WO2007113548A1 - Dérivés de naphtyridine - Google Patents

Dérivés de naphtyridine Download PDF

Info

Publication number
WO2007113548A1
WO2007113548A1 PCT/GB2007/001221 GB2007001221W WO2007113548A1 WO 2007113548 A1 WO2007113548 A1 WO 2007113548A1 GB 2007001221 W GB2007001221 W GB 2007001221W WO 2007113548 A1 WO2007113548 A1 WO 2007113548A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
methoxy
amino
cyano
Prior art date
Application number
PCT/GB2007/001221
Other languages
English (en)
Inventor
Frederic Henri Jung
Remy Robert Morgentin
Patrick Ple
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2007113548A1 publication Critical patent/WO2007113548A1/fr

Links

Classifications

    • 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 a ⁇ , Oncogene, 2000, Jj ) , 5548-5557).
  • the classification includes the EGF family of receptor tyrosine kinases such as the EGF 5 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 family of receptor tyrosine kinases such as the EGF 5 TGF ⁇ , Neu and erbB receptors
  • 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
  • the receptor tyrosine kinase (RTK) subfamily that binds VEGF comprises the kinase insert domain-containing receptor KDR (also referred to as FIk-I), the ⁇ /ms-like tyrosine kinase receptor FIt-I and theyms-like tyrosine kinase receptor Flt-4. 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, 1, 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, 6J_, 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).
  • example 87 there is the disclosure in example 87 therein of a single quinolin-4-yloxy-substituted 2-phenylacetamide, namely of the compound N-(5-chloropyridin-2-yl)-2-[4-(7-methoxyquinolin-4-yloxy)phenyl]acetamide.
  • novel 1,7- or l,5-naphthyridin-4-yloxy- substituted 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). Activity of specific CDKs at specific times is essential both to initiate and coordinate progress through the cell cycle.
  • the 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 IpIl 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.
  • 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.
  • tyrosine kinases for example the PDGF ⁇ and/or PDGF ⁇ receptor tyrosine kinases
  • other tyrosine kinase enzymes for example against one or more other Class III family receptor tyrosine kinases such as Flt3 receptor
  • 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-8C)alkyl; p is 0, 1, 2 or 3; each R 1 group, which may be the same or different, is selected from halogeno, trifiuoromethyl, cyano, hydroxy, mercapto, 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)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, JV-(I -6C)alkylcarbamoyl,
  • X 2 is selected from O, S, SO, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO, OC(R 8 ) 2 and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl
  • Q 1 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l -6C)alkyl, (3-8C)cycloalkenyl, (3-8C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l -6C)alkyl, and wherein any aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl group within a R 1 substituent optionally
  • X 3 is a direct bond or is selected from O and N(R ), wherein R 1 is hydrogen or (l-8C)alkyl, and R 9 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, mercapto-(l-6C)alkyl, (1 -6C)alkoxy-(l -6C)alkyl, (1 -6C)alkylthio-(l -6C)alkyl, (1 -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)alkanoylamin
  • 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-SC)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, TV-(I -6C)alkylcarbamoyl, 7V,TV-di-[(l-6C)alkyl] carbamoyl, halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyan
  • 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, TV-(I -6C)alkylcarbamoyl-(l-6C)alkyl, TV,TV-di-[(l-6C)alkyl]carb
  • X 5 is a direct bond or is selected from O and N(R 14 ), wherein R 14 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 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur; r is 0, 1, 2 or 3; and 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-6C)alkoxy, (l-6C)alkylthio,
  • 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, (1 -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)alkanoy
  • X 7 is a direct bond or is selected from O, S, SO, SO 2 , N(R 17 ), CO 3 CH(OR 17 ), CON(R 17 ), N(R 17 )CO, N(R 17 )CON(R 17 ), SO 2 N(R 17 ), N(R 17 )SO 2 , C(R 17 ) 2 O, C(R 17 ) 2 S and C(R 17 ) 2 N(R 17 ), wherein each R 17 is hydrogen or (l-8C)alkyl, and Q 3 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-6C)alkyl, (3-8C)cycloalkenyl, (3-8C)cycloalkenyl- (l- ⁇ C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(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 5 (3-8C)cycloalkenyl, heteroaryl or heterocyclyl group within an R 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 is a direct bond or is selected from O and N(R ), wherein R is hydrogen or (l-SC)alkyl, and R 20 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,
  • X 9 is a direct bond or is selected from O, CO and N(R 22 ), wherein R 22 is hydrogen or 5 (l-SC)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-8C)alkyl and (l-6C)alkoxy, and wherein any aryl, heteroaryl or heterocyclyl group within an R group optionally bears a (l-3C)alkylenedioxy group, o and wherein any heterocyclyl group within an R 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, mercapto, amino, cyano, carboxy, carbamoyl, ureido, s (2-8C)alkenyl, (2-8C)alkynyl, (1 -6C)alkoxy, (1 -6C)alkylthio, (1 -6C)alkylsulphinyl,
  • N-(l-6C)alkylcarbamoyl N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,
  • N(R 23 ), R 23 may also be (2-6C)alkanoyl; or a pharmaceutically-acceptable salt thereof.
  • (l-8C)alkyl includes both straight-chain and 0 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.
  • An analogous convention applies to other generic terms, for example (l-6C)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, cyclopropylamino, cycl
  • di-[(l-6Calkyl]amino includes di-[(3-6C)cycloalkyl]amino groups and di-[(3-5C)cycloalkyl-(l-2C)alkyl]amino groups, for example dimethylamino, diethylamino, dipropylamino, iV-cyclopropyl-iV-methylamino, iV-cyclobutyl-iV-methylamino, N-cyclohexyl-N-ethylamino, N-cyclopropylmethyl-iV-methylamino, N-(2-cyclopropylethyl)- N-methylamino and iV-cyclopentylmethyl-iV-
  • 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 fo ⁇ nulae drawings or named in the Examples.
  • Ring A may be a pyrazolyl group.
  • 2-position remains unsubstituted.
  • the 3-position on the naphthyridine ring also remains unsubstituted or the R 1 substituent at the 3-position on the naphthyridine ring is a cyano group.
  • R 1 substituents may only be located at the 5- or 6-positions on the naphthyridine ring.
  • an R 1 substituent may only be located at the 6-position on the naphthyridine ring.
  • R 1 substituents there is a hydrogen atom at the 2-position on the naphthyridine ring. It is to be understood thereby that the R 1 substituents may only be located at the 3-, 6-, 7- or 8-positions on the naphthyridine ring i.e. that the 2-position remains unsubstituted. Conveniently, the 3-position on the naphthyridine ring also remains unsubstituted or the R 1 substituent at the 3-position on the naphthyridine ring is a cyano group. More conveniently, R 1 substituents may only be located at the 6- or 7-positions on the naphthyridine ring. Yet more conveniently, 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
  • 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 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 3 and R 4 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-menibered 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,
  • 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 2 or R 6 substituent include :- for halogeno fluoro, chloro, bromo and iodo; for (l-8C)alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, cyclohexylmethyl and
  • JV-methyl-iV' JV'-diethylureido for JV-(I -6C)alkylsulphamoyl: N-methylsulphamoyl and iV-ethylsulphamoyl; for N,N-di-[(l -6C)alkyl] sulphamoyl: iV ⁇ V-dimethylsulphamoyl; for (l-6C)alkanesulphonylamino: methanesulphonylamino and ethanesulphonylamino; for iV-(l-6C)alkyl-(l-6C)alkanesulphonylamino: iV-methylmethanesulphonylamino and io N-methylethanesulphonylamino; for halogeno-(l-6C)alkyl: chloromethyl, 2-fluoroethyl, 2-chloroethyl,
  • N-ethyl-N-methylcarbamoylmethyl N.N-diethylcarbamoylmethyl, 1 -(iV,N-dimethylcarbamoyl)ethyl, 1 -(N,iV-diethylcarbamoyl)ethyl, 2-(N,N-dimethylcarbamoyl)ethyl,
  • N-methylmethanesulphonylaminomethyl 2-(N-methylmethanesulphonylamino)ethyl and l-(N-methylmethanesulphonylamino)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 Q ⁇ -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-SC)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.
  • 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 include, for example, hydroxy-substituted (l-8C)alkyl groups such as hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl, hydroxy-substituted (l-6C)alkoxy groups such as 2-hydroxypropoxy and 3-hydroxypropoxy,
  • (l-6C)alkoxy-substituted (l-6C)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- [( 1 -6C)alkyl] ammo-(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 and hydroxy-substi
