WO2009007390A2 - Dérivés de pyrazine - 954 - Google Patents

Dérivés de pyrazine - 954 Download PDF

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Publication number
WO2009007390A2
WO2009007390A2 PCT/EP2008/058898 EP2008058898W WO2009007390A2 WO 2009007390 A2 WO2009007390 A2 WO 2009007390A2 EP 2008058898 W EP2008058898 W EP 2008058898W WO 2009007390 A2 WO2009007390 A2 WO 2009007390A2
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alkyl
amino
carbamoyl
pyrazin
group
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PCT/EP2008/058898
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WO2009007390A3 (fr
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Linette Rushton
Jon James Gordon Winter
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Astrazeneca Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the invention concerns certain novel pyrazine derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-cancer activity and are accordingly useful in methods of treatment of the human or animal body.
  • the invention also concerns processes for the manufacture of said pyrazine derivatives, pharmaceutical compositions containing them and their use in therapeutic methods, for example in the manufacture of medicaments for use in the prevention or treatment of cancers in a warm-blooded animal such as man, including use in the prevention or treatment of solid tumour disease.
  • Receptor tyrosine kinases are cell surface receptors that transmit signals from the extracellular environment to control growth, differentiation and survival of cells. All RTKs contain an extracellular ligand binding domain and a conserved protein tyrosine kinase cytoplasmic domain. RTKs are activated by growth factors, which promote receptor dimerisation and autophosphorylation of tyrosine residues in the kinase domain (Schles singer. Cell, 2000, 103, 211),
  • RTKs can be classified into distinct subfamilies on the basis of sequence similarities.
  • the AxI receptor subfamily is one of these subfamilies and includes AxI (also called Ark and Ufo), Tyro3 (also called Rse, Brt and Sky) and Mer (also called Nyk and Tyrol2).
  • This RTK family is characterized by an extracellular domain consisting of two immunoglobulin-like and two fibronectin type 3-like domains.
  • the AxI family RTKs are activated by the vitamin K-dependent protein known as growth arrest specific gene 6 (Gas ⁇ ).
  • the affinity of Gas6 for these receptors is Axl>Tyro3>Mer (Nagata et ai, J. Biol. Chem., 1996, 271, 30022).
  • the gene encoding for the AxI protein was originally identified as a transforming gene in chronic myeloid leukemia (O'Bryan etal, MoI Cell Biol, 1991, 11, 5031).
  • the AxI receptor has been shown to be overexpressed in primary colon (Craven et al., Int. J.
  • AxI protein has been shown to disrupt CLl-5 human lung adenocarcinoma cell invasion (Shieh et al, Neoplasia, 2005, 7, 1058) and primary human umbilical vein endothelial cells (HUVEC) cell migration and tube formation (Holland et al,
  • AxI RTKs have also been shown to have roles in immunity (Lu et al, Science, 2001, 293,
  • antagonism of the activity of AxI receptor kinases is expected to be beneficial in the treatment of a number of cell proliferative disorders such as cancer (comprising solid tumours such as carcinomas, sarcomas and the leukaemia and lymphoid malignancies), as well as vascular disease (including but not limited to thrombosis, atherosclerosis and restenosis), kidney disease (including but not limited to acute and chronic glomerulonephritis, diabetic nephropathy and transplant rejection), endometriosis, and diseases where deregulated angiogenesis is important (including but not limited to diabetic retinopathy, retinopathy, psoriasis, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma).
  • cancer comprising solid tumours such as carcinomas, sarcomas and the leukaemia and lymphoid malignancies
  • vascular disease including but not limited to thrombosis,
  • c-Met is also a receptor tyrosine kinase which acts as the cellular receptor for hepatocyte growth factor (HGF/ scatter factor), a dimeric glycoprotein that is synthesized as a single- chain precursor called pro-HGF and comprises a 50 kDa ⁇ -chain and a 145 kDa ⁇ - chain.
  • HGF/ scatter factor hepatocyte growth factor
  • pro-HGF hepatocyte growth factor
  • c-Met activity is required for signal transmission via several signalling pathways.
  • c-Met-Gabl-Shp2 association results in sustained stimulation of the Erk pathway, thus stimulating cell transformation and proliferation (Maroun, C, et al. (2000), MoL Cell. Biol. 20, 8513-8525; Schaeper, U., et al. (2000), J. Cell.
  • c-Met The role of c-Met on these different pathways, means that it is involved in the regulation of a range of different cellular processes such as proliferation, apoptosis, morphogenesis, and migration (Bardelti, A., et al. (1999) Oncogene 18, 1139-1146).
  • c-Met and HGF are expressed in numerous tissues. c-Met expression is normally restricted to cells of endothelial and epithelial origin. HGF is usually expressed in cells of mesenchymal origin and is therefore considered to be a paracrine acting growth factor which induces proliferative, morphogenic and motile responses in proximal target cells (Birchmeier, C, et al. (2003), Nature Rev. MoI. Cell. Biol. 4, 915-925).
  • Activation of c-Met in cancer cells is most commonly driven by ligand-dependent mechanisms, for example, tumour carcinoma or tumour endothelial cells express c-Met but not HGF, which is produced by the surrounding stroma. However, in other tumours, cells may express c-Met and HGF resulting in autocrine c-Met activation. Ligand independent activation is also possible and is observed in cells that express very high levels of c-Met or which harbour activating mutations (Birchmeier et al.). Activating mutations of c-Met have been discovered in sporadic and inherited forms of human renal papillary carcinoma (reviewed in Maulik et al.
  • c-Met therefore represents an attractive target in the pursuit of therapies for the treatment of cancer, and an inhibitor of c-Met activity would be expected to have anti-tumour activity and in particular anti-proliferative, anti-angiogenic and anti-invasive properties.
  • c-Met and HGF in tissue remodelling, particularly in the lungs and liver has also been demonstrated (Michalopoulos, G. & DeFrances, M. (1997) Science 276, 60-6621), and elevated levels of c-Met or HGF have been observed in patients suffering from liver cirrhosis, chronic hepatitis and pulmonary fibrosis. It is therefore further expected that inhibitors of c-Met will be of therapeutic use in the treatment of a number of inflammatory diseases (Funakoshi, H. & Nakamura, T. (2003) CHn. Chim. Acta 327, 1-23).
  • novel pyrazine derivatives possess potent activity against cell proliferative disorders.
  • the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on one or two biological processes, it is believed that the compounds provide a useful treatment of cell proliferative disorders, for example to provide an anti-tumour effect, by way of a contribution from inhibition of AxI and/or c-Met receptor tyrosine kinases.
  • each of G 1 and G 2 is selected from CH and N provided that both are not N;
  • R* is a group of the formula:
  • X 2 is a direct bond or is selected from O, S, SO, SO 2 , N(R 8 ), CO, CH(OR 8 ), CON(R 8 ), N(R 8 JCO, N(R 3 )CON(R 8 ), SO 2 N(R 8 ), N(R 8 JSO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 S, SC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen, (l-SC)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano- (1 -6C) alkyl or halogeno-(l-6C)alkyl, and Q 1 is heterocyclyl, heterocyclyl-(l-6C)
  • X 2 has any of the meanings defined hereinbefore and Q 2 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl or (3-8C)cycloalkyl-(l-6C)alkyl wherein any aryl or (3-8C)cycloalkyI group within a R 1 substituent bears 1, 2 or 3 substituents independently selected from amino, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (R 9 )-amino-(l-6C)alkyl and di-(R 9 )-amino-(l-6C)alkyl, wherein R 9 is (l-6C)aikyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy;
  • n 0, 1, 2 or 3 and, when n is 2 or 3, each R 4 group may be the same or different, and each R 4 group is selected from hydrogeno, halogeno, amino, cyano, sulphamoyl, ⁇ T-(l-6C)alkylsulphamoyI, ⁇ yV-di-[(l-6C)alkyl]suIphamoyl, trifluoromethyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, N-(l-6C)alkylcarbamoyl, WyV-di-[(l-6C)alkyl]carbamoyl and (2-6C)aLkanoylamino; or a pharmaceutically- acceptable salt thereof; with the proviso that said compound is not
  • (l-8C)alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-8C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and also (3-6C)cycloalkyl-(l-2C)alkyl groups such as cyclopropylmethyl, 2-cyclopropylethyI, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylraethyl, 2-cyclopentylethyl, cyclohexylmethyl and 2-cyclohexylethyl.
  • references to individual alkyl groups such as "propyl” are specific for the straight-chain version only
  • references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only
  • references to individual cycloalkyl groups such as “cyclopentyl” are specific for that 5-membered ring only.
  • (l-6C)alkoxy includes (3-6C)cycloalkyloxy groups and cycloalkyl- alkoxy groups having 4 to 6 carbon atoms, for example methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, 2-cycIopropyIethoxy, cyclobutylmethoxy, 2-cycIobutylethoxy and cyclopentylmethoxy;
  • (l-6C)alkylamino includes (3-6C)cycloalkylamino groups and iV-Ccycloalkylalkytyamino groups having 4 to 6 carbon atoms, for example methylamino, ethylamino, propylamino, cyclopropylamino, cyclobutylamino, cyclohe
  • (l-4C)alkyl refers to any of the alkyl groups defined above that posseses 1 to 4, 1 to 3 and 1 to 2 carbon atoms respectively.
  • the same convention applies to other terms used herein, such as, for example, "(l-4C)alkoxy", “(l-3C)alkoxy” and "(l-2C)alkoxy”.
  • heterocyclyl is to be understood as being, for example, a non-aromatic saturated or partially saturated 3 to 12 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur. It is to be understood that the definition of heterocyclyl includes bridged ring systems.
  • Suitable examples include oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothie ⁇ yl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclo[2.2.1]h
  • heteroaryl is to be understood as being, for example an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl,
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • the R 1 group present on the phenyl group may be located at any available position.
  • the R 1 group is located at the 2-, 3- or 4- position on the phenyl group.
  • the R 1 group is located at the 3- or 4- position on the phenyl group.
  • the R 1 group is located at the 3- position on the phenyl group.
  • the R 1 group is located at the 4- position on the phenyl group.
  • Suitable values for the generic radicals referred to above include those set out below.
  • a suitable value for the heterocyclyl group within any R 1 group is, for example, a non- aromatic saturated or partially saturated 3 to 12 membered monocyclic or bicyclic ring with up to Five heteroatoms selected from oxygen, nitrogen and sulphur. It is to be understood that the definition of heterocyclyl includes bridged ring systems.
