WO2007113565A1 - Dérivés de la naphtyridine comme agents anti-cancéreux - Google Patents

Dérivés de la naphtyridine comme agents anti-cancéreux Download PDF

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Publication number
WO2007113565A1
WO2007113565A1 PCT/GB2007/001244 GB2007001244W WO2007113565A1 WO 2007113565 A1 WO2007113565 A1 WO 2007113565A1 GB 2007001244 W GB2007001244 W GB 2007001244W WO 2007113565 A1 WO2007113565 A1 WO 2007113565A1
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alkyl
group
amino
hydrogen
hydroxy
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PCT/GB2007/001244
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English (en)
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Frederic Henri Jung
Georges Rene Pasquet
Patrick Ple
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2007113565A1 publication Critical patent/WO2007113565A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention concerns certain novel naphthyridine 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 naphthyridine 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.
  • Eukaryotic cells are continually responding to many diverse extracellular signals that enable communication between cells within an organism. These signals regulate a wide variety of physical responses in the cell including proliferation, differentiation, apoptosis and motility.
  • the extracellular signals take the form of a diverse variety of soluble factors including growth factors as well as paracrine, autocrine and endocrine factors.
  • growth factor ligands By binding to specific transmembrane receptors, growth factor ligands communicate extracellular signals to the intracellular signalling pathways, thereby causing the individual cell to respond to extracellular signals. Many of these signal transduction processes utilise the reversible process of the phosphorylation of proteins involving specific kinases and phosphatases.
  • phosphorylation is such an important regulatory mechanism in the signal transduction process, it is not surprising that aberrations in the process result in abnormal cell differentiation, transformation and growth.
  • a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene.
  • oncogenes encode proteins which are receptors for growth factors, for example tyrosine kinase enzymes.
  • Tyrosine kinases may also be mutated to constitutively active forms that result in the transformation of a variety of human cells.
  • the over-expression of normal tyrosine kinase enzymes may also result in abnormal cell proliferation.
  • Tyrosine kinase enzymes may be divided into two groups :- the receptor tyrosine kinases and the non-receptor tyrosine kinases.
  • About 90 tyrosine kinase have been identified in the human genome, of which about 60 are of the receptor type and about 30 are of the non-receptor type. These can be categorised into 20 receptor tyrosine kinase sub-families according to the families of growth factors that they bind and into 10 non-receptor tyrosine kinase sub-families (Robinson et al, Oncogene, 2000, 19, 5548-5557).
  • the classification includes the EGF family of receptor tyrosine kinases such as the EGF, TGF ⁇ , Neu and erbB receptors, the insulin family of receptor tyrosine kinases such as the insulin and IGFl receptors and insulin-related receptor (IRR) and the Class III family of receptor tyrosine kinases such as the platelet-derived growth factor (PDGF) receptor tyrosine kinases, for example the PDGF ⁇ and PDGF ⁇ receptors, the stem cell factor receptor tyrosine kinase (SCF RTK, commonly known as c-Kit), the fms-related tyrosine kinase 3 (Flt3) receptor tyrosine kinase and the colony-stimulating factor 1 receptor (CSF-IR) tyrosine kinase.
  • EGF EGF
  • TGF ⁇ TGF ⁇
  • Neu and erbB receptors the insulin family of receptor tyrosine
  • tyrosine kinases are present in a large proportion of common human cancers such as the leukaemias, breast cancer, prostate cancer, non-small cell lung cancer (NSCLC) including adenocarcinomas and squamous cell cancer of the lung, gastrointestinal cancer including colon, rectal and stomach cancer, bladder cancer, oesophageal cancer, ovarian cancer and pancreatic cancer.
  • NSCLC non-small cell lung cancer
  • gastrointestinal cancer including colon, rectal and stomach cancer
  • bladder cancer oesophageal cancer
  • pancreatic cancer pancreatic cancer
  • EGFR tyrosine kinase is mutated and/or over-expressed in several human cancers including in tumours of the lung, head and neck, gastrointestinal tract, breast, oesophagus, ovary, uterus, bladder and thyroid.
  • Platelet-derived growth factor is a major mitogen for connective tissue cells and other cell types.
  • the PDGF receptors comprising PDGF ⁇ and PDGF ⁇ receptor isozymes display enhanced activity in 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).
  • Such enhanced PDGF receptor kinase activity is also observed in other cell proliferative disorders such as fibrotic diseases (for example kidney fibrosis, hepatic cirrhosis, lung fibrosis and multicystic renal dysplasia), glomerulonephritis, 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 and diabetic nephropathy.
  • fibrotic diseases for example kidney fibrosis, hepatic cirrhosis, lung fibrosis and multicystic renal dysplasia
  • glomerulonephritis for example rheumatoid arthritis and inflammatory bowel disease
  • inflammatory diseases for example rheumatoid arthritis and inflammatory bowel disease
  • multiple sclerosis psoriasis
  • hypersensitivity reactions of the skin allergic asthma, insulin-dependent diabetes
  • the PDGF receptors can also contribute to cell transformation in cancers and leukaemias by autocrine stimulation of cell growth. It has been shown that PDGF receptor kinases are mutated and/or over-expressed in several human cancers including in tumours of the lung (non-small cell lung cancer and small cell lung cancer), gastrointestine (such as colon, rectal and stomach tumours), prostate, breast, kidney, liver, brain (such as glioblastoma), oesophagus, ovary, pancreas and skin (such as dermatofibrosarcoma protruberans) and in leukaemias and lymphomas such as chronic myelogenous leukaemia (CML), chronic myelomonocytic leukaemia (CMML), acute lymphocyte leukaemia (ALL) and multiple myeloma.
  • CML chronic myelogenous leukaemia
  • CMML chronic myelomonocytic leukaemia
  • ALL acute lymphocyte leuk
  • Enhanced cell signalling by way of the PDGF receptor tyrosine kinases can contribute to a variety of cellular effects including cell proliferation, cellular mobility and invasiveness, cell permeability and cellular apoptosis. Accordingly, antagonism of the activity of PDGF receptor kinases is expected to be beneficial in the treatment of a number of cell proliferative disorders such as cancer, especially in inhibiting tumour growth and metastasis and in inhibiting the progression of leukaemia.
  • angiogenesis the process of forming new blood vessels, that is critical for continuing tumour growth.
  • angiogenesis plays an important role in processes such as embryonic development, wound healing and several components of female reproductive function.
  • undesirable or pathological angiogenesis has been associated with a number of disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma.
  • Angiogenesis is stimulated via the promotion of the growth of endothelial cells.
  • VEGF vascular endothelial growth factor
  • This cytokine induces a vascular sprouting phenotype by inducing endothelial cell proliferation, protease expression and migration which subsequently leads to the formation of capillary tubes that promote the formation of the hyperpermeable, immature vascular network - A -
  • the receptor tyrosine kinase (RTK) subfamily that binds VEGF comprises the kinase insert domain-containing receptor KDR (also referred to as FIk-I) 5 the./ms-like tyrosine kinase receptor FIt-I and therms-like tyrosine kinase receptor Flt-4.
  • RTKs Two of these related RTKs, namely FIt-I and KDR, have been shown to bind VEGF with high affinity.
  • antagonism of the activity of VEGF is 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.
  • PDGF receptor kinase inhibitory activity It is known that several compounds with PDGF receptor kinase inhibitory activity are progressing toward clinical development.
  • the 2-anilinopyrimidine derivative known as imatinib (STI571: Nature Reviews, 2002, I, 493-502; Cancer Research, 1996, 56, 100-104) has been shown to inhibit PDGF receptor kinase activity although its current clinical use is for the treatment of CML based on its additional activity as an inhibitor of BCR-ABL kinase.
  • STI571 inhibits the growth of glioblastoma tumours arising from injection into the brains of nude mice of the human glioblastoma lines U343 and U87 (Cancer Research, 2000, 60, 5143-5150). The compound also inhibits the in vivo growth of dermatofibrosarcoma protruberans cell cultures (Cancer Research, 2001, 61_, 5778-5783). Based on the PDGF receptor kinase inhibitory activity of the compound, clinical trials are being carried out in glioblastoma and in prostate cancer. Several other PDGF receptor kinase inhibitors are being investigated including quinoline, quinazoline and quinoxaline derivatives (Cytokine & Growth Factor Reviews, 2004, 15, 229-235).
  • 2-phenylacetamide compounds 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 PDGF receptor tyrosine kinases.
  • a further characteristic of hyperproliferative diseases such as cancer is damage to the cellular pathways that control progress through the cell cycle which, in normal eukaryotic cells, involves an ordered cascade of protein phosphorylation.
  • signal transduction mechanisms several families of protein kinases appear to play critical roles in the cell cycle cascade. The most widely studied of these cell cycle regulators is the cyclin dependent kinase family (the CDKs).
  • CDK4 protein appears to control entry into the cell cycle (the GO-Gl-S transition) by phosphorylating the retinoblastoma gene product pRb which stimulates the release of the transcription factor E2F from pRb which, in turn, acts to increase the transcription of genes necessary for entry into S phase.
  • the catalytic activity of CDK4 is stimulated by binding to a partner protein, Cyclin D.
  • Cyclin D a partner protein
  • protein kinases that are structurally distinct from the CDK family have been identified which play critical roles in regulating the cell cycle and which also appear to be important in oncogenesis. They include the human homologues of the Drosophila aurora and S.cerevisiae IpU proteins. The three human homologues of these genes Aurora-A, Aurora-B and Aurora-C encode cell cycle regulated serine-threonine protein kinases that show a peak of expression and kinase activity through G2 and mitosis. Several observations implicate the involvement of human aurora proteins in cancer, especially Aurora-A and Aurora-B.
  • novel 1 ,6-naphthyridin-4-yloxy-substituted 2-phenylacetamide compounds 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 PDGF receptor tyrosine kinases.
  • the compounds of the present invention provide a useful treatment of cell proliferative disorders by way of a contribution from inhibition of the PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinases.
  • Many of the compounds of the present invention possess potent inhibitory activity against the PDGF receptor family of tyrosine kinases, for example the PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinases, whilst possessing less potent inhibitory activity against other tyrosine kinase enzymes, for example against one or more other Class III family receptor tyrosine kinases such as Flt3 receptor tyrosine kinase and the CSF-IR tyrosine kinase, against the EGF receptor tyrosine kinase, or against VEGF receptor tyrosine kinases such as KDR and FIt-I .
  • Class III family receptor tyrosine kinases such as Flt3 receptor tyrosine kinase and the CSF-IR tyrosine kinase
  • EGF receptor tyrosine kinase or against VEGF receptor tyrosine kin
  • certain compounds of the present invention possess substantially better potency against the PDGF receptor family of tyrosine kinases, particularly against the PDGF ⁇ receptor tyrosine kinase than against EGF receptor tyrosine kinase or VEGF receptor tyrosine kinases such as KDR.
  • Such compounds possess sufficient potency that they may be used in an amount sufficient to inhibit the PDGF receptor family of tyrosine kinases, particularly PDGF ⁇ receptor tyrosine kinase whilst demonstrating little activity against EGF receptor tyrosine kinase or against VEGF receptor tyrosine kinases such as KDR.
