Antithrombotic agents

Abstract: Compounds of formula (I) : are antithrombotic agents, having utility in a variety of therapeutic areas including the prevention and/or treatment of deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignancy, prolonged immobilisation trauma, application of lower limb plaster casts, or fractures of the lower limbs or pelvis; recurrent DVT; DVT during pregnancy when there is a previous history thereof; reocclusion following thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; transient ischaemic attacks; disseminated intravascular coagulation; coagulation in extra-corporeal circuits; occlusion of arterio-venous shunts and blood vessel grafts (including coronary artery by-pass grafts); and restenosis and occlusion following angioplasty.

Description: This invention relates to a series of indole, indazole and benzimidazole derivatives, which are antithrombotic agents, having utility in a variety of therapeutic areas including the prevention and/or treatment of deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignancy, prolonged immobilisation trauma, application of lower limb plaster casts, or fractures of the lower limbs or pelvis; recurrent DVT; DVT during pregnancy when there is a previous history thereof; reocclusion following thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; transient ischaemic attacks; disseminated intravascular coagulation; coagulation in extra-corporeal circuits; occlusion of arterio-venous shunts and blood vessel grafts (including coronary artery by-pass grafts); and restenosis and occlusion following angioplasty. They also have utility as an adjunct to thrombolytic therapy. The compounds of the invention are potent and selective inhibitors of thrombin, which is the final serine protease enzyme in the coagulation cascade. The prime function of thrombin is the cleavage of fibrinogen to produce fibrin which forms linear insoluble polymers which, in turn, are cross-linked by factor Xllla, itself activated by thrombin. In addition, thrombin regulates its own production by activation of factors V and VIII earlier in the cascade. It also has important actions at the cellular level, where it acts on specific receptors to cause platelet aggregation, endothelial cell activation and fibroblast proliferation. Thus thrombin has a central regulatory role in haemostasis and thrombus formation. Clearly then, potent, selective and orally bioavailable thrombin inhibitors represent an attractive target for the convenient therapeutic control of thrombosis. In addition, thrombin potently causes neurite retraction and therefore a thrombin inhibitor is of potential therapeutic utility in the treatment of acute and chronic neurodegenerative disorders. Furthermore, the compounds disclosed herein are of potential value in the treatment of inflammatory disorders and scarring, and in wound healing. Because of their potential as substrate mimics, arginine derivatives have been explored as thrombin inhibitors and this work led to the discovery of argatroban (see Cardiovascular Drug Rev., 1991, 9 , 247). In turn, other research groups have sought to express the basic arginine function in alternative structures; for example, WO-A-95/13274 discloses amidinophenylalanine and amidinopyridylalanine derivatives as antithrombotic agents. Further variations on the theme of arginine mimicry amongst thrombin inhibitors are represented by, inter alia , the guanidinyl- and amidinyl-substituted heterocyclic compounds disclosed in EP-A-0623595. In general, however, compounds containing the basic arginine, amidine or guanidine function have poor oral bioavailability and are poorly selective since they inhibit trypsin as well as thrombin. Thrombin inhibitors containing a 3-amino-2-pyridone acetamide template have been disclosed by Corvas Int Inc in PCT patent reference WO 96/18644 and COR Therapeutics Inc in WO 98/16547. Compounds of the type disclosed within WO 96/18644 and WO 98/16547 contain a guanidino function as an arginine mimic and are likely to be irreversible inhibitors of thrombin by virtue of the presence of an aldehyde or an activated carbonyl fragment. Thrombin inhibitors containing a 3-amino-2-pyridone or pyrazinone acetamide fragment and an arginine mimic which is not a guanidine or amidine have been disclosed by Merck in PCT patent reference WO 97/40024, WO 97/01338, WO 97/30708, WO 98/09987, WO 99/11267 and in Bioorg Med Chem Letters. 1997, 7, p1497; 1998, 8, p1719, 1998, 8, p817. The present inventors have now found a class of non basic or weakly basic bicyclic heterocydic arginine mimics which are highly potent, selective, reversible thrombin inhibitors with good oral bioavailability. Accordingly, the present invention provides compound of formula (I): wherein: R 1 is hydrogen or methyl; R 2 is hydrogen, methyl or CF 3 ; R 3 is hydrogen or methyl; R 4 is hydrogen, C 1 -C 4 alkyl; R 5 is hydrogen or C 1 -C 4 alkyl; R 6 is C 1 -C 6 alkyl, C 3 -C 6 carbocyclyl optionally substituted by fluoro, or R 5 and R 6 together form a bridging chain containing 2 or 3 carbon atoms; Y is hydrogen, chloro, fluoro, bromo, methyl or CF 3 ; V is C or N; W and X are independently CH or N; R 7 -B-A is selected from the following radicals: wherein R 7 is hydrogen, C 1 -C 4 alkyl, perfluoroC 1 -C 4 alkyl, OC 1 -C 4 alkyl, perfluoroOC 1 -C 4 alkyl, fluoro or chloro; R 10 and R 11 are independently selected from hydrogen or C 1 -C 4 alkyl optionally containing an oxygen in the chain or at the end of the chain; or R 10 and R 11 together with the nitrogen atom to which they are bonded form a 4 to 6 membered saturated heterocyclic ring wherein when the ring is six membered it may optionally contain one oxygen or an additional nitrogen atom present as N(R 12 ); wherein R 12 is hydrogen or C 1 -C 4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain; R 13 and R 14 are independently hydrogen or C 1 -C 4 alkyl optionally containing one oxygen atom in the chain or at the end of the chain, or R 13 and R 14 together with the carbon atom to which they are bonded form a 4 to 6 membered carbocyclic saturated ring; R 15 and R 16 are independently selected from hydrogen or C 1 -C 4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain, or R 15 and R 16 together with the nitrogen atom to which they are bonded form a 4 to 6 membered saturated heterocyclic ring; R 17 is selected from one or more of C 1 -C 6 alkyl, C 3 -C 6 carbocyclyl or C 3 -C 6 carbocyclylC 1 -C 4 alkyl, said carbocyclyl containing zero, one or more double bonds wherein said alkyl and carbocyclic optionally contain one heteroatom selected from oxygen, sulphur and nitrogen and are further optionally substituted by one or more fluoro, or C 1 -C 4 alkyl optionally containing an oxygen in the alkyl chain or a the end of the chain; R 18 is selected from hydrogen, C 1 -C 6 alkyl and perfluoro C 1 -C 6 alkyl wherein said alkyl optionally contains an oxygen atom in the chain or at the end of the chain; or v is 0 or 1, and pharmaceutically acceptable salts thereof. In the above definition, unless otherwise indicated alkyl and alkoxy groups having three or more carbon atoms may be straight-chain or branched chain. Herein C 1 -C 4 alkyl or C 1 -C 4 alkyl containing fragment means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; and C 1-6 alkyl further includes the various straight and branched pentyl and hexyl fragments (although C 1 -C 4 is preferred). C 3 -C 6 cycloalkyl (used hereinafter means cyclopropyl, cyclobutyl, cyclopenyl and cyclohexyl. Herein C 1 -C 6 alkyl optionally containing an oxygen atom in the chain or at the end of the chain includes moieties of the formula -(CH 2 ) t -O-(CH 2 ) u -CH 3 where t is 1 to 5 and u is 0 to 4 and in C 1 -C 4 alkyl of the same definition, t is 1,2 or 3 and u is 0,1 or 2. The following independently represent preferred subclasses of the compounds of formula I. R 2 is hydrogen or methyl; R 3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; Y is hydrogen, chloro or bromo; V is C; R 10 and R 11 independently represent hydrogen, C 1 -C 4 alkyl optionally containing an oxygen atom in the chain, or R 10 and R 11 together with the nitrogen to which they are bonded form a 5 to 6 membered heterocyclic ring wherein when the ring is six membered it may optionally contain one oxygen or a nitrogen atom present as N(R 12 ). Preferably the C 3 -C 6 carbocyclyl and C 3 -C 6 carbocyclylC 1 -C 4 alkyl moieties of R 17 are an optionally substituted C 3 -C 6 cycloalkyl (such as cyclopentyl) or C 3 -C 6 cycloalkylC 1 -C 4 alkyl, (such as cyclopropylmethyl). More preferably R 17 is cyclopropylmethyl. Examples of radicals are shown below. Preferred compounds according to the invention are as follows: ( R,S )-2-[3-[(2-amino-1-benzylethyl)amino]-6-methyl-2-oxo-1(2 H )-pyridinyl]- N -(1 H -indol-5-ylmethyl)acetamide; 2-[3-(3-[(dimethylamino)methyl]phenethylamino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide; 2-[3-chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide; 2-[3-[(1 S )-1-benzyl-2-(dimethylamino)ethyl]amino-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide; 2-[3-[(1 S )-1-benzyl-2-(dimethylamino)ethyl]amino-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide; N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-([3-[(methylamino)methyl]phenethyl]amino)-2-oxo-1(2 H )-pyrazinyl]acetamide; 2-[3-{[(1 S )-1-benzyl-2-(dimethylamino)ethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(6-methyl-1 H -indazol-5-yl)methyl]acetamide; 2-[3-{[3-(3-azetidinyl)phenethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-{[3-(1-methyl-3-azetidinyl)phenethyl]amino}-2-oxo-1(2 H )-pyrazinyl]acetamide; 2-[3-[(3-{[(2-methoxyethyl)amino]methyl}phenethyl)amino]-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-2-oxo-3-({[(2 R )-1-tetrahydro-2 H -pyran-4-ylpyrrolidinyl]methyl}amino)-1(2 H )-pyrazinyl]acetamide; N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-[({(2 R )-1-[(1-methylcyclopropyl)methyl]pyrrolidinyl}methyl)amino]-2-oxo-1(2 H )-pyrazinyl]acetamide; 2-[3-({[(2 R )-1-(2-methoxyethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-({[(2 R )-1-neopentylpyrrolidinyl]methyl}amino)-2-oxo-1(2 H )-pyrazinyl]acetamide; 2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-(2-methoxyethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; and pharmaceutically acceptable salts thereof. Preferably the compounds of the invention are selected from: 2-[3-(3-[(dimethylamino)methyl]phenethylamino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide; 2-[3-[(1 S )-1-benzyl-2-(dimethylamino)ethyl]amino-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide; N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-([3-[(methylamino)methyl]phenethyl]amino)-2-oxo-1(2 H )-pyrazinyl]acetamide; 2-[3-[(3-{[(2-methoxyethyl)amino]methyl}phenethyl)amino]-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; and pharmaceutically acceptable salts thereof. It will be appreciated that many compounds of formula (I) contain one or more asymmetric centres and will therefore exist in the form of optical isomers. The present invention also includes within its scope all such enantiomers and mixtures thereof, including racemic mixtures thereof. In addition all possible diastereomeric forms (individual diastereoisomers and mixtures thereof) of compounds of formula I are included within the scope of the invention. Another aspect of the present invention provides processes for the preparation of compounds of the general formula (I), their pharmaceutically acceptable salts and acceptable solvates of either entity, as illustrated below. It will be appreciated by persons skilled in the art that, within the various processes described, the order of the synthetic steps employed may be varied and will depend, inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates, and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent for use in the said synthetic steps. It will also be appreciated that various standard transformations within certain compounds of formula (I) will provide other compounds of formula (I); examples are reductive alkylations of N-unsubstituted and N-monosubstituted amines with an appropriate aldehyde or ketone and dealkylation of N-methylamines by treatment with α-chloroethylchloroformate followed by methanolysis. Moreover, persons skilled in the art will be aware of variations of, and alternatives to, those processes described hereinafter in the Examples and Preparations section which allow the compounds defined by formula (I) to be obtained. Accordingly in a further aspect of the present invention there is provided processes for preparing the compounds of general formula (I) and pharmaceutically acceptable salts thereof comprising: (a) coupling of an acid of formula (It) with a heterocyclic amine of formula (III) or (b) coupling a heterocycle of formula (XII) wherein Z is a suitable leaving group, such as halogen, with an amine of formula (V) R 7 -B-A-NH 2 General Method A Compounds of the general formula (la) (Scheme I) may be prepared by coupling of the acid (II) with the appropriate heterocyclic amine (III) (Scheme 1). The coupling may be achieved using conventional amide bond forming techniques, in particular any one of a number of amino acid coupling variations. For example, the acid (II) may be activated using a carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochroride optionally in the presence of 1-hydroxybenzotriazole hydrate and or a catalyst such as 4-dimethylaminopyridine. Such couplings may be performed in a suitable solvent such as dichloromethane or N,N-dimethylacetamide, optionally in the presence of a tertiary amine such as N-methylmorpholine or N,N-diisopropylamine at 0°C. Compounds of the general formula (II) may be prepared from compounds of the general formula (IV) by hydrolysis or hyrogenation of the carboxylic acid ester and dechlorination of the pyrazinone ring (where R 17 is as an aryl moiety or an alkyl moiety susceptible to hydrolysis to form the corresponding carboxylic acid). This conversion may be achieved in a single step where the carboxylic acid ester is removed by catalytic hydrogenation (eg R 17 = benzyl). For example a compound of the general formula (II) can be obtained from a compound of the general formula (IV) where R 17 = benzyl by treatment with a catalytic quantity of Pearlmans catalyst under an atmosphere of hydrogen (preferably 60psi) in a suitable solvent such as methanol, at room temperature for 2 to 24hours. Alternatively a compound of the general formula (IV) may be subject to ester hydrolysis according to the plethora of methods currently available. For example treatment with lithium hydroxide or sodium hydroxide in a mixture of methanol, THF and water at room temperature. Subsequent reduction of the pyrazinone chlorine substituent may be carried out by treatment with a suitable active metal catalyst under an atmosphere of hydrogen for example: Pearlmans catalyst under an atmosphere of hydrogen as described above or by transfer hydrogenation methodology for example: treatment with ammonium formate in methanol, ethanol or iso propanol in the presence of a catalytic amount of palladium on carbon catalyst. Compounds of the general formula (IV) may be prepared by treatment of compounds of the general formula (VI) with a primary amine (V) in a solvent such as ethyl acetate or THF at reflux for 6 to 24hrs in the presence of a suitable tertiary amine base for example triethylamine or N,N-diisopropylethylamine. Compounds of the general formula (VI) may be prepared from a suitable ester derivative of glycine (VIII) according to the method of Hoomaert ( J. Het. Chem. 1983, 20, 919,). Compounds of the general formula (III) may be prepared by reduction of compounds of the general formula (IX) (Scheme 2). Such a reduction may be performed with a variety of reagents; for example, lithium aluminium hydride or hydrogen over Raney Nickel catalysis. Preferred conditions involve the use of Raney Nickel with methanol as solvent which contains 20% ammonia. The reaction is carried out at a temperature of up to 50°C in an autoclave charged with hydrogen at a pressure up to 50 bar. Compounds of the general formula (IX) where W=CH, V = C and R 1 = R 2 = R 3 = R 4 = H are commercially available whilst compounds of the general formula (IX) where W = N or CH, V = C or N, R 1 = R 2 = R 4 = H and R 3 = Me may be prepared from the precursor (X) according to the method of H. D. Porter and W. D Peterson, ( Org Synthesis , Coll Vol III p660). Compounds of the general formula (IX) where W=CH, V = C, R 2 = CH 3 and R 1 = R 3 = R 4 = H may be prepared from commercially available 5-cyano-1H-indole by formylation at the 3-position according to the method of P. N. James and H. R. Snyder, ( Org Synthesis Coll Vol IV, p539) followed by simultaneous reduction of the formyl and cyano groups using a suitable reducing agent such as lithium aluminium hydride in an aprotic solvent for example tetrahydrofuran or diethyl ether. General Method B An alternative method of preparation of compounds of the general formula (la) (Scheme 3) involves dechlorination of compounds of the general formula (Xl) by reduction. Typically this procedure may be performed by treatment with a suitable active metal catalyst under an atmosphere of hydrogen, for example, Pearlmans catalyst under an atmosphere of hydrogen as described above (General Method A); or by transfer hydrogenation methodology, for example; treatment with ammonium formate in methanol, ethanol or isopropanol in the presence of a catalytic amount of palladium on carbon catalyst (General Method A). In scheme 3, Y has been indicated as chloro as a preferred embodiment but it will be appreciated that the reaction scheme is applicable for other components of Y, and therefore as a general principle Y can be indicated generally in scheme 3. Furthermore the chloro leaving group (in position 3) in scheme 3, as a general principle can be indicated as a "leaving group" (formula XII) such as a halogen. Compounds of the general formula (Xl) may be prepared by treatment of compounds of the general formula (XIIA) with a primary amine of the general formula (V) according to the conditions described above in General Method A. Compounds of the general formula (XIIA) may be prepared from the carboxylic acid (XIII) and a suitable amine of the general formula (III) according to the general methods described above (General Method A). Compound (XIII) may be prepared from a compound of the general formula (VI) according to the plethora of methods for the hydrolysis of a carboxylic acid ester (General Method A). Amines of the general formula (V) may be prepared from a variety of precursors. Preferred routes include preparation from the corresponding nitrile such as illustrated by formula (XIV) (Scheme 4). Preparation of the amines (Va) from the nitrites (XIV) may be achieved by reduction of the appropriate nitrites using Raney nickel under an atmosphere of hydrogen. Compounds of the general formula (XIV) may be prepared from compounds of the general formula (XV) by palladium catalysed functionalisation of the halo substituent preferably a bromo substituent (shown for convenience). For example, treatment of compound (XV) wiith a palladium catalyst (palladium acetate or tris triphenyphosphinepalladium) in the presence of sodium formate under an atmosphere of carbon monoxide gives compound (XIV) where R7 = CHO. Subsequent treatment with a primary or secondary amine in the presence of a suitable reducing agent (eg sodium triacetoxyborohydride) in a protic solvent system (eg acetic acid, methanol) gives a compound of the general formula (XIV) where R7 = CH 2 NR 15 R 16 . Alternatively the reaction may be carried out under conventional catalytic hydrogenation conditions. This synthetic methodology allows the preparation of preferred compounds of type (d). In a related methodology palladium catalysed cross coupling of (XV) with the zincate derived from N-Boc-3-iodoazetidine, by direct analogy to the procedure of S. Billotte, ( Synlett , 1998, p379), gives a compound of the general formula (XIV) where R7 = N -BOC-azetidine-3-yl. Deprotection of the nitrogen using standard methodology such as protonolysis using trifluoroacetic acid or hydrogen chloride and, if required, subsequent reductive alkylation with an appropriate aldehyde or ketone allows the preparation of preferred compounds of type (g). In the case of an aldehyde or ketone precursor the reaction may be carried out in the presence of a suitable reducing agent (e.g. sodium triacetoxyborohydride) in a protic solvent system (e.g. acetic acid, methanol). Alternatively the reaction may be carried out under conventional catalytic hydrogenation conditions. Intermediate (XV) can be transmetalated with an appropriate organolithium such as butyllithium and reacted in situ with an N-substituted 2-pyrrolidone and the resulting intermediate (XIV) with R7 = an N-substituted-2-hydroxypyrrolidin-2-yl fragment may be reduced directly using for example platinum oxide under an atmosphere of hydrogen, by direct analogy with the synthetic methodology of H. Malmberg, M. Nilllsson and C. Ullenius, (Acta Chemica Scandinavia , B, 35, 1981, p625), to allow the preparation of intermediate (Va) with R7 = an N-substituted pyrrolidine-2-yl fragment This synthetic methodology allows the preparation of preferred compounds of type (G). Amines of the general formula (Vb) may be prepared from a variety of precursors. Preferred routes include preparation from amino acid derivatives (XVI) (Scheme 5) and from the nitrile derivatives (XIV). Preparation from the amino acid derivatives (XVI) where P is a suitable protecting group for an amine (preferably BOC), may be achieved by reduction of the amide bond using lithium aluminium hydride, borane or lithium borohydride in the presence of trimethylsilyl chloride in an aprotic solvent such as diethyl ether or tetrahydrofuran. Subsequent removal of the nitrogen protecting group may be achieved using trifluoroacetic acid in dichloromethane or dichloromethane saturated with HCI. Amides of the general formula (XVI) may be prepared by coupling of the appropriate amine HNR 10 R 11 with the commercially available amino acid derivatives (XVII). The coupling may be achieved using conventional amide bond forming techniques, in particular any one of a number of amino acid coupling variations described under General Method A. This synthetic methodology allows the preparation of preferred compounds of type (a). Amines of the general formula (Vc) (Scheme 6) may be prepared by treatment of compounds of the general formula (XVIII) where P is a suitable nitrogen protecting group (preferably BOC) with, for example, bromoacetonitrile and a suitable base in an aprotic polar solvent such as tetrahydrofuran, followed by reduction of the nitrile and removal of the nitrogen protecting group using, for example, ether saturated with HCI or trifluoroacetic acid in dichloromethane. Compounds of the general formula (XVIII) are commercially available. This synthetic methodology allows preparation of preferred compounds of the type (b). Amines of the general formula (Vd) (Scheme 7) may be prepared from intermediates of the general formula (XIX) by reduction according to the methods described above. Compounds of the general formula (XIX) may be prepared from compounds of the general formula (XX) by reaction of compounds of the general formula (XX) with sodium cyanide in suitable solvent for example, tetrahydrofuran or acetonitrile. Compounds of the general formula (XX) may be prepared from compounds of the general formula (XXI) by bromination using for example, N-bromosuccinimide as reviewed by L. Homer and E. H. Winkelmann in Angewandte Chemie 1959, 71, 349. Intermediates (XXI) may be prepared from compounds of the general formula (XXII) by nucleophilic attack onto the carbon atom of the cyano group according to the method of Ciganeck ( J. Org. Chem . 