WO2009024825A1 - 2-pyrazinylbenzimidazole derivatives as receptor tyrosine kinase inhibitors - Google Patents

2-pyrazinylbenzimidazole derivatives as receptor tyrosine kinase inhibitors Download PDF

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WO2009024825A1
WO2009024825A1 PCT/GB2008/050726 GB2008050726W WO2009024825A1 WO 2009024825 A1 WO2009024825 A1 WO 2009024825A1 GB 2008050726 W GB2008050726 W GB 2008050726W WO 2009024825 A1 WO2009024825 A1 WO 2009024825A1
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alkyl
piperidin
ethyl
piperazin
amino
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PCT/GB2008/050726
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French (fr)
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Bernard Christophe Barlaam
Claudio Edmundo Chuaqui
Benedicte Delouvrie
Gilles Ouvry
Tao Wang
Jon James Gordon Winter
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority claimed from GB0716278A external-priority patent/GB0716278D0/en
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2009024825A1 publication Critical patent/WO2009024825A1/en

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    • 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
    • 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
    • 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
    • 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

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 (Schlessinger, 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 Tyro 12).
  • 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 (Gas6).
  • the affinity of Gas6 for these receptors is Axl>Tyro3>Mer (Nagata et al, 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 et al., MoI. Cell. Biol., 1991, 11, 5031).
  • the AxI receptor has been shown to be overexpressed in primary colon (Craven et al, Int. J. Cancer., 1995, 60, 791), gastric (Sawabu et al., MoI.
  • Gas6/Axl signalling has been shown to have roles in proliferation, protection from apoptosis, angiogenesis and invasion.
  • the gene encoding for AxI has been shown to transform both NIH-3T3 fibroblasts, enabling them to grow as xenografts in nude mice (O 'Bryan et al, MoI. Cell. Biol, 1991, 11, 5031), and IL-3 dependent hematopoietic 32D cells, enabling IL-3 independent growth (McCloskey et al, Cell Growth Differ., 1994, 5, 1105).
  • Gas6/Axl signalling has also been shown to have a weak mitogenic effect in mouse NIH-3T3 fibroblasts (Goruppi et al, Oncogene, 1996, 12, 471), human C57MG mammary carcinoma cells (Goruppi et al, MoI Cell Biol, 2001, 21, 902) and human DU 145 and PC3 prostate carcinoma cells (Sainaghi et al, J. Cell. Physiol, 2005, 204, 36).
  • AxI protein has been shown to disrupt CL 1-5 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, Cancer Res., 2005, 65, 9294). Furthermore, inhibition of the AxI protein by either knockdown of protein levels (Holland et al, Cancer Res., 2005, 65, 9294) or transfection of a dominant negative AxI mutant gene (Vajkoczy et al, Proc. Natl. Acad. ScL USA, 2006, 103, 5799) has been shown to suppress xenograft growth in vivo.
  • AxI RTKs have also been shown to have roles in immunity (Lu et al, Science, 2001, 293, 306), platelet function (Angelillo-Scherrer et al, Nat. Med., 2001, 7, 215), spermatogenesis (Lu et al, Nature, 1999, 398, 723), vascular calcification (Son et al, Eur. J. Pharmacol, 2007, 556, 1), thrombin induced vascular smooth muscle cell (VSMC) proliferation (Nakano et al, J. Biol.
  • kidney diseases for example acute and chronic glomerulonephritis, diabetic nephropathy and chronic allograft rejection (Yanagita et al, J. Clin. Invest., 2002, 110, 239).
  • 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), MoI. 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 ⁇ Bardelli, 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).
  • c-Met activation promotes tumour growth and metastatic spread.
  • 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.
  • tumour carcinoma or tumour endothelial cells express c-Met but not HGF, which is produced by the surrounding stroma.
  • 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. and Danilkovitch-Miagkova et al.) and, at present, 21 mutations have been described. The majority are localised within the kinase domain and are believed to convert c-Met into a constitutively active form. More recently, a number of additional mutations have been found in other types of primary cancer and metastatic lesions (Lorenzato, A., et al. (2002), Cane. Res. 62, 7025-7030).
  • mice expressing c-Met or HGF as a transgene in specific tissues ultimately develop a broad array of aggressively invasive tumours and metastatic lesions ⁇ Wang, R., et al. (2001), J. Cell Biol. 153, 1023-1034; Gallego, M.,et al. (2003), Oncogene 22, 8498-8508; and Takayama, K, et al. (1997), Proc. Natl. Acad.
  • 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. Additionally, the role of c-Met and HGF in tissue remodelling, particularly in the lungs and liver has also been demonstrated ⁇ Michalopoulos, G. & DeFrances, M.
  • 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 Gi and G 2 is selected from CH and N provided that both are not N;
  • Ring A is a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
  • R 1 is a group of the formula: R 5 -X !
  • X 1 is a direct bond or is selected from O, S, SO, SO 2 , N(R 6 ), CO, CH(OR 6 ), CON(R 6 ), N(R 6 )C0, N(R 6 )CON(R 6 ), SO 2 N(R 6 ), N(R 6 )SO 2 , C(R 6 ) 2 O, OC(R 6 ) 2 , C(R 6 ) 2 S, SC(R 6 ) 2 , C(R 6 ) 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,
  • 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)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)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; m
  • (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-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 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-cyclopropylethoxy, cyclobutylmethoxy, 2- cyclobutylethoxy and cyclopentylmethoxy;
  • (l-6C)alkylamino includes (3- 6C)cycloalkylamino groups and 7V-(cycloalkylalkyl)amino groups having 4 to 6 carbon atoms, for example methylamino, ethylamino, propylamino, cyclopropylamino, cyclobutylamino, cyclohexylamino,
  • (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”, “(1- 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, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, tetrahydro- 1 ,4-thiazinyl, 1 , 1 -dioxotetrahydro- 1 ,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclo[2.2.1
  • 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.
  • a suitable value for Ring A when it is a 5- or 6-membered monocyclic or a 9- or 10- membered bicyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur is, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalin
  • Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur and a suitable value for Ring A is, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl.
  • Ring A is a pyrazolyl or pyridinyl ring. In a further particular group of compounds of the Formula I, Ring A is a pyrazol-4-yl or pyridin-3-yl ring. In yet a further particular group of compounds of the Formula I, Ring A is a pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl ring. In yet a further particular group of compounds of the Formula I, Ring A is a pyrazolyl ring. In yet a further particular group of compounds of the Formula I, Ring A is a pyrazol-4-yl ring.
  • a suitable value for the heterocyclyl group within the 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, 1,1- dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclo[2.2.1]heptyl, qui
  • heterocyclyl ring When Q 1 is an optionally substituted heterocyclyl or heterocyclyl-(l-6C)alkyl, particular examples of the heterocyclyl ring include piperidinyl, piperazinyl and especially piperidin- 4-yl and piperazin-1-yl.
  • heterocyclyl ring when Q 1 is an optionally substituted heterocyclyl or heterocyclyl-(l-6C)alkyl, particular examples of the heterocyclyl ring include piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl and especially piperidin-4-yl, piperidin-3-yl, piperazin-1-yl, morpholin-4-yl and tetrahydropyran-4-yl.
  • Q 1 comprises a heterocyclyl-(l-6C)alkyl substituent group on the heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl ring
  • particular values for the heterocyclyl within the heterocyclyl-(l-6C)alkyl substituent group include tetrahydrofuranyl, tetrahydropyranyl and especially tetrahydrofuran-4-yl or tetrahydropyran-4-yl.
  • a suitable value for the heteroaryl group within the R 1 or R 4 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, benzofurazanyl, quinolyl,
  • R 4 contains an optionally substituted heteroaryl or heteroaryl-(l-6C)alkyl group
  • heteroaryl ring include isoxazolyl and especially isoxazol-3-yl.
  • a suitable value for the aryl group within any R 1 or R 4 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 a heterocyclyl-(l-6C)alkyl is, for example, heterocyclylmethyl, 2-heterocyclylethyl and 3-heterocyclylpropyl.
  • the invention comprises corresponding suitable values 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)cycloalkyl-(l-6C)alkyl group is present.
  • a suitable value for any heterocyclyl group within the R 3 or R 4 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, 1,1- dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclo[2.2.1]heptyl, qui
  • a particular example of a heterocyclyl ring within the R 4 group is, for example, tetrahydrofuranyl and especially tetrahydrofuran-3-yl.
  • the heterocyclyl ring within the R 4 group is, for example, tetrahydrofuranyl or pyrrolidinyl and especially tetrahydrofuran-3-yl or pyrrolidin-3-yl.
  • Suitable values for any of the 'R' groups (R 1 to R 4 ), or for various groups such as R 5 to R 9 within an R 1 substituent or for various groups such as R 10 within a R 3 group and R 1 ⁇ within a R 4 group include, for example :-
  • TV-methyl-TV' ,TV' -diethylureido for TV-(I -6C)alkylsulphamoyl: TV-methylsulphamoyl and TV-ethylsulphamoyl; io for TV,TV-di-[(l-6C)alkyl]sulphamoyl: TV,TV-dimethylsulphamoyl; for (l-6C)alkanesulphonylamino: methanesulphonylamino and ethanesulphony lamino ; for TV-( 1 -6C)alkyl-( 1 -6C)alkanesulphonylamino : TV-methylmethanesulphonylamino and
  • TV-methy lethanesulphony lamino is for halogeno-(l-6C)alkyl: chloromethyl, 2-fluoroethyl, 2-chloroethyl,
  • amino-(l-6C)alkyl aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl and 5- aminopropyl; for ( 1 -6C)alkylamino-( 1 -6C)alkyl: methylaminomethyl, ethylaminomethyl,
  • 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 Ring A and the oxygen atom is attached to the R 5 group.
  • an R 1 group forms a group of the formula Q 1 X 2 or of the formula Q 2 X 2 and, for example, X 2 is a OC(R 8 ) 2 linking group, it is the oxygen atom of the OC(R 8 ) 2 linking group which is attached to the Q 1 or Q 2 group.
  • 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, cyanomethylaminomethyl, 2-cyanoethylaminomethyl, 2-hydroxyethylaminomethyl, 2- methoxyethylaminomethyl, 2-trifluoromethylaminoethyl, 2-(2-hydroxyethylamino)ethyl and 2-(2-methoxyethylamino)ethyl.
  • a suitable value for a di-(R 7 )-amino-(l- 6C)alkyl group or an di-(R 9 )-amino-(l-6C)alkyl group is, for example, di-(2- hydroxyethyl)aminomethyl and di-(2-methoxyethyl)aminomethyl.
  • a suitable value for a (R 10 ) p -(l-8C)alkyl group is, for example, chloromethyl, 2-fluoroethyl, 2-chloroethyl, 1-chloroethyl, 2,2- difiuoroethyl, 2,2,2-trifluoroethyl, 3-fiuoropropyl, 3-chloropropyl, 3,3-difiuoropropyl, 3,3,3-trifluoropropyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 2- hydroxyethyl, 3-hydroxypropyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3- methoxypropyl, 2-aminoethyl, 3-aminopropyl, 5-aminopropyl, 2-methylaminoethyl, 2- ethylamin
  • a suitable value for a (R 10 ) p -(2-8C)alkynyl group is, for example, A- dimethylaminobut-2-ynyl and 4-(heterocyclyl)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, dime thy lamine, 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 I 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. Accordingly, 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.
  • 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.
  • Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, 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- 191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews. 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al, Chem. Pharm. Bull, 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.
  • 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-hvXy ⁇ , (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 1-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 est
  • 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 (1- 10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-[di-( ⁇ - 4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • (1- 10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups
  • (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-[di-( ⁇ - 4C)alkyl] 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, 7V-ethyl-7V-methylamine or diethylamine, a (l-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(l-4C)alkylamine such as benzylamine 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, 7V-ethyl-7V-methylamine or diethylamine
  • 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 aminomethyl, N- alkylaminomethyl, 7V,7V-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)alkylpiperazin-l-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 prodrug).
  • 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 , Ring A, m, n, R 1 , R 2 , R 3 and R 4 has any of the meanings defined hereinbefore or in paragraphs (a) to (iii) hereinafter: -
  • Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
  • Ring A is a 5- membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
  • Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three nitrogen atoms;
  • Ring A is a 5- membered monocyclic heteroaryl ring with up to three nitrogen atoms;
  • Ring A is a 6- membered monocyclic heteroaryl ring with up to three nitrogen atoms;
  • Ring A is furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;
  • Ring A is pyrazolyl or pyridinyl; (1) Ring A is pyrazol-4-yl or pyridin-3-yl;
  • 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, (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,s wherein any heterocyclyl or heteroaryl group within a R 8 ,
  • 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)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)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:
  • 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 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-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 1 substitu
  • R 1 is a group of the formula:
  • R ⁇ 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 ) 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, ( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[( 1 -6C)alkyl] amino-( 1 -6C
  • 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 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-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 1 substitu
  • 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 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 , 2 or 3 substituents independently selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l-6C)
  • R 1 is a group of the formula:
  • X 1 is a direct bond or is selected from O, SO 2 , N(R 6 ), CO, CON(R 6 ), N(R 6 )C0,
  • 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)alkoxy,
  • 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 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-3C)alkyl, heteroaryl, heteroaryl-(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
  • R 1 is a group of the formula:
  • 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 7 is (l-6C)alkyl; or 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)alkoxy, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, halogeno-(l-6C)alkyl, amino-(l-6C)alkyl, ( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[( 1 -6C)alkyl] amino-( 1 -6C)alkyl, ( 1 -6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, TV-(I -6C)alkylcarb
  • 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 or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl or piperazinyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl,
  • R 1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2-
  • R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, and when Ring A is pyridin-3-yl, R 1 is aminomethoxy
  • R 1 is 1 -(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1 -(l-ethylpiperidin-4-yl), 1 -(l-acetylpiperidin-4-yl), 1 -[I -(2-hydroxyethyl)piperidin-4-yl], l- ⁇ l-[2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ (that is each R 1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R 1 is 6-[3-(dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6- (4-methylpiperaz
  • each R 2 group may be the same or different, and each R 2 group present is selected from halogeno, cyano, hydroxy, amino, (1- 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)alkylsulphinyl, (1-
  • 6C)alkylsulphonyl (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, N-(l-6C)alkylcarbamoyl, N,N-di-[( ⁇ - 6C)alkyl]carbamoyl and (2-6C)alkanoylamino;
  • (aa) m is 0 or 1, and when m is 1, the R group present 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, (1- 6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, TV-(I -6C)alkylcarbamoyl, 7V,7V-di-[(l-6C)alkyl]carbamoyl and
  • R 3 is hydrogen, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (R 10 ) 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, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2- 8C)alkynyl and (l-6C)alkoxy; (ff) R 3 is hydrogen, (l-8C)alkyl
  • R 4 is selected from hydrogen, fluoro, chloro, amino, trifluoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy;
  • n 0 or n is 1 and R 4 is selected from hydrogen, fluoro, methoxy, phenylmethoxy or oxolan-3-ylmethoxy;
  • Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is a group of the formula:
  • 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)alkylamino-(l- 3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)alkyl, (R 7 )-amino-(l-3C)alkyl, di-[(R 7 )-amino-(l-
  • 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, 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 or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy,
  • 6C)alkyl halogeno-( 1 -6C)alkyl, amino-( 1 -6C)alkyl, ( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino,
  • R 1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, ethylaminomethyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, diethylaminomethyl, 2-(diethylamino)ethy
  • each R 4 group present may be the same or different, and each R 4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy;
  • Gi is CH and G 2 is N or Gi is N and G 2 is CH;
  • (yy) Ring A is pyrazolyl;
  • (zz) Ring A is pyrazol-4-yl;
  • Ring A is pyridin-3-yl or pyridin-4-yl;
  • Ring A is pyrazol-4-yl, R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl,
  • R 1 is 1 -(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1- ( l-ethylpiperidin-4-yl), 1 -(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4- yl], 1 - ⁇ 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , 1 - ⁇ 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl ⁇ , l-[2-(morpholin-4-yl)ethyl], 1 -(piperidin-4-ylmethyl), 1 -(piperidin-3-ylmethyl), 1 -(piperidin-3-yl), 1 -(tetrahydropyran-4-yl) or l-(4-a
  • R 1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R 1 is 6-[3-(dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l- yl), 6-(4-methylpiperazin-l-yl), 5-(l-methylpiperidin-4-ylcarbamoyl), 5-[3-(4- methylpiperazin-l-yl)propylcarbamoyl] or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R 1 group is located at the stated 5- or 6- position on the pyridin-3-yl ring), and when Ring A is pyridin-4-yl, R 1 is 2-(piperazin-l-yl); (ddd) When Ring A is pyrazol-4-yl, R 1 is l-(piperidin-4-yl), l-(l-
  • (fff) m is 0 or 1 , and when m is 1 , the R group is methyl;
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl;
  • n is 0, 1 or 2, and, when n is 2, each R 4 group present may be the same or different, and each R 4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3-ylmethoxy, methyl, chloro, bromo, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isoxazol-3-ylmethoxy or cyclopropylmethoxy; or (iii) n is 0 or 1 and, when n is 1, R 4 is selected from hydrogen, fluoro, oxolan-3- ylmethoxy, (tetrahydrofuran-2-yl)methoxy or cyclopropylmethoxy.
  • a particular compound of the invention is selected
  • Gi and G 2 are both CH or Gi is N and G 2 is CH;
  • Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
  • 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 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-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 1 substitu
  • 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)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 (1- 6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy;
  • R 11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl, wherein any aryl, heterocyclyl or heteroaryl group within the definition of R 11 optionally bears 1, 2 or 3 substituents independently selected from halogeno, trifluoromethyl, oxo, cyano, hydroxy, amino, carboxy, carbamoyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (l-6C)alkoxy; 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 or Gi is N and G 2 is CH; Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three nitrogen atoms; R 1 is a group of the formula:
  • R ⁇ 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 ) 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,
  • R 1 is a group of the formula: Q 1 X 2 wherein 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 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N
  • R 3 is hydrogen, methyl, ethyl, propyl or (R 10 )-(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,
  • R 4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR 11 , N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-
  • a further particular compound of the invention is a pyrazine derivative of the
  • Ring A is pyrazolyl or pyridinyl
  • R 1 is a group of the formula:
  • 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 1 is (1 -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 or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl or piperazinyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl,
  • R 3 is hydrogen, methyl, ethyl or propyl; n is O or 1 and when n is 1, R 4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR 1 ! , TV-(I -6C)alkylsulphamoyl, 7V,7V-di-[(l -6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, TV,TV-di-[(l- 6C)alkyl]carbamoyl and (2-6C)alkanoylamino, wherein R 11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C
  • 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; Ring A is pyrazolyl or pyridinyl; 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 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 or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy,
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: -
  • Gi is CH and G 2 is N or Gi is N and G 2 is CH;
  • Ring A is pyrazolyl or pyridinyl;
  • 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 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 or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy,
  • (2-6C)alkanoyl TV-(I -6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l- 6C)alkyl group, wherein said heterocyclyl within the heterocyclyl-(l-6C)alkyl substituent group is selected from tetrahydrofuranyl or tetrahydropyranyl; m is O 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, halogeno-(l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)al
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0 or 1 and when n is 1, R 4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR 11 , N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, 7V,7V-di-[(
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: - Ring A is pyrazolyl or pyridinyl; 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 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 or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy,
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0 or 1 and when n is 1, R 4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR 11 , /V-(l-6C)alkylsulphamoyl, /V,/V-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, /V,/V
  • a further particular compound of the invention is a pyrazine derivative of the
  • Ring A 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 1 is suitably as defined in any one of paragraphs (m) to (w) above and is particularly as defined in any one of paragraphs (q) to (w) above;
  • R 2 is suitably as defined in any one of paragraphs (x) to (dd) above, and is particularly as defined in any one of paragraphs (aa) to (dd) above;
  • R 3 is suitably as defined in any one of paragraphs (ee) to (jj) above, and is particularly as defined in any one of paragraphs (gg) to (jj) above; and
  • R 4 is suitably as defined in any one of paragraphs (kk) to (pp) above, and is particularly as defined in any one of paragraphs (nn) to (pp) above.
  • a yet further particular compound of the invention is a pyrazine derivative of the
  • Gi and G 2 are suitably as defined in any one of paragraphs (a) to (d) above;
  • Ring A is suitably as defined in any one of paragraphs (e) to (1) and (qq) above and is particularly as defined in any one of paragraphs (g) to (1) and (qq) above;
  • R 1 is suitably as defined in any one of paragraphs (m) to (w) and (rr) to (uu) above and is particularly as defined in any one of paragraphs (q) to (w) and (rr) to (uu) above;
  • R is suitably as defined in any one of paragraphs (x) to (dd) above, and is particularly as defined in any one of paragraphs (aa) to (dd) above;
  • R 3 is suitably as defined in any one of paragraphs (ee) to (jj) and (w) above, and is particularly as defined in any one of paragraphs (gg) to (jj) and (w) above;
  • R 4 is suitably as defined in any one of paragraphs (kk) to (pp) and (ww) above, and is particularly as defined in any one of paragraphs (nn) to (pp) and (ww) above.
  • a yet 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) and (xx) above;
  • Ring A is suitably as defined in any one of paragraphs (e) to (1) and (qq) and (yy) to (aaa) above and is particularly as defined in any one of paragraphs (g) to (1) and (qq) and (yy) to
  • R 1 is suitably as defined in any one of paragraphs (m) to (w) and (rr) to (uu) and (bbb) to
  • R 2 is suitably as defined in any one of paragraphs (x) to (dd) above and (fff), and is particularly as defined in any one of paragraphs (aa) to (dd) and (fff) above;
  • R 3 is suitably as defined in any one of paragraphs (ee) to (jj) and (w) and (ggg) above, and is particularly as defined in any one of paragraphs (gg) to (jj) and (w) and (ggg) above;
  • R 4 is suitably as defined in any one of paragraphs (kk) to (pp) and (ww) and (hhh) and (iii) above, and is particularly as defined in any one of paragraphs (nn) to (pp) and (ww) and (hhh) and (iii) above.
  • a further particular compound of the invention is a pyrazine derivative of the
  • R 1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2-
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazolyl or pyridinyl; R 1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, ethylaminomethyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, diethylaminomethyl, 2-(diethylamino)ethyl, 3-(diethylamino)propyl aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi is CH and G 2 is N or Gi is N and G 2 is CH;
  • Ring A is pyrazolyl or pyridinyl
  • R 1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2-
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2-
  • R 4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentyloxy
  • a further particular compound of the invention is a pyrazine derivative of the
  • R 1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2-
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Ring A is pyrazol-4-yl or pyridin-3-yl
  • R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, l-[3-(oxan-4-yl)propyl]piperidin-4-yl, l-[2-(oxolan-3- yl)ethyl]piperidin-4-yl or l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, and when Ring A is pyridin-3-yl, R 1 is aminomethoxy, 2-(
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, l-(3-hydroxypropyl)piperidin-4-yl, l-[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2- (tetrahydrofuran-2-yl)ethyl or (3-methyloxetan-3-yl)methyl; n is 0 or n is 1 and R 4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl,
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi is CH and G 2 is N or Gi is N and G 2 is CH; 30 Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl]piperidin-4-yl, 2-
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, l-(3-hydroxypropyl)piperidin-4-yl, l-[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl]piperidin-4
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is located at the 1 position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, 1- acetylpiperidin-4-yl, l-(2-hydroxyethyl)piperidin-4-yl, l-(3-hydroxypropyl)piperidin-4-yl, 1 - [2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - [3 -(tetrahydropyran-4- yl)propyl]piperidin-4-yl, l-(tetrahydrofuran-3-ylmethyl)piperidin-4-yl, l-[2-
  • R 1 is located at the 5- or 6- position and is selected from 2-(amino)ethoxy, 3- (amino)propoxy, 2-(methylamino)ethoxy, 3-(methylamino)propoxy, 2-
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Ring A is pyrazol-4-yl or pyridin-3-yl; When Ring A is pyrazol-4-yl, R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl),
  • R 3 is hydrogen; n is 0 or n is 1 and R 4 is selected from hydrogen, fluoro, methoxy, phenylmethoxy or oxolan-3-ylmethoxy; 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 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , 1 - ⁇ 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ , 1 -[2- (morpholin-4-yl)ethyl], l-(piperidin-4-ylmethyl), l-(piperidin-3-ylmethyl)
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R 4 group present may be the same or different, and each R 4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmeth
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ , l-[2-
  • R 1 is 6-[3- (dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l- yl), 5-(l-methylpiperidin-4-ylcarbamoyl), 5-[3-(4-methylpiperazin-l-yl)propylcarbamoyl] or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R 1
  • 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;
  • Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1-
  • R 1 is 6-[3- (dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l- yl), 5-(l -methylpiperidin-4-ylcarbamoyl), 5-[3-(4-methylpiperazin- 1 -yl)propylcarbamoyl] or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R 1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R 1 is 6-[3- (dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l- yl), 5-(l -methylpiperidin-4-ylcarbamoyl), 5-[3-(4-methylpiperazin- 1 -y
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R 4 group present may be the same or different, and each R 4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol-
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ , l-[2-
  • R 1 is 6-[3- (dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l- yl), 5-(l -methylpiperidin-4-ylcarbamoyl), 5-[3-(4-methylpiperazin-l-yl)propylcarbamoyl] or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R 4 group present may be the same or different, and each R 4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmeth
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Ring A is pyrazol-4-yl
  • R 1 is l-(l-methylpiperidin-4-yl); m is 0; R 3 is hydrogen; n is 0; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the
  • Ring A is pyrazol-4-yl
  • R 1 is l-(l-methylpiperidin-4-yl) or l-(piperidin-4-yl); m is 0;
  • R 3 is hydrogen; n is 0; 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 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , 1 - ⁇ 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ , 1 -[2- (morpholin-4-yl)ethyl], l-(piperidin-3-yl), l-(tetrahydropyran-4-
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi is CH and G 2 is N or Gi is N and G 2 is CH;
  • Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ , l-[2- (morpholin-4-yl)ethyl], l-(piperidin-3-yl), l-(tetrahydropyran-4-yl) or l-(4- aminocyclohex-1-yl) (that is each R 1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R 4 group present may be the same or different, and each R 4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, methyl, chloro, bromo, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2- yl)methoxy, (isoxazol-3-ylmethoxy) or cyclopropylmethoxy; or a pharmaceutically- acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , 1 - ⁇ 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ , 1 -[2- (morpholin-4-yl)ethyl], l-(piperidin-3-yl), l-((piperidin-3-yl),
  • a further particular compound of the invention is a pyrazine derivative of the
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl or pyridin-3-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ or 1- (tetrahydropyran-4-yl) (that is each R 1 group is located at the 1 -position on the pyrazol-4- yl ring), and when Ring A is pyridin-3-yl
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethylcyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R 4 is selected from hydrogen, fluoro, oxolan-3-ylmethoxy,
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi is CH and G 2 is N or Gi is N and G 2 is CH; Ring A is pyrazol-4-yl or pyridin-3-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ or 1- (tetrahydropyran-4-yl) (that is each R 1 group is located at the 1 -position on the pyrazol-4- yl ring), and when Ring A is pyridin-3-yl, R 1 is 6-[3-(dimethylamino)propoxy], (that is each R 1 group is located at the stated 6- position on the pyri
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethylcyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R 4 is selected from hydrogen, fiuoro, oxolan-3-ylmethoxy, (tetrahydrofuran-2-yl)methoxy and cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1-
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethylcyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R 4 is selected from hydrogen, fiuoro, oxolan-3-ylmethoxy,
  • a further particular compound of the invention is a pyrazine derivative of the
  • Ring A is pyrazol-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), l-(l-ethylpiperidin-4-yl), 1-(1- acetylpiperidin-4-yl), 1 -[ 1 -(2-hydroxyethyl)piperidin-4-yl] , 1 - ⁇ 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ or l-(tetrahydropyran- 4-yl) (that is each R 1 group is located at the 1 -position on the pyrazol-4-yl ring); m is 0 or 1 , and when m is 1 , the R 2 group is methyl;
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R 4 is selected from fiuoro, oxolan-3-ylmethoxy, (tetrahydrofuran-2-yl)methoxy or cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi is CH and G 2 is N or Gi is N and G 2 is CH; Ring A is pyrazol-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), l-(l-ethylpiperidin-4-yl), 1-(1- acetylpiperidin-4-yl), 1 -[ 1 -(2-hydroxyethyl)piperidin-4-yl] , 1 - ⁇ 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ or l-(tetrahydropyran- 4-yl) (that is each R 1 group is located at the 1 -position on the pyrazol-4-yl ring); m is 0 or 1 , and when m is 1 , the R 2 group is methyl;
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R 4 is selected from fiuoro, oxolan-3-ylmethoxy,
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Ring A is pyrazol-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), l-(l-ethylpiperidin-4-yl), 1-(1- acetylpiperidin-4-yl), 1 -[ 1 -(2-hydroxyethyl)piperidin-4-yl] , 1 - ⁇ 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ or l-(tetrahydropyran- 4-yl) (that is each R 1 group is located at the 1 -position on the pyrazol-4-yl ring); m is 0 or 1 , and when m is 1 , the R 2 group is methyl;
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R 4 is selected from fiuoro, oxolan-3-ylmethoxy, (tetrahydrofuran-2-yl)methoxy or cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl or pyridin-3-yl; When Ring A is pyrazol-4-yl, R 1 is located at the 1 -position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - (tetrahydrofuran-3-ylmethyl)piperidin-4-yl and tetrahydropyran-4-yl, and when Ring A is pyridin-3-yl, R 1 is located at the 6- position and is 3-(dimethylamino)propoxy; m is 0; R 3 is hydrogen, methyl,
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl or pyridin-3-yl; When Ring A is pyrazol-4-yl, R 1 is located at the 1 -position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - (tetrahydrofuran-3-ylmethyl)piperidin-4-yl and tetrahydropyran-4-yl, and when Ring A is pyridin-3-yl, R 1 is located at the 6- position and is 3-(dimethylamino)propoxy; m is 1 , and R 2 is methyl;
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0, or, when each of Gi and G 2 is CH, n may be 1 and the (R 4 ) n group is selected from 5-fiuoro, 4-tetrahydrofuran-3-ylmethoxy, 4-[(tetrahydrofuran-2-yl)methoxy] and A- cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
  • Particular compounds of the invention are, for example, the pyrazine derivatives of the Formula I that are disclosed within the Examples that are set out hereinafter.
  • a particular compound of the invention is a pyrazine derivative of the
  • a further particular compound of the invention is a pyrazine derivative of the Formula I selected from any one of the following :-
  • a further particular compound of the invention is a pyrazine derivative of the
  • a yet further particular compound of the invention is a pyrazine derivative of the Formula I 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 the following representative process variants in which, unless otherwise stated, G 1 , G 2 , Ring A, 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
  • 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 IV
  • 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 chloro formate such as isobutyl chloro formate; an active ester, for example an ester formed by the reaction of the acid with a phenol such as pentafiuorophenol, 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 diphen
  • 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.
  • 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
  • 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, ⁇ /-dimethylformamide, N,N
  • the reaction is conveniently carried out at a temperature in the range, for example, 0 to 120 0 C, conveniently at or near ambient temperature.
  • an active ester for example an ester formed by the reaction of the acid with an alcohol such as methanol, ethanol, isopropanol, butanol or tert- butanol
  • the reaction is conveniently carried out in the presence of a dipolar aprotic solvent such as 7V,7V-dimethylformamide or 7V,7V-dimethylacetamide at a temperature in the range, for example, 50 to 150 0 C, conveniently at or near 150 0 C.
  • a suitable base such as an alkali or alkaline earth metal (l-6C)alkoxide such as sodium methoxide is used.
  • 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 110 0 C.
  • Pyrazine carboxylic acids of the the Formula II, 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
  • R 2 L wherein each of L 1 and L 2 , which may be the same or different, is a suitable ligand for the boron atom and Ring A, 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 and L 3 is hydrogen or a protecting group such as methyl, whereafter any protecting group that is present is removed.
  • a suitable value for the ligands L 1 and L 2 which are present on the boron atom of the organoboron reagent include, for example, a hydroxy, (l-4C)alkoxy 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 2 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)palladium(0), palladium(II) chloride, palladium(II) bromide, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)nickel(0), nickel(II) chloride, nickel(II) bromide, bis(triphenylphosphine)nickel(II) chloride or [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(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-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 7V,7V-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 0 C.
  • a suitable inert solvent or diluent for example 7V,7V-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 0 C.
  • 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 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, 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 alkali or alkaline earth metal fluoride, for example caesium fluoride, 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 alkali or alkaline earth metal fluoride, for example caesium fluoride, 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 7V,7V-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 0 C.
  • a suitable inert solvent or diluent for example 7V,7V-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 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 wherein L is a displaceable group as defined hereinbefore and PG is a protecting group, with an organoboron reagent of the Formula V
  • R 2 L wherein 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 Ring A, 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 3-chloroperbenzoic acid or a mixture of oxone and acetone, at a suitable temperature such as 0 to 100 0 C, and in a solvent such as tetrahydrofuran.
  • a suitable oxidising agent such as 3-chloroperbenzoic acid or a mixture of oxone and acetone
  • 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 7V-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 30 0 C.
  • 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
  • L is a displaceable group as defined hereinbefore and 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, 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.
  • Synthetic procedures for forming heteroarylboron reagents from heteroaryl halides are well known in the art, for example, 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°C, conveniently in the range 0 to 30 0 C.
  • a boron reagent such as bis(pinacolato)diboron or diborane
  • a suitable base such as pyridine or triethylamine
  • a solvent such as tetrahydrofuran
  • L is a displaceable group as defined hereinbefore and 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, with an organoboron reagent of the Formula V
  • R 2 L wherein 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 Ring A, 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 alkali or alkaline earth metal fluoride, for example caesium fluoride, 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 alkali or alkaline earth metal fluoride, for example caesium fluoride, 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 7V,7V-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 0 C.
  • a suitable inert solvent or diluent for example 7V,7V-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 0 C.
  • L is a displaceable group as defined hereinbefore, may be reacted with a 1 ,2- diamine of the Formula III
  • 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 trie thy lamine, in a solvent such as N, ⁇ /-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 XI may be produced by reacting a carboxylic acid, or a reactive derivative thereof as defined hereinbefore, of the Formula XIIa
  • a halogenating agent for example a brominating agent, such as for example bromine or N-bromosuccinimide to form a compound of the Formula XI, whereafter any protecting group that is present is removed.
  • a carboxylic acid of the Formula XIIa 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 trie thy lamine, in a solvent such as N, ⁇ /-dimethylformamide and a temperature in the range of 0 to 150 0 C, conveniently at or near ambient temperature.
  • an amide coupling reagent such as a uronium compound such as 2-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexaflu
  • Cyclisation of the resultant amide product to form a compound of the Formula XIa 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 0 C.
  • a suitable organic acid such as acetic acid
  • halogenation of compound XIa is suitably carried out in the presence of a solvent or diluent such as for example, N, ⁇ /-dimethylformamide, tetrahydrofuran, 1,4-dioxan, 1 ,2-dimethoxyethane, benzene, or halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example -50 0 C to 100 0 C, preferably in the range 0 0 C to 30 0 C.
  • a solvent or diluent such as for example, N, ⁇ /-dimethylformamide, tetrahydrofuran, 1,4-dioxan, 1 ,2-dimethoxyethane, benzene, or halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example -50 0 C to 100 0 C
  • Ring A, 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, 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, 7V-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.
  • an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, 7V-methylmorpholine or diazabicyclo[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 N, ⁇ /-dimethylformamide
  • 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 , G 2 , R J , n and R 4 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
  • R 2 L wherein 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.
  • 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 7V,7V-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 0 C.
  • a suitable inert solvent or diluent for example 7V,7V-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 0 C.
  • Compounds of the Formula XVI 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.
  • Q 1 - NH(R S ) ⁇ v ⁇ wherein Q 1 and R 8 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a carboxylic acid of the Formula XV or a reactive derivative thereof as defined hereinbefore, wherein Ring A, m, R 2 , 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, whereafter any protecting group that is present is removed.
  • the 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.
  • Compounds of the Formula XVII 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.
  • Q 1 is a heterocyclyl or heteroaryl group as 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 diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium bicarbonate, 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 diazabicyclo[5.4.0]undec-7-ene
  • an alkali or alkaline earth metal carbonate or hydroxide for example sodium bicarbonate, 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, ⁇ /-dimethylformamide
  • L is a displaceable group as defined hereinbefore and 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, with an organoboron reagent of the Formula XX wherein L is a displaceable group as defined hereinbefore and 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 Ring A, 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 7V,7V-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 0 C.
  • a suitable inert solvent or diluent for example 7V,7V-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 0 C.
  • Compounds of the Formula XI may be produced using procedures
  • the reaction is carried out in the presence of a mixture of an azo compound such as diethyl, diisopropyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example tetrahydrofuran or a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 80 0 C, preferably at or near ambient temperature.
  • Ring A, R 1 , m, R 2 , G 1 , G 2 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an appropriate alkylating agent which also has any functional group protected if necessary, whereafter any protecting group that is present is removed.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example N, ⁇ /-dimethylformamide, 7V,A/-dimethylacetamide, N- methylpyrrolidin-2-one or a halogenated solvent such as dichloromethane.
  • the reaction is carried out in dimethylformamide, 7V, ⁇ /-dimethylacetamide or N- methylpyrrolidin-2-one and at a temperature in the range, for example, -10 0 C to 180 0 C, conveniently in the range 0 to 100 0 C, more conveniently at or near ambient temperature.
  • a suitable alkylating agent is, for example, a compound wherein a (l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, or heterocyclyl-(l-6C)alkyl group is attached to a suitable leaving group, for example a chloro, bromo, iodo, methoxysulphonyloxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • a suitable leaving group for example a chloro, bromo, iodo, methoxysulphonyloxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • alkylating agents examples include iodomethane, iodoethane, l-bromo-2-methyl-propane, bromomethylcyclopropane, 2-(2-bromoethoxy)-2-methyl-propane, 2-(3-bromopropoxy)-2- methyl-propane, 2-(bromomethyl)tetrahydrofuran and 3-(chloromethyl)-3-methyl-oxetane.
  • the reaction is conducted in the presence of a suitable base such as an alkali or alkaline earth metal carbonate, for example caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine or a base such as sodium hydride.
  • a suitable base such as an alkali or alkaline earth metal carbonate, for example caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine or a base such as sodium hydride.
  • 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 l-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 for example an acid-addition salt, it may be obtained by, for example, reaction of said pyrazine derivative with a suitable acid.
  • 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.
  • 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.
  • Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents, acylation of substituents, amidation of substituents and oxidation of substituents.
  • the reagents and reaction conditions for such procedures are well known in the chemical art.
  • 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 t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl 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 t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid 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 by 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 acyl 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.
  • 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 t-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 t-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.
  • Certain of the intermediates defined herein are novel and these are provided as a further feature of the invention.
  • many compounds of the Formulae II, XI and XV are novel compounds.
  • 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.
  • the assay used AlphaScreen technology (Gray et ah, Analytical Biochemistry. 2003, 313: 234-245) to determine the ability of 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 SF 126 insect cells and purified using the GST epitope tag, using standard purification techniques.
  • Test compounds were prepared as 1OmM stock solutions in dimethylsulphoxide (DMSO) and diluted in DMSO as required. Aliquots (12OnI) of compound dilutions were filled into the wells of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one) using acoustic dispensing (Labcyte Echo 550).
  • LV low volume
  • a 10 ⁇ 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 20 mM Tris-HCl pH 7.5 buffer, 0.01% v/v Tween, 5 mM dithiothreitol (DTT) and 10 mM manganese chloride] was incubated with the compounds at room temperature for 20 minutes.
  • Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by using 100% DMSO instead of test compound.
  • Control wells that produced a minimum signal corresponding to 100% inhibited enzyme were created by adding 10 ⁇ M of a test compound.
  • This assay uses a conventional ELISA method to determine the ability of test compounds to inhibit phosphorylation of tyrosine residues in AxI.
  • NCI H 1299 lung large cell carcinoma cell line [American Type Culture Collection (ATCC) CRL 5803] was routinely maintained at 37°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 0.9xl0 5 cells per ml. lOO ⁇ l Aliquots were seeded into each of the wells of a clear 96 well tissue culture plate and the plates were incubated overnight at 37°C with 5% CO 2 to allow the cells to adhere to the wells.
  • Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required in DMSO to give a range of concentrations. Aliquots of each compound concentration were added to the cells in each well using the Echo 550 (Labcyte Inc.,
  • Control cells received DMSO only. The cells were incubated for 2 hours at 37°C with 5% CO 2 .
  • the resultant cells were stimulated with 100 ng/ml recombinant mouse GAS6 (RnD systems; Catalogue No. 986-GS) for 10 minutes at 37°C with 5% CO 2 .
  • Cells were lysed by the addition of 50 ⁇ l/well of lysis buffer comprising 2OmM Tris-HCl pH 8.0, 137 mM sodium chloride, 2 mM EDTA, 10% v/v glycerol, 1% v/v Igepal CA-630, 0.5mM sodium orthovanadate, 1 mM sodium pyrophosphate, 10 mM sodium pyrophosphate, 10 mM glycerophosphate and IX protease inhibitor tablets (Roche; catalogue number 11836153001).
  • the resultant tissue culture plates were incubated on ice for 30 minutes to ensure full lysis.
  • High-binding ELISA plates were coated with an anti-Axl antibody (RnD systems; Catalogue No. AF 154) at room temperature for 16 hours.
  • the wells were washed 3 times with 250 ⁇ l per well of PBS containing 0.05% v/v Tween (PBS/T).
  • the wells were treated with 3% w/v BSA in PBS at ambient temperature for 2 hours and subsequently washed 3 times with 250 ⁇ l per well of PBS/T.
  • 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). 100 ⁇ 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 IC50 value. The IC50 value is the concentration of test compound that inhibits 50% of kinase activity.
  • the assay used AlphaScreen technology (Gray et ah, 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, 784075) with a total volume of 12 ⁇ L in each well.
  • Each kinase reaction contained 40pg (10OpM) pY 1234 pY 1235 c-Met(1074-1366) kinase domain, 44ng (10OnM) cMyc-[D1204N,R1208Q]c-Met(1069-1366)-biotin, 25mM HEPES (pH7.4), 0.ImM sodium orthovanadate, ImM DTT, 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 1234/1235 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 25 mM HEPES (pH 7.4), 84.5mM EDTA, 0.3% BSA under low-level light conditions.
  • IC50 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
  • L-glutamine Gibco 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. Once the cells had fully adhered (typically following overnight incubation) plates were dosed with 25 ⁇ l compound (diluted from 10 mM stock in DMSO using serum free DMEM) and the plates were returned to a humidified 37°C (+5% CO 2 ) incubator for one hour. Following incubation the cells were fixed by adding formaldehyde (4% final concentration) and incubating at room temperature for 20 minutes.
  • the fixative solution was then removed and the wells were washed three times with 100 ⁇ l phosphate buffered saline (PBS) before permeabilising the cells by the addition of 50 ⁇ l/well 0.1% triton/ PBS for 20 minutes at room temperature.
  • 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.
  • the antibody solution was removed and the wells were washed twice with 100 ⁇ l/ well PBS.
  • Preferred compounds of the invention possess activity at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d) :-
  • the pyrazine compound disclosed within Example 1 possesses activity in Test (a) with an IC50 versus AxI tyrosine kinase of approximately 20 nM; and activity in Test (b) with an IC50 versus cellular phospho-Axl of approximately 40 nM; and activity in Test (c) with an IC50 versus c-Met tyrosine kinase of approximately 1.04 ⁇ M; and activity in Test (d) with an IC50 versus cellular phospho-c-Met (pYpYpY 1230/4/5 ) of approximately 60 nM.
  • the pyrazine compound disclosed within Example 5 possesses activity in Test (a) with an IC 50 versus AxI tyrosine kinase of approximately 20 nM; and activity in Test (b) with an IC 50 versus cellular phospho-Axl of approximately 20 nM; and activity in Test (c) with an IC50 versus c-Met tyrosine kinase of approximately 0.48 ⁇ M; and activity in Test (d) with an IC50 versus cellular phospho-c-Met (pYpYpY 1230/4/5 ) of approximately 8O nM.
  • pyrazine compounds disclosed within the Examples possess activity in Test (b) at the levels illustrated in Table A.
  • Example 20 had an activity in Test (a) with an IC50 versus AxI tyrosine kinase of approximately 0.016 ⁇ M.
  • ** the compound disclosed in Example 22 had an activity in Test (a) with an IC50 versus AxI tyrosine kinase of approximately 0.002 ⁇ M.
  • Example 23 had an activity in Test (a) with an IC 50 versus AxI tyrosine kinase of approximately 0.003 ⁇ 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.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • 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.
  • 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.
  • 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.
  • AxI and c-Met are involved in 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 there is provided the use of 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 dermato fibrosarcoma 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-accep table 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.
  • 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
  • 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-accep table 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-accep table 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.
  • the anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such 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, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin- C, dactinomycin and mithra
  • 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 ⁇ /-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4- amine (gefitinib, ZD 1839), ⁇ /-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4- amine (erlotinib, OSI-774) and 6-acrylamido- ⁇ /-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family,
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense
  • 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-drug resistance gene therapy
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity 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
  • 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.
  • ⁇ ATU (2.16 g) was added to a mixture of triethylamine (1.13 ml), 4-fluoro-l,2- diaminobenzene (0.72 g) and 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-lH- pyrazol-4-yl)pyrazine-2-carboxylic acid (2.1 g) in DMF (25 ml) at ambient temperature and was stirred for 2 hours. The reaction mixture was diluted with dilute aqueous sodium hydrogen carbonate solution. The precipiate was isolated by filtration and dried in a vacuum oven.