  • 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)aminoniethyl.
  • any CH, CH 2 or CH 3 group within a R 1 or R 6 group optionally bears on each said CH 5 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-SC)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 or R 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 iV-(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 N-(2-hydroxypropionyl)piperidin-4-yl group.
  • two R 6 groups together may form a bivalent group, for example
  • Ring A is, for example, a phenyl group
  • a suitable group so formed is a 2,3-methylenedioxyphenyl or a 3,4-methylenedioxyphenyl group.
  • R 6 group for example a halogeno group
  • 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 Ia or Ib is, for example, an acid-addition salt of a compound of the Formula Ia or Ib 5 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 Ia or Ib which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • a further suitable pharmaceutically-acceptable salt of a compound of the Formula Ia or Ib is, for example, a salt formed within the human or animal body after administration of a compound of the Formula Ia or Ib.
  • a suitable pharmaceutically-acceptable solvate of a compound of the Formula Ia or Ib 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 Ia or Ib also forms an aspect of the present invention. Accordingly, the compounds of the invention may be administered in the form of a pro-drug, that is a compound that is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula Ia or Ib and in vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula Ia or Ib.
  • the present invention includes those compounds of the Formula Ia or Ib 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 Ia or Ib 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 Ia or Ib may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula Ia or Ib is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzvmology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drags, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drag Design and Development, edited by Krogsgaard-Larsen and
  • H. Bundgaard Chapter 5 "Design and Application of Pro-drags", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et ah, Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al, Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drags as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.
  • Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkyl esters such as methyl, ethyl and tert-hvXy ⁇ , (l-6C)alkoxymethyl esters such as methoxymethyl esters, (l ⁇ 6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-l,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and (l-6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1 -methoxycarbonyloxy ethy
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula Ia or Ib 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 Ia or Ib 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,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,N-[di-(l-4C)alkyl]carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula Ia or Ib 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 Ia or Ib 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, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l -4C)alkylpiperazin- 1 -ylmethyl.
  • the in vivo effects of a compound of the Formula Ia or Ib may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula Ia or Ib. As stated hereinbefore, the in vivo effects of a compound of the Formula Ia or Ib 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 Ia, 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 (mmm) immediately hereinafter :- (a) X 1 Is O OrNH;
  • 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, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylsulphonyl-(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 N-(l-6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl, or from a group of the formula :
  • 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 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- ⁇ C)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 5 CH 2 or CH 3 group one or more halogeno or (l-8C)alkyl groups and/or a substituent selected from hydroxy, amino, cyano, carboxy
  • (f) p is 1 and the R 1 group that is present is located at the 6-position and 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,
  • N,N-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 )C0 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-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1 -6C)alkoxy,
  • 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, (l-6C)alkoxy-(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-(l-6C)alkyl or iV-(l-6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl, or from a group of the formula :
  • 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- ⁇ C)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-8C)alkyl groups and/or a substituent selected from hydroxy, amino, cyano, carboxy
  • (g) p is 1 and the R 1 group is located at the 6-position and is selected from cyano, hydroxy, amino, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, diethylamino, iV-methylcarbamoyl, N-ethylcarbamoyl, JV,N-dimethylcarbamoyl, iV,N-diethylcarbamoyl, pyrrolidin-1-ylcarbonyl, morpholinocarbonyl, piperidinocarbonyl, piperazin-1-ylcarbonyl, 2-pyrrolidin- 1 -ylethoxy , 3 -pyrrolidin- 1 -ylpropoxy , 4-pyrrolidin- 1 -ylbutoxy , pyr
  • (h) p is 1 and the R 1 group is located at the 6-position and is selected from cyano, hydroxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methoxy, ethoxy, propoxy, iV-methylcarbamoyl, JV-ethylcarbamoyl, N,iV-dimethylcarbamoyl, JV,N-diethylcarbamoyl, pyrrolidin- 1 -ylcarbonyl, morpholinocarbonyl, piperidinocarbonyl and piperazin- 1 -ylcarbonyl; and wherein 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 isopropylidenedi
  • 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 of G 1 and G 2 is N;
  • R 5 is methyl or ethyl
  • R 6 group is located at the 3-position (relative to the CON(R 5 ) group);
  • any other R 6 group that is present is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l- ⁇ C)alkylamino, di-[(l -6C)alkyl]amino, (2-6C)alkanoylamino and JV-(I -6C)alkyl-(2-6C)alkanoylamino, 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 hal
  • 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- (1 -6C)alkyl, (1 -6C)alkylsulphinyl-(l -6C)alkyl, (1 -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- ⁇ C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, iV-(l-6C)alkyl-(2-6
  • X is a direct bond and R 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- ⁇ C)alkylsulphonyl,
  • X is a direct bond or is selected from O and N(R 1 ), 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
  • (aaa) 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 -methylethyl, 3-methylaminopropyl, methylaminomethyl, 1
  • 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 ⁇ , or each of G 1 and G 2 is ⁇ ; q is 0 or q is 1 and the R group which is located at the 2- or 3 -position (relative to the C(R 3 )(R ) group) is selected from fluoro, chloro
  • 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 :
  • (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; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a naphthyridine derivative of the Formula Ia wherein :-
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6-position and is selected from cyano, carbamoyl, methoxy, JV-methylcarbamoyl and JV,./V-dimethylcarbamoyl; 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 or 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; each of R 3 and R 4 is hydrogen;
  • R 5 is hydrogen or methyl;
  • 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 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, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, aminomethyl, 1-aminoe
  • a further particular compound of the invention is a naphthyridine derivative of the Formula Ia wherein :-
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6-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, ethylaminoniethyl, isopropylaminomethyl, cyclopropylaminomethyl, dimethylaminomethyl, diethylaminomethyl, iV-ethyl- N-methylaminomethyl, N-cyclopropyl-iV-methylaminomethyl, azetidinylmethyl, pyrrolidinylmethyl, morpholinylmethyl, piperidinylmethyl, homopiperidinylmethyl, piperazinylmethyl and homopiperaziny
  • 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, methylamino, ethylamino, dimethylamino, cyclopropylamino, hydroxymethyl, aminomethyl, methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, cyclopropylaminomethyl, dimethylaminomethyl, diethylaminomethyl, iV-ethyl-iV-methylaminomethyl, N-cyclopropyl- N-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 Ia wherein :-
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6-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 Gi 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 1 and the R 2 group is fluoro, chloro, methyl or methoxy; each of R 3 and R 4
  • R 5 is hydrogen, methyl or ethyl
  • X 1 is O; p is 0 or p is 1 and the R 1 group is a 6-cyano or 6-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 ⁇ ; q is 0; each of R 3 and R 4 is hydrogen;
  • a particular compound of the invention is a naphthyridine derivative of the Formula Ia wherein :-