  • X 1 is O or N(R 7 ) where R 7 is hydrogen or (l-SC)alkyl; p is 0, 1, 2 or 3; each R 1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, hydroxy, mercapto, amino, carboxy, (l-6C)alkoxycarbonyl, carbamoyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l- ⁇ C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l- ⁇ C)alkylsul ⁇ hinyl, (l-6C)alkylsul ⁇ honyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, iV ⁇ V-di-
  • X 3 is a direct bond or is selected from O and N(R 10 ), wherein R 10 is hydrogen or (l-8C)alkyl, and R 9 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, mercapto-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylthio-(l-6C)alkyl, (l-6C)alkylsulphinyl-(l-6C)alkyl, (l-6C)alkylsulphonyl-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-
  • X 4 is a direct bond or is selected from O, CO and N(R 11 ), wherein R 11 is hydrogen or (l-8C)alkyl
  • Q 2 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, hydroxy, (l-8C)alkyl and (l-6C)alkoxy, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R 1 optionally bears a (l-3C)alkylenedioxy group, and wherein any heterocyclyl group within a R 1 substituent optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CH, CH 2 or CH 3 group within a R 1 substituent optionally bears
  • G 1 is C(R a ) or N and G 2 is C(R a ) or N wherein each R a group, which may be the same or different, is hydrogen or an R 2 group; q is 0, 1 or 2; each R 2 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, carboxy, hydroxy, amino, carbamoyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, iV-(l-6C)alkylcarbamoyl, iV,N-di-[(l-6C)alkyi]carbamoyL halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl,
  • R 3 is hydrogen, (l-8C)alkyl, (2-8C)alkenyl or (2-8C)alkynyl;
  • R 4 is hydrogen, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, carboxy-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, carbamoyl-(l-6C)alkyl, iV-(l-6C)alkylcarbamoyl-(l-6C)alkyl, N,7V-di-[(l-6C)alkyl]
  • X 5 is a direct bond or is selected from O and N(R 1 ), wherein R 1 is hydrogen or (l-8C)alkyl, and R 13 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl or cyano-(l-6C)alkyl;
  • Ring A is a 6-membered monocyclic or a 10-membered bicyclic aryl ring or a
  • each R 6 group which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, hydroxy, mercapto, amino, carboxy, carbamoyl, sulphamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l- ⁇ C)alkoxy, (l-6C)alkylthio, (l- ⁇ C)alkylsulphinyl, (l- ⁇ C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]ammo, (l- ⁇ C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)al
  • X 6 is a direct bond or is selected from O and N(R 16 ), wherein R 16 is hydrogen or (l-8C)alkyl, and R 15 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, mercapto-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylthio-(l-6C)alkyl, (l-6C)alkylsulphinyl-(l-6C)alkyl, (l-6C)alkylsulphonyl-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl 5
  • (l-6C)alkylamino-(l-6C)alkyl di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino- (l-6C)alkyl, JV-(I -6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl, carboxy-(l -6C)alkyl, (l-6C)alkoxycarbonyl-(l-6C)alkyl, carbamoyl-(l-6C)alkyl, iV-(l-6C)alkylcarbamoyl- (l-6C)alkyl, iV ⁇ -di-[(l-6C)alkyl]carbamoyl-(l-6C)alkyl, sulphamoyl-(l-6C)alkyl, N-(l-6C)alkylsulphamoyl-(l-6C)alkyl,
  • each R 18 is hydrogen, (l-8C)alkyl, (2-8C)alkenyl or (2-8C)alkynyl
  • R 19 is hydrogen, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (2-6C)alkanoyl
  • any aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl group within an R 6 group optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (
  • X 9 is a direct bond or is selected from O, CO and N(R 22 ), wherein R 22 is hydrogen or (l-8C)alkyl
  • Q 4 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, hydroxy, (l-SC)alkyl and (l-6C)alkoxy, and wherein any aryl, heteroaryl or heterocyclyl group within an R 6 group optionally bears a (l-3C)alkylenedioxy group, and wherein any heterocyclyl group within an R 6 group optionally bears 1 or 2 oxo or tbioxo substituents, and wherein any CH, CH 2 or CH 3 group within an R 6 group optionally bears on each said CH, CH
  • (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- ⁇ C)alkoxy includes (3-6C)cycloalkyloxy groups and (3-5C)cycloalkyl-(l-2C)alkoxy groups, 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 (3-5C)cycloalkyl- (l-2C)alkylamino groups, for example methylamino, ethylamino, propylamino, cyclopropylainino, cyclobutylamino, cyclohexylamino, cycloprop
  • 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.
  • tautomerism may affect heteroaryl rings within the definition of Ring A or heterocyclic groups within the R 1 and R 6 groups that bear 1 or 2 oxo or thioxo substituents.
  • 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.
  • Ring A may be a pyrazolyl group.
  • an R 1 substituent may only be located at the 7-position on the naphthyridine ring.
  • any R 6 group may be located at any available position on Ring A.
  • an R 6 group may be located at the 3- or 4-position (relative to the CON(R 5 ) group) when Ring A is a 6-membered ring or, for example, it may be located at the 3-position (relative to the CON(R 5 ) group) when Ring A is a 5-membered ring.
  • Suitable values for the generic radicals referred to above include those set out below.
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 4 ) within the R 1 or R 6 groups when the 'Q' group is aryl or for the aryl group within any 'Q' group is, for example, phenyl or naphthyl, preferably phenyl.
  • a suitable value for any one of the 'Q' groups (Q 1 or Q 3 ) within the R 1 or R 6 groups when the 'Q' group is (3-8C)cycloalkyl or for the (3-8C)cycloalkyl group within any 'Q' group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl or cyclooctyl.
  • a suitable value for the (3-8C)cycloalkyl group formed when R and R together with the carbon atom to which they are attached form a (3-8C)cycloalkyl group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • a suitable value for any one of the 'Q' groups (Q 1 or Q 3 ) within the R 1 or R 6 groups when the 'Q' group is (3-8C)cycloalkenyl or for the (3-8C)cycloalkenyl group within any ⁇ Q' group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl.
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 4 ) within the R 1 or R 6 groups when the 'Q' group is heteroaryl or for the heteroaryl group within any 'Q' 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, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazo
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 4 ) within the R 1 or R 6 groups when the 'Q' group is heterocyclyl or for the heterocyclyl group within any 'Q' group is, for example, a non-aromatic saturated or partially saturated 3 to 10 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl
  • a suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 4-oxo-l,4-dihydropyridinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
  • a suitable value for any 'Q' group when it is heteroaryl-(l-6C)alkyl is, for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl.
  • the invention comprises corresponding suitable values for 'Q' groups when, for example, rather than a heteroaryl-(l-6C)alkyl group, an aryl-(l-6C)alkyl, (3-8C)cycloalkyl-(l-6C)alkyl, (3-8C)cycloalkenyl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group is present.
  • a suitable value for Ring A when it is a 6-membered monocyclic or a 10-membered bicyclic aryl ring or 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, phenyl, naphthyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, in
  • Ring A is a phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring.
  • Ring A is a phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring.
  • Ring A when it is a 5-membered monocyclic 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 or triazolyl.
  • Ring A is an oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl ring.
  • Suitable values for any of the 'R' groups (R 1 to R 23 ), or for various groups within an R 1 , R or R substituent include :- 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- ⁇ C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)al
  • cyano-(l-6C)alkyl cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and
  • amino-(l-6C)alkyl aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl and 5-aminopropyl; for (l-6C)alkylamino-(l-6C)alkyl: methylaminomethyl, ethylaminomethyl,
  • ureido-(l-6C)alkyl ureidomethyl, 2-ureidoethyl and 1-ureidoethyl
  • JV-(I -6C)alkylureido-(l -6C)alkyl N'-methylureidomethyl, 2-(iV'-methylureido)ethyl and l-(iV-methylureido)ethyl
  • a suitable value for a (l-3C)alkylenedioxy group that may be present within a R 1 or R 6 group is, for example, methylenedioxy, ethylidenedioxy, isopropylidenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.
  • an R 1 group forms a group of the formula C ⁇ -X 2 - and, for example, X 2 is a OC(R 8 ) 2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R 8 ) 2 linking group which is attached to the quinoline ring and the oxygen atom is attached to the Q 1 group.
  • an R 6 group forms a group of the formula -X 7 -Q 3 and, for example, X 7 is a C(R 17 ) 2 O linking group, it is the oxygen atom of the C(R 17 ) 2 O linking group which is attached to the Q 3 group.
  • a suitable (2-6C)alkylene chain within a R 1 or R 6 group is, for example, an ethylene, trimethylene, tetramethylene or pentamethylene chain.
  • adjacent carbon atoms in any (2-6C)alkylene chain within a R 1 or R 6 group may be optionally separated by the insertion into the chain of a group such as O, CON(R 12 ) or CON(R 23 ) respectively, and C ⁇ C.
  • insertion of an O atom into the alkylene chain within a 4-methoxybutoxy group gives rise to, for example, a 2-(2-methoxyethoxy)ethoxy group
  • insertion of a C ⁇ C group into the ethylene chain within a 2-hydroxyethoxy group gives rise to a 4-hydroxybut-2-ynyloxy group
  • insertion of a CONH group into the ethylene chain within a 3-methoxypropoxy group gives rise to, for example, a 2-(2-methoxyacetamido)ethoxy group.
  • any CH, CH 2 or CH 3 group within a R 1 or R 6 group optionally bears on each said CH, CH 2 or CH 3 group one or more halogeno or (l-8C)alkyl substituents, there is suitably 1 halogeno or (l-8C)alkyl substituent present on each said CH group, there are suitably 1 or 2 such substituents present on each said CH 2 group and there are suitably 1, 2 or 3 such substituents present on each said CH 3 group.
  • R 1 or R 6 groups so formed include, for example, hydroxy-substituted (l-8C)alkyl groups such as hydroxymethyl, 1 -hydroxy ethyl and 2-hydroxyethyl, hydroxy-substituted (l- ⁇ C)alkoxy groups such as 2-hydroxypropoxy and 3-hydroxypropoxy, (l-6C)alkoxy-substituted (l- ⁇ C)alkoxy groups such as 2-methoxyethoxy and 3-ethoxypropoxy, hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino- 2-hydroxypropoxy, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkoxy groups such as
  • 2-hydroxy-3-methylaminopropoxy hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkoxy groups such as 3-dimethylamino-2-hydroxypropoxy
  • hydroxy-substituted amino-(2-6C)alkylamino groups such as 3-amino-2-hydroxypropylamino
  • hydroxy-substituted (l-6C)alkylamino-(2-6C)alkylamino groups such as 2-hydroxy-3-methylaminopropylamino
  • hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkylamino groups such as 3-dimethylamino-2-hydroxypropylamino.
  • any CH, CH 2 or CH 3 group within a R 1 or R 6 group optionally bears on each said CH, CH 2 or CH 3 group a substituent as defined hereinbefore
  • suitable R 1 or R 6 groups so formed also include, for example, hydroxy-substituted (l-6C)alkylamino-(l-6C)alkyl groups such as 2-hydroxy-3-methylaminopropyl and 2-hydroxyethylaminomethyl and hydroxy-substituted di-[(l -6C)alkyl]amino-(l -6C)alkyl groups such as 3-dimethylamino-2-hydroxypropyl and di-(2-hydroxyethyl)aminomethyl.
  • any CH, CH 2 or CH 3 group within a R 1 or R 6 group optionally bears on each said CH, CH 2 or CH 3 group a substituent as defined hereinbefore, such an optional substituent may be present on a CH, CH 2 or CH 3 group within the hereinbefore defined substituents that may be present on an aryl, heteroaryl or heterocyclyl group within a R 1 or R 6 group.
  • the R 1 or R 6 group includes an aryl or heteroaryl group that is substituted by a (l-8C)alkyl group
  • the (l-8C)alkyl group may be optionally substituted on a CH, CH 2 or CH 3 group therein by one of the hereinbefore defined substituents therefor.
  • the R 1 or R 6 group includes a heteroaryl group that is substituted by, for example, a (l-6C)alkylamino-(l-6C)alkyl group
  • the terminal CH 3 group of the (l-6C)alkylamino group may be further substituted by, for example, a (l-6C)alkylsulphonyl group or a (2-6C)alkanoyl group.
  • the R 1 or R 6 group includes a heterocyclyl group such as a piperidinyl or piperazinyl group that is substituted on a nitrogen atom thereof by, for example, a (2-6C)alkanoyl group
  • the terminal CH 3 group of the (2-6C)alkanoyl group may be further substituted by, for example, a di-[(l-6C)alkyl]amino group.
  • the R 1 or R 6 group may include a ⁇ V-(2-dimethylaminoacetyl)piperidin-4-yl group or a 4-(2-dimethylaminoacetyl)piperazin-l-yl group.
  • the R 1 or R 6 group includes a heterocyclyl group such as a azetidinyl, piperidinyl or piperazinyl group that is substituted on a nitrogen atom thereof by, for example, a (2-6C)alkanoyl group
  • a CH 2 group of the (2-6C)alkanoyl group may be further substituted by, for example, a hydroxy group.
  • the R 1 or R 6 group may include a jV-(2-hydiOxypropionyl)piperidm-4-yl group.
  • two R 6 groups together may form a bivalent group, for example OC(R 18 ) 2 O, that spans adjacent ring positions on Ring A.
  • Ring A is, for example, a phenyl group
  • a suitable group so formed is a 2,3-methylenedioxyphenyl or a
  • a suitable group so formed is, for example, a 6-fluoro- 2,3-methylenedioxyphenyl group.
  • Ring A is, for example, a phenyl group and two R 6 groups together form, for example, a OC(R 18 ) 2 C(R 18 ) 2 group
  • a suitable group so formed is, for example, a 2,3-dihydrobenzofuran-5-yl group or a 2,3-dihydrobenzofuran-6-yl group.
  • Ring A is, for example, a phenyl group and two R 6 groups together form, for example, a N(R 19 )C(R 18 ) 2 C(R 18 ) 2 group
  • a suitable group so formed is, for example, an indolin-5-yl group or a indolin-6-yl group.