  • the 3 -amino-6-( 1 -( 1 -(tert-butoxycarbonyl)piperidin-4-yl)- lH-pyrazol-4- yl)pyrazine-2-carboxylic acid used as a starting material was prepared as follows :- l,r-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.245 g) was added to a mixture of caesium fluoride (18.85 g), methyl 3-amino-6-bromopyrazine-2-carboxylate (14.4 g) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine-l-carboxylate (30.4 g) in methanol (450 ml) at ambient temperature.
  • 2M sodium hydroxide solution (8.70 ml) was added to a solution of methyl 3- i o amino-6-( 1 -( 1 -(tert-butoxycarbonyl)piperidin-4-yl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxylate (3.5 g) in methanol (40 ml) and stirred at ambient temperature for 2 hours. The resultant solution was concentrated in vacuo until half of the methanol had been removed. Water (20 ml) was then added and the solution was acidified to pH4 by addition of 2M hydrochloric acid causing the product to precipitate. This material was filtered and dried is invacuo.
  • Methyl 3-amino-6-[l-(l-tert-butoxycarbonyl-piperidin-4-yl)pyrazol-4-yl]pyrazine- 2-carboxylate 8 g was dissolved in TFA (25 ml) and the mixture was stirred for 1 hour. The resultant mixture was concentrated under reduced pressure. The residue was purified by SCX ion exchange chromatography (eluted using 7M methanolic ammonia). The resulting compound was triturated with diethyl ether.
  • the 3-phenylmethoxybenzene-l,2-diamine used as a reagent to make compound [2] above was prepared as follows: Potassium carbonate (14.83 g) was added in one portion to 2-amino-3-nitrophenol (16.54 g) in ethanol (100 ml) at ambient temperature. The resulting mixture was stirred for 15 minutes. Benzyl chloride (16.05 ml) and sodium iodide (0.184 ml) were added to the reaction mixture and the resulting mixture was stirred at 78 0 C for 2 hours. The reaction mixture was evaporated to dryness and the residue was redissolved in ethyl acetate, and washed sequentially with water and saturated brine.
  • Ammonium formate (0.28 g) was added in one portion to tert-butyl 4-[4-[5-amino-6- (7-phenylmethoxy- lH-benzimidazol-2-yl)pyrazin-2-yl]pyrazol- 1 -yl]piperidine- 1 - carboxylate (0.39 g) and palladium (0.072 g) in methanol (15 ml) at ambient temperature. The resulting suspension was stirred at 70 0 C for 8 hours. The reaction mixture was filtered through celite. The celite was washed with dimethylformamide (50 ml) and combined with the methanol filtrate.
  • Triphenylphosphine (0.028 ml) and diisopropyl azodicarboxylate (0.025 ml) were added in one portion to tert-butyl 4-[4-[5-amino-6-(7-hydroxy-lH-benzimidazol-2- yl)pyrazin-2-yl]pyrazol-l-yl]piperidine-l -carboxylate (0.050 g) and tetrahydrofuran-3- ylmethanol (0.012 ml) in tetrahydrofuran (1 ml) at ambient temperature. The resulting solution was stirred for 2 hours.
  • reaction mixture was then evaporated to dryness and redissolved in dichloromethane (1 ml), and trifiuoroacetic acid (1 ml) was added in one portion. The resulting solution was stirred at ambient temperature for 10 minutes. The reaction mixture was evaporated to dryness and redissolved in DMSO (1.2 ml), and purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% ammonia) and acetonitrile as eluents.
  • HATU 47.6 g was added to a stirred solution of 1 ,2-phenylenediamine (13.54 g), 3-amino-6-bromopyrazine-2-carboxylic acid (26.0 g) and triethylamine (24.93 ml) in DMF (250 mL).
  • the resulting solution was stirred at ambient temperature for 12 hours before the reaction mixture was added to water (250 ml).
  • the resulting precipitate was collected by filtration, washed with water (250 ml) and dried in vacuo. This material was dissolved in acetic acid (200 ml) and heated to 9O 0 C for 4 hours.
  • the reaction mixture was concentrated in vacuo, washed with diethylether.
  • tert-butyl 3-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)methyl)piperidine-l-carboxylate was prepared from tert-butyl 3-
  • the product was obtained by reaction of 5-bromo-3-(5-fiuoro-lH-benzimidazol-2- yl)pyrazin-2-amine and l-(tetrahydropyran-4-yl)-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole according to Example 3 except that the reaction was run in DMA:water (4:1) at 150 0 C in a microwave oven for 30 min using caesium fluoride in place of sodium bicarbonate.
  • the product gave the following characteristising data: Mass Spectrum: M+H + 380.
  • the product was obtained by reaction of tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazol- 1 -yl]piperidine- 1 -carboxylate and 5-bromo-3-(5-chloro-6- fluoro-lH-benzimidazol-2-yl)pyrazin-2-amine according to an analogous procedure to that described in Example 3 except that the reaction was carried out in dioxane using 1,1 '- bis(diphenylphosphino)ferrocenedichloropalladium(II) as the catalyst and aqueous sodium carbonate as the base and the reaction mixture was heated to 100 0 C for 3 hours under microwave irradiation and the resultant intermediate was reacted with trifiuoroacetic acid.
  • 5-Bromo-3-(5-chloro-6-fluoro-lH-benzimidazol-2-yl)pyrazin-2-amine used as starting material was prepared from 3-aminopyrazine-2-carboxylic acid and 4-chloro-5- fluorobenzene-l,2-diamine as described in example 4.03, starting material: 3-amino-N-(2-amino-4-chloro-5-fluorophenyl)pyrazine-2-carboxamide (200 mg).
  • the 5-bromo-3-(5-chloro-6-fluoro-lH-benzimidazol-2-yl)pyrazin-2-amine gave the following characterising data; Mass Spectrum: M+H + 342
  • tert-butyl 4-(4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazol- 1 - yl)cyclohexylcarbamate used as starting material was prepared from tert-butyl N-(4- hydroxycyclohexyl)carbamate using the same sequence as described in Example 4.07.
  • Acetic acid (0.023 ml) was added to a solution of 3-(5-fluoro-lH-benzimidazol-2-yl)- 5-(l-piperidin-4-ylpyrazol-4-yl)pyrazin-2-amine (0.15 g) and formaldehyde (0.041 ml) in methanol (5 ml). The resultant mixture was stirred for 10 minutes at ambient temperature. Sodium cyanoborohydride (0.029 g) was added and the mixture was stirred for 1 hour at ambient temperature. The mixture was filtered, concentrated in vacuo and purified by SCX ion exchange chromatography, with the eluent 2M NH 3 /in methanol. The resultant solid was hen purified by preparative HPLC using decreasingly polar mixtures of water
  • Dichlorobis(triphenylphosphine)palladium(II) (0.012 g) was added to a mixture of ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (0.105 g), 3- (l//-benzimidazol-2-yl)-5-bromopyrazin-2-amine (0.1 g) and 2M sodium bicarbonate (0.207 ml) in a solvent of 2:7:3:2 DMF:DME:ethanol:water (4 ml). The resulting mixture was stirred and heated to 160 0 C for 20 minutes. The residue was evaporated to afford 5- [5-amino-6-(lH-benzimidazol-2-yl)pyrazin-2-yl]pyridine-3-carboxylic acid.
  • Dichlorobis(triphenylphosphine)palladium(II) (0.012 g) was added to 3-(1H- benzimidazol-2-yl)-5-bromopyrazin-2-amine (0.100 g), 2-fluoropyridin-5-ylboronic acid (0.072 g) and 2M sodium bicarbonate (0.207 ml) in a mixture of 2:7:3:2 DMA:DME:ethanol:water (5 ml). The mixture was heated to 160 0 C for 40 minutes in a microwave. Piperidine (0.3 ml) was then added and the solution was heated to 120 0 C for a further 20 minutes. The crude product was purified by SCX ion exchange chromatography.
  • Diisopropyl azodicarboxylate (0.03 ml) was added to a solution of tert-butyl 4-[4-[5- i o amino-6-(7-hydroxy- 1 H-benzimidazol-2-yl)pyrazin-2-yl]pyrazol- 1 -yl]piperidine- 1 - carboxylate (0.06 g, triphenylphosphine (0.04 g), l-methylpyrrolidin-3-ol (0.015 g) in tetrahydrofuran (1.2 ml). The mixture was shaken for 4 days. The resultant mixture was concentrated by evaporation of solvent under reduced pressure.
  • l-Bromo-2-methoxyethane (0.067 ml) was added in one portion to tert-butyl 4-[4- [5 -amino-6-( 1 H-benzimidazol-2-yl)pyrazin-2-yl]pyrazol- 1 -yl]piperidine- 1 -carboxylate (300 mg) and caesium carbonate (424 mg) dissolved in DMF (5 ml). The mixture was stirred at 25°C for 16 hours.
  • Acetic acid 50 ml was added to tert-butyl 4-[4-[5-amino-6-[(2- aminophenyl)carbamoyl]pyrazin-2-yl]pyrazol-l-yl]piperidine-l-carboxylate (10.6 g) and the resulting solution was stirred at 90 0 C for 3 hours.
  • the reaction mixture was allowed to cool to ambient temperature under stirring over a period of 30 minutes, quenched with water, basified with a 2N aqueous solution of sodium hydroxide to pH 4.5 and extracted with ethyl acetate (200 x 3 ml).
  • Example 14 Using analogous procedures to those described in Example 14, the appropriate benzimidazole was reacted with an appropriate alkylating agent to give the compounds described in Table VII.
  • an appropriate alkylating agent As in Example 14, a N-tert-butoxycarbonyl (N-Boc) protecting group was employed. Where necessary, an O-tert-butoxy protecting group was employed on certain alkylating agents. Such protecting groups were removed using conventional treatment with trifluoroacetic acid. Unless otherwise stated, the required appropriate alkylating agents are commercially available. Table VII
  • Formaldehyde (0.028 ml) was added in one portion to a stirred solution of 3-[l-(2- methoxyethyl)benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine (132 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) at 0 0 C under argon. The resulting solution was stirred at 0 0 C for 5 minutes. Sodium triacetoxyhydroborate (80 mg) was added and the mixture was stirred for 5 minutes at 25°C.
  • Formaldehyde (0.012 ml) was added in one portion to a stirred solution of 3 -(I - methylbenzimidazol-2-yl)-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine (52 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) at 0 0 C under argon. The resulting solution was stirred at 0 0 C for 5 minutes. Sodium triacetoxyhydroborate (35.3 mg) was added and the mixture was stirred for 5 minutes at 25°C. A solution of ammonia in methanol 7N (ImI) was added and the mixture was adsorbed on silica gel.
  • ImI ammonia in methanol 7N
  • the tert-butyl 4-(4-(5-amino-6-(3-aminopyridin-4-ylcarbamoyl)pyrazin-2-yl)pyrazol-l- yl)piperidine-l-carboxylate used as starting material was made as follows: Methyl 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)pyrazol-4-yl)pyrazine-2- carboxylate (300 mg) and pyridine-3,4-diamine (407 mg) were dissolved into DMF (5 ml). Sodium methoxide (50 mg) was added to the mixture. The resulting mixture was stirred at 12O 0 C for 12 hours.
  • reaction mixture was then allowed to stir at room temperature over a period of 2 days, quenched with water (2 ml), concentrated to dryness, diluted with ethyl acetate (1500 ml), washed with water (2x1000 ml), brine (1000 ml), dried over magnesium sulfate and concentrated to afford the crude product.
  • reaction mixture was allowed to cool to room temperature under stirring over a period of 1 hour, quenched with water (25 ml) and extracted with ethyl acetate (3 x 40 ml). The combined organic phases were washed with water (3 x 30 ml), brine (1 x 20 ml), dried over magnesium sulfate and concentrated.
  • Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (334 mg), tert-butyl 4-[3-methyl-4- (4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrazol- 1 -yl]piperidine- 1 -carboxylate (563 mg) and bis(triphenylphosphine) palladium (II) chloride (101 mg) and cesium fluoride (656 mg) in MeOH (11 mL) were degassed under vacuum and argon , stirred at 130 0 C for 20mn under microwave conditions. The mixture wac concentrated and the residue was dissolved in dichloromethane and filtered.
  • the resulting suspension was stirred at 25 0 C for overnight.
  • the reaction mixture was purified by preparative HPLC using a Waters X- Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford tert-butyl 4- [4-[5-amino-6-[(2-aminophenyl)carbamoyl]pyrazin-2-yl]-3-methyl-pyrazol- 1 - yl]piperidine-l-carboxylate (182 mg).

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Abstract

The invention concerns pyrazine derivatives of Formula (I) or a pharmaceutically-acceptable salt thereof, wherein each of G1, G2, Ring A, R1, m, R2, R3, n and R4 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositionscontaining them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.

Description

-PYRAZINYLBENZIMIDAZOLE DERIVATIVES AS RECEPTOR TYROSINE KINASE
INHIBITORS
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 (RTKs) 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 (Schlessinger, 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 Tyro 12). 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 (Gas6). The affinity of Gas6 for these receptors is Axl>Tyro3>Mer (Nagata et al, 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 et al., MoI. Cell. Biol., 1991, 11, 5031). The AxI receptor has been shown to be overexpressed in primary colon (Craven et al, Int. J. Cancer., 1995, 60, 791), gastric (Sawabu et al., MoI. Carcinog., 2007, 46, 155), oesophageal (Nemoto et al, Pathobiology, 1997, 65, 195), melanoma (Quong et al, Melanoma Res., 1994, 4, 313), ovarian (Sun et al, Oncology, 2004, 66, 450 ), renal (Chung et al, DNA Cell Biol, 2003, 22, 533), endometrial (Sun et al, Ann. Oncol, 2003, 14, 898), and thyroid (/to et al, Thyroid, 1999, 9, 563) cancers. The presence of the AxI receptor is highly correlated with lymph node status and stage in lung cancer and ER expression in breast cancer (Berclaz et al, Ann. Oncol, 2001, 12, 819).
Gas6/Axl signalling has been shown to have roles in proliferation, protection from apoptosis, angiogenesis and invasion. The gene encoding for AxI has been shown to transform both NIH-3T3 fibroblasts, enabling them to grow as xenografts in nude mice (O 'Bryan et al, MoI. Cell. Biol, 1991, 11, 5031), and IL-3 dependent hematopoietic 32D cells, enabling IL-3 independent growth (McCloskey et al, Cell Growth Differ., 1994, 5, 1105).
The anti-apoptotic effects of Gas6/Axl signalling have been demonstrated in NIH- 3T3 cells (Bellosta et al, Oncogene, 1997, 15, 2387), human oligodendrocytes (Shankar et al, J. Neurosci., 2006, 26, 5638) and in the uveal melanoma cell line Mel 290 (Van Ginkel et al, Cancer Res., 2004, 64, 128). Gas6/Axl signalling has also been shown to have a weak mitogenic effect in mouse NIH-3T3 fibroblasts (Goruppi et al, Oncogene, 1996, 12, 471), human C57MG mammary carcinoma cells (Goruppi et al, MoI Cell Biol, 2001, 21, 902) and human DU 145 and PC3 prostate carcinoma cells (Sainaghi et al, J. Cell. Physiol, 2005, 204, 36).
The depletion of AxI protein has been shown to disrupt CL 1-5 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, Cancer Res., 2005, 65, 9294). Furthermore, inhibition of the AxI protein by either knockdown of protein levels (Holland et al, Cancer Res., 2005, 65, 9294) or transfection of a dominant negative AxI mutant gene (Vajkoczy et al, Proc. Natl. Acad. ScL USA, 2006, 103, 5799) has been shown to suppress xenograft growth in vivo.
AxI RTKs have also been shown to have roles in immunity (Lu et al, Science, 2001, 293, 306), platelet function (Angelillo-Scherrer et al, Nat. Med., 2001, 7, 215), spermatogenesis (Lu et al, Nature, 1999, 398, 723), vascular calcification (Son et al, Eur. J. Pharmacol, 2007, 556, 1), thrombin induced vascular smooth muscle cell (VSMC) proliferation (Nakano et al, J. Biol. Chem., 1995, 270, 5702), and various kidney diseases, for example acute and chronic glomerulonephritis, diabetic nephropathy and chronic allograft rejection (Yanagita et al, J. Clin. Invest., 2002, 110, 239).
Accordingly, 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). 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 α-chain and a 145 kDa β-chain. When HGF non-covalently binds to the extracellular domain of c-Met, receptor oligomerisation occurs. This results in phosphorylation of a number of sites within c-Met such as tyrosine residue γ1234/5 that lies within the c-Met activation loop (a flexible region of amino acids whose conformation controls kinase activity) and tyrosine residue γ1349/56 which forms part of a structurally unique protein docking site. Phosphorylation within the activation loop causes an increase in c-Met kinase activity, whilst phosphorylation of the docking site is essential for binding and subsequent activation of classical intracellular tyrosine kinase effecter proteins such as p85, Gabl and Grb2 {Ponzetto, C, et al. (1994), Cell 77, 261-271). A variety of proteins from different signalling pathways can bind to and be phosphorylated by activated c-Met (Giordano, S., et al. (2000), FASEB J. 14, 401-408 and Giordano, S., et al. (1997), Proc. Natl. Acad. Sci. USA 94, 13868-13872) with the result that c-Met activity is required for signal transmission via several signalling pathways. For example, c-Met-Gabl-Shp2 association results in sustained stimulation of the Erk pathway, thus stimulating cell transformation and proliferation (Maroun, C, et al. (2000), MoI. Cell. Biol. 20, 8513-8525; Schaeper, U, et al. (2000), J. Cell. Biol. 149, 1419-1432; and Paumelle, R., et al. (2002) Oncogene 21, 2309-2319). However, c-Met-p85 association stimulates the PBK pathway thus promoting cell migration and protecting cells from apoptosis following cellular damage (Ponzetto, C, et al. (1993), MoI. Cell. Biol. 13, 4600- 4608; and Xiao, G., (2001) Proc. Natl. Acad. Sci. USA 98, 247-252). 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 {Bardelli, 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).
A significant number of clinical studies have shown that both c-Met and HGF are frequently aberrantly expressed in aggressive carcinomas, in other types of human solid tumours, and in their metastases {reviewed in Truslino et al.; Birchmeier et al.; Maulik, G., et al. (2002), Cytokine & Growth Factor Rev. 13, 41-59; and Danilkovitch-Miagkova, A. & Zbar, B. (2002) J. Clin. Invest. 109, 863-867). Further, the presence of c-Met or HGF in clinical samples often correlates with poor patient prognosis (reviewed in Truslino et al.) suggesting that c-Met activation promotes tumour growth and metastatic spread. 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. and Danilkovitch-Miagkova et al.) and, at present, 21 mutations have been described. The majority are localised within the kinase domain and are believed to convert c-Met into a constitutively active form. More recently, a number of additional mutations have been found in other types of primary cancer and metastatic lesions (Lorenzato, A., et al. (2002), Cane. Res. 62, 7025-7030).
Consequently, a considerable body of evidence supports the theory that primary cancer growth, angiogenesis, local tumour invasion and distant metastasis formation are driven or enhanced by inappropriate c-Met activation. The role of c-Met in angiogenesis has been demonstrated by experiments involving HGF stimulation of new blood vessel growth in rat corneal and mouse matrigel models (Rosen, E.m et al. (1997) Ciba Found. Symp. 212, 215-9 and Rosen, E. & Goldberg, I. (1995) Adv. Cancer Res. 67, 257-279). Mouse and human cell lines that ectopically overexpress either HGF or c-Met, or both, have been observed to become tumorigenic in nude mice and frequently such cells acquire an invasive phenotype that enables them to form metastases in distant organs {reviewed in Truslino, L. and Comoglio, P. (2002), Nature Rev. Cane. 2, 289-300 and Birchmeier et al). Downregulation of c-Met/HGF signalling in human tumour cells (either by biological or small molecule approaches) has also been shown to substantially decrease the cells' tumorigenic potential through a decrease in proliferation, angiogenesis and invasion (Abounader, R., et al. (2002), FASEB J. 16, 108-110 and Christensen, J., et al. (2003), Cane. Res. 63, 7345-7355). Finally, it has also been reported that mouse models expressing c-Met or HGF as a transgene in specific tissues ultimately develop a broad array of aggressively invasive tumours and metastatic lesions {Wang, R., et al. (2001), J. Cell Biol. 153, 1023-1034; Gallego, M.,et al. (2003), Oncogene 22, 8498-8508; and Takayama, K, et al. (1997), Proc. Natl. Acad. ScL USA 94, 701-706) indicating that activation of c-Met is sufficient to initiate tumour formation and promote angiogenesis and invasion {Rosen 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. Additionally, the role of 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) Clin. CHm. Acta 327, 1-23).
We have now found that surprisingly certain novel pyrazine derivatives possess potent activity against cell proliferative disorders. Without wishing to imply that 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. According to one aspect of the invention there is provided a pyrazine derivative of the Formula I
Figure imgf000008_0001
in which: each of Gi and G2 is selected from CH and N provided that both are not N;
Ring A is a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur; R1 is a group of the formula: R5-X! - wherein X1 is a direct bond or is selected from O, S, SO, SO2, N(R6), CO, CH(OR6), CON(R6), N(R6)C0, N(R6)CON(R6), SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2S, SC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 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 R5 is amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (R7)-amino-(l-6C)alkyl or di-(R7)-amino-(l-6C)alkyl, wherein R7 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; or R1 is a group of the formula: Q1 X2 wherein X2 is a direct bond or is selected from O, S, SO, SO2, N(R8), CO, CH(OR8), CON(R8), N(R8)C0, N(R8)CON(R8), SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2S, SC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 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 Q1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R1 substituent optionally bears 1 , 2 or 3 substituents independently selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylsulphonyl-(l-6C)alkyl, cyano-(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, (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)alkanoyloxy, TV-(I -6C)alkylcarbamoyl, N,N-di-[(\ -6C)alkyl] carbamoyl, (2-6C)alkanoylamino, N-(I -6C)alkyl-(2-6C)alkanoylamino, N-(I -6C)alkylureido, N-(I -6C)alkylureido, N',N'-di-[(l-6C)alkyl]ureido, N,N'-di-[(l-6C)alkyl]ureido, N,N ,ΛT-tri-[(l -6C)alkyl]ureido, N-(I -6C)alkylsulphamoyl, 7V,7V-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino, Λ/-(l-6C)alkyl-(l-6C)alkanesulphonylamino or heterocyclyl-(l-6C)alkyl, and any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents; or R1 is a group of the formula:
Q2 X2 wherein X2 has any of the meanings defined hereinbefore and Q2 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 R1 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, (R9)-amino-(l-6C)alkyl and di-(R9)-amino-(l-6C)alkyl, wherein R9 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; m is 0, 1, 2 or 3, and, when m is 2 or 3, each R group may be the same or different, and each R2 group present 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)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, TV-(I -6C)alkylcarbamoyl, 7V,7V-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino and N-(l-6C)alkyl-(2-6C)alkanoylamino; R3 is hydrogen, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (R10)p-(l-8C)alkyl, (R10)p-(2-8C)alkenyl or (R10)p-(2-8C)alkynyl, wherein each p is 1, 2 or 3 and each R10 group, 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, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy; n is 0, 1, 2 or 3 and, when n is 2 or 3, each R4 group may be the same or different, and each R4 group present is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR11, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (1- 8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno- (l-6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, 7V,7V-di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino, wherein R11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl, wherein any aryl, heterocyclyl or heteroaryl group within the definition of R11 optionally bears 1, 2 or 3 substituents independently selected from halogeno, trifluoromethyl, oxo, cyano, hydroxy, amino, carboxy, carbamoyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (l-6C)alkoxy; or a pharmaceutically-acceptable salt thereof.
In this specification the generic term "(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-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl and 2-cyclohexylethyl. However 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 and references to individual cycloalkyl groups such as "cyclopentyl" are specific for that 5-membered ring only. An analogous convention applies to other generic terms, for example (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-cyclopropylethoxy, cyclobutylmethoxy, 2- cyclobutylethoxy and cyclopentylmethoxy; (l-6C)alkylamino includes (3- 6C)cycloalkylamino groups and 7V-(cycloalkylalkyl)amino groups having 4 to 6 carbon atoms, for example methylamino, ethylamino, propylamino, cyclopropylamino, cyclobutylamino, cyclohexylamino, cyclopropylmethylamino, 2-cyclopropylethylamino, cyclobutylmethylamino, 2-cyclobutylethylamino and cyclopentylmethylamino; and di-[(l- 6Calkyl]amino includes di-[(3-6C)cycloalkyl]amino groups and di- [eye loalkylalkyl] amino groups in which the cycloalkylalkyl moiety has 4 to 6 carbon atoms, for example dimethylamino, diethylamino, dipropylamino, TV-cyclopropyl-TV-methylamino, N- cyclobutyl-N-methylamino, N-cyclohexyl-N-ethylamino, N-cyclopropylmethyl-TV- methylamino, Λ/-(2-cyclopropylethyl)-7V-methylamino and 7V-cyclopentylmethyl-7V- methylamino.
A person skilled in the art will appreciate that the terms "(l-4C)alkyl", "(1- 3C)alkyl" and "(l-2C)alkyl" that are used herein refer 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", "(1- 3C)alkoxy" and "(l-2C)alkoxy".
In this specification, unless otherwise specified, the term "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, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, tetrahydro- 1 ,4-thiazinyl, 1 , 1 -dioxotetrahydro- 1 ,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclo[2.2.1]heptyl, quinuclidinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl.
In this specification, unless otherwise specified, the term "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, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl. It is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any 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. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
It is to be understood that certain compounds of Formula I defined above may exhibit the phenomenon of tautomerism. It is to be understood that the present invention includes in its definition any such tautomeric form, or a mixture thereof, which possesses the above- mentioned activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings or named in the Examples. In general, just one of any such tautomeric forms is named in the Examples that follow hereinafter or is presented in any relevant formulae drawings that follow hereinafter. Suitable values for the generic radicals referred to above include those set out below.
A suitable value for Ring A when it is a 5- or 6-membered monocyclic or a 9- or 10- membered bicyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur is, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl. In a particular group of compounds of the Formula I, Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur and a suitable value for Ring A is, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl. In a particular group of compounds of the Formula I, Ring A is a pyrazolyl or pyridinyl ring. In a further particular group of compounds of the Formula I, Ring A is a pyrazol-4-yl or pyridin-3-yl ring. In yet a further particular group of compounds of the Formula I, Ring A is a pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl ring. In yet a further particular group of compounds of the Formula I, Ring A is a pyrazolyl ring. In yet a further particular group of compounds of the Formula I, Ring A is a pyrazol-4-yl ring.
A suitable value for the heterocyclyl group within the R1 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, 1,1- dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclo[2.2.1]heptyl, quinuclidinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl. When Q1 is an optionally substituted heterocyclyl or heterocyclyl-(l-6C)alkyl, particular examples of the heterocyclyl ring include piperidinyl, piperazinyl and especially piperidin- 4-yl and piperazin-1-yl. In a particular group of compounds of the Formula I, when Q1 is an optionally substituted heterocyclyl or heterocyclyl-(l-6C)alkyl, particular examples of the heterocyclyl ring include piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl and especially piperidin-4-yl, piperidin-3-yl, piperazin-1-yl, morpholin-4-yl and tetrahydropyran-4-yl. When Q1 comprises a heterocyclyl-(l-6C)alkyl substituent group on the heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl ring, particular values for the heterocyclyl within the heterocyclyl-(l-6C)alkyl substituent group include tetrahydrofuranyl, tetrahydropyranyl and especially tetrahydrofuran-4-yl or tetrahydropyran-4-yl.
A suitable value for the heteroaryl group within the R1 or R4 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, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl. In a particular group of compounds of the Formula I, when R4 contains an optionally substituted heteroaryl or heteroaryl-(l-6C)alkyl group, particular examples of the heteroaryl ring include isoxazolyl and especially isoxazol-3-yl.
A suitable value for the aryl group within any R1 or R4 group is, for example, phenyl or naphthyl, conveniently phenyl. A suitable value for the (3-8C)cycloalkyl group within any R1 group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl or cyclooctyl.
A suitable value for a heterocyclyl-(l-6C)alkyl is, for example, heterocyclylmethyl, 2-heterocyclylethyl and 3-heterocyclylpropyl. The invention comprises corresponding suitable values 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)cycloalkyl-(l-6C)alkyl group is present.
A suitable value for any heterocyclyl group within the R3 or R4 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, 1,1- dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclo[2.2.1]heptyl, quinuclidinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl. A particular example of a heterocyclyl ring within the R4 group is, for example, tetrahydrofuranyl and especially tetrahydrofuran-3-yl. In a particular group of compounds of the Formula I, the heterocyclyl ring within the R4 group is, for example, tetrahydrofuranyl or pyrrolidinyl and especially tetrahydrofuran-3-yl or pyrrolidin-3-yl. Suitable values for any of the 'R' groups (R1 to R4), or for various groups such as R5 to R9 within an R1 substituent or for various groups such as R10 within a R3 group and R1 λ within a R4 group include, for example :-
for halogeno fluoro, chloro, bromo and iodo; for (l-8C)alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, cyclohexylmethyl and
2-cyclopropylethyl; for (2-8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for (l-6C)alkylthio: methylthio, ethylthio and propylthio; for (l-6C)alkylsulphinyl: methylsulphinyl and ethylsulphinyl; for (l-6C)alkylsulphonyl: methylsulphonyl and ethylsulphonyl; for (l-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di- [( 1 -6C)alkyl] amino : dimethylamino, diethylamino,
7V-ethyl-7V-methylamino and diisopropylamino; for (l-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tøt-butoxycarbonyl; for TV-(I -6C)alkylcarbamoyl: 7V-methylcarbamoyl, N-ethylcarbamoyl and
7V-propylcarbamoyl; for N,N-di-[(l-6C)alkyl]carbamoyl: 7V,7V-dimethylcarbamoyl, N-ethyl-
7V-methylcarbamoyl and 7V,7V-diethylcarbamoyl; for (2-6C)alkanoyl: acetyl, propionyl and isobutyryl; for (2-6C)alkanoyloxy: acetoxy and propionyloxy; for (2-6C)alkanoylamino: acetamido and propionamido; for N-(I -6C)alkyl-(2-6C)alkanoylamino 7V-methylacetamido and N-methylpropionamido; for ΛT-(l-6C)alkylureido: ΛT-methylureido and ΛT-ethylureido; for TV' ,TV' -di- [( 1 -6C)alkyl]ureido : TV' ,TV' -dimethylureido and TV' -methyl-TV - ethylureido; for TV-(I -6C)alkylureido: 7V-methylureido and /V-ethylureido; for 7V,7V'-di-[(l-6C)alkyl]ureido: 7V,7V' -dimethylureido, 7V-methyl-7V' -ethylureido
5 and TV-ethyl-TV' -methylureido; for 7V,7V',7V'-tri-[(l-6C)alkyl]ureido: 7V,7V',7V'-trimethylureido,
7V-ethyl-7V', TV' -dimethylureido and
TV-methyl-TV' ,TV' -diethylureido; for TV-(I -6C)alkylsulphamoyl: TV-methylsulphamoyl and TV-ethylsulphamoyl; io for TV,TV-di-[(l-6C)alkyl]sulphamoyl: TV,TV-dimethylsulphamoyl; for (l-6C)alkanesulphonylamino: methanesulphonylamino and ethanesulphony lamino ; for TV-( 1 -6C)alkyl-( 1 -6C)alkanesulphonylamino : TV-methylmethanesulphonylamino and
TV-methy lethanesulphony lamino ; is for halogeno-(l-6C)alkyl: chloromethyl, 2-fluoroethyl, 2-chloroethyl,
1-chloroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 3-fluoropropyl, 3-chloropropyl,
3,3-difluoropropyl and 3,3,3-trifiuoropropyl; for halogeno-(l-6C)alkoxy fluoromethoxy, chloroethoxy, trifiuoromethoxy,
20 2,2,2-trifluoroethoxy, 3,3-difluoropropoxy, 3,3,3- trifluoropropoxy for hydroxy-(l-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl; for (l-6C)alkoxy-(l-6C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl,
25 2-methoxyethyl, 2-ethoxyethyl and 3- methoxypropyl; for ( 1 -6C)alkylsulphonyl-( 1 -6C)alkyl: methylsulphonylmethyl, ethylsulphonylmethyl,
2-methylsulphonylethyl, 1 -methylsulphonylethyl and 3-methylsulphonylpropyl; 30 for cyano-(l-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and
3-cyanopropyl; for amino-(l-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl and 5- aminopropyl; for ( 1 -6C)alkylamino-( 1 -6C)alkyl: methylaminomethyl, ethylaminomethyl,
1 -methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl; for di- [( 1 -6C)alkyl] amino-( 1 -6C)alkyl: dimethylaminomethyl, diethylaminomethyl,
1-dimethylaminoethyl, 2-dimethylaminoethyl and
3-dimethylaminopropyl.
When, as defined hereinbefore, an R1 group forms a group of the formula R5- X1 - and, for example, X1 is a OC(R6)2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R6)2 linking group which is attached to Ring A and the oxygen atom is attached to the R5 group. Similarly, when, as defined hereinbefore, an R1 group forms a group of the formula Q1 X2 or of the formula Q2 X2 and, for example, X2 is a OC(R8)2 linking group, it is the oxygen atom of the OC(R8)2 linking group which is attached to the Q1 or Q2 group.
Within the definition of the R1 group, a suitable value for an (R7)-amino-(l-6C)alkyl group or an (R9)-amino-(l-6C)alkyl group is, for example, trifluoromethylaminomethyl, cyanomethylaminomethyl, 2-cyanoethylaminomethyl, 2-hydroxyethylaminomethyl, 2- methoxyethylaminomethyl, 2-trifluoromethylaminoethyl, 2-(2-hydroxyethylamino)ethyl and 2-(2-methoxyethylamino)ethyl.
Within the definition of the R1 group, a suitable value for a di-(R7)-amino-(l- 6C)alkyl group or an di-(R9)-amino-(l-6C)alkyl group is, for example, di-(2- hydroxyethyl)aminomethyl and di-(2-methoxyethyl)aminomethyl. Within the definition of the R3 group, a suitable value for a (R10)p-(l-8C)alkyl group is, for example, chloromethyl, 2-fluoroethyl, 2-chloroethyl, 1-chloroethyl, 2,2- difiuoroethyl, 2,2,2-trifluoroethyl, 3-fiuoropropyl, 3-chloropropyl, 3,3-difiuoropropyl, 3,3,3-trifluoropropyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 2- hydroxyethyl, 3-hydroxypropyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3- methoxypropyl, 2-aminoethyl, 3-aminopropyl, 5-aminopropyl, 2-methylaminoethyl, 2- ethylaminoethyl and 3-methylaminopropyl, 2-dimethylaminoethyl, 3- dimethylaminopropyl, heterocyclylmethyl, 2-heterocyclylethyl and 3-heterocyclylpropyl. A suitable value for a (R10)p-(2-8C)alkenyl group is, for example, A- dimethylaminobut-2-enyl and 4-(heterocyclyl)aminobut-2-enyl.
A suitable value for a (R10)p-(2-8C)alkynyl group is, for example, A- dimethylaminobut-2-ynyl and 4-(heterocyclyl)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, dime thy lamine, 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.
It is further to be understood that a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I also forms an aspect of the present invention. Accordingly, 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. Examples of pro-drugs 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. Accordingly, 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. Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, 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- 191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews. 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al, Chem. Pharm. Bull, 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987. 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-hvXy\, (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 1-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). Further suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include (1- 10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-[di-(\- 4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, 7V,7V-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)alkylpiperazin-l-ylmethyl. Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include α-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, 7V-ethyl-7V-methylamine or diethylamine, a (l-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(l-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
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. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, 7V,7V-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)alkylpiperazin-l-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 prodrug).