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6-position and is selected from cyano, hydroxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methoxy, ethoxy, propoxy,
  • 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,
  • 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 5 ) 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-butyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino and diethylamino, or r is 1 or 2 and one R 6 group is located at the 3-position (re
  • a further particular compound of the invention is a naphthyridine derivative of the Formula Ia wherein :- X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6-position and is selected from cyano, carbamoyl, methoxy, JV-methylcarbamoyl and N,iV-dirnethylcarbamoyl; 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 is hydrogen; R 5 is hydrogen or methyl;
  • 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 (
  • a further particular compound of the invention is a naphthyridine derivative of the Formula Ia wherein :- X 1 is O; p is O or p is 1 and the R 1 group is located at the 6-position and is selected from cyano, carbamoyl, methoxy, JV-methylcarbamoyl and JV,iV-dimethylcarbamoyl; 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 Ia wherein :-
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6-position and is selected from cyano, carbamoyl, methoxy, iV-methylcarbamoyl and N,iV-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 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, 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, tert-butyl, cyclopropyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, methylaminomethyl, ethylaminomethyl, isopropylaminomethyl, cyclopropylaminomethyl, dimethylaminomethyl, amino, methylamino, ethylamino, dimethylamino and diethylamino
  • a further particular compound of the invention is a naphthyridine derivative of the Formula Ia wherein :-
  • X 1 is O; p is 0 or p is 1 and the R 1 group is a 6-methoxy group; each Of G 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 is hydrogen; R 5 is hydrogen; Ring A is 2-oxazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,
  • a particular novel compound of this aspect of the invention is a naphthyridine derivative of the Formula Ia 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 ) group).
  • the presence of such a group may be specified by stating that Gi 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 Ia, or a pharmaceutically-acceptable salt thereof, wherein :- p is 0 or p is 1 and the R 1 group is located at the 6-position and is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l- ⁇ C)alkoxycarbonyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l- ⁇ C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, 7V-(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-position (
  • a further particular novel compound of this aspect of the invention is a naphthyridine derivative of the Formula Ia 5 or a pharmaceutically-acceptable salt thereof, wherein :- p is 0 or p is 1 and the R 1 group is located at the 6-position and is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino, N-methylcarbamoyl and N,N-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, methylamin
  • a further particular novel compound of this aspect of the invention is a naphthyridine derivative of the Formula Ia, or a pharmaceutically-acceptable salt thereof, wherein :- p is 0 or p is 1 and the R 1 group is located at the 6-position and is selected from fluoro, chloro, cyano, carbamoyl, methoxycarbonyl, methoxy, ethoxy, N-methylcarbamoyl and N,N-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 carbamoyl, methoxy, ethoxy, N-methylcarbamoyl and N,N-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 meanings defined hereinbefore.
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6-position and is selected from cyano, hydroxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methoxy, ethoxy, propoxy, N-methylcarbamoyl, JV-ethylcarbamoyl, N ⁇ N-dimethylcarbamoyl and N,iV-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, N-ethyl-iV-methylamino and iV-isopropyl-iV-methylamino;
  • G 1 is C(R a ) wherein the R a group is selected from fluoro, chloro, cyano, methyl and methoxy and G 2 is C(R a ) wherein the R a group 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 fluoro, chloro, cyano, methyl and methoxy and G 2 is ⁇ ; q is 0 or q is 1 and the R 2 group is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, methyl, methoxy, methylamino and dimethylamino; each of R 3 and R 4 is hydrogen;
  • 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 5 ) 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-butyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino and diethylamino, or r is 1 or 2 and one R 6 group is located at the 3-position (relative
  • a further particular compound of this aspect of the invention is a naphthyridine derivative of the Formula Ia wherein :- X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6-position and is selected from cyano, carbamoyl, methoxy, JV-methylcarbamoyl and N,iV-dimethylcarbamoyl;
  • 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 5 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 ⁇ ; q is O; each of R 3 and R 4 is hydrogen;
  • 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-bntyl, 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 (
  • a further particular compound of this aspect of the invention is a naphthyridine derivative of the Formula Ia wherein :-
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6-position and is selected from cyano, carbamoyl, methoxy, JV-methylcarbamoyl and N,7V-dimethylcarbamoyl;
  • G 1 is C(R a ) wherein the R a group is selected from fluoro, chloro, cyano, methyl and methoxy and 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 O; each of R 3 and R 4 is hydrogen; R 5 is hydrogen or methyl;
  • a further particular compound of this aspect of the invention is a naphthyridine derivative of the Formula Ia wherein :- X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6-position and is selected from cyano, carbamoyl, methoxy, JV-methylcarbamoyl and iV,iV-dimethylcarbamoyl; G 1 is C(OMe) and G 2 is CH, or G 1 is C(OMe) 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 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, cyclopropyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, methylaminomethyl, ethylaminomethyl, isopropylaminomethyl, cyclopropylaminomethyl, dimethylaminomethyl, amino, methylamino, ethylamino, dimethylamino and diethylamino; or a phannaceutically-acceptable salt thereof.
  • a further particular compound of this aspect of the invention is a naphthyridine derivative of the Formula Ia wherein :- X 1 is O; p is O or p is 1 and the R 1 group is a 6-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 further particular compound of the invention is a naphthyridine derivative of the Formula Ia selected from :- iV-(5-ethyl-lH-pyrazol-3-yl)-2-[4-(l,7-naphthyridin-4-yloxy)phenyl]acetamide, iV-(5-ethyl-lH-pyrazol-3-yl)-2-[4-(6-methoxy-l,7-naphthyridin-4-yloxy)phenyl]acetamide, iV-(5-ethyl-lH-pyrazol-3-yl)-2-[2-methoxy-4-(6-methoxy-l,7-naphthyridin- 4-yloxy)phenyl] acetamide, N-(I -ethyl- 1 H-pyrazol-4-yl)-2- [4-( 1 ,7-naphthyridin-4
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for s example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as
  • Naphthyridine starting materials of the Formula Ha may be obtained by conventional procedures.
  • Acetamide starting materials of the Formula III may be obtained by conventional 0 procedures.
  • 3-ethylcarbodiimide or with a uronium compound such as 2-(7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate(V) or 2-(benzotriazol-l-yl)- 1 , 1 ,3 ,3 -tetramethyluronium tetrafluoroborate.
  • a uronium compound such as 2-(7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate(V) or 2-(benzotriazol-l-yl)- 1 , 1 ,3 ,3 -tetramethyluronium tetrafluoroborate.
  • 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 15O 0 C, preferably at or near ambient temperature.
  • a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride
  • a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride
  • Methods appropriate for the cleavage of a (l- ⁇ C)alkoxycarbonyl group include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis.
  • the 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 0 C to 100 0 C, conveniently at or near ambient temperature.
  • base-catalysed cleavage may be effected at ambient temperature using an alkali metal hydroxide such as lithium hydroxide in an alcohol such as methanol.
  • a pharmaceutically-acceptable pro-drug of a naphthyridine derivative of the Formula Ia When a pharmaceutically-acceptable pro-drug of a naphthyridine derivative of the Formula Ia is required, it may be obtained using a conventional procedure.
  • an in vivo cleavable ester of a naphthyridine derivative of the Formula Ia may be obtained by, for example, reaction of a compound of the Formula Ia containing a carboxy group with a pharmaceutically-acceptable alcohol or by reaction of a compound of the Formula Ia containing a hydroxy group with a pharmaceutically-acceptable carboxylic acid.