  • Suitable examples include oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1- dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclof2.2.11he ⁇ t
  • heterocyclyl group within any R group is a non-aromatic saturated or partially saturated 3 to 7 membered monocyclic ring with up to three heteroatoms selected from oxygen, nitrogen and sulphur.
  • the heterocyclyl group within any R 1 group is pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl and especially pyrrolidin-1-yl, pyrrolidin-3-yl, morpholino, piperidin-l-yl, piperidin-3-yl, piperidin-4-yl or piperazin-1-yl.
  • a suitable value for the heteroaryl group within any R 1 group is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5- triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, be ⁇ zofurazanyl, quinolyl, iso
  • heteroaryl group within any R group is pyrazolyl and especially 2H-pyrazol-3-yl or lH-pyrazol-1-yl.
  • a suitable value for the aryl group within any R 1 group is, for example, phenyl or naphthyl, conveniently phenyl.
  • a suitable value for the (3-8C)cycloalkyl group within any R 1 group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl or cyclooctyl.
  • a suitable value for Q 1 within the R 1 group when Q 1 is heterocyclyl-(l-6C)a!kyl is, for example, heterocyclylmethyl, 2-heterocyclylethyl and 3-heterocyclylpropyl.
  • the invention comprises corresponding suitable values for Q 1 or Q 2 groups when, for example, rather than a heterocyclyl-(l-6C)alkyl group, a heteroaryl-(l-6C)alkyl, an aryl-(l-6C)alkyl or a (3-8C)cycloaIkyl-(l-6C)alkyl group is present.
  • a suitable value for any heterocyclyl group within the R 3 group is, for example, a non- aromatic saturated or partially saturated 3 to 12 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur. It is to be understood that the definition of heterocyclyl includes bridged ring systems.
  • Suitable examples include oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1- dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazoli ⁇ yl, pyrazolidinyl, morpholinyl, tetrahydro- 1 ,4-thiazinyl, 1 , 1 -dioxotetrahydro- 1 ,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclo[2.2.1
  • R 9 within an R 1 substituent or for various groups such as R 10 within a R 3 group include, for example: - for halogeno fluoro, chloro, bromo and iodo; for (l-SC)alkyl: methyl, ethyl, propyl, isopropyl, f ⁇ rt-butyl, cyclobutyl, cyclohexyl, cyclohexyhnethyl and
  • JV-ethyl-N'-methylureido for NJV' JV'-tri-[(l-6C)alkyl]ureido: N ⁇ ' ⁇ V'-trimethylureido, iV-ethyl-N' ⁇ V'-dimethylureido and
  • amino-Cl-6C)alkyI aminomethyl, 2-aminoethyl, 1-aminoethyl,
  • an R 1 group forms a group of the formula R 5- X 1 - and, for example, X 1 is a OC(R 6 ) 2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R 6 ) 2 linking group which is attached to the phenyl ring and the oxygen atom is attached to the R 5 group.
  • an R 1 group forms a group of the
  • a suitable value for an (R 7 )-amino-(l-6C)alkyl group or an (R 9 )-amino-(l-6C)alkyl group is, for example, trifluoromethylaminomethyl, cyanomethyl aminomethyl, 2-cyanoethylaminomethyl, 2-hydroxyethylaminomethyl, 2-methoxyethylaminomethyl, 2- trifluoromethylaminoethyl, 2-(2-hydroxyethylamino)ethyl and 2-(2-methoxyethylamino)ethyl.
  • a suitable value for an di-(R 7 )-amino-(l-6C)atkyl group or an di-(R 9 )-amino-(l-6C)alkyl group is, for example, [(2-hydroxyethyl)(methyl)amino] methyl, di-(2-hydroxyethyl)aminomethyl, di-(2-methoxyethyi)aminomethyl and 1 - [ (hydroxymethyl)(methyl)amino] ethyl .
  • a suitable value for a (R l0 ) p -(l-8C)alkyl group is, for example, chloromethyl,
  • a suitable value for a (R 10 ) p -(2-8C)alkenyl group is, for example, 4-dimethylaminobut- 2-enyl and 4-(heterocycle)aminobut-2-enyl.
  • a suitable value for a (R IO ) p -(2-8C)alkynyl group is, for example, 4-dimethylaminobut- 2-ynyl and 4-(heterocycle)but-2-ynyl.
  • a suitable pharmaceutically- acceptable salt of a compound of the Formula I is, for example, an acid- addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic or citric acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • a further suitable pharmaceutically- acceptable salt of a compound of the Formula I is, for example, a salt formed within the human or animal body after administration of a compound of the Formula I. It is further to be understood that a suitable pharmaceutically-acceptable solvate of a compound of the Formula I also forms an aspect of the present invention.
  • a suitable pharmaceutically-acceptable solvate is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate or an alternative quantity thereof.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula ⁇ also forms an aspect of the present invention.
  • the compounds of the invention may be administered in the form of a pro-drug, that is a compound that is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • pro-drugs examples include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula I and in vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula I.
  • the present invention includes those compounds of the Formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzvmology. Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkyl esters such as methyl, ethyl and tert-buty ⁇ , (l-6C)alkoxymethyl esters such as methoxymethyl esters, (l-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and l-cyclohexylcarbonyloxyethyl esters, 2-oxo-l,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and (l-6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the Formula I containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include (l-lOC)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)a ⁇ koxycarbonyl groups such as ethoxycarbonyl, NJNf- [di-(l-4C)atkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include ⁇ - acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (l-4C)alkylamine such as methylamine, a di-(l-4C)alkylamine such as dimethylamine, ⁇ f-ethyl-iV-methylamine or diethylamine, a (l-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(l -4C) alkyl amine such as benzyl amine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a (l-4C)alkylamine such as methylamine
  • a di-(l-4C)alkylamine such as dimethylamine, ⁇ f-ethyl-iV-methylamine
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (l-lOC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminoraethyl, iV-alkylaminomethyl, W,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-( 1 -4C)alkylpiperazin- 1-ylmethyl.
  • the in vivo effects of a compound of the Formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula I. As stated hereinbefore, the in vivo effects of a compound of the Formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • novel compounds of the invention include, for example, pyrazine derivatives of the Formula I, or pharmaceutically- acceptable salts thereof, wherein, unless otherwise stated, each of Gi, G 2 , m, n, R 1 , R 2 , R 3 and R 4 has any of the meanings defined hereinbefore or in paragraphs (a) to (qq) hereinafter:-
  • Gi and G 2 are both CH or G 1 is N and G 2 is CH; (b) G 1 is CH and G 2 is N;
  • R 1 is a group of the formula:
  • R 5 - X 1 wherein X 1 is a direct bond or is selected from O, SO 2 , N(R 6 ), CO, CON(R 6 ), N(R 6 )C0,
  • R 6 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl,
  • R 5 is amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (R 7 )- amino-(l-6C)alkyl or di-(R 7 )-amino-(l-6C)alkyl, wherein R 7 is (l-6C)alkyl substituted by 1,
  • R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )C0, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R S ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R S ) 2 , wherein each R 8 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl or halogeno-(l-6C)alkyl, and Q 1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R
  • cyano-tl- ⁇ CJalky ⁇ halogeno-tl- ⁇ Oalkyl amino-(l-6C)alkyI, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyllamino-(l-6C)alkyl, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)aIkanoyloxy, N-(l-6C)alkylcarbamoyl,
  • Q 2 X 2 - wherein X 2 has any of the meanings defined hereinbefore and Q 2 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl or ⁇ 3-8C)cycloalkyl-(l-6C)alkyl wherein any aryl or (3-8C)cycloalkyl group within a R 1 substituent bears 1, 2 or 3 substituents independently selected from amino, amino-(l-6C)alkyI, (l-6C)alkylarnino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (R 9 )-amino-(l-6C)alkyl and di-(R 9 )-amino-(l-6C)alkyl, wherein R 9 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy
  • R 1 is a group of the formula:
  • R 5 - X 1 - wherein X 1 is a direct bond or is selected from O, SO 2 , N(R 6 ), CO, CON(R 6 ), N(R 6 )CO, SO 2 N(R 6 ), N(R 6 )SO 2 , C(R 6 ) 2 O, OC(R 6 ) 2 , C(R 6 J 2 , C(R 6 ) 2 N(R 6 ) and N(R 6 )C(R 6 ) 2 , wherein each R 6 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl or halogeno- (l-6C)alkyl, and R 5 is amino-(l-6C)alkyl, (l-6C)alkyl amino- (l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)
  • R 1 is a group of the formula:
  • R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO, SO 2 N(R 8 ), N(R 8 )SO 2 ,C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q 1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryi, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R 1 substituent optionally bears 1, 2 or 3 substituents independently selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l- ⁇ C
  • R 1 is a group of the formula:
  • R 5 -X l wherein X 1 is a direct bond or is selected from O, SO 2 , N(R 6 ), CO, CON(R 6 ), N(R 6 )CO,
  • R 6 is hydrogen or (l-8C)alkyl
  • R 5 is amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (R 7 )-amino-(l-6C)alkyl or di-(R 7 )-amino-(l-6C)alkyl, wherein R 7 is (l-6C)alkyl; or R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO,
  • R 8 is hydrogen or (l-8C)alkyl
  • Q 1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R 1 substituent optionally bears 1 or 2 substituents independently selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l-6C)alkoxy, halogeno- (l- ⁇ C)alkoxy, hydroxy-(l-6C)alkyl,
  • R 1 is a group of the formula:
  • R 5 -X J - wherein X 1 is a direct bond or is selected from O, SO 2 , N(R 6 ), CO, CON(R 6 ), N(R 6 )C0, SO 2 N(R 6 ), N(R 6 JSO 2 , C(R 6 ) 2 O, OC(R 6 ) 2 , C(R 6 ⁇ 1 C(R 6 ) 2 N(R 6 ) and N(R 6 )C(R 6 ) 2 , wherein each R 6 is hydrogen or (l-8C)alkyl; and R 5 is amino-(l-3C)alkyl, (l-6C)alkylamino-(l-3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)aUcyl, (R 7 )-amino-(l-3C)alkyl, di-[(R 7 )-amino-(l-3C)a]kyl; and
  • R 7 is (l-6C)alkyl; or R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )C0,
  • R 8 is hydrogen or (l-8C)alkyl
  • Q 1 is heterocyclyl, heterocyclyl-(l-3C)alkyl, heteroaryl, heteroaryI-(l-3C)alkyl, wherein any heterocyclyl or heteroaryl group within a R 1 substituent optionally bears 1 or 2 substituents independently selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l-6C)alkoxy, halogeno-(l-6C)aIkoxy, hydroxy-(l-6C)alkyl,
  • R 1 is a group of the formula:
  • Q 1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein any heterocyclyl group within a R 1 substituent optionally bears a halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l-6C)aIkoxy, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy ⁇ (l-6C)alkyl, halogeno-(l-6C)alkyl ( arnino-(l-6C)alkyl, (l-6C)alkyIamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)aUcylamino, di-[(l-6C)alkyl] amino, ⁇ r -(l-6C)alkylca ⁇ bamoyl
