MXPA01009502A - Pyridine and pyrimidine derivatives and their use as inhibitors of cytokine mediated disease - Google Patents

Abstract

This invention concerns a bicyclic compound of Formula (I), wherein:G is N, CH or C(CN);ring X is a 5- or 6-membered fused heteroaryl ring which contains 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen;m is 0 - 2;R1 is a group such as hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy and carbamoyl;each of R2 and R3 is hydrogen, halo, C1-6alkyl, C2-6alkenyl or C2-6alkynyl;R4 is a group such as hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, amino and N-C1-6alkylamino;R5 is a group such as hydrogen, halo, trifluoromethyl, cyano, nitro, amino and hydroxy, and q is 0 - 4;or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof;processes for its preparation, a pharmaceutical composition containing it and its use in the treatment of diseases or medical conditions mediated by cytokines.

Description

DERIVATIVES OF PYRIDINE AND PYRIMIDINE AND THEIR USE AS INHIBITORS OF A MEDIATED DISEASE BY CYTOKIN DESCRIPTION OF THE INVENTION This invention has to do with certain amide derivatives and their use as inhibitors of a cytokine-mediated disease. The invention also relates to the processes for the manufacture of novel amide derivatives, the pharmaceutical compositions containing them and their use in therapeutic methods, for example by virtue of the inhibition of a cytokine-mediated disease. The amide derivatives described in the present invention are inhibitors of the production of cytokines such as Tumor Necrosis Factor (hereinafter TNF), for example TNFa, and various members of the interleukin family (hereinafter IL), for example. IL-1, IL-6 and IL-8. Accordingly, the compounds of the invention will be useful in the treatment of diseases or medical conditions in which excessive cytokine production occurs, for example excessive production of TNFa or IL-1. It is known that cytokines are produced by a wide variety of cells such as monocytes and macrophages and that they give rise to a variety of physiological effects that are believed to be important in affective or medical conditions such as inflammation and immunoregulation. For example, TNFa and IL-1 have been implicated in the cell signaling cascade that is believed to contribute to the pathology of affective states such as inflammatory and allergic diseases and cytokine-induced toxicity. It is also known that, in some cellular systems, the production of TNFa precedes and mediates the production of other cytokines such as IL-1. Abnormal levels of cytokines have also been implicated in, for example, the production of physiologically active eicosanoids such as prostaglandins and leukotrienes, stimulation of the release of proteolytic enzymes such as collagenase, activation of the immune system, for example by stimulation of T helper cells, activation of osteoclast activity leading to calcium resorption, stimulation of proteoglycan release from, for example, cartilage, stimulation of cell proliferation and for angiogenesis. Cytokines are also believed to be involved in the production and development of affective states such as inflammatory and allergic diseases, for example inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease). , ulcerative colitis, Crohn's disease and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis, allergic rhinitis, respiratory distress syndrome in adult and chronic obstructive pulmonary disease), and in the production and development of various cardiovascular and cerebrovascular disorders such as congestive heart disease, myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, Alzheimer's disease, reperfusion injury, vascular injury that includes tenosis and peripheral vascular disease, and for example, various disorders of bone metabolism such as osteoporosis (which includes senile and postmenopausal osteoporosis), Paget's disease, bone metastasis, hypercalcemia, hyperparathyroidism, osteosclerosis, osteoporosis and periodontitis, and abnormal changes in the bone metabolism that may accompany rheumatoid arthritis and osteoarthritis. Excessive cytokine production has also been implicated in the mediation of some complications of bacterial, fungal and / or viral infections such as endotoxic shock, septic shock and toxic shock syndrome and in the mediation of some complications of CNS surgery or injury. such as neurotrauma and ischemic attack. Excessive cytokine production has also been implicated in the mediation or exacerbation of the development of diseases involving cartilage or muscle resorption., pulmonary fibrosis, cirrhosis, renal fibrosis, cachexia found in some chronic diseases such as malignant disease and acquired immunodeficiency syndrome (AIDS), tumor invasion and tumor metastasis and multiple sclerosis. Evidence of the central role played by TNFa in the cellular signal cascade that gives rise to rheumatoid arthritis is provided by the efficiency in clinical studies of TNFα antibodies (The Lancet, 1994, 344, 1125 and British Journal of Rheuology, 1995, 34, 334). Thus, cytokines such as TNFa and IL-1 are believed to be important mediators of a considerable range of diseases and medical conditions. Accordingly, it is expected that the inhibition of the production of and / or effects of these cytokines will be of benefit in the prophylaxis, control or treatment of such diseases and medical conditions. Without wishing to imply that the compounds described in the present invention possess pharmacological activity only by virtue of an effect of an individual biological process, it is believed that the compounds inhibit the effects of cytokines by virtue of the inhibition of the enzyme p38 kinase. The p38 kinase, otherwise known as cytokine suppressor binding protein (hereafter CSBP) and reactivating kinase (hereafter RK), is a member of the family of mitogen-activated protein kinase enzymes (from here hereinafter MAP) which are known to be activated by physiological stress such as that induced by ionizing radiation, cytotoxic agents, and toxins, for example endotoxins such as bacterial lipopolysaccharides and by a variety of agents such as cytokines, for example TNFa and IL- 1. It is known that p38 kinase phosphorylates some intracellular proteins that are involved in the cascade of enzymatic steps that leads to the biosynthesis and excretion of cytokines such as TNFa and IL-1. Known inhibitors of p38 kinase have been reviewed by G J Hanson in Expert Opinions on Terapeutic Patents, 1997, 7, 729-733. The p38 kinase is known to exist in isoforms identified as p38a and p38β. The compounds described in the present invention are inhibitors of the production of cytokines such as TNF, in particular of TNFa, and various interleukins, in particular IL-1. It is described in J. Medicinal Chemistry, 1995, 38, 3780-3788, that some 4-anilinopyrido [4, 3-d] pyrimidines are inhibitors of epidermal growth factor receptor tyrosine kinase activity. One of the compounds described therein is 7-amino-4- (3-acetamidoanilino) -pyrido [4, 3-d] pyrimidine. Accordingly, the present invention provides a bicyclic compound of Formula (I): wherein: G is N, CH or C (CN); Ring X is a 5 or 6 membered fused heteroaryl ring containing 1, 2 or 3 heteroatoms selected from oxygen, sulfur and nitrogen; m is 0, 1 or 2; R1 is hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulfamoyl, C6-6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C6_6 alkoxy, -O- ( C? -3) -O-alkyl of C? -6S (O) p- (where n is 0-2), N-alkylamino of C? -6, N, N- (Ci-e alkyl) ) 2-amino, Ci-e alkoxycarbonyl, N-alkylcarbamoyl of C? -6,? T,? T- (Ci-β) alkylcarbamoyl, C2_6 alkanoyl, C? _6 alkanoyloxy, C? -6 alkanoylamino, N-alkylsulfamoyl of C? -6, N, N- (C? _6 alkyl) 2-sulfamollo, C? -6 alkylsulfonylamino, C? - alkylsulfonyl- &N- (Ci-b) alkyl amino, or R1 is of the Formula (IA): A- (CH2) PB- (IA) wherein A is halo, hydroxy, Ci-e alkoxy, C? -6 S (0) n- alkyl (where n is 0 -2), cyano, amino, N-alkylamino of C? -6, N, N- (C? -6-alkyl) 2-amino, carboxy, C? _6-alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl of C? -6 or N, N- (C? _s) 2-carbamoyl alkyl, p is 1-6, and B is a bond, oxy, imino, N- (C? _6 alkyl) imino or -C (0)? H-, with the proviso that p is two or more unless B is a bond or -C (0)? H-, or R1 is of the Formula (IB): D-E- (IB) wherein D is aryl, heteroaryl or heterocyclyl and E is a bond, C6-6 alkylene, C6-6 alkyleneoxy, oxy, imino,? T- (alkyl) Ci-e) imino, C? -6 alkyleneimino, N- (C? -6) alkyl- C? -6-alkylene imino, C? -6 alkylene-C? -6 alkylene, C-alkylene imino? -6-Ci-e-alkylene, 7- (Ci-e-alkyl) -alkyleneimino-C-6-alkylene of C? -6, -C (0)? H-, -S02? H-, - ? HS02- or C2_6 alkanoylimino, and any aryl, heteroaryl or heterocyclyl group in a R1 group may be optionally substituted with one or more groups selected from hydroxy, halo, C6-6alkyl, C6-6alkoxy, carboxy, C6-6alkoxycarbonyl. , carbamoyl, N-alkylcarbamoyl of C? _6, N- (Ci-β) alkylcarbamoyl, C2-6 alkanoyl, amino, N-alkylamino of C? _6 and N, T- (C? -6 alkyl) 2-amino, and any heterocyclyl group in a R1 group can be optionally substituted with one or two oxo or thioxo substituents, and any of the R1 groups defined above comprising a CH2 group that is bonded to two carbon atoms or to a CH3 group that is attached to a carbon atom may optionally carry in each of the groups CH2 or CH3 a substituent selected from hydroxy, amino, C6-6 alkoxy, N-alkylamino of C6-6, N, N- ( C? _6) 2-amino and heterocyclyl; R2 is hydrogen, halo, C? _6 alkyl, alkenyl of C2_6 or C2-6 alkynyl / R3 is hydrogen, halo, C6_6 alkyl, C2_6 alkenyl or C2_6 alkynyl; R 4 is hydrogen, hydroxy, C?-6 alkyl, C?-6 alkoxy, amino, C?-6-N-alkylamino, N, N- (C?-6-alkyl) 2-amino, C 2-6 hydroxyalkoxy , C6-6 alkoxy, C2_6 alkoxy, C2-6 aminoalkoxy, C6-6 alkylamino, C2-6 alkoxy, N, N- (C6-6alkyl) 2-aminoalkoxy of C6-6 or C3_7 cycloalkyl, or R4 is of Formula (IC): -K-J (IC) wherein J is aryl, heteroaryl or heterocyclyl and K is a bond, oxy, imino, N- (Ci-β) -imino alkyl, C?-6-oxyalkylene, C?-6-iminoalkylene, N- (C?-6-alkyl) -iminoalkylene of C?-6, -? HC (O) -, -S02? H-, -? HS02- or -NHC (O) -alkylene of C? -6-, and any aryl, heteroaryl or heterocyclyl group in a group R4 can be optionally substituted by one or more groups selected from hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulfamoyl, C? -6 alkyl, C2-6 alkenyl, C? _6 alkynyl, C? _6, -0- (C? -3 alkyl) -0-, Ci-S (0) alkyl n- (where n is 0-2), N-alkylamino of C? -6, N, N- (C? -6) 2amino alkyl, C? _6 alkoxycarbonyl, C? -6 N-alkylcarbamoyl,? T, N- (Ci-e) alkylcarbamoyl, C? -6 alkanoyl, alkanoyloxy C? -6, C? -6 alkanoylamino,? -C6 alkylsulfamoyl,? 7,? 7, (C? _6 alkyl) 2-sulphamoyl, C? -6 alkylsulfonylamino, and Ci-.beta.-N-alkylsulfonyl - (C? _6) amino alkyl, or any aryl, heteroaryl or heterocyclyl in a group R4 can be optionally substituted with one or more groups of the Formula (IA '): (IA') wherein A1 is halo, hydroxy, C? -6 alkoxy, cyano, amino, N-alkylamino of C? _6, N, N- (C6_6 alkyl) 2-amino, carboxy, C6_6 alkoxycarbonyl, carbamoyl, C6_6-N-alkylcarbamoyl or N, N- (Ci_d) 2carbamoyl alkyl, p is 1-6, and B1 is a bond, oxy, imino, N- (alkyl of C? _6) imino or -? HC (0) -, with the proviso that p is 2 or more unless B1 is a bond or -? HC (0) -, or any aryl, heteroaryl or heterocyclyl group in a R4 group can be optionally substituted with one or more groups of the Formula (IB '): E ^ D1 (IB') wherein D1 is aryl, heteroaryl or heterocyclyl and E1 is a bond, C? _6 alkylene, C? -6 oxyalkylene, oxy, imino, N- (C? _6) imino alkyl, C? _6 iminoalkylene, N- (Ci-e alkyl) -iminoalkylene of C? -6, C? _6-oxyalkylene alkylene of C? -6, C? -6-ip? inoalkylene alkylene of Ci-e, alkylene of C? -6-N- (C? -6 alkyl) ) -iminoalkylene of Cj-6, -NHC (O) -, -NHS02-, -S02NH- or -NHC (O) -alkylene of C? _6-, and any aryl, heteroaryl or heterocyclyl group in a substituent on R4 can optionally substituted with one or more groups selected from hydroxy, halo, C? -6 alkyl, C? _6 alkoxy, carboxy, C? _6 alkoxycarbonyl, carbamoyl, C? -6 N-alkylcarbamoyl, N- ( e) 2-carbamoyl, C2-6 alkanoyl, amino, N-alkylamino of C6-6 and N, N- (C6-6 alkyl) 2-amino, and any cycloalkyl group of C3-7 or heterocyclyl in a group R4 may be optionally substituted with one or two oxo or thioxo substituents, and any of the R4 groups defined above that comprise a CH2 group which is attached to two carbon atoms or a CH3 group that binds to a carbon atom can optionally carry over each CH2 or CH3 group a substituent selected from hydroxy, amino, C6-6 alkoxy, N-alkylamino of C? -6, N, N- (C? -6-alkyl) 2-amino and heterocyclyl; R5 is hydrogen, halo, trifluoromethyl, cyano, nitro, amino, hydroxy, C? -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C? -6 alkoxy, C? -6 N-alkylamino or N, N- (C? _6) 2amino alkyl; q is O, 1, 2, 3 or 4; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof; with the proviso that 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d] pyrimidine is excluded. It is to be understood that the bicyclic ring within the compound of Formula (I) is shown with a hydrogen atom attached to the carbon between the α-atom. and group G to indicate that this position is not replaced. Accordingly, it will be understood that this hydrogen atom can not be replaced by a substituent R1. It should also be understood, however, that when G is a CH group, that CH group can carry any of the substituents R1. It should be understood that, with respect to some of the compounds of Formula (I) defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any racemic or optically active form which possesses the property of inhibiting cytokines, in particular TNF. Syntheses of the optically active forms can be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis of optically active starting materials or by resolution of a racemic form. Likewise, the inhibitory properties against TNF can be evaluated using the standard laboratory techniques referred to hereinafter. To avoid doubt, it should be understood that when, for example, R "1" is a group of Formula (IB): D-E- (IB) and the linking group E is, for example, an alkyleneoxy group of C ? _6 such as -CH2CH20-, is a CH2 group that binds to D and the O atom that binds to the bicyclic ring within Formula (I). Likewise when, for example, R4 is a group of Formula (IB '): -E ^ D1 (IB') and the linking group E1 is, for example, an iminoalkylene group of C? _6 such as -NHCH2CH2-, is a CH2 group that binds to D1 and the NH group that binds to the bicyclic ring within Formula (I). A similar convention applies to other bidentate linking groups.