Particular 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, G2, Ring A, m, n, R1, R2, R3 and R4 has any of the meanings defined hereinbefore or in paragraphs (a) to (iii) hereinafter: -
(a) Gi and G2 are both CH or Gi is N and G2 is CH;
Figure imgf000021_0001
(e) Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
(f) Ring A is a 5- membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
(g) Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three nitrogen atoms;
(h) Ring A is a 5- membered monocyclic heteroaryl ring with up to three nitrogen atoms; (i) Ring A is a 6- membered monocyclic heteroaryl ring with up to three nitrogen atoms; (j) Ring A is furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl; (k) Ring A is pyrazolyl or pyridinyl; (1) Ring A is pyrazol-4-yl or pyridin-3-yl; (m) R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 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 R5 is amino-(l-6C)alkyl, 5 (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (R7)-amino-(l-6C)alkyl or di-(R7)-amino-(l-6C)alkyl, wherein R7 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; or R1 is a group of the formula:
Q1 X2 o wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)CO, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 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 Q1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl,s wherein any heterocyclyl or heteroaryl group within a R1 substituent optionally bears 1, 2 or 3 substituents independently selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylsulphonyl-(l-6C)alkyl, cyano-(l-6C)alkyl, halogeno-(l-6C)alkyl, o amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(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)alkanoyloxy, TV-(I -6C)alkylcarbamoyl, N,N-di-[(\ -6C)alkyl]carbamoyl, (2-6C)alkanoylamino, TV-(I -6C)alkyl-(2-s 6C)alkanoylamino, TV-(I -6C)alkylureido, TV-(I -6C)alkylureido, TV',TV'-di-[(l-
6C)alkyl]ureido, TV5TV' -di-[(l-6C)alkyl]ureido, TV,TV\TV'-tri-[(l-6C)alkyl]ureido, TV-(I- 6C)alkylsulphamoyl, TV,TV-di-[(l -6C)alkyl]sulphamoyl, (1 -6C)alkanesulphonylamino, TV-(I -6C)alkyl-(l-6C)alkanesulphonylamino or heterocyclyl-(l-6C)alkyl, and any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents; or R1 is0 a group of the formula:
Q2 X2 wherein X2 has any of the meanings defined hereinbefore and Q2 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 R1 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, (R9)-amino-(l-6C)alkyl and di-(R9)-amino-(l- 6C)alkyl, wherein R9 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy;
(n) R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 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 R5 is amino-(l-6C)alkyl, (1- 6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (R7)-amino-(l-6C)alkyl or di-(R7)-amino-(l-6C)alkyl, wherein R7 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)C0, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 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 Q1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R1 substituent optionally bears 1 , 2 or 3 substituents independently selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(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, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1- 6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l- 6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, N-(I- 6C)alkylcarbamoyl, TV,TV-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, TV-(I- 6C)alkylureido, TV -(I -6C)alkylureido, TV-(I -6C)alkylsulphamoyl or heterocyclyl-(l- 6C)alkyl and any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents;
(o) R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 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 R5 is amino-(l-6C)alkyl, ( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[( 1 -6C)alkyl] amino-( 1 -6C)alkyl, (R7)-amino-( 1 -6C)alkyl or di-(R7)-amino-(l-6C)alkyl, wherein R7 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)C0, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 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 Q1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R1 substituent optionally bears 1 , 2 or 3 substituents independently selected from halogeno, 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)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, TV-(I -6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l-6C)alkyl, and any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents;
(p) R1 is a group of the formula:
R5-X! - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 is hydrogen or (l-8C)alkyl; and R5 is amino-(l-6C)alkyl,
( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[( 1 -6C)alkyl] amino-( 1 -6C)alkyl, (R7)-amino-( 1 -6C)alkyl or di-(R7)-amino-(l-6C)alkyl, wherein R7 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)C0, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 is hydrogen or (l-8C)alkyl, and Q1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R1 substituent optionally bears 1 , 2 or 3 substituents independently selected from halogeno, 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)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, N-(l-6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l-6C)alkyl, and any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents;
(q) R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)C0,
SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 is hydrogen or (l-8C)alkyl; and R5 is amino-(l-6C)alkyl,
( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[( 1 -6C)alkyl] amino-( 1 -6C)alkyl, (R7)-amino-( 1 -6C)alkyl or di-(R7)-amino-(l-6C)alkyl, wherein R7 is (l-6C)alkyl; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)CO, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 is hydrogen or (l-8C)alkyl, and Q1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R1 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)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)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, N-(l-6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l-6C)alkyl, and any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents;
(r) R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)C0, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 is hydrogen or (l-8C)alkyl; and R5 is amino-(l-3C)alkyl, (l-6C)alkylamino-(l-3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)alkyl, (R7)-amino-(l-3C)alkyl, di-[(R7)-amino-(l-3C)alkyl; and R7 is (l-6C)alkyl; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)C0, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 is hydrogen or (l-8C)alkyl, and Q1 is heterocyclyl, heterocyclyl-(l-3C)alkyl, heteroaryl, heteroaryl-(l-3C)alkyl, wherein any heterocyclyl or heteroaryl group within a R1 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)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)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, TV-(I -6C)alkylcarbamoyl,
(2-6C)alkanoylamino or heterocyclyl-(l-6C)alkyl, and any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents; (s) R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO,
SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 is hydrogen or (l-8C)alkyl; and R5 is amino-(l-3C)alkyl,
(l-6C)alkylamino-(l-3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)alkyl,
(R7)-amino-(l-3C)alkyl, di-[(R7)-amino-(l-3C)alkyl; and R7 is (l-6C)alkyl; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)C0,
SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 is hydrogen or (l-8C)alkyl,
and Q1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein any heterocyclyl group within a R1 substituent optionally bears a halogeno, 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, ( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[( 1 -6C)alkyl] amino-( 1 -6C)alkyl, ( 1 -6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, TV-(I -6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l-6C)alkyl, and any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents;
(t) R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)C0, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 is hydrogen or (l-8C)alkyl; and R5 is amino-(l-3C)alkyl, (l-6C)alkylamino-(l- 3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)alkyl, (R7)-amino-(l-3C)alkyl, di-[(R7)-amino-(l- 3C)alkyl; and R7 is (l-6C)alkyl; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)CO, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 is hydrogen or (l-8C)alkyl, and Q1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl or piperazinyl, each of which 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)alkylamino, di- [(l-6C)alkyl]amino, (2-6C)alkanoyl, TV-(I -6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l-6C)alkyl group, wherein said heterocyclyl within the heterocyclyl-(l- 6C)alkyl substituent group is selected from tetrahydrofuranyl or tetrahydropyranyl;
(u) R1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2-
(dimethylamino)ethyl, 3-(dimethylamino)propyl, ethylaminomethyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, diethylaminomethyl, 2-(diethylamino)ethyl, 3-(diethylamino)propyl aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy, 2- (dimethylamino)ethoxy, 3-(dimethylamino)propoxy, ethylaminomethoxy, 2- (ethylamino)ethoxy, 3-(ethylamino)propoxy, diethylaminomethoxy, 2- (diethylamino)ethoxy, 3-(diethylamino)propoxy, piperidin-4-yl, l-methylpiperidin-4-yl, 1- ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, l-[3-(oxan-4-yl)propyl]piperidin-4-yl, l-[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, piperidin-4-ylmethyl, 1- methylpiperidin-4-ylmethyl, l-ethylpiperidin-4-ylmethyl, l-propylpiperidin-4-ylmethyl, 1- acetylpiperidin-4-ylmethyl, 1 -(2-hydroxyethyl)piperidin-4-ylmethyl, 1 -(3- hydroxypropyl)piperidin-4-ylmethyl, 1 -[2-(oxan-4-yl)ethyl]piperidin-4-ylmethyl, 1 -[3- (oxan-4-yl)propyl]piperidin-4-ylmethyl, l-[2-(oxolan-3-yl)ethyl]piperidin-4-ylmethyl, 1- [3-(oxolan-3-yl)propyl]piperidin-4-ylmethyl, 2-(piperidin-4-yl)ethyl, 2-(l -methylpiperidin- 4-yl)ethyl, 2-(l-ethylpiperidin-4-yl)ethyl, 2-(l-propylpiperidin-4-yl)ethyl, 2-(l- acetylpiperidin-4-yl)ethyl, 2-[l-(2-hydroxyethyl)piperidin-4-yl]ethyl, 2-[l-(3- hydroxypropyl)piperidin-4-yl]ethyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} ethyl, 2- { 1 - [3-(oxan-4-yl)propyl]piperidin-4-yl} ethyl, 2- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl} ethyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl} ethyl, 3-(piperidin-4-yl)propyl, 3-(l - methylpiperidin-4-yl)propyl, 3-(l-ethylpiperidin-4-yl)propyl, 3-(l-propylpiperidin-4- yl)propyl, 3-(l-acetylpiperidin-4-yl)propyl, 3-[l-(2-hydroxyethyl)piperidin-4-yl]propyl, 3- [ 1 -(3-hydroxypropyl)piperidin-4-yl]propyl, 3- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4- yl} propyl, 3 - { 1 - [3 -(oxan-4-yl)propyl]piperidin-4-yl} propyl, 3 - { 1 -[2-(oxolan-3 - yl)ethyl]piperidin-4-yl} propyl, 3-{l-[3-(oxolan-3-yl)propyl]piperidin-4-yl}propyl, piperidin-4-ylcarbamoyl, l-methylpiperidin-4-ylcarbamoyl, l-ethylpiperidin-4- ylcarbamoyl, l-propylpiperidin-4-ylcarbamoyl, l-acetylpiperidin-4-ylcarbamoyl, l-(2- hydroxyethyl)piperidin-4-ylcarbamoyl, 1 -(3-hydroxypropyl)piperidin-4-ylcarbamoyl, 1 -[2- (oxan-4-yl)ethyl]piperidin-4-ylcarbamoyl, l-[3-(oxan-4-yl)propyl]piperidin-4- ylcarbamoyl, 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-ylcarbamoyl, 1 -[3-(oxolan-3- yl)propyl]piperidin-4-ylcarbamoyl, 2-(piperidin-4-yl)ethylcarbamoyl, 2-(l- methylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -ethylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 - propylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -acetylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -(2- hydroxyethyl)piperidin-4-yl)ethylcarbamoyl, 2- [ 1 -(3 -hydroxypropyl)piperidin-4- yl]ethylcarbamoyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} ethylcarbamoyl, 2- { 1 -[3- (oxan-4-yl)propyl]piperidin-4-yl} ethylcarbamoyl, 2- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl} ethylcarbamoyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl} ethylcarbamoyl, 3- (piperidin-4-yl)propylcarbamoyl, 3 -(I -methylpiperidin-4-yl)propylcarbamoyl, 3 -(I - ethylpiperidin-4-yl)propylcarbamoyl, 3-(l-propylpiperidin-4-yl)propylcarbamoyl, 3-(l- acetylpiperidin-4-yl)propylcarbamoyl, 3-(l-(2-hydroxyethyl)piperidin-4- yl)propylcarbamoyl, 3-[l-(3-hydroxypropyl)piperidin-4-yl]propylcarbamoyl, 3-{l-[2- (oxan-4-yl)ethyl]piperidin-4-yl}propylcarbamoyl, 3- { 1 -[3-(oxan-4-yl)propyl]piperidin-4- yl}propylcarbamoyl, 3- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl}propylcarbamoyl, 3- { 1 -[3- (oxolan-3-yl)propyl]piperidin-4-yl}propylcarbamoyl, piperidin-4-ylcarbonyl, 1 - methylpiperidin-4-ylcarbonyl, 1 -ethylpiperidin-4-ylcarbonyl, 1 -propylpiperidin-4- ylcarbonyl, l-acetylpiperidin-4-ylcarbonyl, l-(2-hydroxyethyl)piperidin-4-ylcarbonyl, 1- (3-hydroxypropyl)piperidin-4-ylcarbonyl, 1 -[2-(oxan-4-yl)ethyl]piperidin-4-ylcarbonyl, 1 - [3-(oxan-4-yl)propyl]piperidin-4-ylcarbonyl, l-[2-(oxolan-3-yl)ethyl]piperidin-4- ylcarbonyl, 1 -[3-(oxolan-3-yl)propyl]piperidin-4-ylcarbonyl, 2-(piperidin-4- yl)ethylcarbonyl, 2-(l-methylpiperidin-4-yl)ethylcarbonyl, 2-(l-ethylpiperidin-4- yl)ethylcarbonyl, 2-(l-propylpiperidin-4-yl)ethylcarbonyl, 2-(l-acetylpiperidin-4- yl)ethylcarbonyl, 2-(l -(2-hydroxyethyl)piperidin-4-yl)ethylcarbonyl, 2-[ 1 -(3- hydroxypropyl)piperidin-4-yl]ethylcarbonyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4- yl} ethylcarbonyl, 2- { 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl} ethylcarbonyl, 2- { 1 -[2- (oxolan-3-yl)ethyl]piperidin-4-yl} ethylcarbonyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4- yl} ethylcarbonyl, 3-(piperidin-4-yl)propylcarbonyl, 3-(l -methylpiperidin-4- yl)propylcarbonyl, 3-(l-ethylpiperidin-4-yl)propylcarbonyl, 3-(l-propylpiperidin-4- yl)propylcarbonyl, 3-(l-acetylpiperidin-4-yl)propylcarbonyl, 3 -(I -(2- hydroxyethyl)piperidin-4-yl)propylcarbonyl, 3-[ 1 -(3-hydroxypropyl)piperidin-4- yl]propylcarbonyl, 3- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl}propylcarbonyl, 3- { 1 -[3-(oxan- 4-yl)propyl]piperidin-4-yl}propylcarbonyl, 3- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl}propylcarbaonyl, 3- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl}propylcarbonyl, piperazin- 1 -yl, 4-methyl-piperazin- 1 -yl, 4-ethyl-piperazin- 1 -yl, 4-propyl-piperazin- 1 -yl, 4-acetyl- piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-l-yl, 4-(3-hydroxypropyl)piperazin-l-yl, 4- [2- (oxan-4-yl)ethyl]piperazin-l -yl, 4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl, 4-[2-(oxolan-3- yl)ethyl]piperazin-l-yl, 4-[3-(oxolan-3-yl)propyl]piperazin-l-yl, piperazin-1-ylmethyl, (4- methyl-piperazin- 1 -yl)methyl, (4-ethyl-piperazin- 1 -yl)methyl, (4-propyl-piperazin- 1 - yl)methyl, (4-acetyl-piperazin-l-yl)methyl, [4-(2-hydroxyethyl)piperazin-l-yl]methyl, [4- (3-hydroxypropyl)piperazin-l-yl]methyl, {4-[2-(oxan-4-yl)ethyl]piperazin-l-yl}methyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl}methyl, {4-[2-(oxolan-3-yl)ethyl]piperazin- 1 - yl}methyl, {4-[3-(oxolan-3-yl)propyl]piperazin-l-yl}methyl, 2-(piperazin-l-yl)ethyl, 2- [(4-methyl-piperazin- 1 -yl)] ethyl, 2- [(4-ethyl-piperazin- 1 -yl)]ethyl, 2-[(4-propyl-piperazin- 1 -yl)] ethyl, 2-[(4-acetyl-piperazin-l-yl)]ethyl, 2-{[4-(2-hydroxyethyl)piperazin-l- yl] } ethyl, 2- { [4-(3-hydroxypropyl)piperazin- 1 -yl] } ethyl, 2- {4-[2-(oxan-4- yl)ethyl]piperazin-l-yl} ethyl, 2-{4-[3-(oxan-4-yl)propyl]piperazin-l-yl}ethyl, 2-{4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl} ethyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin-l -yl} ethyl, 3-(piperazin- 1 -yl)propyl, 3 -[(4-methyl-piperazin- 1 -yl)]propyl, 3 - [(4-ethyl-piperazin- 1 - yl)]propyl, 3-[(4-propyl-piperazin-l-yl)]propyl, 3-[(4-acetyl-piperazin-l-yl)]propyl, 3-{[4- (2-hydroxyethyl)piperazin- 1 -yl] } propyl, 3 - { [4-(3 -hydroxypropyl)piperazin- 1 -yl] } propyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 -yl}propyl, 3- {4-[3-(oxan-4-yl)propyl]piperazin- 1 - yl} propyl, 3 - {4-[2-(oxolan-3 -yl)ethy ljpiperazin- 1 -yl} propyl, 3 - {4-[3 -(oxolan-3 - yl)propyl]piperazin- 1 -yl}propyl, piperazin- 1 -ylcarbamoyl, (4-methyl-piperazin- 1 - yl)carbamoyl, (4-ethyl-piperazin-l-yl)carbamoyl, (4-propyl-piperazin-l-yl)carbamoyl, (4- acetyl-piperazin- 1 -yl)carbamoyl, [4-(2-hydroxyethyl)piperazin- 1 -yl] carbamoyl, [4-(3- 5 hydroxypropyl)piperazin-l-yl] carbamoyl, {4-[2-(oxan-4-yl)ethyl]piperazin-l- yl} carbamoyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl} carbamoyl, {4-[2-(oxolan-3- yl)ethyl]piperazin- 1-yl} carbamoyl, {4- [3 -(oxolan-3 -yl)propyl]piperazin- 1 -yl} carbamoyl, 2-(piperazin- 1 -yl)ethylcarbamoyl, 2-(4-methyl-piperazin- 1 -yl)ethylcarbamoyl, 2-(4-ethyl- piperazin- 1 -yl)ethylcarbamoyl, 2-(4-propyl-piperazin- 1 -yl)ethylcarbamoyl, 2-(4-acetyl- i o piperazin- 1 -yl)ethylcarbamoyl, 2- [4-(2-hydroxyethyl)piperazin- 1 -yl] ethylcarbamoyl, 2- [4- (3-hydroxypropyl)piperazin- 1 -yl] ethylcarbamoyl, 2- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 - yl} ethylcarbamoyl, 2- {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl} ethylcarbamoyl, 2- {4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl} ethylcarbamoyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} ethylcarbamoyl, 3 -(piperazin- 1 -yl)propylcarbamoyl, 3 -(4-methyl-piperazin- 1 - is yl)propylcarbamoyl, 3-(4-ethyl-piperazin-l-yl)propylcarbamoyl, 3-(4-propyl-piperazin-l- yl)propylcarbamoyl, 3-(4-acetyl-piperazin-l-yl)propylcarbamoyl, 3-[4-(2- hydroxyethyl)piperazin- 1 -yl]propylcarbamoyl, 3 - [4-(3 -hydroxypropyl)piperazin- 1 - yl]propylcarbamoyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin-l -yl}propylcarbamoyl, 3- {4- [3- (oxan-4-yl)propyl]piperaziny-l-l}propylcarbamoyl, 3-{4-[2-(oxolan-3-yl)ethyl]piperazin-
20 l-yl}propylcarbamoyl, 3-{4-[3-(oxolan-3-yl)propyl]piperazin-l-yl}propylcarbamoyl, piperazin- 1-ylcarbonyl, 4-methylpiperazin-l-ylcarbonyl, 4-ethylpiperazin-l-ylcarbonyl, 4- propylpiperazin- 1 -ylcarbonyl, (4-acetyl-piperazin- 1 -yl)carbonyl, [4-(2- hydroxyethyl)piperazin- 1 -yl] carbonyl, [4-(3 -hydroxypropyl)piperazin- 1 -yl] carbonyl, {4- [2-(oxan-4-yl)ethyl]piperazin- 1 -yl} carbonyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 -
25 yl}carbonyl, {4- [2-(oxolan-3-yl)ethyl]piperazin- 1-yl} carbonyl, {4- [3 -(oxolan-3 - yl)propyl]piperazin- 1 -yl} carbonyl, 2-(piperazin- 1 -yl)ethylcarbonyl, 2-(4-methyl-piperazin- 1 -yl)ethylcarbonyl, 2-(4-ethyl-piperazin- 1 -yl)ethylcarbonyl, 2-(4-propyl-piperazin- 1 - yl)ethylcarbonyl, 2-(4-acetyl-piperazin- 1 -yl)ethylcarbonyl, 2-[4-(2- hydroxyethyl)piperazin- 1 -yl]ethylcarbonyl, 2- [4-(3 -hydroxypropyl)piperazin- 1 -
30 yl]ethylcarbonyl, 2- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 -yl} ethylcarbonyl, 2- {4-[3-(oxan-4- yl)propyl]piperazin- 1 -yl} ethylcarbonyl, 2- {4-[2-(oxolan-3-yl)ethyl]piperazin- 1 - yl} ethylcarbonyl, 2- {4- [3 -(oxolan-3 -yl)propyl]piperazin- 1 -yl} ethylcarbonyl, 3-(piperazin- 1 -yl)propylcarbonyl, 3 -(4-methyl-piperazin- 1 -yl)propylcarbonyl, 3 -(4-ethyl-piperazin- 1 - yl)propylcarbonyl, 3-(4-propyl-piperazin-l-yl)propylcarbonyl, 3-(4-acetyl-piperazin-l- yl)propylcarbonyl, 3-[4-(2-hydroxyethyl)piperazin-l-yl]propylcarbonyl, 3-[4-(3- hydroxypropyl)piperazin- 1 -yl]propylcarbonyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 - yl}propylcarbonyl, 3-{4-[3-(oxan-4-yl)propyl]piperaziny-l-l}propylcarbonyl, 3-{4-[2- (oxolan-3-yl)ethyl]piperazin-l-yl}propylcarbonyl or 3-{4-[3-(oxolan-3- yl)propyl]piperazin- 1 -yl}propylcarbonyl;
(v) When Ring A is pyrazol-4-yl, R1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, and when Ring A is pyridin-3-yl, R1 is aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2-(methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy, 2-(dimethylamino)ethoxy, 3-(dimethylamino)propoxy, piperidin- 1-yl, piperazin-1-yl, 4-methylpiperidin-l-yl, 4-ethylpiperidin-l-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin- 1 -yl, 1 -methylpiperidin-4-ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3 -(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, A- methylpiperazin- 1 -ylcarbonyl, 4-ethylpiperazin- 1 -ylcarbonyl or 4-propylpiperazin- 1 - ylcarbonyl;
(w) When Ring A is pyrazol-4-yl, R1 is 1 -(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1 -(l-ethylpiperidin-4-yl), 1 -(l-acetylpiperidin-4-yl), 1 -[I -(2-hydroxyethyl)piperidin-4-yl], l-{l-[2-(oxan-4-yl)ethyl]piperidin-4-yl}, l-{l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl} (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3-(dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6- (4-methylpiperazin- 1 -yl), 5 -( 1 -methylpiperidin-4-ylcarbamoyl), 5 - [3 -(4-methylpiperazin- l-yl)propylcarbamoyl] or 5 -(4-methylpiperazin- 1 -ylcarbonyl) (that is each R1 group is located at the stated 5- or 6- position on the pyridin-3-yl ring);
(x) m is 0, 1 or 2; (y) m is 0 or 1 ;
(z) m is 0, 1 or 2, and, when m is 2, each R2 group may be the same or different, and each R2 group present is selected from halogeno, cyano, hydroxy, amino, (1- 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)alkylsulphinyl, (1-
6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, N-(l-6C)alkylcarbamoyl, N,N-di-[(\- 6C)alkyl]carbamoyl and (2-6C)alkanoylamino;
(aa) m is 0 or 1, and when m is 1, the R group present 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, (1- 6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, TV-(I -6C)alkylcarbamoyl, 7V,7V-di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino; (bb) m is 0 or 1, and when m is 1, the R2 group present is selected from halogeno, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy, N-(l-6C)alkylcarbamoyl, N,N- di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino; (cc) m is 0 or 1, and when m is 1, the R group present is selected from halogeno, hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy and propoxy; (dd) m is O;
(ee) R3 is hydrogen, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (R10)p-(l-8C)alkyl, wherein each p is 1, 2 or 3 and each R10 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, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2- 8C)alkynyl and (l-6C)alkoxy; (ff) R3 is hydrogen, (l-8C)alkyl or (R10)-(l-8C)alkyl, wherein R10 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; (gg) R3 is hydrogen, methyl, ethyl, propyl or (R10)-(l-8C)alkyl, wherein R10 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; (hh) R3 is hydrogen, methyl, ethyl, propyl or (R10)-(l-3C)alkyl, wherein R10 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; (ii) R3 is hydrogen, methyl, ethyl or propyl; (jj) R3 is hydrogen; (kk) n is 0, 1 or 2; (11) n is O or l; (mm) n is 0, 1 or 2, and, when n is 2, each R4 group present may be the same or different, and each R4 group is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR11, N-(I -6C)alkylsulphamoyl, N,N-di-[(l -6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, N- (l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino, wherein R11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl, wherein any aryl, heterocyclyl or heteroaryl group within the definition of R11 optionally bears 1, 2 or 3 substituents independently selected from halogeno, trifluoromethyl, oxo, cyano, hydroxy, amino, carboxy, carbamoyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (l-6C)alkoxy; (nn) n is 0 or 1 and when n is 1, R4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR1 ! , N-(I -6C)alkylsulphamoyl, N,N-di-[(l -6C)alkyl] sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l- 6C)alkoxy, carbamoyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl] carbamoyl and (2- 6C)alkanoylamino, wherein R11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-
6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl;
(oo) n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, chloro, amino, trifluoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy;
(pp) n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, methoxy, phenylmethoxy or oxolan-3-ylmethoxy;
(qq) Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl; (rr) R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO,
SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 is hydrogen or (l-8C)alkyl; and R5 is amino-(l-3C)alkyl, (l-6C)alkylamino-(l- 3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)alkyl, (R7)-amino-(l-3C)alkyl, di-[(R7)-amino-(l-
3C)alkyl; and R7 is (l-6C)alkyl; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)C0, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 is hydrogen or (l-8C)alkyl, and Q1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (1- 8C)alkyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-
6C)alkyl, halogeno-( 1 -6C)alkyl, amino-( 1 -6C)alkyl, ( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino,
(2-6C)alkanoyl, TV-(I -6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l- 6C)alkyl group, wherein said heterocyclyl within the heterocyclyl-(l-6C)alkyl substituent group is selected from tetrahydrofuranyl or tetrahydropyranyl; (ss) R1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, ethylaminomethyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, diethylaminomethyl, 2-(diethylamino)ethyl, 3-(diethylamino)propyl aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy, 2- (dimethylamino)ethoxy, 3-(dimethylamino)propoxy, ethylaminomethoxy, 2- (ethylamino)ethoxy, 3-(ethylamino)propoxy, diethylaminomethoxy, 2- (diethylamino)ethoxy, 3-(diethylamino)propoxy, piperidin-4-yl, l-methylpiperidin-4-yl, 1- ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, piperidin-4-ylmethyl, 1- methylpiperidin-4-ylmethyl, l-ethylpiperidin-4-ylmethyl, l-propylpiperidin-4-ylmethyl, 1- acetylpiperidin-4-ylmethyl, l-(2-hydroxyethyl)piperidin-4-ylmethyl, l-(3- hydroxypropyl)piperidin-4-ylmethyl, 1 -[2-(oxan-4-yl)ethyl]piperidin-4-ylmethyl, 1 -[3- (oxan-4-yl)propyl]piperidin-4-ylmethyl, 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-ylmethyl, 1 - [3-(oxolan-3-yl)propyl]piperidin-4-ylmethyl, 2-(piperidin-4-yl)ethyl, 2-(l -methylpiperidin- 4-yl)ethyl, 2-(l-ethylpiperidin-4-yl)ethyl, 2-(l-propylpiperidin-4-yl)ethyl, 2-(l- acetylpiperidin-4-yl)ethyl, 2-[l-(2-hydroxyethyl)piperidin-4-yl]ethyl, 2-[l-(3- hydroxypropyl)piperidin-4-yl]ethyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} ethyl, 2- { 1 - [3-(oxan-4-yl)propyl]piperidin-4-yl} ethyl, 2- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl} ethyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl} ethyl, 3-(piperidin-4-yl)propyl, 3-(l - methylpiperidin-4-yl)propyl, 3-(l-ethylpiperidin-4-yl)propyl, 3-(l-propylpiperidin-4- yl)propyl, 3-(l-acetylpiperidin-4-yl)propyl, 3-[l-(2-hydroxyethyl)piperidin-4-yl]propyl, 3- [ 1 -(3-hydroxypropyl)piperidin-4-yl]propyl, 3- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4- yl} propyl, 3 - { 1 - [3 -(oxan-4-yl)propyl]piperidin-4-yl} propyl, 3 - { 1 -[2-(oxolan-3 - yl)ethyl]piperidin-4-yl} propyl, 3-{l-[3-(oxolan-3-yl)propyl]piperidin-4-yl}propyl, piperidin-4-ylcarbamoyl, 1 -methylpiperidin-4-ylcarbamoyl, 1 -ethylpiperidin-4- ylcarbamoyl, l-propylpiperidin-4-ylcarbamoyl, l-acetylpiperidin-4-ylcarbamoyl, l-(2- hydroxyethyl)piperidin-4-ylcarbamoyl, 1 -(3-hydroxypropyl)piperidin-4-ylcarbamoyl, 1 -[2- (oxan-4-yl)ethyl]piperidin-4-ylcarbamoyl, l-[3-(oxan-4-yl)propyl]piperidin-4- ylcarbamoyl, 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-ylcarbamoyl, 1 -[3-(oxolan-3- yl)propyl]piperidin-4-ylcarbamoyl, 2-(piperidin-4-yl)ethylcarbamoyl, 2-( 1 - methylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -ethylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 - propylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -acetylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -(2- hydroxyethyl)piperidin-4-yl)ethylcarbamoyl, 2- [ 1 -(3 -hydroxypropyl)piperidin-4- yl]ethylcarbamoyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} ethylcarbamoyl, 2- { 1 -[3- (oxan-4-yl)propyl]piperidin-4-yl} ethylcarbamoyl, 2- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl} ethylcarbamoyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl} ethylcarbamoyl, 3- (piperidin-4-yl)propylcarbamoyl, 3 -(I -methylpiperidin-4-yl)propylcarbamoyl, 3 -(I - ethylpiperidin-4-yl)propylcarbamoyl, 3-(l-propylpiperidin-4-yl)propylcarbamoyl, 3-(l- acetylpiperidin-4-yl)propylcarbamoyl, 3-(l-(2-hydroxyethyl)piperidin-4- yl)propylcarbamoyl, 3-[ 1 -(3-hydroxypropyl)piperidin-4-yl]propylcarbamoyl, 3- { 1 -[2- (oxan-4-yl)ethyl]piperidin-4-yl}propylcarbamoyl, 3- { 1 -[3-(oxan-4-yl)propyl]piperidin-4- yl}propylcarbamoyl, 3- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl}propylcarbamoyl, 3- { 1 -[3- (oxolan-3-yl)propyl]piperidin-4-yl}propylcarbamoyl, piperidin-4-ylcarbonyl, 1- methylpiperidin-4-ylcarbonyl, 1 -ethylpiperidin-4-ylcarbonyl, 1 -propylpiperidin-4- ylcarbonyl, l-acetylpiperidin-4-ylcarbonyl, l-(2-hydroxyethyl)piperidin-4-ylcarbonyl, 1- (3-hydroxypropyl)piperidin-4-ylcarbonyl, 1 -[2-(oxan-4-yl)ethyl]piperidin-4-ylcarbonyl, 1 - [3-(oxan-4-yl)propyl]piperidin-4-ylcarbonyl, l-[2-(oxolan-3-yl)ethyl]piperidin-4- ylcarbonyl, l-[3-(oxolan-3-yl)propyl]piperidin-4-ylcarbonyl, 2-(piperidin-4- yl)ethylcarbonyl, 2-(l-methylpiperidin-4-yl)ethylcarbonyl, 2-(l-ethylpiperidin-4- yl)ethylcarbonyl, 2-(l-propylpiperidin-4-yl)ethylcarbonyl, 2-(l-acetylpiperidin-4- yl)ethylcarbonyl, 2-(l -(2-hydroxyethyl)piperidin-4-yl)ethylcarbonyl, 2-[ 1 -(3- hydroxypropyl)piperidin-4-yl]ethylcarbonyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4- yl} ethylcarbonyl, 2- { 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl} ethylcarbonyl, 2- { 1 -[2-
(oxolan-3-yl)ethyl]piperidin-4-yl} ethylcarbonyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4- yl} ethylcarbonyl, 3-(piperidin-4-yl)propylcarbonyl, 3-(l -methylpiperidin-4- yl)propylcarbonyl, 3-(l-ethylpiperidin-4-yl)propylcarbonyl, 3-(l-propylpiperidin-4- yl)propylcarbonyl, 3-(l-acetylpiperidin-4-yl)propylcarbonyl, 3-(l-(2- hydroxyethyl)piperidin-4-yl)propylcarbonyl, 3-[ 1 -(3-hydroxypropyl)piperidin-4- yl]propylcarbonyl, 3- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl}propylcarbonyl, 3- { 1 -[3-(oxan- 4-yl)propyl]piperidin-4-yl}propylcarbonyl, 3- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl}propylcarbaonyl, 3- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl}propylcarbonyl, piperazin- 1-yl, 4-methyl-piperazin-l-yl, 4-ethyl-piperazin-l-yl, 4-propyl-piperazin-l-yl, 4-acetyl- piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-l-yl, 4-(3-hydroxypropyl)piperazin-l-yl, 4- [2- (oxan-4-yl)ethyl]piperazin-l -yl, 4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl, 4-[2-(oxolan-3- yl)ethyl]piperazin-l-yl, 4-[3-(oxolan-3-yl)propyl]piperazin-l-yl, piperazin-1-ylmethyl, (4- methyl-piperazin- 1 -yl)methyl, (4-ethyl-piperazin- 1 -yl)methyl, (4-propyl-piperazin- 1 - yl)methyl, (4-acetyl-piperazin-l-yl)methyl, [4-(2-hydroxyethyl)piperazin-l-yl]methyl, [4- (3-hydroxypropyl)piperazin-l-yl]methyl, {4-[2-(oxan-4-yl)ethyl]piperazin-l-yl}methyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl}methyl, {4-[2-(oxolan-3-yl)ethyl]piperazin- 1 - yl}methyl, {4-[3-(oxolan-3-yl)propyl]piperazin-l-yl}methyl, 2-(piperazin-l-yl)ethyl, 2- [(4-methyl-piperazin- 1 -yl)] ethyl, 2- [(4-ethyl-piperazin- 1 -yl)]ethyl, 2- [(4-propyl-piperazin- l-yl)] ethyl, 2-[(4-acetyl-piperazin-l-yl)]ethyl, 2-{[4-(2-hydroxyethyl)piperazin-l- yl] } ethyl, 2- { [4-(3-hydroxypropyl)piperazin- 1 -yl] } ethyl, 2- {4-[2-(oxan-4- yl)ethyl]piperazin-l-yl} ethyl, 2-{4-[3-(oxan-4-yl)propyl]piperazin-l-yl}ethyl, 2-{4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl} ethyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin-l -yl} ethyl, 3-(piperazin- 1 -yl)propyl, 3-[(4-methyl-piperazin- 1 -yl)]propyl, 3 - [(4-ethyl-piperazin- 1 - yl)]propyl, 3-[(4-propyl-piperazin-l-yl)]propyl, 3-[(4-acetyl-piperazin-l-yl)]propyl, 3-{[4- (2-hydroxyethyl)piperazin- 1 -yl] } propyl, 3 - { [4-(3 -hydroxypropyl)piperazin- 1 -yl] } propyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 -yl}propyl, 3- {4-[3-(oxan-4-yl)propyl]piperazin- 1 - yl}propyl, 3-{4-[2-(oxolan-3-yl)ethyl]piperazin-l-yl}propyl, 3-{4-[3-(oxolan-3- yl)propyl]piperazin- 1 -yl}propyl, piperazin- 1 -ylcarbamoyl, (4-methyl-piperazin- 1 - yl)carbamoyl, (4-ethyl-piperazin- l-yl)carbamoyl, (4-propyl-piperazin- l-yl)carbamoyl, (4- acetyl-piperazin- 1 -yl)carbamoyl, [4-(2-hydroxyethyl)piperazin- 1 -yl] carbamoyl, [4-(3- hydroxypropyl)piperazin-l-yl] carbamoyl, {4-[2-(oxan-4-yl)ethyl]piperazin-l- yl} carbamoyl, {4-[3-(oxan-4-yl)propyl]piperazin-l-yl} carbamoyl, {4-[2-(oxolan-3- yl)ethyl]piperazin-l -yl} carbamoyl, {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} carbamoyl, 2-(piperazin- 1 -yl)ethylcarbamoyl, 2-(4-methyl-piperazin- 1 -yl)ethylcarbamoyl, 2-(4-ethyl- piperazin- 1 -yl)ethylcarbamoyl, 2-(4-propyl-piperazin- 1 -yl)ethylcarbamoyl, 2-(4-acetyl- piperazin- 1 -yl)ethylcarbamoyl, 2- [4-(2-hydroxyethyl)piperazin- 1 -yl] ethylcarbamoyl, 2- [4- (3-hydroxypropyl)piperazin- 1 -yl] ethylcarbamoyl, 2- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 - yl} ethylcarbamoyl, 2- {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl} ethylcarbamoyl, 2- {4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl} ethylcarbamoyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} ethylcarbamoyl, 3 -(piperazin- 1 -yl)propylcarbamoyl, 3 -(4-methyl-piperazin- 1 - yl)propylcarbamoyl, 3-(4-ethyl-piperazin-l -yl)propylcarbamoyl, 3-(4-propyl-piperazin- 1 - yl)propylcarbamoyl, 3-(4-acetyl-piperazin-l-yl)propylcarbamoyl, 3-[4-(2- hydroxyethyl)piperazin- 1 -yl]propylcarbamoyl, 3 - [4-(3 -hydroxypropyl)piperazin- 1 - 5 yl]propylcarbamoyl, 3-{4-[2-(oxan-4-yl)ethyl]piperazin-l-yl}propylcarbamoyl, 3- {4- [3- (oxan-4-yl)propyl]piperaziny-l-l}propylcarbamoyl, 3-{4-[2-(oxolan-3-yl)ethyl]piperazin- l-yl}propylcarbamoyl, 3-{4-[3-(oxolan-3-yl)propyl]piperazin-l-yl}propylcarbamoyl, piperazin- 1-ylcarbonyl, 4-methylpiperazin-l-ylcarbonyl, 4-ethylpiperazin-l-ylcarbonyl, 4- propylpiperazin- 1 -ylcarbonyl, (4-acetyl-piperazin- 1 -yl)carbonyl, [4-(2- i o hydroxyethyl)piperazin- 1 -yl] carbonyl, [4-(3 -hydroxypropyl)piperazin- 1 -yl] carbonyl, {4- [2-(oxan-4-yl)ethyl]piperazin- 1 -yl} carbonyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 - yl} carbonyl, {4-[2-(oxolan-3-yl)ethyl]piperazin-l -yl} carbonyl, {4-[3-(oxolan-3- yl)propyl]piperazin- 1 -yl} carbonyl, 2-(piperazin- 1 -yl)ethylcarbonyl, 2-(4-methyl-piperazin- 1 -yl)ethylcarbonyl, 2-(4-ethyl-piperazin- 1 -yl)ethylcarbonyl, 2-(4-propyl-piperazin- 1 - is yl)ethylcarbonyl, 2-(4-acetyl-piperazin-l-yl)ethylcarbonyl, 2-[4-(2- hydroxyethyl)piperazin- 1 -yl]ethylcarbonyl, 2- [4-(3 -hydroxypropyl)piperazin- 1 - yl]ethylcarbonyl, 2- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 -yl} ethylcarbonyl, 2- {4-[3-(oxan-4- yl)propyl]piperazin- 1 -yl} ethylcarbonyl, 2- {4-[2-(oxolan-3-yl)ethyl]piperazin- 1 - yl} ethylcarbonyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} ethylcarbonyl, 3-(piperazin-
20 l-yl)propylcarbonyl, 3 -(4-methyl-piperazin- l-yl)propylcarbonyl, 3-(4-ethyl-piperazin-l- yl)propylcarbonyl, 3-(4-propyl-piperazin-l-yl)propylcarbonyl, 3 -(4-acetyl-piperazin- 1- yl)propylcarbonyl, 3-[4-(2-hydroxyethyl)piperazin-l-yl]propylcarbonyl, 3-[4-(3- hydroxypropyl)piperazin- 1 -yl]propylcarbonyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 - yl}propylcarbonyl, 3-{4-[3-(oxan-4-yl)propyl]piperaziny-l-l}propylcarbonyl, 3-{4-[2-
25 (oxolan-3-yl)ethyl]piperazin- 1 -yl}propylcarbonyl, 3- {4-[3-(oxolan-3-yl)propyl]piperazin- l-yl}propylcarbonyl, piperidin-3-yl, piperidin-4-ylmethyl, piperidin-3-ylmethyl, morpholin-4-yl, 2-(morpholin-4-yl)ethyl or tetrahydropyran-4-yl; (tt) When Ring A is pyrazol-4-yl, R1 is piperidin-4-yl, l-methylpiperidin-4-yl,l- ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2-
30 hydroxyethyl)piperidin-4-yl, l-(3-hydroxypropyl)piperidin-4-yl, l-[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, 2-(morpholin-4-yl)ethyl, piperidin-4-ylmethyl, piperidin-3-ylmethyl, piperidin-3-yl or tetrahydropyran-4-yl and when Ring A is pyridin-3-yl, R1 is aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy , 2-(methylamino)ethoxy , 3 -(methylamino)propoxy , dimethylaminomethoxy, 2-(dimethylamino)ethoxy, 3-(dimethylamino)propoxy, piperidin- 1 -yl, piperazin- 1 -yl, 4-methylpiperidin- 1 -yl, 4-ethylpiperidin- 1 -yl, 4-methylpiperazin- 1 -yl, 4-ethylpiperazin- 1 -yl, 1 -methylpiperidin-4-ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3 -(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, A- methylpiperazin-1-ylcarbonyl, 4-ethylpiperazin- 1-ylcarbonyl or 4-propylpiperazin-l- ylcarbonyl, and when Ring A is pyridin-4-yl, R1 is piperazin- 1-yl; (uu) When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1 -(I -ethylpiperidin-4-yl), 1 -(I -acetylpiperidin-4-yl), 1 -[I -(2-hydroxyethyl)piperidin-4-yl], 1 - { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} , 1 - { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl} , 1 -[2- (morpholin-4-yl)ethyl], 1 -(piperidin-4-ylmethyl), 1 -(piperidin-3-ylmethyl), l-(piperidin-3- yl) or 1 -(tetrahydropyran-4-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3-(dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l-yl), 5-(l-methylpiperidin-4- ylcarbamoyl), 5-[3-(4-methylpiperazin-l-yl)propylcarbamoyl] or 5 -(4-methylpiperazin- 1- ylcarbonyl) (that is each R1 group is located at the stated 5- or 6- position on the pyridin-3- yl ring); and when Ring A is pyridin-4-yl, R1 is 2-(piperazin-l-yl); (w) R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3- methyloxetan-3 -yl)methyl;
(ww) n is 0, 1 or 2, and, when n is 2, each R4 group present may be the same or different, and each R4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; (xx) Gi is CH and G2 is N or Gi is N and G2 is CH; (yy) Ring A is pyrazolyl; (zz) Ring A is pyrazol-4-yl;
(aaa) Ring A is pyridin-3-yl or pyridin-4-yl; (bbb) When Ring A is pyrazol-4-yl, R1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, 2-(morpholin-4- yl)ethyl, 3-(morpholin-4-yl)propyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-3-yl, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl or l-(4-aminocyclohex-l-yl), and when Ring A is pyridin-3-yl, R1 is aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2-(methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy , 2-(dimethylamino)ethoxy , 3 -(dimethylamino)propoxy , piperidin-1-yl, piperazin-1-yl, 4-methylpiperidin-l-yl, 4-ethylpiperidin-l-yl, 4- methylpiperazin-1-yl, 4-ethylpiperazin-l-yl, l-methylpiperidin-4-ylcarbamoyl, 1- ethylpiperidin-4-ylcarbamoyl, 3 -(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4- ethylpiperazin-l-yl)propylcarbamoyl, 4-methylpiperazin- 1-ylcarbonyl, 4- ethylpiperazin-1-ylcarbonyl or 4-propylpiperazin- 1-ylcarbonyl and when Ring A is pyridin-4-yl, R1 is piperazin-1-yl, aminomethoxy, 2-(amino)ethoxy, 3- (amino)propoxy, methylaminomethoxy, 2-(methylamino)ethoxy, 3- (methylamino)propoxy, dimethylaminomethoxy, 2-(dimethylamino)ethoxy, 3- (dimethylamino)propoxy , piperidin- 1 -yl, piperazin- 1 -yl, 4-methylpiperidin- 1-yl, 4- ethylpiperidin-1-yl, 4-methylpiperazin- 1-yl, 4-ethylpiperazin-l-yl, 1- methylpiperidin-4-ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3-(4- methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, 4-methylpiperazin- 1-ylcarbonyl, 4-ethylpiperazin- 1-ylcarbonyl or 4-propylpiperazin- 1-ylcarbonyl;
(ccc) When Ring A is pyrazol-4-yl, R1 is 1 -(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1- ( l-ethylpiperidin-4-yl), 1 -(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4- yl], 1 - { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} , 1 - { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl}, l-[2-(morpholin-4-yl)ethyl], 1 -(piperidin-4-ylmethyl), 1 -(piperidin-3-ylmethyl), 1 -(piperidin-3-yl), 1 -(tetrahydropyran-4-yl) or l-(4-aminocyclohex-l-yl) (that is each
R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3-(dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l- yl), 6-(4-methylpiperazin-l-yl), 5-(l-methylpiperidin-4-ylcarbamoyl), 5-[3-(4- methylpiperazin-l-yl)propylcarbamoyl] or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R1 group is located at the stated 5- or 6- position on the pyridin-3-yl ring), and when Ring A is pyridin-4-yl, R1 is 2-(piperazin-l-yl); (ddd) When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1- (l-ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4- yl], 1 - { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} , 1 - { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl}, l-[2-(morpholin-4-yl)ethyl], l-(piperidin-3-yl), 1 -(tetrahydropyran-4-yl) or l-(4- aminocyclohex-1-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6- [3-
(dimethylamino)propoxy], 6-(piperazin-l-yl), 6-(4-methylpiperazin-l-yl), 5-(l- methylpiperidin-4-ylcarbamoyl) or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R1 group is located at the stated 5- or 6- position on the pyridin-3-yl ring), and when Ring A is pyridin-4-yl, R1 is 2-(piperazin-l-yl); (eee) When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1- (l-ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4- yl], 1 - { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} , 1 - { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl} or 1 -(tetrahydropyran-4-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3- (dimethylamino)propoxy], (that is each R1 group is located at the stated 6- position on the pyridin-3-yl ring);
(fff) m is 0 or 1 , and when m is 1 , the R group is methyl;
(ggg) R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; (hhh) n is 0, 1 or 2, and, when n is 2, each R4 group present may be the same or different, and each R4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3-ylmethoxy, methyl, chloro, bromo, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isoxazol-3-ylmethoxy or cyclopropylmethoxy; or (iii) n is 0 or 1 and, when n is 1, R4 is selected from hydrogen, fluoro, oxolan-3- ylmethoxy, (tetrahydrofuran-2-yl)methoxy or cyclopropylmethoxy. A particular compound of the invention is a pyrazine derivative of the Formula I above wherein: -
Gi and G2 are both CH or Gi is N and G2 is CH;
Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur; R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 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 R5 is amino-(l-6C)alkyl, (1- 6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (R7)-amino-(l-6C)alkyl or di-(R7)-amino-(l-6C)alkyl, wherein R7 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)C0, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 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 Q1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R1 substituent optionally bears 1 , 2 or 3 substituents independently selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylsulphonyl-(l-6C)alkyl, cyano-(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, (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)alkanoyloxy, N-(l-6C)alkylcarbamoyl,
N,N-di-[(\ -6C)alkyl]carbamoyl, (2-6C)alkanoylamino, N-(I -6C)alkyl-(2- 6C)alkanoylamino, N-(l-6C)alkylureido, AT-(I -6C)alkylureido, N' ,N' -di-[(\- 6C)alkyl]ureido, N,N'-di-[(l-6C)alkyl]ureido, N,N',N'-tri-[(l-6C)alkyl]ureido, N-(I- 6C)alkylsulphamoyl, N,N-di-[(l -6C)alkyl]sulphamoyl, (1 -6C)alkanesulphonylamino, N-(l-6C)alkyl-(l-6C)alkanesulphonylamino or heterocyclyl-(l-6C)alkyl, and any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents; or R1 is a group of the formula:
Q2 X2 wherein X2 has any of the meanings defined hereinbefore and Q2 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 R1 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, (R9)-amino-(l-6C)alkyl and di-(R9)-amino-(l-6C)alkyl, wherein R9 is (1- 6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; m is 0, 1 or 2, and, when m is 2, each R2 group present may be the same or different, and each R2 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)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino; R3 is hydrogen, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (R10)P- (l-8C)alkyl, wherein each p is 1, 2 or 3 and each R10 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, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2- 8C)alkynyl and (l-6C)alkoxy; n is 0, 1 or 2, and, when n is 2, each R4 group present may be the same or different, and each R4 group is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR11, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl] sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl,
N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino, wherein R11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl, wherein any aryl, heterocyclyl or heteroaryl group within the definition of R11 optionally bears 1, 2 or 3 substituents independently selected from halogeno, trifluoromethyl, oxo, cyano, hydroxy, amino, carboxy, carbamoyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (l-6C)alkoxy; 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 G2 are both CH or Gi is N and G2 is CH; Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three nitrogen atoms; R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 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 R5 is amino-(l-6C)alkyl,
( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[( 1 -6C)alkyl] amino-( 1 -6C)alkyl, (R7)-amino-( 1 -6C)alkyl or di-(R7)-amino-(l-6C)alkyl, wherein R7 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; or R1 is a group of the formula: Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)C0, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 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 Q1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R1 substituent optionally bears 1 , 2 or 3 substituents independently selected from halogeno, 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)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, TV-(I -6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l-6C)alkyl, and any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents; m is 0 or 1, and when m is 1, the R2 group present is selected from halogeno, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy, N-(l-6C)alkylcarbamoyl, N,N- di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino;
R3 is hydrogen, methyl, ethyl, propyl or (R10)-(l-3C)alkyl, wherein R10 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, R4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR11, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-
6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, 7V,7V-di-[(l-6C)alkyl] carbamoyl and (2-
6C)alkanoylamino, wherein R11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl; or a pharmaceutically- acceptable salt thereof. A further particular compound of the invention is a pyrazine derivative of the
Formula I above wherein: -
Figure imgf000046_0001
Ring A is pyrazolyl or pyridinyl;
R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO,
SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 is hydrogen or (l-8C)alkyl; and R5 is amino-(l-3C)alkyl, (l-6C)alkylamino-(l-
3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)alkyl, (R7)-amino-(l-3C)alkyl, di-[(R7)-amino-(l- 3C)alkyl; and R7 is (1 -6C)alkyl; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)CO, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 is hydrogen or (l-8C)alkyl, and Q1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl or piperazinyl, each of which 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)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, TV-(I -6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l-6C)alkyl group, wherein said heterocyclyl within the heterocyclyl-(l-6C)alkyl substituent group is selected from tetrahydrofuranyl or tetrahydropyranyl; m is O or 1, and when m is 1, the R2 group is selected from halogeno, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy, TV-(I -6C)alkylcarbamoyl, TV,TV- di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino;
R3 is hydrogen, methyl, ethyl or propyl; n is O or 1 and when n is 1, R4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR1 ! , TV-(I -6C)alkylsulphamoyl, 7V,7V-di-[(l -6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, TV,TV-di-[(l- 6C)alkyl]carbamoyl and (2-6C)alkanoylamino, wherein R11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl; 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 G2 are both CH or Gi is N and G2 is CH; Ring A is pyrazolyl or pyridinyl; R1 is a group of the formula:
R5-X! - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 is hydrogen or (l-8C)alkyl; and R5 is amino-(l-3C)alkyl, (l-6C)alkylamino-(l- 3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)alkyl, (R7)-amino-(l-3C)alkyl, di-[(R7)-amino-(l- 3C)alkyl; and R7 is (1 -6C)alkyl; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)C0, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 is hydrogen or (l-8C)alkyl, and Q1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (1- 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)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, TV-(I -6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l- 6C)alkyl group, wherein said heterocyclyl within the heterocyclyl-(l-6C)alkyl substituent group is selected from tetrahydrofuranyl or tetrahydropyranyl; m is O or 1, and when m is 1, the R2 group is selected from halogeno, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy, N-(l-6C)alkylcarbamoyl, N,N- di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is O or 1 and when n is 1, R4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR11, N-(l-6C)alkylsulphamoyl, N,7V-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, /V,/V-di-[(l- 6C)alkyl]carbamoyl and (2-6C)alkanoylamino, wherein R11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: -
Gi is CH and G2 is N or Gi is N and G2 is CH; Ring A is pyrazolyl or pyridinyl; R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 is hydrogen or (l-8C)alkyl; and R5 is amino-(l-3C)alkyl, (l-6C)alkylamino-(l- 3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)alkyl, (R7)-amino-(l-3C)alkyl, di-[(R7)-amino-(l- 3C)alkyl; and R7 is (l-6C)alkyl; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)C0, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 is hydrogen or (l-8C)alkyl, and Q1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (1- 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)alkylamino, di-[(l-6C)alkyl]amino,
(2-6C)alkanoyl, TV-(I -6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l- 6C)alkyl group, wherein said heterocyclyl within the heterocyclyl-(l-6C)alkyl substituent group is selected from tetrahydrofuranyl or tetrahydropyranyl; m is O or 1, and when m is 1, the R2 group is selected from halogeno, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy, N-(l-6C)alkylcarbamoyl, NJf- di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0 or 1 and when n is 1, R4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR11, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, 7V,7V-di-[(l- 6C)alkyl]carbamoyl and (2-6C)alkanoylamino, wherein R11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: -
Figure imgf000050_0001
Ring A is pyrazolyl or pyridinyl; R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 is hydrogen or (l-8C)alkyl; and R5 is amino-(l-3C)alkyl, (l-6C)alkylamino-(l- 3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)alkyl, (R7)-amino-(l-3C)alkyl, di-[(R7)-amino-(l- 3C)alkyl; and R7 is (l-6C)alkyl; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)C0, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 is hydrogen or (l-8C)alkyl, and Q1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (1- 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)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, TV-(I -6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l- 6C)alkyl group, wherein said heterocyclyl within the heterocyclyl-(l-6C)alkyl substituent group is selected from tetrahydrofuranyl or tetrahydropyranyl; m is 0 or 1, and when m is 1, the R2 group is selected from halogeno, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy, N-(l-6C)alkylcarbamoyl, NJV- di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0 or 1 and when n is 1, R4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR11, /V-(l-6C)alkylsulphamoyl, /V,/V-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, /V,/V-di-[(l- 6C)alkyl]carbamoyl and (2-6C)alkanoylamino, wherein R11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl; 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 G2 are suitably as defined in any one of paragraphs (a) to (d) above;
Ring A 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;
R1 is suitably as defined in any one of paragraphs (m) to (w) above and is particularly as defined in any one of paragraphs (q) to (w) above; R2 is suitably as defined in any one of paragraphs (x) to (dd) above, and is particularly as defined in any one of paragraphs (aa) to (dd) above; R3 is suitably as defined in any one of paragraphs (ee) to (jj) above, and is particularly as defined in any one of paragraphs (gg) to (jj) above; and
R4 is suitably as defined in any one of paragraphs (kk) to (pp) above, and is particularly as defined in any one of paragraphs (nn) to (pp) above. A yet further particular compound of the invention is a pyrazine derivative of the
Formula I above wherein :-
Gi and G2 are suitably as defined in any one of paragraphs (a) to (d) above;
Ring A is suitably as defined in any one of paragraphs (e) to (1) and (qq) above and is particularly as defined in any one of paragraphs (g) to (1) and (qq) above; R1 is suitably as defined in any one of paragraphs (m) to (w) and (rr) to (uu) above and is particularly as defined in any one of paragraphs (q) to (w) and (rr) to (uu) above;
R is suitably as defined in any one of paragraphs (x) to (dd) above, and is particularly as defined in any one of paragraphs (aa) to (dd) above;
R3 is suitably as defined in any one of paragraphs (ee) to (jj) and (w) above, and is particularly as defined in any one of paragraphs (gg) to (jj) and (w) above; and
R4 is suitably as defined in any one of paragraphs (kk) to (pp) and (ww) above, and is particularly as defined in any one of paragraphs (nn) to (pp) and (ww) above.
