WO2007066103A1 - Dérivés de pyrimidine utilisés comme inhibiteurs de la pi3k de classe i - Google Patents

Dérivés de pyrimidine utilisés comme inhibiteurs de la pi3k de classe i Download PDF

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WO2007066103A1
WO2007066103A1 PCT/GB2006/004554 GB2006004554W WO2007066103A1 WO 2007066103 A1 WO2007066103 A1 WO 2007066103A1 GB 2006004554 W GB2006004554 W GB 2006004554W WO 2007066103 A1 WO2007066103 A1 WO 2007066103A1
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alkyl
group
formula
hydroxy
methyl
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Simon Philip Mutton
Martin Pass
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Astrazeneca Ab
Astrazeneca Uk Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention concerns certain novel pyrimidine derivatives, or
  • the invention also concerns processes for the manufacture of said pyrimidine derivatives, pharmaceutical compositions containing them and their use in therapeutic methods, for example in the manufacture of medicaments for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.
  • a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene, that is a gene which, on activation, leads to the formation of malignant tumour cells (Bradshaw, Mutagenesis, 1986, 1, 91).
  • oncogenes give rise to the production of peptides which are receptors for growth factors. Activation of the growth factor receptor complex subsequently leads to an increase in cell proliferation. It is known, for example, that several oncogenes encode tyrosine kinase enzymes and that certain growth factor receptors are also tyrosine kinase enzymes
  • the first group of tyrosine kinases to be identified a rose from such viral oncogenes, for example pp60 v"Src tyrosine kinase (otherwise known as v-Src), and the corresponding tyrosine kinases in normal cells, for example pp60 c"Sro tyrosine kinase
  • Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication. They are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation.
  • EGF epidermal growth factor
  • Various classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research. 1993, 60, 43-73) based on families of growth factors which bind to different receptor tyrosine kinases. The classification includes Class I receptor tyrosine kinases comprising the EGF family of receptor tyrosine kinases such as the EGF, TGFa 5 Neu and erbB receptors.
  • tyrosine kinases belong to the class of non-receptor tyrosine kinases which are located intracellularly and are involved in the transmission of biochemical signals such as those that influence tumour cell motility, dissemination and invasiveness and subsequently metastatic tumour growth.
  • Various classes of non-receptor tyrosine kinases are known including the Src family such as the Src, Lyn, Fyn and Yes tyrosine kinases.
  • kinases belong to the class of serine/threonine kinases which are located intracellularly and downstream of tyrosine kinase activation and are involved in the transmission of biochemical signals such as those that influence tumour cell growth.
  • serine/threonine signalling pathways include the Raf-MEK-ERK cascade and those
  • PDK lipid kinase downstream of the lipid kinase known as PDK such as PDK-I 5 AKT and mTOR
  • lipid kinases that belong to the class of lipid kinases are located intracellularly and are also involved in the transmission of biochemical signals such as those that influence tumour cell growth and invasiveness.
  • Various classes of lipid kinases are known including the phosphoinositide 3-kinase (abbreviated hereinafter to PI3K) family that is alternatively known as the phosphatidylinositol-3-kinase family.
  • the PI3K family of lipid kinases is a group of enzymes that phosphorylate the
  • PI3K enzymes Three major groups of PI3K enzymes are known which are classified according to their physiological substrate specificity (Vanhaesebroeck et al, Trends in Biol. ScL, 1997, 22, 267). Class III PI3K enzymes phosphorylate PI alone. In contrast, Class II PI3K enzymes phosphorylate both PI and PI 4-phosphate [abbreviated hereinafter to PI(4)P].