  • novel compounds include, for example, naphthyridine derivatives of the Formula Ib, 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) immediately hereinafter :-
  • 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, carbamoyl, ureido, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di- [(I -6C)alkyl] amino, ( 1 -6C)alkoxycarbonyl, N-( 1 -6C)alkylcarbamoyl, iV,N-di-[(l-6C)alkyl]carb
  • G 1 is C(R a ) wherein the R a group is hydrogen or an R 2 group and G 2 is N; (m) each of G 1 and G 2 is N; (n) q is 0; (o) q is 1 or 2 and each R 2 group, which may be the same or different, is selected from halogeno, trifiuoromethyl, cyano, carbamoyl, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino,
  • (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- ⁇ C)alkoxy group;
  • (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) is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, methyl, methoxy, methylamino and dimethylamino; (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
  • 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
  • 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 6 groups are present, one R 6 group is located at the 3- or 4-position (relative to the CON(R 5 ) group);
  • 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;
  • Ring A is a benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzotriazolyl, lH-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-SC)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, sec-butyl, isobutyl, tert-b ⁇ tyl, 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, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino and diethylamino;
  • (xx) 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 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,
  • (yy) r is 1, 2 or 3 and one R 6 group is a group of the formula :
  • X 7 is a direct bond or is selected from O, N(R 17 ), CON(R 17 ), N(R 17 )C0 and C(R 17 ) 2 O, wherein each R 17 is hydrogen or (l-8C)alkyl
  • Q 3 is 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 7 is selected from O, N(R 17 ), CON(R 17 ) or C(R 17 ) 2 O, there are at least two carbon atoms between X 7 and any heteroatom in Q 3 that is not in a heteroaryl ring, and any other R 6 group that is present is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (
  • R> 21 is hydrogen or (l-8C)alkyl
  • 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 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)
  • 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- (l- ⁇ C)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-(l-6C)alkyl, N-(l-6C)alkyl-(2-6C)alkan
  • X 8 is a direct bond and R 20 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (1 -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 5 CH 2 or CH 3 group 1, 2 or 3 halogeno or (l-SC)alkyl substituents and/or a substituent selected from hydroxy, amino, cyano, (3-8C)alkenyl, (3-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsulphonyl, (l-6C)
  • (aaa) 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, 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
  • any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the R 6 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamine, hydroxymethyl, 2-hydroxy ethyl, 3-hydroxypropyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl and 3 -dimethylaminopropyl
  • X 6 is a direct bond or O and R 15 is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-methoxy-
  • any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the R group optionally bears a substituent selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, methoxy, methylamino and dimethylamino and any such aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the R 6 group optionally bears a substituent selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, methoxy, methylamino and dimethylamino and any such aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the R 6 group optionally bears a substituent selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, methoxy, methylamino and dimethylamino and any such aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group
  • (111) p is O or p is 1 or 2 and the R 1 groups are located at the 6- and/or 7-positions and are selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino, N-methylcarbamoyl and 7V,7V-dimethylcarbamoyl, and q is 1 and the R 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, methylamino, dimethylamino, JV-methylcarbamoyl and 7V,7V-dimethylcarbamo
  • R 1 groups are located at the 6- and/or 7-positions and are selected from fluoro, chloro, cyano, carbamoyl, methoxycarbonyl, methoxy, ethoxy, 7V-methylcarbamoyl and 7V,/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 carbamoyl, methoxy, ethoxy, JV-methylcarbamoyl and TV ⁇ /V-dimethylcarbamoyl; and
  • (nnn) p is O or p is 1 and the R 1 group is located at the 6- or 7-position and is selected from fluoro, cyano, carbamoyl, methoxycarbonyl, methoxy, ethoxy, JV-methylcarbamoyl and /V 5 TV- 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.
  • a particular compound of the invention is a naphthyridine derivative of the Formula Ib wherein :- X 1 is O; p is O or p is 1 and the R 1 group is located at the 6- or 7-position and any R 1 group located at the 6-position is selected from cyano, hydroxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methoxy, ethoxy, propoxy, iV-methylcarbamoyl, JV-ethylcarbamoyl, N ⁇ V-dimethylcarbamoyl, N,iV-diethylcarbamoyl, pyrrolidin-1-ylcarbonyl, morpholinocarbonyl, piperidinocarbonyl and piperazin-1-ylcarbonyl, and any R 1 group located at the 7-position is selected from methoxy, ethoxy, propoxy, 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin-l-ylprop
  • 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 1 and the R 2 group which is located at the 2- or 3-position (relative to the C(R 3 )(R 4 ) group) is selected from fluoro, chloro,
  • 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 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, methylaminoniethyl, 1-methylaminoethyl, 2-methylaminoethyl, 3-methylaminopropyl, ethylaminomethyl, 1-ethylaminoethyl, 2-ethylaminoethyl, 1-ethylamino-l-methylethyl, 3-ethylaminopropyl, iso
  • (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; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a naphthyridine derivative of the Formula Ib wherein :- X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6- or 7-position and any R 1 group located at the 6-position is selected from cyano, carbamoyl, methoxy, iV-methylcarbamoyl and N,iV-dimethylcarbamoyl, and any R 1 group located at the 7-position is selected from methoxy, ethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy, 3 -methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 2- [(3RS,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yl] ethoxy, 3-[(3RS
  • R 5 is hydrogen or methyl
  • 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 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, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, aminomethyl, 1-aminoethyl, 2-aminoeth
  • a further particular compound of the invention is a naphthyridine derivative of the Formula Ib wherein :-
  • 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 6 group that is present is selected from methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, dimethylamino, JV-cyclopropyl-iV-methylamino, pyrrolidin-1-yl, piperidino, morpholino and piperazin-1-yl, and any second R 6 group that is present is selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy, and wherein any heterocyclyl group within
  • 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 5 ) 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-butyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino and diethylamino, or r is 1 or 2 and one R 6 group is located at the 3-position (relative
  • a further particular compound of the invention is a naphthyridine derivative of the Formula Ib wherein :- X 1 is O; p is O or p is 1 and the R 1 group is a 6- or 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 ⁇ ; q is O; each of R 3 and R 4 is hydrogen; R 5 is hydrogen;
  • 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 Ib, or a pharmaceutically-acceptable salt thereof, wherein :- p is 0 or p is 1 or 2 and the R 1 groups are located at the 6- and/or 7-positions and are selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino, JV-methylcarbamoyl and NJV-dimethylcarbamoyl, and q is 1 and the R 2 group which is located at the 2-position (relative to the C(R 3 )(R ) group) is selected from fluoro, chloro, trifluoromethyl, cyano, carbamoyl, hydroxy, amino, methyl, ethyl, methoxy,
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6- or 7-position and any R 1 group located at the 6-position is selected from cyano, hydroxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methoxy, ethoxy, propoxy, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl, and any R 1 group located at the 7-position is selected from methoxy, ethoxy and propoxy; G 1 is C(R a ) wherein the R a group is selected from fluoro, chloro, cyano, methyl and methoxy and G 2 is C(R a ) wherein the R a group is selected from hydrogen, fluoro, chloro, cyano, methyl and methoxy, or G 1 is C(R a ) wherein the R