1992, 57, 4521) or the method of Calderwood, ( Tetrahedron Letters , 1997, 38, 1241). This synthetic methodolgy allows the preparation of preferred compounds of the type (d). Amines of the general formula (Ve) (Scheme 8) may be prepared by reduction of the commercially available nitrile (XXIII) using the method of F. Vogtle et al ( Chem Ber , 1984, 117, 1487). One of the amines in intermediate (XXIV) may be protected with a suitable protecting group P (preferably BOC) using the method of Adamczyk et al; ( Org Prep Proc Int , 1998, 30(3) 339) or the method of Krapcho et al, ( Syn Comm , 1990, 20, 2559) to give compounds of the general structure (XXV). Reductive amination of the unprotected primary amine of compounds of the formula (XXV) and subsequent removal of the protecting group P gives compounds of the general formula (Ve). This synthetic methodology allows the preparation of preferred compounds of type (e). Amines of the general formula (Vf) (Scheme 9) may be prepared from intermediates of the general formula (XXVI) by reduction of the nitrile group using for example, Raney nickel in ethanol saturated with ammonia. Compounds of the general formula (XXVI) may be prepared from compounds of the general formula (XXVII) by removal of the nitrogen protecting group P and subsequent reductive amination. Compounds of the general formula (XXVII) can be prepared by alkylation of the phenol (XXVIII) (or hydroxy methyl phenyl) with a suitably protected alcohol (XXIX) according to the method of O. Mitsonubu, ( Synthesis , 1981,1). Compound (XXVIII) is prepared from commercially available (XXX) by demethylation using for example, a solution of boron tribromide in dichloromethane. This methodology is also applicable for compounds where there is a methylene between the benzene and oxygen, such as shown in the accompanying examples 27 and 28. This said methodology allows the preparation of preferred compounds of the general type (h). Amines of the general formula (Vg) (Scheme 10 and Scheme 11) may be prepared according to the method described by J. Permattam et al (Tett, Let, 1991, 32, p7183). For example, commercially available D-prolinamide (XXXI) can be treated with an aldehyde in the presence of a suitable reducing agent (eg sodium triacetoxyborohydride) in a protic solvent system (eg acetic acid or methanol) or by alkylation with a suitable alkylating agent as described by J. Permattam et al (Tett, Let, 1991, 32, p7183) to give a compound of formula (XXXII). Subsequent reduction of the amide with a suitable reducing agent (for example lithium aluminium hydride) in a suitable aprotic solvent (for example, diethyl ether or tetrahydrofuran) as described by J. Permattam et al (Tett, Let, 1991, 32, p7183) gives a compound of the general formula Vg. This synthetic methodology allows the synthesis of preferred compounds of type (i) and (j). Preferred compounds of the type (k) may be made according to the general method described in Scheme 11. Carboxylic acid (XXXIII) may be prepared according to the method described by G. R. Brown et. Al. in J. Chem. Soc. Perkin Trans I, 1985, 2577. Subsequent formation of the primary amide (XXXIV) may be performed using a suitable carboxylic acid activating agent (for example oxalyl chloride) in a suitable solvent system (for example, dichloromethane with a trace of dimethyl formamide). Reduction of (XXXIV) using a suitable reducing agent (for example lithium aluminium hydride) in a suitable aprotic solvent (for example diethyl ether or tetrahydrofuran) provides compounds of the type (k). General Method C As a general principle, pyridone derivatives of formula (I) - i.e. formula (1b) in scheme 12, can be formed by coupling the heterocycle of formula (1c) with a carbonyl of formula (XXXVII) in the presence of a reducing agent (see hereinbefore). Compounds of the general formula (Ib) may also be prepared by coupling of the acid (XXXV) with the appropriate heterocyclic amine (III) (Scheme 12). The coupling may be achieved using conventional amide bond forming techniques, in particular any one of a number of amino acid coupling variations. For example, the acid (XXXV) may be activated using a carbodiimide such as 1-ethyl-3-(3-dimethylamino-1-propyl)carbodiimide optionally in the presence of 1-hydroxybenzotriazole and or a catalyst such as 4-dimethylaminopyridine. Such couplings may be performed in a suitable solvent such as dichloromethane, optionally in the presence of a tertiary amine such as N-methylmorpholine or N,N-diisopropylamine at 0°C. Compounds of the general formula (XXXV) may be prepared from compounds of the general formula (XXXVI) where P is a suitable carboxylic acid protecting group (preferably P is the tert-butyl group) by hydrolysis of the carboxylic acid ester using, for example if P = tert-butyl, trifluoroacetic acid in a suitable solvent such as dichloromethane at, for example, a temperature between 0°C and room temperature. Compounds of the general formula (XXXVI) may be prepared by the reaction of the amine (XXXVIII) with the desired carbonyl compound (XXXVII) in the presence of a suitable reducing agent. Preferred conditions involve the use of sodium triacetoxyborohydride in tetrahydrofuran and acetic acid. Compound (XXXVIII) may be prepared from the carbamate (XXXIX) by removal of the carbamate protecting group using a suitable catalyst under an atmosphere of hydrogen. Typical conditions involve the use of 10% palladium on carbon, at room temperature in ethyl acetate under a hydrogen pressure of 2 to 20psi. Compound (XXXIX) may be prepared by alkylation of compound (XXXX) using a suitably protected haloacetic acid derivative (XXXXI) where P is the acid protecting group (preferably P = tert-butyl) and a suitable base, for example potassium carbonate, sodium carbonate, caesium carbonate, sodium hydride or potassium hydride in a polar solvent such as acetone, THF, dimethyl formamide or 2-butanone. Preferred conditions involve the use of potassium carbonate in 2-butanone at room temperature. Compound (XXXXI) is prepared from commercially available (XXXXII) following the procedure described for a closely related compound by D. J. Wolanin and C. A. Veale et al, ( J. Med Chem 1994, 37, 3303). Carbonyl compounds of the general formula (XXXVII) may be prepared by oxidation of alcohols of the general formula (XXXXIII) where A 1 is C(R8)(R9), CH 2 C(R8)(R9), or C(R8)(R9)CH 2 , (Scheme 13). Such an oxidation may be performed by a variety of agents known to oxidise an alcohol including CrO 3 /H 2 SO 4 in acetone (Jones Reagent), CrO 3 Pyr 2 (Collins Reagent), MnO 2 or the methods of Swem or Dess-Martin . A preferred method is that of Swem involving the use of dry DMSO and oxalyl chloride in dichloromethane as solvent at -60°C under a nitrogen atmosphere. General Method D Compounds of the general formula (XXXVII) may also be prepared from compounds of the general formula (XXXVIII) by treatment with a suitable triflate of the general formula (XXXXIV) in the presence of a base; for example pyridine, triethylamine or N-ethyl-diisopropylamine in a non protic solvent such as dichloromethane, THF or diethyl ether (scheme 14). Preferred conditions for this reaction involve the use of N-ethyl-diisopropylamine as the base in dichloromethane. Triflates of the general formula (XXXXIV) may be prepared from alcohols of the general formula (XXXXV) by treatment with trifluoromethanesulfonic anhydride in the presence of a suitable base; for example pyridine, triethylamine or N-ethyl-diisopropylamine in a non protic solvent such as dichloromethane, THF or diethyl ether. Preferred conditions include the use of trifluoromethane sulfonic anhydride in dichloromethane with pyridine as the solvent at 0°C to room temperature (scheme 15). Preperation of compounds of the type of example 24 (ie wherein the pyrollidine is attached at the 3-position to the methyl amino moiety), can be prepared according to scheme 16. Amines of the general formula (XXXXVIII) may be made according to the general method described in scheme 16. The mesylate (XXXXVI) may be prepared in a 2-step procedure from (3R)-pyrrolidinol, by suitable protection of the amine (preferably Boc), following such methods as described in "Protective groups in Organic synthesis", by TW Greene and PGM Wutz (1991) or "Protecting Groups" by PJ Kocienski (1994), followed by mesylation of the intermediate alcohol. The alcohol is treated with methanesulphonyl chloride in the presence of a suitable base, such as triethylamine or pyridine, in a non protic solvent such as dichloromethane, at between 0° to room temperature. Amines of general formula (XXXXVII) may be prepared by reaction of compounds of formula (XXXXVI) with potassium cyanide in a suitable high boiling solvent, preferably DMSO, at between room temperature and 100°C. Amines of general formula (XXXXVIII) may be obtained from the nitrile of formula (XXXXVII) by reduction using Raney® nickel in an alcoholic solvent, (eg methanol), under an atmosphere of hydrogen. This following synthetic methodology allows the preparation of preferred compounds of the type analogous to example 29. Palladium catalysed cross coupling of (XV) with vinyl tributyl tin, by analogy with methods described in (Org. React 1997; 50) gave the vinyl acetonitrile, and subsequently the vinyl amine (XXXXIX), by employing a selective reducing agent (eg AlCl 3 /LiAlH 4 ) in a non protic solvent (eg tetrahydrofuran). Protection of the amine with a suitable protecting group (preferably CBz) following methods described in "Protective groups in Organic synthesis", by TW Greene and PGM Wutz (1991) or "Protecting Groups" by PJ Kocienski (1994), followed by asymmetric aminohydroxylation (AA), according to the method of O'Brien et al (J.Chem. Soc.Perk. Trans. 1, 1998, 2519) provided the hydroxyamine of general formula (LI). Subsequent methylation, using an alkylating agent (eg methyl iodide), under phase transfer conditions, using a catalyst such as benzyltriethylammonium chloride, provided the compound of general formula (Lll) Removal of the initial nitrogen protecting group may be achieved by, for example, hydrogenation in the presence of a palladium on carbon catalyst in methanol, at a pressure of, typically 15 psi. Compounds of formula (I) and the various intermediates and reagents required for the processes hereinbefore disclosed, when neither commercially available nor subsequently described, can be obtained either by analogy with the reactions described in the Examples and Preparations sections or by conventional synthetic procedures, in accordance with standard textbooks on organic chemistry or literature precedent, from readily accessible starting materials using appropriate reagents and reaction conditions. The novel intermediates described herein form a further aspect of the invention. Where keto/enol tautomerism is present the keto and enol forms are claimed separately and together (as a mixture). Suitable pharmaceutical and physiologically acceptable salts will be apparant to those skilled in the art and include for example acid addition salts formed with inorganic acids eg. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulphonic, methanesulphonic or napthalenesulphonic acid. Other non-physiologically acceptable salts eg. oxalates may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. The acid addition salts of the compounds of formula (I) may be prepared in a conventional manner. For example a solution of the free base is treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt isolated either by filtration or by evaporation under reduced pressure of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula (I) with the appropriate base. Both types of salt may be formed or interconverted using ion-exchange resin techniques. The subject invention also includes pharmaceutially acceptable solvates (including hydrates), and polymorphs of the compounds of the invention. It will be further appreciated that certain moieties known as "pro-moieties", for example as described in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985 (the disclosured of which is hereby incorporated by reference), may be placed on appropriate functionalities of the compounds of formula 1. Such prodrugs are included within the scope of the invention. The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively. Compounds of the present invention and pharmaceutically acceptable salts of said compounds or which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. In therapy, the compounds of formula (I), their pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of either entity, can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Preferably, they are administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents. They can also be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or glucose to make the solution isotonic with blood. For buccal or sublingual administration they may be administered in the form of tablets or lozenges which can be formulated in a conventional manner. For oral, parenteral, buccal and sublingual administration to patients, the daily dosage level of the compounds of formula (I) and their pharmaceutically acceptable salts and solvates may contain from 1 to 1000 mg (in single or divided doses). Thus tablets or capsules may contain from 0.5 to 500 mg of active compound for administration singly, or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention. The following formulation examples are illustrative only and are not intended to limit the scope of the invention "Active ingredient means a compound according to formula 1 or a pharmaceutically acceptable salt thereof. Formulation 1: A tablet is prepared using the following ingredients : Quantity (mg/tablet) Active ingredient 250 cellulose, microcrystalline 400 silicon dioxide, fumed 10 stearic acid 5 total 665mg the components are blended and compressed to form tablets each weighing 665mg. Formulation 2 : An intrvenous formulstion may be prepared as follows: Active ingredient 100mg isotonic saline 1,000ml Further aspects of the invention are as follows below. (i) Pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier. (ii) A compound of formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament (iii) Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the curative or prophylactic treatment of deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignancy, prolonged immobilisation trauma, application of lower limb plaster casts, or fractures of the lower limbs or pelvis; recurrent DVT; DVT during pregnancy when there is a previous history thereof; reocclusion following thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; transient ischaemic attacks; disseminated intravascular coagulation; coagulation in extra-corporeal circuits; occlusion of arterio-venous shunts and blood vessel grafts (including coronary artery by-pass grafts); restenosis and occlusion following angioplasty; neurodegenerative disorders; inflammatory disorders; or scarring. (iv) A method of treating a mammal (including a human being) to cure or prevent deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignancy, prolonged immobilisation trauma, application of lower limb plaster casts, or fractures of the lower limbs or pelvis; recurrent DVT; DVT during pregnancy when there is a previous history thereof; reocclusion following thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; transient ischaemic attacks; disseminated intravascular coagulation; coagulation in extra-corporeal circuits; occlusion of arterio-venous shunts and blood vessel grafts (including coronary artery by-pass grafts); restenosis and occlusion following angioplasty; neurodegenerative disorders; inflammatory disorders; or scarring; which comprises treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. It will be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment. The syntheses of the compounds of the invention and of the intermediates for use therein are illustrated by the following examples. The purity (Rf) of the compounds was routinely monitored by thin layer chromatography using Merck Kieselgel 60 F 254 plates and the following solvent systems (SS): 1. isobutyl methyl ketone:glacial acetic acid:water, 2:1:1 (upper phase); 2. hexane:ethyl acetate, 1:1; 3. hexane:ethyl acetate, 7:3; 4. dichloromethane:methanol:0.880 aqueous ammonia, 85:15:2; 5. dichloromethane:methanol:0.880 aqueous ammonia, 84:14:2; 6. hexane:ethyl acetate, 6:4; 7. dichloromethane:methanol:0.880 aqueous ammonia, 93:7:1; 8. dichloromethane:methanol, 90:10; 9. dichloromethane:methanol:0.880 aqueous ammonia, 93:7:2; 10. dichloromethane:methanol:0.880 aqueous ammonia, 90:10:1; 11. dichloromethane:methanol, 95:5; 12. dichloromethane:methanol:0.880 aqueous ammonia, 193:7:1; 13. ethyl acetate; 14. hexane:ether, 1:1; 15. hexane:ether, 1:3; 16. dichloromethane:methanol:0.880 aqueous ammonia, 80:20:5; 17. chloroform:methanol, 95:5; 18. hexane:ethyl acetate, 3:7; 19. methanol:ethyl acetate:glacial acetic acid:0.880 aqueous ammonia:water, 60:12:4:4:8. I H Nudear magnetic resonance (NMR) spectra were recorded using either a Varian Inova 300 or a Varian Inova 400 spectrometer and were in all cases consistent with the proposed structures. Mass spectra were obtained with a Fisons Instrument Trio 1000 spectrometer using thermospray ionisation. Room temperature means 20-25°C. Example 1 ( R,S )-2-[3-[(2-Amino-1-benzylethyl)amino]-6-methyl-2-oxo-1(2 H )-pyridinyl]- N -(1 H -indol-5-ylmethyl)acetamide. Preparation 1 ( R,S )-Benzyl N -(2-hydroxy-3-phenylpropyl)carbamate 1-Amino-3-phenyl-2-propanol (3.9g, 25.79mmol; prepared as described in J. Amer. Chem. Soc . 1946, 203) was dissolved in CH 2 Cl 2 (200ml) and treated with triethylamine (0.35ml, 2.58mmol) followed by 1-[(benzyloxy)carbonyl]oxydihydro-1 H -pyrrole-2,5-dione (6.43g, 25.79mmol) and the resultant mixture stirred at room temperature (72hr). The resultant mixture was washed with aq citric acid (1N, 200ml), sat aq brine (2 x 200ml) and dried over MgSO 4 . Removal of the drying agent by filtration followed by evaporation of the solvent gave the desired product as a viscous clear oil (5.18g, 78%). 1 H NMR (CDCl 3 ) d 1.60 (m, 1H), 2.20 (s, br, 1/2H), 2.70 (m, 1H), 2.80 (m, 3/2H), 3.20 (m, 1/2H), 3.45 (m, 1/2H), 3.95 (m, 1H), 5.10 (s, br, 2H), 5.30 (m, 1H), 7.19-7.35 (m, 10H). LRMS m/z = 286.3 (M+1). Preparation 2 Benzyl N -(2-oxo-3-phenylpropyl)carbamate Dry DMSO (3.0ml, 43.54mmol) in CH 2 Cl 2 (6.9ml) was added dropwise to a solution of oxalyl chloride (1.73ml, 19.91mmol) in CH 2 Cl 2 (35ml) at -60°C under a nitrogen atmosphere. After stirring for 2mins at -60°C a solution of ( RS )-benzyl- N -(2-hydroxy-3-phenylpropyl)carbamate (preparation 1) (5.18g, 18.15mmol) in CH 2 Cl 2 (17ml) was added dropwise over 10 mins followed by triethylamine (17.63ml, 90.74mmol). The resultant mixture was allowed to warm to room temperature, whereupon water (100ml) was added. The aqueous mixture was extracted with CH 2 Cl 2 (3 x 100ml) and the combined organic extracts washed with sat aq brine (2 x 250ml) and dried over MgSO 4 . Filtration away from the drying agent followed by evaporation of the solvent gave the crude product which was purified by chromatography (SiO 2 ; eluting with 40:60 hexane:ethyl acetate) to give the desired product (yellow crystalline solid, 4.41g, 86%). 1 H NMR (CDCl 3 )δ :3.72 (s, 2H), 4.11 (d, 2H), 5.09 (s, 2H), 5.45 (s, br, 1H), 7.20-7.37 (m, 10H). LRMS m/z = 301.0 (M+18) + . Preparation 3 Benzyl N -(6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)carbamate A suspension of 6-methyl-2-oxo-2,3-dihydro-3-pyridinecarboxylic acid (20g, 0.13mol) in dioxan (400ml) was treated with triethylamine (22ml, 0.15mol) followed by diphenylphosphoryl azide (30.8ml, 0.14mol) and heated under reflux for 2hr. A further portion of diphenylphosphoryl azide (3ml) and triethylamine (2ml) were added and heated under reflux for a further 1 hr. The resultant mixture was then treated with benzyl alcohol (18.8ml, 0.18mol) and heated under reflux for 18hr. The resultant mixture was cooled, evaporation of the solvent gave a crude solid which was triturated with water. The solid was collected by filtration, washed with HCI (1N, 300ml) then water. The solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried to give the desired product (22g, 65%). 1 H NMR (CDCl 3 )δ 1.20 (s, 1H), 2.30 (s, 3H), 5.20 (s, 2H), 6.05 (d, 1H), 7.40 (m, 5H), 7.70 (s, 1H), 8.00 (d, 1H). LRMS m/z = 259.2 (M+1) + . Preparation 4 tert -Butyl 2-[3-[(benzyloxy)carbonyl]amino-6-methyl-2-oxo-1(2 H )-pyridinyl]acetate A slurry of benzyl N -(6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)carbamate (preparation 3) (20g, 78mmol) in 2-butanone (500ml) was treated with K 2 CO 3 (53.9g, 94mmol) and further 2-butanone (100ml). The resultant mixture was treated cautiously with tert -butyl 2-bromoacetate (15.2ml, 94mmol) and stirred at room temperature for 18hr. The solvent was evaporated and the crude material was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate, the combined organic layers washed with sat aq brine and dried over Na 2 SO 4 . Removal of the drying agent by filtration followed by evaporation of the solvent gave the crude product which was purified by recrystallisation from ethyl acetate : hexane to give the desired product (white solid, 15.1g, 52%). 1 H NMR (CDCl 3 )δ :1.40 (s, 9H), 2.20 (s, 3H), 4.70 (s, 2H), 5.20 (s, 2H), 6.05 (d, 1H), 7.40 (m, 5H), 7.70 (s, br, 1H), 7.90 (d, 1H). LRMS m/z = 373.6 (M+1) + . Preparation 5 tert -Butyl 2-[3-amino-6-methyl-2-oxo-1(2 H )-pyridinyl]acetate tert -Butyl-2-[3-[(benzyloxy)carbonyl]amino-6-methyl-2-oxo-1(2 H )-pyridinyl]acetate (preparation 4) (5g, 13mmol) was dissolved in ethyl acetate (70ml), treated with 10% Pd on carbon catalyst (400mg) and stirred under a hydrogen atmosphere (2psi, room temperature, 3hr). The catalyst was removed by filtration, and the solvent evaporated to dryness to give the desired product as a cream solid (3.08g, 99%). 1 H NMR (CDCl 3 )δ 1.40 (s, 9H), 2.20 (s, 3H), 4.00 (s, br, 2H), 4.70 (s, 2H), 5.90 (d, 1H), 6.45 (d, 1H). LRMS m/z = 239.5 (M+1) + . Preparation 6 ( R,S )- tert -Butyl 2-[3-[(1-benzyl-2-[(benzyloxy)carbonyl]aminoethyl)amino]-6-methyl-2-oxo-1(2 H )-pyridinyl]acetate. tert -Butyl-2-[3-amino-6-methyl-2-oxo-1(2 H )-pyridinyl]acetate (preparation 5) (0.476g, 2.00mmol) and benzyl N -(2-oxo-3-phenylpropyl)carbamate (preparation 2) (0.68g, 2.4mmol) was dissolved in THF (10ml) and acetic add (0.132g, 2.2mmol). This mixture was treated with sodium triacetoxyborohydride (0.634g, 3.0mmol) and the resultant mixture stirred (18hr, room temperature). A further quantity of benzyl N -(2-oxo-3-phenylpropyl)carbamate (0.46g, 1.6mmol) was added followed by sodium triacetoxyborohydride (0.634g, 3.0mmol) and the mixture stirred (room temperature, 18hr). The resultant mixture was diluted with CH 2 Cl 2 (100ml) and washed with sat aq NaHCO 3 (100ml), sat aq brine (100ml) and dried over MgSO 4 . Filtration away from the drying agent and evaporation of the solvent gave a pale yellow oil which was purified by chromatography (SiO 2 , gradient elution 100% hexane; 90:10 hexane:ethyl acetate; 80:20 hexane:ethyl acetate; 75:25 hexane:ethyl acetate). Thedesired product was isolated impure (pale yellow oil, 1.0g). 1 H NMR (CDCl 3 ) δ 1.45 (s, 9H), 2.15 (s, 3H), 2.70 (m, 1H), 2.80 (m, 1H), 3.15 (m, 1H), 3.40 (m. 1H), 3.65 (m, 1H), 4.70 (m, 2H), 5.10 (m, 3H), 5.90 (d, 1H), 6.25 (d, 1H), 7.10-7.40 (m, 11H). LRMS m/z = 506.3 (M+1). Preparation 7 ( R,S )-2-[3-[(1-Benzyl-2-[(benzyloxy)carbonyl]aminoethyl)amino]-6-methyl-2-oxo-1(2 H )-pyridinyl]acetic acid. ( R,S )-tert-Butyl-2-[3-[(1-benzyl-2-[(benzyloxy)carbonyl]aminoethyl)amino]-6-methyl-2-oxo-1(2 H )-pyridinyl]acetate (preparation 6) (1.0g, 1.98mmol), was dissolved in CH 2 Cl 2 (16ml) and treated with TFA (8.0ml). After stirring at room temperature for 5hr, the resultant mixture was evaporated to dryness and azeotroped with CH 2 Cl 2 (x3). Chromatography (SiO 2 , gradient elution 100% CH 2 Cl 2 ; 95:5 CH 2 Cl 2 :MeOH; 90:10 CH 2 Cl 2 :MeOH) gave the desired product (white powder, 0.358g, 40%). 