In this specification the term "alkyl" includes straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific to the straight chain version only. For example, "CiV alkyl includes propyl, isopropyl, and t-butyl." However, references to individual alkyl groups such as "propyl" are specific to the straight chain version only and references to the alkyl chain groups individual branched such as 'isopropyl' are specific for the branched chain version only.An equal convention applies to other radicals, for example "C2-6 aminoalkoxy" includes 2-aminoethoxy, 2-aminopropoxy and 3-amino-2- Methylpropoxy The term "halo" refers to fluoro, chloro, bromo and I. The term "aryl" refers to phenyl or naphthyl When a group R4 involves a group D1 and D1 is aryl, that "aryl" refers to to phenyl, indenyl, indanyl, naphthyl, tetrahydronaphthyl or fluorenyl The term "heteroaryl" refers to, unless otherwise specified, a monocyclic, bicyclic or tricyclic ring of 5 to 14 members which is unsaturated or partially unsaturated, with one to five heteroatoms in the ring selected from nitrogen, oxygen and sulfur, wherein a -CH2- group can be optionally replaced by a -C (0) -, a nitrogen atom in the ring can optionally carry an alkyl group of C? _6 or a nitrogen atom in the ring and / or sulfur in the ring may optionally be oxidized to form N-oxide and / or the S-oxides. Examples of "heteroaryl" include thienyl, furyl, pyranyl, pyrrolyl, pyrazolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl-N-oxide, oxopyridyl, oxoquinolyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzimidazolyl, benzothiazolyl, quinolyl, N-methyloxoquinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl, cinolinolyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl, S, S-dioxodibenzothiophenyl, dibenzo-1,4-dioxinyl, phenoxythinyl, phenoxazinyl, dibenzothiinyl, phenothiazinyl, thiantrenyl, benzofuropyridyl, pyridoindolyl, acridinyl and phenanthridinyl. When a group R4 involves a group D1 and D1 is heteroaryl, this "heteroaryl" preferably refers to furyl, thienyl, pyrrolyl, pyrrolinyl, oxazolyl, isoxazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl. , pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl or xanthenyl, or benzo derivatives such as 2, 3-dihydrobenzofuranyl, 2, 3-dihydrobenzothienyl, indolinyl, isoindolinyl, chromanyl and isochromanyl, more preferably that "heteroaryl" refers to furyl, thienyl, 3-pyrrolinyl, isoxazolyl, thiazolyl, pyridyl, benzothienyl, benzofurazanyl, quinolyl, carbazolyl, dibenzofuranyl or dibenzothiophenyl. Ring X is a 5 or 6 membered fused heteroaryl ring containing 1, 2 or 3 heteroatoms selected from oxygen, sulfur and nitrogen. Suitably, the X ring is unsaturated or partially unsaturated wherein a -CH2- group can optionally be replaced by a -C (O) - a nitrogen atom in the ring can optionally carry a C? -6 alkyl group or an atom of nitrogen in the ring and / or sulfur in the ring can optionally be oxidized to form N-oxide and / or the S-oxides. Examples of suitable fused heteroaryl ring di-radicals include tiendiyl, furandiyl, imidazoldiyl, pyrazoldiyl, oxazoldiyl, isoxazoldiyl, thiazoldiyl, isothiazoldiyl, 1,2, 3-oxadiazoldiyl, 1,2,3-triazoldiyl, pyridindiyl, pyrimidindiyl, pyrazindiyl., pyridazindiyl and 1, 3, 4-triazindiyl. Examples of the mono-radical of suitable bicyclic rings formed by the fusion of the X-ring into the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) include furopyridyl, furopyrimidinyl, thienopyridyl, thienopyrimidinyl, pyrrolpyridyl, pyrrolpyrimidinyl, pyrrolinopyridyl , pirrolinopirimidinilo, oxopirrolino-pyridyl, oxopirrolinopirimidinilo, oxazolpiridilo, oxazolopyrimidinyl, oxazolinopiridilo, oxazolinopirimidinilo, oxooxazolinopiridilo, oxooxazolinopirimidinilo, isoxazol-pyridyl, isoxazolpirimidinilo, tiazolpiridilo, thiazolopyrimidinyl, tiazolinopiridilo, tiazolinopirimidinilo, oxotiazolinopiridilo, oxotiazolinopirimidinilo, isothiazol-pyridyl, isotiazolpirimidinilo, imidazolpiridilo, oxoimidazolinopiridilo imidazolinopiridilo, purinyl, imidazolinopyrimidinyl, oxoimidazolinopyrimidinyl, pyrazol-pyridyl, pyrazolpyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, oxopyrazolinopyridyl, oxopyrazolino-pyrimidinyl, ftiridinyl, pyridopyrimidinyl, pyrimido-pyrimidinyl and pteridinyl. The term "heterocyclyl" refers to, unless otherwise specified, a 3-14 membered mono or bicyclic ring, which is fully saturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulfur wherein a -CH2- group can optionally be replaced by a -C (0) - or a nitrogen atom in the ring can optionally carry an alkyl group of Ci-e. Examples of such heterocyclyls include morpholinyl, 7-methylmorpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, N-methylpiperidinyl, piperazinyl and quinuclidinyl. When a group R4 involves a group D1 and D1 is heterocyclyl, this "heterocyclyl" preferably refers to oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidoisothiazolidinyl, morpholinyl, tetrahydro-1, - thiazinyl, 1,1-dioxotetrahydro-l, 4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl, preferably for, azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, 1, l-dioxidoisothiazolidin-2 -yl, morpholino, 1, l-dioxotetrahydro-4H-l, 4-thiazin-4-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-1-yl, piperidino, piperazin-1-yl or homopiperazin -1-ilo. A suitable value for such a group having 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperi-dinyl, 2,5-dioxopyrrolidinyl, , 5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Where optional substituents are selected from "one or more" groups it can be understood that this definition includes all substituents being selected from one of the specified groups or substituents being selected from two or more of the specified groups. Conveniently there may be 1, 2 or 3 of such optional substituents. For example, where optional substituents are selected from one or more groups selected from halo, C? -6 alkoxy and C? -6 alkyl, examples of possible combinations of substituents include 1) a bromo group, 2) two chlorine groups, 3) a methoxy, ethoxy and propoxy substituent, 4) a fluoro and a methoxy group, 5) a methoxy group, a methyl group and an ethyl group, and 6) a chloro, a methoxy and an ethyl group. Examples of C? -4 alkyl include methyl, ethyl and isopropyl. Examples of C?-6 alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of C? -Salkoxy include C? -4 alkoxy and C2-4 alkoxy and include methoxy, ethoxy, propoxy and t-butoxy. Examples of C? -6 alkanoylamino include formamido, acetamido and propionylamino. Examples of C? -6S (0) n alkyl, wherein n is 0-2 and include methylthio, ethylthio, methylisulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl. Examples of C2-6 alkanoyl include propionyl and acetyl. Examples of N-alkylamino of C? -6 include N-methylamino and N-ethylamino. Examples of N, N- (C6_6 alkyl) 2-amino include N, N-dimethylamino, N, N-diethylamino and N-ethyl-N-methylamino.

Examples of C6-6 alkoxy C2-6 alkoxy include methoxyethoxy and propoxybutoxy. Examples of N- (C6-alkyl) aminoalkoxy of C2-6 include 3- (N-methylamino) propoxy and 4- (α-ethylamino) butoxy.