  • X 1 is O; p is 0 or p is 1 and the R 1 group is located at the 6- or 7-position and any R 1 group located at the 6-position is selected from cyano, carbamoyl, methoxy, JV-methylcarbamoyl and ⁇ N-dimethylcarbamoyl, and any R 1 group located at the 7-position is selected from methoxy and ethoxy;
  • a further particular compound of of this aspect the invention is a naphthyridine derivative of the Formula Ib wherein :-
  • G 1 is C(R a ) wherein the R a group is selected from fluoro, chloro, cyano, methyl and methoxy and G 2 is C(R a ) wherein the R a group 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 fluoro, chloro, cyano, methyl and methoxy and G 2 is ⁇ ; q is O; each of R 3 and R 4 is hydrogen;
  • I 5 Ring A is 2-oxazolyl, 3-isoxazolyl, 2-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl or
  • each R 6 group that is present is selected from methyl, ethyl, propyl, isopropyl, f ⁇ rt-butyl, cyclopropyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, methylaminomethyl, ethylaminomethyl, isopropylaminomethyl, 2Q cyclopropylaminomethyl, dimethylaminomethyl, amino, methylamino, ethylamino, dimethylamino and diethylamino; or a pharmaceutically-acceptable salt thereof.
  • a particular compound of the invention is a naphthyridine derivative of the
  • a naphthyridine derivative of the Formula Ib, 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 Ib 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. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • L is a displaceable group and p and R 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an acetamide of the Formula III
  • 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.
  • the reaction may conveniently be carried out in the presence of a suitable acid or in the presence of a suitable base.
  • 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, trietliylamine, morpholine, iV-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 organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, trietliylamine, morpholine, iV-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene
  • 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 JV,N-dimethylformamide, ⁇ yV-dimethylacetamide, N-methylpyrrolidin-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 such as t
  • Formula III in the presence of an aprotic solvent such as ⁇ ,N-dimethylfo ⁇ namide, 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 15O 0 C, preferably in the range, for example, 0 to 7O 0 C.
  • a base for example potassium carbonate or sodium hexamethyldisilazane
  • the naphthyridine derivative of the Formula Ib 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, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • a suitable base for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydro
  • Naphthyridine starting materials of the Formula lib 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 NH R 6 )r VI wherein 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.
  • 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.
  • 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 dipolar aprotic solvent such as N,N-dimethylformamide, N,
  • Acetic acid derivatives of the Formula V and amines of the Formula VI may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter.
  • R 5 NH ( R 6 )r VI wherein 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,
  • 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 ⁇ N-dimethylforrnamide, N ⁇ V-dimethylacetamide, iV-methylpyrrolidin-2-one or dimethylsulphoxide.
  • a dipolar aprotic solvent such as ⁇ N-dimethylforrnamide, N ⁇ V-dimethylacetamide, iV-methylpyrrolidin-2-one or dimethylsulphoxide.
  • the reaction is conveniently carried out at a temperature in the range, for example, 0 to 120 0 C, preferably at or near ambient temperature.
  • Naphthyridine derivatives of the Formula VIIb and amines of the Formula VI may be
  • Q 1 is an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl- (l-6C)alkyl, heteroaryl-(l-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 VIIIb - Ill -
  • each of p, R 1 , X 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 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 VIIIb may be obtained by conventional procedures.
  • a R group is a group of the formula -X 6 -R 15 wherein X 6 has any of the meanings defined hereinbefore and R 15 is an amino-substituted (l- ⁇ C)alkyl group (such as a dimethylaminomethyl, 2-dimethylaminoethyl or 4-methylpiperazin-l-ylmethyl group)
  • the reaction conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the Formula Ib wherein a R 6 group is a group of the formula - X 6 -R 15 wherein R 15 is a halogeno-substituted (l- ⁇ C)alkyl group with an appropriate amine or with a nitrogen-containing heterocyclyl compound.
  • 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°C, conveniently in the range 20 to 120°C, more conveniently at or near ambient temperature.
  • R 6 group is a group of the formula -X 6 -R 15 wherein R 15 is a halogeno-substituted (l- ⁇ C)alkyl group
  • R 15 is a halogeno-substituted (l- ⁇ C)alkyl group
  • a suitable reducing agent for the reductive amination reaction is, for example, a hydride reducting agent, for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride.
  • a hydride reducting agent for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride.
  • the reaction is conveniently performed in a suitable inert solvent or diluent, for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
  • a suitable inert solvent or diluent for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
  • R group is a group of the formula -X -R 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.
  • Methods appropriate for the cleavage of a (l-6C)alkoxycarbonyl group include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis.
  • the 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°C to 100°C, conveniently at or near ambient temperature.
  • base-catalysed cleavage may be effected at ambient temperature using an alkali metal hydroxide such as lithium hydroxide in an alcohol such as methanol.
  • a pharmaceutically-acceptable salt of a naphthyridine derivative of the Formula Ib is required, 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 Ib When a pharmaceutically-acceptable pro-drug of a naphthyridine derivative of the Formula Ib is required, it may be obtained using a conventional procedure.
  • an in vivo cleavable ester of a naphthyridine derivative of the Formula Ib may be obtained by, for example, reaction of a compound of the Formula Ib containing a carboxy group with a pharmaceutically-acceptable alcohol or by reaction of a compound of the Formula Ib containing a hydroxy group with a pharmaceutically-acceptable carboxylic acid.
  • an in vivo cleavable amide of a quinoline derivative of the Formula Ib may be obtained by, for example, reaction of a compound of the Formula Ib containing a carboxy group with a pharmaceutically-acceptable amine or by reaction of a compound of the Formula Ib containing an amino group with a pharmaceutically-acceptable carboxylic acid.
  • 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
  • test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the tyrosine kinase enzymes PDGFR ⁇ , PDGFR ⁇ and KDR was assessed using conventional ELISA assays.
  • 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.
  • VEGF receptor KDR Genebank Accession No. L04947
  • a DNA fragment encoding most of the cytoplasmic domain, commencing with methionine 806 and including the termination codon may be cloned into a baculoviras transplacement vector [for example pAcYMl (see The Baculovirus Expression System: A Laboratory Guide, L.A. King and R. D.
  • This recombinant construct may be co-transfected into insect cells [for example Spodoptera frugiperda 21(S£21) or Spodoptera frugiperda 9(Sf9)] with viral DNA (for example Pharmingen BaculoGold) to prepare recombinant baculovirus.
  • insect cells for example Spodoptera frugiperda 21(S£21) 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 5 ]VJV ' ⁇ V '-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
  • a substrate solution [100 ⁇ l of a 2 ⁇ g/ml solution of the poly-amino acid 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 Q 96-well MaxiSorp immunoplates (Nunc, Roskilde, Denmark; Catalogue No. 439454) and the plates were sealed and stored at 4°C for 16 hours.
  • PBS phosphate buffered saline
  • 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.
  • Active human PDGFR ⁇ and PDGFR ⁇ recombinant enzyme that had been expressed in 5 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 0 and 0.2 mM 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
  • An MG63 osteosarcoma cell line [American Type Culture Collection (ATCC) CCL 1427] was routinely maintained at 37°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 solution from the wells was removed and the cells were lysed by the addition of 120 ⁇ l/well of RIP A buffer comprising 60 mM tra(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.).
  • the resultant tissue culture plates were shaken for 5 minutes at ambient temperature to ensure full lysis and then frozen at -2O 0 C until required.