1 H NMR (d 6 -DMSO)δ 2.05 (s, 3H), 2.75 (m, 1H), 2.85 (m, 1H), 2.90 (m, 1H), 3.15 (m, 1H), 3.50 (m, 1H), 4.45 (s, br, 2H), 4.95 (d, 1H), 5.0 (s, 2H), 5.90 (d, 1H), 6.25 (d, 1H), 7.10-7.30 (m, 10H), 7.45 (t, br, 1H). LRMS m/z = 450.3 (M+1)+. Found C 56.30, H 4.87, N 7.24%; C 25 H 27 N 3 O 5 requires C 56.42, H 5.33, N 7.50%. Preparation 8 1 H -Indol-5-ylmethylamine A stirred solution of 1 H -indole-5-carbonitrile (4.0g, 28.1mmol) in THF (50ml) at 0°C was treated dropwise with lithium aluminium hydride in THF (1M, 98ml,98mmol). The resultant mixture was stirred, warming to room temperature overnight. Sat. aq. NaHCO 3 (60ml) was added at 0°C and resultant mixture was filtered through filter agent celite 521 and washed with THF. Evaporation of the solvent gave the crude product which was purified by chromatography (SiO 2 , gradient elution with 95:5 CH 2 Cl 2 :MeOH; 90:10 CH 2 Cl 2 :MeOH; 90:10:1 CH 2 Cl 2 :MeOH:NH 3 ) to give the desired product (white powder, 12.9g, 71%). 1 H NMR (CD 3 OD) δ 4.10 (s, 2H), 6.50 (d, 1H), 7.15 (d, 1H), 7.30 (d, 1H), 7.40 (d, 1H), 7.60 (s, 1H). LRMS m/z = 147.2 (M+1) + . Preparation 9 ( R,S )-Benzyl N -2-[(1-2-[(1 H -indol-5-ylmethyl)amino]-2-oxoethyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)amino]-3-phenylpropylcarbamate. ( R,S )-2-[3-[(1-benzyl-2-[(benzyloxy)carbonyl]aminoethyl)amino]-6-methyl-2-oxo-1(2 H )-pyridinyl]acetic acid (preparation 7) (157mg, 0.349mmol), 1 H -indol-5-ylmethylamine (preparation 8) (50mg, 0.349mmol), HOBT (49mg, 0.349mmol), WSCDI.HCI (75mg, 0.391mmol), N-methylmorpholine (145mg, 1.40mmol) and DMF (5.0ml) were stirred at room temperature for 18hr. The reaction mixture was diluted with water (20ml) and ethyl acetate (20ml) and shaken in a separatory funnel. The organic layer was separated, washed with sat aq brine (20ml), dried over MgSO 4 . Filtration away from the drying agent followed by evaporation of the solvent gave the crude product which was purified by chromatography (SiO 2 , gradient elution 50:50 hexane:ethyl acetate; 100% ethyl acetate) to give the desired product (white foam, 0.153g, 76%). 1 H NMR (CDCl 3 ) δ 2.35 (s, 3H), 2.78 (d, 2H), 3.15 (m, 1H), 3.35 (m, 1H), 3.65 (m, 1H), 4.50 (d, 2H), 4.75 (AB Quartet, 2H), 5.0 (s, br, 1H), 5.05 (s, 2H), 5.95 (d, 1H), 6.30 (d, 1H), 6.50 (s, 1H), 6.95 (s, br, 1H), 7.0 (d, 1H), 7.10-7.35 (m, 13H), 7.45 (s, 1H), 8.15, (s, br, 1H). LRMS m/z = 578.4 (M+1). Preparation 10 ( R,S )-2-[3-[(2-Amino-1-benzylethyl)amino]-6-methyl-2-oxo-1(2 H )-pyridinyl]- N -(1 H -indol-5-ylmethyl)acetamide. ( R,S )-Benzyl- N -2-[(1-2-[(1 H -indol-5-ylmethyl)amino]-2-oxoethyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)amino]-3-phenylpropylcarbamate (preparation 9) (0.15g, 0.259mmol) was dissolved in ethanol (10mL), treated with 10% Pd on carbon catalyst (50mg) and stirred under a hydrogen atmosphere (15psi, room temperature, 18hr). A further 50mg of 10% Pd on carbon was added and stirring under hydrogen (15psi) continued for 18hr. The catalyst was removed by filtration, the solvent evaporated to dryness and the resultant crude product purified by chromatography (SiO 2 , gradient elution 90:10 CH 2 Cl 2 :MeOH; 90:10:0.5 CH 2 Cl 2 :MeOH:NH 3 ; 90:10:1 CH 2 Cl 2 :MeOH:NH 3 ) to give, recovered starting material as the first eluted fraction (8mg at 53%) and the desired product as the second eluted fraction (white solid, 28mg at 24%). 1 H NMR (CD 3 OD) δ 2.25 (s, 3H), 2.75-2.90 (m, 3H), 3.0 (dd, 1H), 3.75 (s, 1H), 4.50 (s, 2H), 4.75 (d, 1H), 4.90 (d, 1H), 6.10(d, 1H), 6.40(d, 1H), 6.45 (d, 1H), 7.05 (d, 1H), 7.10-7.30 (m, 6H), 7.35 (d, 1H), 7.50 (s, 1H). LRMS m/z = 444.2 (M+1) + . Example 2 2-[3-(3-[(Dimethylamino)methyl]phenethylamino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide Preparation 11 Methyl 3-[(methylamino)carbonyl]benzoate A slurry of methyl isophthalate (5.10g, 0.028mol) in CH 2 Cl 2 (100ml) at room temperature was treated with oxalyl chloride (6.0ml) followed by DMF (3 drops). The resultant mixture was stirred under reflux (90 mins). The resultant mixture was cooled to room temperature, the solvent removed by evaporation and the residue azeotroped with CH 2 Cl 2 . The resultant mixture was dissolved in THF (100ml), cooled to 0°C and treated with a solution of methylamine (2M, 28ml,56mmol) in THF. The mixture was allowed to warm to room temperature overnight, solvent removed by evaporation and resultant mixture was partitioned between ethyl acetate (200ml) and water (200ml). The organic layer separated and washed with sat aq NaHCO 3 , sat aq brine, and dried over MgSO 4 . Removal of the drying agent by filtration followed by evaporation of the solvent gave the desired product (white solid, 4.60g, 79%). 1 H NMR (CDCl 3 )δ 3.00 (d, 3H), 4.00 (s, 3H), 6.30 (s, br, 1H), 7.50 (t, 1H), 8.00 (d, 1H), 8.20 (d, 1H), 8.40 (s, 1H). LRMS m/z = 211.1 (M+18) + . Preparation 12 3-[(Methylamino)methyl]phenylmethanol A stirred solution of methyl 3-[(methylamino)carbonyl]benzoate (preparation 11) (5.0g, 20.7mmol) in THF (120ml) was treated dropwise with a solution of lithium aluminium hydride (1M, 30ml,30mmol) in THF. The resultant slurry was stirred under reflux overnight, cooled and treated with water (1.1ml), 15%NaOH (1.8ml) and water (2.5ml). The resultant gel was removed by filtration, the liquors concentrated in vacuo and taken up in ethyl acetate (120ml). The organic layer was washed with sat aq brine (100ml) and dried over MgSO 4 . Removal of the drying agent by filtration followed by evaporation of the solvent gave an oil which was purified by chromatography (SiO 2 , gradient elution with CH 2 Cl 2 ; 95:5 CH 2 Cl 2 :MeOH; 90:10 CH 2 Cl 2 :MeOH; 90:10:1 CH 2 Cl 2 :MeOH:NH 3 ; 85:15:1 CH 2 Cl 2 :MeOH:NH 3 ). The second eluted material proved to be the correct product (2.9g, 69%,). 1 H NMR (CDCl 3 ) δ 2.20 (s, 2H), 2.40 (s, 3H), 3.70 (s, 2H), 4.60 (s, 2H), 7.20-7.40 (m, 4H). LRMS m/z = 152.4 (M+1) + . Preparation 13 tert -Butyl N -[3-(bromomethyl)benzyl]- N -methylcarbamate A milky suspension of 3-[(methylamino)methyl]phenylmethanol (preparation 12) (2.7g, 17.9mmol) in THF (60ml) and water (60ml) was treated with di-t-butylpyrocarbonate (5.4g,24.7mmol) and the mixture stirred at room temperature overnight. The THF was evaporated and the aqueous residue treated with ethyl acetate (250ml). The organic layer was washed with sat aq brine (100ml) and dried over MgSO 4 . Filtration away from the drying agent followed by evaporation of the solvent gave the crude product which was purified by chromatography (SiO 2 , eluting with 95:5CH 2 Cl 2 :MeOH) to give the intermediate tert -butyl N -[3-(hydroxymethyl)benzyl]- N -methylcarbamate(4.2g) which was used directly in the next step. A stirred solution of tert -butyl- N -[3-(hydroxymethyl)benzyl]- N -methylcarbamate (4.2g, 16.7mmol) in CH 2 Cl 2 (150ml) at 0°C, was treated with carbon tetrabromide (8.0g, 24.1mmol) and triphenyl phosphine (6.35g, 24.21mmol). The resultant solution was warmed to room temperature and stirred for 4 days. The resultant mixture was evaporated to dryness and the residue purified by chromatography (SiO 2 , gradient elution with 100% hexane; 99:1 hexane:ethyl acetate; 95:5 hexane: ethyl acetate) to give the desired product (3.32g, 60%). 1 H NMR (CDCl 3 )δ 1.50 (s, 9H), 2.80 (s, br, 3H), 4.20 (s, 2H), 4.30 (s, 2H), 7.15 (m, 1H), 7.25 (m, 1H), 7.30 (m, 2H). LRMS m/z = 333.2 (M+18) + . Preparation 14 tert -Butyl N -[3-(cyanomethyl)benzyl]- N -methylcarbamate tert -Butyl- N -[3-(bromomethyl)benzyl]- N -methylcarbamate (preparation 13) (3.2g, 10.18mmol) was dissolved in acetonitrile (50ml) and treated with sodium cyanide (1.23g, 25.10mmol) followed by benzyl triethylammonium bromide (220mg, 0.8mmol) and the resultant mixture stirred at room temperature for 4 days. The resultant slurry was diluted with ethyl acetate (200ml) washed with water, sat aq brine and dried over MgSO 4 . Removal of the drying agent by filtration followed by evaporation of the solvent gave a pale yellow solid which was purified by chromatography (SiO 2 , eluting with 100% CH 2 Cl 2 ) to give the desired product with a trace of impurity (3.0g). 1 H NMR (CDCl 3 )δ 1.50 (s, 9H), 2.80 (s, b, 3H), 3.75 (s, 2H), 4.40 (s, 2H), 7.20 (m, 3H), 7.35 (t, 1H). LRMS m/z = 278.1 (M+18) + . Preparation 15 tert -Butyl N -[3-(2-aminoethyl)benzyl]- N -methylcarbamate tert -Butyl- N -[3-(cyanomethyl)benzyl]- N -methylcarbamate (preparation 14) (3g, 11.5mmol, slightly impure) was dissolved in ethanol saturated with NH 3 (300ml), treated with Raney® Nickel (500mg) and stirred under a hydrogen atmosphere (60psi, room temperature, 18hr). The catalyst was removed by filtration under nitrogen, the solvent evaporated to dryness and the resultant crude product purified by chromatography (SiO 2 , gradient elution with 100% CH 2 Cl 2 ; 95:5 CH 2 Cl 2 :MeOH; 90:10 CH 2 Cl 2 :MeOH) to give the desired product (2.40g, 78%). 1 H NMR (CDCl 3 )δ 1.20 (s, 2H), 1.50 (s, 9H), 2.70-2.90 (m, 5H), 3.00 (s, 2H), 4.20 (s, br, 2H), 7.05 (s, br, 3H), 7.25 (s, br, 1H). LRMS m/z = 265.1 (M+1) + . Preparation 16 ( R,S )-Benzyl 2-[(1-cyanoethyl)amino]acetate hydrochloride A cooled solution of glycine benzylester free base (12.9g, 78.09mmol -from the HCl salt by partition between ethyl acetate and brine basified with sat Na 2 CO 3 solution) in CH 2 Cl 2 (100ml) with 3Å molecular sieves was treated with a solution of acetaldehyde (4.36ml, 78.09mmol) in CH 2 Cl 2 (5ml). After 30mins the mixture was treated dropwise with a solution of TMSCN (10.40ml, 78.09mmol) cautiously, and the temperature maintained at 5°C. The resultant mixture was stirred at room temperature for 3hr, washed with water, the aqueous layer extracted with CH 2 Cl 2 (x2), the combined organic layers dried over MgSO 4 and the solvent evaporated. The resultant pale yellow oil was taken up in ether (150ml) treated with a solution of HCI in ether (1M, 78ml) to precipitate a solid which was collected by filtration, dried to give the desired product (17.85g, 89%). 1 H NMR (CD 3 OD) δ 1.70 (d, 3H), 4.20 (s, 2H), 4.70 (q, 1H), 5.30 (s, 2H), 7.40 (m, 5H). LRMS m/z = 236.3 (M+18) + . Preparation 17 Benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate A suspension of benzyl-2-[(1-cyanoethyl)amino]acetate hydrochloride (preparation 16) (17.8g, 69.88mmol) in toluene (120ml) was treated cautiously with oxalyl chloride (24.38ml). Once effervescence had ceased the reaction was heated at 100°C (24hr). The reaction was cooled, solvent evaporated to dryness and the resultant crude product purified by chromatography (SiO 2 , gradient elution with 70:30 pentane:ethyl acetate; 50:50 pentane:ethyl acetate; 30:70 pentane:ethyl acetate; 100% ethyl acetate). Chromatography again, (SiO 2 , eluting with 100% CH 2 Cl 2 ) gave the desired product as an off-white solid (9.40g, 41%). 1 H NMR (CD 3 OD) δ 2.35 (s, 3H), 4.90 (s, 2H), 5.25 (s, 2H), 7.40 (m, 5H). Preparation 18 Benzyl 2-[3-[(3-[( tert -butoxycarbonyl)(methyl)amino]methylphenethyl)amino]-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate tert-Butyl- N -[3-(2-aminoethyl)benzyl]- N -methylcarbamate (preparation 15) (0.5g, 1.89mmol), benzyl-2-[3,5-dichloro-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (preparation 17) (0.6g, 1.83mmol) and triethylamine (0.5ml, 3.66mmol) in ethyl acetate (30ml) were stirred at reflux for 24hr. The resultant mixture was diluted with ethyl acetate (20ml) and washed with water, sat aq brine, dried over MgSO 4 . Removal of the drying agent by filtration followed by evaporation of the solvent gave a red oil which was purified by chromatography (SiO 2 , gradient elution with 100% CH 2 Cl 2 ; 99:1 CH 2 Cl 2 :MeOH; 98:2 CH 2 Cl 2 :MeOH) to give the desired product (0.76g, 75%). 'H NMR (CDCl 3 ) δ 1.45 (s, 9H), 2.20 (s, 3H), 2.80 (s, br, 3H), 2.90 (t, 2H), 3.70 (m, 2H), 4.20 (s, br, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, br, 1H), 7.10 (m, 3H), 7.25 (m, 1H), 7.35 (m, 5H). LRMS m/z = 555.3 (M+1) + . Found C 62.50, H 6.34, N 9.98%; C 29 H 35 N 4 O 5 Cl requires C 62.75, H 6.36, N 10.09 %. Preparation 19 Benzyl 2-[3-chloro-2-methyl-5-(3-[(methylamino)methyl]phenethylamino)-6-oxo-1(6 H )-pyrazinyl]acetate Benzyl-2-[3-[(3-[( tert -butoxycarbonyl)(methyl)amino]methylphenethyl)amino]-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate (preparation 18) (0.7g, 1.26mmol) was dissolved in CH 2 Cl 2 (10ml) and treated with TFA (1.0ml). After stirring at room temperature for 3hr, the reaction mixture was evaporated to dryness then dissolved in ethyl acetate (200ml) washed with sat. aq NaHCO 3 , sat aq brine, dried over MgSO 4 . Removal of the drying agent by filtration followed by evaporation of the solvent gave a dark brown oil which was purified by chromatography (SiO 2 , gradient elution with 100% CH 2 Cl 2 ; 98:2 CH 2 Cl 2 :MeOH; 95:5 CH 2 Cl 2 :MeOH; 95:5:1 CH 2 Cl 2 :MeOH:NH 3 ) to give the desired product (0.38g, 65%). 1 H NMR (CDCl 3 )δ 2.00 (s, br, 1H), 2.20 (s, 3H), 2.45 (s, 3H), 2.90 (t, 2H), 3.70 (m, 2H), 3.75 (s, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, br, 1H), 7.10 (m, 1H), 7.15 (m, 2H), 7.25 (m, 1H), 7.35 (m, 5H). LRMS m/z = 455.0, 457.2 (M+1) + . Preparation 20 Benzyl 2-[3-chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate A stirred solution of benzyl 2-[3-chloro-2-methyl-5-(3 [(methylamino)methyl]phenethylamino)-6-oxo-1(6 H )-pyrazinyl]acetate (preparation 19) (0.38g, 0.83mmol) in CH 2 Cl 2 (10ml) was treated with formaldehyde (0.31ml). After stirring at room temperature for 45mins, the resultant cloudy mixture was treated with sodium triacetoxyborohydride (253mg,1.19mmol) and stirred at room temperature for a further 2 days. The reaction mixture was diluted with CH 2 Cl 2 (200ml) and washed with sat. aq NaHCO 3 , sat aq brine and dried over MgSO 4 . Removal of the drying agent by filtration followed by evaporation of the solvent gave a crude solid which was purified by chromatography (SiO 2 , gradient elution with 100% CH 2 Cl 2 ; 95:5 CH 2 Cl 2 :MeOH; 90:10 CH 2 Cl 2 :MeOH) to give the desired product (0.30g, 77%). 1 H NMR (CDCl 3 )δ 2.20 (s, 3H), 2.25 (s, 6H), 2.90 (t, 2H), 3.40 (s, 2H), 3.70 (m, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, br, 1H), 7.10-7.20 (m, 3H), 7.25 (m, 1H), 7.35 (m, 5H). LRMS m/z = 469.2, 471.2 (M+1). Preparation 21 2-[3-(3-[(Dimethylamino)methyl]phenethylamino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid Benzyl-2-[3-chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (preparation 20) (137mg,0.29mmol) was dissolved in methanol:water (10:2, 20ml), treated with Pearlman's catalyst (10mg) and stirred under a hydrogen atmosphere (60psi, room temperature, 2.5hr). The catalyst was removed by filtration, followed by evaporation of the solvent and azeotroping with CH 2 Cl 2 to yield a crude yellow solid. To the crude mixture, 1 H -indol-5-ylmethylamine (preparation 8) (43mg, 0.29mmol), HOBT (46mg, 0.34mmol), WSCDI.HCI (74mg, 0.39mmol), N-methylmorpholine (0.061ml, 0.55mmol) and DMF (5ml) were stirred at room temperature for 18hr. The resultant mixture was evaporated to dryness and azeotroped with CH 2 Cl 2 . Water (2ml) was added followed by aq Na 2 CO 3 (a few drops) and the residue treated with ethyl acetate and methanol. The organic layer was separated, dried over MgSO 4 . Filtration away from the drying agent followed by evaporation of the solvent gave the crude product which was purified by chromatography (SiO 2 , gradient elution with 100% CH 2 Cl 2 ; 95:5 CH 2 Cl 2 :MeOH; 95:5:0.5 CH 2 Cl 2 :MeOH:NH 3 ) to give the desired product (10mg, 7%). 1 H NMR (CDCl 3 ) δ 2.10 (s, 3H), 2.20 (s, 6H), 2.90 (t, 2H), 3.45 (s, 2H), 3.60 (t, 2H), 4.45 (s, 2H), 4.70 (s, 2H), 6.40 (m, br, 2H), 6.70 (m, 1H), 7.05 (m, 2H), 7.10-7.30 (m, 4H), 7.35 (m, 2H), 7.50 (m, 2H). LRMS m/z = 473.2 (M+1) + . Example 3 2-[3-Chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide Preparation 22 2-[3-Chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetic acid hydrochloride Benzyl-2-[3-chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (preparation 20) (100mg, 0.21mmol) was dissolved in ethanol (10ml), treated with 10% Pd on carbon catalyst (20mg), aq HCl (1m, 0.1ml) and stirred under a hydrogen atmosphere (20psi, room temperature, 2hr). The catalyst was removed by filtration, the solvent evaporated to dryness and the residue azeotroped with CH 2 Cl 2 to give the desired product, slightly impure (white solid, 85mg). 1 H NMR (CD 3 OD)δ 2.30 (s, 3H), 2.80 (s, 6H), 3.00 (t, 2H), 3.60 (t, 2H), 4.20 (s, 2H), 4.70 (s, 2H), 7.30 (m, 2H), 7.40 (m, 2H). LRMS m/z = 379.1 (M+1) + . Preparation 23 2-[3-Chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide The title compound was prepared by a similar method to preparation 9 from 2-[3-chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetic acid hydrochroride (preparation 22) (85mg, 0.20mmol) and 1 H -indol-5-ylmethylamine (preparation 8) (35mg, 0.24mmol) to give the title compound (100mg, 0.19mmol, 98%). 1 H NMR (CD 3 OD) δ 2.20 (s, 3H), 2.70 (s, 6H), 3.00 (m, 2H), 3.60 (m, 2H), 4.20 (s, 2H), 4.50 (s, 2H), 4.80 (m, 2H), 7.05 (m, 1H), 7.10-7.55 (m, 9H), 7.75 (m, 1H), 7.85 (m, 1H). LRMS m/z = 507.3, 509.3 (M+1) + . Example 4 2-[3-[(1 S )-1-Benzyl-2-(dimethylamino)ethyl]amino-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide Preparation 24 Benzyl 2-[3-[(1 S )-1-benzyl-2-(dimethylamino)ethyl]amino-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate The title compound was prepared by a similar method to preparation 18 from N -[(2 S )-2-amino-3-phenylpropyl]- N,N -dimethylamine (190mg, 1.07mmol; prepared as described in Chem. Pharm. Bull . 1970, 18,1731-1736) and benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (preparation 17) (361mg, 1.10mmol). The crude product was purified by chromatography (SiO 2 ; gradient elution 100% hexane; 80:20 hexane:ethyl acetate; 60:40 hexane:ethyl acetate; 40:60 hexane:ethyl acetate; 20:80 hexane:ethyl acetate) to give the desired product (yellow solid, 260mg, 50%). 1 H NMR (CDCl 3 ) δ 2.20 (m, 9H), 2.30 (m, 1H), 2.20 (m, 1H), 2.85 (m, 1H), 3.10 (m, 1H), 4.25 (m, 1H), 4.80 (s, 2H), 5.20 (s, 2H), 6.20 (m, 1H), 7.20 (m, 5H), 7.35 (m, 5H). LRMS m/z = 469.2, 471.3 (M+1) + . Preparation 25 2-[3-[(1 S )-1-Benzyl-2-(dimethylamino)ethyl]amino-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide The title compound was prepared by a similar method to Example 2 from benzyl 2-[3-[(1 S )-1-benzyl-2-(dimethylamino)ethyl]amino-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate (preparation 24) (240mg, 0.51 mmol) which was treated with Pearlman's catalyst (see example 2) to give a crude acid (168mg, 95%). The crude add (100mg, 0.26mmol) was coupled with 1 H -indol-5-ylmethylamine (preparation 8) (41mg, 0.29mmol), to give a crude mixture which was purified by chromatography (SiO 2 , eluting with 100% CH 2 Cl 2 ; 95:5 CH 2 Cl 2 :MeOH; 95:5:0.5 CH 2 Cl 2 :MeOH:NH 3 ) to give example 5 as the first eluted fraction (yellow foam, 8mg, 6% from crude acid) and desired product as the second eluted fraction (white foam 86mg, 70% from crude acid). 1 H NMR (CDCl 3 ) δ 2.20 (s, 6H), 2.25 (m, 4H), 2.40 (m, 1H), 2.85 (m, 1H), 3.00 (m, 1H), 4.30 (m, 1H), 4.50 (m, 2H), 4.55-4.70 (m, 2H), 6.00 (m, 1H), 6.50 (s, 1H), 6.70 (m, 2H), 7.10 (m, 1H), 7.20 (m, 6H), 7.35 (m, 1H), 7.50 (m, 1H), 8.20 (s, br, 1H). LRMS m/z = 473.4 (M+1) + ; Found C 63.45, H 6.46, N 15.88%; C 27 H 32 N 6 O 2 .0.6 CH 2 Cl 2 requires C 63.32, H 6.39, N 16.05%. Example 5 2-[3-[(1 S )-1-Benzyl-2-(dimethylamino)ethyl]amino-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide 1 H NMR (CDCl 3 )δ 2.20 (s, 7H), 2.35 (s, 3H), 2.50 (m, 1H), 2.80 (m, 1H), 3.00 (m, 1H), 4.30 (m, 1H), 4.40-4.60 (m, 3H), 4.65 (m, 1H), 6.30 (s, br, 1H), 6.50 (s, 1H), 6.80 (s, br, 1H), 7.05 (m, 1H), 7.15-7.40 (m, 7H), 7.50 (s, 1H), 8.30 (s, br, 1H). LRMS m/z = 507.4, 509.6 (M+1) + . Example 7 2-[3-{[(1 S )-1-Benzyl-2-(dimethylamino)ethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(6-methyl-1 H -indazol-5-yl)methyl]acetamide Preparation 31 4-Amino-2,5-dimethylbenzonitrile 2,5-Dimethyl-4-nitrobenzonitrile (500mg, 2.84mmol; purchased from Salor) was dissolved in ethanol (20ml), treated with 10% Pd on carbon catalyst (50mg) and stirred under a hydrogen atmosphere (10psi, room temperature, 3hr). The catalyst was removed by filtration and the solvent evaporated to dryness. The resultant mixture was dissolved in CH 2 Cl 2 and washed with HCI (2N, 4x15ml), aqueous layer was treated with NaHCO 3 then extracted repeatedly with CH 2 Cl 2 . Solvent was evaporated from the organic layer to give the desired product (brown solid, 350mg, 84%). 1 H NMR (CD 3 OD) δ 2.10 (s, 3H), 2.30 (s, 3H), 6.60 (s, 1H), 7.20 (s, 1H). LRMS m/z = 147.4 (M+1) + . Found C 72.12, H 6.86, N 18.53%; C 9 H 10 N 2 .0.2H 2 O requires C 72.16, H 7.00, N 18.70%. Preparation 32 6-Methyl-1 H -indazole-5-carbonitrile A solution of 4-amino-2,5-dimethylbenzonitrile (preparation 31) (111mg, 0.76mmol) in acetic acid (5ml) was treated with a solution of sodium nitrite (53mg, 0.76mmol) in water (1ml). The resultant mixture was stirred at room temperature for 10 mins then left to stand for 48hrs. The solvent was removed by evaporation and the residue purified by chromatography (SiO 2 , eluting with 50:50 hexane: ethyl acetate) to give the desired product (25mg, 21%). 1 H NMR (CD 3 OD) δ 2.60 (s, 3H), 7.50 (s, 1H), 8.15 (s, 1H), 8.20 (s, 1H). LRMS m/z = 158.1 (M+1) + . Preparation 33 (6-Methyl-1 H -indazol-5-yl)methylamine A solution of 6-methyl-1 H -indazole-5-carbonitrile (preparation 32) (230mg, 1.47mmol) in THF (10ml) under nitrogen was treated with a solution of lithium aluminium hydride (1 N, 3.66ml,3.66mmol) in THF at 0°C. The resultant mixture was stirred for 16hr warming to room temperature, then treated with MeOH (12ml), H 2 O (0.8ml), NaOH (4N, 2ml) and H 2 O (4ml). The resultant precipitate was removed by filtration, washed with THF and purified by chromatography (SiO 2 , eluting with 90:10:1 CH 2 Cl 2 :MeOH:NH 3 ) to give the desired product (71mg, 30%). 1 H NMR (CD 3 OD) 8 2.40 (s, 3H), 3.95 (s, 2H), 7.35 (s, 1H), 7.70 (s, 1H), 7.95 (s, 1H). LRMS m/z = 162.0 (M+1) + . Preparation 34 2-[3-{[(1 S )-1-Benzyl-2-(dimethylamino)ethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(6-methyl-1 H -indazol-5-yl)methyl]acetamide The title compound was prepared by a similar method to Example 2 from benzyl 2-[3-[(1 S )-1-benzyl-2-(dimethylamino)ethyl]amino-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate (preparation 24) (240mg, 0.51mmol) which was treated with Pearlman's catalyst (see example 2) to give a crude acid (168mg, 95%). The crude acid (48mg, 0.13mmol) was then coupled with (6-methyl-1 H -indazol-5-yl)methylamine (preparation 33) (22.4mg, 0.14mmol) to give a crude mixture which was purified by chromatography (SiO 2 , eluting with 90:10 CH 2 Cl 2 : MeOH; 90:10:0.2 CH 2 Cl 2 :MeOH:NH 3 ; 90:10:0.4 CH 2 Cl 2 :MeOH:NH 3 ) to give the desired product (yellow solid, 28mg, 46% from crude acid). 1 H NMR (CDCl 3 ) δ 2.15-2.40 (m, 14H), 2.80 (m, 1H), 3.05 (m, 1H), 4.20-4.65 (m, 4H), 4.80 (m, 1H), 6.00-6.30 (m, br, 1H), 6.75 (s, 1H), 7.10 (s, 1H), 7.15-7.30 (m, 6H), 7.50 (s, 1H), 7.80 (s, b, 1H). LRMS m/z = 488.2 (M+1) + . Example 8 N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-({3-[(methylamino)methyl]phenethyl}amino)-2-oxo-1(2 H )-pyrazinyl]acetamide Preparation 35 3-Formyl-1 H -indole-5-carbonitrile Phosphoryl chloride (4.24ml, 45.48mmol) was added dropwise to dimethylformamide (3.52ml, 45.48mmol) and stirred for 30mins at room temperature. A solution of 1 H -indole-5-carbonitrile (5.39g, 37.9mmol) in dimethylformamide (10ml) was added dropwise. A solid precipitated, further dimethylformamide (10ml) was added to aid stirring and the reaction mixture was then stirred at room temperature for 3hr. Water was added to quench the reaction mixture which was then stirred for 18hr. The stirring was stopped and the reaction mixture was left to stand, after 24hr a pink solid had precipitated in the organic layer. The layers were separated and organic layer filtered, washed with water and dried to give the desired product (5.44g, 84%). 1 H NMR (DMSO) δ 7.60-7.80 (m, 2H), 8.20-8.30 (m, 2H), 10.00 (s, 1H), 12.20-12.35 (s, br, 1H). Preparation 36 (3-Methyl-1 H -indol-5-yl)methylamine The title compound was prepared by a similar method to preparation 8 from 3-formyl-1 H -indole-5-carbonitrile (preparation 35) (5.44g, 32mmol) to give the desired product as a white solid (2.57g, 50%). 