Examples of N, N- (C? -6-alkyl) 2-aminoalkoxy of C2-e include 2- (N, N-dimethylamino) ethoxy and 3- (N-methyl-N-ethylamino) propoxy. Examples of C3-7 cycloalkyl include cyclopropyl and cyclohexyl. Examples of C2_6 alkenyl include vinyl, allyl and 1-propenyl. Examples of C2-6 alkynyl include ethynyl, 1-propynyl and 2-propynyl. Examples of C2-6 hydroxyalkoxy include 2-hydroxyethoxy and 2-hydroxyproxy. Examples of C 1-6 alkylsulfonylamino include methanesulfonamido and ethanesulfonamido. Examples of C ?6-N- (C? -6) alkyl amino alkylsulfonyl include N-ethylmetanesulfonamido and N-butylethanesulfonamido. Examples of N- (C6-alkyl) sulfamoyl include N-methylsulfamoyl and N-ethylsulphamoyl. Examples of N, N- (C6_6 alkyl) 2-sulfamoyl include N, N-dimethylsulphamoyl and N-methyl-N-ethylsulphamoyl. Examples of N- (Ci-e alkyl) carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl. Examples of N, N- (C6_6) alkylcarbamoyl include N, N-dimethylcarbamoyl and N-methyl-N-ethylcarbamoyl. Examples of C 1-6 alkanoyloxy include propionyloxy, acetyloxy and formyloxy. Examples of -O-C ?3-0-alkyl include -toxyethoxy- and -oximetoxy- (ie, a bidentate substituent, attached to the ring at two adjacent positions). In linking groups B, E, B ±, E1 and K that fall within the definition of R1 and R4, examples of generic terms include the following. Examples of C? _6 alkylene include -CH2CH2- and -CH2CH (CH3) CH2-. Examples of C 1-6 alkyleneoxy include -CH 2 CH 20- and -CH 2 CH (CH 3) CH 20-. Examples of N- (Ci-β) -imino alkyl include -N (Me) - and -N ^ Pr) -. Examples of alkyleneimino of C? _s include -CH2CH2NH- and -CH2CH (CH3) CH2NH-. Examples of N- (Ci-β alkyl) -alkyleneimino of C? -6 include -CH2CH2? (Me) - and -CH2CH (CH3) CH2? ^ Pr) -. Examples of C2-6 alkanoylimino include -CH2CH2C (0)? H- and -CH2CH (CH3) CH2C (0)? H-. Examples of C? -6 oxyalkylene include -OCH2CH2- and -OCH2CH (CH3) CH2-. Examples of C? -6 iminoalkylene include -? HCH2CH2- and -? HCH2CH (CH3) CH2-. Examples of N- (C? _6 alkyl) iminoalkylene of C? -6 include -? (Me) CH2CH2- and -? (IPr) CH2CH (CH3) CH2-. Examples of -? HC (O) alkylene of C? -6- include -? HC (0) CH2CH2- and -? HC (0) CH2CH (CH3) CH2-. When, as defined above, any of the R1 or R4 groups defined above that comprise a CH2 group that is bonded to 2 carbon atoms or a CH3 group that is attached to a carbon atom may optionally carry in each of the groups CH2 or CH3 of a substituent selected from hydroxy, amino, C? -6 alkoxy, C? -6-N, C, -6-, N- (C? -6 alkyl) 2-amino and heterocyclyl, suitable substituents thus formed include, for example, substituted C? -6 heterocyclylalkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy, substituted C? -6 aminoalkoxy groups such as 3-amino-2-hydroxypropoxy groups N-alkylaminoalkoxy substituted C? -6-alkoxy C6-6 alkoxy such as 2-hydroxy-3-methylaminopropoxy, substituted N, N- (C1-β alkyl) 2-aminoalkoxy groups of C? -6 such as 3-dimethylamino- 2-hydroxypropoxy, 3- [N- (3-dimethylaminopropyl) -N-methylamino] propoxy and 3- [N- (3-dimethylaminopropyl) -N-methylamino] - 2-hydroxypropoxy, substituted C? -6 heterocyclylalkylamino groups such as 2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino, substituted C? -6 aminoalkylamino groups such as 3-amino-2-hydroxypropylamino, N groups -alkylamino of C? -6 substituted C? -6-alkylamino such as 2-hydroxy-3-methylaminopropylamino, substituted N, N- (C? -6 alkyl) 2-aminoalkylamino groups, such as 3-dimethylamino- 2-hydroxypropylamino, 3- [N- (3-dimethylamino-propyl) -N-methylamino] propylamino and 3- [N- (3-dimethylamino-propyl) -N-methylamino] -2-hydroxypropylamino, C N-6-substituted N-alkylamino groups of C ?_6 alkyl substituted such as 2-dimethylaminoethylaminomethyl, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2,2-dimethylpropylaminomethyl, 2-morpholinoethyl-aminomethyl, 2-piperazin-1-ylethylaminomethyl and 3-morpholino-propylaminomethyl. Preferably the values of R1, R2, R3, R4, R5, G, X, q and m are as follows. Preferably G is? or C (C?), more preferably G is? A preferred example of the di-radical of a fused heteroaryl ring suitable for the X-ring is thianediyl, furandiyl, imidazoldiyl, pyrazoldiyl, oxazoldiyl, thiazoldiyl, pyridindiyl, pyrimidindiyl or pyrazindiyl. A more preferred example of the di-radical of a fused heteroaryl ring suitable for the X-ring is thianediyl, thiazoldiyl, pyridindiyl or pyrazindiyl. A preferred example of the mono-radical of a suitable bicyclic ring formed by the fusion of the X ring to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is furopyrimidinyl, thienopyrimidinyl, pyrrolpyrimidinyl, pyrrolinopyrimidinyl, oxopyrrolinopyrimidinyl, oxazolpyrimidinyl , oxazolinopirimidinilo, oxooxazolinopirimidinilo, isoxazol-pyrimidinyl, thiazolopyrimidinyl, tiazolinopirimidinilo, oxotiazolinopirimidinilo, isotiazolpirimidinilo, purinyl, imidazolinopirimidinilo, oxoimidazolinopirimidinilo pyrazol-pyrimidinyl, pirazolinopirimidinilo, oxopirazolino-pyrimidinyl, pyridopyrimidinyl, pyrimidopyrimidinyl or pteridinyl. A more preferred example of the mono-radical of a suitable bicyclic ring formed by the fusion of the X-ring to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is furopyrimidinyl, thienopyrimidinyl, pyrrolpyrimidinyl, oxazolpyrimidinyl, thiazolopyrimidinyl, purinyl, pyridopyrimidinyl, pyrimidopyrimidinyl or pteridinyl. A further, more preferred example of the mono-radical of a suitable bicyclic ring formed by the fusion of the X-ring to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is furo [3,2-d] pyrimidinyl, furo [2,3-d] pyrimidinyl, thieno [3,2-d] pyrimidinyl, thieno [2,3-d] pyrimidinyl, pyrrol [3,2-d] pyrimidinyl, pyrrol [2,3-d] pyrimidinyl, oxazole [5,4-d] pyrimidinyl, oxazol [4, 5-d] pyrimidinyl, thiazole [5,4-d] pyrimidinyl, thiazol [4, 5-d] pyrimidinyl, purinyl, pyrido [2, 3-d] pyrimidinyl , pyrido [3,4-d] pyrimidinyl, pyrido [4, 3-d] pyrimidinyl, pyrido [3,2-d] pyrimidinyl, pyrimido [4,5-d] pyrimidinyl, pyrimido [5,6- d] pyrimidinyl or pteridinyl. A particular preferred example of the mono-radical of a suitable bicyclic ring formed by the fusion of the X-ring to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is 6-oxopyrrolino [2,3-d] pyrimidine- 4-yl, 6-oxopyrrolino [3,2-d] pyrimidin-4-yl, 2-oxooxazolino [5, 4-d] pyrimidin-7-yl, 2-oxothiazolino [5, 4-d] pyrimidin-7- ilo, 2-oxooxazolino [4, 5-d] pyrimidin-7-yl, 2-oxothiazolino [4, 5-d] pyrimidin-7-yl, 2-oxoimidazolino [4, 5-d] pyrimidin-7-yl, 3-oxopyrazolino [3,4-d] pyrimidin-4-yl or 3-oxopyrazolino [4, 3-d] pyrimidin-7-yl. Another more preferred example of the mono-radical of a suitable bicyclic ring formed by the fusion of the X ring to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is thieno [3,2-d] pyrimidinyl, thieno [ 2,3-d] pyrimidinyl, thiazole [5,4-d] pyrimidinyl, pyrido [2, 3-d] pyrimidinyl, pyrido [3,4-d] pyrimidinyl, pyrido [4, 3-d] irimidinyl, pyrido [ 3,2-d] pyrimidinyl or pteridinyl. Particularly, a more preferred example of the mono-radical of a suitable bicyclic ring formed by the fusion of the X-ring to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is thieno [3,2-d] pyrimidine- 4-yl, thieno [2,3-d] pyrimidin-4-yl, thiazol [5,4-d] pyrimidin-7-yl, pyrido [2, 3-d] pyrimidin-4-yl, pyrido [3, 4-d] pyrimidin-4-yl, pyrido [4, 3-d] pyrimidin-4-yl, pyrido [3,2-d] pyrimidin-4-yl or pteridin-4-yl. Preferably m is 0 or m is 1 or 2 and each R "1" is independently hydroxy, halo, C? -6 alkyl, C? -6 alkoxy, C? -6S alkyl (0) n- (where n is 0-2), N, N- (C? -6 alkyl) 2-aminoalkyl of C? -6, N, N- (Ci-e alkyl) 2-carbamoylalkoxy of C? -6, N, N- (C? _6 alkyl) 2? Aminoalkoxy of C? -6, C? -6S alkyl ( 0) 2-alkoxy, N, N- (Ci-e alkyl) 2 amino-N- (Ci-e alkyl) C 1-6 alkylamino, N, N- (C 6 alkyl) 2 amino alkylaminoalkyl of C ? -6, C? -6 heterocyclylalkyl, C? -6 heterocyclylkoxy, heterocyclyloxy, C? -6-C6-C6-heterocyclylalkylamino, or C? _6 heteroaryl-C1-C6-alkyl. Most preferably m is 0 or m is 1 and each R1 is independently hydroxy, halo, C6-6 alkyl, C6-6 alkoxy, C6-6S (0) n- alkyl (where n is 0- 2), N, N- (C? -6 alkyl) 2-aminoalkyl of C? -6, N, N- (Ci-d alkyl) 2-carbamoylalkoxy of C? -6, N, N- (C? _6 alkyl) ) C 2 -6-aminoalkoxy, C ?6S (0) 2-C alco-6 alkoxy, N, N- (Ci-β) alkyl 2-amino- N- (C?-6 alkyl) alkylamino C? _6, N, N- (Ci-e alkyl) 2-aminoalkylamino of C? -6-C? -6 alkyl, piperidin-1-ylalkyl of C? -6, homopiperidin-1-ylalkyl of C? -6 , N- (C? -6 alkyl) piperidin-1-ylalkyl of C? -6, N- ( Ci-β) homopiperidin-1-ylalkyl of C? -6, piperazin-1-ylalkyl of C? -6, 4-alkylpiperazine of C? -6-l-ylalkyl of C? -6, homopiperazinyl-1-ylalkyl of C? _6, 4-alkyl-homopiperazinyl of C? -6-l-ylalkyl of C? -6, pyrrolidinylalkoxy of C? -6, piperidinylalkoxy of C? -6, homopiperidinylalkoxy of C? -6, N- (C? -6) pyrrolidinylalkoxy of C? -6, N- (alkyl of Ci-β) piperidinylalkoxy of C? -6, N- (alkyl of Ci-ß) homopiperidinylalkoxy of C? -6, morpholinylalkoxy of C? -6, piperazinylalkoxy of Ci-β, N- (C? -6 alkyl) piperazinylalkoxy of C? -6, homopiperazinylalkoxy of C? -6, N- (Ci-d alkyl) C? -6 homopiperazinylalkoxy, pyrrolidinyloxy, N- (C? _6 alkyl) pyrrolidinyloxy, piperidinyloxy, N- (Ci-β alkyl) piperidinyloxy, homopiperidinyloxy, N- (C? 6) Homopiperidinyloxy, C? -6-C6-C6-alkyl, C6-6 thiazolylalkoxy or C6-6 pyridylalkoxy. Further more preferably m is 0 or m is 1 and each R1 is independently hydroxy, halo, C6-6 alkyl, C6e alkoxy, Ci-eS alkyl (0) n- (where n is 0-2) , N, N- (C? -6 alkyl) 2-aminoalkyl of C? -6, N, N- (C? -6 alkyl) 2-carbamoyloalkoxy of C? -6, N, N- (C? -6 alkyl) ) C 2 -6-aminoalkoxy, C?-C6-alkyl (0) 2-C alco-6-alkoxy, N, N- (C?-6-alkyl) 2-amino- N- (C?-6-alkyl) C? _6 alkylamino, N, N- (Ci-e alkyl) 2-aminoalkylamino of C? -6-C? -6 alkyl, piperazin-1-ylalkyl of C? -6, 4-alkylpiperazine of C? -6 -l-ilalkyl C? -6, homopiperazinyl-1-ylalkyl of C? -6, 4-alkylhomopiperazinyl of C? -6-l-ylalkyl of C? -6, pyrrolidinylalkoxy of C? _6, pipendylalkyloxy of C? -6, N- ( C? -6 alkyl) pyrrolidinylalkoxy of C? -6, N- (C? _6 alkyl) piperidinylalkoxy of C? -6, morpholinylalkoxy of C? _6, piperazinylalkoxy of C? -6, N- (C? -6) C? -6 piperazinylalkoxy, C? -6 homopiperazinylalkoxy, N- (C? _6 alkyl) C? -6 homopiperazinylalkoxy, pyrrolidinyloxy, piperidinyloxy, C? -6-C? pyridylalkoxy of C? _6. More particularly m is 0 or om is 1 and each R1 is independently methyl, methoxy, methylthio, methylisulfinyl, methylsulfonyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-diisopropylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy , 2-piperidinoethoxy, N-methylpiperidin-2-ylmethoxy, N-methylpiperidin-3-ylmethoxy, 2-pyrrolidin-1-ylethoxy, 2- (N-methylpyrrolidin-2-yl) ethoxy, N-methyl-5-oxopyrrolidin- 2-ylmethoxy, 3-pyrrolidin-1-ylpropoxy, 2- (2-oxoimidazolidin-1-yl) ethoxy, 2- (4-methylpiperazin-1-yl) ethoxy or 3-pyrid-3-ylpropoxy. In addition, more particularly m is 0 or m is 1 and each Rx is independently methyl, methoxy, methylthio, 2-diisopropylaminoethoxy, 3-diethylaminopropoxy, 3-morpholinopropoxy or 3-pyrrolidin-1-ylpropoxy. Even more particularly m is 0 or m is 1 and each R1 is independently methyl or methylthio. Preferably R2 is hydrogen, C? _6 alkyl or halo. Most preferably R2 is hydrogen, alkyl of C? - or halo. Particularly R2 is hydrogen, methyl, fluoro or chloro, more particularly methyl. Preferably R3 is hydrogen, C? -6 alkyl or halo. Most preferably R3 is hydrogen, alkyl of C? -4 or halo. Particularly R3 is hydrogen, methyl, fluoro or chloro, more particularly hydrogen. Preferably q is 0 or 1, more preferably q is 0. Preferably R4 is aryl or heteroaryl optionally substituted by one or more groups selected from halo, cyano, C? -6 alkyl, C? _6 alkoxy, N, N- (C? -6) 2-amino or heterocyclyl alkyl. More preferably R4 is aryl or heteroaryl optionally substituted by one or more groups selected from halo, cyano, C6_6alkyl, C6_6alkoxy, N, N- (C6_6 alkyl) 2amino, pyrrolidine -1-yl, piperidinyl, morpholino, piperazinyl, 4-alkyl-piperazine of C6- l-yl, homopiperazinyl-1-yl or 4-alkyl-homopiperazinyl of C6-6-1-yl. In addition, R 4 is preferably phenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidyl or pyridyl optionally substituted by one or two halo, trifluoromethyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, -0- (C 1-3 alkyl) -O-, N, N- (C? -4) 2-amino alkyl, C 1-6 alkanoylamino , C 1 -C 6 alkylsulfonyl (Cys alkyl) amino, phenyl (optionally substituted by one or two halo groups), furyl, azetidinyl, pyrrolidinyl, 3-pyrrolinyl, piperidino, homopiperidinyl, morpholino, piperazinyl, homopiperazinyl, N - (C? -6 alkyl) piperazinyl and N- (C? -6 alkyl) homopiperazinyl, or R4 is fluorenyl or dibenzofuranyl. Additionally most preferred R 4 is phenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidyl or pyridyl optionally substituted by one or two of halo, cyano, C? _4alkyl, C-4-4 alco alkoxy, N, N- (C alquilo-alkyl) -4) 2-amino, piperidinyl, morpholino or piperazinyl. Particularly R 4 is phenyl, furyl, isoxazolyl or pyridyl optionally substituted by one or more groups selected from fluoro, chloro, cyano, methyl, methoxy, N, N-dimethylamino or morpholino. Particularly in additional form R4 is phenyl, furyl, thienyl or pyridyl optionally substituted by one or two groups selected from fluoro, chloro, trifluoromethyl, cyano, methyl, methoxy, ethoxy, methylenedioxy, N, N-dimethylamino, acetamido, N- methylmetanesulfonamido, phenyl, 4-fluorophenyl, 4-chlorophenyl, furyl, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolin-1-yl, piperidino, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl. Particularly in additional form R4 is phenyl optionally substituted by one or two groups selected from fluoro, chloro, trifluoromethyl, cyano, methyl, methoxy, ethoxy, methylenedioxy, N, N-dimethylamino, acetamido, N-methylmethanesulfonamido, phenyl, 4- fluorophenyl, 4-chlorophenyl, 2-furyl, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolin-1-yl, piperidino, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1 ilo, 4-methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl. Particularly additionally R 4 is 1-fluorenyl or dibenzofuran-4-yl. More particularly R 4 is phenyl, 2-methylphenyl, 3- (N, N-dimethylamino) phenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-cyanophenyl, 3,4-dimethoxyphenyl, 3-morpholinophenyl, 2-furyl, 2-chloropyrid -5-yl, 2-morpholinopyrid-4-yl or isoxazol-5-yl. In a more particular way R4 is phenyl, 3-fluorophenyl, 4-cyanophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3- (N, N-dimethylamino) phenyl, 3-acetamidophenyl, 3- (4-fluorophenyl) phenyl, 3- (2-furyl) phenyl, 3-pyrrolidin-1-ylphenyl, 3-morpholinophenyl, 3-fluoro-5-pyrrolidin-1- ilphenyl, 3-fluoro-5-piperidinophenyl, 3-fluoro-5-morpholinophenyl or 3-morpholino-5-trifluoromethylphenyl. In a more particular way R4 is pyridyl optionally substituted by a group N, N-dimethylamino, N, N-diethylamino, pyrrolidin-1-yl, piperidino or morpholino. In a more particular way R4 is pyridyl optionally substituted by an N, N-dimethylamino, N, N-diethylamino, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolin-1-yl, piperidino, homopipendin-1- ilo, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl or 4-methylhomopiperazin-1-yl.