  • Ring A is, for example, a phenyl group and two R 6 groups together form, for example, a N(R 18 )CO.C(R 18 ) 2 group
  • a suitable group so formed is, for example, a 2-oxoindolin-5-yl group or a 2-oxoindolin-6-yl group.
  • a suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic or citric acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyi)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.
  • 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.
  • the present invention includes those compounds of the Formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in 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.
  • 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-bntyl, (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 (l-lOC)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N 5 N- [di-(l-4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • (l-lOC)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups
  • (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N 5 N- [di-(l-4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, iV-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)alkylpiperazin-l-ylmethyl.
  • 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, N-ethyl-N-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
  • 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, NjN-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)alkylpiperazin-l-ylmethyl.
  • Formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • Particular novel compounds of the invention include, for example, naphthyridine derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of X 1 , p, R 1 , G 1 , G 2 , q, R 2 , R 3 , R 4 , R 5 , Ring A, r and R 6 has any of the meanings defined hereinbefore or in paragraphs (a) to (nnn) hereinafter :-
  • each R 1 group that is present is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carboxy, (l-6C)alkoxycarbonyl, carbamoyl, (l ⁇ 8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, ⁇ r -(l-6C)alkylcarbamoyl and iV,iV-di-[(l-6C)alkyl]carbamoyl, or from a group of the formula :
  • X 2 is selected from O, N(R 8 ), CO, CON(R 8 ), N(R 8 )CO and OC(R 8 ) 2 wherein R 8 is hydrogen or (l-SC)alkyl
  • Q 1 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l -6C)alkyl, heterocyclyl or heterocyclyl-(l -6C)alkyl, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within a substituent on R 1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)
  • X 4 is a direct bond or is selected from O, CO and N(R 11 ), wherein R 11 is hydrogen or (l-8C)alkyl, and Q 2 is heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-8C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears a (l-3C)alkylenedioxy group, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo substituents, and wherein any CH, CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH, CH 2 or CH 3 group one or more halogeno or (l-SC)alkyl groups and/or a substituent selected from hydroxy, amino, cyano, carboxy,
  • X 2 is selected from O, N(R 8 ), CO, CON(R 8 ), N(R 8 )CO and OC(R 8 ) 2 wherein R 8 is hydrogen or (l-8C)alkyl
  • Q 1 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within a substituent on R 1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-SC)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy
  • X 3 is a direct bond or is selected from O and N(R 10 ), wherein R ° is hydrogen or
  • R 9 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylsul ⁇ honyl-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino- (l- ⁇ C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or iV-(l-6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl, or from a group of the formula : -X 4 -Q 2 wherein X 4 is a direct bond or is selected from O, CO and N(R 11 ), wherein R 11 is
  • any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo substituents
  • any CH, CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH, CH 2 or CH 3 group one or more halogeno or (1 -8C)alkyl groups and/or a substituent selected from hydroxy, amino, cyano, carboxy, carbamoyl, ureido, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l- ⁇ C)alkylsulphonyl, (l-6C)alkylamino, di- [( 1 -6C)alkyl] amino, ( 1 -6C)alkoxy carbonyl, N-(I -6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamo
  • I 0 (g) p is 1 and the R 1 group is located at the 7-position and is selected from cyano, hydroxy, amino, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, pyrrolidin-1-ylcarbonyl, morpholinocarbonyl, piperidinocarbonyl, piperazin-1-ylcarbonyl, is 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin-l-ylpropoxy, 4-pyrrolidin-l-ylbutoxy, pyrrolidin-3-yloxy
  • any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl, methoxy, methylenedioxy, ethylidendioxy and isopropylidenedioxy, and a pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin- 1-yl group within a R 1 substituent is optionally JV-substituted
  • (h) p is 1 and the R 1 group is located at the 7-position and is selected from cyano, hydroxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methoxy, ethoxy, propoxy, iV-methylcarbamoyl, JV-ethylcarbamoyl, N,iV-dimethylcarbamoyl and JV,7V-diethylcarbamoyl, and wherein any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said
  • CH 2 or CH 3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, iV-ethyl-N-methylamino and N-isopropyl-JV-methylamino;
  • p is 1 and the R 1 group is located at the 7-position and is selected from methoxy, ethoxy, propoxy, 2 -pyrrolidm- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy , 4-pyrrolidin- 1 -y lbutoxy , pyrrolidin-3 -yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l , 1 -di
  • CH 2 or CH 3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino,
  • (j) p is 1 and the R 1 group is located at the 7-position and is selected from methoxy, ethoxy and propoxy, and wherein any CH 2 or CH 3 group within a R 1 substituent that is not attached to O optionally bears on each said CH 2 or CH 3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino and N-isopropyl-iV-methylamino;
  • each of G 1 and G 2 is C(R a ) wherein each R a group, which may be the same or different, is hydrogen or an R 2 group;
  • G 1 is C(R a ) wherein the R a group is hydrogen or an R 2 group and G 2 is N;
  • each R 2 group which may be the same or different, is selected from halogeno, trifluoroniethyl, cyano, carbamoyl, hydroxy, amino, (l-SC)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino,
  • each R 2 group which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,
  • each R group which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, methyl, methoxy, methylamino and dimethylamino;
  • (r) q is 1 and the R 2 group which is located at the 2-position (relative to the C(R 3 )(R 4 ) group) is a (l-6C)alkoxy group; (s) q is 1 and the R 2 group which is located at the 3-position (relative to the C(R 3 )(R 4 ) group) is a (l-6C)alkoxy group; (t) q is 1 and the R 2 group which is located at the 2-position (relative to the C(R 3 )(R 4 ) group) is selected from fluoro, chloro, trifluoromethyl, cyano, carbamoyl, hydroxy, amino, methyl, methoxy, methylamino, dimethylamino, JV-methylcarbamoyl and iVJV-dimethylcarbamoyl; (u) q is 1 and the R 2 group which is located at the 2-position (relative to the C(R 3 )(R 4 ) group
  • (v) q is 1 and the R 2 group which is located at the 2-position (relative to the C(R 3 )(R 4 ) group) is selected from fluoro, chloro, cyano, methyl and methoxy; (w) q is 1 and the R 2 group which is located at the 3-position (relative to the C(R 3 )(R 4 ) group) is selected from fluoro, chloro, cyano, methyl and methoxy;
  • (x) q is 1 and the R 2 group which is located at the 2-position (relative to the C(R 3 )(R 4 ) group) is a methoxy group;
  • R 3 is hydrogen, methyl or ethyl; (z) R 3 is hydrogen;
  • R 4 is hydrogen, methyl, ethyl, propyl, 2-fluoroethyl, 2,2-difluoroethyl,
  • R 4 is hydrogen, methyl or ethyl
  • R 4 is hydrogen; (dd) R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group;
  • R 5 is hydrogen, methyl, ethyl, propyl, allyl, 2-propynyl, 2-fluoroethyl,
  • R 5 is methyl or ethyl
  • R 5 is hydrogen;
  • Ring A is a 6-niembered monocyclic aryl ring or a 5- or 6-membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
  • Ring A is a phenyl ring
  • Ring A is a 6-membered monocyclic heteroaryl ring with up to three nitrogen heteroatoms
  • 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 phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring;
  • Ring A is a phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring;
  • Ring A is a furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl ring;
  • Ring A when Ring A is a 6-membered ring, and one or two R groups are present, one R group is located at the 3- or 4-position (relative to the CON(R 5 ) group);
  • Ring A is a 5-membered ring, and one or two R 6 groups are present, one R 6 group is located at the 3-position (relative to the CON(R 5 ) group);
  • Ring A is a phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring that bears one or two R 6 groups and one R 6 group is located at the 3- or 4-position (relative to the CON(R 5 ) group);
  • Ring A is a furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl ring that bears one or two R 6 groups and one
  • R 6 group is located at the 3-position (relative to the CON(R 5 ) group);
  • (ss) Ring A is a 9- or 10-membered bicyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
  • (tt) Ring A is a benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzotriazolyl, li/-pyrrolo[3,2- ⁇ ]pyridinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl ring;
  • each R 6 group that is present is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl,
  • each R 6 group which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, methyl, ethyl, propyl, isopropyl, butyl, .seobutyl, isobutyl, tert-butyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino and diethylamino; (ww) r is 1 and the R 6 group is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl, prop
  • X 6 is a direct bond or is selected from O and N(R 16 ), wherein R 16 is hydrogen or (l-8C)alkyl, and R 15 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, merca ⁇ to-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylthio-(l-6C)alkyl, (l-6C)alkylsulphinyl-(l-6C)alkyl, (l-6C)alkylsulphonyl-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino
  • X 8 is a direct bond or is selected from O and N(R 21 ), wherein R 21 is hydrogen or (l-8C)alkyl, and R 20 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl s (l-6C)alkylamino-(l-6C)alkyl or di-[(l-6C)alkyl]amino-(l-6C)alkyl, and wherein any heterocyclyl group within an R 6 group optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CH, CH 2 or CH 3 group within an R 6 group optionally bears on each said
  • CH, CH 2 or CH 3 group one or more halogeno or (l-8C)alkyl substituents and/or a substituent selected from hydroxy, amino, cyano, carboxy, carbamoyl, ureido, (l-6C)alkoxy,
  • (zz) r is 1, 2 or 3 and one R 6 group is a group of the formula :
  • X 6 is a direct bond or is selected from O and N(R 16 ), wherein R 16 is hydrogen or (l-8C)alkyl, and R 15 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylthio-
  • X 8 is a direct bond and R 20 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl or di-[(l-6C)alkyl]amino-(l-6C)alkyl, and wherein any CH, CH 2 or CH 3 group within the R 6 group optionally bears on each said CH, CH 2 or CH 3 group 1, 2 or 3 halogeno or (l-8C)alkyl substituents and/or a substituent selected from hydroxy, amino, cyano, (3-8C)alkenyl, (3-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsul ⁇ honyl, (l- ⁇ C)
  • X is a direct bond or is selected from O and N(R 16 ), wherein R 16 is hydrogen or (l-8C)alkyl, and R 15 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, provided that, when X 6 is O or N(R 16 ), there are at least two carbon atoms between X 6 and any heteroatom in the R 15 group
  • (bbb) r is 1 or 2 and one R 6 group is a group of the formula :
  • X 6 is a direct bond or is selected from O, NH and N(Me)
  • R 15 is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1 -hydroxy- 1-methylethyl, 3-hydroxypropyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-methoxy- 1-methylethyl, 3-methoxypropyl, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1-cyano- 1-methylethyl, 3-cyanopropyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, 1 -amino- 1-methylethyl, 3-aminopropyl, methylaminomethyl, 1 -methylaminoethyl, 2-methylaminoethyl, 1 -methylamino- 1 -methyl ethyl, 3-methylaminopro ⁇ yl, methylaminomethyl, 1
  • X 6 is a direct bond or O and R 15 is hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 1 -methoxy ethyl, 2-methoxy ethyl, 1-methoxy- 1-methylethyl, 3-methoxypropyl, cyanomethyl, 1 -cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, 3-amino ⁇ ro ⁇ yl, methylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl, 3-methylaminopropyl, ethylaminomethyl, 1-ethylaminoethyl, 2-ethylaminoethyl, 1-ethylamino- 1-methylethyl, 3-ethylamino ⁇ ropyl, is
  • (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the R 6 group optionally bears a further substituent selected from hydroxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl, and any second R 6 group that is present is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, methyl, methoxy, methylamino and dimethylamino;
  • (ddd) r is 1 or 2 and the first R 6 group is selected from hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, aminomethyl, 1-aniinoethyl, 2-aminoethyl, methylaminoniethyl, 1-methylaminoethyl, 2-methylarninoethyl, ethylaminomethyl, 1-ethylaminoethyl, 2-ethylaminoethyl, isopropylaminoniethyl, 1-isopropylaminoethyl, 2-isopropylaminoethyl, dimethylaminometliyl, 1-dimethylaminoethyl, 2-dimethylaniinoethyl, phenyl, benzyl,