1 H NMR (CDCl 3 )δ 2.35 (s, 3H), 4.00 (s, 2H), 7.00 (s, 1H), 7.15 (d, 1H), 7.35 (d, 1H), 7.50 (s, 1H), 7.80-8.00 (s, br, 1H). Preparation 37 Benzyl 2-[3-chloro-2-methyl-5-[(3-{[methyl(2,2,2-trifluoroacetyl)amino]methyl}phenethyl)amino]-6-oxo-1(6 H )-pyrazinyl]acetate A solution of 2-[3-chloro-2-methyl-5-(3[(methylamino)methyl]phenethylamino)-6-oxo-1(6 H )-pyrazinyl]acetate (preparation 19) (1.77g, 3.90mmol) in CH 2 Cl 2 (75ml) was treated with pyridine (0.65ml) and trifluoroacetic anhydride (1ml). After stirring at room temperature for 24hr, the reaction mixture was evaporated to dryness and azeotroped with dichloromethane (x3). The residue was dissolved in dichloromethane (400ml) washed with water, sat aq brine and dried over MgSO 4 . Removal of the drying agent by filtration followed by evaporation of the solvent gave a pale orange solid which was recrystallised from boiling methanol to give the desired product. The mother liquors were concentrated under reduced pressure and purified by chromatography (SiO 2 , gradient elution with 100% pentane; 3:1 pentane:ethyl acetate) to give further product (1.47g, 68%). 1 H NMR (CDCl 3 ) δ 2.20 (s, 3H), 3.90 (m, 3H), 3.05 (s, 2H), 3.60-3.70 (m, 2H), 4.60 (s, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.05-6.15 (m, 1H), 7.00-7.15 (m, 2H), 7.15-7.25 (m, 1H), 7.25-7.40 (m, 7H). LRMS m/z = 551.8 (M+1) + . Preparation 38 2,2,2-Trifluoro- N -methyl- N -[3-(2-{[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)benzyl]acetamide Benzyl-2-[3-chloro-2-methyl-5-[(3{[methyl(2,2,2-trifluoroacetyl)amino]methyl} phenethyl) amino]-6-oxo-1(6 H ) pyrazinyl]acetate (preparation 37) (200mg,0.36mmol) was dissolved in methanol (80ml), treated with Pearlman's catalyst (80mg) and stirred under a hydrogen atmosphere (60psi, room temperature, 2.5hr). The catalyst was removed by filtration, followed by evaporation of the solvent and azeotroping with CH 2 Cl 2 to yield a crude solid. To the crude mixture, (3-methyl-1 H -indol-5 yl)methylamine (preparation 36) (60mg, 0.37mmol), HOBT (56mg, 0.41mmol), WSCDI.HCI (91mg, 0.47mmol), N-methylmorpholine (0.073ml, 0.66mmol) and DMF (10ml) were added and stirred at room temperature for 18hr. The resultant mixture was evaporated to dryness and triturated with water. The brown solid was filtered, dried, then purified by chromatography (SiO 2 , gradient elution with 1:2 ethyl acetate:hexane; 2:1 ethyl acetate:hexane) to give the desired product (42mg, 20%). 1 H NMR (CD 3 OD) δ 2.15 (s, 3H), 2.30 (s, 3H), 2.85-3.20 (m, 3H), 3.35 (s, 2H), 3.60 (m, 2H), 4.50 (s, 2H), 4.60-4.65 (m, 2H), 4.75 (s, 2H), 6.65 (s, 1H), 6.95-7.50 (m, 8H). LRMS m/z = 596.5 (M+1) + . Preparation 39 N -[(3 -Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-({3-[(methylamino)methyl]phenethyl}amino)-2-oxo-1(2 H )-pyrazinyl]acetamide 2,2,2-Trifluoro- N -methyl- N -[3-(2-{[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)benzyl]acetamide (preparation 38) (40mg, 0.07mmol) was dissolved in hot methanol (15ml) and treated with an aq. solution of Na 2 CO 3 (0.6ml, 0.46mol) followed by an additional portion of water (1.5ml). The resultant cloudy mixture was stirred at room temperature for 18hr, then evaporated to dryness and dried. The resultant white solid was purified by chromatography (SiO 2 , gradient elution with 90:10 CH 2 Cl 2 :MeOH; 90:10:1 CH 2 Cl 2 :MeOH:NH 3 ) to give the desired product (34mg, 100%). 1 H NMR (CDCl 3 ) δ 2.15 (s, 3H), 2.30 (s, 3H), 2.50 (s, 3H), 2.90 (t, 2H), 3.60 (t, 2H), 3.90 (s, 2H), 4.50 (s, 2H), 4.75 (s, 2H), 6.70 (s, 1H), 7.00 (s, 1H), 7.05 (d, 1H), 7.20-7.40 (m, 5H), 7.45 (s, 1H). LRMS m/z = 473.4 (M+1) + . Example 9 2-[3-{[3-(3-Azetidinyl)phenethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Examples 9 and 10 were prepared following the general methods outlined above, in particular those described for compounds of type (g) and more particularly in accordance with example 8. 1 H NMR (CD 3 OD, 300MHz) δ: 2.18 (s, 3H), 2.28 (s, 3H), 3.05 (t, 2H), 3.78 (m, 2H), 4.17-4.40 (m, 5H), 4.54 (m, 2H), 4.80 (s, 2H), 6.58 (m, 1H), 6.99 (m, 1H), 7.05 (d, 1H), 7.18-7.57 (m, 6H). LRMS m/z = 485 (M+1) + Example 10 N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-{[3-(1-methyl-3-azetidinyl)phenethyl]amino}-2-oxo-1(2 H )-pyrazinyl]acetamide 1 H NMR (CD 3 OD, 300MHz) δ: 2.14 (s, 3H), 2.27 (s, 3H), 2.39 (s, 3H), 2.90 (t, 2H), 3.20-3.38 (m, 3H), 3.58 (t, 2H), 3.78 (m, 2H), 4.49 (s, 2H), 4.75 (s, 2H), 6.66 (s, 1H), 6.98 (s, 1H), 7.02 (d, 2H), 7.12 (m, 2H), 7.18-7.30 (m, 3H), 7.42 (s, 1H). LRMS m/z = 499 (M+1) + Example 11 2-[3-[(3-{[(2-Methoxyethyl)amino]methyl}phenethyl)amino]-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Preparation 40 3-(Cyanomethyl)- N -(methoxymethyl)benzamide 2-(3-Bromophenyl)acetonitrile (40g, 0.20mol) was added to a solution of 2-methoxyethylamine (61.3g, 0.81mol), triphenylphosphine (8.0g, 0.03mol), palladium acetate (4.0g, 0.01mol) and triethylamine (62g, 0.61mol) in tetrahydrofuran (400ml). The reaction mixture was heated to 100°C in a sealed vessel under carbon monoxide @ 100psi for 18hrs, after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:pentane (90:10) changing to dichloromethane (100%) and then to dichloromethane:methanol (98:2) to afford the title compound, 14.57g (33%). 1 H-NMR (300MHz, DMSO) : δ [ppm] 3.26 (3H, s), 3.41 (4H, m), 4.09 (2H, s), 7.65-7.43 (2H, m), 7.78 (1H, m), 7.83 (1H, s), 8.55 (1H, bs). LRMS : m/z = 219 (MH + ). Preparation 41 3-(2-aminoethyl)- N -(2-methoxyethyl)benzamide Borane (1N in tetrahydrofuran, 467ml, 0.467mol) was added dropwise to a solution of 3-(cyanomethyl)- N -(methoxymethyl)benzamide (14.57g, 0.067mol) [see preparation 40] in tetrahydrofuran (30ml) over 20 minutes. The reaction mixture was then stirred at room temperature for 18hrs and then heated to reflux for 2hrs, after which time the solvent was evaporated under reduced pressure and the residue acidified with hydrochloric acid (2N). The resultant mixture was heated to reflux for 10 minutes after which time it was basified with sodium hydroxide. The product was extracted with dichloromethane (3x30ml), the combined organic layers were dried over MgSO 4 and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5) changing to (92.5:7.5:0.25) changing to (90:10:1) to afford the title compound, 6.15g, (44%). 1 H-NMR (300MHz, DMSO) : δ [ppm] 1.60 (2H, bs), 2.62 (4H, m), 2.73 (2H, m), 3.22 (3H, s), 3.40 (2H, t), 3.65 (2H, s), 7.05 (1H, d), 7.10 (2H, d), 7.22 (1H, d). LRMS ; m/z = 209 (MH + ). Preparation 42 Benzyl 2-[3-chloro-5-[(3-{[(2-methoxyethyl)amino]methyl}phenethyl)amino]-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate Benzyl 2-(3,5-dichloro-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (400mg, 1.22mmol) [see preparation 17] was added to a solution of 3-(2-aminoethyl)- N -(2-methoxyethyl)benzamide (260mg, 1.25mmol) [see preparation 41] and triethylamine (0.34ml, 2.4mmol) in ethyl acetate (5ml). The reaction mixture was heated to reflux for 4hrs, after which time the mixture was cooled to room temperature and stirred for a further 56hrs, the mixture was partitioned between ethyl acetate (20ml) and water (20ml). The organic layer was washed with water (2x20ml), brine (20ml) and dried over MgSO 4 the solvent was evaporated under reduced pressure. The crude product was purified by trituration with diethyl ether to afford the title compound, 365mg, (60%). 1 H-NMR (300MHz, DMSO): δ [ppm] 2.20 (3H, s), 2.60 (2H, t), 2.80 (2H, t), 3.30 (3H, s), 3.38 (2H, t), 3.45 (2H, m), 3.70 (2H, s), 4.85 (2H, s), 5.20 (2H, s), 7.07-7.25 (4H, m), 7.35 (5H, m), 7.50 (1H, t). LRMS : m/z = 499 (M + ). Preparation 43 Benzyl 2-[3-chloro-5-[(3-{[(2-methoxyethyl)(2,2,2-trifluoroacetyl)amino]methyl}phenethyl)amino]-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate Trifluoroacetic anhydride (0.17ml, 0.766mmol) was added to a solution of benzyl 2-[3-chloro-5-[(3-{[(2-methoxyethyl)amino]methyl}phenethyl)amino]-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (365mg, 0.73mmol) [see preparation 42] and pyridine (0.077ml, 0.95mmol) in dichloromethane (5ml). The reaction mixture was stirred at room temperature for 18hrs, after which time the mixture was partitioned between dichloromethane (20ml) and water (20ml), the organic layer was washed with brine (20ml) and dried over MgSO 4 and the solvent was evaporated under reduced pressure. The crude product was purified by recrystallisation from methanol to afford the title compound as a white solid, 260mg, (60%). 1 H-NMR (300MHz, DMSO): δ [ppm] 2.20 (3H, s), 2.88 (2H, q), 3.20 (3H, m), 3.40-3.55 (6H, m), 4.65 (2H, d), 4.86 (2H, s), 5.20 (2H, s), 7.03-7.40 (9H, m), 7.55 (1H, m). LRMS : m/z 596 (MH + ). Preparation 44 2-[3-[(3-{[(2-Methoxyethyl)(2,2,2-trifluoroacetyl)amino]methyl}phenethyl)amino]-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid Benzyl 2-[3-chloro-5-[(3-{[(2-methoxyethyl)(2,2,2-trifluoroacetyl)amino]methyl} phenethyl)amino]-2-methyl-6-oxo-1(6 H )pyrazinyl] acetate [see preparation 43] (260mg, 0.437mmol) was dissolved in methanol (10ml) and palladium hydroxide catalyst (30mg) added. The reaction mixture was hydrogenated at 60psi for 4hrs. The catalyst was filtered off and the solvent evaporated under reduced pressure to afford the title compound as a oil,190mg, (92%). LRMS : m/z = 471 (MH + ). Preparation 45 2,2,2-Trifluoro- N -(2-methoxyethyl)- N -[3-(2-{[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)benzyl]acetamide Hydroxybenzotriazole hydrate (60mg, 0.44mmol) and WSCDI.HCI (93mg, 0.47mmol) were added to a solution of 2-[3-[(3-{[(2-methoxyethyl)(2,2,2-trifluoroacetyl)amino]methyl}phenethyl)amino]-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid (190mg, 0.40mmol) [see preparation 44] in N,N-dimethylformamide (3.0ml). N-methylmorpholine (123mg, 1.2mmol) was added followed by (3-methyl-1 H -indol-5-yl)methylamine (72mg, 0.45mmol) [see preparation 36]. The reaction mixture was stirred at room temperature for 18hrs, after which time the mixture was partitioned between ethyl acetate (30ml) and water (30ml). The organic layer was washed with water (3x30ml), brine (30ml) and dried over MgSO 4 and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (99:1:0.1) changing to (98:2:0.2) to afford the title compound as a oil, 113mg (53%). 1 H-NMR (300MHz, CDCl 3 ): δ [ppm] 2.93 (3H, m), 3.45-3.70 (12H, m), 4.50 (2H, d), 4.67 (2H, s), 4.73 (3H, m), 5.90 (1H, m), 6.60 (1H, m), 6.78 (1H, s), 6.95-7.30 (8H, m), 7.41 (1H, s), 7.92 (1H, m). LRMS : m/z = 613 (MH + ). Preparation 46 2-[3-[(3-{[(2-Methoxyethyl)amino]methyl}phenethyl)amino]-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide 2,2,2-Trifluoro- N -(2-methoxyethyl)- N -[3-(2-{[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2 pyrazinyl]amino}ethyl)benzyl]acetamide (preperation 45) (110mg, 0.18mmol) was dissolved in methanol(15ml) and sodium carbonate solution in water (1.5ml, 0.765m, 1.15mmol) was added. The reaction mixture was stirred for 56hrs, after which time the reaction was heated to 50°C and sodium carbonate (1.5ml, 1.15mmol) was added. The mixture was heated for 18hrs and then partitioned between ethyl acetate and water, the organic layer was washed with brine, dried over MgSO 4 and the solvent evaporated under reduced pressure. The crude product was triturated with diethyl ether:methanol (1:1) to afford the title compound, 23mg, (25%). 1 H-NMR (400MHz, CDCl 3 ) : δ [ppm] 2.08 (3H, s), 2.21 (3H, s), 2.60 (1H, t), 2.81 (2H, m), 3.20 (3H, s), 3.30 (3H, m), 3.39 (1H, t), 3.50 (3H, m), 3.57 (1H, m), 4.35 (2H, d), 4.60 (2H, m), 6.64 (1H, s), 6.78 (1H, t), 6.94-7.30 (7H, m), 8.60 (1H, t), 10.21 (1H, bs). LRMS : m/z = 517 (MH + ). Found C, 65.55; H, 6.78; N, 15.48; C 29 H 36 N 6 O 3 .H 2 O requires C, 65.15; H, 7.16; N, 15.72%. Example 12 2-[3-({[(2 R )-1-(Cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Preparation 47 Benzyl 2-[3-chloro-5-({[(2 R )-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate [see preparation 17] and [(2 R )-1-(cyclopropylmethyl)pyrrolidinyl]methylamine [see WO 9839295 A1], to afford the product as a orange oil (100%). LRMS : m/z = 445 (MH + ). Preparation 48 2-[3-({[(2 R )-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid hydrochloride The title compound was prepared by a similar method to preparation 44 from benzyl 2-[3-chloro-5-({[(2 R )-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate [see preparation 47] and palladium hydroxide to afford the product as a oil, 352mg, (100%). 1 H-NMR (300MHz, CDCl 3 ) : δ [ppm] 7.40 (1H, t), 6.65 (1H, s), 4.66 (2H, s), 3.75-3.00 (7H, m), 2.87 (1H, m), 2.08 (3H, s), 1.96-1.71 (4H, m), 1.10 (1H, m), 0.58 (2H, d), 0.35 (2H, m). 1 HMR (300MHz, CDCl 3): δ[ppm} 0.35(2H,m), 0.58(2H,d), 1.10(1H,m), 1.91-1.96(4H,m), 2.08(3H,s), 2.87(1 H,m),3.00-3.75(7H,m), 4.66(2H,s), 6.65(1H,s), 7.40(1H,t). Preparation 49 2-[3-({[(2 R )-1-(Cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide The title compound was prepared by a similar method to preparation 45 from 2-[3-({[(2 R )-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid hydrochloride [see preparation 48] and (3-methyl-1 H -indol-5-yl)methylamine (72mg, 0.45mmol) [see preparation 36]. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (96:3.5:0.5) as the eluant to afford the title compound as a yellow solid, 245mg, (55%). 1 H-NMR (300MHz, MeOD): δ [ppm] 0.27 (2H, d), 0.53 (1H, t), 0.94 (1H, m), 1.70 (1H, m), 1.75 (2H, t), 1.90-2.00 (1H, m), 2.18 (4H, m), 2.20-2.40 (5H, m), 2.80 (2H, m), 3.30 (3H, m), 3.45-3.40 (2H, m), 4.46 (4H, m), 4.73 (1H, s), 6.68 (1H, s), 6.98 (1H, s), 7.06 (1H, m), 7.26 (1H, m), 7.45 (1H, d). LRMS = 463 (MH + ). The hydrochloride salt of the product of preparation 49 was prepared by dissolving the product in methanol (5ml) and adding hydrochloric acid (1N, 0.53ml, 0.53mmol). to afford (2R)-1-(cyclopropylmethyl)-2-({[5-methyl-4-(2-{[(3-methyl-1H-indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}methyl)pyrrolidinium hydrochloride as a solid. 1 H-NMR consistent with free base. Example 13 2-[3-({[(2 R )-1-Cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Preparation 50 tert -Butyl (2 R )-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate 4-Methylbenzenesulfonyl chloride (8.83g, 46.32mmol) was added to a solution of tert -butyl (2 R )-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (5.48g, 27.24mmol) in pyridine (25ml). The reaction mixture was stirred for 2.5hrs, after which time the reaction was diluted with ethyl acetate (100ml) and washed with water (100ml), saturated copper sulphate solution (100ml), dried over MgSO 4 and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane (20:80) as the eluant to afford the title compound as a dear oil, 9.2g, (95%). LRMS : m/z = 356 (MH + ). Found, C, 57.44; H, 7.09; N, 3.94; C 17 H 25 NO 5 S requires C, 57.22; N, 7.15; N, 3.79%. Preparation 51 tert -Butyl (2 R )-2-(azidomethyl)-1-pyrrolidinecarboxylate Sodium azide (2.52g, 38.80mmol) was added to a solution of tert -butyl (2 R )-2-({[(4-methylphenyl)sulfonyl]oxy}methyl}-1-pyrrolidinecarboxylate (9.20g, 25.90mmol) [see preparation 50] in dimethylsulphoxide (100ml). The reaction mixture was heated to 80°C for 18hrs. after which time the cooled mixture was partitioned between diethyl ether (200ml) and water (200ml). The aqueous was washed with diethyl ether (200ml). The combined organic layers were dried over MgSO 4 and the solvent evaporated under reduced pressure to afford the title compound as a clear oil, 5.74g, (98%). 1 H-NMR (400MHz, CDCl 3 ): δ [ppm] 1.48 (9H, s), 1.50 (1H, s), 1.80-2.06 (4H, m), 3.35 (4H, m), 3.90 (1H, m). LRMS : m/z = 227 (MH + ). Preparation 52 tert -butyl (2 R )-2-(aminomethyl)-1-pyrrolidinecarboxylate 10% Palladium on charcoal (750mg) was added to a solution of tert -butyl (2 R )-2-(azidomethyl)-1-pyrrolidinecarboxylate (preperation 51)(5.74g, 25.39mmol) in ethanol (100ml). The reaction mixture was hydrogenated @ 15psi for 2.5hrs, after which time the catalyst was filtered off and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:0.5) as the eluant, to afford the title compound and some starting material. The mixture was dissolved in ethanol (100ml) and 10% palladium on charcoal (500mg) was added, the mixture was hydrogenated at 30psi for 18hrs, after which time the catalyst was filtered off and the solvent evaporated under reduced pressure to afford the title compound as a clear oil, 4.32g, (85%). 1 H-NMR (300MHz, CDCl 3 ) : δ [ppm] 1.30 (2H, bs), 1.45 (9H, s),1.72-2.00 (4H, m), 2.65-2.90 (2H, m), 3.26-3.33 (2H, m), 3.75 (1H, m). LRMS : m/z = 201 (MH + ). Preparation 53 tert -Butyl (2 R )-2-[({4-[2-(benzyloxy)-2-oxoethyl]-6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl}amino)methyl]-1-pyrrolidinecarboxylate The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (preparation 17) and tert -butyl (2 R )-2-(aminomethyl)-1-pyrrolidinecarboxylate [see preparation 52]. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (10:90) changing to (80:20) in 10% increments to afford the title compound as a dear oil, (80%). 1 H-NMR (300MHz, CDCl 3 ) : δ [ppm] 1.43 (9H, s), 1.70-2.08 (4H, m), 2.18 (2H, s), 2.35 (1H, s), 3.26-3.65 (4H, m), 4.00-4.20 (1H, m), 4.80 (2H, s), 5.25 (2H, s), 7.26-7.40 (5H, m). LRMS : m/z = 491 (MH + ). Preparation 54 2-[3-({[(2 R )-1-( tert -butoxycarbonyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid The title compound was prepared by a similar method to preparation 44 from tert -butyl (2 R )-2-[({4-[2-(benzyloxy)-2-oxoethyl]-6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl}amino)methyl]-1-pyrrolidinecarboxylate [see preparation 53] and palladium hydroxide to afford the product as a white foam, (68%). 1 H-NMR (400MHz, DMSO) : δ [ppm] 1.40 (9H, s), 1.68-1.86 (4H, m), 2.00 (2H, s), 3.06-3.25 (4H, m), 3.40 (1H, bs), 3.95 (1H, m), 4.13-4.30 (2H, m), 5.72 (2H, s), 6.48 (1H, s). LRMS : m/z = 367 (MH + ). Preparation 55 tert -butyl (2 R )-2-({[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}methyl)-1-pyrrolidinecarboxylate The title compound was prepared by a similar method to preparation 45 from 2-[3-({[(2 R )-1-( tert -butoxycarbonyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid [see preparation 54] and (3-methyl-1 H -indol-5-yl)methylamine (72mg, 0.45mmol) [see preparation 36]. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0) changing to (95:5) in 1% increments 1 H-NMR indicated starting chloro compound material. A mixture of this product with 10% palladium on charcoal (39.6mg) and ammonium formate (439.5mg,6.98mmol) in dichloromethane (50ml), was then stirred at room temperature overnight. Additional, 10% Palladium on charcoal (49mg) was added and the mixture was heated under reflux for 48hrs, after which time the catalyst was filtered off and the solvent evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100ml) and water (100ml). The organic layer was separated and dried over MgSO 4 and the solvent evaporated under reduced pressure to afford the title compound as a off-white solid, (44%). 1 H-NMR (400MHz, DMSO) : δ [ppm] 1.40 (9H, s), 170-1.86 (4H, m), 2.06 (2H, s), 2.21 (3H, s), 3.23 (4H, m), 3.43 (1H, m), 4.35 (2H, d), 4.63 (2H, s), 6.59 (1H, s), 6.98 (1H, d), 7.07 (1H, s), 7.25 (1H, d), 7.35 (1H, s), 8.60 (1H, m), 10.65 (1H, bs). LRMS : m/z = 509 (MH + ). Preparation 56 N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-2-oxo-3-{[(2 R )pyrrolidinylmethyl]amino}-1(2 H )-pyrazinyl]acetamide tert -Butyl (2 R )-2-({[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino]-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}methyl)-1-pyrrolidinecarboxylate (1.08g, 2.14mmol) [see preparation 55] was dissolved in methanol (10ml) and hydrochloric acid (6N, 10ml, 60mmol) was added. The reaction mixture was stirred for 18hrs, after which time the pH was adjusted to 10 with sodium hydroxide (1 N). The product was then extracted with dichloromethane (100ml) followed by dichloromethane:methanol (90:10) (100ml). Aqueous and organic layers were then concentrated under reduced pressure and the residue triturated with isopropanol (3x100ml) to afford the title compound as a off-white solid, 629mg, (72%). 1 H-NMR (400MHz, DMSO) : δ [ppm] 1.58-1.85 (4H, m), 2.06 (2H, s),2.21 (3H, s), 2.77-2.90 (2H, m), 3.15-3.40 (5H, m), 4.35 (2H, d), 4.61 (2H, s), 6.60 (1H, s), 6.80 (1H, m), 6.98 (1H, d), 7.06 (1H, s), 7.26 (1H, d), 7.37 (1H, s), 8.65 (1H, m), 10.68 (1H, s). LRMS : m/z = 409 (MH + ). Preparation 57 2-[3-({[(2 R )-1-Cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-2-oxo-3 {[(2R)pyrrolidinylmethyl] amino}-1(2 H )-pyrazinyl]acetamide (52.3mg, 0.129mmol) [see preparation 56] and cyclopentanone (22ml, 0.248mmol) were stirred together in N,N- dimethylformamide (2ml). Sodium triacetoxyborohydride (27.3mg, 0.129mmol) was added. The reaction mixture was stirred for 18hrs, after which time the mixture was quenched with water and basified. The product was then extracted with ethyl acetate (4x50ml), the combined organic layers were dried with MgSO 4 and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0) changing to (90:10) and then dichloromethane:methanol:0.88 ammonia (90:10:1) changing to (84:14:2) to afford the title compound as a white solid, 19.4mg, (32%). 1 H-NMR (300MHz, CD 3 OD) : δ [ppm] 1.40-2.00 (12H, m), 2.11 (3H, s), 2.28 (3H, s), 2.55-2.65 (1H, q), 3.00-3.17 (3H, m), 3.20-3.35 (1H, m), 3.47-3.55 (1H, 2xd), 4.46 (2H, s), 4.71 (2H, s), 6.65 (1H, s), 6.98 (1H, s), 7.03 (1H, d), 7.25 (1H, d), 7.41 (1H, s). LRMS : m/z = 477 (MH + ). Examples 14-19 The compounds of the following tabulated examples with the general formula:- were prepared using a similar method to preparation 57 from N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-2-oxo-3-{[(2 R )pyrrolidinylmethyl]amino}-1(2 H )-pyrazinyl]acetamide [see preparation 56] and the corresponding carbonyl compound. Preparation 58 1-Methylcyclopropanecarbaldehyde To a solution of 1-methylcyclopropane methanol (4.86g, 56.4mmol) in dichloromethane (200ml) under an atmosphere of nitrogen was added 4A molecular sieves and N-methylmorpholine-N-oxide (9.916g, 84.64mmol). The reaction mixture was stirred at room temperature for 20 mins, after which time tetrahydrofuran-n-propylammonium perruthenate(VII) (0.992g, 2.82mmol) was added. The mixture was stirred for a further 4hrs, and then filtered through a plug of silica eluting with dichloromethane to afford the crude product which was fractionally distilled to afford the title compound (100%). Example 18 2-[3-({[(2 R )-1-Isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Preparation 59 (2 R )-1-Isobutyl-2-pyrrolidinecarboxamide The title compound was prepared by a similar method to preparation 57 from R-prolinamide and 3-methylbutanal. The crude compound was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (96:3.5:0.5) as the eluant, to afford the product as a white solid, (87%). 1 H-NMR (400MHz, CDCl 3 ) : δ [ppm] 0.88 (3H, d), 0.97 (3H, d), 1.68-1.93 (4H, m), 2.12-2.35 (4H, m), 3.00 (1H, m), 3.17 (1H, m), 6.67 (1H, bs), 7.37 (1H, bs). LRMS : m/z = 171 (MH + ). Preparation 60 [(2 R )-1-isobutylpyrrolidinyl]methanamine Lithium aluminium hydride [1.0mol soln. in tetrahydrofuran] (11.52ml, 11.52mmol) was added to a solution of (2 R )-1-isobutyl-2-pyrrolidinecarboxamide (1.3g, 7.68mmol) [see preparation 59] in tetrahydrofuran (5ml) @ 0°C. The reaction mixture was stirred for 10mins and then heated to reflux for 6hrs. Water (0.5ml) was added to the cooled mixture followed by sodium hydroxide (1.5ml) and water (1.5ml). Tetrahydrofuran (10ml) was added and the mixture was stirred at room temperature for 1hr. The aluminium salts were removed by filtration and washed well with diethyl ether. The filtrate was then evaporated under reduced pressure to afford the title compound as a white solid, 705mg, (58%). 1 H-NMR (400MHz, CDCl 3 ) : δ [ppm] 0.86 (3H, d), 0.92 (3H, d), 1.78-1.86 (5H, m), 2.04-2.10 (2H, m), 2.26-2.38 (2H, m), 2.60 (1H, 2xd), 2.72 (1H, m), 3.09 (1H, m). LRMS m/z = 157 (MH + ). Preparation 61 Benzyl 2-[3-chloro-5-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (preperation 170 and [(2 R )-1-isobutylpyrrolidinyl]methanamine [see preparation 60]. The crude product was purified by column chromatography on silica gel using ethyl acetate as the eluant, to afford the product as a yellow oil, (94%). 