  • Class I PI3K enzymes phosphorylate PI 5 PI(4)P and PI 4,5-bis ⁇ hosphate [abbreviated hereinafter to PI(4,5)P2], although only PI(4,5)P2 is believed to be the physiological cellular substrate. Phosphorylation of PI(4,5)P2 produces the lipid second messenger PI 3,4,5-triphosphate [abbreviated hereinafter to PI(3,4,5)P3]. More distantly related members of this superfamily are Class IV kinases such as mTOR and DNA-dependent kinase that phosphorylate serine/threonine residues within protein substrates. The most studied and understood of these lipid kinases are the Class I PI3K enzymes.
  • Class I PI3K is a heterodimer consisting of a pi 10 catalytic subunit and a regulatory subunit, and the family is further divided into Class Ia and Class Ib enzymes on the basis of regulatory partners and mechanism of regulation.
  • Class Ia enzymes consist of three distinct catalytic subunits (pi 10a, pi lO ⁇ and pi lO ⁇ ) that dimerise with five distinct regulatory subunits (p85 ⁇ , p55 ⁇ , p50 ⁇ , p85 ⁇ and p55 ⁇ ), with all catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers.
  • Class Ia PI3K are generally activated in response to growth factor-stimulation of receptor tyrosine kinases, via interaction of the regulatory subunit SH2 domains with specific phospho-tyrosine residues of the activated receptor or adaptor proteins such as IRS-I. Both pi 10a and pi lO ⁇ are constitutively expressed in all cell types, whereas pi lO ⁇ expression is more restricted to leukocyte populations and some epithelial cells. In contrast, the single Class Ib enzyme consists of a pi lO ⁇ catalytic subunit that interacts with a plOl regulatory subunit. Furthermore, the
  • Class Ib enzyme is activated in response to G-protein coupled receptor (GPCR) systems and its expression appears to be limited to leucocytes.
  • GPCR G-protein coupled receptor
  • Class Ia PI3K contributes to tumourigenic events that occur upstream in signalling pathways, for example by way of ligand-dependent or - A - ligand-independent activation of receptor tyrosine kinases, GPCR systems or integrins (Vara et al, Cancer Treatment Reviews, 2004, 30, 193-204).
  • upstream signalling pathways examples include over-expression of the receptor tyrosine kinase Erb2 in a variety of tumours leading to activation of PI3K-mediated pathways (Harari et al, Oncogene, 2000, 19, 6102-6114) and over-expression of the oncogene Ras (Kauffmann-Zeh et ⁇ /., Nature, 1997, 385_, 544-548).
  • Class Ia PDKs may contribute indirectly to tumourigenesis caused by various downstream signalling events.
  • loss of the effect of the PTEN tumour-suppressor phosphatase that catalyses conversion of PI(3,4,5)P3 back to PI(4,5)P2 is associated with a very broad range of tumours via deregulation of PI3K-mediated production of PI(3,4,5)P3 (Simpson and Parsons, Exp. Cell Res.. 2001, 264, 29-41).
  • augmentation of the effects of other PI3K-mediated signalling events is believed to contribute to a variety of cancers, for example by activation of Akt (Nicholson and Anderson, Cellular Signalling, 2002, IA, 381-395).
  • Class Ia PI3K enzymes will also contribute to tumourigenesis via its function in tumour-associated stromal cells.
  • PI3K signalling is known to play an important role in mediating angiogenic events in endothelial cells in response to pro-angiogenic factors such as VEGF (Abid et al., Arterioscler. Thromb. Vase. Biol., 2004, 24, 294-300).
  • VEGF vascular endothelial cells
  • VEGF vascular endothelial growth factor
  • PI3K inhibitors should provide therapeutic benefit via inhibition of tumour cell invasion and metastasis.
  • Class I PI3K enzymes play an important role in the regulation of immune cells with PI3K activity contributing to pro-tumourigenic effects of inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867).
  • inhibitors of Class I PI3K enzymes should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
  • cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva,
  • PI3K inhibitors LY294002 and wortmannin are not sufficiently selective within the PI3K family to allow dissection of the individual roles of the family members. For this reason, more potent and selective pharmaceutical PI3K inhibitors would be useful to allow a more complete understanding of PI3K function and to provide useful therapeutic agents.