  • R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO, SO 2 N(R 8 ), N(R 8 )SO 2 .C(R 8 ) 2 O, OC(R 8 ) 2) C(R 8 ) 2 , C(R S ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q 1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein any heterocyclyl group within a R 1 substituent is selected from pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and wherein any heterocyclyl group within a R 1 substituent optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbam
  • each R 2 group may be the same or different, and each R 2 group is selected from halogeno, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, halogeno-(l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsul ⁇ hinyl, (l- ⁇ C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl,
  • (p) m is 0 or 1, and when m is 1, the R 2 group is selected from halogeno, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy,
  • R 3 is hydrogen, ( l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (R l0 ) p -( l-8C)alkyl, wherein each p is 1, 2 or 3 and each R 10 which may be the same or different, is selected from halogeno, cyano, hydroxy, (l-6C)alkoxy, amino, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and heterocyclyl, wherein said heterocyclyl group optionally bears 1, 2 or 3 substituents independently selected from halogeno, oxo, trifiuoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l- ⁇ C)alky ⁇ , (2-8C)alkenyl, (2-8
  • R 3 is hydrogen, (l-8C)alkyl or (R 10 )-(l-8C)alkyl, wherein R 10 is selected from halogeno, cyano, hydroxy, (l-6C)alkoxy, amino, (l-6C)alkylamino, di-[(l-6C)a!kyl] amino and heterocyclyl, wherein said heterocyclyl group optionally bears an halogeno, oxo, trifiuoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyI,
  • R 3 is hydrogen, methyl, ethyl, propyl or (R 10 )-(l-8C)alkyl, wherein R i0 is selected from halogeno, cyano, hydroxy, (l- ⁇ C)alkoxy, amino, (l-6C)alkyIamino, di-[(l-6C)alkyl]amino and heterocyclyl, wherein said heterocyclyl group optionally bears an halogeno, oxo, trifiuoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido,
  • R 3 is hydrogen, methyl or (R 10 )-(l-8C)alkyl, wherein R 10 is selected from halogeno, cyano, hydroxy, (l-6C)alkoxy, amino, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and heterocyclyl, wherein said heterocyclyl group optionally bears an halogeno, oxo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl,
  • R 3 is hydrogen, methyl or (R l0 )-(l-3C)alkyl, wherein R 10 is selected from halogeno, cyano, hydroxy, (l-6C)alkoxy, amino, (l-6C)alkylamino, di-[(l-6C)alkyl] amino and heterocyclyl, wherein said heterocyclyl group optionally bears an halogeno, oxo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl,
  • (x) n is 0 or 1 ;
  • each R 4 group may be the same or different, and each R 4 group is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, N-(I- 6C)alkylsulphamoyl, jV ⁇ V-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (1- 6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, N-(I-
  • (z) n is 0 or 1 and when n is 1, the R 4 group is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, N-(l-6C)alkylsulphamoyl, NN-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l- ⁇ C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l- 6C)alkoxy, carbamoyl, N-(l-6C)alkylcarbamoyl, NN-di-[(l-6C)alkyl]carbamoyl and
  • R ! is aminomethyl, methylaminomethyl, dimethylaminomethyl, ethylaminomethyl, diethylaminomethyl, 2-methylaminoethoxy, 3-methylaminopro ⁇ oxy, 2- dimethylaminoethoxy, 3 -dimethyl aminopropoxy, 2-ethylaminoethoxy, 3- ethylaminopropoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, methylaminomethylcarbonylamino, dimethylaminomethylcarbonylamino, ethylaminomethylcarbonylamino, diethylaminomethylcarbonylamino, 2- methylaminoethylcarbonylamino, 3-methylaminopropylcarbonylamino, 2-dimemylaminoethylcarbonylamino,
  • R 1 is aminomethyl, methyl aminomethyl, dimethylaminomethyl, 2-methylaminoethoxy, 3-methylaminopropoxy, 2-dimethylaminoethoxy, 3-dknethylaminopropoxy, 2-ethylaminoethoxy, 3-ethylaminopropoxy, 2-diethylaminoethoxy, 3- diethylaminopropoxy, iV-(2-methylaminoethyl)carbamoyl, N-(3-methylaminopropyl)carbamoyl, ⁇ f-(2-dii ⁇ iethylaminoethyl)carbamoyl, ⁇ -(3-dimethylaminopropyl)carbamoyl, N-(2-ethylaminoethyl)carbamoyl, iV-(3-ethylaminopropyl)carbamoyl, N-(2-diethylaminoe
  • (gg) m is O or m is 1 and R 2 is fluoro, chloro, cyano, hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetoxy;
  • R 3 is hydrogen, methyl, ethyl, propyl, hydroxymethyl, 2-hydroxyethyl, 3- hydroxypropyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, ethoxymethyl, 2- ethoxyethyl, 3-ethoxypropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2- ethylaminoethyl, 3-ethylaminopropyl, 2-dimethylaminoethyl, 3-dimethyIaminopropyl,
  • n 0 or n is 1 and R 4 is selected from hydrogen, fluoro, cyano, sulphamoyl, methoxy and methoxycarbonyl; or (qq) n is O.
  • a particular compound of the invention is a pyrazine derivative of die Formula I above wherein: - G 1 and G 2 are both CH or Gi is N and G 2 is CH; R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO, SO 2 N(R 8 ), N(R 8 )SO 2 ,C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R S )C(R 8 ) 2 , wherein each R 8 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-( 1 -6C)alkyl or halogeno-( 1 -6C)alkyl, and Q 1 is heterocyclyl, heterocyclyl-(l-6C)alkyI, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a
  • a further particular compound of the invention is a pyrazine derivative of the
  • Gi and G 2 are both CH or Gj is N and G 2 is CH;
  • R 1 is a group of the formula:
  • R 6 is hydrogen or (l-8C)alkyl; and R 5 is amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-U-6C)alkyl, (R 7 )-amino-(l-6C)alkyl or di-(R 7 )-amino-(l-6C)alkyl, wherein R 7 is (l-6C)alkyl; or R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q 1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R 1 substituent optionally bears 1 or 2 substituents independently selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l-6C)alk
  • R 3 is hydrogen, (l-8C)alkyl, (R 10 )-(l-8C)alkyl, wherein R 10 is selected from halogeno, cyano, hydroxy, (l-6C)alkoxy, amino, (l-6C)alkylamino, di-[(l-6C)alkyl] amino and heterocyclyl, wherein said heterocyclyl group optionally bears an halogeno, oxo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (l-6C)alkoxy group; n is 0 or 1 and when n is 1, the R 4 group is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, iV-(l-6C)alkylsulphamoyi, ⁇ /yV-di-[(
  • JV-(l-6C)alkylcarbamoyl JV-(l-6C)alkylcarbamoyl, NJV-di-[(l -6C)alkyl] carbamoyl, (2-6C)alkanoylamino; or a pharmaceutically- acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: - G 1 and G 2 are both CH or G 1 is N and G 2 is CH; R is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO, SO 2 N(R 8 ), N(R 8 )SO 2 ,C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2l C(R 8 J 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q !
  • any heterocyclyl group within a R 1 substituent is selected from pyrrolidinyl, morpholinyl, piperidinyl, piperaz ⁇ iyl, and wherein any heterocyclyl group within a R 1 substituent optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, hydroxy- (l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, halogeno-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)
  • R 3 is hydrogen, methyl, (R l0 )-(l-8C)alkyl, wherein R 10 is selected from halogeno, cyano, hydroxy, (l-6C)alkoxy, amino, (l-6C)alkylamino, di-[(l-6C)alkyl] amino and heterocyclyl, wherein said heterocyclyl optionally bears an halogeno, oxo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (l-6C)alkoxy group; n is 0 or 1, and when n is 1, the R 4 group is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, Af-(I -6C)alkylsulphamoyl, ⁇ yV-di-[(l-6C)alky
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein:-
  • R 1 is a group of the formula:
  • R 5 X 1 -o wherein X 1 is a direct bond or is selected from O, SO 2 , N(R 6 ), CO, CON(R 6 ), N(R 6 )CO,
  • R 6 is hydrogen or (l-8C)alkyl; and R 5 is amino-(l-3C)alkyl, (l-6C)alkyIamino-(l-3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)alkyl, (R 7 )-amino-(l-3C)alk:yl, di-[(R 7 )-amino-(l-3C)alkyl; and
  • R 7 is (l-6C)aDcyl; 5 or R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO,
  • R 8 is hydrogen or (l-8C)alkyl, o and Q 1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein any heterocyclyl group within a
  • R ! substituent is selected from pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and wherein any heterocyclyl group within a R 1 substituent optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, hydroxy ⁇ l-6C)alkyl, (l-6C)alkoxy-(l-6C)aIkyI, 5 halogeno-( 1 -6C)alkyl, amino-( 1 -6C)alkyl, ( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[(l-6C)alkyl]amino-(l - ⁇ Qalkyl, (l-6C)alkylamino, di-[(l-6C)alkyI] amino, iV
  • (l-8C)alkyl (2-8C)alkenyl, (2-8C)alkynyI, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, 0 (l-6C)alkylthio, (l-6C)alkyIsulphonyl, (l- ⁇ C)alkylamino, di-[(l-6C)alkyl] amino,
  • R 3 is hydrogen, methyl, (R l0 )-(l-8C)alkyl, wherein R 10 is selected from halogeno, cyano, hydroxy, (l-6C)alkoxy, amino, (l-6C)alkylamino, di-[(l-6C)alkyl] amino and heterocyclyl, wherein said heterocyclyl optionally bears an halogeno, oxo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (l-6C)alkoxy group; n is 0
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: -
  • G 1 is CH and G 2 is N or Gi is N and G 2 is CH;
  • R 1 is a group of the formula:
  • R 7 is (l-6C)alkyI; or R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO, SO 2 N(R 8 ), N(R 8 )SO 2i C(R 8 ) 2 O, OC(R S ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each
  • R 8 is hydrogen or (l-8C)alkyl
  • Q 1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein any heterocyclyl group within a
  • R 1 substituent is selected from pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and wherehi any heterocyclyl group within a R 1 substituent optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyI, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, halogeno-(l-6C)alkyl, amiiio-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino-(l-6C
  • JV-(l-6C)alkylcarbamoyl or (2-6C)aIkanoylamino group m is 0 or 1, and when m is 1, the R group is selected from halogeno, cyano, hydroxy, amino,
  • R 3 is hydrogen, methyl, (R 10 )-(l-8C)alkyl, wherein R 10 is selected from halogeno, cyano, hydroxy, (l-6C)alkoxy, amino, (l-6C)alkyI amino, di-[(l-6C)alkyl] amino and heterocyclyl, wherein said heterocyclyl optionally bears an halogeno, oxo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or
  • (l-6C)alkoxy group n is 0 or 1, and when n is 1, the R 4 group is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, ⁇ T-(l-6C)aIkylsulphamoyl, N, ⁇ L di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-SC)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, iV-(l-6C)aIkylcarbamoyl, N,N-di-[(l-6C)a)ky ⁇ ] carbamoyl and (2-6C)alkanoylamino; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi and G 2 are suitably as defined in any one of paragraphs (a) to (d) above;
  • R 1 is suitably as defined in any one of paragraphs (e) to (1) above and is particularly as defined in any one of paragraphs (g) to (1) above;
  • R 2 is suitably as defined in any one of paragraphs (m) to (q) above, and is particularly as defined in any one of paragraphs (p) to (q) above;
  • R 3 is suitably as defined in any one of paragraphs (r) to (v) above, and is particularly as defined in any one of paragraphs (s) to (v) above;
  • R 4 is suitably as defined in any one of paragraphs (w) to (z) above.