  • a particular compound of the invention is a naphthyridine derivative of the Formula I wherein :- X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 7-position is selected from methoxy, ethoxy, propoxy, 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin-l -ylpropoxy, 4-pyrrolidin-l-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy , 3 -( 1 , 1 -dioxotetrahydro-4H ⁇ - 1 ,4-thiazin- 4-y
  • R 5 is hydrogen, methyl or ethyl
  • Ring A is a phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring; and r is 0 or r is 1 or 2 and one R 6 group is located at the 3- or 4-position (relative to the CON(R 5 ) group), and each R 6 group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, methyl, methoxy, methylamino and dimethylamino, or r is 1 or 2 and one R 6 group is located at the 3- or 4-position (relative to the CON(R 5 ) group) and is a group of the formula : -X 6 -R 15 wherein X 6 is a direct bond or O and R 15 is hydroxymethyl, 1 -hydroxy ethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 1-methoxyethyl, 2-methoxye
  • a further particular compound of the invention is a naphthyridine derivative of the Formula I wherein :- X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from methoxy, ethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(I 5 I -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)eth
  • Ring A is a phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring; and r is 0 or r is 1 or 2 and one R 6 group is located at the 3- or 4-position (relative to the CON(R 5 ) group), and each R 6 group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, methoxy, methylamino and 3Q dimethylamino, or r is 1 or 2 and one R 6 group is located at the 3- or 4-position (relative to the CON(R 5 ) group) and is selected from hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, cyanoniethyl, 1-cyanoethyl, 2-cyanoethyl, aminomethyl, 1-aminoethyl,
  • a further particular compound of the invention is a naphthyridine derivative of the Formula I wherein :- X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from cyano, methoxy, ethoxy, propoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy and 2-(2-methoxyethoxy)ethoxy; each of G 1 and G 2 is C(R a ) wherein each R a group, which may be the same or different, is selected from hydrogen, fluoro, chloro, cyano, methyl and methoxy, or G 1 is C(R a ) wherein the R a group is selected from hydrogen, fluoro, chloro, cyano, methyl and methoxy and G 2 is N; q is O; each of R 3 and R 4 is hydrogen;
  • R 5 is hydrogen, methyl or ethyl
  • Ring A is phenyl; and r is 1 or 2 and the first R 6 group is located at the 3 -position (relative to the CON(R 5 ) group) and is selected from fluoro, chloro, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, cyclopropylamino, N-cyclopropyl-iV-methylamino, hydroxymethyl, aminomethyl, methylaminomethyl, ethylaminomethyl, isopropylaminomethyl, cyclopropylaminomethyl, dimethylaminomethyl, diethylaminomethyl, JV-ethyl- iV-methylaminomethyl, iV-cyclopropyl-N-methylaminomethyl, azetidinylmethyl, pyrrolidinylmethyl, morpholinylmethyl, piperidinylmethyl, homopiperidinylmethyl, piperazinylmethyl and homopiperaziny
  • a further particular compound of the invention is a naphthyridine derivative of the Formula I wherein :-
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from methoxy, ethoxy, 2-hydroxyethoxy and 2-methoxyethoxy; each Of G 1 and G 2 is CH or C(OMe), or G 1 is CH or C(OMe) and G 2 is N; q is O; each of R 3 and R 4 is hydrogen;
  • R 5 is hydrogen, methyl or ethyl
  • Ring A is phenyl; and r is 1 or 2 and the first R group is located at the 3-position (relative to the CON(R 5 ) group) and is selected from fluoro, chloro, methoxy, methylamino, ethylamino, dimethylamino, cyclopropylamino, hydroxymethyl, aminomethyl, methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, cyclopropylaminomethyl, dimethylaminomethyl, diethylaminomethyl, iV-ethyl-N-methylaminomethyl, iV-cyclopropyl- iV-methylaminomethyl, azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl, morpholinomethyl, piperidinomethyl and piperazin-1-ylmethyl, and any second R 6 group that is present is selected from fluoro, chloro, methyl, eth
  • a further particular compound of the invention is a naphthyridine derivative of the Formula I wherein :- X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from cyano, methoxy, ethoxy, propoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy and 2-(2-methoxyethoxy)ethoxy; each of G 1 and G 2 is C(R a ) wherein each R a group, which may be the same or different, is selected from hydrogen, fluoro, chloro, cyano, methyl and methoxy, or G 1 is C(R a ) wherein the R a group is selected from hydrogen, fluoro, chloro, cyano, methyl and methoxy and G 2 is N, or each of G 1 and G 2 is N; q is 0 or q is
  • R 5 is hydrogen, methyl or ethyl
  • Ring A is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; and r is 0, 1 or 2 and each R group that is present is selected from fluoro, chloro, trifluoromethyl, cyano, methyl, ethyl, propyl, isopropyl, tert-buty ⁇ , cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, dimethylamino, JV-cyclopropyl-iV-rnethylamino, acetyl, hydroxymethyl, aminomethyl, methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl,
  • a further particular compound of the invention is a naphthyridine derivative of the Formula I wherein :-
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from methoxy, ethoxy, 2-hydroxyethoxy and 2-methoxyethoxy; each OfG 1 and G 2 is CH or C(OMe), or Gi is CH or C(OMe) and G 2 is N; q is O; each of R 3 and R 4 is hydrogen; R 5 is hydrogen, methyl or ethyl;
  • Ring A is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl or 4-pyridazinyl; and r is 0 or r is 1 or 2 and any first R group that is present is selected from methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, dimethylamino, iV-cyclopropyl-JV-methylamino, pyrrolidin-1-yl, piperidino, morpholino and ⁇ iperazin-1-yl, and any second R group that is present is selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy, and wherein any heterocyclyl group within the R
  • a particular compound of the invention is a naphthyridine derivative of the Formula I wherein :- X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from methoxy, ethoxy, propoxy, 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 4-pyrrolidin-l-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4/i- 1 ,4-thiazin-4-yl)ethoxy , 3 -( 1 , 1 -dioxotetrahydro ⁇ 4H- 1 ,4-thiazin- 4-y
  • R 5 is hydrogen, methyl or ethyl
  • Ring A is a furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl ring; and r is 0 or r is 1 or 2 and one R 6 group is located at the 3 -position (relative to the CON(R ) group), and each R 6 group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-bv ⁇ yl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino and diethylamino, or r is 1 or 2 and one R 6 group is located at the 3-position (
  • X 6 is a direct bond or O and R 15 is hydroxymethyl, 1 -hydroxy ethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-methoxy- 1-methylethyl, 3-methoxypropyl, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl,
  • a further particular compound of the invention is a naphthyridine derivative of the Formula I wherein :- X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 7- ⁇ osition and is selected from methoxy, ethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin- 1 -ylpropoxy, 2-[(3RS,4SR)-3,4-methylenedioxypyrrolidin- 1 -yl]ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypyrrolidin- 1 -yl]propoxy, 2-morpholinoethoxy, 3 -morpholinopropoxy, 2-(l , 1 -dioxotetrahydro-4H- 1 ,4-thi
  • Ring A is an oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl ring; and r is 0 or r is 1 or 2 and one R 6 group is located at the 3-position (relative to the CON(R 5 ) group), and each R 6 group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino and diethylamino, or r is 1 or 2 and one R 6 group is located at the 3-position (rel
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from methoxy, ethoxy, propoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy and 2-(2-methoxyethoxy)ethoxy; each of G 1 and G 2 is C(R a ) wherein each R a group, which may be the same or different, is selected from hydrogen, fluoro, chloro, cyano, methyl and methoxy, or G 1 is C(R a ) wherein the R a group is selected from hydrogen, fluoro, chloro, cyano, methyl and methoxy and G 2 is N; q is 0; each of R 3 and R 4 is hydrogen;
  • R 5 is hydrogen or methyl
  • Ring A is selected from oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl; and r is 0, 1 or 2 and each R 6 group that is present is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, methylaminomethyl, ethylaminomethyl, isopropylaminomethyl, cyclopropylaminomethyl, dimethylaminomethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamin
  • a further particular compound of the invention is a naphthyridine derivative of the Formula I wherein :- X 1 is O; p is O or p is 1 and the R 1 group is located at the 7-position and is selected from cyano, carbamoyl, methoxy, JV-methylcarbamoyl and NyV-dimethylcarbamoyl; each of G 1 and G 2 is CH or C(OMe), or G 1 is CH or C(OMe) and G 2 is ⁇ ; q is O; each of R 3 and R 4 is hydrogen; R 5 is hydrogen or methyl; Ring A is 2-oxazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,
  • each R 6 group that is present is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, methylaminomethyl, ethylaminomethyl, isopropylaminomethyl, cyclopropylaminomethyl, dimethylaminomethyl, amino, methylamino, ethylamino, dimethylamino and diethylamino; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a naphthyridine derivative of the Formula I wherein :- X 1 is O; p is O or p is 1 and the R 1 group is located at the 7-position and is selected from methoxy, ethoxy, 2-hydroxyethoxy and 2-methoxyethoxy; each Of G 1 and G 2 is CH or C(OMe), or G 1 is CH or C(OMe) and G 2 is ⁇ ; q is O; each of R 3 and R 4 is hydrogen;
  • R 5 is hydrogen or methyl
  • Ring A is 2-oxazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isothiazolyl, 5-isothiazolyl, l,2,4-oxadiazol-5-yl or l,3,4-oxadiazol-5-yl; and r is 1 or 2 and each R group that is present is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, methylaminomethyl, ethylaminomethyl, isopropylaminomethyl, cyclopropylaniinomethyl, dimetliylaniinomethyl, amino, methylamino, ethylamino, dimethylamino and diethylamino; or a pharmaceutically
  • a further particular compound of the invention is a naphthyridine derivative of the Formula I wherein :- X 1 is O; p is O or p is 1 and the R 1 group is a 7-methoxy group; each Of G 1 and G 2 is CH or C(OMe), or G 1 is CH or C(OMe) and G 2 is N; q is O; each of R 3 and R 4 is hydrogen;
  • R 5 is hydrogen
  • Ring A is 2-oxazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isothiazolyl, 5-isothiazolyl, l,2,4-oxadiazol-5-yl or l,3,4-oxadiazol-5-yl; and r is 1 or 2 and each R 6 group that is present is selected from methyl, ethyl, propyl, isopropyl and cyclopropyl; or a pharmaceutically-acceptable salt thereof.
  • compounds falling within the following compound definitions of the present invention possess substantially better potency against the PDGF receptor family of tyrosine kinases, particularly against the PDGF ⁇ receptor tyrosine kinase than against VEGF receptor tyrosine kinases such as KDR.
  • a particular novel compound of this aspect of the invention is a naphthyridine derivative of the Formula I wherein the ring that bears the C(R 3 )(R 4 ) group also bears a substituent located at the 2-position relative to that C(R 3 )(R 4 ) group.
  • the presence of such a group may be specified by stating that q is 1 and the R 2 group is located at the 2-position (relative to the C(R 3 )(R 4 ) group).
  • the presence of such a group may be specified by stating that G 1 is a C(R a ) group wherein R a must be a group other than hydrogen.
  • a particular novel compound of this aspect of the invention is a naphthyridine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, wherein :- p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l- ⁇ C)alkoxycarbonyl, (l-8C)alkyl 5 (2-8C)alkenyl, (2-8C)alkynyl, (l- ⁇ C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, iV-(l-6C)alkylcarbamoyl and N,N-di-[(l -6C)alkyl]carbamoyl, and q is 1 and the R 2 group is located at the 2-
  • a further particular novel compound of this aspect of the invention is a naphthyridine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, wherein :- p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy, ethoxy, methylaniino, dimethylamino, iV-methylcarbamoyl and iVJV-dimethylcarbamoyl, and q is 1 and the R 2 group which is located at the 2-position (relative to the C(R 3 )(R 4 ) group) is selected from fluoro, chloro, trifluoromethyl, cyano, carbamoyl, hydroxy, amino, methyl, ethyl, methoxy, ethoxy,
  • a further particular novel compound of this aspect of the invention is a naphthyridine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, wherein :- p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from fluoro, chloro, cyano, carbamoyl, methoxycarbonyl, methoxy, ethoxy, N-methylcarbamoyl and N,iV-dimethylcarbamoyl, and q is 1 and the R 2 group which is located at the 2- ⁇ osition (relative to the C(R 3 )(R 4 ) group) is selected from carbamoyl, methoxy, ethoxy, JV-methylcarbamoyl and iV ⁇ /V-dimethylcarbamoyl; and each of X 1 , G 1 , G 2 , R 3 , R 4 , R 5 , Ring A, r and R 6 has any of the meaning
  • a further particular novel compound of this aspect of the invention is a naphthyridine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, wherein :- p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from fiuoro, cyano, carbamoyl, methoxycarbonyl, methoxy, ethoxy, N-methylcarbamoyl and iV ⁇ V-dimethylcarbamoyl, and q is 1 and the R 2 group which is located at the 2-position (relative to the C(R 3 )(R 4 ) group) is selected from methoxy and ethoxy. and each of X 1 , G 1 , G 2 , R 3 , R 4 , R 5 , Ring A, r and R 6 has any of the meanings defined hereinbefore.