Even more particularly R 4 is 2-morpholinopyrid-4-yl. Preferably R.sup.4 is hydrogen or C? -6 alkoxy, more preferably C? -4 alkoxy, particularly hydrogen or methoxy. Preferably R5 is hydrogen. According to a preferred aspect of the invention, there is provided a compound of the Formula (I) wherein: the bicyclic ring formed by the fusion of the X-ring to the 6-membered heteroaryl ring containing adjacent nitrogen within the Formula (I) is furopyrimidinyl, thienopyrimidinyl, pyrrolpyrimidinyl, oxazolpyrimidinyl, thiazolopyrimidinyl, purinyl, pyridopyrimidinyl, pyrimidopyrimidinyl or pteridinyl; m is O or m is 1 and each R 1 is independently hydroxy, halo, C 6 alkyl, C 6 alkoxy, alkyl C? -6S (0) n- (where n is 0-2), N, N- (C? 6) 2-aminoalkyl of C? -6, N, N- (Ci-e alkyl) 2-carbamoylalkoxy of C? -6, N, N- (C? -6 alkyl) 2-aminoalkoxy of C? _6, alkyl Ci-eS ( O) C 2 -6 alkoxy, N, N (Ci-β alkyl) 2 amino-N- (C?-6 alkyl) C alqu-6 alkylamino, N, N- (alkyl) C? _6) 2-aminoalkylamino of C? -6-C? _6 alkyl, piperidin-1-ylalkyl of C? -6, homopiperidin-1-ylalkyl of Ci-e, N- (C? -6 alkyl) piperidin- 1-ylalkyl of C? -6, N- (Ci-e alkyl) homopiperidin-1-ylalkyl of C? _6, piperazin-1-ylalkyl of C? -6, 4-alkylpiperazine of C? -6-l- C] -6-alkyl, C6-6 homopiperazinyl-1-yl, C4-4-alkyl-homopiperazinyl, Ci-6-l-ylalkyl, C? -6 pyrrolidinylalkoxy, C? -6 piperidinylalkoxy, homopiperidinylalkoxy C? _6, N- (C? _6 alkyl) pyrrolidinylalkoxy of C? -6, N- (C? -6 alkyl) piperidinylalkoxy of C? -6, N- (Ci-e alkyl) homopiperidinylalkoxy of C? -6, C? -6 morpholinylalkoxy, C? _6 piperazinylalkoxy, N- (C? _6 alkyl) pi? Azinylalkoxy of C? -6, homopiperazinylalkoxy of C? -6, N- (Ci-e alkyl) homopiperazinylalkoxy C? -6, pyrrolidinyloxy, N- (C? -6 alkyl) pyrrolidinyloxy, piperidinyloxy, N- (C? -6 alkyl) piperidinyloxy, homopiperidinyloxy, N- (C? -6 alkyl) homopiperidinyloxy, morpholinylalkyl C6-C6-alkyl, C6-6 thiazolylalkoxy or Ci-e pyridylalkoxy; R 2 is hydrogen, C 4 alkyl or halo; R3 is hydrogen, C? _4 alkyl or halo; q is 0; R4 is phenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidyl or pyridyl optionally substituted by one or two of halo, trifluoromethyl, cyano, C? - alkyl, C? - alkoxy, -O- (C? -3 alkyl) ) -0-, N, N- (C? -4) 2amino alkyl, Ci-e alkanoylamino, C? -6 ~ N- (Ci-e alkyl) amino, phenyl (optionally substituted by one or two halo groups), furyl, azetidinyl, pyrrolidinyl, 3-pyrrolinyl, piperidino, homopiperidinyl, morpholino, piperazinyl, homopiperazinyl, N- (Ci-d alkyl) piperazinyl and N- (C6-6 alkyl) homopiperazinyl, or R4 is fluorenyl or dibenzofuranyl; and R5 is hydrogen; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. According to a further preferred aspect of the invention, there is provided a compound of the Formula (I) wherein: the bicyclic ring formed by the fusion of the X ring to the 6-membered heteroaryl ring containing adjacent nitrogen within the Formula (I) is furopyrimidinyl, thienopyrimidinyl, pyrrolpyrimidinyl, oxazolpyrimidinyl, thiazolopyrimidinyl, purinyl, pyridopyrimidinyl, pyrimidopyrimidinyl or pteridinyl; m is 0 or m is 1 and each R1 is independently hydroxy, halo, C6_6 alkyl, C6_6 alkoxy, C6_6S (0) n- alkyl (where n is 0-2), N , N- (C? -6-alkyl) 2-aminoalkyl of C? _6, N, N- (C? _6 alkyl) 2-carbamoylalkoxy of C? -6, N, N- (C? -6 alkyl) 2-aminoalkoxy of C ? -6, alkyl C? -6S (O) 2-C? -6 alkoxy, N, N (C? _6 alkyl) 2 amino- N- (C? _6 alkyl) C? -6 alkylamino, N , N- (Ci-e alkyl) 2-aminoalkylamino of C? -6-C? -6 alkyl, piperazin-1-ylalkyl of C? _6, 4-alkylpiperazine of C? -6-l-ylalkyl of C? -6, homopiperazinyl-1-ylalkyl of C? -6, 4-alkylhomopiperazinyl of C? -6-l-ylalkyl of C? -6, pyrrolidinylalkoxy of C? -6, piperidinylalkoxy of C? -6, N- (alkyl) of C6-6) pyrrolidinylalkoxy of C6-6, N- (C6-6 alkyl) piperidinylalkoxy of C6-6, C6-6 morpholinylalkoxy, C6-6 piperazinylalkoxy, N- C? _6) piperazinylalkoxy of C? _6, homopiperazinylalkoxy of Ci-e, N- (Ci-d alkyl) homopiperazinylalkoxy of C? -6, pyrrolidinyloxy, piperidinyloxy, morpholinylalkyl amino C? -6-C? -5 alkyl or Ci-e pyridylalkoxy; R 2 is hydrogen, C 1-4 alkyl or halo; R3 is hydrogen, C1-4 alkyl or halo; q is 0; R 4 is phenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidyl or pyridyl optionally substituted by one or two of halo, cyano, C 4 alkyl, C 1-4 alkoxy, N, N- (C 4 -4) alkyl 2-amino, piperidinyl, morpholino or piperazinyl; and R5 is hydrogen; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. In a more preferred aspect of the invention there is provided a compound of the Formula (I) wherein: the bicyclic ring formed by the ring X fusion to the 6-membered heteroaryl ring containing adjacent nitrogen within the Formula (I) is furo [3, 2-d] pyrimidinyl, furo [2, 3-d] pyrimidinyl, thieno [3,2-d] pyrimidinyl, thieno [2,3-d] pyrimidinyl, pyrrol [3,2-d] pyrimidinyl , pyrrole [2, 3-d] pyrimidinyl, oxazole [5,4-d] pyrimidinyl, oxazole [4, 5-d] pyrimidinyl, thiazole [5,4-d] pyrimidinyl, thiazole [4, 5-d] pyrimidinyl] , purinyl, pyrido [2, 3-d] pyrimidinyl, pyrido [3,4-d] pyrimidinyl, pyrido [4, 3-d] pyrimidinyl, pyrido [3,2-d] pyrimidinyl, pyrimido [4,5-d] ] pyrimidinyl, pyrimido [5,6-d] pyrimidinyl or pteridinyl; is O or m is 1 and each R 1 is independently methyl, methoxy, methylthio, 2-diisopropylaminoethoxy, 3-diethylaminopropoxy, 3-morpholinopropoxy or 3-pyrrolidin-1-ylpropoxy; R2 is hydrogen, methyl, fluoro or chloro; R3 is hydrogen; q is 0; R 4 is phenyl optionally substituted by one or two groups selected from fluoro, chloro, trifluoromethyl, cyano, methyl, methoxy, ethoxy, methylenedioxy, N, N-dimethylamino, acetamido, N-methylmethanesulfonamido, phenyl, 4-fluorophenyl, 4- chlorophenyl, 2-furyl, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolin-1-yl, piperidino, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4- methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl, or R 4 is pyridyl optionally a group substituted by N, N-dimethylamino, N, N-diethylamino, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolin -l-yl, piperidino, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl or 4-methylhomopiperazin-1-yl, or R 4 is 1-fluorenyl or dibenzofuran-4-yl; and R5 is hydrogen; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. In a more preferred aspect of the invention there is provided a compound of Formula (I) wherein: the bicyclic ring formed by the ring X fusion to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is furo [3,2-d] pyrimidinyl, furo [2, 3-d] pyrimidinyl, thieno [3,2-d] pyrimidinyl, thieno [2,3-d] pyrimidinyl, pyrrol [3,2-d] pyrimidinyl, pyrrole [2, 3-d] pyrimidinyl, oxazole [5,4-d] pyrimidinyl, oxazole [4,5-dlpyrimidinyl, thiazole [5,4-d] pyrimidinyl, thiazole [4,5-d] irimidinyl, purinyl, pyrid [2,3-d] pyrimidinyl, pyrido [3,4-d] pyrimidinyl, pyrido- [4, 3-d] pyrimidinyl, pyrido [3,2-d] pyrimidinyl, pyrimido [4, 5-d] pyrimidinyl, pyrimido [5, 6-d] pyrimidinyl or pteridinyl; m is 0 or m is 1 and each R 1 is independently methyl, methoxy, methylthio, 2-diisopropylaminoethoxy, 3-diethylaminopropoxy, 3-morpholinopropoxy or 3-pyrrolidin-1-ylpropoxy; R2 is hydrogen, methyl, fluoro or chloro; R3 is hydrogen; q is 0; R 4 is pyridyl optionally substituted by a group N, N-dimethylamino, N, N-diethylamino, pyrrolidin-1-yl, piperidino or morpholino; and R5 is hydrogen; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. In one aspect of the invention there is provided a compound of Formula (I) wherein: the bicyclic ring formed by the fusion of ring X to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is thien [3 , 2-d] pyrimidin-4-yl, thieno [2,3-d] pyrimidin-4-yl, thiazole [5,4-d] pyrimidin-7-yl, 6-purinyl, pyrido [2, 3-d] ] pyrimidin-4-yl, pyrido [3,4-d] pyrimidin-4-yl, pyrido [4, 3-d] pyrimidin-4-yl, pyrido [3,2-d] pyrimidin-4-yl or pteridin -4-ilo; m is 0 or m is 1 and R1 is methyl or methylthio; R2 is methyl; R3 is hydrogen; q is 0; R 4 is phenyl, 3-fluorophenyl, 4-cyanophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3- (N, N-dimethylamino) phenyl, 3-acetamidophenyl, 3- (4-fluorophenyl) phenyl, 3- (2-furyl) phenyl, 3-pyrrolidin-1-ylphenyl, 3-morpholinophenyl, 3-fluoro-5-pyrrolidin-1-ylphenyl, 3- fluoro-5-piperidinophenyl, 3-fluoro-5-morpholiniphenyl or 3-morpholino-5-trifluoromethylphenyl, or R4 is 2-morpholinipyrid-4-yl, or R4 is 1-fluorenyl or dibenzofuran-4-yl; and R5 is hydrogen; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. In a more preferred aspect of the invention there is provided a compound of Formula (I) wherein: the bicyclic ring formed by the ring X fusion to the adjacent nitrogen-containing 6-membered heteroaryl ring within Formula (I) is thieno [3,2-d] pyrimidin-4-yl, thieno [2,3-d] pyrimidin-4-yl, thiazol [5,4-d] pyrimidin-7-yl, pyrido [2,3-d] pyrimidine -4-yl, pyrido [3,4-d] pyrimidin-4-yl, pyrido [4, 3-d] pyrimidin-4-yl, pyrido [3,2-d] pyrimidin-4-yl or pteridin-4 -ilo; m is 0 or m is 1 and R1 is methyl or methylthio; R2 is methyl; R3 is hydrogen; q is 0; R 4 is 2-morpholinopyrid-4-yl; and R5 is hydrogen; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. Preferred compounds of the invention are those of Examples 1-3 or pharmaceutically acceptable salts or an in vivo cleavable ester thereof. An especially preferred compound of the invention is, for example, a compound of Formula (I) selected from: - 4- [2-methyl-5- (2-morpholinopyridine-4-carboxamido) -anilino] thieno [3 , 2-d] pyrimidine, 4- [2-methyl-5- (2-morpholinopyridin-4-carboxamido) anilino] irido [4, 3-d] pyrimidine, 4- [2-methyl-5- (2 -morpholinopyridine-4-carboxamido) anilino] pteridine and 6- [2-methyl-5- (2-morpholinopyridine-4-carboxamido) anilino] -purine; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. A suitable pharmaceutically acceptable salt of a compound of Formula (I) is, for example, an acid addition salt of a compound of Formula (I) which is sufficiently basic, for example an acid addition salt with an inorganic acid or organic such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric, or maleic acid; or, for example, a salt of a compound of the formula (I) which is sufficiently acidic, for example an alkali metal or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Idder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5"Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al. , Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al. , Chem Pharm Bull, 32, 692 (1984). Examples of such prodrugs can be used to form in vivo cleavable esters of a compound of Formula (I). An in vivo cleavable ester of a compound of the Formula (I) which contains a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the acid of origin. Pharmaceutically acceptable esters suitable for carboxy include alkoxymethyl esters of C? -6, for example methoxymethyl; alkanoyloxymethyl esters of C? _6, for example pivaloyloxymethyl; phthalidyl esters; C3-8 cycloalkoxycarbonyloxy esters of C? -6 alkyl, for example 1-cyclohexylcabonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters, for example 5-methyl-l, 3-dioxolan-2-ylmethyl; and alkoxycarbonyloxyethyl esters of C? -6, for example 1-methoxycarbonyloxyethyl; and they can be formed in any carboxy group in the compounds of this invention. To use a compound of Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof, for the therapeutic treatment (including prophylactic treatment) of mammals including humans, they are usually formulated in accordance with the practice Pharmaceutical standard as a pharmaceutical composition. According to this aspect of the invention there is provided a pharmaceutical composition comprising a bicyclic compound of the Formula (I), or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, as defined above in association with a pharmaceutically acceptable diluent or carrier. acceptable. The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, powders or dispersible granules, syrups or elixirs), for local use (for example as creams, ointments, gels or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example, as a sterile aqueous or oily solution for intravenous dosing) , subcutaneous, intramuscular or intramuscular as a suppository for rectal dosing). The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, the compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid.; binding agents such as starch, lubricating agents such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate, and antioxidants, such as ascorbic acid. The tablet formulations may be uncoated or coated to modify their disintegration and subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and / or appearance, in any case, using conventional coating agents and well-known procedures in The technique. Compositions for oral use may be in the form of hard gelatine capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin or as soft gelatine capsules in which The active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in finely pulverized form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and acacia gum; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate) or condensation product of ethylene oxide, with long-chain aliphatic alcohols, for example heptadecaethylene oxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example monooleate polyethylenesorbitan. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, antioxidants (such as ascorbic acid), coloring agents, flavoring agents, and / or sweetening agents (such as sucrose, saccharin, or aspartame). The oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). may contain a thickening agent such as beeswax, hard wax, or cetyl alcohol, Sweetening agents such as those noted above, and flavoring agents may also be added to provide a pleasant oral preparation.These compositions may be preserved by the addition of such an antioxidant. as ascorbic acid, powders and dispersible granules suitable for the preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as, for example, liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally occurring gums, such as acacia gum or tragacanth gum, naturally occurring phosphatides such as soy, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides ( for example sorbitan monooleate) and condensation products of the partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. The syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain an emollient, preservative, flavoring and / or coloring agent.