  • a yet further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: -
  • G 1 and G 2 are suitably as defined in any one of paragraphs (a) to (d) and (aa) above;
  • R 1 is suitably as defined in any one of paragraphs (e) to (1) and (bb) to (ff) above and is particularly as defined in any one of paragraphs (g) to (1) and (bb) to (ff) above;
  • R 2 is suitably as defined in any one of paragraphs (m) to (q) and (gg) to (ii) above, and is particularly as defined in any one of paragraphs (p) to (q) and (gg) to (ii) above;
  • R 3 is suitably as defined in any one of paragraphs (r) to (v) and (jj) to (mm) above, and is particularly as defined in any one of paragraphs (s) to (v) and (jj) to (mm) above; and R 4 is suitably as defined in any one of paragraphs (w) to (z) and (nn) to (qq) above.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein:- Gi and G 2 are both CH or G 1 is N and G 2 is CH; R 1 is aminomethyl, methylammomethyl, dimethyl aminomethyl, ethylaminomethyl, diethylaminomethyl, 2-methylaminoethoxy, 3-methylaminopropoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-ethylaminoethoxy, 3-ethylaminopropoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, methylaminomethylcarbonylamino, dimethylaminomethylcarbonylamino , ethylaminomethylcarbonylamino, diethylarainomethylcarbonylamino, 2-methylaminoethylcarbonylamino, 3-methylaminopropylcarbonylarnino, 2-dimethylaminoethylcarbonyla
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: - Gi and G 2 are both CH;
  • R 1 is aminomethyl, methylarainomethyl, dimethylaminomethyl, ethylaminomethyl, diethylaminomethyl, 2-methylaminoethoxy, 3-methylaminopropoxy, 2-dimethylaminoethoxy, 3-dimethylaminopro ⁇ oxy, 2-ethylaminoethoxy, 3-ethylami ⁇ opropoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, methylaminomethylcarbonylamino, dimethylaminomethylcarbonylamino, ediylaminomethylcarbonylamino, diethylaminomethylcarbonylamino, 2-memylaminoethylcarbonyla ⁇ no, 3-methylaminopropylcarbonylamino, 2-dimethylaminoethylcarbonylamino, 3-dimethylaminopro ⁇ ylcarbonylamino, 2-ethyIaminoethylcarbonylamino,
  • R 3 is hydrogen, methyl, ethyl, propyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-ethyIaminoethyl, 3-ethylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-diethylaminoethyI, 3-diethylaminopropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 2-piperidi ⁇ oethyl, 3-piperidinopropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperazin-l-ylethyl, 3-piperazin-l-
  • R 1 is aminomethyl, methylaminomethyl, dimethylaminomethyl, ethylaminomethyl, diethyl aminomethyl, 2-methylaminoethoxy, 3-methylaminopropoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-ethylaminoethoxy, 3-ethylami ⁇ opropoxy, 2-diethylaminoethoxy, 3 -diethylaminopropoxy , methylaminomethylcarbonylamino, dimethylaminomethylcarbonylamino, ethylaminomethylcarbonylamino , diethylaminomethylcarbonylamino, 2-methylaminoethylcarbonylamino, 3-methylami ⁇ opropylcarbonylamino, 2-dimethylaminoethylcarbonylamino, 3-dimethylaminopropylcarbonylamino, 2-ethylaminoethylcarbonylamino, 3-eth
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: - Gi and G 2 are both CH or Gi is N and G 2 is CH;
  • R 1 is aminomethyl, methyl aminomethyl, dimethylaminomethyl, 2-methylaniinoethoxy, 3-methylaminopro ⁇ oxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-ethylaminoethoxy, 3-ethylaminopropoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, iV-(2-methylaminoethyl)carbamoyl , N-(3 -methylaminopropyl)carbamoyl , N-(2-dimethylaminoethyl)carbamoyl, N-(3-dimethylaminopropyl)carbamoyl, ⁇ (2-ethylaminoethyl)carbamoyl, iV-(3 -ethylamino ⁇ ro ⁇ yl)carbamoyl, j/V-(2-diethylaminoethy
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrroHdin-l-ylethyl, 3-pyrrolidin- 1-ylpropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperazin-l-ylethyl, 3-piperazin- 1-ylpro ⁇ yl, 2-(4-methylpiperazin-l-yl)ethyI or 3-(4-methylpiperazin-l-yl)propyl; n is 0 or n is 1 and R 4 is selected from hydrogen, fluoro, chloro, cyano, sulphamoyl, iV-methylsulphamoyl, iV, ⁇ -dimethylsul ⁇ hamoyl, tri
  • R 1 is 4-aminomethyl, 4-(2-dimethylaminoethoxy), 4-[ ⁇ f-(2-dimethylaminoethyl)carbamoyl], 3-[N-(3-dimethylaminopropyl)carbamoyl], 3-morpholino, 3-piperazinyl, 4-piperazinyl, 4-morpholrnomethyl, 4-(l-methylpiperidin-3-yImethoxy), 4-(2-pyrrolidin-lylethoxy),
  • R 3 is hydrogen, methyl, 2-dimethylaminoethyl, 2-morpholinoethyl, 3-morpholinopropyl or
  • n is 0 or n is 1 and R 4 is selected from hydrogen, fluoro, cyano, sulphamoyl, methoxy and methoxycarbonyl; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: - G 1 and G 2 are both CH or Gi is N and G 2 is CH; R 1 is 4-aminomethyl, 4-(2-dimethylaminoethoxy), 4-[N-(2-dimethylaminoethyl)carbamoyl], 3-[iV-(3-dimethylaminopropyl)carbamoyl], 4-[N-(3-dimethylaminopropyl)carbamoyl], 3- (dimethylaminomethyl), 3-mor ⁇ holino, 3-piperazinyl, 4-piperazin-l-yl, 4-piperidin-l-yl, 4- piperidin-4-yl, 3-(2H-pyrazol-3-yl), 4-(2-lH-pyrazol-l-ylethoxy), 4-(lH-pyrazol-l-ylmethyl), 4-morpholinomethyl, 3-morpholinomethyl, 3-(pyrroli
  • a further particular compound of the invention is a pyrazine derivative of the
  • R 1 is 4-aminomethyI, 4-(2-dimethylaminoethoxy), 4-[N-(2-dimethylaminoethyl)carbamoyl], 3-[N-(3-dimethylaminopropyl)carbamoyl], 4-[N-(3-dimethylaminopropyl)carbamoyl], 3- (dimethylaminomethyl), 3-mor ⁇ holino, 3-piperazinyl, 4-piperazin-l-yl, 4-piperidin-l-yI, A- piperidin-4-yI, 3-(2H-pyrazol-3-yl), 4-(2-lH-pyrazol-l-ylethoxy), 4-(lH-pyrazol-l-ylmethyl), 4-morpholinomethyl, 3-morpholinomethyl, 3-(pyrrolidin-l-ylmethyl), ⁇ yrrolidin-1- ylsulphonyl, 4-(l-methylpiperidin-3-ylmethoxy),
  • R 3 is hydrogen, methyl, 2-dimethylaminoethyl, 2-morpholinoethyl, 3-morpholinopropyl or 3 -(4-methylpiperazin- 1 -yl)propyl ; n is 0 or n is 1 and R 4 is selected from hydrogen, fluoro, cyano, sulphamoyl, methoxy and methoxycarbonyl; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: -
  • G 1 is CH and G 2 is N or G 1 is N and G 2 is CH;
  • R 1 is 4-aminomethyl, 4-(2-dimethylaminoethoxy), 4-[ ⁇ r -(2-dimethylaminoethyl)carbamoyl], 3-[N-(3-dimethylaminopropyl)carbamoyl] , 4-[iV-(3-dime ⁇ ylaminopropyl)carbamoyl], 3- (dimethylaminomethyl), 3-morpholino, 3-piperazinyl, 4-piperazin-l-yl, 4-piperidin-l-yl, A- piperidin-4-yl, 3-(2H-pyrazol-3-yl), 4-(2-lH-pyrazol-l-ylethoxy), 4-(lH-pyrazol-l-ylmethyl), 4-morpholinomethyl, 3-morpholinomethyI, 3-(pyrrolidin-l-ylmethyl), ⁇ yrrolidin
  • R 3 is hydrogen, methyl, 2-dimethylaminoethyl, 2-morpholinoethyl, 3-morpholinopropyl or 3 -(4-methylpiperazin- 1 -yl)propyl ; n is 0 or n is 1 and R 4 is selected from hydrogen, fluoro, cyano, sulphamoyl, methoxy and methoxycarbonyl ; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: - Gi and G 2 are both CH; R 1 is 4-aminomethyl, 4-(2-dimethylaminoethoxy), 4-[iV-(2-dimethyIaminoethyl)carbamoyl], S-fN-tS-dimemylaininopropylJcarbamoyll ⁇ -fN-tS-dimethylaminopropy ⁇ carbamoyl], 3- (dimethylaminomethyl), 3-morpholino, 3-piperazinyl, 4-piperazin-l-yl, 4-piperidin-4-yl, 3- (2H-pyrazol-3-yl), 4-(2-lH-pyrazol-l-ylethoxy), 4-(lH-pyrazol-l-ylmethyI), A- morpholinomethyl, 3-mo ⁇ holinomethyl, 3-(pyrrolidin-l-ylmethyl), pyrroli
  • R 3 is hydrogen, methyl, 2-dimethylaminoethyl, 2-morpholinoethyl or 3-morpholhiopropyl; n is 0 or n is 1 and R 4 is selected from hydrogen, fluoro, cyano, sulphamoyl, methoxy and methoxycarbonyl; or a pharmaceutically- acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: - G 1 is CH and G 2 is N or G 1 is N and G 2 is CH;
  • R 1 is 4-aminomethyl, 4-(2-dimethylaminoethoxy), 4-[iV-(2-dimethylaminoethyl)carbamoyl], S-CN-fS-dimethylaminopropyOcarbarnoyll ⁇ -IiV-tS-dimethylaminopropylicarbamoyl], 3- (dimethylaminomethyl), 3-morpholino, 3-piperazinyl, 4-piperazin-l-yl, 4-piperidin-4-yl, 3- (2H-pyrazol-3-yl), 4-(2-l//-pyrazol-l-ylethoxy), 4-(lH-pyrazol-l-ylmethyl), A- morpholinomethyl, 3-morphol ⁇ iomethyl, 3-(pyrrolidin-l-ylmethyl), pyrrolidin-1-yl sulphonyl, 4-(l-methylpiperidin-3-ylmethoxy), 4-(2-pyrrolidin-lylethoxy),
  • R 3 is hydrogen, methyl, 2-dimethylaminoethyl, 2-morpholinoethyl or 3-morpholinopropyl; n is 0 or n is 1 and R is selected from hydrogen, fluoro, cyano, sulphamoyl, methoxy and methoxycarbonyl; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: -
  • G 1 and G 2 are both CH or G 1 is N and G 2 is CH;
  • R 1 is 3-piperazinyl, 4-piperazin-l-yl, 3-piperazin-l-yl, 4-morpholinomethyl, 3- morpholinomethyl, 4-(l-methylpiperidin-3-ylmethoxy), 4-(2-pyrrolidin-lylethoxy) or 3-[N- ( 1 -methylpiperidin- 3-yl)carbamoyl] ;
  • m is 0 or m is 1 and R 2 is a methoxy group;
  • R is hydrogen; n is 0; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the
  • G] and G 2 are both CH;
  • R 1 is 3- ⁇ iperazinyI, 4-piperazin-l-yl, 3-piperazin-l-yl, 4-morpholinomethyl, 3- morpholinomethyl, 4-(l-methylpiperidin-3-ylmethoxy), 4-(2-pyrrolidin-lylethoxy) or 3-[N- (l-methylpiperidin-3-yl)carbamoyl]; m is 0 or m is 1 and R 2 is a methoxy group;
  • R 3 is hydrogen; n is O; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the
  • Gi is CH and G 2 is N or Gi is N and G 2 is CH;