  • a further particular compound of this aspect of the invention is a naphthyridine derivative of the Formula I wherein :-
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from methoxy and ethoxy;
  • G 1 is C(R a ) wherein the R a group is selected from fluoro, chloro, cyano, methyl and methoxy and G 2 is CH, or G 1 is C(R a ) wherein the R a group is selected from fluoro, chloro, cyano, methyl and methoxy and G 2 is N; q is 0; each of R 3 and R 4 is hydrogen; R 5 is hydrogen or methyl;
  • Ring A is selected from oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl; and r is 0, 1 or 2 and each R 6 group that is present is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-bntyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, methylaminomethyl, ethylaminomethyl, isopropylaminomethyl, cyclopropylaminomethyl, dimethylaminomethyl, methoxy, ethoxy, methylamino, ethylamino, dimethyl
  • a further particular compound of this aspect of the invention is a naphthyridine derivative of the Formula I wherein :-
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from cyano, carbamoyl, methoxy, iV-methylcarbamoyl and N,N-dimethylcarbamoyl; G 1 C(OMe) and G 2 is CH, or G 1 is C(OMe) and G 2 is N; q is O; each of R 3 and R is hydrogen; R 5 is hydrogen or methyl;
  • Ring A is 2-oxazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isothiazolyl, 5-isothiazolyl, l,2,4-oxadiazol-5-yl or l,3,4-oxadiazol-5-yl; and r is 1 or 2 and each R group that is present is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, methylaminomethyl, ethylaminomethyl, isopropylaminomethyl, cyclopropylaminomethyl, dimethylaminomethyl, amino, methylamino, ethylamino, dimethylamino and diethylamino; or a pharmaceutically-acceptable salt thereof
  • a further particular compound of this aspect of the invention is a naphthyridine derivative of the Formula I wherein :-
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 7-position and is selected from methoxy and ethoxy;
  • G 1 is C(OMe) and G 2 is CH, or G 1 is C(OMe) and G 2 is N; q is O; each of R 3 and R 4 is hydrogen; R 5 is hydrogen or methyl;
  • Ring A is 2-oxazolyl, 3-isoxazolyl, 2-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl or 3-isothiazolyl; and r is 1 or 2 and each R 6 group that is present is selected from methyl, ethyl, propyl, isopropyl, tert-butyl and cyclopropyl; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of this aspect of the invention is a naphthyridine derivative of the Formula I wherein :- X 1 is O; p is 1 and the R 1 group is a 7-methoxy group; G 1 is C(OMe) and G 2 is CH, or G 1 is C(OMe) and G 2 is N; q is O; each of R 3 and R 4 is hydrogen; R 5 is hydrogen;
  • Ring A is 3-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl or 2-thiazolyl; and r is 1 or 2 and each R 6 group that is present is selected from methyl, ethyl, propyl, isopropyl and cyclopropyl; or a pharmaceutically-acceptable salt thereof.
  • a particular compound of the invention is a naphthyridine derivative of the Formula I selected from :- iV-(5-ethyl-lH-pyrazol-3-yl)-2-[2-methoxy-4-(l,6-naphthyridin-4-yloxy)phenyl]acetamide, iV-(l-ethyl-lH-pyrazol-4-yl)-2-[2-methoxy-4-(l,6-naphthyridin-4-yloxy)phenyl]acetamide, iV-(5-ethylisoxazol-3-yl)-2-[2-methoxy-4-(l,6-naphthyridin-4-yloxy)phenyl]acetamide, iV-(4-methylthiazol-2-yl)-2-[2-methoxy-4-(l,6-naphthyridin-4-yloxy)phenyl]acetamide and
  • a further particular compound of the invention is a naphthyridine derivative of the Formula I selected from :- iV-(5-ethyl-lH-pyrazol-3-yl)-2-[4-(l,6-naphthyridin-4-yloxy)phenyl]acetamide,
  • a napMiyridine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a naphthyridine derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, each of X 1 , p, R 1 , G 1 , G 2 , q, R 2 , R 3 , R 4 , R 5 , Ring A, r and R 6 has any of the meanings defined hereinbefore.
  • Necessary starting materials may be obtained by standard procedures of organic chemistry.
  • X 1 , G 1 , G 2 , q, R 2 , R 3 , R 4 , R 5 , Ring A, r and R 6 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 acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylarnine, morpholine, iV-methylmo ⁇ holine 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, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • 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.
  • 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-dioxane, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as iVyV-dimethylformamide, ⁇ yV-dimethylacetamide, iV-methylpyrrolidm-2-one or dimethylsulphoxide.
  • 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
  • the naphthyridine of the Formula II may be reacted with a compound of the Formula III in the presence of an aprotic solvent such as N ⁇ -dimethylformamide, conveniently in the presence of a base, for example potassium carbonate or sodium hexamethyldisilazane, and at a temperature in the range, for example, 0 to 150°C, preferably in the range, for example, 0 to 7O 0 C.
  • an aprotic solvent such as N ⁇ -dimethylformamide
  • a base for example potassium carbonate or sodium hexamethyldisilazane
  • the naphthyridine derivative of the Formula I may be obtained from this process in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of the formula H-L wherein L has the meaning defined hereinbefore.
  • the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, JV-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • a suitable base for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, JV-methylmorph
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • protecting groups are given below for the sake of convenience, in which "lower”, as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.
  • a carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, and tert-bnty ⁇ ); lower alkoxy- lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl -lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzy
  • hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
  • tri(lower alkyl)silyl for example trimethylsilyl and fert-butyldimethylsilyl
  • aryl-lower alkyl for example benzyl
  • amino protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyl and fer/-butyldimethylsilyl); alkylidene (for example methylidene) and benzylidene and substituted benzylidene groups.
  • aryl-lower alkyl groups for example benzy
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as 2-nitrobenzyloxycarbonyl.
  • groups such as 2-nitrobenzyloxycarbonyl
  • hydrogenation for groups such as benzyl
  • photolytically for groups such as 2-nitrobenzyloxycarbonyl.
  • the reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents and to Protective Groups in Organic Synthesis, 2 nd Edition, by T. Green et ah, also published by John Wiley & Son, for general guidance on protecting groups.
  • Naphthyridine starting materials of the Formula II may be obtained by conventional procedures.
  • a l,4-dihydro-l,6-naphthyridin-4-one of the Formula IV may be obtained by conventional procedures.
  • p and R 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed.
  • a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed.
  • Acetamide starting materials of the Formula III may be obtained by conventional procedures.
  • R 5 , Ring A, r and R 6 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 reactive derivative of an acetic acid of the Formula V is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid with an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid with a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid with a phenol such as pentafluorophenol, with an ester such as pentafluorophenyl trifluoroacetate or with an alcohol such as methanol, ethanol, isopropanol, butanol or JV-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid with an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid with a cyanide such as dieth
  • 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-dioxane, 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-dioxane, an aromatic solvent such as toluene.
  • a suitable inert solvent or diluent for example an alcohol or ester such as m
  • the reaction is conveniently carried out in the presence of a dipolar aprotic solvent such as JV,iV-dimethylformamide, AyV-dimethylacetamide, JV-methylpyrrolidin-2-one or dimethylsulphoxide.
  • a dipolar aprotic solvent such as JV,iV-dimethylformamide, AyV-dimethylacetamide, JV-methylpyrrolidin-2-one or dimethylsulphoxide.
  • the reaction is conveniently carried out at a temperature in the range, for example, 0 to 120 0 C 5 preferably at or near ambient temperature.
  • Acetic acid derivatives of the Formula V and amines of the Formula VI may be obtained by conventional procedures.
  • R 5 , Ring A, r and R 6 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, 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, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • an alkali or alkaline earth metal carbonate or hydroxide for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide
  • an alkali metal amide for example sodium hexamethyldisilazane
  • an alkali metal hydride for example sodium hydride.
  • 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-dioxane, 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-dioxane, an aromatic solvent such as toluene.
  • a suitable inert solvent or diluent for example an alcohol or ester such as m
  • the reaction is conveniently carried out in the presence of a dipolar aprotic solvent such as ⁇ yV-dimethylformamide, ⁇ iV-dimethylacetamide, iV-methylpyriOlidin-2-one or dimethylsulphoxide.
  • a dipolar aprotic solvent such as ⁇ yV-dimethylformamide, ⁇ iV-dimethylacetamide, iV-methylpyriOlidin-2-one or dimethylsulphoxide.
  • the reaction is conveniently carried out at a temperature in the range, for example, 0 to 120°C, preferably at or near ambient temperature.
  • Naphthyridine derivatives of the Formula VII and amines of the Formula VI may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter.
  • Q 1 is an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl 5 (3-7C)cycloalkenyl- (1 -6C)alkyl, heteroaryl-( 1 -6C)alkyl or heterocyclyl-(l -6C)alkyl group or an optionally substituted alkyl group and X 2 is an oxygen atom, the coupling, conveniently in the presence of a suitable dehydrating agent, of a naphthyridine of the Formula VIII
  • each of p, R , 1 , X vl , G 1 , G 2 , q, R , R , R 4 , R , Ring A, r and R 0 has any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an appropriate alcohol wherein any functional group is protected if necessary, whereafter any protecting group that is present is removed.
  • a suitable dehydrating agent is, for example, a carbodiimide reagent such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of an azo compound such as diethyl 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 a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
  • Naphthyridine derivatives of the Formula VIII may be obtained by conventional procedures.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 180 0 C, conveniently in the range 20 to 120 0 C 5 more conveniently at or near ambient temperature.
  • a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 180 0 C, conveniently in the range 20 to 120 0 C 5 more conveniently at or near ambient temperature.
  • a suitable reducing agent for the reductive animation 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.
  • R 6 group is a group of the formula -X 6 -R 15 wherein R 15 is a formyl or (2-6C)alkanoyl group
  • R 15 is a formyl or (2-6C)alkanoyl group
  • a suitable alkylating agent is, for example, a compound wherein a (l-8C)alkyl group is attached to a suitable leaving group, for example a chloro, bromo, iodo, methoxy, phenoxy, pentafluorophenoxy, methoxysulphonyloxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • a suitable leaving group for example a chloro, bromo, iodo, methoxy, phenoxy, pentafluorophenoxy, methoxysulphonyloxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • a pharmaceutically-acceptable salt of a naphthyridine derivative of the Formula I for example an acid-addition salt, it may be obtained by, for example, reaction of said quinoline derivative with a suitable acid.
  • a pharmaceutically-acceptable pro-drug of a naphthyridine derivative of the Formula I for example an acid-addition salt, it may be obtained by, for example, reaction of said quinoline derivative with a suitable acid.
  • Formula I is required, it may be obtained using a conventional procedure.
  • an in vivo cleavable ester of a naphthyridine 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 naphthyridine 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.
  • Many of the intermediates defined herein are novel and these are provided as a further feature of the invention.
  • many compounds of the Formulae III, VI and VII are novel compounds.
  • the following assays can be used to measure the effects of the compounds of the present invention as inhibitors of PDGFR ⁇ , PDGFR ⁇ and KDR tyrosine kinase enzymes, as inhibitors in vitro of the phosphorylation of PDGFR expressed on MG63 osteosarcoma cells, as inhibitors in vitro of the phosphorylation of KDR expressed in human umbilical vein endothelial cells (HUVECs), as inhibitors in vitro of the proliferation of MG63 osteosarcoma cells, as inhibitors in vitro of the proliferation of HUVECs, and as inhibitors in vivo of the growth in nude mice of xenografts of human tumour tissue such as CaLu-6 and Colo205.
  • UUVECs human umbilical vein endothelial cells
  • DNA encoding the PDGFR ⁇ , PDGFR ⁇ or KDR receptor cytoplasmic domains may be obtained by total gene synthesis (International Biotechnology Lab., 1987, 5.(3), 19-25) or by cloning.
  • the DNA fragments may be expressed in a suitable expression system to obtain polypeptide with tyrosine kinase activity.
  • PDGFR ⁇ , PDGFR ⁇ and KDR receptor cytoplasmic domains obtained by expression of recombinant protein in insect cells, can be shown to display intrinsic tyrosine kinase activity.
  • the VEGF receptor KDR Genebank Accession No.
  • a DNA fragment encoding most of the cytoplasmic domain, commencing with methionine 806 and including the termination codon may be cloned into a baculovirus transplacement vector [for example pAcYMl (see The Baculovirus Expression System: A Laboratory Guide, L.A. King and R. D. Possee, Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available from Invitrogen Corporation)].
  • pAcYMl see The Baculovirus Expression System: A Laboratory Guide, L.A. King and R. D. Possee, Chapman and Hall, 1992
  • pAc360 or pBlueBacHis available from Invitrogen Corporation
  • This recombinant construct may be co-transfected into insect cells [for example Spodoptera frugiperda 21(SfZl) or Spodoptera frugiperda 9(Sf9)] with viral DNA (for example Pharmingen BaculoGold) to prepare recombinant baculovirus.