1 H-NMR (400MHz, CDCl 3 ) : δ [ppm] 0.90 (6H, 2xd), 1.60 (1H, m), 1.70 (3H, m), 1.85 (1H, m), 2.08 (2H, m), 2.20 (3H, s), 2.30 (1H, m), 2.62 (1H, m), 3.12 (1H, m), 3.27 (1H, m), 3.55 (1H, m), 4.78 (2H, m), 5.20 (2H, s), 6.66 (1H, m), 7.32 (5H, m). LRMS m/z = 447 (MH + ). Preparation 62 2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid hydrochloride The title compound was prepared by a similar method to preparation 44 from benzyl 2-[3-chloro-5-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate [see preparation 61] and palladium hydroxide, to afford the product as a oil. LRMS : 323 (MH + ) Preparation 63 2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide The title compound was prepared by a similar method to preparation 49 from 2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid hydrochloride [see preparation 62] and (3-methyl-1 H -indol-5-yl)methylamine (72mg, 0.45mmol) [see preparation 36]. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (92:7:1) as the eluant, to afford the product as a foam. This was dissolved in methanol (5ml) and hydrochloric acid (1M, 0.58ml, 0.58mmol), to afford the product, (56%). 1 H-NMR (400MHz, DMSO) : δ [ppm] 0.95 (6H, 2xd), 1.72-2.10 (7H, m), 2.21 (3H, s), 2.86-3.20 (4H, m), 3.33-3.50 (4H, m), 4.35 (2H, d), 4.63 (2H, s), 6.60 (1H, s), 6.98 (1H, d), 7.06 (1H, s), 7.25 (1H, d), 7.35 (1H, s), 7.42 (1H, bs), 8.68 (1H, t), 8.80 (1H, bs), 10.68 (1H, bs). LRMS : m/z = 465 (MH + ). Example 19 and 20 The compounds of the following tabulated examples with the general formula:- Were prepared using a similar method to preparation 57 from N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-2-oxo-3-{[(2 S )pyrrolidinylmethyl]amino}-1(2 H )-pyrazinyl]acetamide [see preparation 67] and the corresponding carbonyl compound. Preparation 64 tert -Butyl(2 S )-2-[({4-[2-(benzyloxy)-2-oxoethyl]-6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl}amino)methyl]-1-pyrrolidinecarboxylate The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (preperation 17) and tert -butyl (2 S )-2-(aminomethyl)-1-pyrrolidinecarboxylate [JP 63183560 A2], to afford the product as a colourless oil,(100%). 1 H-NMR (400MHz, DMSO): δ [ppm] 1.38 (9H, s), 1.68-1.86 (4H, m), 2.19 (3H, s), 3.20-3.30 (3H, m), 3.40 (1H, m), 4.01 (1H, m), 4.86 (2H, s), 5.19 (2H, s), 7.35 (5H, m), 7.45-7.60 (1H, m). LRMS : m/z = 491 (MH + ). Preparation 65 2-[3-({[(2 S )-1-( tert -Butoxycarbonyl)pyrrolidinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid The title compound was prepared by a similar method to preparation 44 from tert -butyl (2 S )-2-[({4-[2-(benzyloxy)-2-oxoethyl]-6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl}amino)methyl]-1-pyrrolidinecarboxylate [see preparation 64] and palladium hydroxide. The title compound was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (90:10:0.5) changing to (80:20:3), to afford the product as a colourless oil, (44%). 1 H-NMR (400MHz, DMSO): δ [ppm] 1.40 (9H, s), 1.68-1.86 (4H, m), 2.00 (3H, s), 3.05-3.27 (3H, m), 3.41 (1H, bs), 3.99 (1H, m), 4.30 (2H, m), 6.50 (1H, s), 6.61-6.80 (1H, m). LRMS : m/z = 367 (MH + ). Preparation 66 tert -Butyl(2 S )-2-({[6-chloro-5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}methyl)-1-pyrrolidinecarboxylate The title compound was prepared by a similar method to preparation 45 from 2-[3-({[(2 S )-1-( tert -butoxycarbonyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid [see preparation 65] and (3-methyl-1 H -indol-5-yl)methylamine (72mg, 0.45mmol) [see preparation 36], to afford the product as a colourless oil, (89%). 1 H-NMR (400MHz, DMSO) : δ [ppm] 1.39 (9H, s), 1.66-1.87 (4H, m), 2.05 (3H, s), 2.21 (3H, s), 3.13-3.30 (4H, m), 3.40 (1H, bs), 4.00 (1H, m), 3.37 (2H, d), 4.61 (2H, s), 6.58 (1H, s), 6.97 (1H, d), 7.07 (1H, s), 7.25 (1H, d), 7.45 (1H, s), 8.60 (1H, t). LRMS : m/z = 509 (MH + ). Preparation 67 N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-2-oxo-3-{[(2 S )pyrrolidinylmethyl]amino}-1(2 H )-pyrazinyl]acetamide The title compound was prepared by a similar method to preparation 56 from tert -butyl (2 S )-2-({[6-chloro-5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}methyl)-1-pyrrolidinecarboxylate [see preparation 66] and 6N hydrochloric acid, to afford the product as a white solid, (60%). 1 H-NMR (400MHz, DMSO) : δ [ppm] 1.35 (1H, m), 1.53-1.78 (3H, m), 2.05 (3H, s), 2.22 (3H, s), 2.75 (2H, m), 3.08-3.32 (4H, m), 4.34 (2H, d), 4.61 (2H, s), 6.60 (1H, s), 6.66 (1H, m), 6.98 (1H, d), 7.06 (1H, s), 7.27 (1H, d), 7.39 (1H, s), 8.61 (1H, t), 10.63 (1H, bs). LRMS : m/z = 409 (MH + ). Example 21 2-[3-({[(2 R )-1-(Cyclopropylmethyl)piperidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Preparation 68 (2 R )-2-Piperidinecarboxamide (2 R )-2-(Methoxycarbonyl)piperidinium chloride (2.6g, 14.5mmol) was dissolved in ammonia (0.88M, 30ml). The reaction mixture was heated at 60°C for 1.5hr. The mixture was partitioned between ethyl acetate (100ml) and sodium hydroxide (1N, 100ml, 100mmol), the aqueous was washed with ethyl acetate (3x100ml). The combined organic layers were dried over sodium sulphate and the solvent evaporated under reduced pressure. Aqueous layer was acidified with hydrochloric acid and evaporated to dryness under reduced pressure. The resultant white solid was triturated with dichloromethane:methanol (9:1), the remaining solid was removed by filtration and the filtrate evaporated under reduced pressure to afford the title compound as a white solid, 1.14g, (61%). LRMS : m/z = 129 (MH + ). Preparation 69 (2 R )-1-(Cyclopropylmethyl)-2-piperidinecarboxamide The title compound was prepared by a similar method to preparation 57 from (2 R )-2-piperidinecarboxamide [see preparation 68] and cyclopropylcarboxaldehye. The crude compound was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (92:7:1) as the eluant to afford the product as a white solid, (44%). 1 H-NMR (300MHz, CDCl 3 ): δ [ppm] 0.00-0.20 (2H, m), 0.40-0.61 (2H, m), 0.79-0.93 (1H, m), 1.18-1.38 (1H, m), 1.40-1.80 (5H, m), 1.87-2.14(3H, m), 2.56 (1H, 2xd), 2.71 (1H, 2xd), 3.30 (1H, m), 5.29 (1H, bs), 6.64 (1H, bs). LAMS : m/z = 183 (MH + ). Preparation 70 [(2 R )-1-(Cyclopropylmethyl)piperidinyl]methylamine The title compound was prepared by a similar method to preparation 60 from (2 R )-1-{cyclopropylmethyl)-2-piperidinecarboxamide [see preparation 69] and lithium aluminium hydride. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:0.1) as the eluant, to afford the product as a yellow oil, (71%). 1 H-NMR (300MHz, CDCl 3 ) : δ [ppm] 0.09 (2H, m), 0.49 (2H, m), 0.82 (1H, m), 1.21-1.80 (9H, m), 2.17-2.27 (3H, m), 2.60 (1H, 2xd), 2.70 (1H, 2xd), 2.87 (1H, 2xd), 3.16 (1H, m). LRMS : m/z = 169 (MH + ). Preparation 71 Benzyl 2-[3-chloro-5-({[(2 R )-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (preperation 17) and [(2R)-1-(cyclopropylmethyl)piperidinyl]methylamine [see preparation 70]. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (95:5), to afford the product as a yellow oil, (87%). 1 H-NMR (400MHz, CDCl 3 ): δ [ppm] 0.10 (2H, m), 0.45 (2H, m), 0.92 (1H, m), 1.20-1.79 (5H, m), 2.20-2.31 (5H, m), 2.57 (2H, m), 3.17 (1H, m), 3.46 (2H, m), 4.80 (2H, s), 5.21 (2H, s), 6.63 (1H, m), 7.18 (1H, d), 7.39 (5H, m). LRMS : m/z = 459 (MH + ). Preparation 72 2-[3-chloro-5-({[(2 R )-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetic acid The title compound was prepared by a similar method to preparation 44 from benzyl 2-[3-chloro-5-({[(2 R )-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate [see preparation 71] and palladium hydroxide. To afford the product as a yellow foam, (100%). LRMS : m/z = 369 (MH + ). Preparation 73 2-[3-Chloro-5-({[(2 R )-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide The title compound was prepared by a similar method to preparation 45 from 2-[3-chloro-5-({[(2 R )-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetic acid [see preparation 72] and (3-methyl-1 H -indol-5-yl)methylamine (preperation 36) to afford the product as a white solid, (14%). LRMS : m/z = 511 (M + ) Preparation 74 2-[3-({[(2 R )-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide The title compound was prepared by a similar method to preparation 44 from 2-[3-chloro-5-({[(2 R )-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide [see preparation 73] and palladium hydroxide. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:1) as the eluant to afford the product as a white solid, (36%). 1 H-NMR (400MHz, CD 3 OD) : δ [ppm] 0.15 (2H, m), 0.53 (2H, m), 0.96 (1H, m), 1.32-1.88 (6H, m), 2.15 (3H, s), 2.29 (3H, s), 2.40 (2H, s), 2.70 (3H, m), 3.20 (1H, m), 3.30 (3H, m), 3.33 (1H, m), 3.39-3.57 (2H, m), 4.48 (2H, s), 4.75 (2H, s), 6.65 (1H, s), 6.98 (1H, s), 7.06 (1H, d), 7.27 (1H, d), 7.43 (1H, s). LRMS : m/z = 477 (MH + ). Example 22 2-[3-({[(2 S )-1-(Cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Preparation 75 Benzyl 2-[3-chloro-5-({[(2 S )-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate A mixture of benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (400mg, 1.22mmol) and [(2 S )-1-(cyclopropylmethyl)pyrrolidinyl]methylamine (WO 87,07271) (190mg, 1.22mmol) and triethylamine (0.51ml, 3.67mmol) in ethyl acetate (20ml) was heated under reflux for 18 hrs. The cooled mixture was partitioned between water and ethyl acetate, the phases separated, and the organic layer dried over MgSO 4 and concentrated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (96:3.5:0.5) as eluant to give the desired product as a yellow oil, (476mg, 88%). 1 H NMR (CDCl 3 , 300MHz) δ: 0.15 (m, 2H), 0.48 (m, 2H), 0.92 (m, 1H), 1.58-1.94 (m, 5H), 2.03 (m, 1H), 2.23 (s, 3H), 2.70 (m, 2H), 3.30 (m, 2H), 3.60 (m, 1H), 4.80 (s, 2H), 5.22 (s, 2H), 6.62 (s, br, 1H), 7.38 (m, 5H). Preparation 76 2-[5-({[(2 S )-1-(Cyclopropylmethyl)pyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetic acid hydrochloride A mixture of benzyl 2-[3-chloro-5-({[(2)-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (preparation 75) (470mg, 1.06mmol) and palladium hydroxide (230mg) in methanol (20ml) was hydrogenated at room temperature and 60 psi for 3 hrs. The reaction mixture was filtered through Arbocel®, washing through with ethanol, and the combined filtrate evaporated under reduced pressure, to give the title compound as a yellow foam, (388mg, 100%). 1 H NMR (d 6 -DMSO, 300MHz) δ: 0.38 (m, 2H), 0.60 (m, 2H), 0.97 (m, 1H), 1.77-1.99 (m, 4H), 2.07 (s, 3H), 2.96 (m, 1H), 3.06-3.76 (m, 6H), 4.66 (s, 2H), 6.64 (s, 1H), 7.40 (t, br,1H), 10.05 (s, br,1H). Preparation 77 2-[3-({[(2 S )-1-(Cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide A mixure of 2-[5-({[(2 S )-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetic acid hydrochloride (preparation 76) (380mg, 1.07mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (171mg, 1.07mmol), HOBT (216mg, 1.60mmol), WSCDI.HCl (255mg, 1.33mmol) and N-methylmorpholine (0.38ml, 3.46mmol) in N,N-dimethylformamide (4ml), was stirred at room temperature for 24 hrs under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (96:3.5:0.5) as eluant. This product was further purified using a Biotage™ (KP-Sil™ 60Å silica gel) cartridge and dichloromethane:methanol:0.88 ammonia (96:3.5:0.5) as eluant to give the title compound as a white solid, (145mg, 29%). 1 H NMR (CDCl 3 , 300MHz) δ: 0.10 (m, 2H), 0.48 (m, 2H), 0.88 (m, 1H), 1.58-1.90 (m, 5H), 2.00 (m, 1H), 2.22 (s, 3H), 2.30 (s, 3H), 2.60-2.80 (m, 2H), 3.25 (m, 2H), 3.52 (m, 1H), 4.52 (d, 2H), 4.62 (s, 2H), 6.37 (s, br, 1H), 6.69 (m, 2H), 6.98 (s, 1H), 7.02 (d, 1H), 7.24 (m, 1H), 7.40 (s, 1H), 8.10 (s, 1H). LRMS : m/z = 463 (M+1) + Example 23 2-[3-({[(3 R )-1-(Cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Preparation 78 tert -Butyl (3 S )-3-[(methylsulphonyl)oxy]-1-pyrrolidinecarboxylate Triethylamine (8.7ml, 62.4mmol) was added to a solution of (3 R )-3-pyrrolidinol (5.16g, 41.7mmol) in dichloromethane (30ml), and the solution stirred for 10 mins. Di- tert -butyl dicarbonate (9.11g, 41.7mmol) was added and the reaction stirred at room temperature for 20 hrs. The reaction mixture was concentrated under reduced pressure and the residue partitioned between water and ethyl acetate, and the layers separated. The organic phase was washed with 1N citric acid, water, and brine, then dried over MgSO 4 , and evaporated under reduced pressure to give a pale yellow oil, 7.14g. This intermediate alcohol was dissolved in dichloromethane (100ml), triethylamine (6.4ml, 45.9mmol) added and the solution cooled in an ice-bath. Methanesulphonyl chloride (3.25ml, 41.9mmol) was added slowly, and the reaction stirred for 2 hrs. The reaction mixture was washed with 1N citric acid, saturated NaHCO 3 solution, brine, the dried over Na 2 SO 4 and evaporated under reduced pressure to afford the title compound as an oil, (9.36g, 85%). 1 H NMR (CDCl 3 , 300MHz) δ: 1.40 (s, 9H), 2.03-2.28 (m, 2H), 2.99 (s, 3H), 3.36-3.60 (m, 4H), 5.18 (m, 1H). LRMS : m/z = 283 (M+18) + Preparation 79 tert -Butyl (3R)-3-cyano-1-pyrrolidinecarboxylate Potassium cyanide (5.80g, 89.0mmol) was added to a solution of tert -butyl (3 S )-3-[(methylsulphonyl)oxy]-1-pyrrolidinecarboxylate (preparation 78) (9.35g, 35.3mmol) in dimethylsulphoxide (100ml), and the reaction stired at room temperature for 18 hrs, and then at 100°C for a further 24 hrs. The cooled mixture was poured into water and extracted well with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:pentane (20:80) as eluant to give the title compound as an oil, (4.28g, 62%). 1 H NMR (CDCl 3 , 300MHz) d: 1.46 (s, 9H), 2.21 (m, 2H), 3.10 (m, 1H), 3.39-3.78 (m, 4H). LRMS : m/z = 214 (M+18) + Preparation 80 tert -Butyl (3 R )-3-aminomethyl-1-pyrrolidinecarboxylate A mixture of tert -butyl (3 R )-3-cyano-1-pyrrolidinecarboxylate (preparation 79) (1.60g, 8.13mmol) and Raney® Nickel (1g) in 0.88 ammonia (20ml) and ethanol (150ml), was hydrogentaed at 60 psi and room temperature for 8 hrs. The mixture was filtered through Arbocel®, and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to yield the desired product as an oil, (1.59g, 98%). 1 H NMR (COCl 3 , 300MHz) δ: 1.39 (s, 2H), 1.48 (s, 9H), 1.59 (m, 1H), 2.00 (m, 1H), 2.22 (m, 1H), 2.74 (m, 2H), 3.00 (m, 1H), 3.30 (m, 1H), 3.38-3.59 (m, 2H). LRMS : m/z = 201 (M+1) + Preparation 81 tert -Butyl(3 R )-3-[({4-[2-(benzyloxy)-2-oxoethyl]-6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl}amino)methyl]-1-pyrrolidinecarboxylate A mixture of benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (647mg, 1.98mmol), tert -butyl (3 R )-3-aminomethyl-1-pyrrolidinecarboxylate (preparation 80), (398mg, 1.98mmol) and triethylamine (830ml, 5.95mmol) in ethyl acetate (25ml) was heated under reflux for 18 hrs. The cooled mixture was washed consecutively with water, 1N citric acid solution, brine, then dried over MgSO 4 , and evaporated under reduced pressure to give the desired compound as a gum, (952mg, 98%). 1 H NMR (CDCl 3 , 300MHz) δ: 1.44 (s, 9H), 1.66 (m, 1H), 2.01 (m, 1H), 2.21 (s, 3H), 2.56 (m, 1H), 3.01 (m, 1H), 3.28-3.59 (m, 5H), 4.80 (s, 2H), 5.22 (s, 2H), 6.15 (t, br,1H), 7.39 (m, 5H). Preparation 82 2-[3-({[(3 R )-1-( tert -Butoxycarbonyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid A mixture of tert -butyl (3 R )-3-[({4-[2-(benzyloxy)-2-oxoethyl]-6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl}amino)methyl]-1-pyrrolidinecarboxylate (preparation 81) (922.3mg, 1.89mmol), ammonium formate (1.19g, 18.9mmol) and 10% palladium on charcoal (166.8mg) in methanol (50ml), was stirred at room temperature under a nitrogen atmosphere for 20 hrs. The mixture was filtered through Arbocel®, and the filtrate evaporated under reduced pressure. The residue was triturated with a 10% dichloromethane:methanol solution, and the resulting solid removed by filtration. The filtrate evaporated under reduced pressure to afford the title compound as a white solid, slightly impure, 703mg. 1 H NMR (d 6 -DMSO, 300MHz) δ: 1.39 (s, 9H), 1.58 (m, 1H), 1.83 (m, 1H), 2.00 (s, 3H), 2.97 (m, 1H), 3.10-3.38 (m, 6H), 4.19 (s, 2H), 6.46 (s, 1H). LRMS : m/z = 367 (M+1) + Preparation 83 tert -Butyl(3 R )-3-({[5-methyl-4-(2-{[(3-methyl-1H-indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}methyl)-1-pyrrolidinecarboxylate A mixture of 2-(3-({[(3 R )-1-( tert -butoxycarbonyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid (preparation 82) (698.2mg, 1.91mmol), 3-methyl-1H-indol-5-yl)methylamine (preparation 36) (306.1mg, 1.91mmol), HOBT (291.2mg, 1.90mmol), WSCDI.HCl (367.2mg, 1.92mmol) and N-methylmorpholine (4.2ml, 3.82mmol) in N,N-dimethylformamide (30ml), was stirred at room temperature for 66 hrs. The reaction was diluted with water, and this mixture extracted with ethyl acetate. The combined organic extracts were washed with 1N citric acid, saturated aqueous NaHCO 3 , and brine, then dried over MgSO 4 and evaporated under reduced pressure to afford the title compound as an off-white solid, (402mg, 42%). 1 H NMR (d 6 -DMSO, 300MHz) δ: 1.39 (s, 9H), 1.58 (m, 1H), 1.83 (m, 1H), 2.04 (s, 3H), 2.21 (s, 3H), 2.73 (s, 2H), 2.86 (s, 2H), 2.98 (m, 1H), 3.14-3.34 (m, 4H), 4.38 (d, 2H), 4.62 (s, 2H), 6.60 (s, 1H), 6.99 (m, 2H), 7.06 (s, 1H), 7.24 (d, 1H), 7.37 (s, 1H), 8.61 (m, 1H), 10.65 (s, 1H). LRMS : m/z = 531 (M+23) + Preparation 84 N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-2-oxo-3-{[(3 R )-pyrrolidinylmethyl]amino}-1(2 H )-pyrazinyl]acetamide tert -Butyl (3 R )-3-({[5-methyl-4-(2-{[(3-methyt-1H-indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}methyl)-1-pyrrolidinecarboxylate (preparation 83) (400mg, 0.79mmol) was dissolved in a solution of methanol (50ml) and 6N hydrochloric acid (50ml), and the reaction stirred at room temperature for 1 ½ hrs. The reaction was neutralised using NaOH solution, the mixture extracted with dichloromethane, and the combined organic extracts evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 95:5:0 to 90:10:1), to provide the title compound. The remaining aqueous solution was evaporated under reduced pressure, the residue triturated with i -propanol, and the filtrate concentrated under reduced pressure .This crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (90:10:1 to 84:14:2 to 80:20:5) to afford more of the desired product as a glass-like solid, (126mg, 39% in total). 1 H NMR (CD 3 OD, 300MHz) δ: 1.66-1.80 (m, 1H), 2.04-2.18 (m, 4H), 2.30 (s, 3H), 2.66 (m, 1H), 2.96 (m, 1H), 3.15 (m, 1H), 3.25 (m, 3H), 3.40 (m, 2H), 4.50 (s, 2H), 4.77 (s, 2H), 6.66 (s, 1H), 6.99 (s, 1H), 7.04 (d, 1H), 7.28 (d, 1H), 7.43 (s, 1H). LRMS : m/z = 409 (M+1) + Preparation 85 2-[3-({[(3 R )-1-(Cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide A mixture of N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-2-oxo-3-{[(3 R )-pyrrolidinylmethyl]amino}-1(2 H )-pyrazinyl]acetamide (preparation 84) (66.8mg, 0.16mmol), cyclopropanecarboxaldehyde (0.12ml, 1.60mmol) and sodium triacetoxyborohydride (35mg, 0.165mmol) in N,N-dimethylformamide (5ml) was stirred at room temperature for 72 hrs. The reaction was diluted with water, basified, and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO 4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (90:10:0.1 to 90:10:1) to yield the title compound, (36mg, 48%). 1 H NMR (d 6 -DMSO, 300MHz) δ: 0.07 (m, 2H), 0.42 (m, 2H), 0.82 (m, 1H), 1.42 (m, 1H), 1.82 (m, 1H), 2.04 (s, 3H), 2.22 (s, 3H), 2.36-2.62 (m, 5H), 3.20 (m, 2H), 4.38 (d, 2H), 4.61 (s, 2H), 6.60 (s, 1H), 6.94 (m, 1H), 6.99 (d, 1H), 7.07 (s, 1H), 7.23 (d, 1H), 7.38 (s, 1H), 8.60 (s, 1H), 10.64 (s, 1H). LAMS : m/z = 463 (M+1) + Example 24 2-[3-{2-[(2 R ,4 R )-1-(Cyclopropylmethyl)-4-methylpiperidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Preparation 86 (2R,4R)-1-Benzyl-4-methyl-2-piperidinecarboxamide HCI gas was bubbled through a solution of (2 R ,4 R )-4-methyl-2-piperidine carboxylic acid (Biochem.Biophys.Res.Comm.1981, 440) (4.2g, 29.0mmol) in methanol (120ml) for 15 mins, and the resulting solution stirred at room temperature overnight. The reaction was concentrated under reduced pressure and azeotroped with dichloromethane to give a pale yellow oil. A solution of this intermediate methyl ester (5.6g, 29mmol) in 0.88 ammonia solution (100ml) was stirred for 2 hrs at 50°C, followed by a further 18 hrs at room temperature. The reaction mixture was concentrated under reduced pressure, the residue azeotroped with toluene, and then dichloromethane, to give a white solid. Benzyl bromide (3.5ml, 29.0mol) was added to a solution of the intermediate carboxamide and triethylamine (8.1ml, 58.0mmol) in dichloromethane (100ml), and the reaction stirred at room temperature for 4 days. The mixture was diluted with dichloromethane (100ml), then washed with water, brine, dried over MgSO 4 , and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0 to 95:5) to give the desired product as a viscous oil, (3.5g, 52%). 1 H NMR (CDCl 3, 300MHz) δ: 0.97 (d, 3H), 1.29-1.50 (m, 3H), 2.04 (m, 1H), 2.63 (m, 1H), 2.84 (m, 1H), 3.22 (t, 1H), 3.68 (d, 1H), 3.89 (d, 1H), 5.88 (s, br, 1H), 7.17 (s, 1H), 7.30 (m, 5H). LAMS : m/z = 233 (M+1) + Preparation 87 [(2 R ,4 R )-1-Benzyl-4-methylpiperidinyl]methylamine Lithium aluminium hydride (9.2ml, 1M in tetrahydrofuran, 9.2mmol) was added to a solution of (2 R ,4 R )-1-benzyl-4-methyl-2-piperidinecarboxamide (preparation 86) (3.5g, 15.0mmol) in tetrahydrofuran (60ml), and the reaction heated under reflux overnight. The reaction was cooled in an ice-bath, water (0.4ml), 15% NaOH solution (0.4ml), and water (1.2ml) were added consecutively, and the resulting precipitate filtered off. The filtrate was concentrated under reduced pressure, re-dissolved in dichloromethane and washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 85:15:1) to give the title compound as a yellow oil, (650mg, 20%). 1 H NMR (CDCl 3, 300MKz) δ: 0.88 (d, 3H), 1.19-1.54 (m, 3H), 1.63 (m, 1H), 2.14 (s, br, 2H), 2.46-2.75 (m, 4H), 2.94 (m, 1H), 3.77 (d, 2H), 7.17-7.37 (m, 5H). LRMS : m/z = 219 (M+1) + Preparation 88 Benzyl 2-[3-({[(2 R ,4 R )-1-benzyl-4-methylpiperidinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate A mixture of benzyl 2-[3-({[(2 R ,4 R )-1-benzyl-4-methylpiperidinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 87) (650mg, 2.98mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (970mg, 3.0mmol) and triethylamine (0.42ml, 3.0mmol) in ethyl acetate (50ml), was heated under reflux for 24 hrs. The cooled reaction was diluted with ethyl acetate, washed with water, brine, then dried over MgSO 4 , and evaporated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 28:72) to give the title compound as an orange oil, (1.2g, 80%). 1 H NMR (CDCl 3, 300MHz) δ: 0.95 (d, 3H), 1.22-1.56 (m, 5H), 1.79 (m, 1H), 2.20 (s, 3H), 2.60 (m, 1H), 2.78 (m, 1H), 2.98 (m, 1H), 3.41-3.60 (m, 2H), 3.80 (d, 1.5H), 4.82 (d, 1.5H), 5.22 (s, 2H), 6.61 (m, 1H), 7.19-7.42 (m, 10H). LRMS m/z = 510 (M+1) + Preparation 89 Benzyl 2-[3-({[(2 R ,4 R )-4-methylpiperidinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate 1-Chloroethyl chloroformate (0.28ml. 2.57mmol) was added to an ice-cooled solution of benzyl 2-[3-({[(2 R ,4 R )-1-benzyl-4-methylpiperidinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 88) (1.2g, 2.36mmol) and 1,8-bis(dimethylamino)naphthalene (100mg) in dichloromethane (15ml), and the reaction stirred at room temperature overnight. Additional 1-chloroethyl chloroformate (0.30ml, 2.75mmol) and 1,8-bis(dimethylamino)naphthalene (700mg) were added and the reaction stirred for a further 4 hrs. The solution was diluted with dichloromethane (200ml), washed with 0.5M citric acid solution (6x50ml), water and then brine, dried over MgSO 4 and evaporated under reduced pressure. The residue was dissolved in methanol (80ml), and the solution heated under reflux for 1 ½ hrs, concentrated under reduced pressure and azeotroped with dichloromethane to give the desired product as a brown foam, slightly impure, 1.1g. LRMS m/z = 419 (M+1) + Preparation 90 Benzyl 2-[3-({[(2 R ,4 R )-4-methyl-1-(2,2,2-trifluoroacetyl)piperidinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate Pyridine (0.39ml, 4.58mmol) followed by trifluoroacetic anhydride (0.42ml, 3.0mmol) were added to a solution of benzyl 2-[3-({[(2 R ,4 R )-4-methylpiperidinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 89) (1.0g, 2.3mmol) in dichloromethane (30ml), and the reaction stirred at room temperature for an hour. The solution was concentrated under reduced pressure and the residual oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 34:66) to give the title compound, (910mg, 77%). 