  • R 1 is 3-piperazinyl, 4-piperazin-l-yl, 3-piperazin-l-yl, 4-morpholinomethyl, 3- morpholinomethyl, 4-(l-methylpiperidin-3-yImethoxy), 4-(2- ⁇ yrrolidin-lylethoxy) or 3-[N- ( 1 -methylpiperidin-3-yl)carbamoyl] ;
  • m is 0 or m is 1 and R is a methoxy group;
  • R is hydrogen;
  • n is O; or a pharmaceutically-acceptable salt thereof.
  • Particular compounds of the invention are, for example, the pyrazine derivatives of the
  • a particular compound of the invention is a pyrazine derivative of the
  • a further particular compound of the invention is a pyridine or pyrazine derivative of the Formula I selected from any one of the following :-
  • a yet further particular compound of the invention is a pyridine or pyrazine derivative of the Formula ⁇ selected from any one of the following: -
  • Another aspect of the present invention provides a process for preparing a compound of the Formula I, or a pharmaceutically-acceptable salt thereof.
  • a suitable process is illustrated by die following representative process variants in which, unless otherwise stated, Gi, G 2 , R 1 , m, R 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore.
  • Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • Suitable process variants include, for example, the following: - (a) The reaction of a carboxylic acid of the Formula II
  • R 3 IV which is cyclised, conveniently in the presence of a suitable acid, to form a compound of the Formula I, whereafter any protecting group that is present is removed.
  • a suitable reactive derivative of a carboxylic acid of the Formula II is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid with an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid with a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid with a phenol such as pentafluorophenol, with an ester such as pentafluorophenyl trifluoroacetate or with an alcohol such as methanol, ethanol, isopropanol, butanol or N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid with an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid with a cyanide such as dieth
  • the amide formation reaction is conveniently carried out in the presence of a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • a suitable base for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate,
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene.
  • a dipolar aprotic solvent such as N ⁇ V-dimethylfo ⁇ namide, J
  • a suitable acid for the cyclisation reaction is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide or, for example, an organic acid such as, for example, acetic acid or trifluoroacetic acid.
  • the reaction is conveniently carried out in the presence of a suitable solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, or a dipolar aprotic solvent as defined hereinbefore.
  • the reaction is conveniently carried out at a temperature in the range, for example, 0 to 150 0 C, conveniently at or near 100°C.
  • Pyrazine carboxylic acids of the the Formula IT including reactive derivatives thereof such as an ester thereof, may, for example, be prepared by the cross coupling reaction, conveniently in the presence of a suitable catalyst, of an organoboron reagent of the Formula V
  • each of L 1 and L 2 which may be the same or different, is a suitable ligand for the boron atom and R 1 , m and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a pyrazine of the Formula VI
  • L is a displaceable group, whereafter any protecting group that is present is removed.
  • a suitable value for the ligands L and L which are present on the boron atom of the organoboron reagent include, for example, a hydroxy, (l-4C)a!koxy or (l-6C)alkyl ligand, for example a hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methyl, ethyl, propyl, isopropyl or butyl ligand.
  • the ligands L 1 and L z may be linked such that, together with the boron atom to which they are attached, they form a ring.
  • L 1 and L 2 together may define an oxy-(2-4C)alkylene-oxy group, for example an oxyethyleneoxy, oxytrimethyleneoxy group or -O-C(CH 3 ) 2 C(CH 3 ) 2 -O- group such that, together with the boron atom to which they are attached, they form a cyclic boronic acid ester group.
  • Particularly suitable organoboron reagents include, for example, compounds wherein each of L 1 and L 2 is a hydroxy, a isopropoxy or an ethyl group or L 1 and L 2 together define a group of formula -O-C(CH 3 ) 2 C(CH 3 ) 2 -O-.
  • a suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • a suitable catalyst for the cross coupling reaction includes, for example, a metallic catalyst such as a palladium(O), palladium(II), nickel(O) or nickel(II) catalyst, for example tetrakis(triphenylphosphine)palIadium(0), palladium(II) chloride, palladium(II) bromide, bis(triphenylphosphine)palladium( ⁇ ) chloride, tetrakis(triphenylphosphine)nickel(0), nickel(II) chloride, nickel(II) bromide, bis(triphenylphosphine)mckeI(II) chloride or [l,r-bis(diphenylphosphino)ferroceneldichloropalladium(II).
  • a free radical initiator may conveniently be added, for example an azo compound such as azo(bisisobutyronitrile).
  • the reaction is conducted in the presence of a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethyIaminopyriduie, triethylamine or morpholine.
  • a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethyIaminopyriduie, triethylamine or morpholine.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example WV-dimethylformamide, water, tetrahydrofuran, 1,4-dioxan, 1,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180°C.
  • a suitable inert solvent or diluent for example WV-dimethylformamide, water, tetrahydrofuran, 1,4-dioxan, 1,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180°C.
  • Compounds of the Formulae V and VI may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter or they are commercially available, known in the literature, or they can be prepared by standard processes known in the art.
  • each of L and L which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and Gi, G 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed,
  • a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-diraethylaminopyridine, triethylamine or morpholine.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example N, ⁇ f-dimethylformamide, water, tetrahydrofuran, 1,4-dioxan,
  • a suitable inert solvent or diluent for example N, ⁇ f-dimethylformamide, water, tetrahydrofuran, 1,4-dioxan,
  • 1,2-dimethoxyethane 1,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180 0 C.
  • Pyrazine compounds of the Formula VII may be prepared, for example, by the cross coupling reaction, conveniently in the presence of a suitable catalyst as defined hereinbefore, of a pyrazine compound of the Formula IX
  • each of L 1 and L 2 which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and R 1 , m and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter the protecting group PG is converted by way of a functional group interconversion into a displaceable group L.
  • a suitable protecting group PG is, for example, a methylthio group that may be converted to a methylsulphonyl group by oxidation with a suitable oxidising agent such as
  • the protecting group PG is, for example, a hydrogen group that may be converted to a bromo group by brominating conditions such as phosphorous tribromide or JV-bromosuccinimide, conveniently in the presence of a suitable base such as pyridine or triethylamine, in a suitable solvent such as methylene chloride and at a suitable temperature such as -30 to 100 0 C, conveniently at or near
  • the protecting group PG is a displaceable group L as defined hereinbefore, in which case, provided that the organoboron reagent of the Formula V reacts selectively with the displaceable group that is located at the 4-position (relative to the amino group) in the pyrazine compound of the Formula IX, no conversion of the protecting group is necessary.
  • Organoboron compounds of the Formula VIII may be prepared by the reaction of a compound of the Formula X wherein L is a displaceable group as defined hereinbefore and Gj, G 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a boron reagent, whereafter any protecting group that is present is removed.
  • L is a halgeno group such as a bromo or iodo group.
  • a 2-halogeno-substituted benzimidazole or azabenzimidazole compound of the Formula X may be reacted with a boron reagent such as bis(pinacolato)diboron or diborane, conveniently in the presence of a suitable base such as pyridine or triethylamine, in a solvent such as tetrahydrofuran and at a temperature in the range -10 to 75 0 C, conveniently in the range 0 to 30 0 C.
  • a boron reagent such as bis(pinacolato)diboron or diborane
  • L is a displaceable group as defined hereinbefore and Gi, G 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an organoboron reagent of the Formula V
  • each of L and L which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and R 1 , m and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed.