A yet further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
Gi and G2 are suitably as defined in any one of paragraphs (a) to (d) and (xx) above;
Ring A is suitably as defined in any one of paragraphs (e) to (1) and (qq) and (yy) to (aaa) above and is particularly as defined in any one of paragraphs (g) to (1) and (qq) and (yy) to
(aaa) above; R1 is suitably as defined in any one of paragraphs (m) to (w) and (rr) to (uu) and (bbb) to
(eee) above and is particularly as defined in any one of paragraphs (q) to (w) and (rr) to
(uu) and (bbb) to (eee) above;
R2 is suitably as defined in any one of paragraphs (x) to (dd) above and (fff), and is particularly as defined in any one of paragraphs (aa) to (dd) and (fff) above; R3 is suitably as defined in any one of paragraphs (ee) to (jj) and (w) and (ggg) above, and is particularly as defined in any one of paragraphs (gg) to (jj) and (w) and (ggg) above; and R4 is suitably as defined in any one of paragraphs (kk) to (pp) and (ww) and (hhh) and (iii) above, and is particularly as defined in any one of paragraphs (nn) to (pp) and (ww) and (hhh) and (iii) above.
A further particular compound of the invention is a pyrazine derivative of the
Formula I above wherein :-
Figure imgf000053_0001
Ring A is pyrazolyl or pyridinyl; R1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2-
(dimethylamino)ethyl, 3-(dimethylamino)propyl, ethylaminomethyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, diethylaminomethyl, 2-(diethylamino)ethyl, 3-(diethylamino)propyl aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy, 2- (dimethylamino)ethoxy, 3-(dimethylamino)propoxy, ethylaminomethoxy, 2- (ethylamino)ethoxy, 3-(ethylamino)propoxy, diethylaminomethoxy, 2- (diethylamino)ethoxy, 3-(diethylamino)propoxy, piperidin-4-yl, l-methylpiperidin-4-yl, 1- ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, l-[3-(oxan-4-yl)propyl]piperidin-4-yl, l-[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, piperidin-4-ylmethyl, 1- methylpiperidin-4-ylmethyl, l-ethylpiperidin-4-ylmethyl, l-propylpiperidin-4-ylmethyl, 1- acetylpiperidin-4-ylmethyl, 1 -(2-hydroxyethyl)piperidin-4-ylmethyl, 1 -(3- hydroxypropyl)piperidin-4-ylmethyl, 1 -[2-(oxan-4-yl)ethyl]piperidin-4-ylmethyl, 1 -[3- (oxan-4-yl)propyl]piperidin-4-ylmethyl, l-[2-(oxolan-3-yl)ethyl]piperidin-4-ylmethyl, 1- [3-(oxolan-3-yl)propyl]piperidin-4-ylmethyl, 2-(piperidin-4-yl)ethyl, 2-(l -methylpiperidin- 4-yl)ethyl, 2-(l-ethylpiperidin-4-yl)ethyl, 2-(l-propylpiperidin-4-yl)ethyl, 2-(l- acetylpiperidin-4-yl)ethyl, 2-[l-(2-hydroxyethyl)piperidin-4-yl]ethyl, 2-[l-(3- hydroxypropyl)piperidin-4-yl]ethyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} ethyl, 2- { 1 - [3-(oxan-4-yl)propyl]piperidin-4-yl} ethyl, 2- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl} ethyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl} ethyl, 3-(piperidin-4-yl)propyl, 3-(l - methylpiperidin-4-yl)propyl, 3-(l-ethylpiperidin-4-yl)propyl, 3-(l-propylpiperidin-4- yl)propyl, 3-(l-acetylpiperidin-4-yl)propyl, 3-[l-(2-hydroxyethyl)piperidin-4-yl]propyl, 3- [ 1 -(3-hydroxypropyl)piperidin-4-yl]propyl, 3- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4- yl} propyl, 3 - { 1 - [3 -(oxan-4-yl)propyl]piperidin-4-yl} propyl, 3 - { 1 -[2-(oxolan-3 - yl)ethyl]piperidin-4-yl} propyl, 3-{l-[3-(oxolan-3-yl)propyl]piperidin-4-yl}propyl, piperidin-4-ylcarbamoyl, l-methylpiperidin-4-ylcarbamoyl, l-ethylpiperidin-4- ylcarbamoyl, l-propylpiperidin-4-ylcarbamoyl, l-acetylpiperidin-4-ylcarbamoyl, l-(2- hydroxyethyl)piperidin-4-ylcarbamoyl, 1 -(3-hydroxypropyl)piperidin-4-ylcarbamoyl, 1 -[2- (oxan-4-yl)ethyl]piperidin-4-ylcarbamoyl, l-[3-(oxan-4-yl)propyl]piperidin-4- ylcarbamoyl, 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-ylcarbamoyl, 1 -[3-(oxolan-3- yl)propyl]piperidin-4-ylcarbamoyl, 2-(piperidin-4-yl)ethylcarbamoyl, 2-(l- methylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -ethylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 - propylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -acetylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -(2- hydroxyethyl)piperidin-4-yl)ethylcarbamoyl, 2- [ 1 -(3 -hydroxypropyl)piperidin-4- yl]ethylcarbamoyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} ethylcarbamoyl, 2- { 1 -[3- (oxan-4-yl)propyl]piperidin-4-yl} ethylcarbamoyl, 2-{l-[2-(oxolan-3-yl)ethyl]piperidin-4- yl} ethylcarbamoyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl} ethylcarbamoyl, 3- (piperidin-4-yl)propylcarbamoyl, 3 -(I -methylpiperidin-4-yl)propylcarbamoyl, 3 -(I - ethylpiperidin-4-yl)propylcarbamoyl, 3-(l-propylpiperidin-4-yl)propylcarbamoyl, 3-(l- acetylpiperidin-4-yl)propylcarbamoyl, 3-(l-(2-hydroxyethyl)piperidin-4- yl)propylcarbamoyl, 3-[l-(3-hydroxypropyl)piperidin-4-yl]propylcarbamoyl, 3-{l-[2- (oxan-4-yl)ethyl]piperidin-4-yl}propylcarbamoyl, 3- { 1 -[3-(oxan-4-yl)propyl]piperidin-4- yl}propylcarbamoyl, 3- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl}propylcarbamoyl, 3- { 1 -[3- (oxolan-3-yl)propyl]piperidin-4-yl}propylcarbamoyl, piperidin-4-ylcarbonyl, 1 - methylpiperidin-4-ylcarbonyl, 1 -ethylpiperidin-4-ylcarbonyl, 1 -propylpiperidin-4- ylcarbonyl, l-acetylpiperidin-4-ylcarbonyl, l-(2-hydroxyethyl)piperidin-4-ylcarbonyl, 1- (3-hydroxypropyl)piperidin-4-ylcarbonyl, 1 -[2-(oxan-4-yl)ethyl]piperidin-4-ylcarbonyl, 1 - [3-(oxan-4-yl)propyl]piperidin-4-ylcarbonyl, l-[2-(oxolan-3-yl)ethyl]piperidin-4- ylcarbonyl, 1 -[3-(oxolan-3-yl)propyl]piperidin-4-ylcarbonyl, 2-(piperidin-4- yl)ethylcarbonyl, 2-(l-methylpiperidin-4-yl)ethylcarbonyl, 2-(l-ethylpiperidin-4- yl)ethylcarbonyl, 2-(l-propylpiperidin-4-yl)ethylcarbonyl, 2-(l-acetylpiperidin-4- yl)ethylcarbonyl, 2-(l -(2-hydroxyethyl)piperidin-4-yl)ethylcarbonyl, 2-[ 1 -(3- hydroxypropyl)piperidin-4-yl]ethylcarbonyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4- yl} ethylcarbonyl, 2- { 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl} ethylcarbonyl, 2- { 1 -[2- (oxolan-3-yl)ethyl]piperidin-4-yl} ethylcarbonyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4- yl} ethylcarbonyl, 3-(piperidin-4-yl)propylcarbonyl, 3-(l -methylpiperidin-4- yl)propylcarbonyl, 3-(l-ethylpiperidin-4-yl)propylcarbonyl, 3-(l-propylpiperidin-4- yl)propylcarbonyl, 3-(l-acetylpiperidin-4-yl)propylcarbonyl, 3 -(I -(2- hydroxyethyl)piperidin-4-yl)propylcarbonyl, 3-[ 1 -(3-hydroxypropyl)piperidin-4- yl]propylcarbonyl, 3- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl}propylcarbonyl, 3- { 1 -[3-(oxan- 4-yl)propyl]piperidin-4-yl}propylcarbonyl, 3- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl}propylcarbaonyl, 3- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl}propylcarbonyl, piperazin- 1-yl, 4-methyl-piperazin-l-yl, 4-ethyl-piperazin-l-yl, 4-propyl-piperazin-l-yl, 4-acetyl- piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-l-yl, 4-(3-hydroxypropyl)piperazin-l-yl, 4- [2- (oxan-4-yl)ethyl]piperazin-l -yl, 4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl, 4-[2-(oxolan-3- yl)ethyl]piperazin-l-yl, 4-[3-(oxolan-3-yl)propyl]piperazin-l-yl, piperazin-1-ylmethyl, (4- methyl-piperazin- 1 -yl)methyl, (4-ethyl-piperazin- 1 -yl)methyl, (4-propyl-piperazin- 1 - yl)methyl, (4-acetyl-piperazin-l-yl)methyl, [4-(2-hydroxyethyl)piperazin-l-yl]methyl, [4- (3-hydroxypropyl)piperazin-l-yl]methyl, {4-[2-(oxan-4-yl)ethyl]piperazin-l-yl}methyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl}methyl, {4-[2-(oxolan-3-yl)ethyl]piperazin- 1 - yl}methyl, {4-[3-(oxolan-3-yl)propyl]piperazin-l-yl}methyl, 2-(piperazin-l-yl)ethyl, 2- [(4-methyl-piperazin- 1 -yl)] ethyl, 2- [(4-ethyl-piperazin- 1 -yl)]ethyl, 2-[(4-propyl-piperazin- 1-yl)] ethyl, 2- [(4-acetyl-piperazin- 1-yl)] ethyl, 2-{[4-(2-hydroxyethyl)piperazin-l- yl] } ethyl, 2- { [4-(3-hydroxypropyl)piperazin- 1 -yl] } ethyl, 2- {4-[2-(oxan-4- yl)ethyl]piperazin- 1-yl} ethyl, 2-{4-[3-(oxan-4-yl)propyl]piperazin-l-yl}ethyl, 2-{4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl} ethyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin-l -yl} ethyl, 3-(piperazin- 1 -yl)propyl, 3-[(4-methyl-piperazin- 1 -yl)]propyl, 3 - [(4-ethyl-piperazin- 1 - yl)]ProPyl:> 3-[(4-propyl-piperazin-l-yl)]propyl, 3-[(4-acetyl-piperazin-l-yl)]propyl, 3-{[4- (2-hydroxyethyl)piperazin- 1 -yl] } propyl, 3 - { [4-(3 -hydroxypropyl)piperazin- 1 -yl] } propyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 -yl}propyl, 3- {4-[3-(oxan-4-yl)propyl]piperazin- 1 - yl} propyl, 3 - {4-[2-(oxolan-3 -yl)ethy l]piperazin- 1 -yl} propyl, 3 - {4-[3 -(oxolan-3 - yl)propyl]piperazin- 1 -yl}propyl, piperazin- 1 -ylcarbamoyl, (4-methyl-piperazin- 1 - yl)carbamoyl, (4-ethyl-piperazin- l-yl)carbamoyl, (4-propyl-piperazin- l-yl)carbamoyl, (4- acetyl-piperazin- 1 -yl)carbamoyl, [4-(2-hydroxyethyl)piperazin- 1 -yl] carbamoyl, [4-(3- hydroxypropyl)piperazin- 1-yl] carbamoyl, {4-[2-(oxan-4-yl)ethyl]piperazin-l- yl} carbamoyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl} carbamoyl, {4-[2-(oxolan-3- yl)ethyl]piperazin- 1-yl} carbamoyl, {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} carbamoyl, 2-(piperazin- 1 -yl)ethylcarbamoyl, 2-(4-methyl-piperazin- 1 -yl)ethylcarbamoyl, 2-(4-ethyl- piperazin- 1 -yl)ethylcarbamoyl, 2-(4-propyl-piperazin- 1 -yl)ethylcarbamoyl, 2-(4-acetyl- piperazin- 1 -yl)ethylcarbamoyl, 2- [4-(2-hydroxyethyl)piperazin- 1 -yl] ethylcarbamoyl, 2- [4- (3-hydroxypropyl)piperazin- 1 -yl] ethylcarbamoyl, 2- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 - yl} ethylcarbamoyl, 2- {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl} ethylcarbamoyl, 2- {4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl} ethylcarbamoyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} ethylcarbamoyl, 3 -(piperazin- 1 -yl)propylcarbamoyl, 3 -(4-methyl-piperazin- 1 - yl)propylcarbamoyl, 3-(4-ethyl-piperazin-l-yl)propylcarbamoyl, 3-(4-propyl-piperazin-l- yl)propylcarbamoyl, 3-(4-acetyl-piperazin-l-yl)propylcarbamoyl, 3-[4-(2- hydroxyethyl)piperazin- 1 -yl]propylcarbamoyl, 3 - [4-(3 -hydroxypropyl)piperazin- 1 - yl]propylcarbamoyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin-l -yl}propylcarbamoyl, 3- {4- [3- (oxan-4-yl)propyl]piperazin-l-yl}propylcarbamoyl, 3-{4-[2-(oxolan-3-yl)ethyl]piperazin- l-yl}propylcarbamoyl, 3-{4-[3-(oxolan-3-yl)propyl]piperazin-l-yl}propylcarbamoyl, piperazin- 1-ylcarbonyl, 4-methylpiperazin-l-ylcarbonyl, 4-ethylpiperazin-l-ylcarbonyl, 4- propylpiperazin- 1 -ylcarbonyl, (4-acetyl-piperazin- 1 -yl)carbonyl, [4-(2- hydroxyethyl)piperazin- 1 -yl] carbonyl, [4-(3 -hydroxypropyl)piperazin- 1 -yl] carbonyl, {4- [2-(oxan-4-yl)ethyl]piperazin- 1 -yl} carbonyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 - yl}carbonyl, {4- [2-(oxolan-3-yl)ethyl]piperazin- 1-yl} carbonyl, {4-[3-(oxolan-3- yl)propyl]piperazin- 1 -yl} carbonyl, 2-(piperazin- 1 -yl)ethylcarbonyl, 2-(4-methyl-piperazin- 1 -yl)ethylcarbonyl, 2-(4-ethyl-piperazin- 1 -yl)ethylcarbonyl, 2-(4-propyl-piperazin- 1 - yl)ethylcarbonyl, 2-(4-acetyl-piperazin- 1 -yl)ethylcarbonyl, 2-[4-(2- hydroxyethyl)piperazin- 1 -yl]ethylcarbonyl, 2- [4-(3 -hydroxypropyl)piperazin- 1 - yl]ethylcarbonyl, 2- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 -yl} ethylcarbonyl, 2- {4-[3-(oxan-4- yl)propyl]piperazin- 1 -yl} ethylcarbonyl, 2- {4-[2-(oxolan-3-yl)ethyl]piperazin- 1 - yl} ethylcarbonyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} ethylcarbonyl, 3-(piperazin- 1 -yl)propylcarbonyl, 3 -(4-methyl-piperazin- 1 -yl)propylcarbonyl, 3 -(4-ethyl-piperazin- 1 - yl)propylcarbonyl, 3-(4-propyl-piperazin-l-yl)propylcarbonyl, 3 -(4-acetyl-piperazin- 1- yl)propylcarbonyl, 3-[4-(2-hydroxyethyl)piperazin-l-yl]propylcarbonyl, 3-[4-(3- hydroxypropyl)piperazin- 1 -yl]propylcarbonyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 - yl}propylcarbonyl, 3-{4-[3-(oxan-4-yl)propyl]piperaziny-l-l}propylcarbonyl, 3-{4-[2- (oxolan-3-yl)ethyl]piperazin-l-yl}propylcarbonyl or 3-{4-[3-(oxolan-3- yl)propyl]piperazin- 1 -yl}propylcarbonyl; m is 0 or 1, and when m is 1, the R2 group is selected from halogeno, hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy and propoxy; R3 is hydrogen, methyl, ethyl or propyl; n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy; or a pharmaceutically-accep table salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
Gi and G2 is selected from CH and N provided that both are not N; Ring A is pyrazolyl or pyridinyl; R1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, ethylaminomethyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, diethylaminomethyl, 2-(diethylamino)ethyl, 3-(diethylamino)propyl aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy, 2- (dimethylamino)ethoxy, 3-(dimethylamino)propoxy, ethylaminomethoxy, 2- (ethylamino)ethoxy, 3-(ethylamino)propoxy, diethylaminomethoxy, 2- (diethylamino)ethoxy, 3-(diethylamino)propoxy, piperidin-4-yl, l-methylpiperidin-4-yl, 1- ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, l-(3-hydroxypropyl)piperidin-4-yl, l-[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, piperidin-4-ylmethyl, 1- methylpiperidin-4-ylmethyl, l-ethylpiperidin-4-ylmethyl, l-propylpiperidin-4-ylmethyl, 1- acetylpiperidin-4-ylmethyl, 1 -(2-hydroxyethyl)piperidin-4-ylmethyl, 1 -(3- hydroxypropyl)piperidin-4-ylmethyl, l-[2-(oxan-4-yl)ethyl]piperidin-4-ylmethyl, l-[3- (oxan-4-yl)propyl]piperidin-4-ylmethyl, 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-ylmethyl, 1 - [3-(oxolan-3-yl)propyl]piperidin-4-ylmethyl, 2-(piperidin-4-yl)ethyl, 2-(l -methylpiperidin- 4-yl)ethyl, 2-(l-ethylpiperidin-4-yl)ethyl, 2-(l-propylpiperidin-4-yl)ethyl, 2-(l- acetylpiperidin-4-yl)ethyl, 2-[l-(2-hydroxyethyl)piperidin-4-yl]ethyl, 2-[l-(3- hydroxypropyl)piperidin-4-yl]ethyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} ethyl, 2- { 1 - [3-(oxan-4-yl)propyl]piperidin-4-yl} ethyl, 2- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl} ethyl, 5 2-{l-[3-(oxolan-3-yl)propyl]piperidin-4-yl}ethyl, 3-(piperidin-4-yl)propyl, 3-(l- methylpiperidin-4-yl)propyl, 3-(l-ethylpiperidin-4-yl)propyl, 3-(l-propylpiperidin-4- yl)propyl, 3-(l-acetylpiperidin-4-yl)propyl, 3-[l-(2-hydroxyethyl)piperidin-4-yl]propyl, 3- [ 1 -(3-hydroxypropyl)piperidin-4-yl]propyl, 3- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4- yl} propyl, 3 - { 1 - [3 -(oxan-4-yl)propyl]piperidin-4-yl} propyl, 3 - { 1 -[2-(oxolan-3 - i o yl)ethyl]piperidin-4-yl} propyl, 3 - { 1 - [3-(oxolan-3 -yl)propyl]piperidin-4-yl} propyl, piperidin-4-ylcarbamoyl, 1 -methylpiperidin-4-ylcarbamoyl, 1 -ethylpiperidin-4- ylcarbamoyl, l-propylpiperidin-4-ylcarbamoyl, l-acetylpiperidin-4-ylcarbamoyl, l-(2- hydroxyethyl)piperidin-4-ylcarbamoyl, 1 -(3-hydroxypropyl)piperidin-4-ylcarbamoyl, 1 -[2- (oxan-4-yl)ethyl]piperidin-4-ylcarbamoyl, l-[3-(oxan-4-yl)propyl]piperidin-4-
15 ylcarbamoyl, l-[2-(oxolan-3-yl)ethyl]piperidin-4-ylcarbamoyl, l-[3-(oxolan-3- yl)propyl]piperidin-4-ylcarbamoyl, 2-(piperidin-4-yl)ethylcarbamoyl, 2-( 1 - methylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -ethylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 - propylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -acetylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -(2- hydroxyethyl)piperidin-4-yl)ethylcarbamoyl, 2- [ 1 -(3 -hydroxypropyl)piperidin-4-
20 yl] ethylcarbamoyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} ethylcarbamoyl, 2- { 1 -[3-
(oxan-4-yl)propyl]piperidin-4-yl} ethylcarbamoyl, 2- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl} ethylcarbamoyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl} ethylcarbamoyl, 3- (piperidin-4-yl)propylcarbamoyl, 3 -(I -methylpiperidin-4-yl)propylcarbamoyl, 3 -(I - ethylpiperidin-4-yl)propylcarbamoyl, 3-(l-propylpiperidin-4-yl)propylcarbamoyl, 3-(l-
25 acetylpiperidin-4-yl)propylcarbamoyl, 3-(l-(2-hydroxyethyl)piperidin-4- yl)propylcarbamoyl, 3-[ 1 -(3-hydroxypropyl)piperidin-4-yl]propylcarbamoyl, 3- { 1 -[2- (oxan-4-yl)ethyl]piperidin-4-yl}propylcarbamoyl, 3- { 1 -[3-(oxan-4-yl)propyl]piperidin-4- yl}propylcarbamoyl, 3- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl}propylcarbamoyl, 3- { 1 -[3- (oxolan-3-yl)propyl]piperidin-4-yl}propylcarbamoyl, piperidin-4-ylcarbonyl, 1 -
30 methylpiperidin-4-ylcarbonyl, l-ethylpiperidin-4-ylcarbonyl, l-propylpiperidin-4- ylcarbonyl, l-acetylpiperidin-4-ylcarbonyl, l-(2-hydroxyethyl)piperidin-4-ylcarbonyl, 1- (3-hydroxypropyl)piperidin-4-ylcarbonyl, 1 -[2-(oxan-4-yl)ethyl]piperidin-4-ylcarbonyl, 1 - [3-(oxan-4-yl)propyl]piperidin-4-ylcarbonyl, l-[2-(oxolan-3-yl)ethyl]piperidin-4- ylcarbonyl, 1 -[3-(oxolan-3-yl)propyl]piperidin-4-ylcarbonyl, 2-(piperidin-4- yl)ethylcarbonyl, 2-(l-methylpiperidin-4-yl)ethylcarbonyl, 2-(l-ethylpiperidin-4- yl)ethylcarbonyl, 2-(l-propylpiperidin-4-yl)ethylcarbonyl, 2-(l-acetylpiperidin-4- yl)ethylcarbonyl, 2-(l-(2-hydroxyethyl)piperidin-4-yl)ethylcarbonyl, 2-[l-(3- hydroxypropyl)piperidin-4-yl]ethylcarbonyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4- yl} ethylcarbonyl, 2- { 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl} ethylcarbonyl, 2- { 1 -[2- (oxolan-3-yl)ethyl]piperidin-4-yl} ethylcarbonyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4- yl} ethylcarbonyl, 3-(piperidin-4-yl)propylcarbonyl, 3-(l -methylpiperidin-4- yl)propylcarbonyl, 3-(l-ethylpiperidin-4-yl)propylcarbonyl, 3-(l-propylpiperidin-4- yl)propylcarbonyl, 3-(l-acetylpiperidin-4-yl)propylcarbonyl, 3 -(I -(2- hydroxyethyl)piperidin-4-yl)propylcarbonyl, 3-[ 1 -(3-hydroxypropyl)piperidin-4- yl]propylcarbonyl, 3- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl}propylcarbonyl, 3- { 1 -[3-(oxan- 4-yl)propyl]piperidin-4-yl}propylcarbonyl, 3- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl}propylcarbaonyl, 3-{l-[3-(oxolan-3-yl)propyl]piperidin-4-yl}propylcarbonyl, piperazin- 1-yl, 4-methyl-piperazin-l-yl, 4-ethyl-piperazin-l-yl, 4-propyl-piperazin-l-yl, 4-acetyl- piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-l-yl, 4-(3-hydroxypropyl)piperazin-l-yl, 4- [2- (oxan-4-yl)ethyl]piperazin-l -yl, 4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl, 4-[2-(oxolan-3- yl)ethyl]piperazin-l-yl, 4-[3-(oxolan-3-yl)propyl]piperazin-l-yl, piperazin-1-ylmethyl, (4- methyl-piperazin- 1 -yl)methyl, (4-ethyl-piperazin- 1 -yl)methyl, (4-propyl-piperazin- 1 - yl)methyl, (4-acetyl-piperazin-l-yl)methyl, [4-(2-hydroxyethyl)piperazin-l-yl]methyl, [4- (3-hydroxypropyl)piperazin-l-yl]methyl, {4-[2-(oxan-4-yl)ethyl]piperazin-l-yl}methyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl}methyl, {4-[2-(oxolan-3-yl)ethyl]piperazin- 1 - yl}methyl, {4-[3-(oxolan-3-yl)propyl]piperazin-l-yl}methyl, 2-(piperazin-l-yl)ethyl, 2- [(4-methyl-piperazin-l-yl)] ethyl, 2-[(4-ethyl-piperazin-l-yl)]ethyl, 2- [(4-propyl-piperazin- l-yl)] ethyl, 2-[(4-acetyl-piperazin-l-yl)]ethyl, 2-{[4-(2-hydroxyethyl)piperazin-l- yl] } ethyl, 2- { [4-(3-hydroxypropyl)piperazin- 1 -yl] } ethyl, 2- {4-[2-(oxan-4- yl)ethyl]piperazin-l-yl} ethyl, 2-{4-[3-(oxan-4-yl)propyl]piperazin-l-yl}ethyl, 2-{4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl} ethyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin-l -yl} ethyl, 3-(piperazin-l-yl)propyl, 3-[(4-methyl-piperazin-l-yl)]propyl, 3- [(4-ethyl-piperazin- 1- yl)]propyl, 3-[(4-propyl-piperazin-l-yl)]propyl, 3-[(4-acetyl-piperazin-l-yl)]propyl, 3-{[4- (2-hydroxyethyl)piperazin- 1 -yl] } propyl, 3 - { [4-(3 -hydroxypropyl)piperazin- 1 -yl] } propyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 -yl}propyl, 3- {4-[3-(oxan-4-yl)propyl]piperazin- 1 - yl} propyl, 3 - {4-[2-(oxolan-3 -yl)ethy l]piperazin- 1 -yl} propyl, 3 - {4-[3 -(oxolan-3 - yl)propyl]piperazin- 1 -yl}propyl, piperazin- 1 -ylcarbamoyl, (4-methyl-piperazin- 1 - yl)carbamoyl, (4-ethyl-piperazin-l-yl)carbamoyl, (4-propyl-piperazin-l-yl)carbamoyl, (4- acetyl-piperazin-l-yl)carbamoyl, [4-(2-hydroxyethyl)piperazin-l-yl] carbamoyl, [4-(3- hydroxypropyl)piperazin-l-yl] carbamoyl, {4-[2-(oxan-4-yl)ethyl]piperazin-l- yl} carbamoyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl} carbamoyl, {4-[2-(oxolan-3- yl)ethyl]piperazin- 1-yl} carbamoyl, {4- [3 -(oxolan-3 -yl)propyl]piperazin- 1 -yl} carbamoyl, 2-(piperazin- 1 -yl)ethylcarbamoyl, 2-(4-methyl-piperazin- 1 -yl)ethylcarbamoyl, 2-(4-ethyl- piperazin- l-yl)ethylcarbamoyl, 2-(4-propyl-piperazin-l-yl)ethylcarbamoyl, 2-(4-acetyl- piperazin- 1 -yl)ethylcarbamoyl, 2- [4-(2-hydroxyethyl)piperazin- 1 -yl] ethylcarbamoyl, 2- [4- (3-hydroxypropyl)piperazin- 1 -yl] ethylcarbamoyl, 2- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 - yl} ethylcarbamoyl, 2- {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl} ethylcarbamoyl, 2- {4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl} ethylcarbamoyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin- 1-yl} ethylcarbamoyl, 3-(piperazin-l-yl)propylcarbamoyl, 3 -(4-methyl-piperazin- 1- yl)propylcarbamoyl, 3-(4-ethyl-piperazin-l -yl)propylcarbamoyl, 3-(4-propyl-piperazin- 1 - yl)propylcarbamoyl, 3-(4-acetyl-piperazin-l-yl)propylcarbamoyl, 3-[4-(2- hydroxyethyl)piperazin- 1 -yl]propylcarbamoyl, 3 - [4-(3 -hydroxypropyl)piperazin- 1 - yl]propylcarbamoyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin-l -yl}propylcarbamoyl, 3- {4- [3- (oxan-4-yl)propyl]piperazin-l-yl}propylcarbamoyl, 3-{4-[2-(oxolan-3-yl)ethyl]piperazin- l-yl}propylcarbamoyl, 3-{4-[3-(oxolan-3-yl)propyl]piperazin-l-yl}propylcarbamoyl, piperazin- 1-ylcarbonyl, 4-methylpiperazin-l-ylcarbonyl, 4-ethylpiperazin-l-ylcarbonyl, 4- propylpiperazin- 1 -ylcarbonyl, (4-acetyl-piperazin- 1 -yl)carbonyl, [4-(2- hydroxyethyl)piperazin- 1 -yl] carbonyl, [4-(3 -hydroxypropyl)piperazin- 1 -yl] carbonyl, {4- [2-(oxan-4-yl)ethyl]piperazin- 1 -yl} carbonyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 - yl} carbonyl, {4-[2-(oxolan-3-yl)ethyl]piperazin-l -yl} carbonyl, {4- [3 -(oxolan-3 - yl)propyl]piperazin- 1 -yl} carbonyl, 2-(piperazin- 1 -yl)ethylcarbonyl, 2-(4-methyl-piperazin- 1 -yl)ethylcarbonyl, 2-(4-ethyl-piperazin- 1 -yl)ethylcarbonyl, 2-(4-propyl-piperazin- 1 - yl)ethylcarbonyl, 2-(4-acetyl-piperazin- 1 -yl)ethylcarbonyl, 2-[4-(2- hydroxyethyl)piperazin- 1 -yl]ethylcarbonyl, 2- [4-(3 -hydroxypropyl)piperazin- 1 - yl]ethylcarbonyl, 2- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 -yl} ethylcarbonyl, 2- {4-[3-(oxan-4- yl)propyl]piperazin- 1 -yl} ethylcarbonyl, 2- {4-[2-(oxolan-3-yl)ethyl]piperazin- 1 - yl} ethylcarbonyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} ethylcarbonyl, 3-(piperazin- 1 -yl)propylcarbonyl, 3 -(4-methyl-piperazin- 1 -yl)propylcarbonyl, 3 -(4-ethyl-piperazin- 1 - yl)propylcarbonyl, 3-(4-propyl-piperazin-l-yl)propylcarbonyl, 3-(4-acetyl-piperazin-l- yl)propylcarbonyl, 3-[4-(2-hydroxyethyl)piperazin-l-yl]propylcarbonyl, 3-[4-(3- hydroxypropyl)piperazin- 1 -yl]propylcarbonyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 - yl}propylcarbonyl, 3-{4-[3-(oxan-4-yl)propyl]piperaziny-l-l}propylcarbonyl, 3-{4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl}propylcarbonyl, 3- {4-[3-(oxolan-3-yl)propyl]piperazin- l-yl}propylcarbonyl, piperidin-3-yl, piperidin-4-ylmethyl, piperidin-3-ylmethyl, morpholin-4-yl, 2-(morpholin-4-yl)ethyl, tetrahydropyran-4-yl or l-(4-aminocyclohex-l- yl); m is 0 or 1, and when m is 1, the R2 group is selected from halogeno, hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy and propoxy; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2- (tetrahydrofuran-2-yl)ethyl or (3-methyloxetan-3-yl)methyl; n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
Gi is CH and G2 is N or Gi is N and G2 is CH;
Ring A is pyrazolyl or pyridinyl;
R1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2-
(methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, ethylaminomethyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, diethylaminomethyl, 2-(diethylamino)ethyl, 3-(diethylamino)propyl aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy, 2- (dimethylamino)ethoxy, 3-(dimethylamino)propoxy, ethylaminomethoxy, 2- (ethylamino)ethoxy, 3-(ethylamino)propoxy, diethylaminomethoxy, 2- (diethylamino)ethoxy, 3-(diethylamino)propoxy, piperidin-4-yl, l-methylpiperidin-4-yl, 1- ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, piperidin-4-ylmethyl, 1- methylpiperidin-4-ylmethyl, l-ethylpiperidin-4-ylmethyl, l-propylpiperidin-4-ylmethyl, 1- acetylpiperidin-4-ylmethyl, l-(2-hydroxyethyl)piperidin-4-ylmethyl, l-(3- hydroxypropyl)piperidin-4-ylmethyl, 1 -[2-(oxan-4-yl)ethyl]piperidin-4-ylmethyl, 1 -[3- (oxan-4-yl)propyl]piperidin-4-ylmethyl, 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-ylmethyl, 1 - [3-(oxolan-3-yl)propyl]piperidin-4-ylmethyl, 2-(piperidin-4-yl)ethyl, 2-(l -methylpiperidin- 4-yl)ethyl, 2-(l-ethylpiperidin-4-yl)ethyl, 2-(l-propylpiperidin-4-yl)ethyl, 2-(l- acetylpiperidin-4-yl)ethyl, 2-[l-(2-hydroxyethyl)piperidin-4-yl]ethyl, 2-[l-(3- hydroxypropyl)piperidin-4-yl]ethyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} ethyl, 2- { 1 - [3-(oxan-4-yl)propyl]piperidin-4-yl} ethyl, 2- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl} ethyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl} ethyl, 3-(piperidin-4-yl)propyl, 3-(l - methylpiperidin-4-yl)propyl, 3-(l-ethylpiperidin-4-yl)propyl, 3-(l-propylpiperidin-4- yl)propyl, 3-(l-acetylpiperidin-4-yl)propyl, 3-[l-(2-hydroxyethyl)piperidin-4-yl]propyl, 3- [ 1 -(3-hydroxypropyl)piperidin-4-yl]propyl, 3- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4- yl} propyl, 3 - { 1 - [3 -(oxan-4-yl)propyl]piperidin-4-yl} propyl, 3 - { 1 -[2-(oxolan-3 - yl)ethyl]piperidin-4-yl} propyl, 3-{l-[3-(oxolan-3-yl)propyl]piperidin-4-yl}propyl, piperidin-4-ylcarbamoyl, 1 -methylpiperidin-4-ylcarbamoyl, 1 -ethylpiperidin-4- ylcarbamoyl, l-propylpiperidin-4-ylcarbamoyl, l-acetylpiperidin-4-ylcarbamoyl, l-(2- hydroxyethyl)piperidin-4-ylcarbamoyl, 1 -(3-hydroxypropyl)piperidin-4-ylcarbamoyl, 1 -[2- (oxan-4-yl)ethyl]piperidin-4-ylcarbamoyl, l-[3-(oxan-4-yl)propyl]piperidin-4- ylcarbamoyl, 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-ylcarbamoyl, 1 -[3-(oxolan-3- yl)propyl]piperidin-4-ylcarbamoyl, 2-(piperidin-4-yl)ethylcarbamoyl, 2-( 1 - methylpiperidin-4-yl)ethylcarbamoyl, 2-(l-ethylpiperidin-4-yl)ethylcarbamoyl, 2-(l- propylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -acetylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -(2- hydroxyethyl)piperidin-4-yl)ethylcarbamoyl, 2- [ 1 -(3 -hydroxypropyl)piperidin-4- yl]ethylcarbamoyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} ethylcarbamoyl, 2- { 1 -[3- (oxan-4-yl)propyl]piperidin-4-yl} ethylcarbamoyl, 2- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl} ethylcarbamoyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl} ethylcarbamoyl, 3- (piperidin-4-yl)propylcarbamoyl, 3 -(I -methylpiperidin-4-yl)propylcarbamoyl, 3 -(I - ethylpiperidin-4-yl)propylcarbamoyl, 3-(l-propylpiperidin-4-yl)propylcarbamoyl, 3-(l- acetylpiperidin-4-yl)propylcarbamoyl, 3-(l-(2-hydroxyethyl)piperidin-4- yl)propylcarbamoyl, 3-[ 1 -(3-hydroxypropyl)piperidin-4-yl]propylcarbamoyl, 3- { 1 -[2- (oxan-4-yl)ethyl]piperidin-4-yl}propylcarbamoyl, 3- { 1 -[3-(oxan-4-yl)propyl]piperidin-4- yl}propylcarbamoyl, 3- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl}propylcarbamoyl, 3- { 1 -[3- (oxolan-3-yl)propyl]piperidin-4-yl}propylcarbamoyl, piperidin-4-ylcarbonyl, 1- methylpiperidin-4-ylcarbonyl, 1 -ethylpiperidin-4-ylcarbonyl, 1 -propylpiperidin-4- ylcarbonyl, l-acetylpiperidin-4-ylcarbonyl, l-(2-hydroxyethyl)piperidin-4-ylcarbonyl, 1- (3-hydroxypropyl)piperidin-4-ylcarbonyl, 1 -[2-(oxan-4-yl)ethyl]piperidin-4-ylcarbonyl, 1 - [3-(oxan-4-yl)propyl]piperidin-4-ylcarbonyl, l-[2-(oxolan-3-yl)ethyl]piperidin-4- ylcarbonyl, l-[3-(oxolan-3-yl)propyl]piperidin-4-ylcarbonyl, 2-(piperidin-4- yl)ethylcarbonyl, 2-(l-methylpiperidin-4-yl)ethylcarbonyl, 2-(l-ethylpiperidin-4- yl)ethylcarbonyl, 2-(l-propylpiperidin-4-yl)ethylcarbonyl, 2-(l-acetylpiperidin-4- yl)ethylcarbonyl, 2-(l -(2-hydroxyethyl)piperidin-4-yl)ethylcarbonyl, 2-[ 1 -(3- hydroxypropyl)piperidin-4-yl]ethylcarbonyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4- yl} ethylcarbonyl, 2- { 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl} ethylcarbonyl, 2- { 1 -[2-
(oxolan-3-yl)ethyl]piperidin-4-yl} ethylcarbonyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4- yl} ethylcarbonyl, 3-(piperidin-4-yl)propylcarbonyl, 3-(l -methylpiperidin-4- yl)propylcarbonyl, 3-(l-ethylpiperidin-4-yl)propylcarbonyl, 3-(l-propylpiperidin-4- yl)propylcarbonyl, 3-(l-acetylpiperidin-4-yl)propylcarbonyl, 3-(l-(2- hydroxyethyl)piperidin-4-yl)propylcarbonyl, 3-[ 1 -(3-hydroxypropyl)piperidin-4- yl]propylcarbonyl, 3- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl}propylcarbonyl, 3- { 1 -[3-(oxan- 4-yl)propyl]piperidin-4-yl}propylcarbonyl, 3- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl}propylcarbaonyl, 3- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl}propylcarbonyl, piperazin- 1-yl, 4-methyl-piperazin-l-yl, 4-ethyl-piperazin-l-yl, 4-propyl-piperazin-l-yl, 4-acetyl- piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-l-yl, 4-(3-hydroxypropyl)piperazin-l-yl, 4-[2- (oxan-4-yl)ethyl]piperazin-l -yl, 4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl, 4-[2-(oxolan-3- yl)ethyl]piperazin-l-yl, 4-[3-(oxolan-3-yl)propyl]piperazin-l-yl, piperazin-1-ylmethyl, (4- methyl-piperazin- 1 -yl)methyl, (4-ethyl-piperazin- 1 -yl)methyl, (4-propyl-piperazin- 1 - yl)methyl, (4-acetyl-piperazin-l-yl)methyl, [4-(2-hydroxyethyl)piperazin-l-yl]methyl, [4- (3-hydroxypropyl)piperazin-l-yl]methyl, {4-[2-(oxan-4-yl)ethyl]piperazin-l-yl}methyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl}methyl, {4-[2-(oxolan-3-yl)ethyl]piperazin- 1 - yl}methyl, {4-[3-(oxolan-3-yl)propyl]piperazin-l-yl}methyl, 2-(piperazin-l-yl)ethyl, 2- [(4-methyl-piperazin- 1 -yl)] ethyl, 2- [(4-ethyl-piperazin- 1 -yl)]ethyl, 2-[(4-propyl-piperazin- 1-yl)] ethyl, 2-[(4-acetyl-piperazin-l-yl)]ethyl, 2-{[4-(2-hydroxyethyl)piperazin-l- yl] } ethyl, 2- { [4-(3-hydroxypropyl)piperazin- 1 -yl] } ethyl, 2- {4-[2-(oxan-4- yl)ethyl]piperazin-l-yl} ethyl, 2-{4-[3-(oxan-4-yl)propyl]piperazin-l-yl}ethyl, 2-{4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl} ethyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin-l -yl} ethyl, 3-(piperazin- 1 -yl)propyl, 3-[(4-methyl-piperazin- 1 -yl)]propyl, 3 - [(4-ethyl-piperazin- 1 - yl)]propyl, 3-[(4-propyl-piperazin-l-yl)]propyl, 3-[(4-acetyl-piperazin-l-yl)]propyl, 3-{[4- (2-hydroxyethyl)piperazin- 1 -yl] } propyl, 3 - { [4-(3 -hydroxypropyl)piperazin- 1 -yl] } propyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 -yl}propyl, 3- {4-[3-(oxan-4-yl)propyl]piperazin- 1 - yl}propyl, 3-{4-[2-(oxolan-3-yl)ethyl]piperazin-l-yl}propyl, 3-{4-[3-(oxolan-3- yl)propyl]piperazin- 1 -yl}propyl, piperazin- 1 -ylcarbamoyl, (4-methyl-piperazin- 1 - yl)carbamoyl, (4-ethyl-piperazin- l-yl)carbamoyl, (4-propyl-piperazin- l-yl)carbamoyl, (4- acetyl-piperazin- 1 -yl)carbamoyl, [4-(2-hydroxyethyl)piperazin- 1 -yl] carbamoyl, [4-(3- hydroxypropyl)piperazin-l-yl] carbamoyl, {4-[2-(oxan-4-yl)ethyl]piperazin-l- yl} carbamoyl, {4-[3-(oxan-4-yl)propyl]piperazin-l-yl} carbamoyl, {4-[2-(oxolan-3- yl)ethyl]piperazin-l -yl} carbamoyl, {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} carbamoyl, 2-(piperazin- 1 -yl)ethylcarbamoyl, 2-(4-methyl-piperazin- 1 -yl)ethylcarbamoyl, 2-(4-ethyl- piperazin- 1 -yl)ethylcarbamoyl, 2-(4-propyl-piperazin- 1 -yl)ethylcarbamoyl, 2-(4-acetyl- piperazin- 1 -yl)ethylcarbamoyl, 2- [4-(2-hydroxyethyl)piperazin- 1 -yl] ethylcarbamoyl, 2- [4- (3-hydroxypropyl)piperazin- 1 -yl] ethylcarbamoyl, 2- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 - yl} ethylcarbamoyl, 2- {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl} ethylcarbamoyl, 2- {4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl} ethylcarbamoyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} ethylcarbamoyl, 3 -(piperazin- 1 -yl)propylcarbamoyl, 3 -(4-methyl-piperazin- 1 - yl)propylcarbamoyl, 3 -(4-ethyl-piperazin- 1 -yl)propylcarbamoyl, 3 -(4-propyl-piperazin- 1 - yl)propylcarbamoyl, 3-(4-acetyl-piperazin-l-yl)propylcarbamoyl, 3-[4-(2- hydroxyethyl)piperazin- 1 -yl]propylcarbamoyl, 3 - [4-(3 -hydroxypropyl)piperazin- 1 - yl]propylcarbamoyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin-l -yl}propylcarbamoyl, 3- {4- [3- (oxan-4-yl)propyl]piperazin-l-yl}propylcarbamoyl, 3-{4-[2-(oxolan-3-yl)ethyl]piperazin- l-yl}propylcarbamoyl, 3-{4-[3-(oxolan-3-yl)propyl]piperazin-l-yl}propylcarbamoyl, piperazin-1-ylcarbonyl, 4-methylpiperazin-l-ylcarbonyl, 4-ethylpiperazin-l-ylcarbonyl, 4- propylpiperazin- 1 -ylcarbonyl, (4-acetyl-piperazin- 1 -yl)carbonyl, [4-(2- hydroxyethyl)piperazin- 1 -yl] carbonyl, [4-(3 -hydroxypropyl)piperazin- 1 -yl] carbonyl, {4- [2-(oxan-4-yl)ethyl]piperazin- 1 -yl} carbonyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 - yl} carbonyl, {4-[2-(oxolan-3-yl)ethyl]piperazin-l -yl} carbonyl, {4-[3-(oxolan-3- yl)propyl]piperazin- 1 -yl} carbonyl, 2-(piperazin- 1 -yl)ethylcarbonyl, 2-(4-methyl-piperazin- 1 -yl)ethylcarbonyl, 2-(4-ethyl-piperazin- 1 -yl)ethylcarbonyl, 2-(4-propyl-piperazin- 1 - yl)ethylcarbonyl, 2-(4-acetyl-piperazin-l-yl)ethylcarbonyl, 2-[4-(2- hydroxyethyl)piperazin- 1 -yljethylcarbonyl, 2- [4-(3 -hydroxypropyl)piperazin- 1 - yl]ethylcarbonyl, 2- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 -yl} ethylcarbonyl, 2- {4-[3-(oxan-4- yl)propyl]piperazin- 1 -yl} ethylcarbonyl, 2- {4-[2-(oxolan-3-yl)ethyl]piperazin- 1 - yl} ethylcarbonyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} ethylcarbonyl, 3-(piperazin- l-yl)propylcarbonyl, 3-(4-methyl-piperazin-l-yl)propylcarbonyl, 3-(4-ethyl-piperazin-l- yl)propylcarbonyl, 3-(4-propyl-piperazin-l-yl)propylcarbonyl, 3 -(4-acetyl-piperazin- 1- yl)propylcarbonyl, 3-[4-(2-hydroxyethyl)piperazin-l-yl]propylcarbonyl, 3-[4-(3- hydroxypropyl)piperazin- 1 -yl]propylcarbonyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 - yl}propylcarbonyl, 3-{4-[3-(oxan-4-yl)propyl]piperaziny-l-l}propylcarbonyl, 3-{4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl}propylcarbonyl, 3- {4-[3-(oxolan-3-yl)propyl]piperazin- l-yl}propylcarbonyl, piperidin-3-yl, piperidin-4-ylmethyl, piperidin-3-ylmethyl, morpholin-4-yl or 2-(morpholin-4-yl)ethyl, tetrahydropyran-4-yl or l-(4-aminocyclohex-l- yi); m is 0 or 1, and when m is 1, the R2 group is selected from halogeno, hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy and propoxy;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2-
(tetrahydrofuran-2-yl)ethyl or (3-methyloxetan-3-yl)methyl; n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the
Formula I above wherein :-
Figure imgf000066_0001
Ring A is pyrazolyl or pyridinyl; R1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2-