  • tissue culture plates with frozen cell lysate were allowed to warm to O 0 C. Aliquots (50 ⁇ l) of the MG63 cell lysate were added to the ELISA plates. Each sample was duplicated on separate plates. The ELISA plates were agitated at ambient temperature for 2 hours. The wells were washed twice with 300 ⁇ l per well of PBST. A 1 : 1000 dilution of phospho PDGFR ⁇ antibody (Cell Signaling Technology, Beverley, MA, USA; Catalogue No. 3161) was made into 1% BSA in PBST. Aliquots (50 ⁇ l) of the antibody solutions were added to each of the wells. The plates were agitated at ambient temperature for 1 hour.
  • the cells were detached from the culture flask using a trypsin/ethylenediaminetetraacetic acid (EDTA) mixture (Invitrogen Ltd.; Catalogue
  • 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, 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.
  • the resultant tissue culture plates were shaken for 5 minutes at ambient temperature to ensure full lysis before being frozen on dry-ice and stored at -2O 0 C until required. MaxiSorp ELISA plates (Nunc; Catalogue No.
  • 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, 1% charcoal-stripped FCS and 2 mM glutamine and the cells were incubated overnight at 37 0 C with 7.5% CO 2 .
  • 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.
  • 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
  • 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, 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 naphthyridine compound disclosed as the third Compound listed in Table II within Example 4 possesses activity in Test (b) with an IC 50 versus phospho-Tyr751 formation in PDGFR ⁇ of approximately 12 nM; and activity in Test (c) with an IC 50 versus phospho-tyrosine formation in KDR of greater than 5 ⁇ M.
  • the naphthyridine compound disclosed as Example 10 possesses activity in Test (b) with an IC 50 versus phospho-Tyr751 formation in PDGFR ⁇ of approximately 20 nM; and activity in Test (c) with an IC 5O versus phospho-tyrosine formation in KDR of greater than l ⁇ M. 5
  • a pharmaceutical composition which comprises a naphthyridine derivative of the Formula Ia or Ib, 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 S 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 0 oily solution for intravenous, subcutaneous, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as S tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • a formulation intended for oral administration to humans will generally contain, for example, from 1 mg to 1 g of active agent (more suitably from 1 to 250 mg, for example from 1 to 100 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • 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 Ia or Ib, 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 Ia or Ib, 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) 3 chronic myelomonocytic leukaemia (CMML), acute lymphocytic leukaemia (ALL), chronic neutrophilic leukaemia (CNL), acute myelogenous leukaemia (AML) and multiple myeloma.
  • CML chronic myelogenous leukaemia
  • a method for treating cell proliferative disorders such as solid tumour disease
  • a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a naphthyridine derivative of the Formula Ia or Ib, 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
  • a naphthyridine derivative of the Formula Ia or Ib, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment (or prevention) of those tumours which are sensitive to inhibition of 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 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 Ia or Ib, 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 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 Ia or Ib, 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 :-
  • 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 fluoropyrimidines like
  • antitumour antibiotics for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirabicin, idarabicin, mitomycin-C, dactinomycin and mithraniycin
  • antimitotic agents for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine, taxoids like taxol and taxotere, and polo kinase inhibitors
  • topoisomerase inhibitors for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran- 4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function];
  • c-Src kinase family inhibitors like 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran- 4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and bosutinib (SKI-606),
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies [for example the anti-erbB2 antibody trastuzumab and the anti-erbBl antibodies cetuximab (C225) and panitumumab]; such inhibitors also include, for example, tyrosine kinase inhibitors [for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib (ZD 1839), erlotinib (OSI-774) and CI 1033, and erbB2 tyrosine kinase inhibitors such as lapatinib), inhibitors of the hepatocyte growth factor family, inhibitors of the insulin growth factor receptor, other inhibitors of the platelet-derived growth factor family and/or bcr/abl kinase such as imatinib, dasatinib (BMS-354825) and nilotinib
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example an anti-vascular endothelial cell growth factor antibody such as bevacizumab (AvastinTM) or, for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SUl 1248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin- l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), or, for example, a compound that works by another mechanism (for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin)];
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy
  • immunotherapy approaches including for example ex- vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokin
  • 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 Ia or Ib as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore.
  • a pharmaceutical product comprising a naphthyridine derivative of the Formula Ia or Ib 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 a combination suitable for use in the treatment of cell proliferative disorders (such as solid tumour disease) comprising a naphthyridine derivative of the Formula Ia or Ib as defined hereinbefore and an antiangiogenic agent as defined hereinbefore.
  • a pharmaceutical product comprising a naphthyridine derivative of the Formula Ia or Ib 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.
  • 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 Ia or Ib as defined hereinbefore and an anti-invasion agent as defined hereinbefore.
  • a pharmaceutical product comprising a naphthyridine derivative of the Formula Ia or Ib 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, vatalanib, sunitinib or AZD2171
  • an anti-invasion agent for example, a c-Src kinase family inhibitor such as AZ
  • a combination suitable for use in the treatment of cell proliferative disorders comprising a naphthyridine derivative of the Formula Ia or Ib 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 Ia or Ib 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 Ia or Ib 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 invention will now be illustrated in the following Examples in which, generally :
  • the 2- [2-methoxy-4-(l,7-naphthyridin-4-yloxy)phenyl] acetic acid used as a starting material was prepared as follows :- tert-Butyl 2-(4-hydroxy-2-methoxyphenyl)acetate 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 0 C. The resultant mixture was heated to that temperature range for
  • a portion (6 g) of the material so obtained was added portionwise to a mixture (360 ml) of biphenyl and diphenyl ether ('Dowtherm A') that had been warmed to 250 0 C and the resultant mixture was heated to 250°C for 5 minutes.
  • the mixture was cooled to ambient temperature and diluted with petroleum ether (b.p. 60-80 0 C). The precipitate was isolated, washed with petroleum ether and dried under vacuum.
  • Phosphorus oxychloride (7.3 ml) was added to a stirred mixture of 1,4-dihydro- l,7-naphthyridin-4-one (5.85 g), diisopropylethylamine (13.8 ml) and acetonitrile (50 ml) and the resultant mixture was heated to 70°C for 2 hours. The mixture was cooled to ambient temperature and concentrated by evaporation. The residue was purified by column chromatography on silica using a solvent gradient from 4:1 to 1:4 of methylene chloride and ethyl acetate as eluent.
  • 2-hydroxypyridine iV-oxide (1.93 g) were added in turn to a stirred mixture of 2-(4-benzyloxy- 2-methoxyphenyl)acetic acid (2.37 g), 5-amino-3-ethyl-lH-pyrazole (1.93 g), diisopropylethylamine (6.07 ml) and DMF (30 ml) at ambient temperature.
  • the resultant mixture was stirred and heated to 70°C for 5 hours.
  • the mixture was evaporated and the residue was partitioned between ethyl acetate and water.
  • the organic solution was dried over magnesium sulphate and evaporated.
  • Acetonitrile (1.17 ml) was added dropwise to a stirred solution of n-butyllithium (1.6M in hexane, 14.06 ml) that had been cooled to -78°C and the mixture was stirred at that temperature for 1 hour.
  • Ethyl propionate (1.5 ml) was added dropwise and the reaction medium was allowed to warm to -45 °C and stirred at that temperature for 2 hours.
  • the resultant mixture was acidifed to pH2 by the addition of 2N aqueous hydrochloric acid and concentrated by evaporation. The residue was extracted with methylene chloride and the organic extract was dried over magnesium sulphate and evaporated.