  • insect cells for example Spodoptera frugiperda 21(SfZl) or Spodoptera frugiperda 9(Sf9)
  • viral DNA for example Pharmingen BaculoGold
  • Sf9 cells were infected with plaque-pure KDR recombinant virus and harvested 48 hours later.
  • Harvested cells were washed with ice cold phosphate buffered saline solution (PBS) containing 10 niM sodium phosphate pH7.4 buffer, 138 mM sodium chloride and 2.7 mM potassium chloride) and resuspended in ice cold cell diluent comprising 20 mM Hepes pH7.5 buffer, 150 mM sodium chloride, 10% v/v glycerol, 1% v/v Triton XlOO, 1.5 mM magnesium chloride, 1 mM ethylene glycol-bis( ⁇ aminoethyl ether) ⁇ JV'-tetraacetic acid (EGTA) and 1 mM PMSF (phenylmethylsulphonyl fluoride) [the PMSF is added just before use from a freshly-prepared 100 mM solution in methanol] using 1 ml cell d
  • PoIy(GIu, Ala, Tyr) 6:3:1 (Sigma-Aldrich Company Ltd., Poole, Dorset; Catalogue No. P3899) in phosphate buffered saline (PBS)] was added to each well of a number of Nunc 96-well MaxiSorp immunoplates (Nunc, Roskilde, Denmark; Catalogue No. 439454) and the plates were sealed and stored at 4°C for 16 hours.
  • test compound was dissolved in DMSO and diluted with a 10% solution of DMSO in distilled water to give a series of dilutions (from 40 ⁇ M to 0.0012 ⁇ M). Aliquots (25 ⁇ l) of each dilution of test compound were transferred to wells in the washed assay plates.
  • Maximum control wells contained diluted DMSO instead of compound. Aliquots (25 ⁇ l) of an aqueous manganese chloride solution (40 mM) containing adenosine-5 '-triphosphate (ATP) was added to all test wells except the "blank" control wells which contained magnesium chloride without ATP.
  • aqueous manganese chloride solution 40 mM
  • ATP adenosine-5 '-triphosphate
  • Active human PDGFR ⁇ and PDGFR ⁇ recombinant enzyme that had been expressed in Sf9 insect cells was obtained from Upstate Biotechnology Inc., Milton Keynes, UK (product 14-467 for PDGFR ⁇ , product 14-463 for PDGFR ⁇ ). Active human KDR recombinant enzyme was expressed in Sf9 insect cells as described above.
  • Each kinase enzyme was diluted immediately prior to use with an enzyme diluent comprising 100 mM Hepes pH7.4 buffer, 0.1 mM sodium orthovanadate, 0.1% Triton X-100 and 0.2 niM dithiothreitol. Aliquots (50 ⁇ l) of freshly diluted enzyme were added to each well and the plates were agitated at ambient temperature for 20 minutes. The solution in each well was discarded and the wells were washed twice with PBST.
  • an enzyme diluent comprising 100 mM Hepes pH7.4 buffer, 0.1 mM sodium orthovanadate, 0.1% Triton X-100 and 0.2 niM dithiothreitol. Aliquots (50 ⁇ l) of freshly diluted enzyme were added to each well and the plates were agitated at ambient temperature for 20 minutes. The solution in each well was discarded and the wells were washed twice with PBST.
  • Mouse IgG anti-phosphotyrosine antibody (Upstate Biotechnology Inc.; product 05-321; 100 ⁇ l) was diluted by a factor of 1 :3667 with PBST containing 0.5% w/v bovine serum albumin (BSA) and aliquots were added to each well. The plates were agitated at ambient temperature for 1.5 hours. The supernatant liquid was discarded and each well was washed with PBST (x2). Horse radish peroxidase (HRP)-linked sheep anti-mouse Ig antibody (Amersham Pharmacia Biotech, Chalfont St Giles, Buckinghamshire, UK; Catalogue No.
  • HRP horse radish peroxidase
  • NXA 931 100 ⁇ l was diluted by a factor of 1:550 with PBST containing 0.5% w/v BSA and added to each well. The plates were agitated at ambient temperature for 1.5 hours. The supernatant liquid was discarded and the wells were washed with PBST (x2).
  • a sodium perborate (PCSB) capsule (Sigma-Aldrich Company Ltd., Poole, Dorset, UK; Catalogue No. P4922) was dissolved in distilled water (100 ml) to provide phosphate-citrate pH5 buffer (50 mM) containing 0.03% sodium perborate.
  • This assay uses a conventional ELISA method to determine the ability of test compounds to inhibit phosphorylation of tyrosine in PDGFR ⁇ .
  • An MG63 osteosarcoma cell line [American Type Culture Collection (ATCC) CCL 1427] was routinely maintained at 37 0 C with 7.5% CO 2 in Dulbecco's modified Eagle's growth medium (DMEM; Sigma-Aldrich; Catalogue No. D6546) containing 10% foetal calf serum (FCS; Sigma-Aldrich; Catalogue No. F7524) and 2mM L-glutamine (Invitrogen Ltd., Paisley, UK; Catalogue No. 25030-024).
  • DMEM Dulbecco's modified Eagle's growth medium
  • FCS 10% foetal calf serum
  • FCS CaFS
  • 2mM L-glutamine Invitrogen Ltd., Paisley, UK; Catalogue No. 25030-024
  • the cells were detached from the culture flask using a trypsin/ethylenediaminetetraacetic acid (EDTA) mixture (Invitrogen Ltd.; Catalogue No. 15400-054) and resuspended in a test medium comprising DMEM without phenol red (Sigma- Aldrich; Catalogue No. D5921) containing 1% charcoal-stripped foetal calf serum (FCS) (Sigma-Aldrich; Catalogue No.
  • EDTA ethylenediaminetetraacetic acid
  • Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required with DMSO to give a range of concentrations. Aliquots (3 ⁇ l) of each compound concentration were added to test medium (300 ⁇ l) to create a second dilution range. Aliquots (16 ⁇ l) of each resultant compound concentration were added to the cells in each well.
  • Maximum control cells received a dilution of DMSO plus test medium only.
  • Minimum control cells received a reference PDGFR inhibitor (16 ⁇ l). The cells were incubated for 90 minutes at 37°C with 7.5% CO 2 .
  • the resultant cells were stimulated with PDGFBB using the following procedure.
  • a lyophilised powder of PDGF BB (Sigma-Aldrich; Catalogue No. P4306) was mixed with sterile water to provide a stock solution of 10 ⁇ g/ml of PDGF B B- A dilution of this stock solution into test medium provided a 182 ng/ml PDGF B B solution. Aliquots thereof (44 ⁇ l) were added to compound treated cells and to the "Maximum” control cells. The "Minimum" control cells received medium only. The cells were incubated at 37°C with 7.5% CO 2 for 5 minutes.
  • the solution from the wells was removed and the cells were lysed by the addition of 120 ⁇ l/well of RIPA buffer comprising 60 mM /m(hydroxymethyl)aminomethane hydrochloride (Tris-HCl), 150 mM sodium chloride, 1 mM EDTA, 1% v/v Igepal CA-630, 0.25% sodium deoxycholate, 1% v/v phosphatase inhibitor cocktail 1 P2850, 1% phosphatase inhibitor cocktail 2 P5726 and 0.5% v/v protease inhibitor cocktail P8340 (all chemicals and inhibitor cocktails were obtainable from the Sigma-Aldrich Company Ltd.).
  • Tris-HCl 60 mM /m(hydroxymethyl)aminomethane hydrochloride
  • 150 mM sodium chloride 1 mM EDTA
  • 1% v/v Igepal CA-630 0.25% sodium deoxycholate
  • 1% v/v phosphatase inhibitor cocktail 1 P2850 1% phosphatas
  • a 1 :2000 dilution of anti-rabbit horseradish peroxidase conjugated secondary antibody (Cell Signaling Technology; Catalogue No. 7074) was made into 1% BSA in PBST. Aliquots (50 ⁇ l) of the resultant dilution were added to each well and the plates were agitated at ambient temperature for 1 hour. The plates were washed 5 times with 300 ⁇ l per well of PBST. Chemiluminescent substrate was made up according to manufacturers instructions (Pierce Biotechnology Inc., Rockford IL, USA; Catalogue No. 34080).
  • Human umbilical vein endothelial cells (HUVECs; PromoCell) were routinely incubated at 37°C with 7.5% CO 2 in 'growth medium' comprising MCDB 131 (Gibco Catalogue No. 10372-019; 500 ml) containing L-glutamine (Sigma Catalogue No. G3126; 0.848 g), 1% Penicillin Streptomycin (Gibco Catalogue No. 15140-122) and Fetal Bovine Serum (PAA Laboratories Catalogue No. Al 5-043; 50 ml).
  • MCDB 131 Gibco Catalogue No. 10372-019; 500 ml
  • L-glutamine Sigma Catalogue No. G3126; 0.848 g
  • Penicillin Streptomycin Gibco Catalogue No. 15140-122
  • Fetal Bovine Serum (PAA Laboratories Catalogue No. Al 5-043; 50 ml).
  • the cells were detached from the culture flask using a trypsin/ethylenediaminetetraacetic acid (EDTA) mixture (Invitrogen Ltd.; Catalogue No. 15400-054) and resuspended in 'test medium' comprising MCDB 131 (500 ml) containing L-glutamine (0.848 g), 1% Penicillin Streptomycin and Fetal Bovine Serum (10 ml). Aliquots (1 ml) were seeded into each well of a 24 well tissue culture plate (Corning Life Sciences; Catalogue No. 3527) to give a density of approximately 3.5xl0 4 cells per well.
  • EDTA ethylenediaminetetraacetic acid
  • the cells were incubated overnight at 37°C with 7.5% CO 2 to allow adherence to the well surface.
  • the plates were incubated at 37°C for 2.5 hours.
  • Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted with DMSO as required. Aliquots (3 ⁇ l) of each concentration of test compound were diluted with 'serum free medium' (300 ⁇ l). Aliquots (50 ⁇ l) of each resultant compound concentration were added to the cells in each well. "Maximum” control cells received only a dilution of DMSO whereas the "minimum” controls received a reference KDR inhibitor to give a final concentration of 1 ⁇ M. The cells were incubated for 90 minutes at 37°C with 7.5% CO 2 .
  • the resultant cells were stimulated with VEGF using the following procedure.
  • a lyophilised powder of VEGF (Sigma-Aldrich; Catalogue No. V7259) was mixed with PBS containing 0.1% filter-sterilised BSA (0.1% BSA/PBS) to provide a stock solution of 10 ⁇ g/ml of VEGF.
  • a dilution of this stock solution into 'serum free medium' provided a 1000 ng/ml VEGF solution. Aliquots thereof (50 ⁇ l) were added to all wells.
  • the cells were incubated at 37°C with 7.5% CO 2 for 5 minutes.
  • the solution from the wells was removed and the cells were lysed by the addition of 100 ⁇ l/well of RIPA buffer comprising 60 mM Tris-HCl, 150 mM sodium chloride, 1 mM EDTA, 1% v/v Igepal CA-630,
  • tissue culture plates were shaken for 5 minutes at ambient temperature to ensure full lysis before being frozen on dry-ice and stored at -20°C until required.
  • tissue culture plates with frozen cell lysate were allowed to warm to 0 0 C. Aliquots (100 ⁇ l) of the HUVEC cell lysate were added and the ELISA plates were agitated at ambient temperature for 3 hours. The wells were washed 3 times with 300 ⁇ l per well of PBST. A dilution of Anti-Phospho-Tyrosine-HRP Detection antibody (R&D Systems; Human Phospho-VEGFR2 ELISA, Catalogue No. DYC 1766) was diluted with 0.1 % BSA in Tris-buffered saline solution containing 0.05% v/v Tween 20 (TBST) to make a working concentration of 600 ng/ml.
  • R&D Systems Human Phospho-VEGFR2 ELISA
  • This assay determined the ability of a test compound to inhibit the proliferation of MG63 osteosarcoma cells (ATCC CCL 1427).
  • MG63 cells were seeded at 1.5 x 10 3 cells per well into 96-well clear tissue culture-treated assay plates (Corning Life Sciences; Catalogue No. 3595) to which had been added 60 ⁇ l per well of test medium comprising DMEM without phenol red,
  • Test compounds were solubilised in DMSO to provide a 10 niM stock solution. Aliquots of the stock solution were diluted with the test medium described above and 20 ⁇ l aliquots of each dilution were added to appropriate wells. Serial dilutions were made to give a range of test concentrations. Control wells to which DMSO solution only was added were included on each plate. Each plate was duplicated.