1 H NMR (Consistent with rotamers) (CDCl 3, 300MHz) δ: 0.97 (d, 3H), 1.10-1.40 (m, 3H), 1.78 (m, 2H), 1.99 (m, 1H), 2.21 (d, 3H), 3.03 (m, 1/3H), 3.40 (m, 2/3H), 3.53-3.91 (m, 4H), 4.77-4.98 (m, 3H), 5.21 (s, 2H), 6.16 (m, 1/3H), 6.26 (m, 2/3H), 7.38 (m, 10H). LRMS : m/z = 516 (M+1) + Preparation 91 2-[3-({[(2R,4R)-4-Methyl-1-(2,2,2-trifluoroacetyl)piperidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid 10% Palladium on charcoal (200mg), followed by ammonium formate (1.1g, 17.4mmol) were added to a solution of benzyl 2-[3-({[(2 R ,4 R )-4-methyl-1-(2,2,2-trifluoroacetyl)piperidinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 90) (900mg, 1.74mmol) in methanol (20ml) and the reaction was stirred at room temperature overnight. Additional 10% palladium on charcoal (50mg) was added and the reaction stirred for a further 24 hrs. The mixture was filtered through Whatman® fibre and the filtrate concentrated under reduced pressure. The residue was suspended in a methanol:dichloromethane (10:90) solution, the resulting precipitate filtered off, and the filtrate evaporated under reduced pressure to provide the title compound as a white solid, (600mg, 92%). LRMS : m/z = 391 (M+1) + Preparation 92 N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-{2-[(2 R ,4 R )-4-methyl-1-(2,2,2-trifluoroacetyl)piperidinyl]ethyl}-2-oxo-1(2 H )-pyrazinyl]acetamide A mixture of 2-[3-({[(2 R ,4 R )-4-methyl-1-(2,2,2-trifluoroacetyl)piperidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 91) (600mg, 1.60mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (256mg, 1.60mmol), HOBT (256mg, 1.90mmol), WSCDl.HCl (364mg, 1.90mmol) and N-methylmorpholine (3.5ml, 3.18mmol) in N,N-dimethylformamide (5ml), was stirred at room temperature overnight. The solution was diluted with water (50ml), and the resulting precipitate filtered off and dried under vacuum. The solid was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (100:0 to 34:66) to give the title compound, (360mg, 42%). 1 H NMR (Consistent with rotamers) (CDCl 3 , 300MHz) δ: 0.97 (d, 3H), 1.06-1.38 (m, 3H), 1.78 (m, 2H), 1.95 (m, 1H), 2.22 (d, 3H), 2.30 (s, 3H), 3.00 (m,1/3H), 3.30 (m, 2/3H), 3.50-3.88 (m, 3H), 4.23 (m, 1/3H), 4.39-4.72 (m, 3H), 4.94 (m, 2/3H), 5.90 (m, 1/3H), 6.00 (t, br,2/3H), 6.70 (m, 2H), 6.98 (s, 1H), 7.03 (d, 1H), 7.26 (m, 1H), 7.40 (s, 1H), 7.97 (s, br,1H). LAMS : m/z = 534 (M+2) + Preparation 93 N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-{2-[(2 R ,4 R )-4-methylpiperidinyl]ethyl}-2-oxo-1(2 H )-pyrazinyl]acetamide A mixture of N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-{2-[(2 R ,4 R )-4-methyl-1-(2,2,2-trifluoroacetyl)piperidinyl]ethyl}-2-oxo-1(2 H )-pyrazinyl]acetamide (preparation 92) (360mg, 0.68mmol) and aqueous Na 2 CO 3 solution (6ml, 0.76M, 4.6mmol) in methanol (50ml) and water (10ml) was stirred at room temperature for 3 days, followed by a further 3 hrs, heating under reflux. The solution was concentrated under reduced pressure and extracted with a dichloromethane:methanol (90:10) solution (3x100ml), and the combined organic extracts evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford the title compound, (300mg, 100%). 1 H NMR (CD 3 OD, 300MHz) δ: 1.06 (d, 3H), 1.44 (m, 1H), 1.60 (m, 1H), 1.75-1.95 (m, 2H), 2.03 (m, 1H), 2.18 (s, 3H), 2.30 (s, 3H), 3.08 (m, 1H), 3.20 (m, 1H), 3.55 (m, 2H), 3.70 (m, 1H), 4.50 (s, 2H), 4.78 (s, 2H), 6.70 (s, 1H), 6.99 (s, 1H), 7.04 (d, 1H), 7.27 (d, 1H), 7.42 (s, 1H). LRMS : m/z = 437 (M+1) + Preparation 94 2-[3-{2-[(2 R ,4 R )-1-(Cyclopropylmethyl)-4-methylpiperidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide The title compound was obtained as a white solid, (56%) from N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-{2-[(2 R ,4 R )-4-methylpiperidinyl]ethyl}-2-oxo-1(2 H )-pyrazinyl]acetamide (preparation 93) and cyclopropanecarboxaldehyde, following the procedure described in preparation 85. 1 H NMR (CD 3 OD, 300MHz) δ: 0.18 (m, 2H), 0.54 (m, 2H), 0.94 (m, 4H), 1.22-1.42 (m, 2H), 1.52-1.66 (m, 2H), 1.78 (m, 1H), 2.15 (s, 3H), 2.30 (s, 3H), 2.42 (m, 1H), 2.70 (m, 2H), 2.82 (m, 1H), 3.20 (m, 1H), 3.48 (m, 2H), 4.48 (s, 2H), 4.75 (s, 2H), 6.64 (s, 1H), 6.99 (s, 1H), 7.04 (d, 1H), 7.26 (d, 1H), 7.42 (s, 1H). LRMS : m/z =513 (M+23) + Example 25 2-[3-({[(3 R )-4-(Cyclopropylmethyl)morpholinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Preparation 95 [(3 R )-4-Benzylmorpholinyl]methylamine Oxalyl chloride (4ml, 45.8mmol) was added carefully to a slurry of 4-benzyl-(2 R )-5-oxo-2-morpholinecarboxylic acid (J.Chem.Soc.Perk.I; 1985;2577) (7.3g, 31mmol) in dichloromethane (90ml), followed by N,N-dimethylformamide (3 drops), and the reaction stirred at room temperature for 2 hrs. The mixture was concentrated under reduced pressure, azeotroped with dichloromethane (3x), and the resulting oil, dried under vacuum. Ammonia gas was bubbled through an ice-cold solution of this intermediate acid chloride in ether (50ml), for 15 minutes, and the resulting solution stirred at room temperature for 72 hrs. The reaction mixture was evaporated under reduced pressure to give a buff-coloured solid, 8.6g. Lithium aluminium hydride (35.8ml, 1M in tetrahydrofuran, 35.8mmol) was added carefully to a slurry of this amide in tetrahydrofuran (100ml), and the resulting mixture stirred at room temperature for 30 minutes, and then heated under reflux for 24 hrs. Additional lithium aluminium hydride (25ml, 1M in tetrahydrofuran, 25mmol) was added, and the reaction heated under reflux for a further 48 hrs. The mixture was then cooled in an ice-bath, and treated sequentially, with stirring, with water (2.7ml), 15% NaOH solution (2.7ml), and water (8ml), and the resulting precipitate filtered off. The filtrate was concentrated under reduced pressure and the residual gum purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 85:15:1) to afford the title compound, (4.2g, 65%). LRMS : m/z = 207 (M+1) + Preparation 96 Benzyl 2-[3-({[(3 R )-4-benzylmorpholinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate A solution of [(3 R )-4-benzylmorpholinyl]methylamine (preparation 95) (4.2g, 20.4mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (1g, 3.06mmol), and triethylamine (0.7ml, 5.0mmol) in ethyl acetate (25ml) was heated under reflux for 18 hrs. The cooled reaction mixture was diluted with ethyl acetate, washed with water, then brine, dried over MgSO 4 and concentrated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 100:0) to give the title compound as a white solid, (500mg, 32%). LRMS : m/z = 515 (M+18) + Preparation 87 Benzyl 2-[3-({[(3 R )-morpholinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate 1,8-Bis(dimethylamino)naphthalene (250mg, 1.17mmol) was added to a solution of benzyl 2-[3({[(3 R )-4-benzylmorpholinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 96) (570mg, 1.1mmol) in dichloromethane (15ml), followed by 1-chloroethyl chloroformate (120ml, 1.1mmol), and the reaction stirred at room temperature for 18 hrs. Additional 1,8-bis(dimethylamino)naphthalene (250mg, 1.16mmol) and 1-chloroethyl chloroformate (120ml, 1.1mmol), were added and the reaction stirred for a further 4 days at room temperature and under reflux for the final 24 hrs. The solution was diluted with dichloromethane (200ml), and washed with 0.5N citric acid (5x), brine, then dried over MgSO 4 , and concentrated under reduced pressure. The crude brown solid was heated under reflux in methanol (30ml), ovemight, the cooled mixture filtered, the filtrate concentrated under reduced pressure and azeotroped with dichloromethane to yield the desired product as a brown foam, slightly impure, 520mg. LRMS : m/z 406 (M) + Preparation 98 Benzyl 2-[3-chloro-2-methyl-6-oxo-5-({[(3 R )-4-(2,2,2-trifluoroacetyl)morpholinyl]methyl}amino)-1(6 H )-pyrazinyl]acetate Pyridine (31ml, 0.38mmol) followed by trifluoroacetic anhydride (44ml, 0.31 mmol) were added to an ice-cold solution of benzyl 2-[3-({[(3 R )-morpholinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 97) (120mg, 0.29mmol) in dichloromethane (7ml), and the reaction stirred at 0°C for 10 mins, and then at room temperature for a further 2 hrs. The reaction was quenched with water the layers separated, and the organic phase dried over MgSO 4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:pentane (30:70) as eluant to give the title compound as a yellow solid, (83mg, 56%). 1 H NMR (CDCl 3 , 300MHz) δ: 2.20 (s, 3H), 3.40-4.20 (m, 9H), 4.80 (s, 2H), 5.21 (s, 2H), 6.20 (m, 1H), 7.36 (m, 5H). LRMS : m/z = 502 (M) + Preparation 99 2-[3-Chloro-2-methyl-6-oxo-5-({[(3 R )-4-(2,2,2-trifluoroacetyl)morpholinyl]methyl}amino)-1(6 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide A mixture of benzyl 2-[3-chloro-2-methyl-6-oxo-5-({[(3 R )-4-(2,2,2-trifluoroacetyl)morpholinyl]methyl}amino)-1(6 H )-pyrazinyl]acetate (preparation 98) (300mg, 0.60mmol), and palladium hydroxide (80mg) in methanol (4ml), was hydrogenated at room temperature and 15 psi for 18 hrs. The reaction mixture was filtered through Whatman® fibre, and the filter pad washed well with ethyl acetate. The combined filtrate was evaporated under reduced pressure to give a pale yellow solid, 180mg. (3-Methyl-1H-indol-5-yl)methylamine (preparation 36) (76mg, 0.48mmol), HOBT (64mg, 0.48mmol), WSCDI.HCl (91mg, 0.48mmol) and N-methylmorpholine (79mg, 0.71mmol), were added to a solution of the intermediate acid in N,N-dimethylformamide (4ml), and the reaction stirred at room temperature for 72 hrs. The reaction mixture was purified directly by column chromatography on silica gel using dichloromethane:methanol (90:10) as eluant to afford the title compound as an off-white solid, (162mg, 52%). 1 H NMR (CDCl 3 , 400MHz) δ: 2.30 (s, 3H), 2.38 (s, 2H), 2.40 (s, 1H), 3.50 (m, 1H), 3.62 (m, 2H), 3.75 (m, 1H), 3.92-4.26 (m, 4H), 4.42-4.59 (m, 3H), 4.65 (m, 2H), 6.25 (m, 1H), 6.55 (m, 1/3H), 6.65 (m, 2/3H), 6.98 (s, 1H), 7.02 (m, 1H), 7.27 (m, 1H), 7.40 (s, 1H), 7.99 (s, 1H). LRMS : m/z = 555 (M+1) + Preparation 100 2-[3-Chloro-2-methyl-5-{[(3 R )morpholinylmethyl]amino]-6-oxo-1(6 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide A mixture of 2-[3-chloro-2-methyl-6-oxo-5-({[(3 R )-4-(2,2,2-trifluoroacetyl)morpholinyl]methyl}amino)-1(6 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide (preparation 99) (162mg, 0.31mmol) and Na 2 CO 3 (600mg, 5.66mmol) in water (8ml), and methanol (6ml), was stirred at 40°C for 18 hrs. The cooled reaction was concentrated under reduced pressure to remove the methanol, and the remaining aqueous solution extracted with ethyl acetate. The combined organic extracts were dried over MgSO 4 , and evaporated under reduced pressure to give the title compound, (140mg, slightly impure). 1 H NMR (CDCl 3 , 400MHz) δ: 2.30 (s, 3H), 2.39 (s, 3H), 2.90 (m, 2H), 3.08 (m, 1H), 3.30 (m, 2H), 3.49 (m, 1H), 3.60-4.00 (m, 3H), 4.54 (d, 2H), 4.62 (s, 2H), 6.34 (m, 1H), 6.54 (m, 1H), 6.98 (s, 1H), 7.03 (d, 1H), 7.28 (d, 1H), 7.40 (s, 1H), 7.96 (s, 1H). LRMS : m/z = 459,461 (M+1) + Preparation 101 2-[3-Chloro-5-({[(3 R )-4-(cyclopropylmethyl)morpholinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide A mixture of 2-[3-chloro-2-methyl-6-oxo-5-({[(3 R )-4-morpholinyl]methyl}amino)-1(6 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide (preparation 100) (140mg, 0.33mmol), cyclopropanecarboxaldehyde (26ml, 0.35mmol) and sodium triacetoxyborohydride (105mg, 0.49mmol) in tetrahydrofuran (4ml) was stirred at room temperature under a nitrogen atmosphere for 16 hrs. The solution was partitioned between water and ethyl acetate, the layers separated, and the organic phase dried over MgSO 4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (95:5 to 90:10) to afford the title compound (121mg, 72%). 1 H NMR (CDCl 3 , 400MHz) δ: 0.10 (m, 2H), 0.45 (m, 2H), 0.86 (m, 1H), 2.19 (m, 1H), 2.30 (s, 3H), 2.40 (s, 3H), 2.48 (m, 1H), 2.60-2.75 (m, 2H), 3.02 (m, 1H), 3.42 (m, 3H), 3.62 (m, 1H), 3.74 (m, 1H), 3.80 (m, 1H), 4.56 (m, 2H), 4.66 (s, 2H), 6.48 (m, 1H), 6.56 (m, 1H), 6.98 (s, 1H), 7.05 (d, 1H), 7.30 (d, 1H), 7.42 (s; 1H), 7.92 (s, 1H). LRMS : m/z = 513, 515 (M+1) + Preparation 102 2-[3-({[(3 R )-4-(Cyclopropylmethyl)morpholinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide A mixture of 2-[3-chloro-5-({[(3 R )-4-(cyclopropylmethyl)morpholinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide (preparation 101) (120mg, 0.23mmol), ammonium formate (44mg, 0.7mmol) and 10% palladium on charcoal (catalytic) in methanol (5ml) was stirred at room temperature under a nitrogen atmosphere for 64 hrs. The reaction mixture was filtered through a Whatman® filter, washing through with ethyl acetate. The combined filtrate was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:0.5) as eluant to give the title compound as a white solid, (15mg, 14%). 1 H NMR (CDCl 3 , 400MHz) δ: 0.12 (m, 2H), 0.50 (m, 2H), 0.86 (m, 1H), 2.18 (m, 1H), 2.24 (s, 3H), 2.30 (s, 3H), 2.46 (m, 1H), 2.65 (m, 2H), 3.02 (m, 1H), 3.40 (m, 2H), 3.46-3.83 (m, 4H), 4.55 (m, 2H), 4.64 (s, 2H), 6.35 (s, br,1H), 6.60 (s, br,1H), 6.72 (s, 1H), 6.98 (s, 1H), 7.04 (d, 1H), 7.18 (m, 1H), 7.60 (s, 1H), 7.94 (s, br,1H). LAMS : m/z = 478 (M+1) + Example 26 2-[3-({3-[(2-Aminoethoxy)methyl]phenethyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Preparation 103 tert -Butyl 2-{[3-(bromomethyl)benzyl]oxy}ethylcarbamate Sodium hydride (125mg, 60% dispersion in mineral oil, 3.13mmol) was added portionwise to an ice-cooled soluton of tert -butyl 2-hydroxyethylcarbamate (500mg, 3.10mmol), and 1,3-bis(bromomethyl)benzene (8.2g, 31.0mmol) in tetrahydrofuran (15ml), and the reaction stirred at 0°C for an hour under a nitrogen atmosphere, then allowed to warm to room temperature. Saturated ammonium chloride solution (10ml) was added, and the mixture partitioned between water and ethyl acetate, and the layers separated. The organic phase was then dried over MgSO 4 , and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (15:85 to 75:25) to give the title compound as a colourless oil, (796mg, 74%). 1 H NMR (CDCl 3 , 300MHz) δ: 1.42 (s, 9H), 3.38 (m, 2H), 3.56 (t, 2H), 4.50 (2xs, 4H), 4.88 (s, br, 1H), 7.38 (m, 4H). LRMS : m/z = 362 (M+18) + Preparation 104 tert -Butyl 2-{[3-(cyanomethyl)benzyl]oxy}ethylcarbamate Sodium cyanide (284mg, 5.78mmol) and benzyl triethylammonium bromide (63mg, 0.23mmol) were added to a solution of tert -butyl 2-{[3-(bromomethyl)benzyl]oxy}ethylcarbamate (preparation 103) (798mg, 2.31 mmol) in acetonitrile (5ml), and the reaction stirred at room temperature for 4 days. The mixture was partitioned between water and ethyl acetate and the layers separated. The organic phase was dried over MgSO 4 and evaporated under reduced pressure, to afford the desired product as an oil, (654mg, 97%). 1 H NMR (CDCl 3 , 400MHz) δ: 1.42 (s, 9H), 3.37 (m, 2H), 3.57 (t, 2H), 3.78 (s, 2H), 4.54 (s, 2H), 4.86 (s, br, 1H), 7.26 (m, 3H), 7.37 (m, 1H). LRMS : m/z = 291 (M+1) + Preparation 105 tert -Butyl 2-{[3-(2-aminoethyl)benzyl]oxy}ethylcarbamate Raney® nickel (170mg) was added to a solution of tert -butyl 2-{[3-(cyanomethyl)benzyl]oxy}ethylcarbamate (preparation 104) (654mg, 2.26mmol) ii ethanolic ammonia solution (15ml), and the mixture hydrogenated at 60 psi and room temperature for 24 hrs. The reaction mixture was filtered through Arbocel®, and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:1) to afford the title compound, (536mg, 80%). 1 H NMR (CDCl 3 , 300MHz) δ: 1.25 (s, br,2H), 1.43 (s, 9H), 2.78 (t, 2H), 2.98 (t, 2H), 3.36 (m, 2H), 3.57 (t, 2H), 4.50 (s, 2H), 4.88 (s, br, 1H), 7.18 (m, 2H), 7.28 (m, 2H). Preparation 106 Benzyl 2-[3-{[3-({2-[( tert -butoxycarbonyl)amino]ethoxy}methyl)phenethyl]amino}-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate A mixture of tert -butyl 2-{[3-(2-aminoethyl)benzyl]oxy}ethylcarbamate (preparation 105) (270mg, 0.92mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (300mg, 0.92mmol), and triethylamine (140ml, 1.01mmol) in ethyl acetate was heated under reflux ovemight. The cooled suspension was diluted with ethyl acetate, then washed with hydrochloric acid (2N), NaHCO 3 solution, brine, then dried over MgSO 4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane (40:60) as eluant, and triturated with ether, to give the title compound as a white solid, (243mg, 45%). Re-purifiing the ether filtrate by column chromatography on silica gel provided an additional (176mg, 33%) of the desired product 1 H NMR (CDCl 3 , 300MHz) d: 1.42 (s, 9H), 2.20 (s, 3H), 2.95 (t, 2H), 3.36 (m, 2H), 3.56 (t, 2H), 3.68 (m, 2H), 4.50 (s, 2H), 4.80 (s, 2H), 4.99 (m, 1H), 5.21 (s, 2H), 6.12 (s, br,1H), 7.19 (m, 3H), 7.23-7.40 (m, 6H). LAMS : m/z = 607 (M+23) + Preparation 107 2-[3-{[3-({2-[( tert -Butoxycarbonyl)amino]ethoxy}methyl)phenethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid Ammonium formate (425mg, 6.74mmol) and 10% palladium on charcoal (200mg) was added to a solution of benzyl 2-[3-{[3-({2-[( tert -butoxycarbonyl)amino]ethoxy}methyl)phenethyl]amino}-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate (preparation 106) (392mg, 0.67mmol) in acetonitrile (10ml), and the reaction stirred at room temperature overnight. The reaction mixture was filtered through Whatman® fibre, and the filtrate concentrated under reduced pressure. The residue was suspended in dichloromethane, basified using 1N NaOH solution, and re-acidified to pH 4, using 1N hydrochloric acid. This solution was extracted with ethyl acetate (3x), and the combined organic extracts dried over MgSO 4 and evaporated under reduced pressure to give the title compound as a white foam, (180mg, 58%). 1 H NMR (d 6 -DMSO, 400MHz) δ: 1.37 (s, 9H), 2.02 (s, 3H), 2.82 (t, 2H), 3.10 (t, 2H), 3.40 (t, 2H), 3.46 (m, 2H), 4.42 (m, 4H), 6.60 (s, 1H), 6.74 (t, br, 1H), 6.80 (t, br, 1H), 7.15 (m, 3H), 7.24 (m, 1H). LRMS : m/z = 461 (M+1) + Preparation 108 tert -Butyl 2-{[3-(2-{[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)benzyl]oxy}ethylcarbamate A mixture of 2-[3-{[3-({2-[( tert -butoxycarbonyl)amino]ethoxy)methyl)phenethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid (preparation 107) (174mg, 0.38mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (67mg, 0.42mmol), HOBT (77mg, 0.57mmol), WSCDI.HCl (91mg, 0.47mmol) and N-methylmorpholine (124ml, 1.13mmol) in N,N-dimethylformamide (5ml), was stirred at room temperature for 20 hrs. The reaction mixture was partitioned between ethyl acetate and water and the phases separated. The organic layer was dried over MgSO 4 and evaporated under reduced pressure to give the title compound as a white solid, (220mg, 96%). 1 H NMR (d 6 -DMSO, 300MHz) δ: 1.37 (s, 9H), 2.05 (s, 3H), 2.22 (s, 3H), 2.82 (t, 2H), 3.10 (m, 2H), 3.39 (t, 2H), 3.46 (m, 2H), 4.36 (d, 2H), 4.41 (s, 2H), 4.61 (s, 2H), 6.62 (s, 1H), 6.81 (m, 2H), 6.98 (d, 1H), 7.08 (s, 1H), 7.15 (m, 3H), 7.23 (m, 2H), 7.37 (s, 1H), 8.62 (t, br, 1H), 10.68 (s, 1H). LRMS : m/z = 603 (M+1) + Preparation 109 2-[3-({3-[(2-Aminoethoxy)methyl]phenethyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Hydrochloric acid (10ml, 6N, 60.0mmol) was added to a solution of tert -butyl 2-{[3-(2-{[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)benzyl]oxy}ethylcarbamate (preparation 108) (220mg, 0.36mmol) in methanol (10ml), and the reaction stirred for an hour at room temperature. The mixture was basified using NaOH (1N) solution, and the mixture extracted with ethyl acetate (2x), and dichloromethane (1x). The combined organic extracts were dried over MgSO 4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:1) to afford the title compound as a white solid, (100mg, 55%). 1 H NMR (d 6 -DMSO, 400MHz) δ: 2.05 (s, 3H), 2.21 (s, 3H), 2.72 (t, 2H), 2.82 (t, 2H), 3.40 (t, 2H), 3.48 (m, 2H), 4.38 (d, 2H), 4.43 (s, 2H), 4.61 (s, 2H), 6.62 (s, 1H), 6.79 (t, br,1H), 6.98 (d, 1H), 7.06 (s, 1H), 7.15 (m, 3H), 7.24 (m, 2H), 7.37 (s, 1H), 8.60 (t, br,1H), 10.65 (s, 1H). LRMS : m/z = 503 (M+1) + Example 27 N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-[(3-{[2-(methylamino)ethoxy]methyl}phenethyl)amino]-2-oxo-1(2 H )-pyrazinyl]acetamide Preparation 110 tert -Butyl methyl[2-({3-[bromomethyl]benzyl}oxy)ethyl]carbamate The title compound was obtained (85%) from tert -butyl 2-hydroxyethyl(methyl)carbamate (Synth. Commun. 23;17;1993;2443) and 1,3-bis(bromomethyl)benzene following the procedure described in preparation 103. 1 H NMR (CDCl 3 , 300MHz) δ: 1.43 (s, 9H), 2.95 (s, 3H), 3.42 (s, br,2H), 3.60 (s, br,2H), 4.50 (2xs, 4H), 7.25 (m, 1H), 7.35 (m, 3H). Preparation 111 tert -Butyl methyl[2-({3-[cyanomethyl]benzyl}oxy)ethyl]carbamate The title compound was obtained (94%) as an oil, from tert -butyl methyl[2-({3-[bromomethyl]benzyl}oxy)ethyl]carbamate (preparation 110), following the procedure described in 104. 1 H NMR (CDCI 3 , 300MHz) d: 1.41 (s, 9H), 2.95 (s, 3H), 3.42 (s, br,2H), 3.60 (s, br,2H), 3.77 (s, 2H), 4.54 (s, 2H), 7.25 (m, 3H), 7.36 (m, 1H). LRMS : m/z =305 (M+1) + Preparation 112 tert -Butyl methyl[2-({3-[2-(methylamino)ethyl]benzyl}oxy)ethyl]carbamate The title compound was obtained as an oil (99%) from tert -butyl methyl[2-({3-[cyanomethyl]benzyl}oxy)ethyl]carbamate (preparaton 111), following the procedure described in 105. 1 H NMR (CDCl 3 , 400MHz) δ: 1.26 (s, br,2H), 1.43 (s, 9H), 2.77 (t, 2H), 2.94 (s, 3H), 2.98 (t, 2H), 3.42 (s, br,2H), 3.60 (s, br,2H), 4.50 (s, 2H), 7.14 (d, 1H), 7.18 (m, 2H), 7.28 (m, 1H). LRMS : m/z = 309 (M+1) + Preparation 113 Benzyl 2-[3-{[3-({2-[( tert -butoxycarbonyl)(methyl)amino]ethoxy}methyl)phenethyl]amino}-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate The title compound was obtained as a white crystalline solid (64%) from tert -butyl methyl[2-({3-[2-(methylamino)ethyl]benzyl}oxy)ethyl]carbamate (preparation 112) and benzyl 2-[3,5-dichtoro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17), following the procedure described in preparation 106. 1 H NMR (CDCl 3 , 400MHz) δ: 1.42 (s, 9H), 2.21 (s, 3H), 2.95 (m, 5H), 3.42 (s, br,2H), 3.60 (s, br, 2H), 3.68 (m, 2H), 4.50 (s, 2H), 4.80 (s, 2H), 5.21 (s, 2H), 6.10 (t, br, 1H), 7.17 (d, 1H), 7.20 (m, 2H), 7.26 (m, 1H), 7.36 (m, 5H). Preparation 114 2-[3-{[3-({2-[( tert -Butoxycarbonyl)(methyl)amino]ethoxy}methyl)phenethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid Ammonium formate (368mg, 5.83mmol), followed by 10% palladium on charcoal (200mg), were added to a solution of benzyl 2-[3-{[3-({2-[( tert -butoxycarbonyl)(methyl)amino]ethoxy}methyl)phenethyl]amino}-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate (preparation 113) (350mg, 0.58mmol) in methanol (10ml), and the reaction stirred at room temperature overnight. The reaction mixture was filtered through Whatman® fibre, and the filtrate concentrated under reduced pressure. The residue was triturated with dichloromethane, the resulting suspension filtered again through Whatman® fibre, then through celite, and this filtrate evaporated under reduced pressure. The residual solid was dissolved in dichloromethane, the solution washed with water, brine, then dried over MgSO 4 and evaporated under reduced pressure to give the desired product as a gum, (213mg, 79%). 1 H NMR (d 6 -DMSO, 300MHz) δ: 1.36 (s, 9H), 1.98 (s, 3H), 2.03 (s, 3H), 2.82 (m, 2H), 3.30 (t, 2H), 3.48 (m, 4H), 4.43 (s, 2H), 4.52 (s, 2H), 6.60 (s, 1H), 6.78 (t, br,1H), 7.15 (m, 3H), 7.24 (m, 1H). LRMS : m/z = 474 (M) + Preparation 115 tert -Butyl methyl(2-{[3-(2-{[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)benzyl]oxy}ethyl)carbamate The title compound was obtained as a white solid (97%) from 2-[3-{[3-({2-[( tert -butoxycarbonyl)(methyl)amino]ethoxy}methyl)phenethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid (preparation 114) and (3-methyl-1H-indol-5-yl)methylamine (preparation 36), following a similar procedure to that described in preparation 108. 1 H NMR (d 6 -DMSO, 400MHz) δ: 1.37 (s, 9H), 2.04 (s, 3H), 2.21 (s, 3H), 2.80 (m, 5H), 3.35 (t, 2H), 3.48 (m, 4H), 4.38 (d, 2H), 4.43 (s, 2H), 4.62 (s, 2H), 6.61 (s, 1H), 6.79 (t, br,1H), 6.98 (d, 1H), 7.06 (s, 1H), 7.15 (m, 3H), 7.24 (m, 2H), 7.37 (s, 1H), 8.80 (t, br,1H), 10.64 (s, 1H). LRMS : m/z = 618 (M+1) + Preparation 116 N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-[(3-{[2-(methylamino)ethoxy]methyl}phenethyl)amino]-2-oxo-1(2 H )-pyrazinyl]acetamide The title compound was obtained as a cream coloured solid, from tert -butyl methyl(2-{[3-(2-{[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)benzyl]oxy}ethyl)carbamate (preparation 115), following a similar procedure to that desribed in preparation 109. 