  • the reaction is conducted in the presence of a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example N ⁇ V-dimethylformamide, water, tetrahydrofuran, 1,4-dioxan, 1,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 18O 0 C.
  • a suitable inert solvent or diluent for example N ⁇ V-dimethylformamide, water, tetrahydrofuran, 1,4-dioxan, 1,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 18O 0 C.
  • L is a displaceable group as defined hereinbefore, may be reacted with a 1,2-diamine of the Formula III
  • G 1 , G 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, to provide an amide of the Formula XHI
  • a carboxylic acid of the Formula XII and a 1,2-diamine of the Formula III may be reacted in the presence of an amide coupling reagent such as a uronium compound such as 2-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate(V) or a carbodiimide such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, conveniently in the presence of an organic base such as pyridine or triethylamine, in a solvent such as iVJV-dimethylformamide and a temperature in the range of 0 to 150 0 C, conveniently at or near ambient temperature.
  • Cyclisation of the resultant amide product may conveniently be carried out in the presence of a suitable organic acid such as acetic acid and at a temperature in the range, for example, 0 to 150 0 C, conveniently at or near 100
  • Compounds of the Formula XII may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter or they are commercially available, known in the literature, or they can be prepared by standard processes known in the art.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dirnethylaminopyridine, triethylamine, morpholine, N-methylmorphoIine or diazabicyclo[5.4.0]undeo7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dirnethylaminopyridine, triethylamine, morpholine, N-methylmorphoIine or diazabicyclo[5.4.0]undeo7-ene
  • an alkali or alkaline earth metal carbonate or hydroxide for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene.
  • a dipolar aprotic solvent such as N ⁇ V-dimethylformamide, iV ⁇
  • Compounds of the Formula XIV may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter or they are commercially available, known in the literature, or they can be prepared by standard processes known in the art.
  • Carboxylic acid starting materials of the Formula XV may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter. For example, using an analogous procedure to that described in process variant (c), a compound of the Formula XI
  • L is a displaceable group as defined hereinbefore and G 1 , Gz, R , n and R have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted, conveniently in the presence of a suitable catalyst as defined hereinbefore, with an organoboron reagent of the Formula XVI
  • each of L 1 and L 2 which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and m and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed.
  • a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example iV ⁇ V-dimethylformamide, water, tetrahydrofuran, 1,4-dioxan,
  • a suitable inert solvent or diluent for example iV ⁇ V-dimethylformamide, water, tetrahydrofuran, 1,4-dioxan,
  • 1,2-dimethoxyethane 1,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 25O 0 C, preferably in the range 60 to 180 0 C.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, such as those defined hereinbefore for process variant (d).
  • a suitable inert solvent or diluent such as those defined hereinbefore for process variant (d).
  • the reaction is conveniently carried out at a temperature in the range, for example, 0 to 120 0 C, preferably at or near ambient temperature.
  • R5 L xix wherein L is a displaceable group as defined hereinbefore and R 5 has any of the meanings defined hereinbefore except that any functional group is protected if necessary,whereafter any protecting group that is present is removed.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicycIo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicycIo[5.4.0]undec-7-ene
  • an alkali or alkaline earth metal carbonate or hydroxide for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene.
  • a dipolar aprotic solvent such as NJV-dimethylformamide, JV ⁇ -d
  • the displaceable group L may be a hydroxy group, in which case the reaction is carried out in the presence of a suitable dehydrating agent, for example, a carbodiimide reagent such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyi)- 3-ethylcarbodiimide or a mixture of an azo compound such as diethyl or di-te/t-butyl azodicarboxylate and a phosphine such as triphenylphosphine.
  • a suitable dehydrating agent for example, a carbodiimide reagent such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyi)- 3-ethylcarbodiimide or a mixture of an azo compound such as diethyl or di-te/t-butyl azodicarboxylate and a phosphine such as triphenylphos
  • the dehydration reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150 0 C, preferably at or near ambient temperature.
  • a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150 0 C, preferably at or near ambient temperature.
  • R 1 is a group of the formula R 5 - X 1 wherein X 1 is O
  • R 3 is, for example, a (R l0 ) p -(l-8C)alkyl group wherein p and R 10 have any of the meanings stated hereinbefore.
  • a carboxylic acid of the Formula XX and a 1,2-diamine of the Formula III may be reacted in the presence of an amide coupling reagent such as 1-hydroxybenzotriazole or a uronium compound such as 2-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium io hexafluorophosphate(V), conveniently in the presence of an organic base such as pyridine or triethylamine in a solvent such as iVyV-diiriethylformarnide and a temperature in the range of 0 to 15O 0 C, conveniently at or near ambient temperature.
  • Cyclisation of the resultant amide product may conveniently be carried out in the presence of a suitable organic acid such as acetic acid and at a temperature in the range, for example, 0 to 150°C, conveniently at or near
  • each of L 1 and L 2 which may be the same or different, is a suitable Kgand for the boron atom as defined hereinbefore and m and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a pyrazine of the Formula VI
  • the alkylation reaction is conveniently carried out in the presence of a suitable base as defined hereinbefore, hi the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 to 15O 0 C, conveniently in the range, for example, 50 to 120 0 C.
  • the displaceable group L may be a hydroxy group, hi which case the reaction is carried out in the presence of a suitable dehydrating agent as defined hereinbefore.
  • R group is hydrogen, it will be appreciated that alkylation may occur at both the phenolic OH group and at the NH group forming part of the benzimidazole ring.
  • R 1 is a group of the formula Q 1 - X 2 - wherein Q 1 is a heterocyclyl, heterocyclyl-(l-6C)alkyl or heteroaryl-(l-6C)alkyl group and X 2 is O, and wherein R 3 is, for example, a (R 10 ) p -(l-8C)alkyl group wherein p and R 10 have any of the meanings stated hereinbefore.
  • Compounds of the Formula XXIII may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter or they are commercially available, known in the literature, or they can be prepared by standard processes known in the art.
  • m, R 2 , Gi , G 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an alkylating agent of the Formula xxrv Q2 " L xxiv wherein L is a displaceable group as defined hereinbefore and Q 2 has any of the meanings defined immediately above except that any functional group is protected if necessary,whereafter any protecting group that is present is removed.
  • the alkylation reaction is conveniently carried out in the presence of a suitable base as defined hereinbefore, in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 to 15O 0 C, conveniently in the range, for example, 50 to 120 0 C.
  • the displaceable group L may be a hydroxy group, in which case the reaction is carried out in the presence of a suitable dehydrating agent as defined hereinbefore.
  • R 3 group is hydrogen
  • alkylation may occur at both the phenolic OH group and at the NH group forming part of the benzimidazole ring.
  • R ! is a group of the formula Q 2 - X 2 - wherein Q 2 is a aryl-(l-6C)alkyl, cycloalkyl or cycloalkyl-(l-6C)alkyl group and X 2 is O, and wherein R 3 is, for example, a
  • any compound of Formula I obtained by any of the processes described hereinbefore can be converted into another compound of the Formula I if required.
  • a reductive amination reaction can be carried out to couple a compound of Formula I obtained by any of the processes described hereinbefore having a nitrogen containing heterocyclyl ring such as, for example, piperidin-4-yl as an R 1 group with a suitable aldehyde or ketone to obtain another compound of the Formula I, for example, if formaldehyde, or a equivalent thereof, is used, a compound of Formula I having a 1- methylpiperidin-4-yl R 1 group may be obtained.
  • a suitable reducing agent for such a reductive amination reaction is, for example, a hydride reducting agent, for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride.
  • a hydride reducting agent for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride.
  • the reaction is conveniently performed in a suitable inert solvent or diluent, for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
  • a suitable inert solvent or diluent for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
  • a pharmaceutically-acceptable salt of a pyrazine derivative of the Formula I for example an acid-addition salt, it may be obtained by, for example, reaction of said pyrazine derivative with a suitable acid.
  • a pharmaceutically-acceptable pro-drug of a pyrazine derivative of the Formula I When a pharmaceutically-acceptable pro-drug of a pyrazine derivative of the Formula I is required, it may be obtained using a conventional procedure.
  • an in vivo cleavable ester of a pyrazine derivative of the Formula I may be obtained by, for example, reaction of a compound of the Formula I containing a carboxy group with a pharmaceutically-acceptable alcohol or by reaction of a compound of the Formula I containing a hydroxy group with a pharmaceutically-acceptable carboxylic acid.
  • an in vivo cleavable amide of a pyrazine derivative of the Formula I may be obtained by, for example, reaction of a compound of the Formula I containing a carboxy group with a pharmaceutically-acceptable amine or by reaction of a compound of the Formula I containing an amino group with a pharmaceutically-acceptable carboxylic acid.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or f-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection5 conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alianoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a f-butoxycarbonyl group may be removed, for example, by treatment with a suitable acido as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by5 treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl0 group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a ?-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a ?-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • the following assays can be used to measure the effects of the compounds of the present invention as inhibitors of AxI and cMet tyrosine kinase enzymes, as inhibitors in vitro of the phosphorylation of AxI expressed on NCI H 1299 lung large cell carcinoma cells and as inhibitors in vitro of the phosphorylation of cMet expressed on MKN45 cells.
  • N-terminal GST-AxI kinase domain encompassing amino acids 473 to 894 of AxI
  • Test compounds were prepared as 1OmM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 ⁇ l) of each compound dilution were placed into a well of a Greiner 384- well low volume (LV) white polystyrene plate (Greiner Bio-one). A lO ⁇ l mixture of recombinant purified AxI enzyme, biotinylated peptide substrate (Biotin poly-GAT; CisBio, Catalogue No. 6 IGATBLB), 0.2 ⁇ M Adenosine triphosphate (ATP) and a buffer solution [comprising 2OmM Tris-HCl pH7.5 buffer,
  • the IC 50 value is the concentration of test compound that inhibits 50% of kinase activity.
  • test compounds to inhibit phosphorylation by recombinant AxI tyrosine kinase.
  • N-terminal GST-AxI kinase domain encompassing amino acids 473 to 894 of AxI was expressed in SF126 insect cells and purified using the GST epitope tag, using standard purification techniques.
  • Test compounds were prepared as 1OmM stock solutions in Dimethyl Sulphoxide (DMSO) and diluted in DMSO as required. Aliquots (12OnI) of compound dilutions were fired into the wells of a Greiner 384- well low volume (LV) white polystyrene plate (Greiner Bio-one) using acoustic dispensing (Labcyte Echo 550). A lO ⁇ l mixture of recombinant purified AxI enzyme, biotinylated peptide substrate (Biotin poly-GAT; CisBio, Catalogue No.