(dimethylamino)ethyl, 3-(dimethylamino)propyl, ethylaminomethyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, diethylaminomethyl, 2-(diethylamino)ethyl, 3-(diethylamino)propyl aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy, 2- (dimethylamino)ethoxy, 3-(dimethylamino)propoxy, ethylaminomethoxy, 2- (ethylamino)ethoxy, 3-(ethylamino)propoxy, diethylaminomethoxy, 2- (diethylamino)ethoxy, 3-(diethylamino)propoxy, piperidin-4-yl, l-methylpiperidin-4-yl, 1- ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, l-[3-(oxan-4-yl)propyl]piperidin-4-yl, l-[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, piperidin-4-ylmethyl, 1- methylpiperidin-4-ylmethyl, l-ethylpiperidin-4-ylmethyl, l-propylpiperidin-4-ylmethyl, 1- acetylpiperidin-4-ylmethyl, 1 -(2-hydroxyethyl)piperidin-4-ylmethyl, 1 -(3- hydroxypropyl)piperidin-4-ylmethyl, 1 -[2-(oxan-4-yl)ethyl]piperidin-4-ylmethyl, 1 -[3- (oxan-4-yl)propyl]piperidin-4-ylmethyl, l-[2-(oxolan-3-yl)ethyl]piperidin-4-ylmethyl, 1- [3-(oxolan-3-yl)propyl]piperidin-4-ylmethyl, 2-(piperidin-4-yl)ethyl, 2-(l -methylpiperidin- 4-yl)ethyl, 2-(l-ethylpiperidin-4-yl)ethyl, 2-(l-propylpiperidin-4-yl)ethyl, 2-(l- acetylpiperidin-4-yl)ethyl, 2-[l-(2-hydroxyethyl)piperidin-4-yl]ethyl, 2-[l-(3- hydroxypropyl)piperidin-4-yl]ethyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} ethyl, 2- { 1 - [3-(oxan-4-yl)propyl]piperidin-4-yl} ethyl, 2- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl} ethyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl} ethyl, 3-(piperidin-4-yl)propyl, 3-(l - methylpiperidin-4-yl)propyl, 3-(l-ethylpiperidin-4-yl)propyl, 3-(l-propylpiperidin-4- yl)propyl, 3-(l-acetylpiperidin-4-yl)propyl, 3-[l-(2-hydroxyethyl)piperidin-4-yl]propyl, 3- [ 1 -(3-hydroxypropyl)piperidin-4-yl]propyl, 3- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4- yl} propyl, 3 - { 1 - [3 -(oxan-4-yl)propyl]piperidin-4-yl} propyl, 3 - { 1 -[2-(oxolan-3 - yl)ethyl]piperidin-4-yl} propyl, 3-{l-[3-(oxolan-3-yl)propyl]piperidin-4-yl}propyl, piperidin-4-ylcarbamoyl, l-methylpiperidin-4-ylcarbamoyl, l-ethylpiperidin-4- ylcarbamoyl, l-propylpiperidin-4-ylcarbamoyl, l-acetylpiperidin-4-ylcarbamoyl, l-(2- hydroxyethyl)piperidin-4-ylcarbamoyl, 1 -(3-hydroxypropyl)piperidin-4-ylcarbamoyl, 1 -[2- (oxan-4-yl)ethyl]piperidin-4-ylcarbamoyl, l-[3-(oxan-4-yl)propyl]piperidin-4- ylcarbamoyl, 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-ylcarbamoyl, 1 -[3-(oxolan-3- yl)propyl]piperidin-4-ylcarbamoyl, 2-(piperidin-4-yl)ethylcarbamoyl, 2-(l- methylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -ethylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 - propylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -acetylpiperidin-4-yl)ethylcarbamoyl, 2-( 1 -(2- hydroxyethyl)piperidin-4-yl)ethylcarbamoyl, 2- [ 1 -(3 -hydroxypropyl)piperidin-4- yl]ethylcarbamoyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} ethylcarbamoyl, 2- { 1 -[3- (oxan-4-yl)propyl]piperidin-4-yl} ethylcarbamoyl, 2-{l-[2-(oxolan-3-yl)ethyl]piperidin-4- yl} ethylcarbamoyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl} ethylcarbamoyl, 3- (piperidin-4-yl)propylcarbamoyl, 3 -(I -methylpiperidin-4-yl)propylcarbamoyl, 3 -(I - ethylpiperidin-4-yl)propylcarbamoyl, 3-(l-propylpiperidin-4-yl)propylcarbamoyl, 3-(l- acetylpiperidin-4-yl)propylcarbamoyl, 3-(l-(2-hydroxyethyl)piperidin-4- yl)propylcarbamoyl, 3-[l-(3-hydroxypropyl)piperidin-4-yl]propylcarbamoyl, 3-{l-[2- (oxan-4-yl)ethyl]piperidin-4-yl}propylcarbamoyl, 3- { 1 -[3-(oxan-4-yl)propyl]piperidin-4- yl}propylcarbamoyl, 3- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl}propylcarbamoyl, 3- { 1 -[3- (oxolan-3-yl)propyl]piperidin-4-yl}propylcarbamoyl, piperidin-4-ylcarbonyl, 1 - methylpiperidin-4-ylcarbonyl, 1 -ethylpiperidin-4-ylcarbonyl, 1 -propylpiperidin-4- ylcarbonyl, l-acetylpiperidin-4-ylcarbonyl, l-(2-hydroxyethyl)piperidin-4-ylcarbonyl, 1- (3-hydroxypropyl)piperidin-4-ylcarbonyl, 1 -[2-(oxan-4-yl)ethyl]piperidin-4-ylcarbonyl, 1 - [3-(oxan-4-yl)propyl]piperidin-4-ylcarbonyl, l-[2-(oxolan-3-yl)ethyl]piperidin-4- ylcarbonyl, 1 -[3-(oxolan-3-yl)propyl]piperidin-4-ylcarbonyl, 2-(piperidin-4- yl)ethylcarbonyl, 2-(l-methylpiperidin-4-yl)ethylcarbonyl, 2-(l-ethylpiperidin-4- yl)ethylcarbonyl, 2-(l-propylpiperidin-4-yl)ethylcarbonyl, 2-(l-acetylpiperidin-4- yl)ethylcarbonyl, 2-(l -(2-hydroxyethyl)piperidin-4-yl)ethylcarbonyl, 2-[ 1 -(3- hydroxypropyl)piperidin-4-yl]ethylcarbonyl, 2- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4- yl} ethylcarbonyl, 2- { 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl} ethylcarbonyl, 2- { 1 -[2- (oxolan-3-yl)ethyl]piperidin-4-yl} ethylcarbonyl, 2- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4- yl} ethylcarbonyl, 3-(piperidin-4-yl)propylcarbonyl, 3-(l -methylpiperidin-4- yl)propylcarbonyl, 3-(l-ethylpiperidin-4-yl)propylcarbonyl, 3-(l-propylpiperidin-4- yl)propylcarbonyl, 3-(l-acetylpiperidin-4-yl)propylcarbonyl, 3 -(I -(2- hydroxyethyl)piperidin-4-yl)propylcarbonyl, 3-[ 1 -(3-hydroxypropyl)piperidin-4- yl]propylcarbonyl, 3- { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl}propylcarbonyl, 3- { 1 -[3-(oxan- 4-yl)propyl]piperidin-4-yl}propylcarbonyl, 3- { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl}propylcarbaonyl, 3- { 1 -[3-(oxolan-3-yl)propyl]piperidin-4-yl}propylcarbonyl, piperazin- 1-yl, 4-methyl-piperazin-l-yl, 4-ethyl-piperazin-l-yl, 4-propyl-piperazin-l-yl, 4-acetyl- piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-l-yl, 4-(3-hydroxypropyl)piperazin-l-yl, 4- [2- (oxan-4-yl)ethyl]piperazin-l -yl, 4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl, 4-[2-(oxolan-3- yl)ethyl]piperazin-l-yl, 4-[3-(oxolan-3-yl)propyl]piperazin-l-yl, piperazin-1-ylmethyl, (4- methyl-piperazin- 1 -yl)methyl, (4-ethyl-piperazin- 1 -yl)methyl, (4-propyl-piperazin- 1 - yl)methyl, (4-acetyl-piperazin-l-yl)methyl, [4-(2-hydroxyethyl)piperazin-l-yl]methyl, [4- (3-hydroxypropyl)piperazin-l-yl]methyl, {4-[2-(oxan-4-yl)ethyl]piperazin-l-yl}methyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl}methyl, {4-[2-(oxolan-3-yl)ethyl]piperazin- 1 - yl}methyl, {4-[3-(oxolan-3-yl)propyl]piperazin-l-yl}methyl, 2-(piperazin-l-yl)ethyl, 2- [(4-methyl-piperazin- 1 -yl)] ethyl, 2- [(4-ethyl-piperazin- 1 -yl)]ethyl, 2-[(4-propyl-piperazin- 1-yl)] ethyl, 2- [(4-acetyl-piperazin- 1-yl)] ethyl, 2-{[4-(2-hydroxyethyl)piperazin-l- yl] } ethyl, 2- { [4-(3-hydroxypropyl)piperazin- 1 -yl] } ethyl, 2- {4-[2-(oxan-4- yl)ethyl]piperazin- 1-yl} ethyl, 2-{4-[3-(oxan-4-yl)propyl]piperazin-l-yl}ethyl, 2-{4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl} ethyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin-l -yl} ethyl, 3-(piperazin- 1 -yl)propyl, 3-[(4-methyl-piperazin- 1 -yl)]propyl, 3 - [(4-ethyl-piperazin- 1 - yl)]ProPyl:> 3-[(4-propyl-piperazin-l-yl)]propyl, 3-[(4-acetyl-piperazin-l-yl)]propyl, 3-{[4- (2-hydroxyethyl)piperazin- 1 -yl] } propyl, 3 - { [4-(3 -hydroxypropyl)piperazin- 1 -yl] } propyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 -yl}propyl, 3- {4-[3-(oxan-4-yl)propyl]piperazin- 1 - yl} propyl, 3 - {4-[2-(oxolan-3 -yl)ethy l]piperazin- 1 -yl} propyl, 3 - {4-[3 -(oxolan-3 - yl)propyl]piperazin- 1 -yl}propyl, piperazin- 1 -ylcarbamoyl, (4-methyl-piperazin- 1 - yl)carbamoyl, (4-ethyl-piperazin- l-yl)carbamoyl, (4-propyl-piperazin- l-yl)carbamoyl, (4- acetyl-piperazin- 1 -yl)carbamoyl, [4-(2-hydroxyethyl)piperazin- 1 -yl] carbamoyl, [4-(3- hydroxypropyl)piperazin- 1-yl] carbamoyl, {4-[2-(oxan-4-yl)ethyl]piperazin-l- yl} carbamoyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl} carbamoyl, {4-[2-(oxolan-3- yl)ethyl]piperazin- 1-yl} carbamoyl, {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} carbamoyl, 2-(piperazin- 1 -yl)ethylcarbamoyl, 2-(4-methyl-piperazin- 1 -yl)ethylcarbamoyl, 2-(4-ethyl- piperazin- 1 -yl)ethylcarbamoyl, 2-(4-propyl-piperazin- 1 -yl)ethylcarbamoyl, 2-(4-acetyl- piperazin- 1 -yl)ethylcarbamoyl, 2- [4-(2-hydroxyethyl)piperazin- 1 -yl] ethylcarbamoyl, 2- [4- (3-hydroxypropyl)piperazin- 1 -yl] ethylcarbamoyl, 2- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 - yl} ethylcarbamoyl, 2- {4-[3-(oxan-4-yl)propyl]piperazin- 1 -yl} ethylcarbamoyl, 2- {4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl} ethylcarbamoyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} ethylcarbamoyl, 3 -(piperazin- 1 -yl)propylcarbamoyl, 3 -(4-methyl-piperazin- 1 - yl)propylcarbamoyl, 3-(4-ethyl-piperazin-l-yl)propylcarbamoyl, 3-(4-propyl-piperazin-l- yl)propylcarbamoyl, 3-(4-acetyl-piperazin-l-yl)propylcarbamoyl, 3-[4-(2- hydroxyethyl)piperazin- 1 -yl]propylcarbamoyl, 3 - [4-(3 -hydroxypropyl)piperazin- 1 - yl]propylcarbamoyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin-l -yl}propylcarbamoyl, 3- {4- [3- (oxan-4-yl)propyl]piperazin-l-yl}propylcarbamoyl, 3-{4-[2-(oxolan-3-yl)ethyl]piperazin- l-yl}propylcarbamoyl, 3-{4-[3-(oxolan-3-yl)propyl]piperazin-l-yl}propylcarbamoyl, piperazin- 1-ylcarbonyl, 4-methylpiperazin-l-ylcarbonyl, 4-ethylpiperazin-l-ylcarbonyl, 4- propylpiperazin- 1 -ylcarbonyl, (4-acetyl-piperazin- 1 -yl)carbonyl, [4-(2- hydroxyethyl)piperazin- 1 -yl] carbonyl, [4-(3 -hydroxypropyl)piperazin- 1 -yl] carbonyl, {4- [2-(oxan-4-yl)ethyl]piperazin- 1 -yl} carbonyl, {4-[3-(oxan-4-yl)propyl]piperazin- 1 - yl}carbonyl, {4- [2-(oxolan-3-yl)ethyl]piperazin- 1-yl} carbonyl, {4-[3-(oxolan-3- yl)propyl]piperazin- 1 -yl} carbonyl, 2-(piperazin- 1 -yl)ethylcarbonyl, 2-(4-methyl-piperazin- 1 -yl)ethylcarbonyl, 2-(4-ethyl-piperazin- 1 -yl)ethylcarbonyl, 2-(4-propyl-piperazin- 1 - yl)ethylcarbonyl, 2-(4-acetyl-piperazin- 1 -yl)ethylcarbonyl, 2-[4-(2- hydroxyethyl)piperazin- 1 -yl]ethylcarbonyl, 2- [4-(3 -hydroxypropyl)piperazin- 1 - yl]ethylcarbonyl, 2- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 -yl} ethylcarbonyl, 2- {4-[3-(oxan-4- yl)propyl]piperazin- 1 -yl} ethylcarbonyl, 2- {4-[2-(oxolan-3-yl)ethyl]piperazin- 1 - yl} ethylcarbonyl, 2- {4-[3-(oxolan-3-yl)propyl]piperazin- 1 -yl} ethylcarbonyl, 3-(piperazin- 1 -yl)propylcarbonyl, 3 -(4-methyl-piperazin- 1 -yl)propylcarbonyl, 3 -(4-ethyl-piperazin- 1 - yl)propylcarbonyl, 3-(4-propyl-piperazin-l-yl)propylcarbonyl, 3 -(4-acetyl-piperazin- 1- yl)propylcarbonyl, 3-[4-(2-hydroxyethyl)piperazin-l-yl]propylcarbonyl, 3-[4-(3- hydroxypropyl)piperazin- 1 -yl]propylcarbonyl, 3- {4-[2-(oxan-4-yl)ethyl]piperazin- 1 - yl}propylcarbonyl, 3-{4-[3-(oxan-4-yl)propyl]piperaziny-l-l}propylcarbonyl, 3-{4-[2- (oxolan-3-yl)ethyl]piperazin- 1 -yl}propylcarbonyl, 3- {4-[3-(oxolan-3-yl)propyl]piperazin- l-yl}propylcarbonyl, piperidin-3-yl, piperidin-4-ylmethyl, piperidin-3-ylmethyl, morpholin-4-yl or 2-(morpholin-4-yl)ethyl, tetrahydropyran-4-yl or l-(4-aminocyclohex-l- yi); m is 0 or 1 , and when m is 1 , the R2 group is selected from halogeno, hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy and propoxy; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2- (tetrahydrofuran-2-yl)ethyl or (3-methyloxetan-3-yl)methyl; n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
Figure imgf000070_0001
Ring A is pyrazol-4-yl or pyridin-3-yl;
When Ring A is pyrazol-4-yl, R1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, l-[3-(oxan-4-yl)propyl]piperidin-4-yl, l-[2-(oxolan-3- yl)ethyl]piperidin-4-yl or l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, and when Ring A is pyridin-3-yl, R1 is aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy , 2-(methylamino)ethoxy , 3 -(methylamino)propoxy , dimethylaminomethoxy, 2-(dimethylamino)ethoxy, 3-(dimethylamino)propoxy, piperidin- 1 -yl, piperazin- 1 -yl, 4-methylpiperidin- 1 -yl, 4-ethylpiperidin- 1 -yl, 4-methylpiperazin- 1 -yl, 4-ethylpiperazin- 1 -yl, 1 -methylpiperidin-4-ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3 -(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, 4- methylpiperazin-1-ylcarbonyl, 4-ethylpiperazin-l-ylcarbonyl or 4-propylpiperazin-l- ylcarbonyl; m is 0 or 1, and when m is 1, the R2 group is selected from halogeno, hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy and propoxy; R3 is hydrogen or methyl; n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy; or a pharmaceutically-accep table salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
Gi and G2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl; When Ring A is pyrazol-4-yl, R1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperidin-3- ylmethyl, 2-piperidin-3-ylethyl, piperidin-3-yl, tetrahydropyran-4-yl or tetrahydropyran-4- ylmethyl, and when Ring A is pyridin-3-yl, R1 is aminomethoxy, 2-(amino)ethoxy, 3- (amino)propoxy, methylaminomethoxy, 2-(methylamino)ethoxy, 3- (methylamino)propoxy, dimethylaminomethoxy, 2-(dimethylamino)ethoxy, 3- (dimethylamino)propoxy , piperidin- 1 -yl, piperazin- 1 -yl, 4-methylpiperidin- 1-yl, 4- ethylpiperidin-1-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, l-methylpiperidin-4- ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3-(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, 4-methylpiperazin- 1 -ylcarbonyl, 4- ethylpiperazin-1-ylcarbonyl or 4-propylpiperazin-l -ylcarbonyl and when Ring A is pyridin-4-yl, R1 is piperazin- 1-yl, aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2-(methylamino)ethoxy , 3 -(methylamino)propoxy , dimethylaminomethoxy, 2-(dimethylamino)ethoxy, 3-(dimethylamino)propoxy, piperidin- 1-yl, piperazin-1-yl, 4-methylpiperidin-l-yl, 4-ethylpiperidin-l-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin- 1 -yl, 1 -methylpiperidin-4-ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3 -(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, A- methylpiperazin-1-ylcarbonyl, 4-ethylpiperazin- 1-ylcarbonyl or 4-propylpiperazin-l- ylcarbonyl; m is 0 or 1, and when m is 1, the R2 group is selected from halogeno, hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy and propoxy; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2- (tetrahydrofuran-2-yl)ethyl or (3-methyloxetan-3-yl)methyl; n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; 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 G2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl; When Ring A is pyrazol-4-yl, R1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, l-(3-hydroxypropyl)piperidin-4-yl, l-[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperidin-3- ylmethyl, 2-piperidin-3-ylethyl, piperidin-3-yl, tetrahydropyran-4-yl, tetrahydropyran-4- ylmethyl or l-(4-aminocyclohex-l-yl), and when Ring A is pyridin-3-yl, R1 is aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy, 2- (dimethylamino)ethoxy, 3-(dimethylamino)propoxy, piperidin-1-yl, piperazin-1-yl, 4- methylpiperidin-1-yl, 4-ethylpiperidin-l-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, 1 -methylpiperidin-4-ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3-(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, 4-methylpiperazin- 1 - 5 ylcarbonyl, 4-ethylpiperazin- 1 -ylcarbonyl or 4-propylpiperazin- 1 -ylcarbonyl and when Ring A is pyridin-4-yl, R1 is piperazin-1-yl, aminomethoxy, 2-(amino)ethoxy, 3- (amino)propoxy, methylaminomethoxy, 2-(methylamino)ethoxy, 3- (methylamino)propoxy, dimethylaminomethoxy, 2-(dimethylamino)ethoxy, 3- (dimethylamino)propoxy, piperidin-1-yl, piperazin-1-yl, 4-methylpiperidin-l-yl, 4- i o ethylpiperidin- 1 -yl, 4-methylpiperazin- 1 -yl, 4-ethylpiperazin- 1 -yl, 1 -methylpiperidin-4- ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3 -(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, 4-methylpiperazin- 1 -ylcarbonyl, 4- ethylpiperazin-1 -ylcarbonyl or 4-propylpiperazin- 1 -ylcarbonyl; m is 0 or 1, and when m is 1, the R2 group is selected from halogeno, hydroxy, is amino, methyl, ethyl, propyl, methoxy, ethoxy and propoxy;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2- (tetrahydrofuran-2-yl)ethyl or (3-methyloxetan-3-yl)methyl; n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl,
20 methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; or a
25 pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi is CH and G2 is N or Gi is N and G2 is CH; 30 Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
When Ring A is pyrazol-4-yl, R1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperidin-3- ylmethyl, 2-piperidin-3-ylethyl, piperidin-3-yl, tetrahydropyran-4-yl, tetrahydropyran-4- ylmethyl or l-(4-aminocyclohex-l-yl), and when Ring A is pyridin-3-yl, R1 is aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy, 2- (dimethylamino)ethoxy, 3-(dimethylamino)propoxy, piperidin-1-yl, piperazin-1-yl, 4- methylpiperidin-1-yl, 4-ethylpiperidin-l-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, 1 -methylpiperidin-4-ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3-(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, 4-methylpiperazin- 1 - ylcarbonyl, 4-ethylpiperazin- 1-ylcarbonyl or 4-propylpiperazin-l-ylcarbonyl and when Ring A is pyridin-4-yl, R1 is piperazin-1-yl, aminomethoxy, 2-(amino)ethoxy, 3- (amino)propoxy, methylaminomethoxy, 2-(methylamino)ethoxy, 3-
(methylamino)propoxy, dimethylaminomethoxy, 2-(dimethylamino)ethoxy, 3- (dimethylamino)propoxy, piperidin-1-yl, piperazin-1-yl, 4-methylpiperidin-l-yl, 4- ethylpiperidin-1-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, l-methylpiperidin-4- ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3 -(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- l-yl)propylcarbamoyl, 4-methylpiperazin- 1-ylcarbonyl, 4- ethylpiperazin- 1-ylcarbonyl or 4-propylpiperazin-l-ylcarbonyl; m is 0 or 1, and when m is 1, the R2 group is selected from halogeno, hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy and propoxy; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2- (tetrahydrofuran-2-yl)ethyl or (3-methyloxetan-3-yl)methyl; n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
Figure imgf000075_0001
Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl; When Ring A is pyrazol-4-yl, R1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, l-(3-hydroxypropyl)piperidin-4-yl, l-[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperidin-3- ylmethyl, 2-piperidin-3-ylethyl, piperidin-3-yl, tetrahydropyran-4-yl, tetrahydropyran-4- ylmethyl or l-(4-aminocyclohex-l-yl), and when Ring A is pyridin-3-yl, R1 is aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy, 2- (dimethylamino)ethoxy, 3-(dimethylamino)propoxy, piperidin-1-yl, piperazin-1-yl, 4- methylpiperidin-1-yl, 4-ethylpiperidin-l-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, l-methylpiperidin-4-ylcarbamoyl, l-ethylpiperidin-4-ylcarbamoyl, 3-(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, 4-methylpiperazin- 1 - ylcarbonyl, 4-ethylpiperazin- 1-ylcarbonyl or 4-propylpiperazin-l-ylcarbonyl and when Ring A is pyridin-4-yl, R1 is piperazin-1-yl, aminomethoxy, 2-(amino)ethoxy, 3- (amino)propoxy, methylaminomethoxy, 2-(methylamino)ethoxy, 3- (methylamino)propoxy, dimethylaminomethoxy, 2-(dimethylamino)ethoxy, 3-
(dimethylamino)propoxy, piperidin-1-yl, piperazin-1-yl, 4-methylpiperidin-l-yl, 4- ethylpiperidin-1-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, l-methylpiperidin-4- ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3 -(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, 4-methylpiperazin- 1 -ylcarbonyl, 4- ethylpiperazin- 1 -ylcarbonyl or 4-propylpiperazin- 1 -ylcarbonyl; m is 0 or 1, and when m is 1, the R2 group is selected from halogeno, hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy and propoxy; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2- (tetrahydrofuran-2-yl)ethyl or (3-methyloxetan-3-yl)methyl; n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; or a pharmaceutically-accep table salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi and G2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
When Ring A is pyrazol-4-yl, R1 is located at the 1 position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, 1- acetylpiperidin-4-yl, l-(2-hydroxyethyl)piperidin-4-yl, l-(3-hydroxypropyl)piperidin-4-yl, 1 - [2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - [3 -(tetrahydropyran-4- yl)propyl]piperidin-4-yl, l-(tetrahydrofuran-3-ylmethyl)piperidin-4-yl, l-[2-
(tetrahydrofuran-3 -yl)ethyl]piperidin-4-yl, 1 - [3 -(tetrahydrofuran-3 -yl)propyl]piperidin-4- yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, piperidin-4-ylmethyl, 2-piperidin-4- ylethyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-3-yl, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl and l-(4-aminocyclohex-l-yl), and when Ring A is pyridin-3- yl, R1 is located at the 5- or 6- position and is selected from 2-(amino)ethoxy, 3- (amino)propoxy, 2-(methylamino)ethoxy, 3-(methylamino)propoxy, 2- (dimethylamino)ethoxy, 3-(dimethylamino)propoxy, piperidin-1-yl, piperazin-1-yl, 4- methylpiperidin-1-yl, 4-ethylpiperidin-l-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, 1 -methylpiperidin-4-ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3-(4-methylpiperazin- l-yl)propylcarbamoyl, 3-(4-ethylpiperazin-l-yl)propylcarbamoyl, 4-methylpiperazin-l- ylcarbonyl, piperazin-1-ylcarbonyl, 4-ethylpiperazin-l-ylcarbonyl and 4-propylpiperazin- 1-ylcarbonyl and when Ring A is pyridin-4-yl, R1 is located at the 3- position and is selected from piperazin-1-yl, 2-(amino)ethoxy, 3-(amino)propoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, 2-(dimethylamino)ethoxy, 3- (dimethylamino)propoxy, piperidin-1-yl, piperazin-1-yl, 4-methylpiperidin-l-yl, A- ethylpiperidin-1-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, l-methylpiperidin-4- ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3 -(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3-(4-ethylpiperazin- 1 -yl)propylcarbamoyl, piperazin- 1 -ylcarbonyl, 4-methylpiperazin- 1 - ylcarbonyl, 4-ethylpiperazin-l -ylcarbonyl and 4-propylpiperazin-l -ylcarbonyl; m is 0 or 1 , and when m is 1 , the R2 group is selected from methyl and ethyl; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2- (tetrahydrofuran-2-yl)ethyl or (3-methyloxetan-3-yl)methyl; n is 0, or, when each of Gi and G2 is CH, n may be 1 or 2 and the (R4)n groups are selected from 5-fluoro, 5,6-difluoro, 4-methoxy, 4-ethoxy, 4-phenylmethoxy, 4-tetrahydrofuran-3- ylmethoxy, 5-trifluoromethyl, 4-methyl, 5-methyl, 4,5-dimethyl, 4-ethyl, 5-ethyl, 4,5- diethyl, 5-chloro, 5-bromo, 4-[(l-methylpyrrolidin-3-yl)oxy], 4-cyclopentyloxy, A- isobutoxy, 4-[(tetrahydrofuran-2-yl)methoxy], 4-[2-(tetrahydrofuran-2-yl)ethoxy], A- isopropoxy, 4-ethoxy, 4-(isoxazol-3-ylmethoxy), 4-cyclopentylmethoxy, A- cyclopropylmethoxy and 4-(2-phenylethoxy); or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
Figure imgf000077_0001
Ring A is pyrazol-4-yl or pyridin-3-yl; When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl),
1 -(I -ethylpiperidin-4-yl), 1 -(I -acetylpiperidin-4-yl), 1 -[I -(2-hydroxyethyl)piperidin-4-yl], 1 - { 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl} or 1 - { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl} (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3-(dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l- yl), 6-(4-methylpiperazin-l-yl), 5-(l-methylpiperidin-4-ylcarbamoyl), 5-[3-(4- methylpiperazin-l-yl)propylcarbamoyl] or 5-(4-methylpiperazin-l -ylcarbonyl) (that is each R1 group is located at the stated 5- or 6- position on the pyridin-3-yl ring); m is 0;
R3 is hydrogen; n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, methoxy, phenylmethoxy or oxolan-3-ylmethoxy; 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 G2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl; When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1-{1- [2-(oxan-4-yl)ethyl]piperidin-4-yl} , 1 - { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl} , 1 -[2- (morpholin-4-yl)ethyl], l-(piperidin-4-ylmethyl), l-(piperidin-3-ylmethyl), l-(piperidin-3- yl) or l-(tetrahydropyran-4-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3-(dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l-yl), 5-(l-methylpiperidin-4- ylcarbamoyl), 5-[3-(4-methylpiperazin-l-yl)propylcarbamoyl] or 5-(4-methylpiperazin-l- ylcarbonyl) (that is each R1 group is located at the stated 5- or 6- position on the pyridin-3- yl ring), and when Ring A is pyridin-4-yl, R1 is 2-(piperazin-l-yl); m is 0;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R4 group present may be the same or different, and each R4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; 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 G2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1-{1- [2-(oxan-4-yl)ethyl]piperidin-4-yl}, l-{l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl}, l-[2-
(morpholin-4-yl)ethyl], l-(piperidin-4-ylmethyl), l-(piperidin-3-ylmethyl), l-(piperidin-3- yl), l-(tetrahydropyran-4-yl) or l-(4-aminocyclohex-l-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3- (dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l- yl), 5-(l-methylpiperidin-4-ylcarbamoyl), 5-[3-(4-methylpiperazin-l-yl)propylcarbamoyl] or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R1 group is located at the stated 5- or 6- position on the pyridin-3-yl ring), and when Ring A is pyridin-4-yl, R1 is 2-(piperazin-l- yi); m is 0 or 1 , and when m is 1 , the R2 group is methyl; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R4 group present may be the same or different, and each R4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol-
3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the
Formula I above wherein :-
Gi is CH and G2 is N or Gi is N and G2 is CH;
Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1-{1-
[2-(oxan-4-yl)ethyl]piperidin-4-yl} , 1 - { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl} , 1 -[2-
(morpholin-4-yl)ethyl], l-(piperidin-4-ylmethyl), l-(piperidin-3-ylmethyl), l-(piperidin-3- yl), l-(tetrahydropyran-4-yl) or l-(4-aminocyclohex-l-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3- (dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l- yl), 5-(l -methylpiperidin-4-ylcarbamoyl), 5-[3-(4-methylpiperazin- 1 -yl)propylcarbamoyl] or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R1 group is located at the stated 5- or 6- position on the pyridin-3-yl ring), and when Ring A is pyridin-4-yl, R1 is 2-(piperazin-l- yi); m is 0 or 1 , and when m is 1 , the R2 group is methyl;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R4 group present may be the same or different, and each R4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol-
3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
Figure imgf000080_0001
Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1-{1- [2-(oxan-4-yl)ethyl]piperidin-4-yl}, l-{l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl}, l-[2-
(morpholin-4-yl)ethyl], l-(piperidin-4-ylmethyl), l-(piperidin-3-ylmethyl), l-(piperidin-3- yl), l-(tetrahydropyran-4-yl) or l-(4-aminocyclohex-l-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3- (dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l- yl), 5-(l -methylpiperidin-4-ylcarbamoyl), 5-[3-(4-methylpiperazin-l-yl)propylcarbamoyl] or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R1 group is located at the stated 5- or 6- position on the pyridin-3-yl ring), and when Ring A is pyridin-4-yl, R1 is 2-(piperazin-l- yi); m is 0 or 1 , and when m is 1 , the R2 group is methyl;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R4 group present may be the same or different, and each R4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
Figure imgf000081_0001
Ring A is pyrazol-4-yl;
R1 is l-(l-methylpiperidin-4-yl); m is 0; R3 is hydrogen; n is 0; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the
Formula I above wherein :-
Figure imgf000081_0002
Ring A is pyrazol-4-yl;
R1 is l-(l-methylpiperidin-4-yl) or l-(piperidin-4-yl); m is 0;
R3 is hydrogen; n is 0; 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 G2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl; When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1-{1- [2-(oxan-4-yl)ethyl]piperidin-4-yl} , 1 - { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl} , 1 -[2- (morpholin-4-yl)ethyl], l-(piperidin-3-yl), l-(tetrahydropyran-4-yl) or l-(4- aminocyclohex-1-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3-(dimethylamino)propoxy], 6-(4- methylpiperazin-1-yl), 5-(l-methylpiperidin-4-ylcarbamoyl) or 5-(4-methylpiperazin-l- ylcarbonyl) (that is each R1 group is located at the stated 5- or 6- position on the pyridin-3- yl ring), and when Ring A is pyridin-4-yl, R1 is 2-(piperazin-l-yl); m is 0 or 1 , and when m is 1 , the R2 group is methyl; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R4 group present may be the same or different, and each R4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, methyl, chloro, bromo, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2- yl)methoxy, (isoxazol-3 -ylmethoxy) or cyclopropylmethoxy; or a pharmaceutically- acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
Gi is CH and G2 is N or Gi is N and G2 is CH;
Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1-{1- [2-(oxan-4-yl)ethyl]piperidin-4-yl}, l-{l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl}, l-[2- (morpholin-4-yl)ethyl], l-(piperidin-3-yl), l-(tetrahydropyran-4-yl) or l-(4- aminocyclohex-1-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3-(dimethylamino)propoxy], 6-(piperazin- 1-yl), 6-(4-methylpiperazin-l-yl), 5-(l-methylpiperidin-4-ylcarbamoyl) or 5-(4- methylpiperazin-1-ylcarbonyl) (that is each R1 group is located at the stated 5- or 6- position on the pyridin-3-yl ring), and when Ring A is pyridin-4-yl, R1 is 2-(piperazin-l- yi); m is 0 or 1 , and when m is 1 , the R2 group is methyl;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R4 group present may be the same or different, and each R4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, methyl, chloro, bromo, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2- yl)methoxy, (isoxazol-3-ylmethoxy) or cyclopropylmethoxy; or a pharmaceutically- acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
Figure imgf000083_0001
Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl; When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1-{1- [2-(oxan-4-yl)ethyl]piperidin-4-yl} , 1 - { 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl} , 1 -[2- (morpholin-4-yl)ethyl], l-(piperidin-3-yl), l-(tetrahydropyran-4-yl) or l-(4- aminocyclohex-1-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3-(dimethylamino)propoxy], 6-(piperazin- 1-yl), 6-(4-methylpiperazin-l-yl), 5-(l-methylpiperidin-4-ylcarbamoyl),or 5-(4- methylpiperazin-1-ylcarbonyl) (that is each R1 group is located at the stated 5- or 6- position on the pyridin-3-yl ring), and when Ring A is pyridin-4-yl, R1 is 2-(piperazin-l- yi); m is 0 or 1 , and when m is 1 , the R2 group is methyl; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R4 group present may be the same or different, and each R4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, methyl, chloro, bromo, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2- yl)methoxy (isoxazol-3-ylmethoxy) or cyclopropylmethoxy; 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 G2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl or pyridin-3-yl; When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1-{1- [2-(oxan-4-yl)ethyl]piperidin-4-yl}, l-{l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl} or 1- (tetrahydropyran-4-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4- yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3-(dimethylamino)propoxy], (that is each R1 group is located at the stated 6- position on the pyridin-3-yl ring), m is 0 or 1 , and when m is 1 , the R2 group is methyl;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethylcyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R4 is selected from hydrogen, fluoro, oxolan-3-ylmethoxy,
(tetrahydrofuran-2-yl)methoxy and cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi is CH and G2 is N or Gi is N and G2 is CH; Ring A is pyrazol-4-yl or pyridin-3-yl;
When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1-{1- [2-(oxan-4-yl)ethyl]piperidin-4-yl}, l-{l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl} or 1- (tetrahydropyran-4-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4- yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3-(dimethylamino)propoxy], (that is each R1 group is located at the stated 6- position on the pyridin-3-yl ring), m is 0 or 1 , and when m is 1 , the R2 group is methyl;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethylcyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R4 is selected from hydrogen, fiuoro, oxolan-3-ylmethoxy, (tetrahydrofuran-2-yl)methoxy and cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the
Formula I above wherein :-
Figure imgf000085_0001
Ring A is pyrazol-4-yl or pyridin-3-yl;
When Ring A is pyrazol-4-yl, R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1-{1-
[2-(oxan-4-yl)ethyl]piperidin-4-yl}, l-{l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl} or 1-
(tetrahydropyran-4-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4- yl ring), and when Ring A is pyridin-3-yl, R1 is 6-[3-(dimethylamino)propoxy], (that is each R1 group is located at the stated 6- position on the pyridin-3-yl ring), m is 0 or 1 , and when m is 1 , the R2 group is methyl;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethylcyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R4 is selected from hydrogen, fiuoro, oxolan-3-ylmethoxy,
(tetrahydrofuran-2-yl)methoxy and cyclopropylmethoxy; 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 G2 is selected from CH and N provided that both are not N;
Ring A is pyrazol-4-yl; R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), l-(l-ethylpiperidin-4-yl), 1-(1- acetylpiperidin-4-yl), 1 -[ 1 -(2-hydroxyethyl)piperidin-4-yl] , 1 - { 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl}, l-{l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl} or l-(tetrahydropyran- 4-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring); m is 0 or 1 , and when m is 1 , the R2 group is methyl;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R4 is selected from fiuoro, oxolan-3-ylmethoxy, (tetrahydrofuran-2-yl)methoxy or cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi is CH and G2 is N or Gi is N and G2 is CH; Ring A is pyrazol-4-yl;
R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), l-(l-ethylpiperidin-4-yl), 1-(1- acetylpiperidin-4-yl), 1 -[ 1 -(2-hydroxyethyl)piperidin-4-yl] , 1 - { 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl}, l-{l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl} or l-(tetrahydropyran- 4-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring); m is 0 or 1 , and when m is 1 , the R2 group is methyl;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R4 is selected from fiuoro, oxolan-3-ylmethoxy,
(tetrahydrofuran-2-yl)methoxy or cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
Figure imgf000086_0001
Ring A is pyrazol-4-yl;
R1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), l-(l-ethylpiperidin-4-yl), 1-(1- acetylpiperidin-4-yl), 1 -[ 1 -(2-hydroxyethyl)piperidin-4-yl] , 1 - { 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl}, l-{l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl} or l-(tetrahydropyran- 4-yl) (that is each R1 group is located at the 1 -position on the pyrazol-4-yl ring); m is 0 or 1 , and when m is 1 , the R2 group is methyl;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R4 is selected from fiuoro, oxolan-3-ylmethoxy, (tetrahydrofuran-2-yl)methoxy or cyclopropylmethoxy; 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 G2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl or pyridin-3-yl; When Ring A is pyrazol-4-yl, R1 is located at the 1 -position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - (tetrahydrofuran-3-ylmethyl)piperidin-4-yl and tetrahydropyran-4-yl, and when Ring A is pyridin-3-yl, R1 is located at the 6- position and is 3-(dimethylamino)propoxy; m is 0; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0, or, when each of Gi and G2 is CH, n may be 1 and the (R4)n group is selected from 5-fiuoro, 4-tetrahydrofuran-3-ylmethoxy, 4-[(tetrahydrofuran-2-yl)methoxy] and 4- cyclopropylmethoxy; 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 G2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl or pyridin-3-yl; When Ring A is pyrazol-4-yl, R1 is located at the 1 -position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - (tetrahydrofuran-3-ylmethyl)piperidin-4-yl and tetrahydropyran-4-yl, and when Ring A is pyridin-3-yl, R1 is located at the 6- position and is 3-(dimethylamino)propoxy; m is 1 , and R2 is methyl;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0, or, when each of Gi and G2 is CH, n may be 1 and the (R4)n group is selected from 5-fiuoro, 4-tetrahydrofuran-3-ylmethoxy, 4-[(tetrahydrofuran-2-yl)methoxy] and A- cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
Particular compounds of the invention are, for example, the pyrazine derivatives of the Formula I that are disclosed within the Examples that are set out hereinafter.
For example, a particular compound of the invention is a pyrazine derivative of the
Formula I selected from any one of the following:-
3-(5-Fluoro- lH-benzimidazol-2-yl)-5-[ 1 -(4-piperidyl)pyrazol-4-yl]pyrazin-2-amine; 3-(7-methoxy-lH-benzimidazol-2-yl)-5-[l-(l-methyl-4-piperidyl)pyrazol-4-yl]pyrazin-2- amine;
3-(7-phenylmethoxy- l//-benzimidazol-2-yl)-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine;
3-[7-(tetrahydrofuran-3-ylmethoxy)-lH-benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4- yl]pyrazin-2-amine;
3-(lH-benzimidazol-2-yl)-5-[6-(3-dimethylaminopropoxy)pyridin-3-yl]pyrazin-2-amine;
3-(lH-benzimidazol-2-yl)-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine;
3-(lH-benzimidazol-2-yl)-5-(6-piperazin-l-ylpyridin-3-yl)pyrazin-2-amine;
3-(5-fluoro-lH-benzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine;
5-[l-(l-ethyl-4-piperidyl)pyrazol-4-yl]-3-(5-fluoro-lH-benzimidazol-2-yl)pyrazin-2- amine;
3-(5-fluoro- l//-benzimidazol-2-yl)-5-[ 1 -[ 1 -[2-(tetrahydropyran-4-yl)ethyl]-piperidin-4- yl]pyrazol-4-yl]pyrazin-2-amine; 3-(5-fluoro- l//-benzimidazol-2-yl)-5-[l -[ 1 -((tetrahydrofuran-3-yl)methyl)-piperidin-4- yl]pyrazol-4-yl]pyrazin-2-amine; 2-[4-[4-[5-amino-6-(5-fluoro- l//-benzimidazol-2-yl)pyrazin-2-yl]pyrazol- 1 -yl]-piperidin- l-yl]ethanol;
3-(lH-benzimidazol-2-yl)-5-[l-(l-methyl-piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine; l-[4-[4-[5-amino-6-(lH-benzimidazol-2-yl)pyrazin-2-yl]pyrazol-l-yl]-piperidin-l- yljethanone;
5 - [5 -amino-6-( lH-benzimidazol-2-yl)pyrazin-2-yl]-Λ/-( 1 -methylpiperidin-4-yl)pyridine-3 - carboxamide;
5 - [5 -amino-6-( lH-benzimidazol-2-yl)pyrazin-2-yl]-7V- [3 -(4-methylpiperazin- 1 - yl)propyl]pyridine-3-carboxamide; 5-[5-amino-6-(lH-benzimidazol-2-yl)pyrazin-2-yl]-Λ/-(3-dimethylaminopropyl)pyridine-3- carboxamide;
[5-[5-amino-6-(lH-benzimidazol-2-yl)pyrazin-2-yl]pyridin-3-yl]-(4-methylpiperazin-l- yl)methanone;
3-(lH-benzimidazol-2-yl)-5-[6-(piperidin-l-yl)pyridin-3-yl]pyrazin-2-amine; and 3-(lH-benzimidazol-2-yl)-5-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]pyrazin-2-amine; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the Formula I selected from any one of the following :-
5-[l-(l-methyl-piperidin-4-yl)pyrazol-4-yl]-3-[5-(trifluoromethyl)-lH-benzimidazol-2- yl]pyrazin-2-amine;
3-(5-methyl-lH-benzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine; 3-(4-methyl-lH-benzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine;
3-(5-chloro-lH-benzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine;
3-(5-bromo-lH-benzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine;
3-(4,5-dimethyl-lH-benzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4- yl]pyrazin-2-amine; 3-(5,6-difluoro-lH-benzimidazol-2-yl)-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine;
5-[l-(piperidin-4-yl)pyrazol-4-yl]-3-[5-(trifluoromethyl)-lH-benzimidazol-2-yl]pyrazin-2- amine;
3-(5-fluoro-lH-benzimidazol-2-yl)-5-(2-piperazin-l-ylpyridin-4-yl)pyrazin-2-amine; 3-(5-fluoro- lH-benzimidazol-2-yl)-5-[ 1 -(2-morpholinoethyl)pyrazol-4-yl]pyrazin-2- amine;
3-(5-fluoro-lH-benzimidazol-2-yl)-5-[l-(piperidin-4-ylmethyl)pyrazol-4-yl]pyrazin-2- amine;
3-(5-fluoro-lH-benzimidazol-2-yl)-5-[l-(piperidin-3-ylmethyl)pyrazol-4-yl]pyrazin-2- amine;
3-(5-fluoro-lH-benzimidazol-2-yl)-5-[l-(piperidin-3-yl)pyrazol-4-yl]pyrazin-2-amine;
3-(5-fluoro-lH-benzimidazol-2-yl)-5-[l-(tetrahydropyran-4-yl)pyrazol-4-yl]pyrazin-2- amine;
3-[4-(l-methylpyrrolidin-3-yl)oxy-lH-benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4- yl]pyrazin-2-amine;
3-[4-(cyclopentyloxy)- lH-benzimidazol-2-yl]-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine;
3-(4-isobutoxy- lH-benzimidazol-2-yl)-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine;
3-[4-((tetrahydrofuran-2-yl)methoxy)-lH-benzimidazol-2-yl]-5-(l-piperidin-4-ylpyrazol-4- yl)pyrazin-2-amine;
3-(4-isopropoxy- lH-benzimidazol-2-yl)-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine;
3-(4-ethoxy- lH-benzimidazol-2-yl)-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine;
3-[4-(isoxazol-3-ylmethoxy)- lH-benzimidazol-2-yl]-5-[ 1 -(piperidin-4-yl)pyrazol-4- yl]pyrazin-2-amine;
3-[4-(cyclopentylmethoxy)-lH-benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4- yl]pyrazin-2-amine;
3-[4-(cyclopropylmethoxy)-lH-benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4- yl]pyrazin-2-amine; 3-(4-phenethyloxy- lH-benzimidazol-2-yl)-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine; 3-(lH-imidazo[4,5-c]pyridin-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine;
3-[l-(2-methoxyethyl)benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine; 3 -(I -methylbenzimidazol-2-yl)-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine; 3-(l -ethylbenzimidazol-2-yl)-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine; 3-(l -isobutylbenzimidazol-2-yl)-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine; 3-[l-(cyclopropylmethyl)benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine; 2-[2-[3-amino-6-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-yl]benzimidazol-l-yl]ethanol; 3-[2-[3-amino-6-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-yl]benzimidazol-l-yl]propan-l- ol;
5 - [ 1 -(piperidin-4-yl)pyrazol-4-yl] -3 - [ 1 -(tetrahydrofuran-2-ylmethyl)benzimidazol-2- yl]pyrazin-2-amine; 3-[l-[(3-methyloxetan-3-yl)methyl]benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4- yl]pyrazin-2-amine;
3-[l-(2-methoxyethyl)benzimidazol-2-yl]-5-[l-(l-methylpiperidin-4-yl)pyrazol-4- yl]pyrazin-2-amine;
3-(l-methylbenzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine;
3-(6-fluoro-l-methylbenzimidazol-2-yl)-5-(l-piperidin-4-ylpyrazol-4-yl)pyrazin-2-amine; and 3-(5-fluoro- 1 -methylbenzimidazol-2-yl)-5-(l -piperidin-4-ylpyrazol-4-yl)pyrazin-2- amine; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrazine derivative of the
Formula I selected from any one of the following :-
3-(5-chloro-6-fluoro-lH-benzimidazol-2-yl)-5-[l-(4-piperidyl)pyrazol-4-yl]pyrazin-2- amine;
5-[l-(4-aminocyclohexyl)pyrazol-4-yl]-3-(6-fluoro-lH-benzimidazol-2-yl)pyrazin-2- amine;
3-(l-ethylbenzimidazol-2-yl)-5-[l-(l-methyl-4-piperidyl)pyrazol-4-yl]pyrazin-2-amine;
3-(lH-Imidazo[4,5-c]pyridin-2-yl)-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine; 3-(l-ethylbenzimidazol-2-yl)-5-[3-methyl-l-(4-piperidyl)pyrazol-4-yl]pyrazin-2-amine; 3-(l-ethylbenzimidazol-2-yl)-5-[3-methyl-l-(l-methyl-4-piperidyl)pyrazol-4-yl]pyrazin-2- amine;
3-(lH-benzimidazol-2-yl)-5-[3-methyl-l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine; and
3-(lH-benzimidazol-2-yl)-5-[3-methyl-l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine; or a pharmaceutically-acceptable salt thereof.
