines: VG Micromass Platform (electrospray positive or negative), HP5989A Engine (thermospray positive) or Finnigan-MAT LCQ (ion trap) mass spectrometer. Analytical thin layer chromatography (tlc) was used to verify the purity of some intermediates which could not be isolated or which were too unstable for full characterisation, and to follow the progess of reactions. Unless otherwise stated, this was done using silica gel (Merck Silica Gel 60 F254). Unless otherwise stated, column chromatography for the purification of some compounds used Merck Silica gel 60 (Art. 1.09385, 230-400 mesh), and the stated solvent system under pressure. Petrol refers to petroleum ether, either the fraction boiling at 40-60°C, or at 60-80°C. Ether refers to diethylether. DMAP refers to 4-dimethylaminopyridine. DMF refers to dimethylformamide. DMSO refers to dimethylsulphoxide. THF refers to tetrahydrofuran. TMEDA refers to N,N,N',N'-tetramethylethylenediamine. TFA refers to trifluoroacetic acid. HPLC refers to high pressure liquid chromatography. RT refers to retention time. Useful preparative techniques are described in WO96/09294, WO97/03069 and WO97/13771; also described in these publications are appropriate intermediate compounds other than those detailed below. The optionally substituted bicyclic species and the specified amine were mixed in an appropriate solvent (acetonitrile unless otherwise specified), and heated to reflux. When the reaction was complete (as judged by tlc), the reaction mixture was allowed to cool. The resulting suspension was diluted, e.g. with acetone, and the solid collected by filtration, washing e.g. with excess acetone, and dried at 60°C A stirred mixture of the product from Procedure (A), (containing a suitable leaving group such as chloro, bromo, iodo or triflate), a heteroaryl stannane and a suitable palladium catalyst, such as bis-(triphenylphosphine)palladium (II) chloride or 1,4-bis(diphenylphosphino)-butane palladium (II) chloride (prepared as described in C.E. Housecroft et. al., Inorg. Chem., (1991), 30(1), 125-130), together with other appropriate additives, were heated at reflux in dry dioxane or another suitable solvent under nitrogen until the reaction was complete. The resulting mixture was generally purified by chromatography on silica. The product of Procedure (A) (containing a suitable leaving group such as chloro) was dissolved in an excess of the desired amine (or a solution thereof) and heated in a pressure vessel (e.g. at 130°C for 17hr). The cooled mixture was generally purified by chromatography on silica. Dry dimethylsulphoxide (20 ml) was added to potassium hydroxide (4.2 g, 0.074 mol) (crushed pellets) and the mixture was stirred under nitrogen for 5 mins. 5-Nitroindole (commercially available) (3.0 g, 0.019 mol) was then added and the red mixture stirred for 30 min at room temperature. The mixture was then cooled to -10 °C, benzyl bromide (4.4 ml, 0.037 mol) was slowly added and the mixture stirred and allowed to warm to room temperature over a period of 40 mins. Water (50 ml) was then added and the mixture was extracted with diethyl ether (2 x 200 ml). The extracts were washed with water (4 x 50 ml), dried over sodium sulphate and evaporated to leave an oily solid. The excess benzyl bromide was removed by dissolving the whole in diethyl ether (50 ml), diluting this solution with 40-60 petrol (50 ml) and then gradually removing the diethyl ether A solution of 1-benzyl-5-nitroindole (0.51 g, 0.02 mol) in a mixture of ethyl acetate (25 ml) and methanol (25 ml) was carefully added to 10% palladium on charcoal (45 mg). The resulting suspension was stirred at room temperature under an atmosphere of hydrogen. When the reaction was complete (indicated by tlc or calculated uptake of hydrogen) the suspension was filtered through a pad of Hyflo™, and the filtrate evaporated to dryness to give 5-amino-1-benzylindole (0.40 g, 91%) as an off-white solid; m.p. 66-68 °C; δH [2H6]-DMSO 7.30-7.12 (6H, m, 2-H, 2"-H, 3"-H, 4"-H, 5"-H, 6"-H), 7.08 (1H, d, J 8, 7-H), 6.70 (1H, s, 4-H), 6.49 (1H, d, J 8, 6-H), 6.18 (1H, s, 3-H), 5.28 (2H, s, CH2), 4.38 (2H, br s, NH2). A mixture of 4-nitro-o-phenylene diamine (1.54g) and phenylacetic acid (2.04g) in 5N aqueous HCI (16ml) were heated at 110 °C under nitrogen for 22 hours. The mixture was cooled to room temperature and the accumulated black solid collected by filtration. This crude residue was then adsorbed onto silica and chromatographed to give the title compound (0.84g) as a purple foam; δH CDCl3 9.70 (1H, bs), 8.15 (1H, d), 7.30 (7H, m), 4.30 (2H,s); m/z (M + 1)+ 254. The title compound was prepared from 5-nitro-2-benzylbenzimidazole by an analogous reduction method to that described above for 5-amino-1-benzyl-1H-indole; m/z (M + 1)+ 224. Also note the published method (J. Het. Chem., 23, 1109-13, (1986)). A stirred mixture of 5-nitroindazole (50g), potassium carbonate (46.6g, 1.1 equiv.) and benzyl bromide (57.6g, 1.1 equiv) in Also note the published method in FR 5600, 8 January 1968. 