1 H NMR (d 6 -DMSO, 300MHz) δ: 2.05 (s, 3H), 2.20 (s, 3H), 2.24 (s, 3H), 2.61 (t, 2H), 2.82 (t, 2H), 3.45 (m, 4H), 4.38 (d, 2H), 4.42 (s, 2H), 4.61 (s, 2H), 6.62 (s, 1H), 6.78 (t, br, 1H), 6.98 (d, 1H), 7.05 (s, 1H), 7.14 (m, 3H), 7.22 (m, 2H), 7.38 (s, 1H), 8.80 (t, br, 1H), 10.64 (s, 1H). LRMS : m/z = 517 (M+1) + Example 28 2-[3-({3-[(1 R / S )-1-Amino-2-methoxyethyl]phenethyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide Preparation 117 3-Vinylphenylethylamine A mixture of 3-bromophenylacetonitrile (3.31ml, 25.5mmol), vinyl tributyl tin (16.17g, 51.0mmol), bis(triphenylphosphine)palladium(ll) chloride (1.48g, 1.28mmol) and lithium chloride (3.24g, 76.5mmol) in tetrahydrofuran (500ml), was heated under reflux for 6 hrs, and stirred for a further 18 hrs at room temperature. The reaction mixture was concentrated under reduced pressure, the residue dissolved in ethyl acetate and washed with NaHCO 3 solution (2x), then brine, dried over MgSO 4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:hexane (16:84) as eluant to afford a yellow oil. A solution of aluminium chloride (1.44g, 10.8mmol) in tetrahydrofuran (25ml) was added carefully to lithium aluminium hydride (1.23g, 32.4mmol) in tetrahydrofuran (25ml), and the mixture stirred at room temperature for 10 mins. A solution of the intermediate acetonitrile in tetrahydrofuran (50ml) was then added and the reaction stirred at room temperature for 3 hrs. The reaction was quenched by the addition of hydrochloric acid, then basified using aqueous NaOH solution. The mixture was extracted with ethyl acetate, the combined organic extracts dried over MgSO 4 and evaporated under reduced pressure. The crude product was redissolved in ethyl acetate, extracted into citric acid, and these aqueous extracts rebasified using aqueous NaHCO 3 solution. This was then re-extracted with ethyl acetate, and the combined extracts evaporated under reduced pressure to provide the title compound as a yellow oil, (1.79g, 47%). 1 H NMR (CDCl 3 , 300MHz) δ: 1.18 (s, br,2H), 2.75 (t, 2H), 2.97 (t, 2H), 5.22 (d, 1H), 5.76 (d, 1H), 6.70 (dd, 1H), 7.07 (m, 1H), 7.22 (m, 3H). Preparation 118 Benzyl 3-vinylphenethylcarbamate A mixture of 3-vinylphenylethylamine (preparation 117) (1.78g, 12.1mmol), N-(benzyloxy)succinimide (3.62g, 14.52mmol) and triethylamine (2.53ml, 18.15mmol) in dichloromethane (60ml), was stirred at room temperature under a nitrogen atmosphere overnight The reaction mixture was washed with citric acid solution, saturated aqueous NaHCO 3 , brine, then dried over MgSO 4 , and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane as eluant to give the desired product as a colourless oil, (1.43g, 41%). 1 H NMR (CDCl 3 , 300MHz) δ: 2.80 (t, 2H), 3.44 (t, 2H), 4.96 (s, br, 1H), 5.12 (s, 2H), 5.24 (d, 1H), 5.78 (d, 1H), 6.70 (dd, 1H), 7.08 (m, 1H), 7.20-7.41 (m, 8H). Preparation 119 Benzyl 3-{(1 R / S )-1-[( tert -butoxycarbonyl)amino]-2-hydroxyethyl}phenethylcarbamate A solution of NaOH (1.22g, 30.5mmol) in water (70ml), followed by hypochlorous acid tert -butyl ester (3.5ml, 30.5mmol) were added to a solution of tert -butylcarbamate (3.57g, 30.5mmol) in n-propanol (75ml), in an amber glass flask. This solution was stirred at room temperature for 5 mins, then cooled in an ice-bath. Solutions of (DHQ) 2 PHAL (480mg, 0.6mmol) in n-propanol (40ml), and benzyl 3-vinylphenethylcarbamate (preparation 118) (2.81g, 10mmol) in n-propanol (70ml) were added, followed by potassium osmate dihydrate (184mg, 0.5mmol) in water (5ml) and the reaction then stirred at 0°C for 4 hrs, and at room temperature for a further 18 hrs. Saturated sodium dithionite solution (100ml) was added, the phases separated, and the aqueous layer extracted with ethyl acetate (2x100ml). The combined organic extracts were dried over MgSO 4 and evaporated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel twice, using an elution gradient of ethyl acetate:pentane (25:75 to 50:50) to give the desired product as a colourless oil, (603mg, 15%). 1 H NMR (CDCl 3 , 300MHz) δ: 1.42 (s, 9H), 2.52 (s, br, 1H), 2.80 (t, 2H), 3.46 (m, 2H), 3.80 (m, 2H), 4.74 (s, br, 1H), 4.84 (s, br, 1H), 5.07 (s, 2H), 5.32 (d; 1H), 7.11 (m, 3H), 7.30 (m, 6H). Preparation 120 Benzyl 3-{(1 R / S )-1-[( tert -butoxycarbonyl)amino]-2-methoxyethyl}phenethylcarbamate A mixture of methyl iodide (98ml, 1.57mmol), benzyl 3-{(1 R / S )-1-[( tert -butoxycarbonyl)amino]-2-hydroxyethyl}phenethylcarbamate (preparation 119) (590mg, 1.4mmol), benzyltriethylammonium chloride (325mg, 1.4mmol) and NaOH solution (185ml, 10M, 1.85mmol) in dichloromethane (10ml), was stirred at room temperature for 3 days. The reaction mixture was partitioned between dichloromethane and water, the phases separated, and the organic layer dried over MgSO 4 and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 50:50) to provide the title compound as a colourless oil, (289mg, 47%). 1 H NMR (CD 3 OD, 300MHz) δ: 1.40 (s, 9H), 2.78 (t, 2H), 3.32 (m, 5H), 3.50 (d, 2H), 4.75 (m, 1H), 4.80 (s, 2H), 5.05 (s, 2H), 7.00-7.36 (m, 9H). Preparation 121 tert -Butyl(1 R / S )-1-[3-(2-aminoethyl)phenyl]-2-methoxyethylcarbamate A mixture of benzyl 3-{(1 R / S )-1-[( tert -butoxycarbonyl)amino]-2-methoxyethyl}phenethylcarbamate (preparation 120) (289mg, 0.68mmol) and 10% palladium on charcoal (30mg) in methanol (10ml) was hydrogenated at 15 psi and room temperature for 16 hrs. The reaction mixture was filtered through Arbocel®, and the filtrate evaporated under reduced pressure to give the title compound, (196mg, 98%). 1 H NMR (CD 3 OD, 300MHz) δ: 1.41 (s, 9H), 2.78 (t, 2H), 2.88 (t, 2H), 3.52 (d, 2H), 4.72-4.80 (m, 5H), 7.11 (d, 1H), 7.18 (m, 2H), 7.24 (m, 1H). LRMS : m/z = 295 (M+1) + Preparation 122 Benzyl 2-[3-[(3-{(1 R / S )-1-[( tert -butoxycarbonyl)amino]-2-methoxyethyl}phenethyl)amino]-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate A mixture of tert -butyl (1 R / S )-1-[3-(2-aminoethyl)phenyl]-2-methoxyethylcarbamate (preparation 121) (196mg, 0.67mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (182mg, 0.56mmol) and triethylamine (368ml, 2.78mmol) in ethyl acetate (5ml) was heated under reflux for 18 hrs. The cooled mixture was washed with brine (15ml), dried over MgSO 4 and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0 to 99:1) to afford the titie compound as a colourless oil, (248mg, 76%). 1 H NMR (CDCl 3 , 300MHz) δ: 1.40 (s, 9H), 2.20 (s, 3H), 2.90 (t, 2H), 3.35 (s, 3H), 3.52-3.70 (m, 4H), 4.80 (m, 3H), 5.22 (m, 3H), 6.15 (t, br, 1H), 7.17 (m, 3H), 7.24 (m, 1H), 7.37 (m, 5H). LRMS : m/z = 585 (M+1) + Preparation 123 2-[3-[(3-{(1 R / S )-1-[( tert -Butoxycarbonyl)amino]-2-methoxyethyl}phenethyl)amino]-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid A mixture of benzyl 2-[3-[(3-{(1 R / S )-1-[( tert -butoxycarbonyl)amino]-2-methoxyethyl}phenethyl)amino]-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate (preparation 122) (248mg, 0.42mmol), ammonium formate (265mg, 4.2mmol) and 10% palladium on charcoal (100mg) in methanol (10ml) was heated under reflux for 25 hrs. The cooled reaction was filtered through Arbocel®, and NaOH (420ml, 10M, 4.2mmol) was added to the filtrate. This mixture was evaporated under reduced pressure, triturated and filtered with a dichloromethane:methanol (91:9) solution (3x), and the combined filtrates evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0 to 93:7) to give the title compound as an oil, (35mg, 18%). 1 H NMR (CD 3 OD, 300MHz) δ: 1.40 (s, 9H), 2.18 (s, 3H), 2.90 (m, 2H), 3.35 (s, 3H), 3.55 (m, 4H), 4.60 (s, 2H), 4.80 (m, 1H), 6.66 (s, 1H), 7.17 (m, 2H), 7.24 (m, 2H). LRMS : m/z = 483 (M+1) + Preparation 124 tert -Butyl (1 R / S )-2-methoxy-1-[3-(2-{[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)phenyl]ethylcarbamate A mixture of 2-[3-[(3-{(1 R / S )-1-[( tert -butoxycarbonyl)amino]-2-methoxyethyl}phenethyl)amino]-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid (preparation 123) (35mg, 0.076mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (13mg, 0.08mmol), HOBT (11mg, 0.08mmol), WSCDl.HCl (16mg, 0.08mmol) and N-methylmorpholine (16ml, 0.15mmol) in N,N-dimethylformamide (2ml), was stirred at room temperature for 18 hrs. Additional (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (8mg, 0.038mmol), was added, and stirring continued for a further 72 hrs at room temperature. The reaction mixture was poured into water (10ml), and the resulting precipitate filtered, and dried to give the desired product, (26mg, 57%). 1 H NMR (CD 3 OD, 300MHz) δ: 1.41 (s, 9H), 2.16 (s, 3H), 2.29 (s, 3H), 2.94 (t, 2H), 3.34 (s, 3H), 3.50 (d, 2H), 3.59 (t, 2H), 4.48 (s, 2H), 4.76 (s, 2H), 4.82 (m, 1H), 6.66 (s, 1H), 6.98 (s, 1H), 7.05 (d, 1H), 7.16 (d, 2H), 7.22 (m, 3H), 7.42 (s, 1H). LRMS : m/z = 625 (M+23) + Preparation 125 2-[3-({3-[(1 R / S )-1-Amino-2-methoxyethyl]phenethyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide A solution of tert -butyl (1 R / S )-2-methoxy-1-[3-(2-{[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)phenyl]ethylcarbamate (preparation 124) (26mg, 0.043mmol) in hydrochloric acid (2ml, 6N, 12mmol) and methanol (2ml), was stirred under a nitrogen atmosphere for 3 hrs. The reaction mixture was basified to pH 10 using 1N NaOH solution, extracted with dichloromethane (4x10ml), and ethyl acetate (3x10ml). The combined organic extracts were dried over MgSO 4 , and evaporated under reduced pressure to give the title compound as a white solid, (13mg, 60%). Both R, and S isomers are present although their relative proportions have not been determined. 1 H NMR (CD 3 OD, 300MHz) δ:2.13 (s, 3H), 2.26 (s, 3H), 2.90 (t, 2H), 3.35 (s, 3H), 3.41 (m, 1H), 3.49 (m, 1H), 3.58 (m, 2H), 4.06 (m, 1H), 4.45 (s, 2H), 4.74 (s, 2H), 6.64 (s, 1H), 6.98 (s, 1H), 7.02 (d, 1H), 7.18 (m, 2H), 7.24 (m, 3H), 7.42 (s, 1H). LRMS : m/z =503 (M+1) + Example 29 2-[3-{[2-(2-Aminoethoxy)phenethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide hydrochloride Preparation 126 3-Hydroxyphenyl acetonitrile Boron tribromide (68ml, 1M in dichloromethane, 68mmol) was added dropwise to an ice-cooled solution of (3-methoxyphenyl)acetonitrile (5.0g, 34mmol) in dichloromethane (50ml), and once addition was complete, the reaction was allowed to warm to room temperature and stirred overnight The reaction was poured into an ice/water solution, the mixture was basified using NaHCO 3 and extracted with dichloromethane. The combined organic extracts were dried over MgSO 4 and evaporated under reduced pressure to give the desired product as a brown oil, (4.13g, 91%). 1 H NMR (CDCl 3 , 300MHz) δ: 3.72 (s, 3H), 5.99-6.20 (s, br, 1H), 6.82 (m, 3H), 7.22 (m, 1H). LRMS : m/z = 151 (M+18) + Preparation 127 tert -Butyl 2-[2-(cyanomethyl)phenoxy]ethylcarbamate Diethyl azodicarboxylate (6.2ml, 39.4mmol) was added dropwise to an ice-cooled solution of 3-hydroxyphenyl acetonitrile (preparation 126) (4.2g, 31.5mmo1), triphenylphosphine (10.34g, 39.4mmol) and tert -butyl 2-hydroxyethylcarbamate (5.4ml, 34.9mmol) in tetrahydrofuran (70ml), and once addition was complete, the reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (400ml), washed with 1N NaOH solution, water, brine, then dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:pentane (30:70) as eluant to give the desired product as a yellow/green oil, that crystallised on standing, (5.88g, 68%). 1 H NMR (CDCl 3 , 300MHz) δ: 1.44 (s, 9H), 3.59 (m, 2H), 3.68 (s, 2H), 4.10 (t, 2H), 5.08 (s, br, 1H), 6.86 (d, 1H), 6.98 (m, 1H), 7.34 (m, 2H). LMS : m/z = 299 (M+23) + Preparation 128 tert -Butyl 2-[2-(aminomethyl)phenoxy]ethylcarbamate The title compound was obtained as a pale yellow crystalline solid, (51%) from tert -butyl 2-[2-(cyanomethyl)phenoxy]ethylcarbamate (preparation 127), following the procedure described in preparation 105. 1 H NMR (CDCl 3 , 300MHz) δ: 1.43 (s, 9H), 1.54 (s, br,2H), 2.80 (t, 2H), 2.98 (t, 2H), 3.58 (m, 2H), 4.02 (t, 2H), 5.28 (s, br,1H), 6.81 (d, 1H), 6.92 (m, 1H), 7.18 (m, 2H). LRMS : m/z = 281 (M+1) + Preparation 129 Benzyl 2-[3-{[3-({2-[( tert -butoxycarbonyl)amino]ethoxy})phenethyl]amino}-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate A mixture of benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (300mg, 0.92mmol), tert -butyl 2-[2-(aminomethyl)phenoxy]ethylcarbamate (preparation 128), (257mg, 0.92mmol) and triethylamine (140ml, 1.0mmol) in ethyl acetate (6ml) was heated under reflux for 18 hrs. The cooled mixture was partitioned between ethyl acetate (80ml) and hydrochloric acid (2N, 30ml) and the phases separated. The organic layer was washed consecutively with hydrochloric acid (2N), saturated NaHCO 3 solution, brine, then dried over MgSO 4 , and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane (50:50) as eluant to give the title compound as an orange foam, (500mg, 95%). 1 H NMR (CDCl 3 , 300MHz) δ: 1.40 (s, 9H), 2.20 (s, 3H), 2.98 (t, 2H), 3.60 (m, 4H), 4.10 (t, 2H), 4.80 (s, 2H), 5.21 (s, 2H), 5.68 (s, br, 1H), 6.57 (s, br, 1H), 6.68-6.88 (m, 2H), 7.18 (m, 2H), 7.37 (m, 5H). LRMS : m/z = 571, 573 (M+1) + Preparation 130 2-[3-{[3-({2-[( tert -Butoxycarbonyl)amino]ethoxy})phenethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid 10% Palladium on charcoal (125mg), followed by ammonium formate (553mg, 8.77mmol) were added to a solution of benzyl 2-[3-{[3-({2-[( tert -butoxycarbonyl)amino]ethoxy})phenethyl]amino}-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate (preparation 129) (500mg, 0.88mmol) in methanol (10ml), and the reaction stirred at room temperature overnight. The reaction mixture was filtered through Whatman® fibre, NaOH solution (8.77ml, 1N, 8.77mmol) was added to the filtrate, and the solution evaporated under reduced pressure. The residue was triturated with a 10% methanol:dichloromethane solution, the suspension filtered, the filtrate dried over MgSO 4 and evaporated under reduced pressure to give the title compound as a white solid, (289mg, 69%). 1 H NMR (d 6 -DMSO, 300MHz) δ: 1.37 (s, 9H), 2.01 (s, 3H), 2.80 (t, 2H), 3.35 (t, 2H), 3.41 (t, 2H), 3.94 (t, 2H), 4.19 (s, 2H), 6.55 (s, 1H), 6.80-6.92 (m, 2H), 7.14 (m, 2H). Preparation 131 tert -Butyl 2-[2-(2-{[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)phenoxy]ethylcarbamate A mixture of 2-[3-{[3-({2-[( tert -Butoxycarbonyl)amino]ethoxy})phenethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid (preparation 130) (268mg,0.60mmol), and (3-Methyl-1H-indol-5-yl)methylamine (preparation 36) (106mg, 0.66mmol) was added to a solution of HOBT (122mg, 0.90mmol), WSCDI.HCI (144mg, 0.75mmol) and N-methylmorpholine (198ml, 1.8mmol) in N,N-dimethylformamide (5ml), and the reaction stirred at room temperature for 20 hrs. The mixture was poured into water (100ml), with vigorous stirring, and the resulting precipitate filtered off. This solid was washed well with water, triturated with ether and dried under vacuum, to afford the title compound, (315mg, 89%). 1 H NMR (d 6 -DMSO, 300MHz) δ: 1.37 (s, 9H), 2.04 (s, 3H), 2.22 (s, 3H), 2.82 (t, 2H), 3.37 (m, 2H), 3.43 (m, 2H), 3.95 (t, br,2H), 4.37 (d, 2H), 4.62 (s, 2H), 6.61 (s, 1H), 6.78 (t, br, 1H), 6.83 (m, 1H), 6.90 (d, 1H), 6.98 (d, 1H), 7.04-7.19 (m, 4H), 7.24 (d, 1H), 7.38 (s, 1H), 8.60 (t, br, 1H), 10.66 (s, 1H). LRMS : m/z = 589 (M+1) + Preparation 132 2-[3-{[2-(2-Aminoethoxy)phenethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide hydrochloride Hydrochloric acid (10ml, 6N, 60mmol) was added to a solution of tert -butyl 2-[2-(2-{[5-methyl-4-(2-{[(3-methyl-1 H -indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)phenoxy]ethylcarbamate (preparation 131) (315mg, 0.54mmol) in methanol (10ml), and the reaction stirred at room temperature for 1 ½ hrs. The reaction mixture was basified using NaOH (2N), and the resulting precipitate filtered off. This yellow solid was pre-adsorbed onto silica gel, and purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (92:7:1) as eluant, to give a cream coloured solid, 169mg. This was dissolved in a 10% methanol:dichloromethane solution, hydrochloric acid (1 N, 1 equiv) was added, the solution stirred for 5 minutes then evaporated under reduced pressure. The product was triturated with a methanol:ether solution, to give the title compound as a white solid, (153mg, 54%). 1 H NMR (d 6 -DMSO, 300MHz) δ: 2.05 (s, 3H), 2.22 (s, 3H), 2.88 (t, 2H), 3.32 (m, 2H), 3.42 (t, 2H), 4.18 (t, 2H), 4.38 (d, 2H), 4.62 (s, 2H), 6.63 (s, 1H), 6.96 (m, 4H), 7.08 (s, 1H), 7.19 (m, 2H), 7.23 (d, 1H), 7.38 (s, 1H), 8.17 (s, br, 3H), 8.66 (t, br, 1H), 10.70 (s, 1H). LRMS : m/z = 489 (M+1) + Found: C, 59.78; H, 6.47; N, 15.54. C 27 H 32 N 6 O 3 ;HCl;H 2 O requires C, 59.71; H, 6.51; N, 15.47%. Example 31 N -(1 H -Indol-5-ylmethyl)-2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetamide Preparation 139 N -(1 H -Indol-5-ylmethyl)-2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetamide HOBT (24mg, 0.18mmol), WSCDI.HCI (29mg, 0.15mmol), N-methylmorpholine (39ml, 0.36mmol) and 1H-indol-5-ylmethylamine (preparation 8) (19mg, 0.13mmol) were added to a solution of 2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 62) (38mg, 0.12mmol) in N,N-dimethylformamide (2ml), and the reaction was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant. The product was repurified using a Biotage™ (KP-Sil™ 60Å silica gel) cartridge and dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant to afford the title compound, (16mg, 30%). 1 H NMR (CDCl 3 , 400MHz) δ: 0.83 (d, 3H), 0.90 (d, 3H), 1.56-1.78 (m, 5H), 1.82 (m, 1H), 2.07 (m, 2H), 2.24 (s, 3H), 2.60 (m, 1H), 3.16 (m, 1H), 3.21 (m, 1H), 3.52 (m, 1H), 4.50 (d, 2H), 4.63 (s, 2H), 6.42 (m, 1H), 6.50 (s, 1H), 6.63 (s, br,1H), 6.70 (s, 1H), 7.05 (d, 1H), 7.20 (m, 1H), 7.34 (d, 1H), 7.49 (s, 1H), 8.20 (s, br,1H). LRMS : m/z = 450 (M) + Example 32 2-[3-({[(2 R )-1-(Cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide Preparation 140 2-[3-({[(2 R )-1-(Cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide The title compound was obtained as a partially crystallised oil (32%), from 2-[3-({[(2 R )-1-(cyclopropylmethyl)pyrrolidinyl]methyl)amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 48) and 1H-indol-5-ylmethylamine (preparation 8), using the procedure described in preparation 45. 1 H NMR (CD 3 OD, 300MHz) δ: 0.17 (m, 2H), 0.50 (m, 2H), 0.94 (m, 1H), 1.62 (m, 1H), 1.78 (m, 2H), 1.94 (m, 1H), 2.08 (m, 4H), 2.32 (m, 1H), 2.75 (m, 2H), 3.28 (m, 2H), 3.57 (m, 1H), 4.44 (s, 2H), 4.70 (s, 2H), 6.40 (d, 1H), 6.62 (s, 1H), 7.03 (d, 1H), 7.20 (d, 1H), 7.34 (d, 1H), 7.46 (s, 1H). Example 33 2-[3-({[(2 R )-1-(Cyclopentyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide Preparation 142 (2 R )-1-Cyclopentyl-2-pyrrolidinecarboxamide Cyclopentanone (388ml, 4.38mmol), acetic acid (251ml, 4.38mmol) and sodium triacetoxyborohydride (1.4g, 6.6mmol) were added consecutively to a solution of (2 R )-pyrrolidinecarboxamide (500mg, 4.38mmol) in dichloromethane (10ml), and the solution stirred at room temperature for 4 hrs. Saturated NaHCO 3 solution (100ml), was added and the mixture extracted with ethyl acetate. The combined organic extracts were washed with water, brine, then dried over MgSO 4 and concentrated under reduced pressure. The residue was triturated with ether, to afford the title compound as a white solid, (320mg, 40%). 1 H NMR (CDCl 3 , 400MHz) d: 1.39-1.81 (m, 10H), 1.95 (m, 1H), 2.10 (m, 1H), 2.42 (m, 1H), 2.86 (t, 1H), 3.17 (m, 2H), 5.36 (s, br,1H), 7.38 (s, br,1H). LRMS : m/z =183 (M+1) + Preparation 143 [(2 R )-1-Cyclopentylpyrrolidinyl]methylamine Lithium aluminium hydride (2.63ml, 1M in tetrahydrofuran, 2.63mmol) was added dropwise to a solution of (2 R )-1-cyclopentyl-2-pyrrolidinecarboxamide (preparation 142) (320mg, 1.76mmol) in tetrahydrofuran (5ml), and once addition was complete, the reaction was stirred at room temperature for 4 hrs. Water was added to quench the reaction, the mixture diluted with ethyl acetate and dried over MgSO 4 . This mixture was filtered through Whatman® fibre, and the filtrate evaporated under reduced pressure. The residue was purified by chromatography using a Biotage™ (KP-Sil™ 60Å silica gel) cartridge and an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5 to 90:10:1) to give the desired product as a dear oil, (208mg, 71%). 1 H NMR (CDCl 3 , 400MHz) δ: 1.19 (s, br,2H), 1.40-1.94 (m, 12H), 2.44 (dd, 1H), 2.57-2.77 (m, 3H), 2.88 (m, 1H), 3.00 (m, 1H). LAMS : m/z=169 (M+1) + Preparation 144 Benzyl 2-[3-chloro-5-({[(2 R )-1-cyclopentylpyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate Benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (404mg, 1.23mmol) was added to a solution of [(2 R )-1-cyclopentylpyrrolidinyl]methylamine (preparation 143) (208mg, 1.23mmol) in ethyl acetate (10ml), followed by triethylamine (190ml, 1.36mmol), and the reaction heated under reflux overnight under a nitrogen atmosphere. The cooled mixture was diluted with ethyl acetate, washed with water, brine, then dried over MgSO 4 and concentrated under reduced pressure. The crude product was purified by chromatography using a Biotage™ (KP-Sil™ 60Å silica gel) cartridge and an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 95:5:0.5) to give the desired product as a cream solid, (450mg, 80%). 1 H NMR (CDCl 3 , 400MHz) δ: 1.42-1.59 (m, 10H), 1.86 (m, 2H), 2.20 (s, 3H), 2.47 (m, 1H), 2.90 (m, 1H), 2.98 (m, 1H), 3.04 (m, 1H), 3.22 (m, 1H), 3.54 (m, 1H), 4.80 (s, 2H), 5.21 (s, 2H), 6.58 (s, br,1H), 7.37 (m, 5H). LRMS : m/z = 458, 460 (M+1) + Preparation 145 2-[3-({[(2 R )-1-Cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid hydrochloride A mixture of benzyl 2-[3-({[(2 R )-1-cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetate (preparation 144) (450mg, 0.98mmol), and palladium hydroxide (200mg) in methanol was hydrogenated at 60 psi and room temperature overnight. The mixture was filtered through Whatman® fibre, and the filtrate concentrated under reduced pressure. The residue was azeotroped with dichloromethane several times to give the title compound as a green foam, (370mg, 100%). 1 H NMR (d 6 -DMSO, 400MHz) δ: 1.50 (m, 2H), 1.69 (m, 4H), 1.82 (m, 2H), 1.96 (m, 4H), 2.06 (s, 3H), 3.08 (m, 1H), 3.20-3.62 (m, 4H), 3.78 (m, 1H), 4.62 (s, 2H), 6.63 (s, 1H), 7.36 (s, br, 1H). LRMS : m/z = 335 (M+1) + Preparation 146 2-[3-({[(2 R )-1-Cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide The title compound was prepared from 2-[3-({[(2 R )-1-cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid hydrochloride (preparation 145) and 1H-indol-5-ylmethylamine (preparation 8), following the procedure described in preparation 45. The crude product was purified by chromatography using a Biotage™ (KP-Sil™ 60Å silica gel) cartridge and dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant. The product was further purified using preparative tic and dichloromethane:methanol:0.88 ammonia (90:10:1) as eluant to afford the title compound, (11mg, 16%). 1 H NMR (CD 3 OD, 400MHz) δ: 1.50-1.62 (m, 4H), 1.65-1.82 (m, 5H), 1.83-2.00 (m, 3H), 2.18 (s, 3H), 2.60 (m, 1H), 3.00-3.17 (m, 3H), 3.26 (m, 1H), 3.57 (m, 1H), 4.50 (s, 2H), 4.78 (s, 2H), 6.43 (d, 1H), 6.70 (s, 1H), 7.10 (d, 1H), 7.24 (d, 1H), 7.38 (d, 1H), 7.54 (s, 1H). LRMS : m/z = 463 (M+1) + Example 34 2-[3-({[(2 R )-1-(Cyclohexyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide Preparation 147 (2 R )-1-Cyclohexyl-2-pyrrolidinecarboxamide The title compound was obtained as a white solid (55%) from cyclohexanone and (2 R )-pyrrolidinecarboxamide, following the procedure described in preparation 142. 1 H NMR (CDCl 3 , 400MHz) δ: 1.02-1.25 (m, 6H), 1.77 (m, 5H), 1.92 (m, 2H), 2.02 (m, 1H), 2.36 (m, 1H), 2.50 (m, 1H), 3.08 (t, 1H), 3.24 (dd, 1H), 5.38 (s, br,1H), 7.39 (s, br,1H). Preparation 148 [(2 R )-1-Cyclohexylpyrrolidinyl]methylamine Lithium aluminium hydride (7.3ml, 1M in tetrahydrofuran, 7.3mmol) was added dropwise to a solution of (2 R )-1-cyclohexyl-2-pyrrolidinecarboxamide (preparation 147) (950mg, 4.85mmol) in tetrahydrofuran (15ml) and once addition was complete, the reaction was heated under reflux for 20 hrs. The cooled mixture was carefully quenched with water, and extracted with ethyl acetate. The combined organic extracts were then dried over MgSO 4 and evaporated under reduced pressure. The residue was suspended in dichloromethane, filtered through Whatman® fibre and the filtrate evaporated under reduced pressure to give the desired product as an oil (849mg, 96%). 