  • NCI Hl 299 lung large cell carcinoma cell line [American Type Culture Collection (ATCC) CRL 5803] was routinely maintained at 37 D C with 5% CO 2 in RPMI containing 10% foetal calf serum (FCS) and 2mM L-glutamine.
  • FCS foetal calf serum
  • the cells were detached from the culture flask with 'Accutase' (Innovative Cell Technologies Inc., San Diego, CA, USA; Catalogue No. AT 104) using standard tissue culture methods and re-suspended in media to give O.9xlO 5 cells per ml.
  • ELISA plates were incubated for 16 hours at 4°C and then washed 3 times with 250 ⁇ J per well of PBS/T.
  • the cells were incubated for 1 hour at room temperature with a mouse anti- Phospho tyrosine antibody (Upstate, Catalogue No 05-321) diluted in 1% w/v BSA in PBS. Plates were washed three times with 250 ⁇ l per well of PBS/T. Subsequently, plates were incubated for 1 hour at room temperature with an anti-mouse horseradish peroxidase conjugated secondary antibody diluted in 1% w/v BSA in PBS.
  • the plates were washed 3 times with 250 ⁇ l per well of PBS/T. Fluorogenic substrate was made up according to manufacturers instructions (Pierce Biotechnology Inc., Rockford IL, USA; Catalogue No. 15169). lOO ⁇ l aliquots of substrate solution were added to each of the wells and fluorescence was read on a Tecan Ultra plate reader (Tecan UK Ltd., Reading, Berkshire, UK). Fluorescence dose response data obtained with each compound were analysed and the degree of inhibition of phospho-Axl was expressed as an IC 50 value.
  • the IC 50 value is the concentration of test compound that inhibits 50% of kinase activity.
  • the assay used AlphaScreen technology (Gray et at, Analytical Biochemistry. 2003, 313: 234-245) to determine the ability of test compounds to prevent the activation of c-Met, in which wild type activated c-Met phosphorylates a mutant form of c-Met lacking catalytic activity but retaining the ability to be phosphorylated on the activating residues.
  • Kinase activity assays were performed in 384- well low- volume white plates (Greiner,
  • Each kinase reaction contained 40pg (10OpM) P Y 1234 pY l235 c-Met(1074-1366) kinase domain, 44ng (10OnM) cMyc- [D1204N,R1208Q]c-Met(1069-1366)-biotin, 25mM HEPES (pH7.4), O.lmM sodium orthovanadate, ImM DTT 1 0.01% (v/v) Tween-20, 1OmM Magnesium Chloride, 0.1% BSA, 50 ⁇ M ATP.
  • test compounds were each added in 6% (v/v) DMSO to yield a final assay DMSO concentration of 1% (v/v).
  • the kinase reactions were incubated at room temperature for 60 minutes and stopped by adding 5 ⁇ L containing 0.5ng anti- pYpY I234/1235 c-Met rabbit polyclonal antibody (AstraZeneca Pharmaceuticals) with 200ng rabbit IgG Protein A Alphascreen acceptor beads (Perkin Elmer 6760617R) & 200ng streptavidin donor beads (Perkin Elmer 6760617R) in 25mM HEPES (pH 7.4), 84.5mM EDTA, 0.3% BSA under low-level light conditions.
  • IC 50 value is the concentration of test compound that inhibits 50% of c-Met kinase activity.
  • test compounds can be used to indicate the ability of a test compound to inhibit c-Met mediated cellular signalling in mammalian cell lines, for example the human tumour cell line MKN45. This is achieved by measuring the amount of phosphorylated c-Met within a cell following compound treatment.
  • MKN45 cells were routinely passaged in DMEM (Gibco BRL, product number 41966-029) plus 10% foetal calf serum (FCS), 1% L-glutamine (Gibco BRL, product number 25030024), to a confluence not greater than 85%.
  • FCS foetal calf serum
  • 1% L-glutamine Gabco BRL, product number 25030024
  • MKN45 cells were seeded at 2xlO 4 cells/ well in DMEM plus 0.5% foetal calf serum, 1% L-glutamine in 96 well plates (Costar, product number 3904) and incubated at 37°C (+5% CO 2 ) in a humidified incubator.
  • the permeabilisation solution was then removed and the cells washed twice more with lOO ⁇ l/ well PBS before the addition of 40 ⁇ l/well anti-phospho pYpYpY 1230/4/5 c-Met (Biosource, product number 44-888G-CS2), diluted 1/500 with PBS plus 10% FCS. Following incubation at room temperature for 1 hour, the antibody solution was removed and the wells were washed twice with lOO ⁇ l/ well PBS. 50 ⁇ I/ well 1/400 goat anti-rabbit Alexa Fluor 594 secondary antibody (Molecular Probes, product number Al 1012) and 1/10000 Hoescht (Molecular Probes, product number H-3570) diluted with PBS plus 10% FCS was added and the plate incubated in the dark at room temperature for one hour.
  • the plates were washed three times with lOO ⁇ l/ well PBS, leaving the final wash in the wells before sealing the plates.
  • the plates were read using an Arrayscan H (Cellomics).
  • the mean average intensity fluorescence values for each test compound concentration, untreated control wells and 100% inhibition control wells were used to determine the test compound's IC 50 value.
  • the IC50 value is the concentration of test compound that inhibits 50% of c-Met phosphorylation.
  • Preferred compounds of the invention possess activity at the following concentrations or doses in one or more of the above tests (a), (aa), (b), (c) and (d) :- Test (a) or (aa):- IC50 versus AxI tyrosine kinase in the range, for example,
  • the pyrazine compound disclosed within Example 1 possesses activity in Test (a) with an IC50 versus AxI tyrosine kinase of approximately 34 nM; and activity in Test (b) with an IC50 versus cellular phospho-Axl of approximately 6 nM; and activity in Test (c) with an IC50 versus c-Met tyrosine kinase of approximately 18.7 ⁇ M; and activity in Test (d) ⁇ 5 with an IC 50 versus cellular phospho-c-Met (pYpYpY 1230W/5 ) of approximately 0.84 ⁇ M.
  • Example 5.19 had an activity in Test (aa) with an IC 50 versus AxI tyrosine kinase of approximately 0.057 ⁇ M.
  • Example 5 had an activity in Test (aa) with an IC 50 versus AxI tyrosine kinase of approximately 0.158 ⁇ M.
  • the compound disclosed in Example 11 had an activity in Test (aa) with an IC 50 versus AxI tyrosine kinase of approximately 0.084 ⁇ M.
  • a pharmaceutical composition which comprises a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixi
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • a formulation intended for oral administration to humans will generally contain, for example, from 1 mg to 1 g of active agent (more suitably from 1 to 250 mg, for example from 1 to 100 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range for example, 1 mg/kg to 100 mg/kg body weight is received, given if required in divided doses.
  • lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, 1 mg/kg to 25 mg/kg body weight will generally be used.
  • a dose in the range for example, 1 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration is however preferred, particularly in tablet form, Typically, unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention.
  • antagonism of the activity of AxI and/or c-Met receptor kinases is expected to be beneficial in the treatment of a number of cell proliferative disorders such as cancer.
  • the novel pyrazine derivatives described herein possess potent activity against cell proliferative disorders. It is believed that the compounds provide a useful treatment of cell proliferative disorders, for example to provide an anti-tumour effect, by way of a contribution from inhibition of AxI and/or c-Met receptor tyrosine kinases, hi addition, as stated hereinbefore, AxI and c-Met are involved hi angiogenesis, the process of forming new blood vessels that is critical for continuing tumour growth. It is therefore believed that the compounds of the present invention are expected to be beneficial in the treatment of a number of disease states that are associated with angiogenesis and/or increased vascular permeability such as cancer, especially in inhibiting the development of tumours.
  • Particular compounds of the invention possess better potency against AxI receptor tyrosine kinases than against c-Met receptor kinases.
  • a pyrazine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment (or prophylaxis) of cell proliferative disorders or in the treatment (or prophylaxis) of disease states associated with angiogenesis and/or vascular permeability.
  • a method for the treatment (or prophylaxis) of cell proliferative disorders in a warm-blooded animal in need of such treatment (or prophylaxis) or for the treatment (or prophylaxis) of disease states associated with angiogenesis and/or vascular permeability in a warm-blooded animal in need of such treatment (or prophylaxis) which comprises administering to said animal an effective amount of a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • Suitable cell proliferative disorders include neoplastic disorders, for example, cancers of the lung (non-small cell lung cancer, small cell lung cancer and bronchioalveolar cancer), gastrointestine (such as colon, rectal and stomach tumours), prostate, breast, kidney, liver, brain (such as glioblastoma), bile duct, bone, bladder, head and neck, oesophagus, ovary, pancreas, testes, thyroid, cervix and vulva and skin (such as dermatofibrosarcoma protruberans) and in leukaemias and lymphomas such as chronic myelogenous leukaemia (CML), chronic myelomonocytic leukaemia (CMML), acute lymphocytic leukaemia (ALL), chronic neutrophilic leukaemia (CNL), acute myelogenous leukaemia (AML) and multiple myeloma.
  • CML chronic myelogenous leukaemia
  • a method for treating cell proliferative disorders such as solid tumour disease
  • a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • Suitable cell proliferative disorders include non-malignant disorders such as blood vessel disease (for example atherosclerosis and restenosis, for example in the process of restenosis subsequent to balloon angioplasty and heart arterial by-pass surgery), fibrotic diseases (for example kidney fibrosis, hepatic cirrhosis, lung fibrosis and multicystic renal dysplasia), glomerulonephritis, benign prostatic hypertrophy, inflammatory diseases (for example rheumatoid arthritis and inflammatory bowel disease), multiple sclerosis, psoriasis, hypersensitivity reactions of the skin, allergic asthma, insulin-dependent diabetes, diabetic retinopathy, diabetic nephropathy and endometriosis.
  • blood vessel disease for example atherosclerosis and restenosis, for example in the process of restenosis subsequent to balloon angioplasty and heart arterial by-pass surgery
  • fibrotic diseases for example kidney fibrosis, hepatic cirrhosis, lung fibrosis and multicys
  • Suitable disease states associated with angiogenesis and/or vascular permeability include, for example, the undesirable or pathological angiogenesis seen in diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma.