1-Benzyl-5-nitroindazole (400g) was suspended in ethanol (5 litre) and hydrogenated in the presence of 5% platinum on carbon catalyst (20g) operating at 1 bar pressure and 50-60°C. When hydrogen uptake was complete the reactor contents were heated to 70°C, discharged and filtered while still hot and the filtrate concentrated to ∼4 litre which caused some crystallisation. Water (4 litre) was then gradually added with stirring and the mixture was stirred at 5°C overnight. The resultant crystals were filtered off and air-dried at ambient temperature to give 305g (86%) of material, m.pt.150-152°C; HPLC (Supelcosil ABZ +, gradient 0.05% trifluoroacetic acid in water/0.05% trifluoroacetic acid in acetonitrile,1.5ml/min, 220nm) showed <1% of the corresponding 2-N-isomer (RT-1 Also note the published method in FR 5600, 8 January 1968. 2-Fluoro-5-nitroacetophenone (H. Sato et al, Bioorganic and Medicinal Chemistry Letters, 5(3), 233-236, 1995) (0.24g) was treated with triethylamine (0.73ml)and benzyl hydrazine dihydrochloride (0.255g) in ethanol (20ml) at reflux under N2 for 8 days. The mixture was cooled and the solid 1-benzyl-3-methyl-5-nitroindazole (0.16g) was collected by filtration; m/z (M+1)+ 268. 1-Benzyl-3-methyl-5-nitroindazole (0.15g) in THF (15ml) was treated with platinum on carbon (0.05g, 5%) under an atmosphere of hydrogen at room temperature. When hydrogen uptake was complete, the mixture was filtered and concentrated The relevant nitro-substituted 1H-indazole was treated with a base such as potassium carbonate or sodium hydroxide in a suitable solvent, such as acetone or acetonitrile. The appropriate aryl halide or heteroaryl halide was added and the reaction mixture heated or stirred at room temperature overnight. Subsequent concentration Amines prepared by such methods and specifically used in the preparation of the later Examples include:- Other amines prepared by such methods include: 1-Benzenesulphonylindol-5-yl-amine was prepared according to the published method (J. Org. Chem., 55, 1379-90, (1990)). 3-Benzenesulphonyl-6-nitroindole (K. Wojciechowski and M Makosza, Tet. Lett.,25 (42), p4793, 1984) was hydrogenated by analogy with the procedures above to give the title compound; δH [2H6]DMSO 11.64 (1 H,s), 7.94 (2H,m), 7.81 (1H,s), 7.57 (3H,m), 7.49(1H,d), 6.60(1H,s), 6.55 (1H,dd), 5.40 (2H,s). A stirred solution of 6-chloronicotinic acid (47.3g), diphenylphosphoryl azide (89.6g) and triethylamine (46ml) in t-butanol (240ml) were heated under reflux under nitrogen for 2.5 hours. The solution was cooled and concentrated This material may subsequently be carried forward to the appropriately substituted pyridopyrimidine intermediate according to the procedures as described in WO95/19774, J. Med. Chem., 1996, 39, pp 1823-1835, and J. Chem. Soc., Perkin Trans. 1, 1996, pp 2221-2226. Specific compounds made by such procedures include 6-chloro-pyrido[3,4-d]pyrimidin-one and 4,6-dichloro-pyrido[3,4-d]pyrimidine. 2-Chloro-4-nitropyridine (0.64g) was treated with aqueous dimethylamine (10ml, 25%) at reflux for 30 minutes. The mixture was diluted with water and filtered. The solid was washed with water and dried 2-N,N-Dimethylamino-4-nitropyridine (0.67g) in ethanol (50ml) was added to 10% palladium on charcoal and stirred under an atmosphere of hydrogen. When the reaction was complete, the suspension was filtered through a pad of Hyflo™ and the filtrate concentrated 2- 2-( 5-Amino-2-(N,N-dimethylamino)-pyridine-4-carboxylic acid (0.54g) was treated with formamidine acetate (3.12g) in glacial acetic acid (20ml) and heated at reflux for 16 hours. The mixture was cooled, evaporated to dryness Alternatively, 6-chloro-pyrido[3,4-d]pyrimidin-4-one (26.14g) was treated with 2N dimethylamine in ethanol (200ml) and heated at 130°C in a Parr bomb for 3 days. The cooled mixture was filtered and triturated from isopropanol to give the title compound (16.61g) as a yellow solid; m/z (M+1+) 191. 6-( 6-Chloro-pyrido[3,4-d]pyrimidin-4-one (10g) in 1-methyl-2-pyrrolidinone (100ml) was treated with copper (I) iodide (10.52g) and potassium cyanide (7.10g) at 215°c for 72 hours under N2. Further potassium cyanide was added (3.58g) and heating continued at 230°C for 70 hours. The 1-methyl-2-pyrrolidinone was removed by distillation at reduced pressure and the residue absorbed onto silica. Chromatography gave the title compound (2.4g) as a beige solid; δH [2H6]DMSO 13.0(1H,bs), 9.25 (1H,s), 8.55 (1H,s), 8.50 (1H,s); m/z (M-1+) 171. 