  • JV-(I -ethyl- li ⁇ -pyrazol-4-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide used as a io starting material was prepared as follows :-
  • 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 0 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 pH5 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.
  • 1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.243 g) were added in turn to a stirred mixture of 2-[2-methoxy-4-(l,7-naphthyridin-4-yloxy)phenyl]acetic acid (0.17 g), 3-amino-5-ethylisoxazole (0.072 g) and DMF (3 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. The resultant mixture was evaporated and the residue was purified by column chromatography on silica using a solvent gradient from 19:1 to 9:1 mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound.
  • Example 8 iV-(4,5-dimethyl-l/- r -pyrazol-3-yl)-2-[2-inethoxy-4-(6-methoxy-l,7-iiaphthyridin- 4-yloxy)phenyl] acetamide
  • 4-chloro-6-methoxy-l ,7-naphthyridine 0.1 g
  • iV-(4,5-dimethyl- lH-pyrazol-3-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide (0.141 g)
  • caesium carbonate 0.502 g
  • DMF 1.5 ml
  • the resultant mixture was cooled to ambient temperature and filtered.
  • the filtrate was purified by reversed-phase preparative HPLC on a Waters ' ⁇ Basic HypersiF 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 4-amino-l,3-dimethyl-li/-pyrazole used as a starting material was obtainable commercially from Sigma-Aldrich, Gillingham, SP 8 4XT 5 UK.
  • the compound may also be 0 prepared according to the procedure disclosed in Chemical Abstracts volume 94, Abstract No. 103228 (Zhurnal Obshchei Khimii, 1980, 50, 2106-9).
  • the resultant mixture was stirred at ambient temperature for 18 hours.
  • the mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution.
  • the organic solution was dried over magnesium sulphate and evaporated.
  • the residue was purified by column chromatography on silica using a solvent gradient from 19:1 to 9:1 mixtures of methylene chloride and methanol as eluent.
  • the 2-(4-hydroxy-2-methoxyphenyl)acetic acid was prepared as follows :- A mixture of 2-(4-benzyloxy-2-methoxyphenyi)acetic acid (2.18 g), 10% platinum-on- carbon catalyst (0.3 g), ethanol (10 ml) and ethyl acetate (80 ml) was stirred under 3 atmospheres pressure of hydrogen for 2 hours. The reaction mixture was filtered and the filtrate was evaporated.
  • Diisopropylethylamine (58.2 ml) was added to a stirred suspension of 3-aminopyridine- iV-oxide hydrochloride salt (49 g) and 5-(methoxymethylidene)-2,2-dimethyl-l,3-dioxane- 4,6-dione (62.2 g) in isopropanol (150 ml) and the resultant mixture was heated to 9O 0 C for 20 minutes. The mixture was cooled in an ice bath and the precipitate was isolated and washed in turn with cool isopropanol and diethyl ether and dried under vacuum at 50 0 C.
  • a portion (11 g) of the material so obtained was added portionwise to a mixture (120 ml) of biphenyl and diphenyl ether ('Dowtherm A') that had been warmed to 26O 0 C and the resultant mixture was heated to 260 0 C for 10 minutes.
  • the mixture was cooled to ambient temperature and diluted with petroleum ether (b.p. 60-80 0 C). The precipitate was isolated, washed with petroleum ether and dried under vacuum.
  • Iron powder (3.45 g) was added to a solution of 4-hydroxy-5-oxido-l,5-naphthyridine (5 g) in a mixture of acetic acid (100 ml) and pyridine (20 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The mixture was filtered and the solid was washed with acetic acid. The filtrate and washings were combined and concentrated by evaporation. The resultant residue was triturated under acetone. The solid so obtained was recovered, washed with acetone and dried under vacuum.
  • 1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.243 g) were added in turn to a stirred mixture of 2-[2-methoxy-4-(l,5-naphthyridin-4-yloxy)phenyl]acetic acid (0.17 g), 3-amino-5-ethylisoxazole (0.072 g) and DMF (3 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. The resultant mixture was evaporated and the residue was purified by column chromatography on silica using a solvent gradient from 19:1 to 9:1 mixtures of methylene chloride and methanol as eluent.
  • the 4-chloro-6-methoxy-l,5-naphthyridine used as a starting material was prepared as follows :- o 5-(Methoxymethylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione (0.7 g) was added portionwise to a stirred solution of 3-amino-6-rnethoxypyridine (0.516 g) in isopropanol (4 ml). The resultant mixture was stirred and heated to reflux for 1 hour. The mixture was cooled to ambient temperature. The precipitate was isolated and washed with isopropanol.
  • the 4-chloro-7-methoxy-l,5-naphthyridine used as a starting material was prepared as follows :-
  • Phosphorus oxychloride (0.607 ml) was added dropwise to a stirred mixture of 7-methoxy-4-oxo-l,4-dihydro-l,5-naphthyridine (0.83 g), diisopropylethylamine (1.98 ml) and acetonitrile (8.5 ml) that had been cooled to 0°C.
  • the resultant mixture was heated to reflux for 1 hour.
  • the mixture was cooled to ambient temperature and concentrated by evaporation.
  • the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic solution was dried over magnesium sulphate and evaporated.
  • Example 15 Using an analogous procedure to that described in Example 13, the appropriate
  • the 4,7-dichloro-l,5-naphthyridine used as a starting material was prepared as follows :- 5-(Methoxymethylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione (4.3 g) was added portionwise to a stirred solution of 3-amino-5-chloropyridine (4.3 g) in isopropanol (90 ml) and the resultant mixture was heated to 75°C for 1 hour. The mixture was diluted with diethyl ether and the solid was isolated and washed with diethyl ether.
  • the material so obtained was added portionwise to a mixture (90 ml) of biphenyl and diphenyl ether ('Dowtherm A') that had been warmed to 160°C and the resultant mixture was stirred and heated to 210°C for 5 minutes. The mixture was cooled to ambient temperature and diluted with petroleum ether (b.p. 60-80°C). The precipitate was isolated by filtration. A suspension of the precipitate in a 1:1 mixture (100 ml) of methanol and ethanol was stirred for 1 hour. The resultant suspension was filtered.
  • 'Dowtherm A' biphenyl and diphenyl ether
  • Phosphorus oxychloride (1.13 ml) was added dropwise to a stirred mixture of 7-chloro- 4-oxo-l,4-dihydro-l,5-na ⁇ hthyridine (1.6 g), diisopropylethylamine (2.31 ml) and chlorobenzene (5 ml) that had been cooled to 14°C.
  • the resultant mixture was heated to 70°C for 3 hours.
  • the mixture was cooled to ambient temperature and diluted with a saturated aqueous sodium bicarbonate solution.
  • the mixture was extracted with diethyl ether.
  • the organic solution was dried over magnesium sulphate and evaporated.
  • N-(l-methyl-lH-pyrazol-4-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide used as a starting material was prepared as follows :-
  • the 4-chloro-7-ethoxy-l,5-naphthyridine used as a starting material was prepared as follows :- Under an atmosphere of argon, ethanol (4.86 ml) was added dropwise to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 3.33 g) in DMF (30 ml) that had been cooled to 0°C. The mixture was stirred at 0°C for 30 minutes. 3,5-Dibromopyridine (9.86 g) was added and the resultant mixture was allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with water (200 ml) and the aqueous phase was extracted with diethyl ether.
  • each reaction product was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. Unless otherwise stated, each amine was a commercially available material.
  • NMP NMP was used as the reaction solvent and the reactants were heated to 85°C for 16 hours.
  • the reaction product was purified by column chromatography on silica using
  • reaction mixture was allowed to warm to ambient temperature and poured into a stirred mixture of water (300 ml) and diethyl ether (300 ml).
  • the aqueous phase was extracted with diethyl ether.
  • the organic phases were combined, dried over magnesium sulphate and evaporated.
  • the residue was purified by column chromatography on silica using a solvent gradient of 4:1 to 1 :1 petroleum ether and diethyl ether as eluent.
  • 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 50°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 residue was passed through silica (70 g) using a 1 :1 mixture of petroleum 01221
  • 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.
  • 1-tert-Butylhydrazine hydrochloride (1.55 g) was added to a stirred solution of 2-methyl- 3-oxobutanenitrile (1 g) in ethanol (10 ml) and the resultant mixture was heated to 85°C for 5 hours. The mixture was concentrated by evaporation and 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 ethyl acetate as eluent.
  • the 5-amino-l-tert-butyl-4-ethylpyrazole used as a starting material was prepared as follows :- s Under an atmosphere of argon, a solution of a mixture of butyronitrile (2.18 ml) and ethyl formate (2.11 ml) in THF (4 ml) was added dropwise to a stirred suspension of potassium fert-butoxide (6.18 g) in THF (40 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residual solid was suspended in ether, isolated by filtration and washed with diethyl ether.