  • a lyophilised powder of PDGFBB was mixed with 4 mM aqueous hydrochloric acid containing 0.1% filter-sterilised BSA to provide a stock solution of 10 ⁇ g/ml of PDGFBB- A dilution of this stock solution into test medium provided a 250 ng/ml PDGF B B solution. Aliquots (20 ⁇ l) thereof were added to one set of control wells to give the "maximum” control. Aliquots (20 ⁇ l) thereof were added to one set of the duplicate compound-treated plates and these were denoted as the "PDGFBB stimulated" plates. The second set of duplicate compound-treated plates received media only and these were denoted as the "basal” plates. The "minimum” controls received media only. The plates were incubated at 37°C with 7.5% CO 2 for 72 hours.
  • BrdU labelling reagent (Roche Diagnostics Ltd., Lewes, East Canal, UK; Catalogue No. 647 229) was diluted by a factor of 1 : 100 in DMEM medium containing
  • Aqueous sulphuric acid (IM; 50 ⁇ l) was added to the appropriate wells to stop any further reaction and the absorbance of the wells was measured at 450nm. The extent of inhibition of cellular proliferation at a range of concentrations of each test compound was determined and an anti-proliferative IC 50 value was derived.
  • This assay determines the ability of a test compound to inhibit the growth factor- stimulated proliferation of human umbilical vein endothelial cells (HUVECs).
  • HUVECs human umbilical vein endothelial cells
  • HUVECs were isolated in MCDB 131 (Gibco BRL) and 7.5% v/v foetal calf serum (FCS) and were plated out (at passage 2 to 8) in a mixture of MCDB 131, 2% v/v FCS 5 3 ⁇ g/ml heparin and 1 ⁇ g/ml hydrocortisone, at a concentration of 1000 cells/well in 96 well plates. After a minimum of 4 hours, the cells were dosed with the appropriate growth factor (for example VEGF) and with the test compound. The cultures were incubated for 4 days at 37°C under 7.5% CO 2 .
  • FCS foetal calf serum
  • the cell cultures were pulsed with 1 ⁇ Ci/well of tritiated- thymidine (Amersham product TRA 61) and incubated for 4 hours.
  • the cells were harvested using a 96- well plate harvester (Tomtek) and assayed for incorporation of tritium with a Beta plate counter. Incorporation of radioactivity into cells, expressed as counts per minute (cpm), was used to measure inhibition of growth factor-stimulated cell proliferation by each test compound.
  • the naphthyridine compound disclosed as Example 1 possesses activity in
  • the naphthyridine compound disclosed as the 3rd Compound listed in Table I within Example 2 possesses activity in Test (b) with an IC 50 versus phospho-Tyr751 formation in PDGFR ⁇ of approximately 1 nM; and activity in Test (c) with an IC 50 versus phospho-tyrosine formation in KDR of approximately 0.6 ⁇ M.
  • the naphthyridine compound disclosed as the 8th Compound listed in Table I within Example 2 possesses activity in Test (b) with an IC 50 versus phospho-Tyr751 formation in PDGFR ⁇ of approximately 5 nM; and activity in Test (c) with an IC 50 versus phospho-tyrosine formation in KDR of approximately 0.25 ⁇ M.
  • the naphthyridine compound disclosed as the 10th Compound listed in Table I within Example 2 possesses activity in Test (b) with an IC 50 versus phospho-Tyr751 formation in PDGFR ⁇ of approximately 5 nM; and activity in Test (c) with an IC 50 versus phospho-tyrosine formation in KDR of greater than 2 ⁇ M.
  • Table I within Example 2 possesses activity in Test (b) with an IC 50 versus phospho-Tyr751 formation in PDGFR ⁇ of approximately 3 nM; and activity in Test (c) with an IC 50 versus phospho-tyrosine formation in KDR of greater than 1 ⁇ M.
  • the naphthyridine compound disclosed as the 14th Compound listed in Table I within Example 2 possesses activity in Test (b) with an IC 50 versus phospho-Tyr751 formation in PDGFR ⁇ of approximately 3 nM; and activity in Test (c) with an IC 50 versus phospho-tyrosine formation in KDR of approximately 1 ⁇ M.
  • a pharmaceutical composition which comprises a naphthyridine 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.
  • More potent compounds will generally be administered so that a daily oral dose in the range, for example, 1 mg/kg to 25 mg/kg body weight is received.
  • the most potent compounds will generally be administered so that a daily oral dose in the range, for example, 1 mg/kg to 15 mg/kg body weight is received.
  • unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention.
  • antagonism of the activity of PDGF receptor kinases is expected to be beneficial in the treatment of a number of cell proliferative disorders such as cancer, especially in inhibiting tumour growth and metastasis and in inhibiting the progression of leukaemia.
  • the novel naphthyridine 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 PDGF receptor tyrosine kinases.
  • PDGF is 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.
  • a naphthyridine 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.
  • a naphthyridine 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 naphthyridine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • Suitable cell proliferative disorders include neoplastic disorders, for example, cancers of the lung (non-small cell lung cancer, small cell lung cancer and bronchioalveolar cancer), gastrointestine (such as colon, rectal and stomach tumours), prostate, breast, kidney, liver, brain (such as glioblastoma), bile duct, bone, bladder, head and neck, oesophagus, ovary, pancreas, testes, thyroid, cervix and vulva and skin (such as dermatofibrosarcoma protruberans) and in leukaemias and lymphomas such as chronic myelogenous leukaemia (CML), chronic myelomonocytic leukaemia (CMML), acute lymphocytic leukaemia (ALL) 5 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 naphthyridine derivative of the Formula I 5 or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • Suitable cell proliferative disorders include non-malignant disorders such as blood vessel disease (for example atherosclerosis and restenosis, for example in the process of restenosis subsequent to balloon angioplasty and heart arterial by-pass surgery), fibrotic diseases (for example kidney fibrosis, hepatic cirrhosis, lung fibrosis and multicystic renal dysplasia), glomerulonephritis, benign prostatic hypertrophy, inflammatory diseases (for example rheumatoid arthritis and inflammatory bowel disease), multiple sclerosis, psoriasis, hypersensitivity reactions of the skin, allergic asthma, insulin-dependent diabetes, diabetic retinopathy and diabetic nephropathy.
  • 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
  • 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.
  • PDGF receptor enzymes such as PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinase
  • PDGF receptor enzymes such as PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinase
  • a method for the treatment (or prevention) of a warm-blooded animal having tumours which are sensitive to inhibition of PDGF receptor enzymes such as PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinase
  • tumours which are sensitive to inhibition of PDGF receptor enzymes (such as PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinase) that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells
  • PDGF receptor enzymes such as PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinase
  • a PDGF receptor enzyme inhibitory effect such as a PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinase inhibitory effect.
  • a naphthyridine 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 PDGF receptor enzyme inhibitory effect (such as a PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinase inhibitory effect).
  • a PDGF receptor enzyme inhibitory effect such as a PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinase inhibitory effect.
  • a method for inhibiting a PDGF receptor enzyme (such as the PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinase) which comprises administering an effective amount of a naphthyridine derivative of the Formula I 5 or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a PDGF receptor enzyme such as the PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinase
  • anti-cancer treatment may be applied as a sole therapy or may involve, in addition to the naphthyridine derivative of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumour agents :- (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example antifolates such as fluoropvrimidin.es like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthracyclines like adriamycin,
  • 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 BRC A2, 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
  • 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.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • 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 combination suitable for use in the treatment of cell proliferative disorders comprising a naphthyridine derivative of the Formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore.
  • a pharmaceutical product comprising a naphthyridine derivative of the Formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer.
  • the anti-cancer treatment defined hereinbefore may involve the naphthyridine derivative of the invention in combination with an antiangiogenic agent, for example, an anti-vascular endothelial cell growth factor antibody such as bevacizumab and/or a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib or AZD2171.
  • an antiangiogenic agent for example, an anti-vascular endothelial cell growth factor antibody such as bevacizumab and/or a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib or AZD2171.
  • a combination suitable for use in the treatment of cell proliferative disorders comprising a naphthyridine derivative of the formula I as defined hereinbefore and an antiangiogenic agent as defined hereinbefore.
  • a pharmaceutical product comprising a naphthyridine derivative of the Formula I as defined hereinbefore and an antiangiogenic agent as defined hereinbefore for the conjoint treatment of cancer.
  • the anti-cancer treatment defined hereinbefore may also involve the naphthyridine derivative of the invention in combination with an anti -invasion agent, for example, a c-Src kinase family inhibitor such as AZD0530 or bosutinib.
  • a combination suitable for use in the treatment of cell proliferative disorders comprising a naphthyridine derivative of the Formula I as defined hereinbefore and an anti-invasion agent as defined hereinbefore.
  • a pharmaceutical product comprising a naphthyridine derivative of the Formula I as defined hereinbefore and an anti- invasion agent as defined hereinbefore for the conjoint treatment of cancer.
  • the anti-cancer treatment defined hereinbefore may also involve the naphthyridine derivative of the invention in combination with both an antiangiogenic agent, for example, an anti-vascular endothelial cell growth factor antibody such as bevacizumab and/or a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib or AZD2171, and an anti-invasion agent, for example, a c-Src kinase family inhibitor such as AZD0530 or bosutinib.
  • an antiangiogenic agent for example, an anti-vascular endothelial cell growth factor antibody such as bevacizumab and/or a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalani
  • a combination suitable for use in the treatment of cell proliferative disorders comprising a naphthyridine derivative of the Formula I as defined hereinbefore, an antiangiogenic agent as defined hereinbefore and an anti-invasion agent as defined hereinbefore.
  • a pharmaceutical product comprising a naphthyridine derivative of the formula I as defined hereinbefore, an antiangiogenic agent as defined hereinbefore and an anti-invasion agent as defined hereinbefore for the conjoint treatment of cancer.
  • a bisphosphonate compound may optionally also be present.
  • Bisphosphonate compounds are diphosphonic acid derivatives that are capable of regulating metal cation (especially calcium) processing within warm-blooded animals such as humans. Accordingly, bisphosphonates are useful in the prevention or treatment of diseases such as osteoporosis and osteolytic bone disease, for example the osteolytic lesions that may occur with metastatic cancers such as renal, thyroid and lung cancers, in particular with breast and prostate cancers.
  • Suitable bisphosphonates include tiludronic acid, ibandronic acid, incadronic acid, risedronic acid, zoledronic acid, clodronic acid, neridronic acid, pamidronic acid and alendronic acid.
  • 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 PDGF 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 2-[2-methoxy-4-(l,6 ⁇ naphthyridm-4-yloxy)phenyi]acetic acid used as a starting material was prepared as follows :- A mixture of 4-hydroxy-2-methoxybenzaldehyde (5.57 g), benzyl bromide (3.98 ml), potassium iodide (8.22 g), potassium carbonate (6.83 g) and DMA (20 ml) was stirred and heated to 50°C for 2 hours. The resultant mixture was cooled and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of diethyl ether and ethyl acetate as eluent.
  • Dimethylformamide di-tert-butyl acetal (5.93 ml) was added dropwise to a stirred solution of 2-(4-benzyloxy-2-methoxyphenyl)acetic acid (6.8 g) in toluene (68 ml) that had been heated to 90-95°C. The resultant mixture was heated to that temperature range for 1 hour. The mixture was cooled and the solvent was evaporated. The residue was partitioned between diethyl ether and a 10% aqueous citric acid solution. The organic phase was washed with water and with an aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated.
  • 4-Nitropyrazole is available commercially from the N.D. Zelinsky Institute, Organic Chemistry, Leninsky prospect 47, 117913 Moscow B-334, Russia.
  • the compound may also be prepared as follows :-
  • Fuming nitric acid (9.5 ml) was added drop wise to a stirred solution of pyrazole (13.6 g) in glacial acetic acid (51 ml) that had been cooled to -10°C using an ice-salt bath. A voluminous precipitate was formed.
  • Acetic anhydride (27 ml) was added dropwise and the resultant mixture was stirred at ambient temperature for 2.5 hours. The mixture was poured onto ice and the acidity of the mixture was reduced to p ⁇ 5 by the addition of potassium carbonate. The precipitate was isolated by filtration. The resultant solid was dissolved in water and the aqueous solution was extracted with diethyl ether. The organic solution was dried over magnesium sulphate and filtered.
  • Petroleum ether (b.p. 60-80 0 C, 50 ml) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. This solid was believed to be 1-nitropyi-azole (20.6 g); 1 H NMR Spectrum: (DMSOd 6 ) 6.71 (s, IH), 7.88 (s, IH), 8.81 (s, IH). The compound may be explosive and should be handled cautiously.