6-Cyano-pyrido[3,4-d]pyrimidin-4-one (0.3g) in diglyme (2ml) was treated with tributyl tin azide (0.49g) at reflux under N2 for 15 hours. The cooled mixture was partitioned between ethyl acetate and water and the aqueous phase extracted further with ethyl acetate. The aqueous phase was concentrated 6-(1,2,3,4-Tetrazol-5-yl)-pyrido[3,4-d]pyrimidin-4-one (1.4g) in acetic anhydride (10ml) was heated at reflux under N2 for 2.5 hours. The cooled mixture was absorbed onto silica and purified by chromatography to give the title compound (0.14g) as a beige solid; δH [2H6]DMSO 13.0(1H,bs), 9.30 (1H,s), 8.66 (1H,s), 8.47 (1H,s) 2.75 (3H,s); m/z (M+1+) 230. 6-(5-Methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-one (0.5g) was treated with phosphorus oxychloride at room temperature under N2. After 1 hour at room temperature and 1 hour at 50°C, the mixture was concentrated Sodium hydride (8.14g of 60% dispersion with mineral oil, 203.5mmol) was suspended in benzyl alcohol (200ml) under a nitrogen atmosphere. 6-Chloropyrido[3,4-d]pyrimidine (9.081g, 50.0mmol) was added and the mixture was heated at 150°C for 18 hours. When cool, the mixture was partitioned between water (200ml) and ether (200ml), the layers were separated, and the aqueous layer was washed with further ether. The aqueous solution was then acidified to pH1 by the addition of dilute HCI causing the precipitation of the title compound as a cream solid (7.885g, 31.1 mmol, 62%); δH [2H6]DMSO 8.71(1H,s), 7.89(1H,s), 7.25-7.48 (6H,m), 5.40 (2H,s); m/z (M+1+) 254. 6-Benzyloxy-4-hydroxy-pyrido[3,4-d]pyrimidine (1.033g, 4.1mmol) was suspended in thionyl chloride (10ml) under a nitogen atmosphere. DMF (3 drops) was added and the mixture was heated to reflux with stirring for 5.5 hours to give a dark solution, and then left to stand under nitrogen overnight. The mixture was concentrated 2-Furoic acid (9.0g, 80.3mmol) was added to a solution of 3-methyl-3-oxetanemethanol (16.5g, 161.6mmol), 1,3-dicyclohexylcarbodiimide (25.0g, 121.1mmol) and DMAP (0.50g, 4.1mmol) in dichloromethane (250ml), and the mixture was stirred under a nitrogen atmosphere overnight. The mixture was filtered, and the filtrate was concentrated (3-Methyl-3-oxetane)methyl 2-furoate (11.8g, 60.1 mmol) was dissolved in dichloromethane (250ml) and the solution was cooled to 0°C. Boron trifluoride-etherate (10 drops) was added and the mixture stirred at room temperature, and then left to stand for two months. Triethylamine (0.5ml, 0.36g, 3.6mmol) was added and the mixture concentrated to give a sticky white solid. Trituration with ether/acetone gave the title compound as a white solid (2.2g, 11.2mmol, 19%); δH [2H6]DMSO 8.00 (1H,s), 7.34 (1H,d), 7.71 (1H, dd), 4.44 (2H,d), 4.35 (2H,s), 4.28 (2H,d), 1.31 (3H,s). 2-(4-Methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)furan (2.0g, 10.2mmol) was dissolved in THF (20ml) and the solution was cooled to -78°C. n-BuLi (1.6M solution in hexanes, 7.7ml, 12.32mmol) was added and the mixture stirred at -78°C for 30min, allowed to warm to 0°C for 20 min. and then recooled to -78°C. The tributyltin chloride (3.5ml, 4.68g, 14.4mmol) was added and stirring was continued at -78°C for 15min. The mixture was allowed to warm gradually to room temperature and stirring continued for three days. The reaction was quenched by the addition of water, and extracted with ethyl acetate. This solution was washed with water, dried (MgSO4), and concentrated (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido-[3,4-d]pyrimidin-4-yl)-amine (0.425g, 1.10mmol), 5-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-2-[tri( Prepared according to Procedure A from 1-benzyl-1H-indazol-5-ylamine and 4,6-dichloro-pyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 9.08 (1H,s), 8.92 (1H,s), 8.82 (1H,s), 8.23 (1H,d), 8.19 (1H,s), 7.80 (1H,d), 7.70 (1H,dd), 7.38-7.22 (5H,m), 5.69 (2H,s); m/z (M + 1)+ 387. A stirred solution of (1-benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (0.5g) in 33% aqueous dimethylamine (5ml) was heated at 130°C in a reacti-vial for 17 hr. The cooled mixture was dissolved in chloroform, absorbed onto silica and chromatographed to give the title compound (Procedure C) as a yellow solid; δH [2H6]-DMSO 9.00(1H,s), 8.51(1H,s), 8.09(2H,d), 7.55(1H,dd), 7.25(7H,m), 6.39(1H,m), 5.60(2H,s) 3.20 (6H,s); m/z (M + 1)+ 396. Alternatively, 4-chloro-6-( The hydrochloride salt was partitioned between dichloromethane and 2N sodium carbonate. Extraction of the aqueous layer with dichloromethane was followed by drying of the organic phase and concentration A stirred solution of (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (0.2g) in 2-methylaminoethanol (4ml) was heated at 130°C in a reacti-vial for 96 hr (Procedure C). The cooled mixture was partitioned between ethyl acetate and water. The aqueous phases were extracted with ethyl acetate. The dried extracts were concentrated A stirred solution of (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (0.165g), 2-(tri-n-butylstannyl)furan (0.139g) and bis-(triphenylphosphine)palladium (II) chloride (30mg) in dioxane (10ml) was heated at reflux under nitrogen for 65 hr (Procedure B). The cooled mixture was absorbed onto silica and chromatographed to give the title compound as an orange solid; δH CDCl3 9.34(1 H,s), 8.82(1H,s), 8.70(1 H,d), 8.15(1H,d), 8.10(1 H,s), 7.65(1 H,d), 7.60(1H,s),7.53(1H,dd), 7.40(1H,d), 7.25(6H,m), 5.60(2H,s); m/z (M + 1)+ 353. Prepared according to Procedure A from 5-amino-2-benzyl-1H-benzimidazole and 4,6-dichloro-pyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 9.13(1H,s), 8.93(1H,s), 8.84(1H,s), 8.60(1H,s), 8.05(1H,dd), 7.88(2H,d), 7.50(6H, m), 4.61(2H,s); m/z (M + 1)+ 387. The title compound was prepared from (1-benzyl-1H-indol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine by an analogous method to Example 2 (Procedure C) as a yellow solid; δH CDCl3 8.98(1H,s), 8.50(1H,s), 7.93(1H,s), 7.30(5H,m), 7.15(2H,m), 6.60(1H,d), 6.38(1H,s), 5.35(2H,s), 3.20(6H,s); m/z (M + 1)+ 395. The title compound was prepared from (2-benzyl-1H-benzimidazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine by an analogous method to Example 2 (Procedure C) as a yellow solid; δH [2H6]-DMSO 9.75(1 H,s), 8.80(1 H,s), 8.32(1H,s), 8.08(1H,bs), 7.50(2H,m), 7.30(5H,m), 4.20(2H,s); m/z (M + 1)+ 396. (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (4.28g), 2-(tributylstannyl)-5-(1,3-dioxolan-2-ylmethyl)-furan (J. Chem Soc., Chem. Commun., (1988), p560) (10g) and 1,4-bis(diphenylphosphino)butane palladium (II) chloride (1g) were heated at reflux in dioxane (150ml) for 24 hr (Procedure B). The solvent was removed (1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolanyl]-furan-2-yl)-pyrido[3,4-d]-pyrimidin-4-yl)-amine (3.03g) and 2N HCI (50ml) were stirred in THF (50ml) for 16 hr. The resulting precipitate was filtered and washed with water to give thehydrochloride salt of the product; δH [2H6]DMSO 11.70 (1H,s), 9.74 (1H,s) 9.30 (1H,s), 9.27 (1H,s), 8.85 (1H,s), 8.23 (1H,s), 8.18 (1H,s), 7.68-7.87 (3H,m), 7.55 (1H,d), 7.22-7.38 (5H,m), 5.71 (2H,s). Subsequent neutralisation with triethylamine in ethanol/water gave the title compound; δH [2H6] -DMSO 9.64(1H,s), 9.19 (1H,s), 9.09(1H,s), 8.72(1H,s), 8.12(2H,m), 7.71(2H,m), 7.63(1H,dd), 7.43(1H,d), 7.20(5H,m), 5.62(2H,s). 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (800mg) and L-prolinamide (1.0g) were mixed in dichloromethane (8ml) at 25°C for 1 hr. The solution was cooled to 0°C and sodium triacetoxyborohydride (2.0g) was added. After 4 hr at 25°C the reaction mixture was subjected to flash chromatography directly on silica using 3% methanol in chloroform, to give the free base as a yellow solid; δH [2H6]DMSO 10.33 (1H,s), 9.13(1H,s) 8.65 (1H,s), 8.61 (1H,s), 8.26 (1H,s), 8.16 (1H,s), 7.75 (2H,m), 7.12-7.33 (7H,m), 7.09 (1H,d), 6.56 (1H,d), 5.69 (2H,s), 3.84 (2H,s), 3.31-3.39 (1H, obscured by water), 3.09-3.14 (2H,m), 1.70-2.20 (4H,m); m/z (M+1+) 545. Treatment with saturated HCI in ethyl acetate gave the title compound; δH [2H6] -DMSO 12.25 (1H, s), 9.52(1H, s), 9.27 (1H, s), 8.80(1H, s), 8.53(1H, s), 8.27(1H, s), 8.21(1H, s), 7.83(2H, m), 7.72(1 H, s), 7.30(6H, m), 6.93(1 H, d), 5.72(2H, s), 4.88(1 H, m), 4.60(2H, s), 3.20(2H, s), 1.90(4H, m); m/z (M + 1)+ 545. (1-Benzyl-1 H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (0.70g, 1.81 mmol), 1-methyl-5-[tri(n-butyl)stannyl]imidazole (prepared according to the published method: K. Gaare et. al., Acta Chem. Scand., (1993), 47(1), p57-62) (2.2g, 6mmol), 1,4-bis(diphenylphosphino)-butane palladium (II) chloride (0.41g, 0.7mmol) and silver oxide (0.224g, 1.8mmol) were reacted in dry dioxane according to Procedure B. Purification by silica gel chromatography, eluting with 10%MeOH/EtOAc, gave the product as a pale brown solid (0.16g, 0.37mmol, 20%); δH CDCl3 10.62 (1H,s), 9.25 (1H,s), 8.75 (1H,s), 8.60 (1H,s), 8.13 (1H,s), 8.03 (1H,s), 7.20-7.78 (9H,m), 5.61 (2H,s), 3.96 (3H,s); m/z (M+1+) 433. Prepared according to Procedure A from 1-(2-Pyridylmethyl)indazol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.75(1H,s), 9.92(1H,s), 8.62(1H,s), 8.55(1H,d), 8.24(1H,s), 8.14(1H,s), 7.75(4H,m), 7.33(1H,m), 7.08(1H,d), 5.82(2H,s), 3.20(6H,s); m/z (M+1+) 397. Prepared according to Procedure A from 1-(3-Pyridylmethyl)-1H-indazol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.50(1H,s), 9.90(1H,s), 8.65(1H,d), 8.60(2H,m), 8.25(1H,s), 8.14(1H,s), 7.91(1H,d), 7.75(2H,m), 7.70(1H,s), 7.50(1H,m), 5.80(2H,s), 3.20(6H,s); m/z (M+1+) 397. Prepared according to Procedure A from 1-Benzyl-3-methyl-1H-indazol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.75(1H,s), 8.90(1 H,s), 8.62(1 H,s), 8.02(1 H,s), 7.70(3H,m), 7.30(5H,m), 5.62(2H,s), 3.30(6H,s) 2.50(3H,s); m/z (M+1+) 410. Prepared according to Procedure A from 1-(2-Fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.45(1H,s), 8.90(1H,s), 8.63(1H,s), 8.24(1H,s), 8.13(1H,s), 7.87(1H,d), 7.70(1H,d), 