The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Suppository formulations can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. Local formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, can generally be obtained by formulating an active ingredient with a conventional locally acceptable vehicle or diluent using conventional procedures well known in the art. The compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 μm or much less, the powder itself comprising the active ingredient alone or diluted with one or more carriers physiologically acceptable such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, one to 50 mg of active ingredient for use with a turbo inhaler device, such as is used for insufflation of the known agent sodium cromoglycate. The compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to distribute the active ingredient as an aerosol containing finely divided solid or droplets of liquid. Conventional aerosol propellants such as hydrocarbons or volatile fluorinated hydrocarbons can be used and the aerosol device is conveniently arranged to deliver a measured amount of the active ingredient. For additional information on the Formulation, refer to the reading of Chapter 25.2 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990. The amount of an active ingredient that is combined with one or more excipients for producing an individual dosage form will necessarily vary depending on the host treated and the particular route of administration.

For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 2 g of the active agent compound with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For additional information on Administration Routes and Dosage Regimens, refer to the reading of Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch, Chairman of Editorial Borad), Pergamon Press 1990. The size of the dose for therapeutic purposes or prophylactics of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, in accordance with well-known principles of medicine. To use a compound of Formula (I) for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range of, for example, 0.5 mg to 75 mg per kg of body weight, preferably 0.5 mg, is received. at 40 mg per kg of body weight, administered if required in divided doses. In general, lower doses will be administered when a parenteral route is used. A) Yes, for example, for intravenous administration, a dose in the range of, for example, 0.5 mg to 30 mg per kg of body weight will generally be used. Similarly, for administration by inhalation, a dose in the range of, for example, 0.5 mg to 25 mg per kg of body weight will be used. However, oral administration is preferred. Particularly in the form of tablets. Typically, the unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. The compounds of this invention can be used in combination with other drugs and therapies used in the treatment of affective states that would benefit from the inhibition of cytokines, in particular TNF and IL-1. For example, the compounds of Formula (I) could be used in combination with drugs and therapies used in the treatment of rheumatoid arthritis, asthma, irritable bowel disease, multiple sclerosis, AIDS, septic shock, ischemic heart disease, psoriasis and others. affective states mentioned earlier in this specification. For example, by virtue of their ability to inhibit cytokines, the compounds of Formula (I) are of value in the treatment of some inflammatory and non-inflammatory diseases that are currently treated with a non-steroidal anti-inflammatory drug cyclooxygenase inhibitor (NSAID). ) such as indomethacin, ketorolac, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxican. Co-administration of a compound of Formula (I) with an NSAID can result in a reduction in the amount of the last agent needed to produce a therapeutic effect. As a result, the likelihood of adverse side effects of the NSAID such as gastrointestinal effects is reduced. Thus according to a further feature of the invention there is provided a pharmaceutical composition comprising a compound of the Formula (I) or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, together with or prepared with a non-steroidal anti-inflammatory agent inhibiting cyclooxygenase , and a pharmaceutically acceptable diluent or carrier. The compounds of the invention can also be used with anti-inflammatory agents, such as an inhibitor of the enzyme 5-lipoxygenase (such as those described in European Patent Applications Nos. 0351194, 0375368, 0375404, 0375452, 0375457, 0381375, 0385662 , 0385663, 0385679, 0385680). The compounds of Formula (I) can also be used in the treatment of conditions such as rheumatoid arthritis in combination with anti-arthritic agents such as gold, methotrexate, steroids and penicillinamine, and under conditions such as osteoarthritis in combination with steroids. The compounds of the present invention can also be administered in degradative diseases, for example osteoarthritis, with chondroprotective, anti-degradative and / or reparative agents such as Diacerhein, hyaluronic acid formulations such as Hyalan, Rumalon, Arteparon and glucosamine salts such as Antril. . The compounds of Formula (I) can be used in the treatment of asthma in combination with antiasthmatic agents such as bronchodilators and leukotriene antagonists. If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agents within their approved dosage range. Sequential use is contemplated when the combination formulation is inappropriate. Although the compounds of Formula (I) are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful where required to inhibit the effects of cytokines. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. According to a further aspect of the present invention, a process is provided for preparing a compound of Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof, whose process (wherein G, R1, R2, R3, R4, R °, ring X , m and q are as defined for Formula (I) unless otherwise indicated) comprises: a) reacting an aniline of Formula (II): with an acyl compound of Formula (III): wherein L is a displaceable group as defined below; b) reacting an activated bicyclic heteroaryl ring of the Formula (IV): wherein L is a displaceable group as defined below, with an aniline of the Formula (V): or c) for the preparation of a compound of the formula (I) wherein R 1 or a substituent on R 4 is C? -6 alkoxy or substituted C? -6 alkoxy, Ci-eS- alkyl, C-N-alkylamino ? -6, N, N- (C? -6) 2amino alkyl or substituted C? -6 alkylamino, the alkylation, conveniently in the presence of a suitable base as defined below, of a compound of the Formula (I) ) wherein R1 or a substituent on R4 is hydroxy, mercapto or amino as appropriate; and after that if necessary: i) converting a compound of the Formula (I) to another compound of the Formula (I); ii) eliminate any protective groups; and iii) forming a pharmaceutically acceptable salt or ester cleavable in vivo. The specific reaction conditions for the variants of the above process are as follows: For process variant a) A suitable displaceable group L is, for example, a halogen, an activated phenoxy group or a sulfonyloxy group, for example a chlorine , bromine, pentafluorophenoxy or methanesulphonyloxy or toluene-4-sulfonyloxy group. Especially the preferred displaceable groups are chloro and pentafluorophenoxy. The anilines of the Formula (II) and the acyl compounds of the Formula (III) can be reacted together in a suitable inert solvent or diluent, for example dichloromethane, acetonitrile, butanol, tetramethylsulphone, tetrahydrofuran, 1,2-dimethoxyethane, N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidin-2-one, optionally in the presence of a base such as an alkali metal or alkaline earth metal carbonate, alkoxide or hydroxide, for example sodium carbonate or potassium carbonate, or , such as, an organic amine base, for example, pindine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo [5.4.0] undec-7-ene, and at a temperature in the range of, for example, 0 ° to 50 ° C, conveniently at or near room temperature. The anilines of Formula (II) can be prepared according to the following scheme: Q is -NH2 or, if R2 and R3 are not identical and a specific stereo reaction is desired, Q can be amino protected by a suitable protecting group (such as those defined later) or nitro. After the above reaction, the protecting group is removed, or the nitro group is reduced (for example with iron powder and acetic acid) to generate an aniline of the Formula (II). The activated heteroaryls of the Formula (IV) are known compounds, are commercially available or are prepared by processes known in the art. For example, where L is chloro or pentafluorophenoxy, compounds of Formula (IV) can be prepared by the following scheme: (1VC) For process variant b) A suitable displaceable L group as defined above. The activated heteroaryl of the formula (IV) and anilines of the formula (V) can be reacted together in the presence of a protic solvent, for example, isopropanol, in the presence of an acid, for example hydrogen chloride gas in ether diethyl, or hydrochloric acid, and at a temperature in the range of, for example, 0 ° to 150 ° C, conveniently at or near reflux. The anilines of Formula (V) are known compounds, are commercially available, or are made by processes known in the art. For example, the anilines of Formula (V) can be prepared according to the following scheme: (VA) (VB) where Q is as defined above. The compounds of the formulas (IIB), (III), (VA) and (VB) are known compounds, are commercially available or are prepared by processes known in the art. For variant c) of the process A suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy in alkoxy or substituted alkoxy, or for the alkylation of mercapto in alkylthio, or for the alkylation of amino in alkylamino or substituted alkylamino, for example an alkyl or alkyl halide substituted, for example a C? -6 alkyl chloride, bromide or iodide or substituted C? -6 alkyl chloride, bromide or iodide, in the presence of a suitable base as defined below, in an inert solvent or diluent adequate as defined above for variant a) of the process. A suitable base is, for example, an alkali metal or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, hydride sodium or potassium hydride, or an organometallic base such as an alkyl lithium, for example n-butyllithium, or a dialkylamino lithium, for example di-isopropylamide-lithium, or, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo [5.4.0] undec-7-ene. The reaction is conveniently carried out at a temperature in the range of, for example, 10 to 150 ° C, preferably in the range of 20 to 80 ° C.

Any necessary protecting groups can generally be selected from any of the groups described in the literature or known to the skilled chemist as is appropriate for the protection of the group in question and can be introduced by conventional methods. The protecting groups can be removed by any convenient method as described in the literature or known to the skilled chemist as is appropriate for the removal of the protective group in question, such methods being selected in such a way as to effect removal of the protecting group with minimal disturbance. of the groups in another part of the molecule. Specific examples of protecting groups are given subsequently for reasons of convenience in which "lower", as in, for example, lower alkyl, means that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods are given for the removal of protecting groups that are given subsequently are equally non-exhaustive. The use of protective agents and methods for deprotection not specifically mentioned are, of course, within the scope of the invention. A carboxy protecting group may be the residue of an aliphatic or arylaliphatic alcohol which forms ester or of a lower one (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); lower alkoxycarbonyl groups (for example benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); trialkylsilyl lower (for example trimethylsilyl, tert-butyldimethylsilyl) and aryl lower alkyl groups (for example benzyl). Examples of protective amino groups include formyl, aralkyl groups (for example benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); lower arylalkoxycarbonyl groups (for example benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl) alkylidene (for example methylidene), substituted benzylidene and benzylidene groups. of hydroxy and amino protecting groups include, for example, acid, basic, metallic, or enzymatically catalyzed hydrolysis for groups such as p-nitrobenzyloxycarbonyl, ester forming silanol (preferably containing 1-20 carbon atoms or silanol). carboxy protecting groups include straight or branched chain C? _?? alkyl groups (eg, isopropyl, tert-butyl), lower alkoxy-lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl), lower aliphatic acyloxy-lower alkyl groups , (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl, piva loyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); lower arylalkyl groups (for example benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri (lower alkyl) silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); tri (lower alkyl) silyl-lower alkyl groups (for example trimethylsilylethyl); and alkenyl groups of C? _6 (for example allyl and vinylethyl). Particularly suitable methods for the removal of carboxyl protecting groups include for example acid, basic, metallic or enzymatically catalyzed hydrolysis. Examples of hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); alkanoyl groups hydrogenation for groups such as benzyl and photolytically for groups such as o-nitrobenzyloxycarbonyl. Reference is made to the reading of Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & amp; amp;; Sons 1992, for general guidance on reaction conditions and reagents. Reference is made to the reading of Protective Groups in Oganic Synthesis, 2nd Edition, by Green et al. , published by John Wiley & Sons for general guidance on protective groups. According to a further aspect of the present invention there is provided a bicyclic compound of the Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof as defined above, for use in a method for treating the human body or animal for therapy. In a further aspect of the present invention there is provided a bicyclic compound of the Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof as defined above, for use as a medicament. In a further aspect, the present invention provides the use of a bicyclic compound of the Formula(I), or a pharmaceutically acceptable salt or in vivo cleavable ester thereof as defined above, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d] pyrimidine in the manufacture of a drug for use in the treatment of diseases or medical conditions mediated by cytokines. In a further aspect the present invention provides a method for treating diseases or medical conditions mediated by cytokines which comprises administering to a warm-blooded animal an effective amount of a bicyclic compound of the Formula (I) or a pharmaceutically acceptable salt or an unfolding ester. in vivo thereof as defined above, or of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d] pyrimidine. In a further aspect, the present invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof as defined above, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d] pyrimidine in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by TNF, IL-1, IL-6 or IL-8. In a further aspect, the present invention provides a method for treating diseases or medical conditions mediated by TNF, IL-1, IL-6 or IL-8 which comprises administering to a warm-blooded animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof as defined above, or of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d] pyrimidine. In a further aspect, the present invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof as defined above, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4,3-d] pyrimidine in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by TNF. In a further aspect, the present invention provides a method for treating diseases or medical conditions mediated by TNF which comprises administering to a warm-blooded animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt or an ester in vivo cleavable thereof as defined above, or the compound 7-amino-4- (3-acetamidoanilino) pyrido [4-3d] pyrimidine. In a further aspect the present invention provides the use of a compound of the Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof as defined above, or the use of the 7-amino-4- ( 3-acetamidoanilino) pyrido [4, 3-d] pyrimidine in the manufacture of a medicament for use in the inhibition of TNF, IL-1, IL-6 or IL-8. In a further aspect, the present invention provides a method for inhibiting TNF, IL-1, IL-6 or IL-8 comprising administering to a warm-blooded animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof as defined above, or of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d] pyrimidine. In a further aspect, the present invention provides the use of a compound of the Formula (I), or a pharmaceutically acceptable salt or a cleavable ester thereof in vi thereof as defined above, or the use of the compound 7-amino-4 - (3-acetamidoanilino) pyrido [4, 3-d] pyrimidine in the manufacture of a medicament for use in inhibiting TNF. In a further aspect, the present invention provides a method for inhibiting TNF which comprises administering to a warm-blooded animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or in vivo cleavable ester thereof as was defined above, or of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4-3d] pyrimidine. In an additional aspect, the present invention provides the use of a compound of the Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof as defined above, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d] pyrimidine in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by p38 kinase. In a further aspect, the present invention provides a method for treating diseases or medical conditions mediated by p38 kinase which comprises administering to a warm-blooded animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof as defined above, or of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4-3d] pyrimidine. In a further aspect, the present invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof as defined above, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d] pyrimidine in the manufacture of a medicament for use in the production of an inhibitory effect of p38 kinase. In a further aspect the present invention provides a method for providing an inhibitory effect of p38 kinase which comprises administering to a warm-blooded animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a splittable ester in alive thereof as defined above, or of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d] pyrimidine. In a further aspect, the present invention provides the use of a compound of the Formula (I), or a pharmaceutically acceptable salt or a cleavable ester thereof in vi thereof as defined above, or the use of the compound 7-amino-4 - (3-acetamidoanilino) pyrido [4,3-d] pyrimidine in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, asthma, irritable bowel disease, multiple sclerosis, AIDS, septic shock, ischemic heart disease or psoriasis. The following biological tests and Examples serve to illustrate the present invention. Biological Tests The following tests can be used to measure the inhibitory effects of p38 kinase, TNF inhibitors and anti-arthritic compounds of the present invention: Enzyme test in vitro The ability of the compounds of the invention to inhibit the p38 enzyme was assessed kinase The activity of the particular test compounds against each of the p38a and p38β isoforms of the enzyme was determined.