Abstract

L'invention concerne des dérivés de naphtyridine répondant à la formule Ia ou Ib (il convient d'insérer une formule chimique à cet endroit – prière de consulter la copie papier accompagnante) ou un sel pharmaceutiquement acceptable desdits dérivés, les valeurs X1, p, R1, G1, G2, q, R2, R3, R4, R5, Noyau A, r et R6 ayant chacune l'une quelconque des significations définies précédemment dans la description; l'invention concerne également des compositions pharmaceutiques contenant lesdits dérivés et leur utilisation dans le traitement de troubles liés à une prolifération cellulaire ou d'états pathologiques associés à l'angiogenèse et/ou la perméabilité vasculaire.
PCT/GB2007/001221 2006-04-06 2007-04-04 Dérivés de naphtyridine WO2007113548A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP06300336 2006-04-06
EP06300336.2 2006-04-06
EP06300812 2006-07-19
EP06300816.3 2006-07-19
EP06300816 2006-07-19
EP06300812.2 2006-07-19

Publications (1)

Publication Number Publication Date
WO2007113548A1 true WO2007113548A1 (fr) 2007-10-11

Family

ID=38219515

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2007/001221 WO2007113548A1 (fr) 2006-04-06 2007-04-04 Dérivés de naphtyridine

Country Status (1)

Country Link
WO (1) WO2007113548A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7973164B2 (en) 2006-03-02 2011-07-05 Astrazeneca Ab Quinoline derivatives
US8153643B2 (en) 2004-10-12 2012-04-10 Astrazeneca Ab Quinazoline derivatives
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
US9029378B2 (en) 2011-07-26 2015-05-12 Gruenenthal Gmbh Substituted bicyclic aromatic carboxamide and urea compounds as vanilloid receptor ligands
CN105683182A (zh) * 2013-08-30 2016-06-15 埃姆比特生物科学公司 联芳基乙酰胺化合物及其使用方法
US10647705B2 (en) 2017-11-14 2020-05-12 Merck Sharp & Dohme Corp. Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US10851092B2 (en) 2016-09-29 2020-12-01 Daiichi Sankyo Company, Limited Pyridine compound
US11498904B2 (en) 2017-11-14 2022-11-15 Merck Sharp & Dohme Llc Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0929526A1 (fr) * 1996-09-25 1999-07-21 Zeneca Limited Derives quinolines inhibant les effets de facteurs de croissance tels que le facteur de croissance endotheliale vasculaire
WO2005021554A1 (fr) * 2003-08-29 2005-03-10 Pfizer Inc. Thienopyridine-phenylacetamides et leurs derives utiles comme nouveaux agents anti-angiogeniques
US20060058523A1 (en) * 2002-12-24 2006-03-16 Astrazeneca Ab Quinazoline compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0929526A1 (fr) * 1996-09-25 1999-07-21 Zeneca Limited Derives quinolines inhibant les effets de facteurs de croissance tels que le facteur de croissance endotheliale vasculaire
US20060058523A1 (en) * 2002-12-24 2006-03-16 Astrazeneca Ab Quinazoline compounds
WO2005021554A1 (fr) * 2003-08-29 2005-03-10 Pfizer Inc. Thienopyridine-phenylacetamides et leurs derives utiles comme nouveaux agents anti-angiogeniques

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8153643B2 (en) 2004-10-12 2012-04-10 Astrazeneca Ab Quinazoline derivatives
US7973164B2 (en) 2006-03-02 2011-07-05 Astrazeneca Ab Quinoline derivatives
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
US9029378B2 (en) 2011-07-26 2015-05-12 Gruenenthal Gmbh Substituted bicyclic aromatic carboxamide and urea compounds as vanilloid receptor ligands
CN105683182A (zh) * 2013-08-30 2016-06-15 埃姆比特生物科学公司 联芳基乙酰胺化合物及其使用方法
US10851092B2 (en) 2016-09-29 2020-12-01 Daiichi Sankyo Company, Limited Pyridine compound
US10647705B2 (en) 2017-11-14 2020-05-12 Merck Sharp & Dohme Corp. Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US10995085B2 (en) 2017-11-14 2021-05-04 Merck Sharp & Dohme Corp. Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US11498904B2 (en) 2017-11-14 2022-11-15 Merck Sharp & Dohme Llc Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors

Similar Documents

Publication Publication Date Title
US7973164B2 (en) Quinoline derivatives
EP1802591B1 (fr) Derives de quinazoline
WO2007113565A1 (fr) Dérivés de la naphtyridine comme agents anti-cancéreux
US20090233950A1 (en) Quinazoline derivatives
US20090036474A1 (en) Quinazoline derivatives for use against cancer
CA2571756A1 (fr) Pyrimidines 2,4,6-trisubstitutees utilisees comme inhibiteurs de phosphotidylinositol (pi) 3-kinase et leur utilisation dans le traitement du cancer
US20090042910A1 (en) Quinoline derivatives for treating cancer
WO2007113548A1 (fr) Dérivés de naphtyridine
US20090036485A1 (en) Quinoline derivatives
US20090076075A1 (en) Quinoline derivatives
US20120165351A1 (en) Quinazoline derivatives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07732271

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07732271

Country of ref document: EP

Kind code of ref document: A1