  • Class I PI3K enzymes play a role in other diseases (Wymann et al, Trends in PharmacoloRJcal Science, 2003, 24, 366-376). Both Class Ia PI3K enzymes and the single Class Ib enzyme have important roles in cells of the immune system (Koyasu, Nature Immunology, 2003, 4, 313-319) and thus they are therapeutic targets for inflammatory and allergic indications. Inhibition of PI3K is also useful to treat cardiovascular disease via anti-inflammatory effects or directly by affecting cardiac myocytes (Prasad et al, Trends in Cardiovascular Medicine. 2003, 13, 206-212). Thus inhibitors of Class I PI3K enzymes are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer.
  • 2-aryl-4-piperazin-l-ylpyrimidine compounds such as :- 2-(3-chlorophenyl)-6-morpholino-4-[4-(3-trifluoromethylpyridin-2-yl)piperazin-l- yl]pyrimidine and
  • the compounds of the present invention are also useful in inhibiting the uncontrolled cellular proliferation which arises from various non-malignant diseases such as inflammatory diseases (for example rheumatoid arthritis and inflammatory bowel disease), fibrotic diseases (for example hepatic cirrhosis and lung fibrosis), glomerulonephritis, multiple sclerosis, psoriasis, benign prostatic hypertrophy (BPH), hypersensitivity reactions of the skin, blood vessel diseases (for example atherosclerosis and restenosis), allergic asthma,
  • inflammatory diseases for example rheumatoid arthritis and inflammatory bowel disease
  • fibrotic diseases for example hepatic cirrhosis and lung fibrosis
  • glomerulonephritis for example hepatic cirrhosis and lung fibrosis
  • multiple sclerosis multiple sclerosis
  • psoriasis glomerulonephritis
  • benign prostatic hypertrophy (BPH) benign prostatic hypertrophy
  • the compounds of the present invention possess potent inhibitory activity against Class I PI3K enzymes, particularly against Class Ia PI3K enzymes, whilst possessing less potent inhibitory activity against tyrosine kinase enzymes such as the receptor tyrosine kinases, for example EGF receptor tyrosine kinase and/or VEGF receptor tyrosine kinase, or against non-receptor tyrosine kinases such as Src.
  • the receptor tyrosine kinases for example EGF receptor tyrosine kinase and/or VEGF receptor tyrosine kinase
  • non-receptor tyrosine kinases such as Src.
  • certain compounds of the present invention possess substantially better potency against Class I PI3K enzymes, particularly against Class Ia PBK enzymes, than against EGF receptor tyrosine kinase or VEGF receptor tyrosine kinase or Src non-receptor tyrosine kinase.
  • Such compounds possess sufficient potency against Class I PI3K enzymes that they may be used in an amount sufficient to inhibit Class I PBK enzymes, particularly to inhibit Class Ia PBK enzymes, whilst demonstrating little activity against EGF receptor tyrosine kinase or VEGF receptor tyrosine kinase or Src non-receptor tyrosine kinase.
  • the mammalian target of the macrolide antibiotic Rapamycin is the enzyme mTOR that belongs to the phosphatidylinositol (PI) kinase-related kinase (PIKK) family of protein kinases, which includes ATM, ATR, DNA-PK and hSMG-1.
  • PI phosphatidylinositol
  • PIKK phosphatidylinositol
  • mTOR phosphatidylinositol
  • PIKK phosphatidylinositol
  • PIKK phosphatidylinositol
  • PIKK phosphatidylinositol
  • mTOR phosphatidylinositol
  • PIKK phosphatidylinositol
  • PIKK phosphatidylinositol
  • mTOR kinase-related kinase
  • Much of the knowledge of mTOR signalling is
  • mTOR protein consists of a catalytic kinase domain, an FKBP12-Rapamycin binding (FRB) domain, a putative repressor domain near the C-terminus and up to 20 tandemly-repeated HEAT motifs at the iV-terminus, as well as FRAP-ATM-TRRAP (FAT) and FAT C-terminus domain (Huang and Houghton, Current Opinion in Pharmacology, 2003, 3, 371-377).