  • the 2- [4-(7-chloro-l,6-naphthyridin-4-yloxy)-2-methoxyphenyl] acetic acid used as a starting material was prepared as follows :- 5-(Methoxymethylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione (11.16 g) was added to a suspension of 2,6 ⁇ dichloropyridine-4-amine (8.15 g) in isopropanol (125 ml) at ambient temperature. The resultant mixture was stirred and heated to 75°C for 45 minutes. The mixture was cooled to 1O 0 C and diluted with diethyl ether. The precipitate was isolated.
  • fert-Butyl 2-(4-hydroxy-2-methoxyphenyl)acetate (1.19 g) was added to a stirred mixture of 4,7-dichloro-l,6-naphthyridine (0.995 g), caesium carbonate (3.25 g) and DMF (10 ml) and the resultant mixture was heated to 45°C for 2 hours. The mixture was poured in water and extracted with ethyl acetate. The organic solution was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a solvent gradient from methylene chloride to a 9:1 mixture of methylene chloride and diethyl ether as eluent.
  • Phosphorus oxychloride (0.77 ml) was added to a stirred mixture of 7-methoxy- l,4-dihydro-l,6-naphthyi ⁇ din-4-one (1.06 g), diisopropylethylamine (1.56 ml) and 1,4-dichlorobenzene (18 ml) that had been cooled to 10 0 C.
  • the resultant mixture was heated to 70 0 C for 1.5 hours.
  • the mixture was cooled to ambient temperature and concentrated by
  • tert-Butyl 2-(4-hydroxy-2-methoxyphenyl)acetate (1.04 g) was added to stirred mixture of 4-chloro-7-methoxy-l,6-na ⁇ hthyridine (0.852 g), caesium carbonate (2.85 g) and DMF (8.5 ml) and the resultant mixture was heated to 70°C for 2.5 hours. The mixture was cooled to ambient temperature and evaporated. The residue was purified by column chromatography on silica using a solvent gradient from methylene chloride to a 7:3 mixture of methylene chloride and diethyl ether as eluent.
  • the 4-amino-l -methyl- lH-pyrazole used as a starting material was prepared as follows :- Dimethyl sulphate (5 ml) was slowly added to a stirred solution of 4-nitropyrazole (2 g) in IN aqueous sodium hydroxide solution (20 ml) that had been warmed to 3O 0 C and the resultant mixture was stirred at that temperature for 48 hours. The mixture was cooled to ambient temperature and the precipitate was isolated, washed with cold water and dried under vacuum. There was thus obtained l-methyl-4-nitro-li ⁇ -pyrazole (1.5 g); 1 H NMR Spectrum: (DMSOd 6 ) 3.91 (s, IH), 8.24 (s, IH), 8.85 (s, IH).
  • reaction mixture was purified by reversed-phase preparative HPLC on a Waters ' ⁇ Basic Hypersil' reversed-phase preparative column (5 microns silica, 30 mm diameter, 250 mm length) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent.
  • the material so obtained was triturated under a 19:1 mixture of diethyl ether and ethanol.
  • reaction mixture was purified by reversed-phase preparative HPLC on a Waters ' ⁇ Basic Hypersil' reversed-phase preparative column (5 microns silica, 30 mm diameter, 250 mm length) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent.
  • the material so obtained was triturated under a 19:1 mixture of diethyl ether and ethanol.
  • reaction mixture was purified by reversed-phase preparative HPLC on a Waters ' ⁇ Basic Hypersil' reversed-phase preparative column (5 microns silica, 30 mm diameter, 250 mm length) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent.
  • the solid so obtained was triturated under a 19:1 mixture of diethyl ether and ethanol.
  • the resultant product gave the following characterising data :- 1 H NMR Spectrum: (DMSOd 6 ) 1.89 (s, 3H) 5 3.74 (s, 2H), 3.78 (s, 3H),
  • the 3-amino-4-methylisoxazole used as starting material was prepared as follows :- Bromine (1.9 ml) was added to a solution of methacrylonitrile (3.65 ml) in methanol (6 ml) that had been cooled to 0 0 C. The resultant mixture was stirred and heated to 35°C for o 2 hours. The mixture was cooled to O 0 C. Hydroxyurea (4.3 g) was added followed by the dropwise addition of a solution of sodium hydroxide (4.72 g) in water (5 ml). The resultant mixture was heated to reflux for 2.5 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water.
  • the 4-chloro-5-dimethylamino-l,6-naphthyridine used as starting material was prepared as follows :- A mixture of 5,7-dichloro-l,4-dihydro-l,6-naphthyridin-4-one (3.5 g) and dimethylamine (40% aqueous solution; 24.7 ml) was stirred at ambient temperature for 1 hour. The resultant precipitate was collected by filtration and dried under vacuum to give 7-chloro- 5-dimethylamino-l,4-dihydro-l,6-naphthyridin-4-one (2.9 g); Mass Spectrum: M-H " 222.
  • the iV-(l-ethylpyrazol-4-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide used as starting 0 material was prepared as follows :- l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.845 g) was added to a stirred mixture of 2-(4-benzyloxy-2-methoxyphenyl)acetic acid (0.4 g), 1-ethyl- 4-aminopyrazole hydrochloride (0.239 g), 2-hydroxypyridine iV-oxide (0.327 g), diisopropylethylamine (1.03 ml) and DMF (5 ml) and the resultant mixture was stirred at S ambient temperature for 16 hours.
  • the reaction mixture was cooled to ambient temperature and diethyl ether was added.
  • the resultant solid was removed by filtration.
  • the filtrate was extracted with 0.2N aqueous hydrochloric acid.
  • the aqueous extract was basified by the portionwise addition of sodium bicarbonate and extracted with ethyl acetate.
  • the organic phase was dried over magnesium sulphate and evaporated.
  • the residue was purified by column chromatography on silica using a 49:1 mixture of methylene chloride and methanol as eluent.
  • the material so obtained was triturated under a 19:1 mixture of diethyl ether and ethanol.
  • the resultant solid was isolated and dried under vacuum.
  • Example 7 iV-methyl-7V-(5-methylthiazol-2-yl)-2-[2-methoxy-4-(7-methoxy-l,6-naphthyridin- 4-y loxy)pheny 1] acetamide Using an analogous procedure to that described in Example 1, 2-[2-methoxy-
  • the 5-methyl-2-methylaminothiazole used as a starting material was prepared as follows :- Pyridine (0.107 ml) was added to a stirred suspension of 2-amino-5-methylthiazole
  • Example 9 iV-(l-ethyl-ljH r -pyrazoI-4-yl)-2-[3-methoxy-5-(l,6-naphthyridin-4-yloxy)pyridin- 2-yl]acetamide l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.42 g) was added to a stirred mixture of 2-[3-methoxy-5-(l,6-naphthyridin-4-yloxy)pyridin-2-yl]acetic acid (0.225 g), 4-amino-l -ethyl- l ⁇ T-pyrazole hydrochloride (0.14 g), diisopropylethylamine (0.5 ml), 2-hydroxypyridine iV-oxide (0.16 g) and DMF (2 ml).
  • the resultant mixture was stirred at ambient temperature for 16 hours.
  • a second portion (0.4 g) of 4-amino-l-ethyl- lH-pyrazole hydrochloride was added and the mixture was stirred at ambient temperature for 4 hours.
  • the reaction mixture was purified by reversed-phase preparative HPLC on a Waters ' ⁇ Basic Hypersil' reversed-phase preparative column (5 microns silica, 30 mm diameter, 250 mm length) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent.
  • the material so obtained was triturated under a 19:1 mixture of diethyl ether and ethanol.
  • the resultant product was isolated and dried under vacuum.
  • Trimethylsilyl chloride (21.55 ml) was added to a stirred mixture of 2-(5-bromo- 3-methoxypyridin-2-yl)acetonitrile (6.6 g) and methanol (70 ml). The resultant mixture was heated to 5O 0 C for 12 hours. The mixture was concentrated by evaporation and the residue was dissolved in diethyl ether. A saturated aqueous sodium bicarbonate solution was added until gas evolution ceased. The resultant aqueous phase was separated and extracted with diethyl ether. The organic phases were combined, dried over magnesium sulphate and evaporated.
  • the material so obtained was dissolved in methylene chloride (300 ml). An aqueous hydrogen peroxide solution (30%, 15 ml) was added and the resultant mixture was stirred vigorously at ambient temperature for 2 hours. The two phases were separated. The aqueous phase was extracted with methylene chloride. The organic phases were combined, washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of diethyl ether and ethyl acetate as eluent.
  • the 4-amino-l-isopropyl-lH-pyrazole used as a starting material was prepared as follows :-
  • Dimethylformamide di-tert-butyl acetal (5.93 ml) was added dropwise to a stirred solution of 2-(4-benzyloxy-2-methoxyphenyl)acetic acid (6.8 g) in toluene (68 ml) that had been heated to 90-95°C. The resultant mixture was heated to that temperature range for 1 hour. The mixture was cooled and the solvent was evaporated. The residue was partitioned between diethyl ether and a 10% aqueous citric acid solution. The organic phase was washed with water and with an aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated.
  • n-butyl lithium (2.5 M in THF 5 72 ml) was added dropwise to a stirred solution of tert-butyl 2-(4-benzyloxy-2-methoxyphenyl)acetate (3.28 g) in THF (100 ml) that had been cooled to -78°C.
  • THF 100 ml
  • Methyl iodide (1.02 ml) was added at this temperature and the resultant mixture was allowed to warm to ambient temperature over 1 hour.
  • the mixture was diluted with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and evaporated.

Abstract

L'invention concerne des dérivés naphtyridine de Formule (I) : ou leurs sels pharmaceutiquement acceptables, où chacun des X1, p, R1, G1, G2, q, R2, R3, R4, R5, Anneau A, r et R6 a l'une quelconque des significations définies ci-avant dans la description ; des compositions pharmaceutiques qui les contiennent et leur utilisation dans le traitement de troubles cellulaires prolifératifs ou d'états pathologiques associés à une angiogenèse et/ou à une perméabilité vasculaire.
PCT/GB2007/001244 2006-04-06 2007-04-04 Dérivés de la naphtyridine comme agents anti-cancéreux WO2007113565A1 (fr)

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JP2015526526A (ja) * 2012-08-30 2015-09-10 キネックス ファーマシューティカルズ リミテッド ライアビリティー カンパニー タンパク質チロシンキナーゼ調節因子としてのｎ−（３−フルオロベンジル）−２−（５−（４−モルホリノフェニル）ピリジン−２−イル）アセトアミド
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US11498904B2 (en) 2017-11-14 2022-11-15 Merck Sharp & Dohme Llc Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
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CN102762558A (zh) * 2009-11-23 2012-10-31 赛诺菲 吡啶并吡啶酮衍生物、其制备及治疗用途
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JP2015526526A (ja) * 2012-08-30 2015-09-10 キネックス ファーマシューティカルズ リミテッド ライアビリティー カンパニー タンパク質チロシンキナーゼ調節因子としてのｎ−（３−フルオロベンジル）−２−（５−（４−モルホリノフェニル）ピリジン−２−イル）アセトアミド
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US10106505B2 (en) 2012-08-30 2018-10-23 Athenex, Inc. Composition and methods for modulating a kinase cascade
CN105263907B (zh) * 2012-08-30 2018-11-20 阿西纳斯公司 作为蛋白质酪氨酸激酶调节剂的n-(3-氟苄基)-2-(5-(4-吗啉代苯基)吡啶-2-基)乙酰胺
US10851092B2 (en) 2016-09-29 2020-12-01 Daiichi Sankyo Company, Limited Pyridine compound
US11261184B2 (en) 2017-10-02 2022-03-01 Boehringer Ingelheim International Gmbh [1,6]naphthyridine compounds and derivatives as CDK8/CDK19 inhibitors
CN111163775A (zh) * 2017-10-02 2020-05-15 勃林格殷格翰国际有限公司 作为cdk8/cdk19抑制剂的新型[1,6]萘啶化合物和衍生物
WO2019068613A1 (fr) * 2017-10-02 2019-04-11 Boehringer Ingelheim International Gmbh Nouveaux composés de [1,6]naphthyridine et dérivés utilisés en tant qu'inhibiteurs de cdk8/cdk19
CN111163775B (zh) * 2017-10-02 2023-07-11 勃林格殷格翰国际有限公司 作为cdk8/cdk19抑制剂的新型[1,6]萘啶化合物和衍生物
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US10647705B2 (en) 2017-11-14 2020-05-12 Merck Sharp & Dohme Corp. Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
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