7.62(1H,s), 7.36(1H,m), 7.20 (3H,m), 5.75(2H,s), 3.22(6H,s); m/z (M+) 413. Prepared according to Procedure A from 1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.52(1H,s), 8.90(1H,s), 8.60(1H,s), 8.24(1H,s), 8.14(1H,s), 7.85(2H,m), 7.70(1H,d), 7.49(1H,m), 7.10 (3H,m), 5.72(2H,s), 3.19(6H,s); m/z (M+1+) 414. Prepared according to Procedure A from 1-(4-Fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.42(1H,s), 8.90(1H,s), 8.60(1H,s), 8.22(1H,s), 8.14(1H,s), 7.86(1H,d), 7.65(1H,d), 7.61(1H,s), 7.32(2H,dd), 7.17 (2H,dd), 5.70(2H,s), 3.23(6H,s); m/z (M+) 414. Prepared according to Procedure A from 1-benzenesulphonyl-1H-indol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.64(1H,s), 8.90(1 H,s), 8.60(1 H,s), 8.05(4H,m), 7.90(1 H,d), 7.65(5H,m), 6.92(1 H,d), 3.20(6H,s); m/z (M+) 445. Prepared according to Procedure A from 3-benzenesulphonyl-1H-indol-6-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.55(1H,s), 11.50(1H,s), 8.90(1 H,s), 8.60(1 H,s), 8.79(1 H,d), 8.00(3H,m), 7.86(1H,d), 7.60(5H,m), 3.20(6H,s); m/z (M+) 445. Imidazole (0.8g) in dry DMSO was treated with sodium hydride (60%, 0.47g) and (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine in a reacti-vial and heated at 120°C. After 7 days, the mixture was poured onto water and extracted with ethyl acetate. Purification using a Bond Elute ™ cartridge gave the title compound as a brown solid after trituration from water; δH [2H6]DMSO 10.28(1 H,s), 9.25(1 H,s), 8.90(1 H,s), 8.78(1 H,s), 8.67(1 H,s), 8.40(1 H,s), 8.30(1 H,s), 8.10(1H,s), 7.88(2H,m), 7.40(5H,m), 5.70(2H,s); m/z (M+) 419. 1,2,4-triazole was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 20 to give the title compound; δH [2H6]DMSO 10.53(1H,s), 9.46(1H,s), 9.14(1H,s), 9.01(1H,s), 8.65(1H,s), 8.40(1H,s), 8.25(1H,s), 8.15(1H,s), 7.75(2H,s), 7.25(5H,m), 5.65(2H,s); m/z (M+) 418. 1,2,3-triazole was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 21 to give the title compound; δH [2H6]DMSO 10.62(1H,s), 9.24(2H,s), 8.73(1H,s), 8.33(3H,s), 8.21(1H,s), 7.80(1H,s), 7.33(5H,m), 5.73(2H,s); m/z (M+) 420. 1,2,3-triazole was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 21 to give the title compound; δH [2H6]DMSO 10.53(1H,s), 9.28(1H,s), 9.13(1H,s), 8.89(1H,s), 8.64(1H,s), 8.23(1H,s), 8.10(1H,s), 8.00(1 H,s), 7.69(2H,s), 7.23(5H,m), 5.62(2H,s); m/z (M+) 420. Pyrrolidine (2ml) was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (0.4g) in a reacti-vial at 100°C (Procedure C). After 18 hours, the cooled mixture was poured onto water and the precipitate washed with hot ether and crystallised from acetone to give the title compound; δH [2H6]DMSO 10.53(1H,s), 9.75(1H,s), 8.79(1H,s), 8.30(1H,s), 8.23(1H,s), 8.14(1H,s), 7.70(2H,m), 7.28(5H,m), 7.14(1H,s), 5.68(2H,s) 3.50(4H,m), 2.02(4H,m); m/z (M+) 422. Piperidine was reacted with(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 24 to give the title compound (Procedure C); δH [2H6]DMSO 9.80(1H,s), 8.80(1H,s), 8.33(1H,s), 8.22(1H,s), 8.15(1H,s), 7.70(2H,m), 7.50(1 H,s), 7.28(5H,m), 5.68(2H,s) 3.65(4H,m), 1.65(6H,m); m/z (M+) 436. Ethylmethylamine was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 2 to give the title compound (Procedure C); δH [2H6]DMSO 9.87(1H,s), 8.86(1H,s), 8.37(1H,s), 8.25(1H,s), 8.20(1H,s), 7.76(2H,m), 7.35(5H,m), 5.75(2H,s) 3.79(2H,q), 3.18(3H,s), 1.19(3H,t); m/z (M+) 410. 4-Isopropylacetamido-1,4-piperazine (Aldrich) was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 24 to give the title compound (Procedure C); δH [2H6]DMSO 8.85(1H,s), 8.35(1H,s), 8.20(2H,d), 7.72(2H,m), 7.55(1 H,s), 7.30(5H,m), 5.70(2H,s) 3.95(1H,m), 3.68(4H,bs), 3.00(2H,s), 2.60(4H,bs), 1.10(6H,d); m/z (M+) 535. N-Morpholinylacetamido-1,4-piperazine (Emkachem) was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 24 to give the title compound (Procedure C); δH [2H6]DMSO 9.80(1 H,s), 8.83(1 H,s), 8.38(1H,s), 8.22(1H,s), 8.15(1H,s), 7.75(1H,d), 7.66(1H,dd), 7.55(1H,s), 7.28(5H,m), 5.70(2H,s) 3.60(10H,m), 3.50(2H,m), 3.28(3H,s), 2.62(4H,bs); m/z (M+) 564. 4-Chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl) pyrido[3,4-d]pyrimidine (0.02g) was reacted with 1-benzylindazol-5-ylamine according to Procedure A to give the title compound as a yellow solid; δH [2H6]DMSO 11.50(1 H,s), 9.55(1 H,s), 9.43 (1 H,s), 8.95(1H,s), 8.34(2H,m), 7.91(1H,d), 7.83(1H,dd), 7.40(5H,m), 5.80 (2H,s), 2.75 (3H,s); m/z (M+1+) 435. Prepared according to Procedure A from 1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.50(1H,s), 9.53(1H,s), 9.41 (1H,s), 8.94(1H,s), 8.30(2H,s), 7.90(1H,d), 7.80(1H,dd), 7.45(1H,d), 7.25(3H,m), 5.80(2H,s), 2.75 (3H,s); m/z (M+1+) 453. Prepared according to Procedure A from 1-benzyl-1H-indol-5-ylamine and 4,6-dichloro-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.45(1H,s), 9.08(1 H,s), 8.95(1H,s), 8.80(1H,s), 7.98(1H,d), 7.60(2H,m), 7.30(6H,m), 6.60(1H,d), 5.48(2H,s); m/z (M+1+) 386. 