  • FKBP 12 FKBP12-Rapamycin binding
  • mTOR kinase is a key regulator of cell growth and has been shown to regulate a wide range of cellular functions including translation, transcription, mRNA turnover, protein stability, actin cytoskeleton reorganisation and autophagy (Jacinto and Hall, Nature Reviews Molecular and Cell Biology, 2005, 4, 117-126).
  • mTOR kinase integrates signals from growth factors (such as insulin or insulin-like growth factor) and nutrients (such as amino acids and glucose) to regulate cell growth.
  • growth factors such as insulin or insulin-like growth factor
  • nutrients such as amino acids and glucose
  • mTOR kinase The most well characterised function of mTOR kinase in mammalian cells is regulation of translation through two pathways, namely activation of ribosomal S6K1 to enhance translation of mRNAs that bear a 5 '-terminal oligopyrimidine tract (TOP) and suppression of 4E-BP1 to allow CAP-dependent mRNA translation.
  • TOP 5 '-terminal oligopyrimidine tract
  • 4E-BP1 4E-BP1
  • Rapamycin displays variable inhibitory actions on mTOR signalling functions and suggest that direct inhibition of the mTOR kinase domain may display substantially broader anti-cancer activities than that achieved by Rapamycin (Edinger et al., Cancer Research, 2003, 63, 8451-8460). For this reason, potent and selective inhibitors of mTOR kinase activity would be useful to allow a more complete understanding of mTOR kinase function and to provide useful therapeutic agents.
  • PI3K pathway components of the PI3K pathway that are mutated in different human tumours include activating mutations of growth factor receptors and the amplification and/or overexpression of PI3K and Akt.
  • endothelial cell proliferation may also be dependent upon mTOR signalling.
  • Endothelial cell proliferation is stimulated by vascular endothelial cell growth factor (VEGF) activation of the PI3K-Akt-mTOR signalling pathway (Dancey, Expert Opinion on Investigational Drugs, 2005, H, 313-328).
  • VEGF vascular endothelial cell growth factor
  • mTOR kinase signalling is believed to partially control VEGF synthesis through effects on the expression of hypoxia- inducible factor- l ⁇ (HIF- l ⁇ ) (Hudson etal, Molecular and Cellular Biology. 2002, 22, 7004- 7014).
  • tumour angiogenesis may depend on mTOR kinase signalling in two ways, through hypoxia-induced synthesis of VEGF by tumour and stromal cells, and through VEGF stimulation of endothelial proliferation and survival through PI3K-Akt-mTOR signalling.
  • pharmacological inhibitors of mTOR kinase should be of therapeutic value for treatment of the various forms of the disease of cancer comprising solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies.
  • tumour suppressor proteins such as TSCl, TSC2, PTEN and LKBl tightly control mTOR kinase signalling. Loss of these tumour suppressor proteins leads to a range of hamartoma conditions as a result of elevated mTOR kinase signalling (Tee and Blenis, Seminars in Cell and Developmental Biology. 2005, V6, 29-37).
  • mTOR kinase Syndromes with an established molecular link to dysregulation of mTOR kinase include Koz-Jeghers syndrome (PJS), Cowden disease, Bannayan-Riley- Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and TSC
  • Rapamycin has been demonstrated to be a potent immunosuppressant by inhibiting antigen-induced proliferation of T cells, B cells and antibody production (Sehgal, Transplantation Proceedings, 2003, 35_, 7S-14S) and thus mTOR kinase inhibitors may also be useful immunosuppressives.
  • Inhibition of the kinase activity of mTOR may also be useful in the prevention of restenosis, that is the control of undesired proliferation of normal cells in the vasculature in response to the introduction of stents in the treatment of vasculature disease (Morice et ah, New England Journal of Medicine. 2002, 346, 1773-1780).