A yet further particular compound of the invention is a pyrazine derivative of the Formula I selected from any one of the following :-
3-(lH-benzimidazol-2-yl)-5-[ 1 -[ 1 -(2-tetrahydropyran-4-ylethyl)piperidin-4-yl]pyrazol-4- yl]pyrazin-2-amine;
3-(lH-benzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine;
3-(l -ethylbenzimidazol-2-yl)-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine; 3-[l-(cyclopropylmethyl)benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine;
3-(5-fluoro-lH-benzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine; l-[4-[4-[5-amino-6-(l//-benzimidazol-2-yl)pyrazin-2-yl]pyrazol-l-yl]-l- piperidyl]ethanone;
3 -(I -ethylbenzimidazol-2-yl)-5-[ 1 -(I -methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine;
3 -(I -ethylbenzimidazol-2-yl)-5- [3 -methyl- 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine;
3-[l-(2-methoxyethyl)benzimidazol-2-yl]-5-[l-(l-methylpiperidin-4-yl)pyrazol-4- yl]pyrazin-2-amine; 3-(l-ethylbenzimidazol-2-yl)-5-[3-methyl-l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-
2-amine; and
3-(lH-benzimidazol-2-yl)-5-[3-methyl-l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine; or a pharmaceutically-acceptable salt thereof.
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 the following representative process variants in which, unless otherwise stated, G1, G2, Ring A, R1, m, R2, R3, n and R4 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
Figure imgf000093_0001
( R2 L or a reactive derivative thereof, wherein Ring A, R1, m and R2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a 1,2- diamine of the Formula III
Figure imgf000093_0002
wherein G1, G2, R3, n and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, to provide an amide of the Formula IV
Figure imgf000093_0003
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 chloro formate such as isobutyl chloro formate; an active ester, for example an ester formed by the reaction of the acid with a phenol such as pentafiuorophenol, 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 diethylphosphoryl cyanide; or the product of the reaction of the acid with a carbodiimide such as dicyclohexylcarbodiimide or with a uronium compound such as
2-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafiuorophosphate(V) or with 1 -hydroxybenzotriazole. 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. 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. Conveniently, the reaction is carried out in the presence of a dipolar aprotic solvent such as N,Λ/-dimethylformamide, N,N- dimethylacetamide, 7V-methylpyrrolidin-2-one or dimethyl sulphoxide. The reaction is conveniently carried out at a temperature in the range, for example, 0 to 1200C, conveniently at or near ambient temperature. If the reactive derivative of a carboxylic acid of the Formula II is, for example, an active ester, for example an ester formed by the reaction of the acid with an alcohol such as methanol, ethanol, isopropanol, butanol or tert- butanol, the reaction is conveniently carried out in the presence of a dipolar aprotic solvent such as 7V,7V-dimethylformamide or 7V,7V-dimethylacetamide at a temperature in the range, for example, 50 to 1500C, conveniently at or near 1500C. Optionally, a suitable base such as an alkali or alkaline earth metal (l-6C)alkoxide such as sodium methoxide is used.
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 1500C, conveniently at or near 1100C. Pyrazine carboxylic acids of the the Formula II, 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
Figure imgf000095_0001
( R2 L wherein each of L1 and L2, which may be the same or different, is a suitable ligand for the boron atom and Ring A, R1, m and R2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a pyrazine of the Formula VI
Figure imgf000095_0002
or a reactive derivative thereof as defined hereinbefore, wherein L is a displaceable group and L3 is hydrogen or a protecting group such as methyl, whereafter any protecting group that is present is removed.
A suitable value for the ligands L1 and L2 which are present on the boron atom of the organoboron reagent include, for example, a hydroxy, (l-4C)alkoxy or (l-6C)alkyl ligand, for example a hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methyl, ethyl, propyl, isopropyl or butyl ligand. Alternatively the ligands L1 and L2 may be linked such that, together with the boron atom to which they are attached, they form a ring. For example, L1 and L2 together may define an oxy-(2-4C)alkylene-oxy group, for example an oxyethyleneoxy, oxytrimethyleneoxy group or -O-C(CH3)2C(CH3)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 L1 and L2 is a hydroxy, a isopropoxy or an ethyl group or L1 and L2 together define a group of formula -O-C(CH3)2C(CH3)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)palladium(0), palladium(II) chloride, palladium(II) bromide, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)nickel(0), nickel(II) chloride, nickel(II) bromide, bis(triphenylphosphine)nickel(II) chloride or [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II). In addition, a free radical initiator may conveniently be added, for example an azo compound such as azo(bisisobutyronitrile).
Conveniently, 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. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example 7V,7V-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 2500C, preferably in the range 60 to 1800C.
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. (b) The cross coupling reaction, conveniently in the presence of a suitable catalyst as defined hereinbefore, of a pyrazine compound of the Formula VII
Figure imgf000097_0001
( R2 L Vl1 wherein L is a displaceable group as defined hereinbefore and Ring A, R1, m and R2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an organoboron reagent of the Formula VIII
L1
Figure imgf000097_0002
wherein each of L1 and L2, which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and G1, G2, R3, n and R4 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.
Conveniently, 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 alkali or alkaline earth metal fluoride, for example caesium fluoride, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example 7V,7V-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 2500C, preferably in the range 60 to 1800C.
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
Figure imgf000098_0001
wherein L is a displaceable group as defined hereinbefore and PG is a protecting group, with an organoboron reagent of the Formula V
Figure imgf000098_0002
( R2 L wherein each of L1 and L2, which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and Ring A, R1, m and R2 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 3-chloroperbenzoic acid or a mixture of oxone and acetone, at a suitable temperature such as 0 to 1000C, and in a solvent such as tetrahydrofuran. Alternatively, 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 7V-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 1000C, conveniently at or near 300C.
Conveniently, 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.
Compounds of the Formula IX are commercially available, known in the literature or can be prepared by standard processes known in the art. Organoboron compounds of the Formula VIII may be prepared by the reaction of a compound of the Formula X
Figure imgf000099_0001
wherein L is a displaceable group as defined hereinbefore and G1, G2, R3, n and R4 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.
Conveniently, L is a halgeno group such as a bromo or iodo group. Synthetic procedures for forming heteroarylboron reagents from heteroaryl halides are well known in the art, for example, 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°C, conveniently in the range 0 to 300C. Compounds of the Formula X are commercially available, known in the literature, or can be prepared by standard processes known in the art.
(c) The cross coupling reaction, conveniently in the presence of a suitable catalyst as defined hereinbefore, of a compound of the Formula XI
Figure imgf000099_0002
wherein L is a displaceable group as defined hereinbefore and G1, G2, R3, n and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an organoboron reagent of the Formula V
Figure imgf000100_0001
( R2 L wherein each of L1 and L2, which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and Ring A, R1, m and R2 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.
Conveniently, 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 alkali or alkaline earth metal fluoride, for example caesium fluoride, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example 7V,7V-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 2500C, preferably in the range 60 to 1800C.
Compounds of the Formula XI may be produced using analogous procedures to those described in process variant (a) hereinbefore. For example, a carboxylic acid, or a reactive derivative thereof as defined hereinbefore, of the Formula XII
Figure imgf000100_0002
wherein L is a displaceable group as defined hereinbefore, may be reacted with a 1 ,2- diamine of the Formula III
Figure imgf000100_0003
III wherein G1, G2, R3, n and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, to provide an amide of the Formula XIII
Figure imgf000101_0001
which is cyclised, conveniently in the presence of a suitable acid as defined hereinbefore, to form a compound of the Formula XI.
For example, 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 trie thy lamine, in a solvent such as N,Λ/-dimethylformamide and a temperature in the range of 0 to 1500C, 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 1500C, conveniently at or near 1000C.
Alternatively, compounds of the Formula XI may be produced by reacting a carboxylic acid, or a reactive derivative thereof as defined hereinbefore, of the Formula XIIa
Figure imgf000101_0002
with a compound of the Formula III:
Figure imgf000102_0001
III wherein G1, G2, R3, n and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, to provide an amide of the Formula XIIIa:
Figure imgf000102_0002
XIIIa which is cyclised, conveniently in the presence of a suitable acid as defined hereinbefore to form a compound of the Formula XIa
Figure imgf000102_0003
which is halogenated by reaction with a halogenating agent, for example a brominating agent, such as for example bromine or N-bromosuccinimide to form a compound of the Formula XI, whereafter any protecting group that is present is removed.
For example, a carboxylic acid of the Formula XIIa 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 trie thy lamine, in a solvent such as N,Λ/-dimethylformamide and a temperature in the range of 0 to 1500C, conveniently at or near ambient temperature. Cyclisation of the resultant amide product to form a compound of the Formula XIa 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 1500C, conveniently at or near 1000C.
The halogenation of compound XIa is suitably carried out in the presence of a solvent or diluent such as for example, N,Λ/-dimethylformamide, tetrahydrofuran, 1,4-dioxan, 1 ,2-dimethoxyethane, benzene, or halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example -500C to 1000C, preferably in the range 00C to 300C.
Compounds of the Formula XII and XIIa 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.
(d) For the production of those compounds of the Formula I wherein R1 is a group of the formula R5- X1 - wherein X1 is N(R6)CO, the acylation, conveniently in the presence of a suitable base, of an amine of the Formula XIV
Figure imgf000103_0001
wherein R5 and R6 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a carboxylic acid of the Formula XV
or a reactive derivative thereof as defined hereinbefore, wherein Ring A, m, R2, Gi, G2, R3, n and R4 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 is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, 7V-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.
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. Conveniently, the reaction is carried out in the presence of a dipolar aprotic solvent such as N,Λ/-dimethylformamide, 7V,7V-dimethylacetamide, N- methylpyrrolidin-2-one or dimethyl sulphoxide. The reaction is conveniently carried out at a temperature in the range, for example, 0 to 1200C, preferably at or near ambient temperature.
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
Figure imgf000104_0001
wherein L is a displaceable group as defined hereinbefore and G1, G2, RJ, n and R4 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
Figure imgf000105_0001
( R2 L wherein each of L1 and L2, which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and m and R2 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.
Conveniently, 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. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example 7V,7V-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 2500C, preferably in the range 60 to 1800C.
Compounds of the Formula XVI 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.
(e) For the production of those compounds of the Formula I wherein R1 is a group of the formula Q1 X2- wherein X2 is N(R8)CO, the acylation, conveniently in the presence of a suitable base as defined hereinbefore, of an amine of the Formula XVII
Q1 - NH(RS) χvπ wherein Q1 and R8 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a carboxylic acid of the Formula XV
Figure imgf000106_0001
or a reactive derivative thereof as defined hereinbefore, wherein Ring A, m, R2, G1, G2, R3, n and R4 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 conveniently carried out in the presence of 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 1200C, preferably at or near ambient temperature.
Compounds of the Formula XVII 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.
(f) For the production of those compounds of the Formula I wherein R1 is a group of the formula Q1 X2 - wherein Q1 is a heterocyclyl or heteroaryl group and X2 is a direct bond, the reaction of a compound of the Formula XVIII
Figure imgf000106_0002
XVIII wherein L is a suitable displaceable group as defined hereinbefore and Ring A, m, R2, G1, G2, R3, n and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an agent of the Formula XIX
Q1 - H XIX wherein Q1 is a heterocyclyl or heteroaryl group as defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed.
The reaction is conveniently carried out in the presence of a suitable base as defined hereinbefore. For example, 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 diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium bicarbonate, 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. Conveniently, the reaction is carried out in the presence of a dipolar aprotic solvent such as N,Λ/-dimethylformamide, 7V,7V-dimethylacetamide, N- methylpyrrolidin-2-one or dimethyl sulphoxide. The reaction is conveniently carried out at a temperature in the range, for example, 0 to 1500C, conveniently in the range, for example, 50 to 1200C.
Compounds of the Formula XVIII may be prepared using analogous procedures to those described in process variant (c) hereinbefore. For example, compounds may be prepared by a cross coupling reaction, conveniently in the presence of a suitable catalyst as defined hereinbefore, of a compound of the Formula XI
Figure imgf000107_0001
wherein L is a displaceable group as defined hereinbefore and G1, G2, R3, n and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an organoboron reagent of the Formula XX
Figure imgf000108_0001
wherein L is a displaceable group as defined hereinbefore and each of L1 and L2, which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and Ring A, R1, m and R2 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.
Conveniently, 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.
The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example 7V,7V-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 2500C, preferably in the range 60 to 1800C. Compounds of the Formula XI may be produced using procedures described in process variant (c) hereinbefore. Compounds of the Formula XX 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.
(g) For the production of those compounds of the Formula I wherein R4 is (l-6C)alkoxy or a group of formula OR11, wherein R11 is aryl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl and wherein any aryl or heterocyclyl group within the definition of R11 optionally bears 1, 2 or 3 substituents as defined hereinbefore, the reaction of a compound of the Formula XXI:
Figure imgf000109_0001
wherein Ring A, R1, m, R2, G1, G2, R3 and n have any of the meanings defined hereinbefore and R4 has any of the meanings defined hereinbefore other than (l-6C)alkoxy or OR11, except that any functional group is protected if necessary, with an appropriate alcohol, whereafter any protecting group that is present is removed.
Suitably, the reaction is carried out in the presence of a mixture of an azo compound such as diethyl, diisopropyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example tetrahydrofuran or a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 800C, preferably at or near ambient temperature.
Compounds of the Formula XXI may be prepared using analogous procedures to those described in process variant (c) hereinbefore.
(h) For the production of those compounds of the Formula I wherein R3 is (l-8C)alkyl or a group of the formula (R10)p-(l-8C)alkyl, wherein R10 and p have any of the meanings defined hereinbefore, the alkylation, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the Formula XXII:
Figure imgf000109_0002
wherein Ring A, R1, m, R2, G1, G2, n and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an appropriate alkylating agent which also has any functional group protected if necessary, whereafter any protecting group that is present is removed. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example N,Λ/-dimethylformamide, 7V,A/-dimethylacetamide, N- methylpyrrolidin-2-one or a halogenated solvent such as dichloromethane. Preferably, the reaction is carried out in dimethylformamide, 7V,Λ/-dimethylacetamide or N- methylpyrrolidin-2-one and at a temperature in the range, for example, -100C to 1800C, conveniently in the range 0 to 1000C, more conveniently at or near ambient temperature.
A suitable alkylating agent is, for example, a compound wherein a (l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, or heterocyclyl-(l-6C)alkyl group is attached to a suitable leaving group, for example a chloro, bromo, iodo, methoxysulphonyloxy, methanesulphonyloxy or toluene-4-sulphonyloxy group. Examples of suitable alkylating agents include iodomethane, iodoethane, l-bromo-2-methyl-propane, bromomethylcyclopropane, 2-(2-bromoethoxy)-2-methyl-propane, 2-(3-bromopropoxy)-2- methyl-propane, 2-(bromomethyl)tetrahydrofuran and 3-(chloromethyl)-3-methyl-oxetane. Conveniently, the reaction is conducted in the presence of a suitable base such as an alkali or alkaline earth metal carbonate, for example caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine or a base such as sodium hydride.
Compounds of the Formula XXII may be prepared using analogous procedures to those described in any of the process variants hereinbefore. It is to be understood that 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. For example, 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 R1 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 l-methylpiperidin-4-yl R1 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. 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. The reaction is performed at a temperature in the range, for example, 10 to 800C, conveniently at or near ambient temperature.
When a pharmaceutically-acceptable salt of a pyrazine derivative of the Formula I is required, for example an acid-addition salt, it may be obtained by, for example, reaction of said pyrazine derivative with a suitable acid. When a pharmaceutically-acceptable pro-drug of a pyrazine derivative of the
Formula I is required, it may be obtained using a conventional procedure. For example, 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. For example, 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. It will also be appreciated by the person skilled in the organic synthetic arts that certain of the ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents, acylation of substituents, amidation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of 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.
It will also be appreciated that, in some of the reactions mentioned hereinbefore, it may be necessary or desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.
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 t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl 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. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid 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 by 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. Thus, for example, an acyl 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. Alternatively 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 t-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. Certain of the intermediates defined herein are novel and these are provided as a further feature of the invention. For example, many compounds of the Formulae II, XI and XV are novel compounds.
Biological Assays 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.
(a) In Vitro AxI Kinase Assay
The assay used AlphaScreen technology (Gray et ah, Analytical Biochemistry. 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant AxI tyrosine kinase.
N-terminal GST-AxI kinase domain encompassing amino acids 473 to 894 of AxI (GenBank Accession No NM_021913) was expressed in SF 126 insect cells and purified using the GST epitope tag, using standard purification techniques. Test compounds were prepared as 1OmM stock solutions in dimethylsulphoxide (DMSO) and diluted in DMSO as required. Aliquots (12OnI) of compound dilutions were filled into the wells of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one) using acoustic dispensing (Labcyte Echo 550). A 10 μl mixture of recombinant purified AxI enzyme, biotinylated peptide substrate (Biotin poly-GAT;
CisBio, Catalogue No. 6 IGATBLB), 0.2 μM adenosine triphosphate (ATP) and a buffer solution [comprising 20 mM Tris-HCl pH 7.5 buffer, 0.01% v/v Tween, 5 mM dithiothreitol (DTT) and 10 mM manganese chloride] was incubated with the compounds at room temperature for 20 minutes. Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by using 100% DMSO instead of test compound. Control wells that produced a minimum signal corresponding to 100% inhibited enzyme were created by adding 10 μM of a test compound.
Each reaction was stopped by the addition of 5 μl of a mixture of 50OmM EDTA, 3mg/ml bovine serum albumin (BSA) and 20 mM Tris-HCl pH 7.4 buffer containing
40ng/μl AlphaScreen Streptavidin donor and anti-p-Tyr-100 acceptor beads (Perkin Elmer, Catalogue No. 6760620M). The resultant signals arising from laser light excitation at 680 nM were read using a Packard Envision instrument. The mean data values for each test compound concentration, 100% DMSO control wells and 100% inhibition control wells were used to determine the test compound's IC50 value. The IC50 value is the concentration of test compound that inhibits 50% of kinase activity.
(b) Cellular phospho-Axl ELISA Assay
This assay uses a conventional ELISA method to determine the ability of test compounds to inhibit phosphorylation of tyrosine residues in AxI.
An NCI H 1299 lung large cell carcinoma cell line [American Type Culture Collection (ATCC) CRL 5803] was routinely maintained at 37°C with 5% CO2 in RPMI containing 10% foetal calf serum (FCS) and 2mM L-glutamine. For the assay, 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 0.9xl05 cells per ml. lOOμl Aliquots were seeded into each of the wells of a clear 96 well tissue culture plate and the plates were incubated overnight at 37°C with 5% CO2 to allow the cells to adhere to the wells.
Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required in DMSO to give a range of concentrations. Aliquots of each compound concentration were added to the cells in each well using the Echo 550 (Labcyte Inc.,
Sunnyvale, California, US). Control cells received DMSO only. The cells were incubated for 2 hours at 37°C with 5% CO2.
The resultant cells were stimulated with 100 ng/ml recombinant mouse GAS6 (RnD systems; Catalogue No. 986-GS) for 10 minutes at 37°C with 5% CO2. Cells were lysed by the addition of 50 μl/well of lysis buffer comprising 2OmM Tris-HCl pH 8.0, 137 mM sodium chloride, 2 mM EDTA, 10% v/v glycerol, 1% v/v Igepal CA-630, 0.5mM sodium orthovanadate, 1 mM sodium pyrophosphate, 10 mM sodium pyrophosphate, 10 mM glycerophosphate and IX protease inhibitor tablets (Roche; catalogue number 11836153001). The resultant tissue culture plates were incubated on ice for 30 minutes to ensure full lysis.
High-binding ELISA plates were coated with an anti-Axl antibody (RnD systems; Catalogue No. AF 154) at room temperature for 16 hours. The wells were washed 3 times with 250 μl per well of PBS containing 0.05% v/v Tween (PBS/T). The wells were treated with 3% w/v BSA in PBS at ambient temperature for 2 hours and subsequently washed 3 times with 250 μl per well of PBS/T.
50 μl Aliquots of the NCI H1299 cell lysates were added to the ELISA plates. The ELISA plates were incubated for 16 hours at 40C and then washed 3 times with 250 μl 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 μl 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 μl per well of PBS/T. Fluorogenic substrate was made up according to manufacturers instructions (Pierce Biotechnology Inc., Rockford IL, USA; Catalogue No. 15169). 100 μl 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 IC50 value. The IC50 value is the concentration of test compound that inhibits 50% of kinase activity.
(c) In Vitro c-Met Kinase Assay
The assay used AlphaScreen technology (Gray et ah, 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, 784075) with a total volume of 12 μL in each well. Each kinase reaction contained 40pg (10OpM) pY1234pY1235c-Met(1074-1366) kinase domain, 44ng (10OnM) cMyc-[D1204N,R1208Q]c-Met(1069-1366)-biotin, 25mM HEPES (pH7.4), 0.ImM sodium orthovanadate, ImM DTT, 0.01% (v/v) Tween-20, 1OmM Magnesium Chloride, 0.1% BSA, 50μM ATP.
Various concentrations of 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 μL containing 0.5ng anti- pYpY1234/1235c-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 25 mM HEPES (pH 7.4), 84.5mM EDTA, 0.3% BSA under low-level light conditions. Plates were sealed under low-level light conditions & incubated in the dark for 20 hours. Plates were read using an Envision (Perkin Elmer) with excitation at 680 nM, emission 520-620 nM. The mean data values for each test compound concentration, untreated control wells and 100% inhibition control wells were used to determine the test compound's IC50 value. The IC50 value is the concentration of test compound that inhibits 50% of c-Met kinase activity.
(d) Cellular c-Met Inhibition Assay
These and other assays 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%. To undertake the assay,
MKN45 cells were seeded at 2xlO4 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% CO2) in a humidified incubator. Once the cells had fully adhered (typically following overnight incubation) plates were dosed with 25 μl compound (diluted from 10 mM stock in DMSO using serum free DMEM) and the plates were returned to a humidified 37°C (+5% CO2) incubator for one hour. Following incubation the cells were fixed by adding formaldehyde (4% final concentration) and incubating at room temperature for 20 minutes. The fixative solution was then removed and the wells were washed three times with 100 μl phosphate buffered saline (PBS) before permeabilising the cells by the addition of 50 μl/well 0.1% triton/ PBS for 20 minutes at room temperature. The permeabilisation solution was then removed and the cells washed twice more with lOOμl/ well PBS before the addition of 40μl/well anti-phospho pYpYpY1230/4/5 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 100 μl/ well PBS. 50 μl/ 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. Finally, the plates were washed three times with 100 μl/ well PBS, leaving the final wash in the wells before sealing the plates. The plates were read using an Arrayscan II (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 IC50 value. The IC50 value is the concentration of test compound that inhibits 50% of c-Met phosphorylation. Although the pharmacological properties of the compounds of the Formula I vary with structural change as expected, in general activity possessed by compounds of the Formula I may be demonstrated at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d) :-
Test (a):- IC50 versus AxI tyrosine kinase in the range, for example, InM - 20 μM;
Test (b):- IC50 versus cellular phospho-Axl in the range, for example,
InM - 20 μM; Test (c):- IC50 versus c-Met tyrosine kinase, in the range for example,
0.1 - 20 μM; Test (d):- IC50 versus cellular phospho-c-Met (pYpYpY1230/4/5) in the range, for example, 0.01 - 20 μM;
Preferred compounds of the invention possess activity at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d) :-
Test (a):- IC50 versus AxI tyrosine kinase in the range, for example,
InM - 5 μM; Test (b):- IC50 versus cellular phospho-Axl in the range, for example,
InM - 10 μM; Test (c):- IC50 versus c-Met tyrosine kinase in the range, for example,
0.1 - 10 μM; Test (d):- IC50 versus cellular phospho-c-Met (pYpYpY1230/4/5) in the range, for example, 0.01 - 5 μM;
For example, the pyrazine compound disclosed within Example 1 possesses activity in Test (a) with an IC50 versus AxI tyrosine kinase of approximately 20 nM; and activity in Test (b) with an IC50 versus cellular phospho-Axl of approximately 40 nM; and activity in Test (c) with an IC50 versus c-Met tyrosine kinase of approximately 1.04 μM; and activity in Test (d) with an IC50 versus cellular phospho-c-Met (pYpYpY1230/4/5) of approximately 60 nM.
For example, the pyrazine compound disclosed within Example 5 possesses activity in Test (a) with an IC50 versus AxI tyrosine kinase of approximately 20 nM; and activity in Test (b) with an IC50 versus cellular phospho-Axl of approximately 20 nM; and activity in Test (c) with an IC50 versus c-Met tyrosine kinase of approximately 0.48 μM; and activity in Test (d) with an IC50 versus cellular phospho-c-Met (pYpYpY1230/4/5) of approximately 8O nM.
For example, the pyrazine compounds disclosed within the Examples possess activity in Test (b) at the levels illustrated in Table A.
Table A
Example number Test (b) IC50 (μM)
1 0.04
2.1 0.16
2.2 0.16, 0.23#
2.3 0.05, 0.10#
2.4 0.47
2.5 0.09, 0.11#
2.6 0.11
2.7 0.25
2.8 <0.13
2.9 0.49 3 0.08, 0.06#
4.1 0.05
4.2 0.14
4.3 0.23
4.4 0.38
4.5 0.26
4.6 0.20
4.7 1.15
4.8 0.50
4.9 0.12 4.10 0.10 4.11 0.23 4.12 0.17 Example number Test (b) IC50 (μM)
5 0.02
6.1 0.02 6.2 0.01 6.3 0.03 6.4 0.07, 0.08# 6.5 0.03
7 0.42
8.1 1.98 8.2 0.23 8.3 0.76
9 15.15 10.1 0.19, 0.23#
11 0.50 12.1 0.29 12.2 0.29 12.3 0.08 12.4 0.38 12.5 0.38 12.6 0.12 12.7 0.81 12.8 0.08 12.9 0.61
13 0.14
14 0.10 15.1 0.09 15.2 0.01 15.3 0.18 15.4 0.01 15.5 0.15 15.6 0.05 Example number Test (b) IC50 (μM)
15.7 0.10
15.8 0.13
16 0.07
17 0.16 17.1 0.04
18 0.02
19 0.04, 0.08#
20 *
21 0.05
22 **
23 ***
# this is a mean IC50 value calculated from a larger number of replicates than were used to calculate the first value quoted for the given Example.
* the compound disclosed in Example 20 had an activity in Test (a) with an IC50 versus AxI tyrosine kinase of approximately 0.016 μM. ** the compound disclosed in Example 22 had an activity in Test (a) with an IC50 versus AxI tyrosine kinase of approximately 0.002 μM.
*** the compound disclosed in Example 23 had an activity in Test (a) with an IC50 versus AxI tyrosine kinase of approximately 0.003 μM.
No untoward toxicological effects are expected when a compound of Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore is administered at the dosage ranges defined hereinafter.
According to a further aspect of the invention there is provided 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.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, 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).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, 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.
In using a compound of the Formula I for therapeutic or prophylactic purposes it will generally be administered so that 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. In general, lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 1 mg/kg to 25 mg/kg body weight will generally be used. Similarly, for administration by inhalation, 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. As stated above, 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. We have now found that 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. In addition, as stated hereinbefore, AxI and c-Met are involved in 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.
According to this further aspect of the invention there is provided a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use as a medicament in a warm-blooded animal such as man.
According to a further aspect of the invention, there is provided a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore 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. According to a further aspect of the invention, there is provided the use of 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. According to this aspect of the invention there is also provided 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 dermato fibrosarcoma 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. According to this aspect of the invention there is also provided a method for treating cell proliferative disorders (such as solid tumour disease) in 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-accep table salt thereof, as defined hereinbefore. Other 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.
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.
According to a further aspect of the invention there is provided a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in the treatment (or prevention) of those tumours which are sensitive to inhibition of AxI and/or c-Met that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells. According to a further feature of this aspect of the invention there is provided the use of a pyrazine derivative of the Formula I, or a pharmaceutically-accep table 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.
According to a further feature of this aspect of the invention there is provided 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-accep table salt thereof, as defined hereinbefore.
According to a further aspect of the invention there is provided 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.
According to a further feature of this aspect of the invention there is provided the use of 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 providing a AxI and/or c-Met receptor enzyme inhibitory effect.
According to a further aspect of the invention there is also provided 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. The anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such 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, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin- C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) 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 5α-reductase such as finasteride; (iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7- [2-(4-methylpiperazin- 1 -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. Chem.. 2004, 47, 6658- 6661), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase); (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], 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. 54, pp 11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as Λ/-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4- amine (gefitinib, ZD 1839), Λ/-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4- amine (erlotinib, OSI-774) and 6-acrylamido-Λ/-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet- derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZDl 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fiuoro-2-methylindol-5-yloxy)-6- methoxy-7-(3-pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin)]; (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) 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-drug resistance gene therapy; and (ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity 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.
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.
According to this aspect of the invention there is provided 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.
Although 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, i.e. in the range 17 to 25°C and under an atmosphere of an inert gas such as nitrogen unless otherwise stated; (ii) evaporations were carried out by rotary evaporation or utilising Genevac equipment in vacuo and work-up procedures were carried out after removal of residual solids by filtration;
(iii) column chromatography (by the flash procedure) was performed on Merck Kieselgel silica (Art. 9385) obtained from E. Merck, Darmstadt, Germany or using proprietory pre-packed normal phase silica cartridges, for example SiliCycle (TM) disposable chromatography cartridges, or high pressure liquid chromatography (HPLC) was performed on C 18 reverse phase silica, for example on a X Bridge 5μm C-18 6θA preparative reversed-phase column;
(iv) ion exchange chromatography was performed using pre-packed 1ST Isolute® SCX-2 columns;
(v) preparative chromatography was performed on a Gilson instrument with an X Bridge 5μm C18 column (19 x 100 mm), with a flow rate of 25 ml/min and solvent system of 1% aqueous ammonia : acetonitrile with a gradient in the range of 25-95% (this is described hereinafter as 'X Bridge preparative chromatography);
(vi) yields, where present, are not necessarily the maximum attainable;
(vii) in general, the structures of end-products of the Formula I were confirmed by nuclear magnetic resonance (NMR) spectroscopy; NMR chemical shift values were measured on the delta scale [proton magnetic resonance spectra were determined using a Bruker DPX 400 (400 MHz) or a Bruker DRX 500 (500 MHz) instrument]; measurements were taken at ambient temperature unless otherwise specified; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad and dq, doublet of quartets.
(viii) in general, end-products of the Formula I were also characterised by mass spectroscopy following liquid chromatography (LCMS); LCMS was carried out using an Agilent 1100 or Waters Alliance HT (2790 & 2795) fitted with a Waters ZQ ESCi mass spectrometer and an X Bridge 5μm C-18 column (2.1 x 50 mm) at a flow rate of 1.1 ml/min, using a solvent system of 95% A + 5% C to 95% B + 5% C over 4 minutes, where A = water, B = acetonitrile, C = 1:1 acetonitrile: water 1% ammonia; in general, the retention time (RT) of each product under these chromatographic conditions was noted;
(ix) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, mass spectral, HPLC and/or NMR analysis; (x) the following abbreviations have been used:-
DMF 7V,Λ/-dimethylformamide
DMSO dimethyl sulphoxide
CDCl3 deutero-chloroform
HATU O-(7-azabenzotriazol- 1 -yl)-N,N,N',N -tetramethyluronium
Hexafiuorophosphate
NBS 7V-bromosuccinimide
TFA trifluoroacetic acid
DCM dichloromethane Example 1 3-(5-Fluoro-lH-benzimidazol-2-yl)-5-(l-piperidin-4-ylpyrazol-4-yl)pyrazin-2-amine
Figure imgf000130_0001
ΗATU (2.16 g) was added to a mixture of triethylamine (1.13 ml), 4-fluoro-l,2- diaminobenzene (0.72 g) and 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-lH- pyrazol-4-yl)pyrazine-2-carboxylic acid (2.1 g) in DMF (25 ml) at ambient temperature and was stirred for 2 hours. The reaction mixture was diluted with dilute aqueous sodium hydrogen carbonate solution. The precipiate was isolated by filtration and dried in a vacuum oven. The material so obtained was added to acetic acid (20 ml), and the resulting mixture was stirred and heated to 1100C for 3 hours. The solvent was then evaporated in vacuo and the residue was added to trifiuoroacetic acid (20 ml) and stirred at ambient temperature for 1 hour. The solvent was evaporated in vacuo and the crude product was purified by SCX ion exchange chromatography. The desired product was eluted from the column using 7M NΗVmethanol and the eluent was evaporated. There was thus obtained the title compound (3.05 g); NMR Spectrum: (DMSOd6) 1.91 (m, 2Η), 2.09 (d, 2H), 2.70 (t, 2H), 3.13 (d, 2H), 4.25 (m, IH), 7.08 (t, IH), 7.43 (brs, IH), 7.54 (s, IH), 7.68 (brs, IH), 8.10 (s, IH), 8.33 (s, IH), 8.47 (s, IH); Mass Spectrum: M+H+ 379; RT 2.16 min.
The 3 -amino-6-( 1 -( 1 -(tert-butoxycarbonyl)piperidin-4-yl)- lH-pyrazol-4- yl)pyrazine-2-carboxylic acid used as a starting material was prepared as follows :- l,r-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.245 g) was added to a mixture of caesium fluoride (18.85 g), methyl 3-amino-6-bromopyrazine-2-carboxylate (14.4 g) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine-l-carboxylate (30.4 g) in methanol (450 ml) at ambient temperature. The resulting mixture was stirred at 600C for 1 hour at which time a further portion of tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate (15.0 g) was added and the resultant mixture was stirred for a further 3 hours at 600C. The reaction mixture was evaporated in vacuo and the residue was redissolved in ethyl acetate (500 ml). The organic solution was washed twice with water (2 x 250 ml), dried with magnesium sulphate, filtered and evaporated in vacuo. The material so obtained was purified by flash silica chromatography on Flash 75 equipment, elution gradient 0 to 4% methanol in dichloromethane. Pure fractions were evaporated to dryness. There was 5 thus obtained methyl 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-lH-pyrazol-4- yl)pyrazine-2-carboxylate (24.98 g); NMR Spectrum: (DMSOd6) 1.50 (s, 9H), 1.66 (s, 2H), 1.98 (m, 2H), 2.18 (d, 2H), 2.93 (t, 2H), 3.98 (s, 3H), 4.30 (m, IH), 6.37 (brs, 2H), 7.92 (s, IH), 7.95 (s, IH), 8.44 (s, IH); Mass Spectrum: M-H+ 401; RT 2.09 min.
2M sodium hydroxide solution (8.70 ml) was added to a solution of methyl 3- i o amino-6-( 1 -( 1 -(tert-butoxycarbonyl)piperidin-4-yl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxylate (3.5 g) in methanol (40 ml) and stirred at ambient temperature for 2 hours. The resultant solution was concentrated in vacuo until half of the methanol had been removed. Water (20 ml) was then added and the solution was acidified to pH4 by addition of 2M hydrochloric acid causing the product to precipitate. This material was filtered and dried is invacuo. There was thus obtained 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)- lH-pyrazol-4-yl)pyrazine-2-carboxylic acid (3.25 g); NMR Spectrum: (DMSOd6) (DMSOd6) 1.45 (s, 9H), 1.82 (m, 2H), 2.06 (d, 2H), 2.95 (t, 2H), 4.07 (d, 2H), 4.40 (m, IH), 7.32 (brs, 2H), 8.07 (s, IH), 8.43 (s, IH), 8.67 (s, IH); Mass Spectrum: M-H+ 387; RT 1.86 min.
20
Example 2
Using an analogous procedure to that described in Example 1 , the appropriate 1 ,2- diaminobenzene was reacted with the appropriate pyrazine-2-carboxylic acid to give the compounds described in Table I. Unless otherwise stated, the required 1,2- 25 diaminobenzenes and pyrazine-2-carboxylic acids are commercially available.
Table I
Figure imgf000131_0001
Figure imgf000132_0001
Notes The products gave the characterising data shown below.
[1] Mass Spectrum: M+H+ 405; RT 2.06 min. NMR Spectrum: (DMSOd6) 2.07 (m, 6H), 2.26 (s, 3H), 2.90 (d, 2H), 4.02 (s, 3H), 4.19 (m, IH), 6.79 (m, IH), 7.23 (d, IH), 7.91 (brs, 2H), 8.18 (s, IH), 8.47 (s, IH), 8.53 (s, IH), 12.82 (brs, IH).
The 3-amino-6-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazine-2-carboxylic acid used as a starting material to make compound [1] was prepared as follows:
Methyl 3-amino-6-[l-(l-tert-butoxycarbonyl-piperidin-4-yl)pyrazol-4-yl]pyrazine- 2-carboxylate (8 g) was dissolved in TFA (25 ml) and the mixture was stirred for 1 hour. The resultant mixture was concentrated under reduced pressure. The residue was purified by SCX ion exchange chromatography (eluted using 7M methanolic ammonia). The resulting compound was triturated with diethyl ether. There was thus obtained methyl 3- amino-6-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazine-2-carboxylate (6.01 g); Mass Spectrum: M+H+ 303.3; RT 1.39 min; NMR Spectrum: (DMSOd6) 8.66 (s, IH), 8.22 (s, IH), 7.91 (s, IH), 7.22 (s, 2H), 4.25 (m, IH), 3.88 (s, 3H), 3.07 (d, 2H), 2.61 (t, 2H), 1.96 (d, 2H), 1.82 (m, 2H). Formaldehyde (1.588 ml) was added to a mixture of methyl 3-amino-6-[l-
(piperidin-4-yl)pyrazol-4-yl]pyrazine-2-carboxylate (4.3 g), acetic acid (0.081 ml) and methanol (100 ml). The resulting solution was stirred for 10 minutes at ambient temperature. Sodium cyanoborohydride (1.073 g) was added and the resulting solution was stirred for 1 hour. The mixture was evaporated under reduced pressure. The residue was purified by SCX ion exchange chromatography (eluted with 7M methanolic ammonia). The resultant crude product was purified by flash silica chromatography (elution gradient 1 to 10% methanol in DCM). There was thus obtained methyl 3-amino-6-[l-(l- methylpiperidin-4-yl)pyrazol-4-yl]pyrazine-2-carboxylate (4.5 g); Mass Spectrum: M+H+ 317.35; RT 1.38 min; NMR Spectrum: (DMSOd6) 8.66 (s, IH), 8.27 (s, IH), 7.93 (s, IH), 7.22 (s, 2H), 4.19 (m, IH), 3.89 (s, 3H), 2.88 (d, 2H), 2.22 (s, 3H), 2.02 (m, 6H).
2M Aqueous Sodium hydroxide solution (4.27 ml) was added to methyl 3-amino-6-[l- (l-methyl-piperidin-4-yl)pyrazol-4-yl]pyrazine-2-carboxylate (2.70 g) in methanol (15 ml) and the mixture was stirred for 2 hours at ambient temperature. The resultant mixture was concentrated under reduced pressure. The crude product was purified by SCX ion exchange chromatography, (elution with 10% triethylamine in methanol). The resultant solid was triturated diethyl ether. There was thus obtained 3-amino-6-[l-(l-methyl- piperidin-4-yl)pyrazol-4-yl]pyrazine-2-carboxylic acid (2.58 g); Mass Spectrum: M+H+ 301.32; RT 0.71 min; NMR Spectrum: (DMSOd6) 8.41 (s, IH), 8.25 (s, IH), 7.94 (s, IH), 7.30 (brs, 2H), 4.18 (m, IH), 2.95 (m, 2H), 2.92 (q, 4H) (residual triethylamine), 2.32 (s, 3H), 2.20 (d, 2H), 2.04 (m, 4H), 1.11 (t, 6H) (residual triethylamine).
[2] Mass Spectrum: M+H+ 467; RT 2.32 min. NMR Spectrum: (DMSOd6) δ 1.83 (dq, 2H), 2.04 (d, 2H), 2.63 (td, 2H), 3.08 (d, 2H), 4.18 - 4.28 (m, IH), 5.42 (s, 2H), 6.85 (dd, IH), 7.17 - 7.28 (m, 2H), 7.32 - 7.38 (m, IH), 7.42 (t, 2H), 7.55 (d, 2H), 7.87 (s, 2H), 8.16 (s, IH), 8.44 (s, IH), 8.50 (s, IH), 12.84 (s, IH).
The 3-phenylmethoxybenzene-l,2-diamine used as a reagent to make compound [2] above was prepared as follows: Potassium carbonate (14.83 g) was added in one portion to 2-amino-3-nitrophenol (16.54 g) in ethanol (100 ml) at ambient temperature. The resulting mixture was stirred for 15 minutes. Benzyl chloride (16.05 ml) and sodium iodide (0.184 ml) were added to the reaction mixture and the resulting mixture was stirred at 78 0C for 2 hours. The reaction mixture was evaporated to dryness and the residue was redissolved in ethyl acetate, and washed sequentially with water and saturated brine. The organic layer was dried over magnesium sulphate, filtered and evaporated, then purified by flash silica chromatography (elution gradient 0 to 10% ethyl acetate in isohexane). Pure fractions were evaporated to dryness to afford 2-(benzyloxy)-6-nitroaniline (14.81 g) as a red oil. Iron (0.145 ml) was added in one portion to 2-(benzyloxy)-6-nitroaniline (0.5 g) in acetic acid (8.2 ml) and ethanol (7.4 ml) at ambient temperature. The resulting suspension was stirred at 75°C for 15 minutes. The mixture was allowed to cool before it was poured into ice water. The resultant reaction mixture was neutralised to pH 7.25 with ION NaOH and then extracted twice with etheyl acetate. The organic layer was dried over magnesium sulphate, filtered and evaporated to afford a brown gum. This material was purified by
SCX ion exchange chromatography. The desired product was eluted from the column using 7M NH3/MeOH and product fractions were evaporated to dryness. There was thus obtained 3-phenylmethoxybenzene-l,2-diamine(0.37 g).