  • a pyrazine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment (or prevention) of those tumours which are sensitive to inhibition of AxI and/or c-Met receptor enzymes that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
  • a method for the treatment (or prevention) of a warm-blooded animal having tumours which are sensitive to inhibition of AxI or c-Met receptor enzymes that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells which comprises administering to said animal an effective amount of a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a pyrazine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in providing an AxI and/or c-Met receptor enzyme inhibitory effect.
  • a method for inhibiting an AxI and/or c-Met receptor enzyme which comprises administering an effective amount of a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • anti-cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumour agents:- (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubi
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341 ) and N-(2- chloro-6-methylphenyl)-2- ⁇ 6- [4-(2-hydroxyethyl)piperazin- 1 -yl] -2-methylpyrimidin-4- ylamino ⁇ thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med.
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-te
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morphoIinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), iV-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-iV-(3-chloro-4-fiuorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family,
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drag resistance gene therapy; and
  • immunotherapy approaches including for example ex- vivo and in- vivo approaches to increase the irnmunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically- active agent within its approved dosage range.
  • a pharmaceutical product comprising a pyrazine derivative of the Formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer.
  • the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of AxI or c-Met receptor tyrosine kinase enzymes. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the invention will now be illustrated in the following Examples in which, generally: (i) operations were carried out at ambient temperature, Le. in the range 17 to 25°C and under an atmosphere of an inert gas such as nitrogen unless otherwise stated;
  • HATU (0.11 g) was added to a mixture of 3-amino-6-[3-methoxy-4-(2-pyrrolidin-l- ylethoxy) ⁇ henyl]pyrazine-2-carboxylic acid (0.1 g), 3-methoxybenzene-l,2-diamine (0.04 g), triethylamine (0.058 ml) and DMF (3 ml).
  • the reaction was stirred at ambient temperature for 12 hours.
  • the mixture was diluted with methanol and added to an SCX ion exchange column. This was eluted with methanol followed by 2M methanolic ammonia solution.
  • the material so obtained was dissolved into acetic acid (3 ml) and heated at 90 0 C for 5 hours.
  • the resultant mixture was diluted with methanol and added to an SCX ion exchange column which was eluted with methanol followed by 2M methanolic ammonia solution.
  • the resulting solution was evaporated to dryness, dissolved in DMF (2 ml) and purified by X Bridge preparative chromatography.
  • the 3-amino-6-[3-methoxy-4-(2-pyrrolidin-l-ylethoxy)phenyl]pyrazine-2-carboxylic acid used as a starting material was prepared as follows :- l-(2-Chloroethyl)pyrrolidi ⁇ e (3.25 g) was added to a mixture of 2-methoxy-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (4.35 g), caesium carbonate (14.14 g) and DMF (80 ml) and the reaction mixture was heated to 75°C for 3 hours.
  • the resultant mixture was evaporated and the residue was partitioned between ethyl acetate and water.
  • the aqueous layer was extracted twice with ethyl acetate and the organic extracts were combined, dried with magnesium sulphate and evaporated.
  • the residue was purified by column chromatography using increasingly polar portions of methylene chloride and methanol as eluent.
  • ⁇ ATU (7.3 g) was added to a mixture of 3-amino-6-bromopyrazine-2-carboxylic acid (4 g), 1,2-phenylenediamine (2.07 g), triethylamine (3.8 ml) and DMF (40 ml) and the reaction mixture was stirred at ambient temperature for 1 hour. The resultant mixture was poured into aqueous sodium hydrogen carbonate solution and the resultant precipitate was isolated. The material so obtained was dissolved in acetic acid (20 ml) and heated to 90 0 C for 3 hours. The resultant mixture was evaporated and the residue was triturated under methylene chloride.
  • the mixture was allowed to cool and then partitioned between ethyl acetate (20 ml) and water (20 ml), the organic layer was collected, and the aqueous layer extracted with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine (20 ml), dried over magnesium sulfate, filtered and evaporated under reduced pressure.
  • the crude product was purified by flash silica chromatography (elution gradient 0 to 20% ethyl acetate in isohexane).
  • HATU (0.063 g) was added to a mixture of 3-[5-amin ⁇ -6-(lH-benzimidazol-2- yl)pyrazin-2-yl] benzoic acid (0.05 g), 3-piperidinopropylamine (0.024 g), triethylamine (0.032 mi) and DMF (3 ml) and the reaction mixture was stirred at ambient temperature for 12 hours.
  • Example 7 Using an analogous procedure to that described in Example 6, the appropriate amine was reacted with the appropriate benzoic acid to give the compounds described in Table in.
  • 3-Chloromethyl-l-methylpiperidine hydrochloride (0.051 g) was added to a mixture of 3-(lH-henzimidazol-2-yl)-5-(4-hydroxy-3-methoxyphenyl)pyrazin-2-amine (0.083 g), potassium carbonate (0.138 g) and DMA (2 ml). The reaction mixture was heated to 100 0 C for four hours. The mixture was cooled to ambient temperature and filtered.
  • the 3-( lH-benzimidazol-2-yl)-5-(4-hydroxy-3-methoxyphenyl)pyrazin-2-amine used as a starting material was prepared as follows :- 2-Methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (5.38 g) was added to a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (5.0 g) and potassium phosphate (16 g) in a 1:1:2 mixture of toluene: water:methanol (120 ml).
  • Formaldehyde (6.98 ⁇ l) was added to a mixture of 3-(lH-benzimidazol-2-yl)-5-(3- piperazin-l-ylphenyl)pyrazin-2-amine (0.023 g) and acetic acid (3.90 ⁇ l) in methanol (3 ml). The resultant solution was stirred at ambient temperature for 15 minutes, then sodium cyanoborohydride (0.005 g) was added. The resultant solution was stirred for a further 2 hours, then the solution was purified by SCX ion exchange chromatography. The desired product was eluted from the column using 7M ammonia in methanol and pure fractions were evaporated to dryness.
  • tert-butyl 2-[3-(bis(tert-butoxycarbonyl)amino)-6-[3-[3-(piperidin- l-yl)propoxyj- phenyl]pyrazin-2-yi]benzimidazole-l-carboxylate used as a reagent was prepared as follows: Di-tert-butyl dicarbonate (51.3 ml) was added to a mixture of 3-(lH-benzimidazol-2- yl)-5-bromo-pyrazin-2-amine (16.02 g), triethylamine (23.03 ml) and 4- dimethylaminopyridine (0.675 g) in THF (20 ml) under nitrogen.
  • the resultant solution was stirred at 70 0 C for 2 hours.
  • the reaction mixture was then evaporated to dryness and redissolved in ethyl acetate (100 ml), and washed sequentially with water (100 ml) and saturated brine (100 ml).
  • the organic layer was dried over magnesium sulfate, filtered and evaporated.
  • the crude material was purified by flash silica chromatography (elution gradient 10 to 20% ethyl acetate in isohexane).
  • Dichlorobis(triphenylphosphine)palladium(II) (0.059 g) was added to a mixture of tert-butyl 2-[3-(bis(tert-butoxycarbonyl)amino)-6-bromo-pyrazui-2-yl]benzimidazole-l- carboxylate (1.00 g), 3-hydroxyphenylboronic acid (0.304 g) and saturated sodium carbonate solution (1.694 ml) in DMF: DME: ethanol: water 2:7:2:1 (15 ml) at ambient temperature. The resultant mixture was stirred at 70 0 C for 1 hour.
  • the reaction mixture was then diluted with ethyl acetate (100 ml) and washed with water (100 ml). The aqueous layer was washed again with ethyl acetate (100 ml) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure.
  • the crude product was purified by flash silica chromatography (elution gradient 10 to 50% ethyl acetate in isohexane).
  • tert-Butyl 2-[3-(bis(tert-butoxycarbonyl)amino)-6-(3-hydroxyphenyl)pyrazin-2- yl]benzimidazole-l -carboxylate (0.420 g) was added to a mixture of l-bromo-3- chloropropane (0.344 ml) and potassium carbonate (0.481 g) in DMA (10 ml). The resultant mixture was stirred at 8O 0 C for 2 hours in a CEM microwave. The reaction mixture was then diluted with ethyl acetate (10 ml) and washed with water (10 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure.
  • Piperidine (0.3 ml) was added to a mixture of lithium iodide (0.016 g) and tert-butyl 2- [3-(bis(tert-butoxycarbonyl)amino)-6-[3-(3-chloropropoxy)phenyl]pyrazin-2- yl]benzimidazole-l -carboxylate (0.080 g) in DMA (1 ml) and the resultant mixture was stirred at 80 °C for 2 hours in a CEM microwave.
  • [4-(2-Pyrazol-l-yletho ⁇ y)phenyl]boronic acid (0.086 g) was added to a mixture of 5- bromo-3-(6- ⁇ uoro-lH-benzimidazol-2-yl)pyrazin-2-amine (0.075 g), 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.018 g) and caesium fluoride (0.111 g) in dioxane (1.2 ml) and water (0.3 ml) was degassed under nitrogen, then heated in a microwave for 2 hours at 110 0 C.
  • the 5-bromo-3-(6-fluoro-lH-benzimidazol-2-yl)pyrazin-2- amine used as a reagent was prepared as follows:
  • ⁇ ATU (4.2 g) was added to a mixture of 3-aminopyrazine-2-carboxylic acid (1.39 g), 1 ,2-diamine-4-fluoro-benzene ( 1.26 g) and Diisopropylethylam ⁇ ne (DIEA) ( 1.7 ml) in DMF (50 ml).
  • DIEA Diisopropylethylam ⁇ ne
  • N-Bromosuccinimide (0.17 g) was added to a mixture of 3-(6-fluoro-lH- benzimidazol-2-yl)pyrazin-2-amine (0.2 g) in T ⁇ F (5 ml). The reaction mixture was stirred at ambient temperature for 1 hour. Saturated sodium sulfite solution (10 ml) was added and the resultant mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure and then purified by flash column chromatography (eluting with a pentanerethyl acetate 10:1 mixture).

Abstract

La présente invention concerne des dérivés de pyrazine de formule (I) ou un sel pharmaceutiquement acceptable de ceux-ci, chacun des symboles G1, G2, R1, m, R2, R3, n et R4 ayant les significations définies précédemment dans la description. L'invention concerne des procédés de leur préparation, des compositions pharmaceutiques les contenant et leur utilisation pour la fabrication d'un médicament destiné au traitement de troubles de prolifération cellulaire.
PCT/EP2008/058898 2007-07-09 2008-07-09 Dérivés de pyrazine - 954 WO2009007390A2 (fr)

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