Human recombinant MKK6 (Accession number GenBank G1209672) was isolated from the clone of Image 45578 (Genomics, 1996, 33, 151) and used to produce protein in the form of a GST fused protein in a pGEX vector using procedures analogous to those described by J. Han et al. , Journal of Biological Chemistry, 1996, 271, 2886-2891. P38a (GenBank Accession Number G529039) and p38β (GenBank Accession Number G1469305) were isolated by PCR amplification of human lymphoblastoid cDNA (GenBank accession number GM1416) and human fetal brain cDNA [synthesized from mRNA (Clontech, Catalog No. 6525-1) using a Gibco writing cDNA synthesis kit respectively using oligonucleotides designed for the 5 'and 3' ends of the human p38a and p38β genes using methods analogous to those described by J. Han et al. ., Biochimica et Biophysica Acta, 1995, 1265, 224-227 and Y. Jiang et al., Journal of Biological Chemistry, 1996, 271, 17920-17926. Both isoforms of the p38 protein were expressed in e coli in PET vectors. Recombinant human p38a and p38ß isorfornas were produced as proteins labeled 6His, 5 'c-myc. Both MKK6 and p38 proteins were purified using standard protocols: GST MKK6 was purified using a glutathione sepharose column and p38 proteins were purified using nickel chelated columns.

The p38 enzymes were activated before use by incubation with MKK6 for 3 hours at 30 ° C. MKK6 expressed non-activated coli retained sufficient activity to fully activate both isoforms of p38. The activation incubation comprises p38a (lOμl of lOmg / ml) or p38β (lOμl of 5mg / ml) together with MKK6 (lOμl of lmg / ml), 'kinase regulator * [lOOμl; pH 7.4 regulator comprising Tris (50mM), EGTA (0.1mM), sodium orthovanadate (0.1mM) and β-mercaptoethanol (0.1%)] and MgATP (30μl of 50mM Mg (0C0CH3) 2 and 0.5mM ATP). This produces enough p38 enzyme activated for 3 microtiter plates. The test compounds were solubilized in DMSO and lOμl of a sample diluted 1:10 in a 'kinase regulator' were added to a well in a microtiter plate. For the individual dose test, the compounds were tested at 10 μM. 'Kinase Test Mix' [30μl; which comprises Protein Basic Myelin (Gibco BRL catalog No. 1322B-010, one ml of a 3.33 mg / ml solution in water), activated p38 enzyme (50μl) and 'Kinase Regulator' (2ml)] was then added followed by 'ATP Marked1 [lOμl; comprising 50μM ATP, 0.1μCi33P ATP (Amersham International catalog No. BFIOOO) and 50mM Mg (OCOCH3) 2]. Plates were incubated at room temperature with gentle shaking. The plates containing p38a were incubated for 90 minutes and the plates containing p38β were incubated for 45 minutes. Incubation was stopped by the addition of 50μl of 20% trichloroacetic acid TCA). The precipitated protein was phosphorylated by p38 kinase and the test compounds were assessed for their ability to inhibit this phosphorylation. The plates were filtered using a Canberra Packard Unifilter and washed with 2% TCA, dried overnight and counted on a Top Count scintillation counter. The test compounds were initially tested at a single dose and the active compounds were retested to allow IC5 values to be determined. In vitro tests based on cells (i) PBMC The ability of the compounds of this invention to inhibit the production of TNFα was assessed using human peripheral blood mononuclear cells that synthesize and secrete TNFα when stimulated with lipopolysaccharide. Peripheral blood mononuclear cells (PBMC) were isolated from heparinized human blood (10 units / ml heparin) by density centrifugation (Lymphoprep ™, Nycomed). The mononuclear cells were resuspended in a culture medium [RPMI 1640 medium (Gibco) supplemented with 50 units / ml of penicillin, 50μg / ml streptomycin, 2mM glutamine and 1% heat-inactivated human AB serum (Sigma H-1513)]. The compounds were solubilized in DMSO at a concentration of 50mM, were diluted in a 1: 100 culture medium and subsequently serial dilutions were made in a culture medium containing 1% DMSO. The PBMCs (2.4xl05 cells in 160μl of culture medium). They were incubated with 20μl of various concentrations of test compound (cultures in triplicate) or 20μl of a culture medium containing 1% DMSO (control well) for 30 minutes at 37 ° C in a humidified incubator (5% C02 / 95% air) (Falcon 3072; 96 well flat bottom tissue culture plates). 20 μl of lipopolysaccharide [LPS E. Coli 0111.B4 (Sigma L-4130), final concentration of 10 μg / ml] solubilized in a culture medium was added to the appropriate wells. 20μl of a culture medium was added to control wells of a "medium alone". Six "LPS alone" and four controls of a "medium alone" were included in each 96-well plate. Various concentrations of a known inhibitor of TNFa were included in each test, ie an inhibitor of the PDE Type IV enzyme (for example see Semmler, J. Wachtel H. and Endres, S., Int. J. Immunopharmac. (1993) , 15 (3), 409-413) or an inhibitor of proTNFa convertase (for example, see, McGeehan, GM et al., Nature (1994) 370, 558-561). The plates were incubated for 7 hours at 37 ° C (humidified incubator) after which lOOμl of the supernatant from each well was removed and stored at -70 ° C (96 well round bottom plates, Corning 25850). TNFa levels were determined in each sample using ELISA to human TNFa (see W092 / 10190 and Current Protocols in Molecular Biology, vol 2 by Frederick M. Ausbel et al., John Wiley and Sons Inc.). % inhibition = (single-medium LPS only) - (test-medium concentration alone) X 100 (single-medium LPS only) (ii) Total Human Blood The ability of the compounds of this invention to inhibit the production of TNFa was also assessed on a human total blood test. Total human blood secretes TNFα when stimulated with LPS. This property of blood forms the basis of a test that is used as a secondary test for compounds that profile as active in the PBMC test. Heparinized human blood (10 units / ml) was obtained from volunteers. 160μl of whole blood was added to 96-well round bottom plates (Corning 25850). The compounds were solubilized and serially diluted in RPMI 1640 medium (Gibco) supplemented with 50 units / ml penicillin, 50μg / ml streptomycin and 2mM glutamine, as detailed above. 20μl of each test concentration was added to the appropriate wells (triplicate cultures). 20μl of an RPMI 1640 medium supplemented with antibiotics and glutamines was added to the control wells. The plates were incubated for 30 minutes at 37 ° C (humidified incubator), before the addition of 20 μl of LPS (final concentration of 10 μg / ml). An RPMI 1640 medium was added to the control wells. Six controls of "LPS alone" and four of a "medium alone" were included in each plate. A known inhibitor of synthesis / secretion of TNFa was included in each test. The plates were incubated for six hours at 37 ° C (humidified incubator). Plates were centrifuged (2000 rpm for 10 minutes) and lOOμl of plasma was removed and stored at -70 ° C (Corning plates 25850). TNFa levels were measured by ELISA (see WO92 / 10190 and Current Protocols in Molecular Biology, vol. 2 by Frederick M. Ausbel et al., John Wiley and Sons Inc.). The paired antibodies that were used in the ELISA were obtained from R & D Systems (anti-human TNFa coating antibody number MAB610, antibody detecting biotinylated TNFα biotinylated BAF210). Ex vivo / In vivo titration The ability of the compounds of this invention as ex vivo TNFa inhibitors was assessed in the rat or mouse. Briefly, groups of male Wistar Alderley Park (AP) rats (180-210g) were dosed with compound (6 rats) or drug vehicle (10 rats) by the appropriate route, for example peroral (po), intraperitoneal (ip) or subcutaneous (s.c.) ninety minutes later the rats were sacrificed using an increasing concentration of CO 2 and they were bled by means of the posterior vena cava in 5 units of sodium heparin / ml of blood. The blood samples were immediately placed on ice and centrifuged at 2000 rpm for 10 minutes at 4 ° C and the harvested plasmas were frozen at -20 ° C for subsequent testing on their effect on TNFa production by human blood stimulated by LPS. . The rat plasma samples were thawed and 175 μl of each sample was added to a layout format pattern on a 96 well round bottom plate (Corning 25850). 50μl of heparinized human blood were then added to each well, mixed and the plate incubated for 30 minutes at 37 ° C (humidified incubator). LPS (25μl, final concentration of 10μg / ml) was added to the wells and incubation continued for an additional 5.5 hours. The control wells were incubated with 25μl of a single medium. The plates were then centrifuged for 10 minutes at 2000 rpm and 200μl of the supernatants were transferred to a plaque. 96 wells and were frozen at -20 ° C for subsequent analysis of TNF concentration by ELISA. The analysis is data by software calculations dedicated to each compound / dose:% inhibition of TNFa = Medium TNFa (Mean TNFa-Controls (treated) x 100 Mean TNFa (Controls) Alternatively, mice could be used instead of rats in the procedure Previous: Testing as an anti-arthritic agent The activity of a compound as an antiarthritic agent was tested as follows: It was shown by Trentham et al. [1] that native type II collagen soluble in acid is arthritogenic in rats.; caused polyarthritis when administered in incomplete Freunds adjuvant. This is now known as collagen-induced arthritis (CIA) and the same conditions can be induced in mice and primates. Recent studies have shown that anti-TNF monoclonal antibodies [2] and fused IgG-receptor proteins of TNF [3] improve the established CIA indicating that TNF plays a major role in the pathophysiology of CIA. In addition, the remarkable reported efficiency for anti-TNF monoclonal antibodies in recent clinical trials of rheumatoid arthritis indicates that TNF plays a major role in this chronic inflammatory disease. Thus CIA in DBA / 1 mouse as described in references 2 and 3 is a tertiary model that can be used to demonstrate the anti-arthritic activity of a compound. See also reference 4. 1. Trentham, D.E. et al. , (1977) J. Exp. Med., 146, 857. 2. Williams, R.O. et al. , (1992) Proc. Natl. Acad. Sci., 89, 9784. 3. Williams, R.O. et al. , (1995) Immunology, 84, 433. 4. Badger, M. B. et al. , (1996) The Journal of Pharmacology and Experimental Therapeutics, 279, 1453-1461.

Although the pharmacological properties of the compounds of Formula (I) vary with the structural change as expected, in general a compound of Formula (I) gives about 30% inhibition of p38a and / or p38β at concentrations up to 10. μM and over 30% inhibition in the PBMC test at concentrations of up to 50 μM. Physiological toxicity was not observed to be unacceptable at the effective dose of the tested compounds of the present invention. As an example: - Examples The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise indicated: - (i) the operations were carried out at room temperature, i.e. in the range of 17 to 25 ° C and under an atmosphere of an inert gas such as argon unless otherwise indicated; (ii) the evaporations were carried out by rotary vacuum evaporation and the processing procedures were carried out after the removal of the residual solids by filtration; (iii) column chromatography (by the instantaneous procedure) was performed on silica Merck Kieselgel (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) or reverse phase silica obtained from E. Merck, Darmstadt, Germany; (iv) the returns when present are given for illustration only and are not necessarily the maximum obtainable; (v) in general, the final products of Formula (I) have satisfactory microanalyses and their structures were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrum techniques; the fast atom bombardment (FAB) mass spectrum data were obtained using a Platform spectrometer and, where appropriate, positive ion data or negative ion data were collected; the chemical change values of NMR were measured on the delta scale [the proton magnetic resonance spectra were determined using a Varian Gemini 2000 spectrometer operating at a 300 MHz field strength or an AM250 spectrometer operating at a field strength of 250 MHz ]; the following abbreviations have been used: s, simple; d, double; t, triple; m, multiple; br, broad; Unless otherwise indicated, the solvent used was deuterated dimethylsulfoxide (DMS0-d6); Example 1 4- [2-Methyl-5- (2-morpholinopyridine-4-carboxamido) anilino] -thieno [3,2-d] pyrimidine A mixture of N- (3-amino-4-methylphenyl) -2-morpholinopyridine 4-carboxamide (0.312 g), 4-chlorothieno [3,2-d] pyrimidine (PCT patent application W095 / 19774; 0.171 g), triethylamine (0.15 ml) and N, N-dimethylformamide (5 ml) was stirred and heated at 120 ° C for 36 hours. The mixture was cooled to room temperature and poured into water. The resulting precipitate was isolated and purified by column chromatography on silica using a 19: 1 mixture of ethyl acetate and methanol as eluent. Thus, the title compound was obtained as a solid (0.216 g, 48%); NMR: 2.14 (s, 3H), 3.51 (m, 4H), 3.69 (m, 4H), 7.08 (d, 1H), 7.21 (s, 1H), 7.29 (d, 1H), 7.37 (d, 1H), 7.68 (d, 1H), 7.74 (s, 1H), 8.08 (d, 1H), 8. 26 (d, 1H), 8.43 (s, 1H), 9.48 (s, 1H), 10.29 (s, 1H); Mass: M + H + 447. The N- (3-amino-4-methylphenyl) -2-morpholinopyridine-4-carboxamide used as an initial material was obtained as follows: - Triethylamine (31.8 ml) was added to a stirred mixture of 4-methyl-3-nitroaniline (15.8 g), 2-chloropyridine-4-carbonyl chloride (20 g) and methylene chloride (1 liter) and the resulting mixture was stirred at room temperature for 16 hours. The precipitate was isolated, washed with a saturated solution of aqueous sodium bicarbonate and with methylene chloride and dried under vacuum at 40 ° C. Thus, 2-chloro-N- (4-methyl-3-nitrophenyl) pyridine-4-carboxamide (10.2 g) was obtained. The organic filtrate was washed with a saturated aqueous sodium bicarbonate solution, dried (MgSO 4) and evaporated. The residue was triturated under methylene chloride and the resulting solid was isolated and dried under vacuum at 40 ° C. Thus, a second culture (8.13 g) of 2-chloro-N- (4-methyl-3-nitrophenyl) pyridine-4-carboxamide was obtained.; NMR: 2.48 (s, 3H), 7.51 (d, 1H), 7.86 (m, 1H), 7.96 (m, 2H), 8.49 (m, 1H), 8.64 (m, 1H), 10.85 (s, 1H); Mass: M + H + 292 and 294. A mixture of the pyridine-4-carboxamide thus produced and morpholine (250 ml) was stirred and heated at 100 ° C for 18 hours. The mixture was poured into water (250 ml) and stirred for 10 minutes. Methylene chloride (30 ml) was added and the resulting mixture was stirred for 30 minutes. The resulting solid was isolated, washed with methylene chloride and dried in a vacuum oven at 40 ° C for 18 hours. Thus, N- (4-methyl-3-nitrophenyl) -2-morpholinopyridine-4-carboxamide (17.34 g) was obtained; NMR: 2.48 (s, 3H), 3.52 (m, 4H), 3.71 (m, 4H), 7.1 (d, 1H), 7.25 (s, 1H), 7.49 (d, 1H), 7.97 (m, 1H) , 8.29 (m, 1H), 8.49 (m, 1H), 10.62 (s, 1H); Mass: M + Hx 343.