4-Methylpiperazine was reacted with (1-Benzyl-1 H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 24 to give the title compound (Procedure C); δH [2H6]DMSO 9.80(1H,s), 8.82(1H,s), 8.47(1H,s), 8.23(1H,s), 8.15(1H,s), 7.75(1 H,d), 7.67(1 H,d), 7.54 (1H,s), 7.28(5H,m), 5.68(2H,s) 3.64(4H,m), 3.34(4H,m), 2.27(3H,s); m/z (M+) 451. 6-Benzyloxy-4-chloro-pyrido[3,4-d]pyrimidine (0.54g, ca.2mmol) and 5-amino-1-benzyl-1 H-indazole (0.458g, 2.05mmol) were reacted according to Procedure A to give the title compound as a yellow solid (0.740g, 1.50mmol, 75%); δH [2H6]DMSO 11.50 (1H,s), 9.00 (1H,s), 8.77 (1H,s), 8.16-8.33 (3H,m), 7.83 (1H,d), 7.71 (1H,dd), 7.13-7.58 (10H,m), 5.69 (2H,s), 5.55 (2H,s); m/z (M+1+) 459. 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (0.709, 1.81mmol), 2-(methanesulphonyl)ethylamine hydrochloride (1.30g, 8.14mmol) and triethylamine (0.65ml, 0.47g, 4.7mmol) were stirred in dichloromethane (7ml) at room temperature for 1 hour forming a precipitate. The mixture was cooled to 0°C and sodium triacetoxyborohydride (1.60g, 7.5mmol) was added. The temperature was maintained at 0°C for 15min and then stirring was continued at room temperature overnight. The reaction mixture was diluted with water, and the resulting pale yellow precipitate was collected and washed with water and acetone. This was resuspended in a mixture of acetone and methanol and acidified with ethereal HCI. The solvents were removed (1-Benzylindazol-5-yl)-(6-[5-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-furan-2-yl]-pyrido-[3,4-d]pyrimidin-4-yl)-amine (0.445g, 0.81 mmol) was suspended in a mixture of THF (15ml) and dilute HCI (15ml) and stirred at room temperature for 18 hours. The mixture was diluted with water to preciptate the intermediate (partial hydrolysis) which was collected by filtration and washed with water. This solid was suspended in a mixture of THF (10ml) and NaOH (1M, 10ml) and stirred at room tmperature for 18 hours. The THF was removed 5-[4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido-[3,4-d]pyrimidin-6-yl]-furan-2-carboxylic acid hydrochloride (0.125g, 0.25mmol) and carbonyl diimidazole (0.052g, 0.33mmol) were suspended in dry THF (3ml) under a nitrogen atmosphere and stirred at room temperature for 7 hours. 2-(Methanesulphonyl)ethylamine hydrochloride (0.080g, 0.50mmol) and triethylamine (0.15ml, 0.11g, 1.08mmol) were added, together with further THF (2ml), and the resulting mixture was stirred at room temperature for 18 hours. The mixture was adsorbed onto silica gel and purified by column chromatography, eluting with 2-10% MeOH/DCM. Concentration of the relevant fractions gave a pale yellow solid. This was resuspended in methanol and treated with ethanolic HCI to give the product as an orange solid, which was collected by filtration, washed with methanol, acetone and ether, and dried Prepared by incubation of N4-(1-Benzyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine with The microorganism was grown in SB1 medium at a temperature of 28°C. Flasks were shaken at 250rpm. The SB1 culture medium consisted of Arkasoy (25g; British Arcady Company), Bacto yeast extract (5g; Difco Laboratories) and KH2PO4 (5g) in distilled water (900ml). The pH of the culture medium was adjusted to 7.2 using conc. NaOH prior to autoclaving (15min./121°C). 100ml of a 20% (w/v) solution of glucose (filter sterilised) was added post sterilisation. N4-(1-Benzyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine (12.5mg) in methanol (1.0ml) was added to each culture flask after 72 hours growth. Cultures were harvested 7 days after compound addition. Isolation: The culture broth (2 x 50ml) was mixed with an equal volume of methanol (containing 0.6% (v/v) TFA), centrifuged (4000rpm, 4.C, 30min) and the supernatant concentrated under a stream of nitrogen gas. The resulting concentrated aqueous extract was adsorbed onto a water-equilibrated C18 SPE cartridge (2g; Varian Ltd., Walton-on Thames, UK) which was washed with water (5 volumes), then eluted with 3 x 5ml methanol (containing 0.3% (v/v) TFA). The eluent was then diluted (mobile phase A, 10ml) and filtered (0.2mm PTFE filter) prior to preparative HPLC using the following system: - Spherisorb SB5 C6 15cm x 20mm, flow rate 20ml/min, detection wavelength 232nm; mobile phase A: 50mM ammonium acetate containing 3ml/l TFA; mobile phase B: 50% acetonitrile, 50mM ammonium acetate containing 3ml/l TFA; gradient: 0 to 30 min, 100%A - 100%B; 30 to 35 min, 100%B; 35 to 37 min, 100%B - 100%A; 37 to 40 min, 100%A. Appropriate fractions were adsorbed onto water-equilibrated C18 SPE cartridges (200mg; Varian Ltd., Walton-on-Thames, UK), which were washed with water (5 volumes) then eluted with 2 x 1 ml methanol (containing 0.3% (v/v) TFA). The solvent was removed The following compounds (and their hydrochlorides, if appropriate) are