[3] Mass Spectrum: M+H+ 461; RT 1.82 min. NMR Spectrum: (DMSOd6) IH NMR δ 1.72 - 1.89 (m, 3H), 1.99 - 2.14 (m, 3H), 2.63 (td, 2H), 2.76 - 2.87 (m, IH), 3.08 (d, 2H), 3.63 - 3.75 (m, 2H), 3.79 - 3.91 (m, 2H), 4.16 - 4.30 (m, 3H), 6.80 (dd, IH), 7.19 - 7.26 (m, 2H), 7.88 (s, 2H), 8.16 (s, IH), 8.43 (s, IH), 8.50 (s, IH), 12.83 (s, IH).
Compound [3] above was made from tert-butyl 4-[4-[5-amino-6-(7-phenylmethoxy- l//-benzimidazol-2-yl)pyrazin-2-yl]pyrazol-l-yl]piperidine-l-carboxylate as follows:
Ammonium formate (0.28 g) was added in one portion to tert-butyl 4-[4-[5-amino-6- (7-phenylmethoxy- lH-benzimidazol-2-yl)pyrazin-2-yl]pyrazol- 1 -yl]piperidine- 1 - carboxylate (0.39 g) and palladium (0.072 g) in methanol (15 ml) at ambient temperature. The resulting suspension was stirred at 700C for 8 hours. The reaction mixture was filtered through celite. The celite was washed with dimethylformamide (50 ml) and combined with the methanol filtrate. The reaction mixture was evaporated to dryness and redissolved in ethyl acetate and washed sequentially with water and saturated brine. The organic layer was dried over magnesium sulphate, filtered and evaporated to afford tert-butyl 4-[4-[5- amino-6-(7-hydroxy- lH-benzimidazol-2-yl)pyrazin-2-yl]pyrazol- 1 -yl]piperidine- 1 - carboxylate (0.30 g) as a brown solid: Mass Spectrum: M+H+ 477; RT 2.12 min.
Triphenylphosphine (0.028 ml) and diisopropyl azodicarboxylate (0.025 ml) were added in one portion to tert-butyl 4-[4-[5-amino-6-(7-hydroxy-lH-benzimidazol-2- yl)pyrazin-2-yl]pyrazol-l-yl]piperidine-l -carboxylate (0.050 g) and tetrahydrofuran-3- ylmethanol (0.012 ml) in tetrahydrofuran (1 ml) at ambient temperature. The resulting solution was stirred for 2 hours. The reaction mixture was then evaporated to dryness and redissolved in dichloromethane (1 ml), and trifiuoroacetic acid (1 ml) was added in one portion. The resulting solution was stirred at ambient temperature for 10 minutes. The reaction mixture was evaporated to dryness and redissolved in DMSO (1.2 ml), and purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% ammonia) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness and there was thus obtained 3-[7-(tetrahydrofuran-3-ylmethoxy)-lH- benzimidazol-2-yl]-5-(l-piperidin-4-ylpyrazol-4-yl)pyrazin-2-amine (0.011 g). [4] Mass Spectrum: M+H+ 443; RT 2.42 min. [5] Mass Spectrum: M+H+ 389; RT 2.17 min. [6] Mass Spectrum: M+H+ 389; RT 2.19 min. [7] Mass Spectrum: M+H+ 409; RT 2.29 min. [8] Mass Spectrum: M+H+ 453; RT 2.38 min. [9] Mass Spectrum: M+H+ 402; RT 2.45 min.
Example 3
3-(lH-Benzimidazol-2-yl)-5-[6-(3-dimethylaminopropoxy)pyridin-3-yl]pyrazin-2- amine
Figure imgf000136_0001
Dichlorobis(triphenylphosphine)palladium(II) (0.004 g) was added to N ,N- dimethyl-3-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-l- amine (0.101 g), 3-(lH-benzimidazol-2-yl)-5-bromopyrazin-2-amine (0.08 g) and 2M aqueous sodium bicarbonate (0.33 ml) in a solvent of 2:7:3:2 DMF:DME:ethanol:water (3 ml). The resulting mixture was stirred and heated to 1600C in a IOOW microwave for 7 minutes. The resultant mixture was evaporated to dryness and the residue was purified by X bridge preparative chromatography. There was thus obtained the title compound (0.029 g). Mass Spectrum: M+H+ 390; RT 2.92 min.
The 3-(lH-benzimidazol-2-yl)-5-bromopyrazin-2-amine used as a starting material was prepared as follows:-
HATU (47.6 g) was added to a stirred solution of 1 ,2-phenylenediamine (13.54 g), 3-amino-6-bromopyrazine-2-carboxylic acid (26.0 g) and triethylamine (24.93 ml) in DMF (250 mL). The resulting solution was stirred at ambient temperature for 12 hours before the reaction mixture was added to water (250 ml). The resulting precipitate was collected by filtration, washed with water (250 ml) and dried in vacuo. This material was dissolved in acetic acid (200 ml) and heated to 9O0C for 4 hours. The reaction mixture was concentrated in vacuo, washed with diethylether. The ether washings were evaporated and triturated in hexane. There was thus obtained 3-(lH-benzimidazol-2-yl)-5-bromopyrazin-2-amine (5.Og); Mass Spectrum: M-H+ 290; RT 2.46 min. NMR Spectrum: (DMSOd6) 7.32 (m, 2H), 7.60 (d, IH), 7.78 (d, IH), 8.31 (s, IH), 13.2 (s, IH). Example 4
Using an analogous procedure to that described in Example 3, the appropriate boronate ester was reacted with the appropriate 5-bromopyrazine to give the compounds described in Table II. Unless otherwise stated, the required boronate esters and the required 5-bromopyrazines are commercially available.
Table II
Figure imgf000137_0001
Figure imgf000137_0002
Notes The products gave the characterising data shown below. [1] The reagent used for this synthesis was tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazol-l-yl]piperidine-l-carboxylate. The 7V-tert-butoxycarbonyl group on the resultant product was removed by conventional treatment with trifluoroacetic acid. The derived product so obtained gave the following characterising data. Mass Spectrum: M+H+ 361; RT 2.26 min. NMR Spectrum: (DMSOd6) 1.86 (m, 2H), 2.07 (d, 2H), 2.66 (t, 2H), 3.11 (d, 2H), 4.24 (m, IH), 7.32 (m, 2H), 7.63 (d, IH), 7.78 (d, IH), 8.01 (brs, 2H), 8.18 (s, IH), 8.46 (s, IH), 8.54 (s, IH), 12.87 (brs, IH).
[2] The reagent used for this synthesis was tert-butyl 4-[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]piperazine-l-carboxylate. The 7V-tert-butoxycarbonyl group on the resultant product was removed by conventional treatment with trifluoroacetic acid. The derived product so obtained gave the following characterising data. Mass Spectrum: M+H+ 373; RT 2.59 min.
[3] The product was obtained by the reaction of tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazol-l-yl]piperidine-l-carboxylate and 5-bromo-3-(5,6-difluoro-lH- benzimidazol-2-yl)pyrazin-2-amine according to Example 3 except that the reaction was carried out in dioxane, the reaction mixture was heated to 1000C using an oil bath and the resultant intermediate was reacted with trifluoroacetic acid. The product gave the following characteristising data: Mass Spectrum: M+H+ 397. NMR Spectrum: (CD3OD) 2.42 (m, 4 H), 3.28 (m, 2H), 3.55 (m, 2H), 4.58 (m, IH), 7.56 (m, 2H), 7.95 (s, IH), 8.15 (s, IH), 8.35 (s, IH).
The 5-bromo-3-(5,6-difluoro-lH-benzimidazol-2-yl)pyrazin-2-amine used as starting material mas prepared as follows:
A mixture of 3-aminopyrazine-2-carboxylic acid (348 mg), 4,5-difiuorobenzene- 1,2-diamine (360 mg), HATU (951 mg) and N,N-diisopropylethylamine (0.52 ml) in DMF (3 ml) was stirred at ambient temperature overnight. Brine was added to the mixture and the resulting suspension was filtered and the solid was dried to give 3-amino-N-(2-amino- 4,5-difluorophenyl)pyrazine-2-carboxamide (659 mg).
A mixture of a portion (200 mg) of this carboxamide was dissolved in acetic acid (5 ml) and the mixture was heated in a microwave at 1000C for 3 hours. Solvent was removed and the residue was dissolved in DMF (4 ml). 7V-bromosuccinimide (161 mg) was added to the solution and the reaction mixture was stirred at ambient temperature for 2 hours. More 7V-bromosuccinimide (40 mg) was added to drive the reaction to completion. Sodium bisulphite (200 mg) was added to the reaction mixture and the mixture was stirred for 25 minutes. Brine (4 ml) was added to the mixture and the solid was collected to give 5-bromo-3-(5,6-difluoro-lH-benzimidazol-2-yl)pyrazin-2-amine (185 mg). Mass Spectrum: M+H+ 327. NMR Spectrum: (DMSO-J6) 7.49 (m, IH), 7.84 (m, IH), 7.94 (s, IH), 8.29 (s, IH), 13.26 (s, IH).
[4] The product was obtained by reaction of tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazol- 1 -yl]piperidine- 1 -carboxylate and 5-bromo-3-[5- trifluoromethyl-lH-benzimidazol-2-yl]pyrazin-2-amine according to Example 3 except that the reaction was carried out in dioxane, the reaction mixture was heated to 1000C using an oil bath and the resultant intermediate was reacted with trifluoroacetic acid. The product gave the following characterising data: Mass Spectrum: M+H+ 429. NMR Spectrum: (CD3OD) 2.31 - 2.42 (m, 4 H), 3.23 - 3.34 (m, 2H), 3.60 (m, 2H), 4.61 (m, IH), 7.56 (m, IH), 7.80 (m, IH), 8.00 (s, IH), 8.26 (m, IH), 8.35 (m, IH), 8.42 (s, IH).
The 5-bromo-3-[5-trifluoromethyl-lH-benzimidazol-2-yl]pyrazin-2-amine used as a starting material was prepared from 3-aminopyrazine-2-carboxylic acid and A- trifluoromethylbenzene-l,2-diamine according to the procedure described in Note [3] hereinbefore. Mass Spectrum: M-H+ 356.
[5] The product was obtained by reaction of 5-bromo-3-(5-fiuoro-lH-benzimidazol-2- yl)pyrazin-2-amine and tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl]piperazine-l -carboxylate according to Example 3 except that caesium fluoride was used in place of sodium bicarbonate, the reaction was carried out in dioxane at 1000C under thermal conditions, and the resultant intermediate was reacted with 0.22M HCl in dichloromethane: diethyl ether (8:1). The product gave the following characterising data: Mass Spectrum: M+H+ 391. NMR Spectrum: (DMSOd6) 3.32 (s, 4H), 4.14 (s, 4H), 7.19 (t, IH), 7.54 (d, IH), 7.77 (dd, IH), 7.99 (d, IH), 8.03 (s, IH), 8.18 (d, IH), 9.51 (s, 2H).
The 5-bromo-3-(5-fluoro-lH-benzimidazol-2-yl)pyrazin-2-amine used as a starting material was made from 3-aminopyrazine-2-carboxylic acid and 4-fluorobenzene-l,2- diamine according to the procedure described in Note [3] hereinbefore. Mass Spectrum: M+H+ 309.
[6] The product was obtained by reaction of 5-bromo-3-(5-fiuoro-lH-benzimidazol-2- yl)pyrazin-2-amine and 4-(2-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazol- l-yl)ethyl)morpholine according to Example 3 except that caesium fluoride was used in place of sodium bicarbonate and the reaction was carried out in dioxane at 1000C under thermal conditions. The product gave the following characterising data: Mass Spectrum: M+H+ 409. NMR Spectrum: (DMSO-J6) 2.42 (s, 4H), 2.77 (s, 2H), 3.55 (s, 4H), 4.26 (m, 2H), 7.16 (dd, IH), 7.37 (m, IH), 7.56 (m, 2H), 7.75 (m, IH), 8.17 (s, IH), 8.37 (s, IH), 8.50 (d, IH), 12.97 (s, IH).
[7] The product was obtained by reaction of 5-bromo-3-(5-fluoro-lH-benzimidazol-2- yl)pyrazin-2-amine and tert-butyl 4-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)methyl)piperidine-l-carboxylate according to Example 3 except that caesium fluoride was used in place of sodium bicarbonate, the reaction was run in methanol at
1000C for 2 h in a microwave oven, and the resultant intermediate was reacted with 0.66M HCl in dichloromethane: diethyl ether (2:1). The product gave the following characterising data: Mass Spectrum: M+H+ 393. NMR Spectrum: (DMSOd6) 1.41 (m, 2H), 1.63 (m, 2H), 2.16 (m, IH), 2.82 (m, 2H), 3.23 (m, 2H), 4.10 (dd, 2H), 7.15 (m, IH), 7.46 (m, IH), 7.72 (m, IH), 8.21 (s, IH), 8.41 (s, IH), 8.51 (s, IH).
The tert-butyl 4-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)methyl)piperidine-l-carboxylate was prepared as follows:
To a solution of tert-butyl 4-(hydroxymethyl)piperidine-l-carboxylate (2.5 g) and triethylamine (1.9 ml) in methylene chloride (30 ml) at 0 0C was added methanesulphonyl chloride (1.6 g) dropwise. After addition, the reaction was allowed to stir overnight at room temperature. The mixture was washed with water, aqueous HCl (IN), and brine. The organic layer was dried over sodium sulphate, filtered, and concentrated to give tert-butyl 4-(methylsulfonyloxymethyl)piperidine-l-carboxylate (3.2 g).
To a solution of 4-bromo-lH-pyrazole (230 mg) in DMF at 0 0C was added sodium hydride (60% in oil, 45 mg) portionwise. After addition, the reaction was allowed to stir at room temperature for about 30-40 min, followed by the addition of tert-butyl 4- (methylsulfonyloxymethyl)piperidine-l-carboxylate (500 mg). The resulting mixture was set to heat at 80 0C overnight. The reaction mixture was concentrated in vacuo to remove DMF, followed by an aqueous and ethyl acetate workup. The organic was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using petroleum ether - ethyl acetate) to afford tert-butyl 4-[(4- bromopyrazol-l-yl)methyl]piperidine-l-carboxylate (200 mg). To a sparged mixture of tert-butyl 4-[(4-bromopyrazol-l-yl)methyl]piperidine-l- carboxylate (200 mg), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (180 mg), and potassium acetate (220 mg) in DMSO (5 ml) was added tetrakis(triphenylphosphine)- palladium(O) (34 mg) under nitrogen. The mixture was sparged with nitrogen again and set 5 to heat to 800C overnight. The mixture was poured into water, followed by an ethyl acetate extraction. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford tert-butyl 4-((4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 - yl)methyl)piperidine-l-carboxylate (150 mg); Mass Spectrum: M+H+ 392. NMR o Spectrum: (CDCl3) 1.16 (m, 2H), 1.27 (s, 12 H), 1.31 (s, 9H), 1.55 (m, 2H), 2.02 (m,lH), 2.61 (m, 2H), 3.99 (m, 2H), 4.26 (m, 2H), 7.64 (s, IH), 7.80 (s, IH). [8] The product was obtained by reaction of 5-bromo-3-(5-fiuoro-lH-benzimidazol-2- yl)pyrazin-2-amine and tert-butyl 3-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)methyl)piperidine-l-carboxylate according to Example 3 except that caesiums fluoride was used in place of sodium bicarbonate, the reaction was carried out in dioxane at 1000C under thermal conditions and the resultant intermediate was reacted with 0.22M HCl in dichlorome thane: diethyl ether (8:1). The product gave the following characteristising data: Mass Spectrum: M+H+ 393. NMR Spectrum: (DMSO-d6) 1.21 (m, 2H), 1.66 (m, 2H), 1.76 (m, IH), 2.35 (m, IH), 2.71 (m, 2H), 3.10 (m, IH), 4.14 (d, 2H), 7.14 (m, IH),0 7.45 (m, IH), 7.69 (brs, IH), 8.22 (s, IH), 8.42 (s, IH), 8.51 (s, IH).
The tert-butyl 3-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)methyl)piperidine-l-carboxylate was prepared from tert-butyl 3-
(hydroxymethyl)piperidine-l-carboxylate according to the procedure described in Note [7] hereinbefore; Mass Spectrum: M+H+ 392. NMR Spectrum: (CDCl3) 1.31 (s, 12H), 1.425 (brs, 1 IH), 1.66 (m, 2H), 2.09 (m,lH), 2.66 (m, IH), 2.90 (m, IH), 3.74 (m, 2H), 4.02 (m, 2H), 7.66 (s, IH), 7.79 (s, IH).
[9] The product was obtained by reaction of 5-bromo-3-(5-fiuoro-lH-benzimidazol-2- yl)pyrazin-2-amine and tert-butyl 3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazol-l-yl]piperidine-l-carboxylate according to Example 3 except that caesiumo fluoride was used in place of sodium bicarbonate, the reaction was in dioxane at 1000C under thermal conditions and the resultant intermediate was reacted with 0.22M HCl in dichloromethane: ether (8:1). The product gave the following characteristising data: Mass Spectrum: M+H+ 379. NMR Spectrum: (DMSO-d6) 1.93 (s, 2H), 2.09 (s, IH), 2.21 (s, IH), 2.93 (s, IH), 3.31 (d, 2H), 3.55 (s, IH), 4.67 (s, IH), 7.15 (t, IH), 7.47 (d, IH), 7.70 (d, IH), 8.27 (s, IH), 8.54 (s, IH), 8.58 (s, IH).
The tert-butyl 3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-l- yl]piperidine-l-carboxylate used as starting material was made from tert-butyl 3- hydroxypiperidine-1-carboxylate according to the procedure described in Note [7] hereinbefore; Mass Spectrum: M+H+ 378. NMR Spectrum: (CDCl3) 1.36 (s, 12H), 1.49 (s, 9H), 1.66 (m, IH), 1.78 (m, IH), 2.09 (m, 2H), 2.91 (t, IH), 3.26 (m, IH), 3.91 (m, IH), 4.37 (m, 2H), 7.76 (s, IH), 7.81(s, IH). [10] The product was obtained by reaction of 5-bromo-3-(5-fiuoro-lH-benzimidazol-2- yl)pyrazin-2-amine and l-(tetrahydropyran-4-yl)-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole according to Example 3 except that the reaction was run in DMA:water (4:1) at 1500C in a microwave oven for 30 min using caesium fluoride in place of sodium bicarbonate. The product gave the following characteristising data: Mass Spectrum: M+H+ 380. NMR Spectrum: (Acetone-d6) 2.08 (m, 4H), 3.55 (m, 2H), 4.04 (m, 2H), 4.46 (m, IH), 7.09 (m, IH), 7.39 (brs, IH), 7.66 (brs, IH), 8.06 (s, IH), 8.28 (s, IH), 8.49 (s, IH).
The 1 -(tetrahydropyran-4-yl)-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H- pyrazole used as starting material was made from tetrahydro-2H-pyran-4-ol as the starting material according to the procedure described in Note [7] hereinbefore; Mass Spectrum: M+H+ 279. NMR Spectrum: (CDCl3) 1.31 (s, 12H), 2.06 (m, 4H), 3.52 (m, 2H), 4.08 (m, 2H), 4.38 (m,lH), 7.75 (s, IH), 7.80 (s, IH).
[11] The product was obtained by reaction of tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazol- 1 -yl]piperidine- 1 -carboxylate and 5-bromo-3-(5-chloro-6- fluoro-lH-benzimidazol-2-yl)pyrazin-2-amine according to an analogous procedure to that described in Example 3 except that the reaction was carried out in dioxane using 1,1 '- bis(diphenylphosphino)ferrocenedichloropalladium(II) as the catalyst and aqueous sodium carbonate as the base and the reaction mixture was heated to 1000C for 3 hours under microwave irradiation and the resultant intermediate was reacted with trifiuoroacetic acid. The product gave the following characterising data: Mass Spectrum: M+H+ 413; NMR Spectrum (400 MHz, CD3OD) 1.34 (dd, 4 H), 2.28 - 2.41 (m, 4 H), 3.16 - 3.24 (m, 2 H), 3.58 (d, 2 H), 4.58 (bs, IH), 7.46 (d, 1 H), 7.70 (d, 1 H), 8.18 (s, 1 H), 8.32 (d, 2 H). 5-Bromo-3-(5-chloro-6-fluoro-lH-benzimidazol-2-yl)pyrazin-2-amine used as starting material was prepared from 3-aminopyrazine-2-carboxylic acid and 4-chloro-5- fluorobenzene-l,2-diamine as described in example 4.03, starting material: 3-amino-N-(2-amino-4-chloro-5-fluorophenyl)pyrazine-2-carboxamide (200 mg). The 5-bromo-3-(5-chloro-6-fluoro-lH-benzimidazol-2-yl)pyrazin-2-amine gave the following characterising data; Mass Spectrum: M+H+ 342
[12] The product was obtained by reaction of tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazol- 1 -yl)cyclohexylcarbamate, 5-bromo-3-(5-fluoro- IH- benzimidazol-2-yl)pyrazin-2-amine according to Example 3 except that the reaction was carried out in dioxane-water using l,r-bis(diphenylphosphino)ferrocenedichloropalladium(II) - CH2Cl2 adduct as the catalyst and aqueous potassium carbonate as the base, the reaction mixture was heated to 1000C for 1 hour in an oil bath and the resultant intermediate in methanol:DCM (1:1) was reacted with IM hydrogen chloride in ether. The product gave the following characterising data: Mass Spectrum: M+H+ 393: NMR Spectrum (300 MHz, DMSO-J6): 1.63 - 2.05 (m, 6 H), 2.36 (bs, 2 H), 3.32 (bs, 1 H), 4.36 (bs, 1 H), 7.16 (t, 1 H), 7.48 (bs, 1 H), 7.66 - 7.75 (m, 1 H), 8.22 (s, 1 H), 8.50 (s, 1 H), 8.56 (s, 1 H).
The tert-butyl 4-(4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazol- 1 - yl)cyclohexylcarbamate used as starting material was prepared from tert-butyl N-(4- hydroxycyclohexyl)carbamate using the same sequence as described in Example 4.07. The starting materials gave the following chararctering data: 4-(tert-butoxycarbonylamino)cyclohexyl methanesulfonate; NMR Spectrum (CDCl3): 1.24 (m, 2 H), 1.44 (s, 9 H), 1.70 (m, 2 H), 2.15 (m, 4 H); 3.01(s, 3 H); 3.47 (m, IH), 4.39 (m, 1 H), 4.63 (m, 1 H). tert-butyl 4-(4-bromopyrazol-l-yl)cyclohexylcarbamate; NMR Spectrum (CDCI3): 1.12 (s, 9 H), 1.39 (m, 2 H), 1.60 (m, 4 H), 1.82 (m, 2 H), 3.50 (m, 1 H); 3.86 (m, 1 H); 7.09 (s, 1 H), 7.36 (s, 1 H). tert-butyl 4-(4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 - yl)cyclohexylcarbamate; Mass Spectrum: : M+Na+ 414; NMR Spectrum (CDCl3): 1.31 (s, 12 H), 1.47 (s, 9 H), 1.74 (m, 2 H), 1.85 (m, 2 H); 1.99 (m, 4 H); 3.80 (m, 1 H), 4.18 (m, 1 H), 4.74 (m, 1 H), 7.76 (s, 1 H), 7.8 l(s, 1 H).
Example 5
3-(5-Fluoro-lH-benzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin- 2-amine
Figure imgf000144_0001
Acetic acid (0.023 ml) was added to a solution of 3-(5-fluoro-lH-benzimidazol-2-yl)- 5-(l-piperidin-4-ylpyrazol-4-yl)pyrazin-2-amine (0.15 g) and formaldehyde (0.041 ml) in methanol (5 ml). The resultant mixture was stirred for 10 minutes at ambient temperature. Sodium cyanoborohydride (0.029 g) was added and the mixture was stirred for 1 hour at ambient temperature. The mixture was filtered, concentrated in vacuo and purified by SCX ion exchange chromatography, with the eluent 2M NH3/in methanol. The resultant solid was hen purified by preparative HPLC using decreasingly polar mixtures of water
(containing 0.1% NH3) and acetonitrile as eluents. There was thus obtained 3-(5-fluoro- l//-benzimidazol-2-yl)-5-[ 1 -(I -methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine (0.16 g); Mass Spectrum: M+H+ 393; RT 2.17 min. NMR Spectrum: (DMSOd6) 1.95-2.14 (m, 6H), 2.26 (s, 3H), 2.92 (d, 2H), 4.18 (m, IH), 7.15 (m, IH), 7.38-7.49 (m, IH), 7.61-7.81 (m, IH), 7.88 (brs, 2H), 8.18 (s, IH), 8.47 (s, IH), 8.55 (d, IH), 12.90 (s, IH).
Example 6
Using an analogous procedure to that described in Example 5, the appropriate aldehyde or ketone was reacted with the appropriate l-piperidin-4-ylpyrazole to give the compounds described in Table III. Unless otherwise stated, the required adehydes or ketones and the required l-piperidin-4-ylpyrazoles are commercially available. Table III
Figure imgf000145_0001
Figure imgf000145_0002
Notes The products gave the characterising data shown below.
[1] Mass Spectrum: M+H+ 407; RT 2.31 min.
[2] Mass Spectrum: M+H+ 491; RT 2.24 min.
[3] Mass Spectrum: M+H+ 463; RT 2.08 min.
[4] Mass Spectrum: M+H+ 423; RT 2.24 min.
[5] Mass Spectrum: M+H+ 375; RT 2.11 min. NMR Spectrum: (DMSOd6) 2.07 (m, 6H),
2.28 (s, 3H), 2.91 (d, 2H), 4.19 (m, IH), 7.32 (m, 2H), 7.65 (d, IH), 7.78 (d, IH), 7.91 (brs,
2H), 8.18 (s, IH), 8.47 (s, IH), 8.53 (s, IH), 12.82 (brs, IH). Example 7
5-[5-amino-6-(lH-benzimidazol-2-yl)pyrazin-2-yl]-ΛL(l-methylpiperidin-4- yl)pyridine-3-carboxamide
Figure imgf000146_0001
ΗATU (0.24 g) was added to a stirred solution of 5-[5-amino-6-(lH-benzimidazol-2- yl)pyrazin-2-yl]pyridine-3-carboxylic acid (0.2 g), l-methylpiperidin-4-amine (0.103 g) and triethylamine (0.126 ml) in DMF (5 ml). The resulting solution was stirred at ambient temperature for 2 hours. The mixture was concentrated in vacuo and the residue was purified by SCX ion exchange chromatography. The desired product was eluted from the column using 7M ammonia in methanol and evaporated to dryness. The material so obtained was further purified by preparative ΗPLC using decreasingly polar mixtures of water (containing 0.1% NH3) and acetonitrile as eluents. There was thus obtained the title compound (0.258 g); Mass Spectrum: M+H+ 429; RT 2.13 min.
The 5-[5-amino-6-(lH-benzimidazol-2-yl)pyrazin-2-yl]pyridine-3-carboxylic acid used as a starting material was prepared as follows:-
Dichlorobis(triphenylphosphine)palladium(II) (0.012 g) was added to a mixture of ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (0.105 g), 3- (l//-benzimidazol-2-yl)-5-bromopyrazin-2-amine (0.1 g) and 2M sodium bicarbonate (0.207 ml) in a solvent of 2:7:3:2 DMF:DME:ethanol:water (4 ml). The resulting mixture was stirred and heated to 1600C for 20 minutes. The residue was evaporated to afford 5- [5-amino-6-(lH-benzimidazol-2-yl)pyrazin-2-yl]pyridine-3-carboxylic acid.
Example 8
Using an analogous procedure to that described in Example 7, the appropriate amine was reacted with the appropriate carboxylic acid to give the compounds described in Table IV. Unless otherwise stated, the required each appropriate amine is commercially available. Table IV
Figure imgf000147_0001
Figure imgf000147_0003
Notes The products gave the characterising data shown below.
[1] Mass Spectrum: M+H+ 472; RT 1.87 min. NMR Spectrum: (DMSOd6) 1.73 (m, 2H), 2.12 (s, 3H), 2.38 (m, 8H), 3.40 (m, 4H), 7.32 (m, 2H), 7.65 (d, IH), 7.78 (d, IH), 8.76 (t, IH), 8.88 (s, IH), 8.92 (s, IH), 8.99 (s, IH), 9.65 (s, IH), 13.13 (brs, IH). [2] Mass Spectrum: M+H+ 417; RT 2.23 min. [3] Mass Spectrum: M+H+ 415; RT 1.84 min.
Example 9 3-(lH-benzimidazol-2-yl)-5-(6-piperidin-l-ylpyridin-3-yl)pyrazin-2-amine
Figure imgf000147_0002
Dichlorobis(triphenylphosphine)palladium(II) (0.012 g) was added to 3-(1H- benzimidazol-2-yl)-5-bromopyrazin-2-amine (0.100 g), 2-fluoropyridin-5-ylboronic acid (0.072 g) and 2M sodium bicarbonate (0.207 ml) in a mixture of 2:7:3:2 DMA:DME:ethanol:water (5 ml). The mixture was heated to 1600C for 40 minutes in a microwave. Piperidine (0.3 ml) was then added and the solution was heated to 1200C for a further 20 minutes. The crude product 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. The crude product was purified by preparative ΗPLC, using decreasingly polar mixtures of water (containing 1% NΗ3) and acetonitrile as eluents. There was thus obtained the title compound (0.128 g); Mass Spectrum: M+H+ 372; RT 2.87 min.
Example 10
Using an analogous procedure to that described in Example 9, the appropriate amine was reacted with the appropriate fluoro-substituted heteroaryl to give the compounds described in Table V. Unless otherwise stated, the required each appropriate amine and the required appropriate fluoro-substituted heteroaryls are commercially available.
Table V
Figure imgf000148_0001
Figure imgf000148_0002
Notes The product gave the characterising data shown below. [1] Mass Spectrum: M+H+ 387; RT 2.25 min. NMR Spectrum: (DMSOd6) 2.25 (s, 3H), 2.47 (m, 4H), 3.61 (m, 4H), 6.96 (d, IH), 7.28 (t, IH), 7.33 (t, IH) 7.64 (d, IH), 7.78 (d, IH), 8.04 (brs, 2H), 8.42 (dd, IH), 8.73 (s, IH), 9.07 (s, IH), 12.99 (s, IH).
5 Example 11
3-[4-(l-Methylpyrrolidin-3-yloxy)-lH-benzimidazol-2-yl]-5-[l-(piperidin-4- yl)pyr azol-4-yl] pyrazin-2-amine
Figure imgf000149_0001
Diisopropyl azodicarboxylate (0.03 ml) was added to a solution of tert-butyl 4-[4-[5- i o amino-6-(7-hydroxy- 1 H-benzimidazol-2-yl)pyrazin-2-yl]pyrazol- 1 -yl]piperidine- 1 - carboxylate (0.06 g, triphenylphosphine (0.04 g), l-methylpyrrolidin-3-ol (0.015 g) in tetrahydrofuran (1.2 ml). The mixture was shaken for 4 days. The resultant mixture was concentrated by evaporation of solvent under reduced pressure. The residue was dissolved in DCM (3 ml) and trifiuoroacetic acid was added (0.1 ml). The mixture was stirred for 5 is minutes. The resultant mixture was concentrated under reduced pressure and the residue was purfied by preparative HPLC. There was thus obtained the title compound (0.004 g); Mass Spectrum: M+H+ 460.41; RT 1.71 min.
Example 12
20 Using an analogous procedure to that described in Example 11 , the appropriate alcohol was reacted with tert-butyl 4-[4-[5-amino-6-(4-hydroxy-lH-benzimidazol-2- yl)pyrazin-2-yl]pyrazol-l-yl]piperidine-l -carboxylate and the protecting group was removed using conventional treatment with trifiuoroacetic acid to give the compounds described in Table VI.
25 Table VI
Figure imgf000150_0001
Figure imgf000150_0002
Notes: The product gave the characterising data shown below.
[1] Mass Spectrum: M+H+ 445.42; RT 2.23 min.
[2] Mass Spectrum: M+H+ 433.43; RT 2.23 min.
[3] Mass Spectrum: M+H+ 461.43; RT 1.81 min.
[4] Mass Spectrum: M+H+ 419.35; RT 2.28 min; NMR Spectrum: (400.132 MHz, DMSO)
12.83 (IH, s), 8.51 (IH, s), 8.45 (IH, s), 8.17 (IH, s), 7.20 (2H, d), 6.76 (IH, t), 5.03 (IH, quintet), 4.17 - 4.30 (IH, m), 3.08 (2H, d), 2.63 (2H, dd), 2.04 (2H, d), 1.82 (2H, qd), 1.39 (6H, d).
[5] Mass Spectrum: M+H+ 405.43; RT 1.83 min; NMR Spectrum: (400.132 MHz, DMSO)
12.84 (IH, s), 8.50 (IH, s), 8.44 (IH, s), 8.17 (IH, s), 7.22 (IH, d), 7.21 (IH, s), 6.76 (IH, dd), 4.30 (2H, q), 4.18 - 4.28 (IH, m), 3.07 (2H, d), 2.62 (2H, t), 2.04 (2H, d), 1.82 (2H, qd), 1.46 (3H, t).
[6] Mass Spectrum: M+H+ 458.41; RT 1.76 min. [7] Mass Spectrum: M+H+ 459.45; RT 2.46 min. [81 Mass Spectrum: M+H+ 431.39; RT 2.01 min. [9] Mass Spectrum: M+H+ 481.4; RT 2.32 min.
Example 13
3-(lH-Imidazo[4,5-c]pyridin-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin- 2-amine
Figure imgf000151_0001
Using an analogous procedure to that described in Example 1, pyridine-3,4-diamine was reacted with 3-amino-6-[l-(l-methyl-piperidin-4-yl)pyrazol-4-yl]pyrazine-2- carboxylic acid to give the title compound (0.078 g); Mass Spectrum: M+H+ 375; RT 1.64 min.
Example 14
3- [l-(2-Methoxyethyl)benzimidazol-2-yl] -5- [l-(piperidin-4-yl)pyrazol-4-yl] pyrazin-2- amine
Figure imgf000151_0002
l-Bromo-2-methoxyethane (0.067 ml) was added in one portion to tert-butyl 4-[4- [5 -amino-6-( 1 H-benzimidazol-2-yl)pyrazin-2-yl]pyrazol- 1 -yl]piperidine- 1 -carboxylate (300 mg) and caesium carbonate (424 mg) dissolved in DMF (5 ml). The mixture was stirred at 25°C for 16 hours. The mixture was filtered and purified by preparative HPLC using a Waters X-Terra reverse-phase column (5 microns silica, 30 mm diameter, 250 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford tert-butyl 4- [4-[5-amino-6-[l-(2-methoxyethyl)benzimidazol-2-yl]pyrazin-2-yl]pyrazol-l- yl]piperidine-l-carboxylate as a solid (268 mg) . Mass Spectrum: M+H+ 519. NMR Spectrum: (CDCl3): 1.49 (s, 9H), 2.93-2.06 (m, 2H), 2.16-2.24 (m, 2H), 2.85-3.03 (m, 2H), 3.40 (s, 3H), 3.93 (t, 2H), 4.30 (bs, 2H), 4.31-4.38 (m, IH), 5.05 (t, 2H), 7.33 (dd, IH), 7.38 (dd, IH), 7.45 (bs, 2H), 7.56 (d, IH), 7.80 (d, IH), 7.95 (s, IH), 7.97 (s, IH), 8.31 (s, IH) Under argon atmosphere, trifluoroacetic acid (3 ml) was added in one portion to a stirred suspension of tert-butyl 4-[4-[5-amino-6-[l-(2-methoxyethyl)benzimidazol-2- yl]pyrazin-2-yl]pyrazol-l-yl]piperidine-l-carboxylate (330 mg). The resulting solution was stirred at 25 0C for 2 hours. The mixture was evaporated. A commercial 7N solution of ammonia in methanol (2 ml) was cooled to 00C and added to the residue. The mixture was adsorbed onto silica gel and purified by flash chromatography on silica gel eluting with 1 to 4% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness. The solid was stirred overnight in acetonitrile. The suspension was filtered to afford the title compound 3-[l-(2-methoxyethyl)benzimidazol-2-yl]-5-[l-(piperidin-4- yl)pyrazol-4-yl]pyrazin-2-amine as a solid (232 mg). Mass Spectrum: M+H+ 419. NMR Spectrum: (CDC13): 1.93-2.05 (m, 2H), 2.21-2.29 (m, 2H), 2.78-2.87 (m, 2H), 3.27-3.33 (m, 2H), 3.39 (s, 3H), 3.94 (t, 2H), 4.25-4.34 (m, IH), 5.06 (t, 2H), 7.33 (dd, IH), 7.38 (dd, IH), 7.44 (bs, 2H), 7.56 (d, IH), 7.789 (d, IH), 7.95 (s, IH), 7.96 (s, IH), 8.32 (s, IH) The tert-butyl 4-[4-[5-amino-6-(lH-benzimidazol-2-yl)pyrazin-2-yl]pyrazol-l- yl]piperidine-l-carboxylate used as a starting material was prepared as follows: A slurry of benzotriazol-l-yl-[bis(dimethylamino)methylene]oxonium tetrafluoroborate (9.03 g) was added to 3-amino-6-[l-(l-(tert-butoxycarbonyl)piperidin-4- yl]-l//-pyrazol-4-yl)pyrazine-2-carboxylic acid (8.4 g), benzene- 1,2-diamine (2.339 g) and triethylamine (0.883 ml) dissolved in DMF (80 ml) over a period of 10 minutes. The resulting solution was stirred at 25°C over night. The mixture was evaporated and a saturated solution of dilute aqueous sodium bicarbonate (50ml) was added to the residue, which was extracted with methylene chloride (50ml x2). The organic extract was dried over magnesium sulphate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel eluting with 1 to 4% methanol in dichloromethane. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[5-amino-6-[(2- aminophenyl)carbamoyl]pyrazin-2-yl]pyrazol-l-yl]piperidine-l-carboxylate (11.6 g, purity 70%) as a solid. Mass Spectrum: M+H+ 479. NMR Spectrum: (CDCB) 1.48 (s, 9H), 1.77- 2.22 (m, 4H), 2.92 (bs, 2H), 3.89 (bs, 2H), 4.12-4.41 (m, 3H), 6.65 (bs, 2H), 6.85-6.91 (m, 2H), 7.11 (ddd, IH), 7.46 (d, IH), 7.88 (s, IH), 7.94 (s, IH), 8.45 (s, IH), 9.65 (s, IH)
Acetic acid (50 ml) was added to tert-butyl 4-[4-[5-amino-6-[(2- aminophenyl)carbamoyl]pyrazin-2-yl]pyrazol-l-yl]piperidine-l-carboxylate (10.6 g) and the resulting solution was stirred at 900C for 3 hours. The reaction mixture was allowed to cool to ambient temperature under stirring over a period of 30 minutes, quenched with water, basified with a 2N aqueous solution of sodium hydroxide to pH 4.5 and extracted with ethyl acetate (200 x 3 ml). The combined organic phases were washed with a saturated aqueous solution of brine dried over magnesium sulphate and concentrated to afford the crude product as a foam. The crude product was purified by flash chromatography on silica gel eluting with 60 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[5-amino-6-(lH-benzimidazol- 2-yl)pyrazin-2-yl]pyrazol-l-yl]piperidine-l-carboxylate (3.0 g) as a solid. Mass Spectrum: M+H+ 461. NMR Spectrum: (CDC13): 1.49 (s, 9H), 1.92-2.05 (m, 2H), 2.17-2.25 (m, 2H), 2.92 (bs, 2H), 4.19-4.44 (m, 3H), 7.13 (bs, 2H), 7.30-7.38 (m, 2H), 7.62 (bs, IH), 7.76 (bs, IH), 7.94 (s, IH), 7.97 (s, IH), 8.33 (s, IH), 10.41 (bs, IH).
Example 15
Using analogous procedures to those described in Example 14, the appropriate benzimidazole was reacted with an appropriate alkylating agent to give the compounds described in Table VII. As in Example 14, a N-tert-butoxycarbonyl (N-Boc) protecting group was employed. Where necessary, an O-tert-butoxy protecting group was employed on certain alkylating agents. Such protecting groups were removed using conventional treatment with trifluoroacetic acid. Unless otherwise stated, the required appropriate alkylating agents are commercially available. Table VII
Figure imgf000154_0001
Figure imgf000154_0002
Notes The products gave the characterising data shown below.
[1] 3-(l-methylbenzimidazol-2-yl)-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine .
Iodomethane was used as the alkylating agent in the preparation of this product. The initial N-Boc protected precursor gave the following characterising data: Mass Spectrum: M+H+ 475. NMR Spectrum: (CDC13): 1.49 (s, 9H), 1.92-2.08 (m, 2H), 2.15-2.25 (m, 2H), 2.84- 3.02 (m, 2H), 4.30 (bs, 2H), 4.30-4.38 (m, IH), 4.36 (s, 3H), 7.30 (bs, 2H), 7.33 (ddd, IH), 7.38 (ddd, IH), 7.47 (d, IH), 7.80 (d, IH), 7.84 (s, IH), 7.97 (s, IH), 8.29 (s, IH). After the deprotection step, the final product gave the following characterising data: Mass Spectrum: M+H+ 375. NMR Spectrum: (CDC13): 1.91-2.03 (m, 2H), 2.17-2.25 (m, 2H), 2.76-2.85 (m, 2H), 3.24-3.32 (m, 2H), 4.25-4.34 (m, IH), 4.36 (s, 3H), 7.22 (bs, 2H), 7.34 (ddd, IH), 7.38 (ddd, IH), 7.47 (d, IH), 7.80 (d, IH), 7.86 (s, IH), 7.96 (s, IH), 8.29 (s, IH). [2] 3-(l-ethylbenzimidazol-2-yl)-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine
Iodoethane was used as the alkylating agent in the preparation of this product. The initial N-Boc protected precursor gave the following characterising data: Mass Spectrum: M+H+ 489. NMR Spectrum: (CDCB): 1.49 (s, 9H), 1.69 (t, 3H), 1.93-3.04 (m, 2H), 2.16-2.24 (m, 2H), 2.87-3.01 (m, 2H), 4.29 (bs, 2H), 4.29-4.37 (m, IH), 4.92 (q, 2H), 7.33 (dd, IH), 7.38 (dd, IH), 7.43 (bs, 2H), 7.49 (d, IH), 7.81 (d, IH), 7.83 (s, IH), 7.96 (s, IH), 8.28 (s, IH). After the deprotection step, the final product gave the following characterising data: Mass Spectrum: M+H+ 389. NMR Spectrum: (CDC13): 1.62 (t, 3H), 1.94 (dd, IH), 1.99 (dd, IH), 2.20-2.27 (m, 2H), 2.81 (ddd, 2H), 3.24-3.32 (m, 2H), 4.25-4.33 (m, IH), 4.71 (q, 2H), 7.32 (dd, IH), 7.37 (dd, IH), 7.39 (bs, 2H), 7.48 (d, IH), 7.81 (d, IH), 7.85 (s, IH), 7.95 (s, IH), 8.29 (s, IH).
[3] 3-(l-isobutylbenzimidazol-2-yl)-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine
Isobutyl bromide was used as the alkylating agent in the preparation of this product. The initial N-Boc protected precursor gave the following characterising data: Mass Spectrum: M+H+ 517. NMR Spectrum: (CDCl3): 0.90 (d, 6H), 1.49 (s, 9H), 1.91-2.05 (m, 2H), 2.15- 2.25 (m, 2H), 2.31-2.42 (m, IH), 2.85-3.01 (m, 2H), 4.29 (bs, 2H), 4.30-4.40 (m, H), 4.81 (d, 2H), 7.31 (dd, IH), 7.35 (dd, IH), 7.41 (bs, 2H), 7.46 (d, IH), 7.80 (d, IH), 7.83 (s, IH), 7.95 (s, IH), 8.27 (s, IH). After the deprotection step, the final product gave the following characterising data: Mass Spectrum: M+H+ 417. NMR Spectrum: (CDC13): 0.91 (d, 6H), 1.93 (dd, IH), 1.98 (dd, IH), 2.21-2.29 (m, 2H), 2.32-2.42 (m, IH), 2.81 (ddd, 2H), 3.25-3.32 (m, 2H), 4.25-4.34 (m, IH), 4.82 (d, 2H), 7.31 (ddd, IH), 7.35 (ddd, IH), 7.38 (bs, 2H), 7.46 (d, IH), 7.80 (d, IH), 7.86 (s, IH), 7.95 (s, IH), 8.29 (s, IH).
[4] 3-[l-(cyclopropylmethyl)benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4- yl]pyrazin-2-amine cyclopropylmethylbromide was used as the alkylating agent in the preparation of this product. The initial N-Boc protected precursor gave the following characterising data: Mass Spectrum: M+H+ 515. NMR Spectrum: (CDC13): 0.47-0.62 (m, 4H), 1.49 (s, 9H), 1.55-1.65 (m, IH), 1.91-2.05 (m, 2H), 2.17-2.26 (m, 2H), 2.83-3.02 (m, 2H), 4.28 (bs, 2H), 4.29-4.35 (m, IH), 4.82 (d, 2H), 7.32 (dd, IH), 7.36 (dd, IH), 7.40 (bs, 2H), 7.44 (d, IH), 7.80 (d, IH), 7.89 (s, IH), 8.01 (s, IH), 8.29 (s, IH). After the deprotection step, the final product gave the following characterising data: Mass Spectrum: M+H+ 415. NMR Spectrum: (DMSOdό): 0.43-055 (m, 4H), 1.44-1.55 (m, IH), 2.00 (dd, IH), 2.06 (dd, IH), 2.13-2.22 (m, 2H), 2.90-2.99 (m, 2H), 3.30 (bs partially hidden by H2O, 2H), 4.40-4.50 (m, IH), 4.84 (d, 2H), 7.31 (dd, IH), 7.37 (dd, IH), 7.74 (d, IH), 7.78 (d, IH), 8.06 (s, IH), 8.16 (bs, 2H), 8.31 (s, IH), 8.55 (s, IH).