A mixture of a portion (8.5 g) of the obtained material, 5% palladium on carbon catalyst (0.85 g) and methanol (600 ml) was stirred under a pressure atmosphere of hydrogen gas for 18 hours. Methylene chloride (400 ml) was added and the reaction mixture was filtered through the diatomacea. The filtrate was evaporated to give N- (3-amino-4-methylphenyl) -2-morpholinopyridine-4-carboxamide, (6.41 g), NMR: 2.01 (s, 3H), 3.52 (m, 4H), 3.73 (m, 4H), 4.83 (s, 2H), 6.7 (d, 1H), 6.84 (d, 1H), 7.04-7.08 (m, 2H), 7.2 (s, 1H), 8.2 (d, 1H), 9.95 (s) , 1 HOUR); Mass: M + H + 313. EXAMPLE 2 4- [2-Methyl-5- (2-morpholinopyridine-4-carboxamido) anilino] -5-methylthieno [2,3-d] pyrimidine. A 1M solution of hydrogen chloride in the diethyl ether (0.2 ml) was added to a mixture of N- (3-amino-4-methylphenyl) -2-morpholinopyridine-4-carboxamide, (0.056 g), 4-chloro-5-methylthiene [2, 3-d] pyrimidine [Maybridge Chemica Company, Trevillet, Tintagel, Cornwall, PL34 0HW, GB; 0.037 g) and isopropanol (2 ml) and the reaction mixture was stirred and heated at 88 ° C for 18 hours. The reaction mixture was cooled to room temperature and the precipitate was isolated and washed in turn with isohexane and diethyl ether. Thus, the title compound (0.021 g) was obtained; Mass: M + H + 461.

Example 3 Using an analogous procedure to that described in Example 2, the appropriate 4-chloroheterocycle (obtained, unless otherwise indicated from Maybridge Chemical Company, Trevillet, Tintagel, Cornwall, PL34 OHW, GB) was reacted with the appropriate aniline to give the compounds described in the following Table.

Notes a) The product gave the following data: Mass: M + H + 461. b) The 4-chlorothieno [2,3-d] pyrimidine used as an initial material was obtained as described in the PCT patent application WO 95 / 19774. The product gave the following data: Mass: M + H + 447. c) The product gave the following data: Mass: M + H + 494. d) The product gave the following data: Mass: M + H + 442. The 4-chloropyrido [4, 3-d] pyrimidine used as an initial material obtained as follows: - A mixture of pyrido [4, 3-d] pyrimidin-4 (1H) -one (PCT Patent Application WO 95/19774; 0.03 g) and thionyl chloride (2 ml) was stirred and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and evaporated to give the required starting material which was used without further purification. e) The product gave the following data: Mass: M + H + 442. The 4-chloropyrido [2,3-d] pyrimidine used as an initial material was obtained as follows: - A mixture of pyrido [2, 3-d] pyrimidin-4 (1H) -one (PCT Patent Application WO 95/19774; 0.03 g) and thionyl chloride (2 ml) was stirred and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and evaporated to give the required starting material which was used without further purification. f) The product gave the following data: Mass: M + H + 443. g) The product gave the following data: NMR: 2.18 (s, 3H), 3.52 (m, 4H), 3.75 (m, 4H), 7.09 ( m, 1H), 7.22 (m, 2H), 7.55 (m, 1H), 7.84 (broad s, 1H), 8.18 (broad s, 1H), 8.24 (m, 2H), 9.14 (broad s, 1H), 10.26 (s, 1H); Mass: M + H + 431.

Example 4 Pharmaceutical Compositions The following illustrates representative pharmaceutical dosage forms of the invention as defined herein (the active ingredient being called "Compound X"), for therapeutic or prophylactic use in humans: (a) Table I mg / tablet Compound X 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Corn starch paste (5% weight / volume paste) 2.25 Magnesium stearate 3.0 (b) Tablet II mg / tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Corn starch 15.0 Polyvinylpyrrolidone (paste at 5% w / v) 2.25 Magnesium stearate 3.0 (c) Tablet III mg / tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0 Corn starch paste (paste at 5% w / v) 0.75 Magnesium stearate 1.0 (d) Capsule mg / capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium 1.5 (e) Injection I (50 mg / ml) Compound X 5.0% w / v Sodium hydroxide solution 1 M 15.0% volume / volume 0.1M hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w / v Water for injection up to 100% (f) Injection II (10 mg / ml) Compound X 1.0% w / v Sodium Phosphate BP 3.6% w / v 0.1M sodium hydroxide solution 15.0% volume / volume Water for injection up to 100% (g) Injection III (lmg / ml, regulated at pH6) Compound X 0.1% w / v Sodium Phosphate BP 2.26% w / v Citric acid 0.38% w / v Polyethylene glycol 400 3.5% w / v Water for injection up to 100% (h) Aerosol I mg / ml Compound X 10.0 Sorbitan triolate 13.5 Trichlorofluoromethane 910.0 Dichlorodifluoromethane 490.0 (i) Aerosol II mg / ml Compound X 0.2 Sorbitan triolate 0.27 Trichlorofluoromethane 70.0 Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j) Aerosol III mg / ml Compound X 2.5 Sorbitan triolate 3.38 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg / ml Compound X 2.5 Lecithin from Soya 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (1) Ointment ml Compound X 40 mg Ethanol 300 μl Water 300 μl l-Dodecylazacycloheptane-2-one 50 μl Propylene glycol up to 1 ml Note The above formulations p They can be obtained by conventional procedures well known in the pharmaceutical art. Tablets (a) - (c) can be enteric coated by conventional means, for example to provide a cellulose acetate phthalate coating. The aerosol formulations (h) - (k) may be used in conjunction with standard metered dose aerosol dispensers, and the sorbitan triolate suspension agents and soy lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate, or oleic acid.

Claims (12)