prepared by analogous techniques using the appropriate starting materials: Compounds of the present invention were tested for protein tyrosine kinase inhibitory activity in substrate phosphorylation assays and cell proliferation assays. The substrate phosphorylation assays use baculovirus expressed, recombinant constructs of the intracellular domains of c-erbB-2 and c-erbB-4 that are constitutively active and EGFr isolated from solubilised A431 cell membranes. The method measures the ability of the isolated enzymes to catalyse the transfer of the γ-phosphate from ATP onto tyrosine residues in a biotinylated synthetic peptide (Biotin-GluGluGluGluTyrPheGluLeuVal). The enzyme is incubated for 30 minutes, at room temperature, with 10mM MnCl2, ATP and peptide at Km concentrations, and test compound (diluted from a 5mM stock in DMSO, final DMSO concentration is 2%) in 40mM HEPES buffer, pH 7.4. The reaction is stopped by the addition of EDTA (final concentration 0.15mM) and a sample is transferred to a streptavidin-coated 96-well plate. The plate is washed and level of phosphotyrosine on the peptide is determined using a Europium-labelled antiphosphotyrosine antibody and quantified with a time-resolved fluorescence technique. The results are shown in Table 1 as the IC50 values in nM. The cell proliferation assay uses an immortalised human breast epithelial cell line (HB4a) which has been transformed by over-expression of c-erbB-2. Growth of these cells in low serum is dependent upon the c-erbB-2 tyrosine kinase activity. The specificity of the effect of the test compounds on tyrosine kinase dependent growth over general toxicity is assessed by comparison to an HB4a cell line which has been transfected with ras. Cells are plated at 3000/well in 96-well plates in 0.1 ml medium and allowed to attach overnight. test compound is added in 0.1 ml medium, with a final concentration of 0.5% DMSO, and the plates incubated for 4 days at 37°C. The cells are then examined microscopically for evidence of morphological detransformation and cell mass is estimated by staining with methylene blue and measuring the absorbance at 620nm. The results are shown in Table 1 below as the IC50 values in nM. Activity against a range of naturally occurring EGFr or c-erbB-2 over-expressing human tumour cell lines (BT474-breast, HN5-head and neck, N87-gastric and Calu3-lung) is assessed with selected compounds by the same methodology. The results are also shown in Table 1 below as the IC50 values in nM. Susbtituted heteroaromatic compounds, and in particular substituted bicyclic heteroamromatic compounds of formula (i), wherein x is n or ch; a represents a fused 5, 6 or 7-membered heterocyclic ring containing 1 to 5 heteroatoms which may be the same or different and which are selected from n, o or s(o)m, wherein m is as defined above, the heterocyclic ring containing a of 1,2 or 3 double bonds inclusive of the bond in the pyridine or pyrimidine ring to which it is fused, with the provisos that the heterocyclic ring does not form part of a purine and that the fused heterocyclic ring does not contain two adjacent o ro s(o)m atoms. U represents a 5 to 10-membered mono or bicyclic ring system in which one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from n,o and s(o)m, wherein m is 0,1 or 2 and wherein the ring system is substituted by at least one independently selected r6 group and is otpionally substituted by at least one indepenently selected r4 group, with the proviso that u does not represent phenyl, are protein tyrosine kinase inhibitors. The compounds are described as are methods for their preparation, pharmaceutical compositions including such compounds and their use in medicine, for example in the treatment of cancer and psoriasis. The use of a therapeutically effective amount of a compound which inhibits the activity of both EGFR and erbB-2 in a human or animal subject in the treatment of a susceptible malignancy in said subject. The use of a therapeutically effective amount of a compound which inhibits the activity of both EGFR and erbB-2 in a human or animal subject in the preparation of a medicament for the treatment of a susceptible malignancy in said subject. The use as claimed in claim 1 or claim 2 wherein the subject is a human. The use as claimed in any one of claims 1 to 3 wherein the susceptible malignancy is cancer. The use as claimed in any one of claims 1 to 3 wherein the susceptible malignancy is a malignant tumour. The use as claimed in any one of claims 1 to 3 wherein the susceptible malignancy is breast cancer, ovarian cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer, bladder cancer, or head and neck cancer. The use as claimed in any one of claims 1 to 3 wherein the susceptible malignancy is a breast tumour, non-small cell lung tumour, ovarian tumour, stomach tumour, or pancreatic tumour.