[5] 2-[2-[3-amino-6-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-yl]benzimidazol-l- yljethanol
2-tert-butoxyethyl bromide was used as alkylating agent in the preparation of this product. The initial N-Boc and O-tert-butyl protected precursor gave the following characterising data: Mass Spectrum: M+H+ 561. NMR Spectrum: (CDC13): 1.07 (s, 9H), 1.49 (s, 9H), 1.95-2.07 (m, 2H), 2.14-2.24 (m, 2H), 2.84-3.00 (m, 2H), 3.87 (t, 2H), 4.28 (bs, 2H), 4.30- 4.38 (m, (IH), 5.00 (t, 2H), 7.32 (dd, IH), 7.37 (dd, IH), 7.42 (bs, 2H), 7.57 (d, IH), 7.79 (d, IH), 7.91 (s, IH), 7.99 (s, IH), 8.29 (s, lH)._After the deprotection step, the final product gave the following characterising data: Mass Spectrum: M+H+ 405. NMR Spectrum: (DMSOdό): 2.12 (dd, IH), 2.17 (d, IH), 2.22-2.30 (m, 2H), 3.11 (ddd, IH), 3.39-3.47 (m, 2H), 3.91-3.97 (m, 2H), 4.50-4.50 (m, IH), 4.88-4.97 (m, 2H), 5.03 (s, IH), 7.31 (dd, IH), 7.38 (dd, IH), 7.72 (d, IH), 7.77 (d, IH), 8.08 (s, IH), 8.33 (s, IH), 8.45 (bs, 2H), 8.54 (s, IH).
[6] 3-[2-[3-amino-6-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-yl]benzimidazol-l- yl]propan-l-ol. 3-tert-butoxypropyl bromide was used as alkylating agent in the preparation of this product. The initial N-Boc and O-tert-butyl protected precursor gave the following characterising data: Mass Spectrum: M+H+ 575. NMR Spectrum: (CDC13): 1.14 (s, 9H), 1.49 (s, 9H), 1.92- 2.05 (m, 2H), 2.14-2.26 (m, 4H), 2.85-3.06 (m, 2H), 3.36 (t, 2H), 4.28 (m, 2H), 4.29-4.38 (m, IH), 4.99 (t, 2H), 7.31 (dd, IH), 7.36 (dd, IH), 7.40 (bs, 2H), 7.60 (d, IH), 7.79 (d, IH), 7.83 (s, IH), 7.96 (s, IH), 8.27 (s, IH). After the deprotection step, the final product gave the following characterising data: Mass Spectrum: M+H+ 419. NMR Spectrum: (DMSOdό): 1.83 (dd, IH), 1.89 (dd, IH), 1.98-2.10 (m, 4H), 2.66 (ddd, IH), 3.07-3.14 (m, 2H), 3.50-3.56 (m, 2H), 4.23-4.31 (m, IH), 4.75 (bs, IH), 4.97 (t, 2H), 7.31 (dd, IH), 7.38 (dd, IH), 7.72 (d, IH), 7.78 (d, IH), 8.01 (s, IH), 8.12 (bs, 2H), 8.34 (s, IH), 8.52 (s, IH). [7] 3-[l-(tetrahydrofuran-2-ylmethyl)benzimidazol-2-yl]-5-(l-piperidin-4-ylpyrazol-4- yl)pyrazin-2-amine. 2-(Bromomethyl)tetrahydrofuran was used as the alkylating agent in the preparation of this product. The initial N-Boc protected precursor gave the following characterising data: Mass Spectrum: M+H+ 545. NMR Spectrum: (CDCl3): 1.49 (s, 9H), 1.72-1.82 (m, IH), 1.84-2.07 (m, 5H), 2.16-2.27 (m, 2H), 2.85-3.04 (m, 2H), 3.71-3.79 (m, IH), 3.90-3.99 (m, IH), 4.29 (bs, 2H), 4.30-4.39 (m, (IH), 4.63-4.61 (m, IH), 4.74 (dd, IH), 5.20 (dd, IH), 7.32 (dd, IH), 7.37 (dd, IH), 7.44 (bs, 2H), 7.53 (d, IH), 7.79 (d, IH), 7.95 (s, IH), 8.16 (s, IH), 8.31 (s, IH). After the deprotection step, the final product gave the following characterising data: Mass Spectrum: M+H+ 445. NMR Spectrum: (DMSOdό): 1.67-1.95 (m, 4H), 2.08-2.18 (m, 2H), 2.21-2.30 (m, 2H), 3.09 (ddd, 2H),
3.38-3.44 (m, 2H), 3.55-3.62 (m, IH), 3.71-3.78 (m, IH), 4.34-4.41 (m, IH), 4.48-4.57 (m, IH), 4.83 (dd, IH), 5.05 (dd, IH), 7.30 (dd, IH), 7.37 (dd, IH), 7.76 (d, IH), 7.77 (d, IH), 8.08 (s, IH), 8.21 (bs, 2H), 8.35 (s, IH), 8.54 (s, IH).
[8] 3-[l-[(3-methyloxetan-3-yl)methyl]benzimidazol-2-yl]-5-[l-(piperidin-4- yl)pyrazol-4-yl]pyrazin-2-amine . 3-(Chloromethyl)-3-methyl-oxetane was used as alkylating agent in the preparation of this product. The initial N-Boc protected precursor gave the following characterising data: Mass Spectrum: M+H+ 545. NMR Spectrum: (CDC13): 1.41 (s, 3H), 1.49 (s, 9H), 1.91-2.03 (m, 2H), 2.16-2.25 (m, 2H), 2.84-3.01 (m, 2H), 4.16 (d, 2H), 4.29 (bs, 2H), 4.29-4.37 (m, IH), 4.60 (d, 2H), 5.29 (s, 2H), 7.29-7.40 (m, 4H), 7.43 (bs, 2H), 7.83 (s, IH), 7.88 (s, IH), 8.28 (s, IH). After the deprotection step, the final product gave the following characterising data: Mass Spectrum: M+H+ 445. NMR Spectrum: (DMSOdό): 1.28 (s, 3H), 1.91-2.04 (m, 2H), 2.09-2.19 (m, 2H), 2.81-2.90 (m, 2H), 3.20-3.28 (m, 2H), 4.00 (d, 2H), 4.32-4.44 (m, 3H), 5.25 (s, 2H), 7.33 (dd, IH), 7.39 (dd, IH), 7.76 (d, IH), 7.81 (d, IH) 7.98 (s, IH), 8.09 (bs, 2H), 8.28 (s, IH), 8.53 (s, IH). Example 16
3-[l-(2-Methoxyethyl)benzimidazol-2-yl]-5-[l-(l-methyl-piperidin-4-yl)pyrazol-4- yl] pyrazin-2-amine
Figure imgf000158_0001
Formaldehyde (0.028 ml) was added in one portion to a stirred solution of 3-[l-(2- methoxyethyl)benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine (132 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) at 00C under argon. The resulting solution was stirred at 0 0C for 5 minutes. Sodium triacetoxyhydroborate (80 mg) was added and the mixture was stirred for 5 minutes at 25°C. A solution of ammonia in methanol 7N (1 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 5% methanolic ammonia
(7 N) in dichloromethane. The solvent was evaporated to dryness. The solid so obtained was stirred overnight in acetonitrile. The resultant solution was filtered to afford 3-[l-(2- methoxyethyl)benzimidazol-2-yl]-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine as a solid (72.0 mg). Mass Spectrum: M+H+ 433. NMR Spectrum: (DMSOdό): 1.94-2.12 (m, 6H), 2.22 (s, 3H), 2.83-2.93 (m, 2H), 3.24 (s, 3H), 3.85 (t, 2H), 4.11-4.21 (m, IH), 5.06 (t, 2H), 7.31 (dd, IH), 7.37 (dd, IH), 7.73 (d, IH), 7.77 (d, IH), 7.99 (s, IH), 8.12 (bs, 2H), 8.32 (s, IH), 8.52 (s, IH)
Example 17 3-(l-Methylbenzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine
Figure imgf000158_0002
Formaldehyde (0.012 ml) was added in one portion to a stirred solution of 3 -(I - methylbenzimidazol-2-yl)-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine (52 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) at 00C under argon. The resulting solution was stirred at 0 0C for 5 minutes. Sodium triacetoxyhydroborate (35.3 mg) was added and the mixture was stirred for 5 minutes at 25°C. A solution of ammonia in methanol 7N (ImI) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness. The solid so obtained was stirred overnight in acetonitrile. The resultant solution was filtered to afford 3-(l-methylbenzimidazol-2-yl)-5-[l-(l-methyl-piperidin-4-yl)pyrazol-4- yl]pyrazin-2-amine as a solid (32.0 mg). Mass Spectrum: M+H+ 389. NMR Spectrum: (DMSOdό): 1.97-2.11 (m, 6H), 2.22 (s, 3H), 2.84-2.94 (m, 2H), 4.12-4.23 (m, IH), 4.32 (s, 3H), 7.31 (dd, IH), 7.37 (dd, IH), 7.71 (d, IH), 7.77 (d, IH), 8.01 (s, IH), 8.02 (bs, 2H), 8.34 (s, IH), 8.51 (s, IH)
Example 17-1
3-(l-Ethylbenzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine
Figure imgf000159_0001
3 -(I -Ethylbenzimidazol-2-yl)-5-(l -(piperidin-4-yl)pyrazol-4-yl)pyrazin-2-amine (210 mg, Example 15.02) was reacted with formaldehyde as described in Example 17 to afford the title compound (175 mg). Mass spectrum: M+H+ 403; NMR Spectrum (DMSO-d6): 1.50 (t, 3H), 1.95-2.11 (m, 6H), 2.22 (s, 3H), 2.83-2.92 (m, 2H), 4.14-4.23 (m, IH), 4.91 (q, 2H), 7.31 (ddd, IH), 7.34 (ddd, IH), 7.73 (d, IH), 7.78 (d, IH), 7.97 (s, IH), 8.09 (bs, 2H), 8.29 (s, IH), 8.52 (s, IH) Example 18 l-[4-[4-[5-Amino-6-(lH-benzimidazol-2-yl)pyrazin-2-yl]pyrazol-l-yl]piperidin-l- yljethanone.
Figure imgf000160_0001
3-(lH-benzimidazol-2-yl)-5-(l-piperidin-4-ylpyrazol-4-yl)pyrazin-2-amine (0.070 g) was added to a mixture of acetic anhydride (0.023 ml) and pyridine (0.02 ml) in DCM (2 ml), and stirred for 16 hours. Methanol (1 ml) was added and the resultant mixture was then concentrated in vacuo and purified by preparative HPLC. The resultant material was triturated with diethyl ether. There was thus obtained l-[4-[4-[5-amino-6-(lH- benzimidazol-2-yl)pyrazin-2-yl]pyrazol-l-yl]piperidin-l-yl]ethanone (0.042 g); Mass Spectrum: M+H+ 403; RT 2.00 min. NMR Spectrum: (DMSOd6) 1.78-2.0 (m, 2H), 2.07 (s, 3H), 2.15 (t, 2H), 2.79 (t, 2H), 3.96 (d, IH), 4.49 (m, 2H) 7.28 (t, IH), 7.33 (t, IH), 7.65 (d, IH), 7.77 (d, 2H), 7.92 (brs, 2H), 8.19 (s, IH), 8.46 (s, IH), 8.52 (s, IH), 12.82 (brs, IH).
Example 19
3-(6-fluoro-l-methylbenzimidazol-2-yl)-5-(l-piperidin-4-ylpyrazol-4-yl)pyrazin-2- amine and 3-(5-fluoro-l-methylbenzimidazol-2-yl)-5-(l-piperidin-4-ylpyrazol-4- yl)pyrazin-2-amine
Figure imgf000160_0002
To a solution of tert-butyl 4-(4-(5-amino-6-(6-fluoro-lH-benzimidazol-2-yl)pyrazin-2- yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (319 mg, 0.67 mmol) in DMF (1 ml) at room temperature was added cesium carbonate (434 mg, 1.33 mmol) and iodomethane (0.046 mL, 0.73 mmol). The reaction mixture was stirred at room temperature overnight. To the mixture was added water and ethyl acetate and two layers were separated. The organic layer was concentrated. The residue was dissolved in DCM (5 ml) and trifluoroacetic acid (0.4 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours. After removal of the solvent, purification by reversed phase chromatography gave a 1:1 mixture (106 mg) of 3-(6-fluoro-l-methylbenzimidazol-2-yl)- 5-(l-piperidin-4-ylpyrazol-4-yl)pyrazin-2-amine and 3-(5-fluoro-l-methylbenzimidazol-2- yl)-5-(l-piperidin-4-ylpyrazol-4-yl)pyrazin-2-amine as a solid. Mass spectrum: MH+ 393; 1H NMR (DMSO- d6) 2.13-2.27 (m, 4H) 3.08-3.15 (m, 2H) 3.44-3.47 (m, 2H) 4.29 (m, 3H) 4.58 (m, IH) 7.16 - 7.28 (m, IH) 7.60-7.68 (m, IH) 7.77-7.80 (m, IH) 8.09 (s, 2H) 8.40 (m, IH), 8.55 (s, IH) 8.68 (m, IH).
The tert-butyl 4-(4-(5-amino-6-(6-fluoro-lH-benzimidazol-2-yl)pyrazin-2-yl)-lH- pyrazol-l-yl)piperidine-l-carboxylate used as starting material was prepared from 4- fluoro- 1 ,2-diaminobenzene and 3-amino-6-(l -(I -(tert-butoxycarbonyl)piperidin-4-yl)- IH- pyrazol-4-yl)pyrazine-2-carboxylic acid according to Example 1 except that treatment with TFA was omitted. Mass spectrum: MH+ 479
Example 20 3-(l//-Imidazo [4,5-c] pyridin-2-yl)-5- [l-(piperidin-4-yl)pyrazol-4-yl] pyrazin-2-amine
Figure imgf000161_0001
Tert-butyl 4-(4-(5-amino-6-(3-aminopyridin-4-ylcarbamoyl)pyrazin-2-yl)pyrazol- 1 - yl)piperidine-l-carboxylate (66 mg) was dissolved into acetic acid (2 ml) and TFA (1 ml). The resulting solution was heated to 1000C for 4 hours. The resulting mixture was concentrated, and the residue was dissolved into methanol (2 ml). The methanol solution was purified by HPLC to yield the desired product (13 mg). Mass spectrum: M+H+ 362. 1R NMR (CD3OD) 2.30 (m, 4H), 3.60 (m, 2H), 4.00 (m, 2H), 4.50 (br, IH), 8.20 (br, IH), 8.25 (d, IH), 8.40 (s, IH), 8.55 (br, IH), 8.60 (d, IH), 9.30 (s, IH). The tert-butyl 4-(4-(5-amino-6-(3-aminopyridin-4-ylcarbamoyl)pyrazin-2-yl)pyrazol-l- yl)piperidine-l-carboxylate used as starting material was made as follows: Methyl 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)pyrazol-4-yl)pyrazine-2- carboxylate (300 mg) and pyridine-3,4-diamine (407 mg) were dissolved into DMF (5 ml). Sodium methoxide (50 mg) was added to the mixture. The resulting mixture was stirred at 12O0C for 12 hours. Water (10 ml) was added into the mixture, and IM hydrochloric acid was added to adjust the pH to 8. The precipitate was collected. The collected solid was washed with ethyl acetate (2 ml) to give tert-butyl 4-(4-(5-amino-6-(3-aminopyridin-4- ylcarbamoyl)pyrazin-2-yl)pyrazol- 1 -yl)piperidine- 1 -carboxylate. Mass spectrum: M+H+ 480.
Example 21
3-(l-Ethylbenzimidazol-2-yl)-5-(3-methyl-l-(piperidin-4-yl)pyrazol-4-yl)pyrazin-2- amine
Figure imgf000162_0001
TFA (3 ml) was added to a solution of tert-butyl 4-(4-(5-amino-6-(l-ethylbenzimidazol-2- yl)pyrazin-2-yl)-3-methylpyrazol-l-yl)piperidine-l -carboxylate (368 mg) in DCM (3 ml) and the mixture was stirred for 2 hours. After concentration, the residue was dissolved in DCM- 7N methanolic ammonia and concentrated. The mixture was purified by flash chromatography on silica gel eluting with 2 to 15% 7N methanolic ammonia in DCM. The solvent was evaporated to dryness to afford a solid which was stirred in acetonitrile overnight to give the title compound (260 mg). Mass spectrum: M+H+ 403; NMR Spectrum (DMSO-d6): 1.41 (t, 3H), 1.76 (dd, IH), 1.81 (dd, IH), 1.94-2.01 (m, 2H), 2.06 (bs, IH), 2.42 (s, 3H), 2.54-2.63 (m, 2H), 3.00-3.08 (m, 2H), 4.12-4.21 (m, IH), 4.92 (q, 2H), 7.32 (ddd, IH), 7.38 (ddd, IH), 7.71 (d, IH), 7.78 (d, IH), 8.04 (bs, 2H), 8.06 (s, IH), 8.35 (s, IH)
The tert-butyl 4-(4-(5-amino-6-(l-ethylbenzimidazol-2-yl)pyrazin-2-yl)-3-methylpyrazol- l-yl)piperidine-l-carboxylate used as starting material was prepared as follows:
A mixture of 5-bromo-3-(l-ethylbenzimidazol-2-yl)pyrazin-2-amine (340 mg), tert-butyl 4-(3-methyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazol- 1 -yl)piperidine- 1 - carboxylate (418 mg), bis(triphenylphosphine) palladium(II) chloride (75 mg) and cesium fluoride (487 mg) in methanol (7 ml) under argon was stirred at 130 0C for 20 mn The mixture was concentrated. The residue was dissolved in dichloromethane-methanol, filtered and purified by flash chromatography on silica gel eluting with 50 to 100% ethyl acetate in petroleum ether to afford tert-butyl 4-(4-(5-amino-6-(l-ethylbenzimidazol-2- yl)pyrazin-2-yl)-3-methylpyrazol-l-yl)piperidine-l -carboxylate (387 mg). Mass spectrum: M+H+ 503; NMR Spectrum (CDC13): 1.49 (s, 9H), 1.54 (t, 3H), 1.82 (bs, IH), 1.88-2.00 (m, 2H), 2.15-2.23 (m, 2H), 2.51 (s, 3H), 2.83-2.98 (m, 2H), 4.17-4.37 (m, 3H), 4.92 (q, 2H), 7.33 (dd, IH), 7.38 (dd, IH), 7.48 (d, IH), 7.72 (s, IH), 7.82 (d, IH), 8.23 (s, IH)
5-Bromo-3-(l-ethylbenzimidazol-2-yl)pyrazin-2-amine was prepared as follows:
Iodoethane (0.182 ml) was added to a mixture of 3-(lH-benzimidazol-2-yl)-5- bromopyrazin-2-amine (440 mg, Example 3 starting material) and potassium carbonate
(419 mg) in DMF (5 mL). The mixture was stirred at room temperature for 18 hours.
Water (20 ml) was added. The solid was filtered, washed with water (10 ml) and ether (5 ml), and dried under vacuum over phosphorus pentoxide (P2O5) to give 5-bromo-3-(l- ethylbenzimidazol-2-yl)pyrazin-2-amine (405 mg) as a solid. Mass spectrum: M+H+ 318; NMR Spectrum (CDC13): 1.53 (t, 3H), 4.80 (q, 2H), 7.33
(ddd, IH), 7.39 (ddd, IH), 7.47 (d, IH), 7.79 (d, IH), 8.12 (s, IH)
The tert-butyl 4-(3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-l- yl)piperidine-l -carboxylate was prepared as follows:
Sodium hydride (11.53 g) was added portionwise to a stirred solution of 4-bromo-3- methyl-lH-pyrazole (42.2 g) dissolved in DMF (600 ml) over a period of 15 minutes at 00C under nitrogen. The resulting slurry was stirred at 00C for 1 hour. Then tert-butyl 4- methylsulfonyloxypiperidine-1-carboxylate (73.2 g) was added and the mixture was stirred 1 hour at room temperature then heated to 900C overnight. The reaction mixture was then allowed to stir at room temperature over a period of 2 days, quenched with water (2 ml), concentrated to dryness, diluted with ethyl acetate (1500 ml), washed with water (2x1000 ml), brine (1000 ml), dried over magnesium sulfate and concentrated to afford the crude product. A purification by flash chromatography on silica gel eluting with 20 % ethyl acetate in petroleum ether afforded tert-butyl 4-(4-bromo-5-methyl-pyrazol-l- yl)piperidine-l-carboxylate (22.5 g) (NMR Spectrum: (DMSOdό) 1.42 (s, 9H), 1.72-1.86 (m, 4H), 2.28 (s, 3H), 2.91 (bs, 2H), 3.96-4.13 (m, 2H), 4.34-4.43 (m, IH), 7.50 (s, IH); Mass spectrum: M-tBu: 288), and tert-butyl 4-(4-bromo-3-methyl-pyrazol-l-yl)piperidine- 1-carboxylate (28.7 g) (NMR Spectrum (DMSOdό): 1.44 (s, 9H), 1.70 (dd, IH), 1.75 (dd, IH), 1.91-1.99 (m, 2H), 2.11 (s, 3H), 2.87 (bs, 2H), 4.95-4.10 (m, 2H), 4.21-4.30 (m, IH), 7.95 (s, IH); Mass spectrum: M-tBu: 288). A mixture of tert-butyl 4-(4-bromo-3-methyl-pyrazol-l-yl)piperidine-l-carboxylate (2.7 g), 4,4,4',4>,5,5,5>,5>-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (4.98 g), 1,1 '- bis(diphenylphosphino)ferrocenedichloropalladium(II) - CH2Cl2 adduct (0.634 g) and potassium acetate (2.31 g) in DMSO (40 ml) was stirred at 80 0C for 4 hours. The reaction mixture was allowed to cool to room temperature under stirring over a period of 1 hour, quenched with water (25 ml) and extracted with ethyl acetate (3 x 40 ml). The combined organic phases were washed with water (3 x 30 ml), brine (1 x 20 ml), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 10 to 30% ethyl acetate in petroleum ether to afford tert-butyl 4-(3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol- l-yl)piperidine-l-carboxylate (0.937 g, 30.5 %) as a white solid. NMR Spectrum
(DMSOdό): 1.24 (s, 12H), 1.41 (s, 9H), 1.71 (dd, IH), 1.76 (dd, IH), 1.89-1.96 (m, 2H), 2.22 (s, 3H), 2.85 (bs, 2H), 3.95-4.07 (m, 2H), 4.20-4.29 (m, IH), 7.82 (s, IH) Example 22
3-(l-Ethylbenzimidazol-2-yl)-5-[3-methyl-l-(l-methyl-4-piperidyl)pyrazol-4- yl] pyrazin-2-amine
Figure imgf000165_0001
3 -(I -Ethylbenzimidazol-2-yl)-5 -(3 -methyl- 1 -(piperidin-4-yl)pyrazol-4-yl)pyrazin-2-amine (204 mg, from Example 21) was reacted with formaldehyde according to procedure in Example 17 to give the title compound (160 mg). Mass spectrum: MH+ 417; NMR Spectrum (DMSO-d6): 1.40 (t, 3H), 1.90-2.09 (m, 6H), 2.21 (s, 3H), 2.41 (s, 3H), 2.83- 2.90 (m, 2H), 4.04-4.13 (m, IH), 4.92 (q, 2H), 7.31 (ddd, IH), 7.38 (ddd, IH), 7.72 (d, IH), 7.78 (d, IH), 8.04 (bs, 2H), 8.08 (s, IH), 8.35 (s, IH)
Example 23 3-(lH-benzimidazol-2-yl)-5-[3-methyl-l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine
Figure imgf000165_0002
Tert-butyl 4-[4-[5-amino-6-[(2-aminophenyl)carbamoyl]pyrazin-2-yl]-3-methyl-pyrazol- 1 - yl]piperidine-l-carboxylate (173 mg) in acetic acid (900 μl) was stirred at 130 0C for 1 hour in a microwave. The reaction mixture was concentrated and purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 3- (lH-benzimidazol-2-yl)-5 -[3 -methyl- l-(4-piperidyl)pyrazol-4-yl]pyrazin-2-amine (78 mg). Mass spectrum: M+H+ 375; NMR Spectrum(DMSOd6): 1.74-1.88 (m, 2H), 1.94-2.05 (m, 2H), 2.07 (bs, IH), 2.47 (s, 3H), 2.56-2.66 (m, 2H), 3.02-3.11 (m, 2H), 4.07-4.19 (m, IH), 7.26 (dd, IH), 7.31 (dd, IH), 7.65 (d, IH), 7.76 (d, IH), 7.93 (bs, 2H), 8.30 (s, IH), 8.35 (s, IH)
The tert-butyl 4-[4-[5-amino-6-[(2-aminophenyl)carbamoyl]pyrazin-2-yl]-3-methyl- pyrazol-l-yl]piperidine-l-carboxylate used as starting material was prepared as follows:
Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (334 mg), tert-butyl 4-[3-methyl-4- (4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrazol- 1 -yl]piperidine- 1 -carboxylate (563 mg) and bis(triphenylphosphine) palladium (II) chloride (101 mg) and cesium fluoride (656 mg) in MeOH (11 mL) were degassed under vacuum and argon , stirred at 130 0C for 20mn under microwave conditions. The mixture wac concentrated and the residue was dissolved in dichloromethane and filtered. The filtrate was purified by flash chromatography on silica gel eluting with 50 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford methyl 3-amino-6-[l-(l-tert-butoxycarbonyl-4- piperidyl)-3-methyl-pyrazol-4-yl]pyrazine-2-carboxylate (421 mg). Mass spectrum: M+H+ 417. Retention time: 3.47min
Sodium hydroxide 2N (1.008 mL) was added to a stirred suspension of methyl 3-amino-6- [l-(l-tert-butoxycarbonyl-4-piperidyl)-3-methyl-pyrazol-4-yl]pyrazine-2-carboxylate (420 mg) in MeOH (10 ml) The mixture was stirred at 50 0C for 2 hours. One eq. of HCl 2N was added. The mixture was concentrated and purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 250 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 3-amino-6-[l- (l-tert-butoxycarbonyl-4-piperidyl)-3-methyl-pyrazol-4-yl]pyrazine-2-carboxylic acid (226 mg). Mass spectrum: M+H+ 403; NMR Spectrum (DMSOdό): 1.42 (s, 9H), 1.73 (dd, IH), 1.78 (dd, IH), 1.96-2.05 (m, 2H), 2.39 (s, 3H), 2.89 (bs, 2H), 3.97-4.11 (m, 2H), 4.22-4.31 (m, IH), 7.29 (bs, 2H), 8.20 (s, IH), 8.37 (s, IH) 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan- 1 -amine hydrochloride (154 mg,), 2-hydroxypyridine 1-oxide (89 mg, 0.80 mmol) were added to a stirred suspension of 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-methyl-lH- pyrazol-4-yl)pyrazine-2-carboxylic acid (215 mg) and benzene- 1,2-diamine (60.7 mg) dissolved in DMF (3 mL) at 25 0C . The resulting suspension was stirred at 25 0C for overnight. The reaction mixture was purified by preparative HPLC using a Waters X- Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford tert-butyl 4- [4-[5-amino-6-[(2-aminophenyl)carbamoyl]pyrazin-2-yl]-3-methyl-pyrazol- 1 - yl]piperidine-l-carboxylate (182 mg). Mass spectrum: M+H+ 493; NMR Spectrum (DMSOdό): 1.42 (s, 9H), 1.75 (dd, IH), 1.79 (dd, IH), 1.99-2.07 (m, 2H), 2.48 (s, 3H), 2.91 (bs, 2H), 3.98-4.13 (m, 2H), 4.23-4.32 (m, IH), 4.92 (s, 2H), 6.67 (dd, IH), 6.83 (d, IH), 6.96 (dd, IH), 7.46 (bs, 2H), 7.52 (d, IH), 8.41 (s, IH), 8.56 (s, IH), 9.75 (s, IH)

Claims

1. A pyrazine derivative of the Formula I
Figure imgf000168_0001
in which: each of Gi and G2 is selected from CH and N provided that both are not N;
Ring A is a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, S, SO, SO2, N(R6), CO, CH(OR6), CON(R6), N(R6)CO, N(R6)CON(R6), SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2S, SC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 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 R5 is amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (R7)-amino-(l-6C)alkyl or di-(R7)-amino-(l-6C)alkyl, wherein R7 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, S, SO, SO2, N(R8), CO, CH(OR8), CON(R8), N(R8)C0, N(R8)CON(R8), SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2S, SC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 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 Q1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R1 substituent optionally bears 1 , 2 or 3 substituents independently selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylsulphonyl-(l-6C)alkyl, cyano-(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, (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)alkanoyloxy, TV-(I -6C)alkylcarbamoyl, /V,/V-di-[(l -6C)alkyl] carbamoyl, (2-6C)alkanoylamino, /V-(l-6C)alkyl-(2-6C)alkanoylamino, /V-(l-6C)alkylureido, /V'-(l-6C)alkylureido, N',N'-di- [(l-6C)alkyl]ureido, /V,/V'-di-[(l-6C)alkyl]ureido, /V,/V\/V'-tri-[(l-6C)alkyl]ureido,
TV-(I -6C)alkylsulphamoyl, /V,/V-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino, Λ/-(l-6C)alkyl-(l-6C)alkanesulphonylamino or heterocyclyl-(l-6C)alkyl, and any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents; or R1 is a group of the formula: Q2 X2 wherein X2 has any of the meanings defined hereinbefore and Q2 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 R1 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, (R9)-amino-(l-6C)alkyl and di-(R9)-amino-(l-6C)alkyl, wherein R9 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; m is 0, 1, 2 or 3, and, when m is 2 or 3, each R2 group may be the same or different, and each R2 group present 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)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2- 6C)alkanoyloxy, 7V-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2- 6C)alkanoylamino and N-(l-6C)alkyl-(2-6C)alkanoylamino; R3 is hydrogen, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (R10)p-(l-8C)alkyl, (R10)p-(2-8C)alkenyl or (R10)p-(2-8C)alkynyl, wherein each p is 1, 2 or 3 and each R10 group, 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, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy; n is 0, 1, 2 or 3 and, when n is 2 or 3, each R4 group may be the same or different, and each R4 group is selected from halogeno, amino, cyano, sulphamoyl, OR11, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl] sulphamoyl, trifluoromethyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, N,N-di-[(l- 6C)alkyl]carbamoyl and (2-6C)alkanoylamino, wherein R11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl, wherein any aryl, heterocyclyl or heteroaryl group within the definition of R11 optionally bears 1, 2 or 3 substituents independently selected from halogeno, trifluoromethyl, oxo, cyano, hydroxy, amino, carboxy, carbamoyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (l-6C)alkoxy; or a pharmaceutically-acceptable salt thereof.
2. A pyrazine derivative of the Formula I according to claim 1, wherein Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur; or a pharmaceutically-acceptable salt thereof.
3. A pyrazine derivative of the Formula I according to claim 1 or 2, wherein R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 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 R5 is amino-(l-6C)alkyl, ( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[( 1 -6C)alkyl] amino-( 1 -6C)alkyl, (R7)-amino-( 1 -6C)alkyl or di-(R7)-amino-(l-6C)alkyl, wherein R7 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)CO, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 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 Q1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R1 substituent optionally bears 1 , 2 or 3 substituents independently selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(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, (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)alkanoyloxy, N-(I -6C)alkylcarbamoyl, N,N-di-[(\ -6C)alkyl] carbamoyl, (2-6C)alkanoylamino, TV-(I -6C)alkylureido, ΛT-(l-6C)alkylureido,
TV-(I -6C)alkylsulphamoyl or heterocyclyl-(l-6C)alkyl and any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents; or a pharmaceutically-acceptable salt thereof.
4. A pyrazine derivative of the Formula I according to any one of claims 1 to 3, wherein m is 0, 1 or 2, and, when m is 2, each R2 group may be the same or different, and each R2 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)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, TV-(I -6C)alkylcarbamoyl, /V,/V-di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino; or a pharmaceutically-acceptable salt thereof.
5. A pyrazine derivative of the Formula I according to any one of claims 1 to 4, wherein R3 is hydrogen, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (R10)p-(l-8C)alkyl, wherein each p is 1, 2 or 3 and each R10 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, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2- 8C)alkynyl and (l-6C)alkoxy; or a pharmaceutically-acceptable salt thereof.
6. A pyrazine derivative of the Formula I according to any one of claims 1 to 5, wherein n is 0, 1 or 2, and, when n is 2, each R4 group may be the same or different, and each R4 group is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR11, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl] sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl,
TV-(I -6C)alkylcarbamoyl, 7V,7V-di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino, wherein R11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl, wherein any aryl, heterocyclyl or heteroaryl group within the definition of R11 optionally bears 1, 2 or 3 substituents independently selected from halogeno, trifluoromethyl, oxo, cyano, hydroxy, amino, carboxy, carbamoyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (l-6C)alkoxy; or a pharmaceutically-acceptable salt thereof.
7. A pyrazine derivative of the Formula I according to claim 1, wherein: Gi and G2 are both CH or Gi is N and G2 is CH;
Ring A is pyrazolyl or pyridinyl; R1 is a group of the formula:
R^X1 - wherein X1 is a direct bond or is selected from O, SO2, N(R6), CO, CON(R6), N(R6)CO, SO2N(R6), N(R6)SO2, C(R6)2O, OC(R6)2, C(R6)2, C(R6)2N(R6) and N(R6)C(R6)2, wherein each R6 is hydrogen or (l-8C)alkyl; and R5 is amino-(l-3C)alkyl, (l-6C)alkylamino-(l- 3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)alkyl, (R7)-amino-(l-3C)alkyl, di-[(R7)-amino-(l- 3C)alkyl; and R7 is (l-6C)alkyl; or R1 is a group of the formula:
Q1 X2 wherein X2 is a direct bond or is selected from O, SO2, N(R8), CO, CON(R8), N(R8)CO, SO2N(R8), N(R8)SO2, C(R8)2O, OC(R8)2, C(R8)2, C(R8)2N(R8) and N(R8)C(R8)2, wherein each R8 is hydrogen or (l-8C)alkyl, and Q1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (1- 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)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, /V-(l-6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l- 6C)alkyl group, wherein said heterocyclyl within the heterocyclyl-(l-6C)alkyl substituent group is selected from tetrahydrofuranyl or tetrahydropyranyl; m is O or 1, and when m is 1, the R2 group is selected from (l-8C)alkyl, (2-8C)alkenyl and (2-8C)alkynyl; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is O or 1 and when n is 1, R4 is selected from halogeno, amino, cyano, sulphamoyl, OR11, TV-(I -6C)alkylsulphamoyl, /V,/V-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, /V-(I- 6C)alkylcarbamoyl, 7V,7V-di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoylamino, wherein R11 is aryl, aryl-(l-6C)alkyl (wherein said aryl or the aryl within the aryl-(l-6C)alkyl group is phenyl), heterocyclyl, heterocyclyl-(l-6C)alkyl (wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-6C)alkyl group is selected from tetrahydrofuranyl and pyrrolidinyl), heteroaryl or heteroaryl-(l-6C)alkyl (wherein said heteroaryl or the heteroaryl within the heterocyclyl-(l-6C)alkyl group is isoxazlyl); or a pharmaceutically- acceptable salt thereof.
8. A pyrazine derivative of the Formula I according to claim 1, wherein: Gi and G2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl; When Ring A is pyrazol-4-yl, R1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperidin-3- ylmethyl, 2-piperidin-3-ylethyl, piperidin-3-yl, tetrahydropyran-4-yl, tetrahydropyran-4- ylmethyl or l-(4-aminocyclohex-l-yl), and when Ring A is pyridin-3-yl, R1 is aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy, 2- (dimethylamino)ethoxy, 3-(dimethylamino)propoxy, piperidin-1-yl, piperazin-1-yl, 4- methylpiperidin-1-yl, 4-ethylpiperidin-l-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, 1 -methylpiperidin-4-ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3-(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, 4-methylpiperazin- 1 - ylcarbonyl, 4-ethylpiperazin- 1-ylcarbonyl or 4-propylpiperazin-l-ylcarbonyl and when Ring A is pyridin-4-yl, R1 is piperazin-1-yl, aminomethoxy, 2-(amino)ethoxy, 3- (amino)propoxy, methylaminomethoxy, 2-(methylamino)ethoxy, 3- (methylamino)propoxy, dimethylaminomethoxy, 2-(dimethylamino)ethoxy, 3- (dimethylamino)propoxy, piperidin-1-yl, piperazin-1-yl, 4-methylpiperidin-l-yl, 4- ethylpiperidin-1-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, l-methylpiperidin-4- ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3 -(4-methylpiperazin- l-yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, 4-methylpiperazin- 1 -ylcarbonyl, 4- ethylpiperazin- 1-ylcarbonyl or 4-propylpiperazin-l-ylcarbonyl; m is 0 or 1, and when m is 1, the R2 group is selected from halogeno, hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy and propoxy; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2- (tetrahydrofuran-2-yl)ethyl or (3-methyloxetan-3-yl)methyl; n is 0 or n is 1 and R4 is selected from hydrogen, fluoro, chloro, amino, trifluoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy; or a pharmaceutically-acceptable salt thereof.
9. A pyrazine derivative of the Formula I according to claim 1, wherein: Gi and G2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
When Ring A is pyrazol-4-yl, R1 is located at the 1 position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, 1- acetylpiperidin-4-yl, l-(2-hydroxyethyl)piperidin-4-yl, l-(3-hydroxypropyl)piperidin-4-yl, 1 - [2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - [3 -(tetrahydropyran-4- yl)propyl]piperidin-4-yl, 1 -(tetrahydrofuran-3-ylmethyl)piperidin-4-yl, 1 -[2- (tetrahydrofuran-3 -yl)ethyl]piperidin-4-yl, 1 - [3 -(tetrahydrofuran-3 -yl)propyl]piperidin-4- yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, piperidin-4-ylmethyl, 2-piperidin-4- ylethyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-3-yl, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl and l-(4-aminocyclohex-l-yl), and when Ring A is pyridin-3- yl, R1 is located at the 5- or 6- position and is selected from 2-(amino)ethoxy, 3- (amino)propoxy, 2-(methylamino)ethoxy, 3-(methylamino)propoxy, 2- (dimethylamino)ethoxy, 3-(dimethylamino)propoxy, piperidin-1-yl, piperazin-1-yl, 4- methylpiperidin-1-yl, 4-ethylpiperidin-l-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, l-methylpiperidin-4-ylcarbamoyl, l-ethylpiperidin-4-ylcarbamoyl, 3-(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3 -(4-ethylpiperazin- 1 -yl)propylcarbamoyl, 4-methylpiperazin- 1 - ylcarbonyl, piperazin-1-ylcarbonyl, 4-ethylpiperazin- 1-ylcarbonyl and 4-propylpiperazin- 1-ylcarbonyl and when Ring A is pyridin-4-yl, R1 is located at the 3- position and is selected from piperazin-1-yl, 2-(amino)ethoxy, 3-(amino)propoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, 2-(dimethylamino)ethoxy, 3-
(dimethylamino)propoxy, piperidin-1-yl, piperazin-1-yl, 4-methylpiperidin-l-yl, 4- ethylpiperidin-1-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, l-methylpiperidin-4- ylcarbamoyl, 1 -ethylpiperidin-4-ylcarbamoyl, 3-(4-methylpiperazin- 1 -yl)propylcarbamoyl, 3-(4-ethylpiperazin- 1 -yl)propylcarbamoyl, piperazin- 1 -ylcarbonyl, 4-methylpiperazin- 1 - ylcarbonyl, 4-ethylpiperazin-l -ylcarbonyl and 4-propylpiperazin-l -ylcarbonyl; m is 0 or 1 , and when m is 1 , the R2 group is selected from methyl and ethyl; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2- (tetrahydrofuran-2-yl)ethyl or (3-methyloxetan-3-yl)methyl; n is 0, or, when each of Gi and G2 is CH, n may be 1 or 2 and the (R4)n groups are selected from 5-fluoro, 5,6-difluoro, 4-methoxy, 4-ethoxy, 4-phenylmethoxy, 4-tetrahydrofuran-3- ylmethoxy, 5-trifluoromethyl, 4-methyl, 5-methyl, 4,5-dimethyl, 4-ethyl, 5-ethyl, 4,5- diethyl, 5-chloro, 5-bromo, 4-[(l-methylpyrrolidin-3-yl)oxy], 4-cyclopentyloxy, 4- isobutoxy, 4-[(tetrahydrofuran-2-yl)methoxy], 4-[2-(tetrahydrofuran-2-yl)ethoxy], 4- isopropoxy, 4-ethoxy, 4-(isoxazol-3-ylmethoxy), 4-cyclopentylmethoxy, 4- cyclopropylmethoxy and 4-(2-phenylethoxy); or a pharmaceutically-acceptable salt thereof.
10. A pyrazine derivative of the Formula I according to claim 1, wherein: Gi and G2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl; When Ring A is pyrazol-4-yl, R1 is located at the 1 -position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - (tetrahydrofuran-3 -ylmethyl)piperidin-4-yl, 2-(morpholin-4-yl)ethyl, piperidin-4-ylmethyl, piperidin-3-ylmethyl, piperidin-3-yl, tetrahydropyran-4-yl or 4-aminocyclohex-l-yl, and when Ring A is pyridin-3-yl, R1 is located at the stated 5- or 6- position and is selected from a 6-[3-(dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4- methylpiperazin- 1 -yl), 5 -( 1 -methylpiperidin-4-ylcarbamoyl), 5 - [3 -(4-methylpiperazin- 1 - yl)propylcarbamoyl] or 5 -(4-methylpiperazin- 1 -ylcarbonyl) group, and when Ring A is pyridin-4-yl, R1 is located at the 2-position and is piperazin- 1-yl; m is 0 or 1 , and when m is 1 , the R2 group is methyl; R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, or, when each of Gi and G2 is CH, n may be 1 or 2 and the (R4)n groups are selected from 5-fluoro, 5,6-difluoro, 4-methoxy, 4-phenylmethoxy, 4-tetrahydrofuran-3-ylmethoxy, 5-trifluoromethyl, 4-methyl, 5-methyl, 4,5-dimethyl, 5-chloro, 5-bromo, 4-[(l- methylpyrrolidin-3-yl)oxy], 4-cyclopentyloxy, 4-isobutoxy, 4-[(tetrahydrofuran-2- yl)methoxy], 4-isopropoxy, 4-ethoxy, 4-(isoxazol-3-ylmethoxy), 4-cyclopentylmethoxy, 4- cyclopropylmethoxy and 4-(2-phenylethoxy); or a pharmaceutically-acceptable salt thereof.
11. A pyrazine derivative of the Formula I according to claim 1 , wherein: Gi and G2 is selected from CH and N provided that both are not N;
Ring A is pyrazol-4-yl or pyridin-3-yl; When Ring A is pyrazol-4-yl, R1 is located at the 1 -position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - (tetrahydrofuran-3-ylmethyl)piperidin-4-yl and tetrahydropyran-4-yl, and when Ring A is pyridin-3-yl, R1 is located at the 6- position and is 3-(dimethylamino)propoxy; m is 0;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0, or, when each of Gi and G2 is CH, n may be 1 and the (R4)n group is selected from
5-fluoro, 4-tetrahydrofuran-3-ylmethoxy, 4-[(tetrahydrofuran-2-yl)methoxy] and 4- cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
12. A pyrazine derivative of the Formula I according to claim 1, wherein: Gi and G2 is selected from CH and N provided that both are not N;
Ring A is pyrazol-4-yl or pyridin-3-yl; When Ring A is pyrazol-4-yl, R1 is located at the 1 -position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - (tetrahydrofuran-3-ylmethyl)piperidin-4-yl and tetrahydropyran-4-yl, and when Ring A is pyridin-3-yl, R1 is located at the 6- position and is 3-(dimethylamino)propoxy; m is 1 , and R2 is methyl;
R3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0, or, when each of Gi and G2 is CH, n may be 1 and the (R4)n group is selected from 5-fiuoro, 4-tetrahydrofuran-3-ylmethoxy, 4-[(tetrahydrofuran-2-yl)methoxy] and A- cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
13. A pyrazine derivative of the Formula I according to claim 1 selected from any one of the following :-
3-(lH-benzimidazol-2-yl)-5-[l-[l-(2-tetrahydropyran-4-ylethyl)piperidin-4-yl]pyrazol-4- yl]pyrazin-2-amine;
3-(lH-benzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine; 3-(l-ethylbenzimidazol-2-yl)-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine;
3-[l-(cyclopropylmethyl)benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine;
3-(5-fluoro-lH-benzimidazol-2-yl)-5-[l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2- amine; l-[4-[4-[5-amino-6-(l//-benzimidazol-2-yl)pyrazin-2-yl]pyrazol-l-yl]-l- piperidyl]ethanone;
3 -(I -ethylbenzimidazol-2-yl)-5-[ 1 -(I -methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine;
3 -(I -ethylbenzimidazol-2-yl)-5- [3 -methyl- 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine;
3-[l-(2-methoxyethyl)benzimidazol-2-yl]-5-[l-(l-methylpiperidin-4-yl)pyrazol-4- yl]pyrazin-2-amine;
3-(l-ethylbenzimidazol-2-yl)-5-[3-methyl-l-(l-methylpiperidin-4-yl)pyrazol-4-yl]pyrazin-
2-amine; and
3-(lH-benzimidazol-2-yl)-5-[3-methyl-l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine; or a pharmaceutically-acceptable salt thereof.
14. A pharmaceutical composition, which comprises a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to any one of claims 1 to 13 in association with a pharmaceutically-acceptable diluent or carrier.
15. A pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to any one of claims 1 to 13 for use in therapy.
16. Use of a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to any one of claims 1 to 13 in the manufacture of a medicament for use in the treatment or prevention of tumours which are sensitive to inhibition of AxI and/or c- Met receptor enzymes.
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