1. CLAIMS 1. A bicyclic compound of the formula (I) characterized in that: G is N, CH or C (CN); ring X is a 5 or 6 membered fused heteroaryl ring containing 1, 2 or 3 heteroatoms selected from oxygen, sulfur and nitrogen; m is 0, 1 or 2; R1 is hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulfamoyl, Ci-e alkyl, C2-6 alkenyl, C2_6 alkynyl, C6_6 alkoxy, -O- ( C? -3) -O-alkyl of Ci-eS (O) p- (wherein n is 0-2), N-alkylamino of C? -6, N, N- (C? -6 alkyl) ) 2-amino, C6-6 alkoxycarbonyl, N-alkylcarbamoyl of Ci-e, N, N- (Ci-e) alkylcarbamoyl, C2-6 alkanoyl, C6-6 alkanoyloxy, C6-6 alkanoylamino , N-alkylsulfoyl sulphonyl of C? -6, N, N- (alkyl of d-6) 2sulfamoyl, alkylsulfonylamino of C? -6, alkylsulfonyl of C? -6-N- (alkyl of Ci-β) amino, or R1 is of Formula (IA): A- (CH2) PB- (IA) wherein A is halo, hydroxy, C? -6 alkoxy, Ci-dS alkyl (0) n- (where n is 0-2), cyano, amino, N-alkylamino of C? -6, N, N- (C? -6-alkyl) 2-amino, carboxy, C? -6-alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl of C? _6 or N, N- (C? -6) 2-carbamoyl alkyl, p is 1-6, and B is a bond, oxy, imino,
2. ? T- (Ci-e) imino alkyl or -C (0)? H-, with the proviso that p is two or more unless B is a bond or -C (0)? H-, or R1 is of Formula (IB): D-E- (IB) wherein D is aryl, heteroaryl or heterocyclyl, and E is a bond, C6-6 alkylene, C6-6 alkyleneoxy, oxy, imino, N- (alkyl) Ci-e) imino, C? -6 alkyleneimino, N- (Ci-e-alkyl) -C6-6alkyleneimino, C? -6-alkylene-C6-6alkylene, C6-6-alkylene-alkyleneimino of Ci-e, N- (C? -6 alkyl) -alkyleneimino of C? -6-alkylene of C? _6, -C (0)? H-, -S02? H-, -? HS02- or alkanoyl of C2-6, and any aryl, heteroaryl or heterocyclyl group in a R1 group may be optionally substituted with one or more groups selected from hydroxy, haloC6 alkyl, C6-6 alkoxy, carboxy, alkoxycarbonyl C? -6, carbamoyl, N-alkylcarbamoyl of C? -6, N- (C? -6) alkylcarbamoyl, C2-6 alkanoyl, amino, N-alkylamino of C? -6 and N, N- ( C? -6) 2amino alkyl, and any heterocyclyl group in a R1 group may be optionally substituted with one or two oxo or thioxo substituents, and any of the R1 groups defined above that comprise a CH2 group that is bonded to two carbon atoms or to a CH3 group that is attached to a carbon atom may optionally carrying in each of the CH2 or CH3 groups a substituent selected from hydroxy, amino, C? -6 alkoxy, C? -6 N-alkylamino, N, N- (C? -6) alkyl, and heterocyclyl; R 2 is hydrogen, halo, Ci-β alkyl, C 2-6 alkenyl or C 2-6 alkynyl; R3 is hydrogen, halo, C6_6 alkyl, C2_6 alkenyl or C2_6 alkynyl; R 4 is hydrogen, hydroxy, C 6 alkyl, alkoxy
3. C? -6, amino, N-alkylamino of Ci-e, N, N- (C? -6-alkyl) 2-amino, C2-6 hydroxyalkoxy, C? -6 alkoxy of C2-e alkoxy, aminoalkoxy of C2_6, N-C2-6 alkylamino of C2-6alkoxy, N, N- (C6-6alkyl) 2-aminoalkoxy of C2-6 or cycloalkyl of C3-7, or R4 is of the Formula (IC) : -K-J (IC) wherein J is aryl, heteroaryl or heterocyclyl and K is a bond, oxy, imino, N- (Ci-d) imino alkyl, C? -6 oxyalkylene, C? -iminoalkylene. 6, N- (C? -6 alkyl) iminoalkylene of C? -6, -? HC (O) -, -S02? H-, -? HS02- or -? HC (0) -alkylene of C? - 6-, and any aryl, heteroaryl or heterocyclyl group in a R4 group can be optionally substituted by one or more groups selected from hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulfamoyl, alkyl of C? -6, C2-6 alkenyl, C? -6 alkynyl, Ci-e alkoxy, -0- (C? _3 alkyl) -0-, C? -6 S (0) n alkyl - (where n is 0-2), N-alkylamino of C? -6, N, N- (C? -6 alkyl) 2-amino , Ci-e alkoxycarbonyl, N-alkylcarbamoyl of C? -6, N, N- (Ci-β) alkylcarbamoyl, C? -6 alkanoyl, alkanoyloxy
4. C? -6, C? -6-alkanoylamino, N-alkylsulfamoyl of C? _6, N, N- (Ci-β) alkyl sulfamoyl, C? -6 alkylsulfonylamino and C? -6-N- alkylsulfonyl ( C? _6) amino alkyl, or any aryl, heteroaryl or heterocyclyl group in a R4 group may be optionally substituted with one or more groups of Formula (IA '): -B CHzJp-A1 (IA *) wherein A1 is halo , hydroxy, C? -6 alkoxy, cyano, amino, N-alkylamino of Ci-β, N, N- (C? -6 alkyl) 2-amino, carboxy, C? -6 alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl of C? _6 or N, N- (Ci-e) 2-carbamoyl alkyl, p is 1-6, and B1 is a bond, oxy, imino, N- (Ci-6 alkyl) imino or -NHC (O) -, with the proviso that p is 2 or more unless B1 is a bond or -NHC (O) -, or any aryl, heteroaryl or heterocyclyl group in a R4 group can be optionally substituted with one or more groups of the Formula (IB '): E ^ D1 (IB') where D1 is aryl, heteroaryl or heterocyclyl and E1 is a bond, C? -6 alkylene, C? Oxyalkylene 6, oxy, imino, N- (Ci-e alkyl) imino, C? -6-iminoalkylene, N- (C? -6-alkyl) -iminoalkylene of C? _6, C? _6-oxyalkylene alkylene of C ? -6, C? _6-iminoalkylene alkylene of C? _6, C? -6-N- (C? -e) -iminoalkylene alkylene of C? _6,
5. -? HC (O) -, -? HS02-, -S02? H- or -? HC (O) -alkylene of C? -6-, and any aryl, heteroaryl or heterocyclyl group in a substituent on R4 can optionally be substituted with one or more groups selected from hydroxy, halo, C? -6 alkyl, C? -6 alkoxy, carboxy, C? _6 alkoxycarbonyl, carbamoyl, C? -6 N-alkylcarbamoyl, N- (alkyl) of Ci-β) 2carbamoyl, C2_6 alkanoyl, amino, N-alkylamino of C? -6 and N, N- (C? -6-alkyl) 2-amino, and any cycloalkyl group of C3-7 or heterocyclyl in a group R4 it may be optionally substituted with one or two oxo or thioxo substituents, and any of the groups R4 defined above comprising a CH2 group that binds to two carbon atoms or a CH3 group that binds to a carbon atom may optionally carry about each CH2 or CH3 group a substituent selected from hydroxy, amino, C? -6 alkoxy, C? -6 N-alkylamino, N, N- (C? -6-alkyl) 2-amino and heterocyclyl; R5 is hydrogen, halo, trifluoromethyl, cyano, nitro, amino, hydroxy, C? -6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C? _6 alkoxy, C? -6 N or N-alkylamino, N- (C? -6) 2amino alkyl; q is O, 1, 2, 3 or 4; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof; with the proviso that 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-dipyrimidine] is excluded. 2. The bicyclic compound of Formula (I) according to claim 1, characterized in that: the bicyclic ring formed by fusion of the X ring to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is furopyrimidinyl, thienopyrimidinyl, pyrrolpyrimidinyl, oxazolpyrimidino, thiazolopyrimidinyl, purinyl, pyridopyrimidinyl, pyrimidopyrimidinyl or pteridinyl; m is 0 or m is 1 and each R1 is independently hydroxy, halo, C6-6 alkyl, C6-6 alkoxy, C6-6S (0) n- alkyl (where n is 0-2), N , N- (Ci-β) alkyl 2-aminoalkyl of C? -6, N, N- (Ci-e alkyl) 2-carbamoylalkoxy of C? -6, N, N- (C? _6 alkyl) 2-aminoalkoxy of C? -6, alkyl of i-eS (O) 2-C6-alkoxy, N, N (C6-6 alkyl) 2 amino- N- (C6-6 alkyl) C6-6 alkylamino, N , N- (Ci-6-alkyl) 2-aminoalkylamino of C? _6-C? -6 alkyl, piperidin-1-ylalkyl of Ci-e, homopiperidin-1-ylalkyl of Ci-e, N- (C? -6) piperidin-1-ylalkyl of C? -6, N- (C? _6 alkyl) homopiperidin-1-ylalkyl of C? -6, piperazin-1-ylalkyl of C? -6, 4-alkylpiperazine of C ? -6-l-C 1-6 -alkyl, homopiperazinyl-1-ylalkyl of C? -6,4-alkylhomopiperazinyl of C? -6-l-ylalkyl of C? -6, pyrrolidinylalkoxy of C? -6, piperidinylalkoxy of C? _6, homopiperidinylalkoxy of C? -6, N- (C? _6 alkyl) pyrrolidinylalkoxy of C? _6, N- (C? -d) alkyl piperidinylalkoxy of C? _6, N- (CI-T alkyl) C6-6 homopiperidinylalkoxy, C? -6 morpholinylalkoxy, C? _6 piperazinylalkoxy, N- (C? _6 alkyl) piperazinylalkoxy of C? -6, homopiperazinylalkoxy of C? 6, N- (C6-6 alkyl) homopiperazinylalkoxy of C6-6, pyrrolidinyloxy, N- (Ci-e alkyl) pyrrolidinyloxy, piperidinyloxy, N- (Ci-β alkyl) piperidinyloxy, homopiperidinyloxy, N- (alkyl) of Ci-e) homopiperidinyloxy, C 1 -C 6 -morphonylalkyalkylamino-C 6 alkyl, thiazolylalkoxy of C 6 -6 or pyridylalkoxy of C 6 -6; R ^ is hydrogen, C? -4 alkyl or halo; R3 is hydrogen, C1-4 alkyl or halo; q is 0; R 4 is phenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidyl or pyridyl optionally substituted by one or two of halo, trifluoromethyl, cyano, C ?- alkyl, C? -4 alco alkoxy, -O- (C?-Alkyl) 3) -0-, N, N- (alkyl of
6. C? _4) 2-amino, C? _6 alkanoylamino, C? _6-N- (Ci_e alkyl) amino alkylsulfonyl, phenyl (optionally substituted by one or two halo groups), furyl, azetidinyl, pyrrolidinyl, 3-pyrrolinyl, piperidino, homopiperidinyl, morpholino, piperazinyl, homopiperazinyl, N- (
7. C? -6) piperazinyl and N- (Ci-β alkyl) homopiperazinyl, or R4 is fluorenyl or dibenzofuranyl; and R5 is hydrogen; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. 3. The bicyclic compound of Formula (I) according to claim 1, characterized in that: the bicyclic ring formed by fusion of the X ring to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is furopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, oxazolpyrimidinyl, thiazolopyrimidinyl, purinyl, pyridopyrimidinyl, pyrimidopyrimidinyl or pteridinyl; m is 0 or m is 1 and each R 1 is independently hydroxy, halo, C 1-6 alkyl, C 1-6 alkoxy, C? -6S alkyl (0) n- (where n is 0-2), N, N- (C? _6) -aminoalkyl of C? -6, N, N- (C? -6 alkyl) 2-carbamoylalkoxy of C? -6, N, N- (C? _6 alkyl) 2-aminoalkoxy of C? _6, C C-C6-alkyl (O) 2-C alco-C6-alkoxy, N, N- (C?-6-alkyl) 2-amino- N- (Ci-e alkyl) C?-6 alkylamino, N , N- (C? _6 alkyl) 2-aminoalkylamino of C? _6-C? -6 alkyl, piperazin-1-ylalkyl of C? -6, 4-alkylpiperazin of C? -6-l-ylalkyl of C? 6, Ci-e homopiperazinyl-1-ylalkyl of C? -6, 4-alkylhomopiperazinyl of C? -6-l-ylalkyl of Ci-e, pyrrolidinylalkoxy of C? -6, piperidinylalkoxy of C? -6, N- (C-alkyl) ? 6) pyrrolidinylalkoxy of C? -6, N- (alkyl of
8. Ci-e) C? -6 piperidinylalkoxy, C? -6 morpholinylalkoxy, C? _6 piperazinylalkoxy, C? -6 N- (C? -6 alkyl) piperazinylalkoxy, C? -6 homopiperazinylalkoxy, N-? (C? -6 alkyl) C? -6 homopiperazinylalkoxy, pyrrolidinyloxy, piperidinyloxy, C? -6-C? -6-alkyl-C6-6 alkyl or C? -6 pyridylalkoxy, "R2 is hydrogen, C1-4 alkyl or halo, R 3 is hydrogen, C 1-4 alkyl or halo, q is 0, R 4 is phenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidyl or pyridyl optionally substituted by one or two halo, cyano, C? 4, C 1 -4 alkoxy, N, N- (C 4 -4) alkylamino, piperidinyl, morpholino or piperazinyl, and R 5 is hydrogen, or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. bicyclic compound of Formula (I) characterized in that: the bicyclic ring formed by fusion of the X ring to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is furo [3,2-d] pirim idinyl, furo [2, 3-d] pyrimidinyl, thieno [3,2-d] pyrimidinyl, thieno [2,3-d] pyrimidinyl, pyrrol [3,2-d] pyrimidinyl, pyrrole [2, 3-d] pyrimidinyl, oxazole [5,4-d] pyrimidinyl, oxazole [4, 5-d] pyrimidinyl, thiazole [5,4-d] pyrimidinyl, thiazole [4, 5-d] pyrimidinyl, purinyl, pyrido [2, 3] d] pyrimidinyl, pyrido [3,4-d] pyrimidinyl, pyrido [4, 3-d] pyrimidinyl, pyrido [3,2-d] pyrimidinyl, pyrimido [4, 5-d] pyrimidinyl, pyrimido [5,6- d] pyrimidinyl or pteridinyl; m is 0 or m is 1 and each R 1 is independently methyl, methoxy, methylthio, 2-diisopropylaminoethoxy, 3-diethylaminopropoxy, 3-morpholinopropoxy or 3-pyrrolidin-1-ylpropoxy; R2 is hydrogen, methyl, fluoro or chloro; R3 is hydrogen; q is 0; R 4 is phenyl optionally substituted by one or two groups selected from fluoro, chloro, trifluoromethyl, cyano, methyl, methoxy, ethoxy, methylenedioxy, N, N-dimethylamino, acetamido, N-methylmethanesulfonamido, phenyl, 4-fluorophenyl, 4- chlorophenyl, 2-furyl, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolin-1-yl, piperidino, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4- methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl, or R 4 is pyridyl optionally a group substituted by N, N-di-ethylamino, N, N-diethylamino, azetidin-1-yl, pyrrolidin-1-yl, 3- pyrrolin-1-yl, piperidino, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl or 4-methylhomopiperazin-1-yl, or R 4 is 1-fluorenyl or dibenzofuran-4-yl; and R5 is hydrogen; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. 5. The bicyclic compound of the formula (I) according to claim 1, characterized in that: the bicyclic ring formed by fusion of the X ring to the 6-membered heteroaryl ring containing adjacent nitrogen within the formula (I) is furo [ 3, 2-d] pyrimidinyl, furo [2, 3-d] pyrimidinyl, thieno [3,2-d] pyrimidinyl, thieno [2, 3 d] pyrimidinyl, pyrrol [3,2-d] pyrimidinyl, pyrrole [2] , 3-d] pyrimidinyl, oxazole [5, 4-d] pyrimidinyl, oxazole [4,5-dlpyrimidinyl, thiazole [5, 4-d] pyrimidinyl, thiazole [4,5-d] pyrimidinyl, purinyl, pyrido [2 , 3-d] pyrimidinyl, pyrido [3,4-d] pyrimidinyl, pyrido [4, 3-d] pyrimidinyl, pyrido [3,2- d] pyrimidinyl, pyrimido [4,5-d] pyrimidinyl, pyrimido [5] , 6-d] pyrimidinyl or pteridinyl; m is 0 or m is 1 and each R 1 is independently methyl, methoxy, methylthio, 2-diisopropylaminoethoxy, 3-diethylaminopropoxy, 3-morpholinopropoxy or 3-pyrrolidin-1-ylpropoxy; R2 is hydrogen, methyl, fluoro or chloro; R3 is hydrogen; q is 0; R 4 is pyridyl, a group optionally substituted by an N, N-dimethylamino, N, N-diethylamino, pyrrolidin-1-yl, piperidino or morpholino; and R5 is hydrogen; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. 6. The bicyclic compound of Formula (I) according to claim 1, characterized in that: the bicyclic ring formed by fusion of the X ring to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is thien [ 3, 2-d] pyrimidin-4-yl, thieno [2,3-d] pyrimidin-4-yl, thiazol [5, 4-d] pyrimidin-7-yl, 6-purinyl, pyrido [2, 3- d] pyrimidin-4-yl, pyrido [3,4-d] pyrimidin-4-yl, pyrido [4, 3-d] pyrimidin-4-yl, pyrido [3,2-d] pyrimidin-4-yl or pteridin-4-yl; m is 0 or m is 1 and R1 is methyl or methylthio; R2 is methyl; R3 is hydrogen; q is 0; R 4 is phenyl, 3-fluorophenyl, 4-cyanophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3- (N, N-dimethylamino) phenyl , 3-acetamidophenyl, 3- (4-fluorophenyl) phenyl, 3- (2-furyl) phenyl, 3-pyrrolidin-1-ylphenyl, 3-morpholinophenyl, 3-fluoro-5-pyrrolidin-1-ylphenyl, 3-fluoro -5-piperidinophenyl, 3-fluoro-5-morpholinophenyl or 3-morpholino-5-trifluoromethylphenyl, or R4 is 2-morpholinopyrid-4-yl, or R4 is 1-fluorenyl or dibenzofuran-4-yl; and R5 is hydrogen; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. 7. The bicyclic compound of Formula (I) according to claim 1, characterized in that: the bicyclic ring formed by fusion of the X ring to the 6-membered heteroaryl ring containing adjacent nitrogen within Formula (I) is thien [ 3, 2-d] pyrimidin-4-yl, thieno [2,3-d] pyrimidin-4-yl, thiazol [5, 4-d] pyrimidin-7-yl, pyrido [2, 3-d] pyrimidin-4-yl, pyrido [3, -d] pyrimidin-4-yl, pyrido [4, 3-d] pyrimidin-4-yl, pyrido [3,2-d] pyrimidin-4-yl or pteridin-4 -ilo; m is 0 or m is 1 and R1 is methyl or methylthio; R2 is methyl; R3 is hydrogen; q is 0; R 4 is 2-morpholinopyrid-4-yl; and R5 is hydrogen; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. 8. The bicyclic compound of the formula (I) according to claim 1, characterized in that it is selected from: - 4- [2-methyl-5- (2-morpholinopyridine-4-carboxamido) ani-lino] thieno [3, 2-d] pyrimidine, 4- [2-methyl-5- (2-morpholinopyridin-4-carboxamido) anilino] pyrido [4, 3-d] pyrimidine, 4- [2-methyl-5- (2-morpholinopyridine-4-carboxamido) anilino] pteridine and 6- [2-methyl-5- (2-morpholinopyridine-4-carboxamido) anilino] -purine; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. 9. The process for preparing a compound of the Formula (I), or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof, according to claim 1, characterized in that it comprises: a) reacting an aniline of the Formula ( II): with an acyl compound of Formula (III) OX "XCH2) and q" (III) wherein G, R1, R2, R3, R4, R5, ring X, myq is a displaceable group as defined in claim 1 and L is a displaceable group; b) reacting an activated bicyclic heteroaryl ring of Formula (IV): wherein G, R1, the X and m ring as defined in claim 1, wherein L is a displaceable group with an aniline of the Formula (V):
9. (V) wherein R2, R3, R4, R5 and q are as defined in claim 1; or c) for the preparation of a compound of the
10. Formula (I) wherein R1 or a substituent on R4 is C6-6 alkoxy or substituted C6-6 alkoxy, Ci-ßS- alkyl, N-alkylamino of C? -6, N, N- ( C? -6) 2amino alkyl or substituted C? -6 alkylamino, the alkylation, conveniently in the presence of a suitable base, of a compound of the Formula
11. (I) wherein R1 or a substituent on R4 is hydroxy, mercapto or amino as appropriate; and after that if necessary: i) converting a compound of the Formula (I) to another compound of the Formula (I); ii) remove any protective group; and iii) forming a pharmaceutically acceptable salt or ester cleavable in vivo. 10. The pharmaceutical composition characterized in that it comprises a bicyclic compound of the formula (I), or an acceptable pharmaceutical salt or in vivo cleavable ester thereof, according to claim 1, in association with an acceptable pharmaceutical carrier or diluent. 11. The use of a bicyclic compound of the Formula (I) or an acceptable pharmaceutical salt or an in vivo cleavable ester thereof, according to claim 1, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d] pyrimidine in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by cytokines.
12. 12. A method for treating diseases or medical conditions mediated by cytokines characterized in that it comprises administering to a warm-blooded animal an effective amount of a bicyclic compound of the Formula (I), or an acceptable pharmaceutical salt or an in vivo cleavable ester thereof, according to claim 1 or of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d] pyrimidine.