1 H NMR (CDCl 3 , 400MHz) δ: 1.03-1.54 (m, 8H), 1.54-1.90 (m, 8H), 2.40 (m, 1H), 2.45-2.63 (m, 3H), 2.79 (m, 1H), 2.94 (m, 1H). LAMS : m/z 183 (M+1) + Preparation 149 Benzyl 2-[3-chloro-5-({[(2 R )-1-cyclohexylpyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate The title compound was obtained as a pale brown solid (60%), from [(2 R )-1-cyclohexylpyrrolidinyl]methylamine (preparation 148) and benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17), following the procedure described in preparation 144. 1 H NMR (CDCl 3 , 400MHz) δ: 1.07-1.34 (m, 6H), 1.58-1.83 (m, 7H), 1.92 (m, 1H), 2.20 (s, 3H), 2.43 (m, 1H), 2.58 (m, 1H), 2.98 (m, 1H), 3.16 (m, 2H), 3.48 (m, 1H), 4.80 (s, 2H), 5.21 (s, 2H), 6.58 (s, br,1H), 7.38 (m, 5H). LRMS : mz = 473, 475 (M+1) + Preparation 150 2-[3-({[(2 R )-1-Cyclohexylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetic acid hydrochloride The title compound was obtained (100%) from benzyl 2-[3-chloro-5-({[(2 R )-1-cyclohexylpyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (preparation 149) following a similar procedure to that described in preparation 145. 1 H NMR (d 6 -DMSO, 400MHz) δ: 1.01-1.29 (m, 4H), 1.38 (m, 2H), 1.58 (m, 1H), 1.75-2.17 (m, 8H), 3.04-3.39 (m, 5H), 3.58 (m, 2H), 3.83 (m, 1H), 4.62 (s, 2H), 6.62 (s, 1H), 7.38 (s, br,1H). Preparation 151 2-[3-({[(2 R )-1-(Cydohexyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide The title compound was obtained as a white powder after trituration with ether (40%), from 2-[3-({[(2 R )-1-cyclohexylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1 (2 H )-pyrazinyl]acetic acid hydrochloride (preparation 150) and 1H-indol-5-ylmethylamine (preparation 8), following a similar procedure to that described in preparation 139. 1 H NMR (CD 3 OD, 400MHz) δ: 1.12-1.34 (m, 5H), 1.60-1.82 (m, 7H), 1.92 (m, 1H), 1.98 (m, 1H), 2.14 (s, 3H), 2.52 (m, 1H), 2.61 (m, 1H), 2.98 (m, 1H), 3.20 (m, 2H), 3.42 (m, 1H), 4.44 (s, 2H), 4.75 (s, 2H), 6.40 (d, 1H), 6.64 (s, 1H), 7.04 (d, 1H), 7.20 (d, 1H), 7.34 (d, 1H), 7.48 (s, 1H). LRMS : m/z = 476 (M+1) + Example 35 2-[3-({[1-{{(2 R )-1-Methylcyclopropyl}methyl}pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide Preparation 152 (2 R )-1-[(1-Methylcyclopropyl)methyl]-2-pyrrolidinecarboxamide (2 R )-Pyrrolidinecarboxamide (1.0g, 8.73mmol) was added to a solution of 1-methylcyclopropanecarbaldehyde (preparation 58) (412ml, 0.04M, 17.6mmol in dichloromethane) and the solution stirred at room temperature for 30 mins. Acetic acid (502ml, 8.73mmol) followed by sodium triacetoxyborohydride (2.8g, 13.2mmol) were added and the reaction stirred at room temperature overnight. The mixture was concentrated under reduced pressure to a volume of 200ml, then basified using saturated NaHCO 3 solution, and the phases separated. The orgahic layer was dried over MgSO 4 and evaporated under reduced pressure. The crude product was purified by chromatography using a Biotage™ (KP-Sil™ 60Å silica gel) cartridge with dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant to give the desired product, (771 mg, 48%). 1 H NMR (CDCl 3 , 300MHz) δ: 0.22 (m, 2H), 0.36 (m, 2H), 1.13 (s, 3H), 1.72-1.97 (m, 4H), 2.07-2.28 (m, 2H), 2.98 (m, 2H), 3.31 (m, 1H), 5.38 (s, br,1H), 7.24 (s, br,1H). LRMS : m/z = 182 (M) + Preparation 153 {(2 R )-1-[(1-Methylcyclopropyl)methyl]pyrrolidinyl}methylamine The title compound was obtained as an oil (72%) from (2 R )-1-[(1-methylcyclopropyl)methyl]-2-pyrrolidinecarboxamide (preparation 152) following the procedure described in preparation 148. 1 H NMR (CDCl 3 , 400MHz) δ: 0.19 (m, 2H), 0.32 (m, 2H), 1.06 (s, 3H), 1.26 (s, br,2H), 1.52 (d, 1H), 1.56-1.82 (m, 4H), 2.05 (dd, 1H), 2.34 (m, 1H), 2.60 (d, 1H), 2.76 (dd, 1H), 2.97 (d, 1H), 3.23 (m, 1H). LRMS : m/z = 168 (M) + Preparation 154 Benzyl 2-[3-chloro-2-methyl-5-[({(2 R )-1-[(1-methylcyclopropyl)methyl]-2-pyrrolidinyl}methyl)amino]-6-oxo-1(6 H )-pyrazinyl]acetate The title compound was obtained as a yelow oil (81%), from {(2 R )-1-[(1-methylcydopropyl)methyl]-2-pyrrolidinyl}methylamine (preparation 153) and benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17), following a similar procedure to that described in preparation 144. 1 H NMR (CDCl 3 , 300MHz) δ: 0.20 (m, 2H), 0.34 (m, 2H), 1.11 (s, 3H), 1.56-1.90 (m, 5H), 2.11 (m, 1H), 2.20 (s, 3H), 2.61 (m, 1H), 3.00 (d, 1H), 3.30 (m, 2H), 3.60 (m, 1H), 4.80 (s, 2H), 5.20 (s, 2H), 6.75 (m, 1H), 7.38 (m, 5H). LRMS : m/z = 459, 461 (M+1) + Preparation 155 2-[2-Methyl-5-[({(2 R )-1-[(1-methylcyclopropyl)methyl]-2-pyrrolidinyl}methyl)amino]-6-oxo-1(6 H )-pyrazinyl]acetic acid hydrochloride The title compound was obtained as a yellow oil (100%) from benzyl 2-[3-chloro-2-methyl-5-[({(2 R )-1-[(1-methylcydopropyl)methyl]-2-pyrrolidinyl}methyl)amino]-6-oxo-1(6 H )-pyrazinyl]acetate (preparation 154), following the procedure described in preparation 145. 1 H NMR (d 6 -DMSO, 400MHz) δ: 0.39 (m, 2H), 0.50 (m, 1H), 0.59 (m, 1H), 1.18 (s, 3H), 1.70-1.97 (m, 3H), 2.02 (m, 4H), 2.78 (m, 1H), 3.05 (m, 1H), 3.20-3.65 (m, 5H), 4.65 (s, 2H), 6.62 (s, 1H), 7.40 (s, br,1H). LRMS: m/z = 335 (M+1) + Preparation 156 N -(1 H -Indol-5-ylmethyl)-2-[6-methyl-3-[({(2 R )-1-[(1-methylcyclopropyl)methyl]-2-pyrrolidinyl}methyl)amino]-2-oxo-1(2 H )-pyrazinyl]acetamide The title compound was prepared from 2-[2-methyl-5-[({(2 R )-1-[(1-methylcyclopropyl)methyl]-2-pyrrolidinyl}methyl)amino]-6-oxo-1(6 H )-pyrazinyl]acetic acid hydrochloride (preparation 155) using the method described in preparaton 139. The product was further purified by column chromatography on silica gel using hexane: i -propanol:0.88 ammonia (75:25:2) as eluant to afford the title compound as a white foam, (99mg, 48%). 1 H NMR (CDCl 3 , 400MHz) δ: 0.18 (m, 2H), 0.30 (m, 2H), 1.02 (s, 3H), 1.50-1.84 (m, 5H), 2.08 (m, 1H), 2.20 (s, 3H), 2.60 (s, br, 1H), 2.99 (d, 1H), 3.28 (m, 2H), 3.54 (m, 1H), 4.52 (d, 2H), 4.62 (s, 2H), 6.45 (m, 2H), 6.61 (s, br, 1H), 6.70 (s, 1H), 7.04 (d, 1H), 7.20 (s, 1H), 7.34 (d, 1H), 7.48 (s, 1H), 8.18 (s, br, 1H). LAMS : m/z 463 (M+1) + Example 36 N -(1 H -Indol-5-ylmethyl)-2-[6-methyl-2-oxo-3-({[(2 R )-1-tertrahydro-2 H -pyran-4-yl-2-pyrrolidinyl]methyl}amino)-1(2 H )-pyrazinyl]acetamide Preparation 157 [(2 R )-1-Tetrahydro-2 H -pyran-4-yl-2-pyrrolidinyl]methylamine Tetrahydro-4H-pyran-4-one (291ml, 3.15mmol) and acetic acid (181ml, 3.15mmol) were added to a slurry of (2 R )-pyrrolidinecarboxamide (360mg, 3.15mmol) in tetrahydrofuran (8ml), followed by sodium triacetoxyborohydride (1.0g, 4.73mmol), and the reaction stirred at room temperature overnight. Water was added, the mixture extracted with ethyl acetate, and the combined organic extracts evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (95:5) as eluant to give a white solid. Lithium aluminium hydride (5ml, 1M in tetrahydrofuran, 5.0mmol) was added to a solution of the intermediate amide in tetrahydrofuran (8ml), and the reaction heated under reflux overnight. The cooled reaction was quenched with water (1.5ml), dried over MgSO 4 , filtered, and the filter pad washed well with ethyl acetate. The combined filtrates were evaporated under reduced pressure to give the title compound as an oil, (460mg, 79%). 1 H NMR (CDCl 3 , 400MHz) δ: 1.39-1.84 (m, 9H), 2.50-2.73 (m, 3H), 2.81 (m, 1H), 2.98 (m, 1H), 3.38 (m, 2H), 4.00 (m, 2H). LRMS : m/z = 185(M+1) + Preparation 158 Benzyl 2-[3-chloro-2-methyl-6-oxo-5-({[(2 R )-1-tetrahydro-2 H -pyran-4-yl-2-pyrrolidinyl]methyl}amino)-1(6 H )-pyrazinyl]acetate A mixture of [(2 R )-1-tetrahydro-2 H -pyran-4-yl-2-pyrrolidinyl]methylamine (preparation 157) (460mg, 2.50mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17), and triethylamine (870ml, 6.24mmol) in ethyl acetate (8ml) was heated under reflux for 18 hrs, then cooled. Water (1.5ml) was added, the reaction mixture dried over MgSO 4 , and filtered through celite, washing the filter pad well with ethyl acetate. The combined filtrates were concentrated under reduced pressure and the residue purified by column chromatography on silica gel using hexane:ethyl acetate (50:50) as eluant to give the desired product as a white solid, (970mg, 82%). 1 H NMR (CDCl 3 , 400MHz) δ: 1.55-1.94 (m, 8H), 2.20 (s, 3H), 2.58 (m, 1H), 2.71 (m, 1H), 3.00 (m, 1H), 3.16 (m, 2H), 3.38 (m, 2H), 3.52 (m, 1H), 4.00 (m, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.48 (s, 1H), 7.37 (m, 5H). LRMS : m/z = 475 (M+1) + Preparation 159 2-[6-Methyl-2-oxo-3-({[(2 R )-1-tetrahydro-2 H -pyran-4-yl-2-pyrrolidinyl]methyl}amino)-1(2 H )-pyrazinyl]acetic acid hydrochloride A mixture of benzyl 2-[3-chloro-2-methyl-6-oxo-5-({[(2 R )-1-tetrahydro-2 H -pyran-4-yl-2-pyrrolidinyl]methyl}amino)-1(6 H )-pyrazinyl]acetate (preparation 158) (970mg, 2.04mmol) and palladium hydroxide (80mg) in ethanol (8ml) was hydrogenated at 15 psi and room temperature for 20 hrs. The reaction mixture was filtered through Whatman® fibre, and the filtrate evaporated under reduced pressure to give the desired compound, (680mg, 95%). LRMS : m/z = 351 (M+1) + Preparation 160 N -(1 H -Indol-5-ylmethyl)-2-[6-methyl-2-oxo-3-({[(2 R )-1-tetrahydro-2 H -pyran-4-yl-2-pyrrolidinyl]methyl}amino)-1(2 H )-pyrazinyl]acetamide The title compound was obtained as a white powder (31%), from 2-(6-Methyl-2-oxo-3-({[(2 R )-1-tetrahydro-2 H -pyran-4-yl-2-pyrrolidinyl]methyl}amino)-1(2 H )-pyrazinyl]acetic acid hydrochloride (preparation 159) and 1H-indol-5-ylmethylamine (preparation 8), using a similar procedure to that described in preparation 45. 1 H NMR (CDCl 3 , 400MHz) δ: 1.54-1.84 (m, 8H), 2.23 (s, 3H), 2.57 (m, 1H), 2.70 (m, 1H), 2.99 (m, 1H), 3.15 (m, 2H), 3.37 (m, 2H), 3.46 (m, 1H), 3.99 (m, 2H), 4.52 (d, 2H), 4.63 (s, 2H), 6.27 (s, br, 1H), 6.52 (s, 1H), 6.59 (s, br, 1H), 6.73 (s, 1H), 7.06 (d, 1H), 7.20 (s, 1H), 7.37 (d, 1H), 7.50 (s, 1H), 8.22 (s, br, 1H). LRMS : m/z = 478 (M) + Example 37 2-[5-({[(2 R ,4 R )-1-Cyclopentyl-4-methylpiperidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]- N -(1 H -indol-4-ylmethyl)acetamide Preparation 161 Benzyl 2-[3-chloro-5-({[(2 R ,4 R )-1-cyclopentyl-4-methylpiperidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate A mixture of (2 R ,4 R )-4-methyl-2-piperidinecarboxamide (prepared as in preparation 86) (5.0g, crude), cyclopentanone (3.1ml, 35mmol), sodium triacetoxyborohydride (9.5g, 45.5mmol) and acetic acid (2ml, 35mmol) in tetrahydrofuran (30ml), was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, to give the crude carboxamide (6g). This intermediate (3g) was suspended in tetrahydrofuran (20ml), lithium aluminium hydride (17ml, 1M in tetrahydrofuran, 17mmol) added, and the reaction heated under reflux for 18 hrs. Water was added to the cooled reaction, the mixture dried over MgSO 4 , and filtered, washing well with ethyl acetate. The combined filtrates were concentrated under reduced pressure and the residue re-dissolved in ethyl acetate (12ml). Triethylamine (1.3ml, 9mmol) and benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17), (2.0g, 6.11mmol) were added, and the reaction heated under reflux for 20 hrs. The cooled mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel using ethyl acetate:pentane (5:95) as eluant to afford the title compound as a white solid, (850mg, 12%). 1 H NMR (CDCl 3 , 400MHz) δ: 0.88 (d, 3H), 1.20-1.60 (m, 8H), 1.70 (m, 3H), 1.85 (m, 1H), 1.97 (m, 1H), 2.20 (s, 3H), 2.61 (m, 1H), 2.81 (m, 1H), 3.17 (m, 2H), 3.42 (m, 1H), 3.58 (m, 1H), 4.80 (s, 2H), 5.20 (s, 2H), 6.50 (s, br,1H), 7.36 (m, 5H). LRMS : m/z = 487, 489 (M+1) + Preparation 162 2-[5-({[(2 R ,4 R )-1-Cyclopentyl-4-methylpiperidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]- N -(1 H -indol-4-ylmethyl)acetamide A mixture of benzyl 2-[3-chloro-5-({[(2 R ,4 R )-1-cyclopentyl-4-methylpiperidinyl]methyl}amino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]acetate (preparation 161) (320mg, 0.66mmol), and palladium hydroxide (85mg) in methanol (6ml) was hydrogenated at 15 psi and room temperature overnight. The incomplete reaction was filtered, the filtrate evaporated under reduced pressure and the residue re-dissolved in methanol (8ml). Palladium hydroxide (85mg) was added and the reaction hydrogenated at 30psi and room temperature overnight. The reaction mixture was filtered through Whatman® fibre, and the filtrate evaporated under reduced pressure to afford an oil, 200mg, A mixture of 1H-indol-5-ylmethylamine (preparation 8) (85mg, 0.56mmol), HOBT (78mg, 0.56mmol), WSCDI.HCI (111mg, 0.56mmol) and N-methylmorpholine (96ml, 0.87mmol), were added to a solution of the intermediate acid in dichloromethane (6ml), and the reaction stirred at room temperature for 20 hrs. The reaction mixture was loaded directly onto a silica column and purified using dichloromethane:methanol:0.88 ammonia 995:5;0.5) as eluant, to give the title compound as a white powder, (22mg, 8%). 1 H NMR (CDCl 3 , 400MHz) δ: 0.86 (d, 3H), 1.20-1.99 (m, 13H), 2.28 (s, 3H), 2.60 (m, 1H), 2.81 (m, 1H), 3.16 (m, 2H), 3.40 (m, 1H), 3.55 (m, 1H), 4.50 (d, 2H), 4.63 (m, 2H), 6.42 (s, br,1H), 6.52 (m, 2H), 7.04 (d, 1H), 7.20 (m, 1H), 7.35 (d, 1H), 7.50 (s, 1H), 8.24 (s, br,1H). Example 38 N -(1 H -Benzimidazol-6-ylmethyl)-2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetamide Preparation 163 N -(1 H -Benzimidazol-6-ylmethyl)-2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetamide HOBT (25mg, 0.19mmol), WSCDI.HCI (31mg, 0.16mmol), N-methylmorpholine (41ml, 0.37mmol) and 1 H -benzimidazol-6-ylmethylamine (21mg, 0.14mmol) were added to a solution of 2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 62) (40mg, 0.12mmol) in N,N-dimethylformamide (2ml), and the reaction was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and the residue pre-adsorbed on to silica gel, and then purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant to provide the title compound (6mg, 10%). 1 H NMR (CDCl 3 , 400MHz) δ: 0.82 (d, 3H), 0.87 (d, 3H), 1.52-1.84 (m, 5H), 2.07 (m, 2H), 2.22 (s, 3H), 2.30 (m, 1H), 2.60 (m, 1H), 3.14 (m, 1H), 3.20 (m, 1H), 3.48 (m, 1H), 4.53 (m, 2H), 4.62-4.78 (m, 2H), 6.40 (s, br, 1H), 6.74 (s, 1H), 7.10 (m, 2H), 7.28-7.70 (m, 2H), 8.00 (s, 1H). LRMS : m/z = 452 (M+1) + Example 39 N -(1 H -Benzimidazol-6-ylmethyl)-2-[3-({[(2 R )-1-cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetamide Preparation 164 N -(1 H -Benzimidazol-6-ylmethyl)-2-[3-({[(2 R )-1-cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]acetamide The title compound as obtained as a white foam (42%) from 2-[3-({[(2 R )-1-cyclopentyl-2-pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1 (2 H )-pyrazinyl]acetic acid hydrochloride (preparation 145) and 1 H -benzimidazol-6-ylmethylamine following the procedure described in preparation 163. 1 H NMR (CDCl 3 , 400MHz) δ: 1.40-1.92 (m, 10H), 2.21 (s, 3H), 2.38 (m, 1H), 2.50 (m, 1H), 2.92 (m, 1H), 3.00 (m, 2H), 3.20 (m, 2H), 3.42 (m, 1H), 4.54 (d, 2H), 4.66 (s, 2H), 6.35 (s, br, 1H), 6.69 (s, 1H), 7.04-7.20 (m, 2H), 7.38-7.60 (m, 2H), 7.98 (s, 1H). LAMS : m/z = 463 (M+1) + Abbreviations DIBAL Diisobutylaluminium hydride HOBT 1-Hydroxybenzotriazole hydrate LRMS Low resolution mass spectroscopy TFA Trifluoroacetic acid TMSCN Trimethylsilyl cyanide WSCDI.HCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride The biological activities of the compounds of the present invention were determined by the following test methods. Chromogenic Assays The inhibition of thrombin, trypsin, plasmin or factor Xa is measured in 96 well plate chromogenic assays. The percentage inhibition and IC 50 are calculated from triplicate samples of an 8 concentration dose-response curve. From the substrate Km and IC 50 , the Ki for each inhibitor is calculated. All assays are carried out in a total incubation of 200µl of 50mM HEPES and 150mM NaCl at pH 8.0, and all compound dilutions are preincubated with enzyme at room temperature for 15 minutes prior to addition of substrate. After 30 minutes incubation at 30°C, the O.D. is measured at 405 nM in a 96 well plate reader. Thrombin activity is measured using bovine thrombin and S2238 (H-D-Phe-Pip-Arg-pNA), bovine pancreatic trypsin is assayed with S2222 (Benz-Isoleu-Glu-Gly-Arg-pNA), bovine plasma plasmin is assayed with Chromozym PL (Tosyl-Gly-Pro-Lys-pNA) and bovine factor Xa is assayed in 50mM Tris, 150mM NaCl, pH 7.5 buffer with S2222. Clotting Assays Thrombin time (TT) and activated partial thromboplastin time (APTT) are measured using Instrumentation Laboratories (IL) Test TT reagent and IL Test APTT (ellagic acid) reagent respectively in an Automated Coagulation Laboratory (ACL), according to the manufacturer's instructions. In Vitro To 1ml aliquots of rat pooled plasma (citrated), a 1/100 volume of a range of compound concentrations is added and the resulting mixtures preincubated at room temperature for 15 minutes, after which the TT and APTT are measured. Ex Vivo Compounds are dosed per os , intravenously or intraduodenally to rats. Pre- and post-dose blood samples are taken into citrate solution and plasma prepared. TT and APTT are measured as for in vitro assays. All compounds specifically exemplified exhibited measured in vitro inhibitory activities against thrombin with Ki < 3 x 10 -7 M and in vitro inhibitory potency versus trypsin with Ki > I x 10 -5 M

Claims: A compound of formula I wherein: R 1 is hydrogen or methyl; R 2 is hydrogen, methyl or CF 3 ; R 3 is hydrogen or methyl; R 4 is hydrogen, C 1 -C 4 alkyl; R 5 is hydrogen or C 1 -C 4 alkyl; R 6 is C 1 -C 6 alkyl, C 3 -C 6 carbocyclyl optionally substituted by fluoro, or R 5 and R 6 together form a bridging chain containing 2 or 3 carbon atoms; Y is hydrogen, chloro, fluoro, bromo, methyl or CF 3 ; V is C or N; W and X are independently CH or N; R 7 -B-A is selected from the following radicals: wherein R 7 is hydrogen, C 1 -C 4 alkyl, perfluoroC 1 -C 4 alkyl, OC 1 -C 4 alkyl, perfluoroOC 1 -C 4 alkyl, fluoro or chloro; R 10 and R 11 are independently selected from hydrogen or C 1 -C 4 alkyl optionally containing an oxygen in the chain or at the end of the chain; or R 10 and R 11 together with the nitrogen atom to which they are bonded form a 4 to 6 membered saturated heterocyclic ring wherein when the ring is six membered it may optionally contain one oxygen or an additional nitrogen atom present as N(R 12 ); wherein R 12 is hydrogen or C 1 -C 4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain; R 13 and R 14 are independently hydrogen or C 1 -C 4 alkyl optionally containing one oxygen atom in the chain or at the end of the chain, or R 13 and R 14 together with the carbon atom to which they are bonded form a 4 to 6 membered carbocyclic saturated ring; R 15 and R 16 are independently selected from hydrogen or C 1 -C 4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain, or R 15 and R 16 together with the nitrogen atom to which they are bonded form a 4 to 6 membered saturated heterocyclic ring; R 17 is selected from one or more of C 1 -C 6 alkyl, C 3 -C 6 carbocyclyl or C 3 -C 6 carbocyclylC 1 -C 4 alkyl, said carbocyclyl containing zero, one or more double bonds wherein said alkyl and carbocyclic optionally contain one heteroatom selected from oxygen, sulphur and nitrogen and are further optionally substituted by one or more fluoro, or C 1 -C 4 alkyl optionally containing an oxygen in the alkyl chain or a the end of the chain; R 18 is selected from hydrogen, C 1 -C 6 alkyl and perfluoro C 1 -C 6 alkyl wherein said alkyl optionally contains an oxygen atom in the chain or at the end of the chain; or v is 0 or 1, and pharmaceutically acceptable salts thereof. A compound as claimed in claim 1 and pharmaceutically acceptable salts thereof wherein R 2 is hydrogen or methyl. A compound as claimed in any one of the preceding claims and pharmaceutically acceptable salts thereof wherein R 4 is hydrogen. A compound as claimed in any one of the preceding claims and pharmaceutically acceptable salts thereof wherein R 5 is hydrogen. A compound as claimed in any one of the preceding claims and pharmaceutically acceptable salts thereof wherein Y is hydrogen, chloro or bromo. A compound as claimed in any preceding claim and pharmaceutically acceptable salts thereof wherein R 17 is cyclopropylmethyl. A compound as claimed in any preceding claim wherein R 7 -B-A- is selected from: A compound as claimed in any one of the preceding claims selected from the group consisting of: ( R,S )-2-[3-[(2-amino-1-benzylethyl)amino]-6-methyl-2-oxo-1(2 H )-pyridinyl]- N -(1 H -indol-5-ylmethyl)acetamide; 2-[3-(3-[(dimethylamino)methyl]phenethylamino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide; 2-[3-chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide; 2-[3-[(1 S )-1-benzyl-2-(dimethylamino)ethyl]amino-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide; 2-[3-[(1 S )-1-benzyl-2-(dimethylamino)ethyl]amino-5-chloro-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide; N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-([3-[(methylamino)methyl]phenethyl]amino)-2-oxo-1(2 H )-pyrazinyl]acetamide; 2-[3-{[(1 S )-1-benzyl-2- (dimethylamino)ethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(6-methyl-1 H -indazol-5-yl)methyl]acetamide; 2-[3-{[3-(3-azetidinyl)phenethyl]amino}-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-{[3-(1-methyl-3-azetidinyl)phenethyl]amino}-2-oxo-1(2 H )-pyrazinyl]acetamide; 2-[3-[(3-{[(2-methoxyethyl)amino]methyl}phenethyl)amino]-6-methyl-2-oxo-1(2 H )-pyrazinyl)- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-2-oxo-3-({[(2 R )-1-tetrahydro-2 H -pyran-4-ylpyrrolidinyl]methyl}amino)-1(2 H )-pyrazinyl]acetamide; N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-[({(2 R )-1-[(1-methylcyclopropyl)methyl]pyrrolidinyl}methyl)amino]-2-oxo-1(2 H )-pyrazinyl]acetamide; 2-[3-({[(2 R )-1-(2-methoxyethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; N -[(3-methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-({[(2 R )-1-neopentylpyrrolidinyl]methyl}amino)-2-oxo-1(2 H )-pyrazinyl]acetamide; 2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-(2-methoxyethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; and pharmaceutically acceptable salts thereof. A compound as claimed in claim 8 selected from the group consisting of: 2-[3-(3-[(dimethylamino)methyl]phenethylamino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -(1 H -indol-5-ylmethyl)acetamide; 2-[3-[(1 S )-1-benzyl-2-(dimethylamino)ethyl]amino-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N- (1 H -indol-5-ylmethyl)acetamide; N -[(3-Methyl-1 H -indol-5-yl)methyl]-2-[6-methyl-3-([3-[(methylamino)methyl]phenethyl]amino)-2-oxo-1(2 H )-pyrazinyl]acetamide; 2-[3-[(3-{[(2-methoxyethyl)amino]methyl}phenethyl)amino]-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; 2-[3-({[(2 R )-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2 H )-pyrazinyl]- N -[(3-methyl-1 H -indol-5-yl)methyl]acetamide; and pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of the preceding claims together with a pharmaceutically acceptable carrier. A compound of a formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of the claims 1 to 9 for use in medicine. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 9 in the manufacture of a medicament for the treatment or prophylaxis of deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignancy, prolonged immobilisation trauma, application of lower limb plaster casts, or fractures of the lower limbs or pelvis; recurrent DVT; DVT during pregnancy when there is a previous history thereof; reocclusion following thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; transient ischaemic attacks; disseminated intravascular coagulation; coagulation in extra-corporeal circuits; occlusion of arterio-venous shunts and blood vessel grafts (including coronary artery by-pass grafts); restenosis and occlusion following angioplasty; neurodegenerative disorders; inflammatory disorders; or scarring.

Inventors: BLAGG JULIAN, BROWN ALAN DANIEL, GAUTIER ELISABETH COLETTE LOUI, MCELROY ANDREW BRIAN, SMITH JULIAN DUNCAN, BLAGG, JULIAN, BROWN, ALAN DANIEL, GAUTIER, ELISABETH COLETTE LOUISE, MCELROY, ANDREW BRIAN, SMITH, JULIAN DUNCAN
Applicants: PFIZER, PFIZER LTD, PFIZER INC., PFIZER LIMITED
Application year: 1999
Main classification: C07K5
IPC codes: A61K31, A61P9, C07D401, A61P7, C07D405, A61K38, C07K5, C07D403, C07D413