and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof.
and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof.
and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof.General Procedures
(A) Reaction of an amine with a bicyclic species containing a 4-chloropyrimidine ring
(B) Reaction of a product from Procedure (A) with a heteroaryl tin reagent
(C) Reaction of the product from Procedure (A) with a second amine
Preparation Of Intermediates
1-Benzyl-5-nitro-1H-indole
5-Amino-1-benzyl-1H-indole
2-Benzyl-5-nitro-1H-benzimidazole
5-Amino-2-benzyl-1H-benzimidazole
1-
5-Amino-1-
1-Benzyl-3-methyl-5-nitro-1H-indazole
1-Benzyl-3-methyl-1H-indazol-5-ylamine
Further amino-indazole intermediates
3-Benzenesulphonylindol-6-yl-amine
N-5-[
2-
2-
2-(
5-Amino-2-(
6-(N,N-Dimethylamino)-pyrido[3,4-d]pyrimidin-4-one
4-Chloro-6-(
6-Cyano-pyrido[3,4-d]pyrimidin-4-one
6-(1,2,3,4-Tetrazol-5-yl)-pyrido[3,4-d]pyrimidin-4-one
6-(5-Methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-one
4-Chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidine
6-Benzyloxy-4-hydroxy-pyrido[3,4-d]pyrimidine
6-Benzyloxv-4-chloro-pyrido[3,4-d]pyrimidine
(3-Methyl-3-oxetane)methyl 2-furoate
2-(4-Methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)furan
5-(4-Methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)-2-[tri(
(1-Benzyl-1H-indazol-5-yl)-(6-[5-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-furan-2-yl]-pyrido-[3,4-d]pyrimidin-4-yl)-amine
Examples
Example 1
(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine hydrochloride
Example 2
N4-(1-Benzyl-1H-indazol-5-yl)-
Example 3
(1-Benzyl-1H-indazol-5-yl)-6-(N-(2-hydroxyethyl)-N-methylamino)-pyrido[3,4-d]pyrimidin-4-yl)-amine
Example 4
(1-Benzyl-1H-indazol-5-yl)-(pyrido[3,4-d]pyrimidin-4-yl)-amine
Example 5
(2-Benzyl-1H-benzimidazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine
Example 6
N4-(1-Benzyl-1H-indol-5-yl)-
Example 7
N4-(2-Benzyl-1H-benzimidazol-5-yl)-
Example 8
(1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-pyrido[3,4-d]-pyrimidin-4-yl)-amine
Example 9
5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde
Example 10
(2S)-1-(5-(4-(1-Benzyl-1H-indazol-5-ylamino)-6-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-ylmethyl)-pyrrolidine-2-carboxvlic acid amide hydrochloride
Example 11
(1-Benzyl-1H-indazol-5-yl)-(6-(3-methyl-3H-imidazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine
Example 12
N6,N6-Dimethyl-N4-(1-pyridin-2-ylmethyl-1H-indazol-5-yl)-pyrido[3,4-d]pyrimidine-4,6-diamine hydrochloride
Example 13
N6,N6-Dimethyl-N4-(1-pyridin-3-ylmethyl-1H-indazol-5-yl)-pyrido[3,4-d]pyrimidine-4,6-diamine hydrochloride
Example 14
N4-(1-Benzyl-3-methyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine
Example 15
N4-(1-(2-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine hydrochloride
Example 16
N4-(1-(3-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine hydrochloride
Example 17
N4-(1-(4-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine hydrochloride
Example 18
N4-(1-Benzenesulphonyl-1H-indol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine hydrochloride
Example 19
N4-(3-Benzenesulphonyl-1H-indol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine hydrochloride
Example 20
(1-Benzyl-1H-indazol-5-yl)-(6-imidazol-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine
Example 21
(1-Benzyl-1H-indazol-5-yl)-(6-(1,2,4-triazol-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine
Example 22
(1-Benzyl-1H-indazol-5-yl)-(6-(1,2,3-triazol-2-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine
Example 23
(1-Benzyl-1H-indazol-5-yl)-(6-(1,2,3-triazol-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine
Example 24
(1-Benzyl-1H-indazol-5-yl)-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine
Example 25
(1-Benzyl-1H-indazol-5-yl)-(6-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine
Example 26
N4-(1-Benzyl-1H-indazol-5-yl)-N6-ethyl-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine
Example 27
2-(4-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-piperazin-1-yl)-N-isopropyl-acetamide
Example 28
2-(4-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-piperazin-1-yl)-1-morpholin-4-yl-ethanone
Example 29
(1-Benzyl-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine hydrochloride
Example 30
(1-(3-Fluoro-benzyl)-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine hydrochloride
Example 31
(1-Benzyl-1H-indol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine hydrochloride
Example 32
(1-Benzyl-1H-indazol-5-yl)-(6-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine
Example 33
(1-Benzyl-1H-indazolyl-5-yl)-(6-benzyloxy-pyrido[3,4-d]pyrimidin-4-yl)-amine hydrochloride
Example 34
(1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesuphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido-[3,4-d]pyrimidin-4-yl)-amine hydrochloride
Example 35
5-[4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido-[3,4-d]pyrimidin-6-yl]-furan-2-carboxylic acid hydrochloride
Example 36
5-[4-(1-benzyl-1H-indazol-5-ylamino)-pyrido-[3,4-d]pyrimidin-6-yl]-furan-2-carboxylic acid 2-methanesulphonyl-ethylamide hydrochloride
Examples 37 and 38
Examples 39 to 41
Biological Data