  • the Rapamycin analogue, everolimus can reduce the severity and incidence of cardiac allograft vasculopathy
  • mTOR kinase inhibitors are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer.
  • each R 1 group which may be the same or different, is selected from halogeno, ti ⁇ fluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, ureido, (l-SC)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy,
  • (l-6C)alkylsulphonyl (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l- ⁇ C)alkoxycarbonyl, iV-(l-6C)alkylcarbamoyl, N ⁇ V-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl,
  • N-(l-6C)alkyl-(3-6C)alkynoylamino iV'-(l-6C)alkylureido, iV' ⁇ '-di-[(l-6C)alkyl]ureido, iV-(l-6C)alkylureido, JV,;V'-di-[(l-6C)alkyl]ureido, iV,N' ⁇ '-tri-[(l-6C)alkyl]ureido,
  • any CH, CH 2 or CH 3 group within a R 1 substiruent 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, (l- ⁇ C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylammo, di-[(l-6C)alkyl]amino, (l- ⁇ C)alkoxycarbonyl, ⁇ r -(l-6C)alkylcarbamoyl,
  • R 6 is hydrogen or (l-8C)alkyl
  • Q 3 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 s group within a substituent
  • X 4 is a direct bond or is selected from O and N(R 8 ), wherein R 8 is hydrogen or (l-SC)alkyl, and R 7 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, cyano ⁇ (l -6C)alkyl,
  • X 5 is a direct bond or is selected from O, CO and N(R 9 ), wherein R 9 is hydrogen or (l-8C)alkyl, and 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- ⁇ C)alkoxy,
  • q O, 1, 2, 3 or 4;
  • each R 3 group which may be the same or different, is (l-8C)alkyl or a group of the formula :
  • X 6 is a direct bond or is selected from O and N(R 12 ), wherein R 12 is hydrogen or
  • R 11 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl,
  • r 0, 1 or 2;
  • each R 4 group which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, mercapto, amino, carboxy, carbamoyl, ureido,
  • JV-(I -6C)alkylsulphamoyl iVJV-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(I -6C)alkyl-(l -6C)alkanesulphonylamino;
  • X 1 is selected from CO, S, SO, SO 2 , CON(R 13 ), COC(R 13 ) 2 O, COC(R 13 ) 2 S,
  • Q 1 is (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, halogeno-(l-6C)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,
  • any CH, CH 2 or CH 3 group within the Q 1 group optionally bears on each said CH, CH 2 or CH 3 group one or more halogeno or (1 -8C)alkyl substituents and/or a substituent selected from hydroxy, mercapto, amino, cyano, carboxy, carbamoyl, ureido, formamido, (l- ⁇ C)alkoxy, (l-6C)alkylthio 5 (l- ⁇ C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, JV-(I -6C)alkylcarbamoyl, JV,JV-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkano
  • any aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl group within the Q 1 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, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy,
  • (l- ⁇ C)alkylsulphonyl (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, JV-(I -6C)alkylcarbamoyl, JV,JV-di-[(l -6C)aIkyl] carbamoyl, (2-6C)alkanoylamino, JV-(l-6C)alkyl-(2-6C)alkanoylamino, JV'-(l-6C)alkylureido,
  • X 7 is a direct bond or is selected from O and N(R 15 ), wherein R 15 is hydrogen or (l-8C)alkyl, and R 14 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
  • any heterocyclyl group within the Q 1 group optionally bears 1 or 2 oxo or thioxo substituents
  • (l-8C)alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also
  • (3-8C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and also (3-6C)cycloalkyl-(l-2C)alkyl groups such as cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl,
  • 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, cyclobutylamino, cyclohexylamino, cyclopropylmethylamino,
  • cyclopentylmethylamino and 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, N-cyclopropyl-iV-methylammo, N-cyclobutyl-N-methylamino, N-cyclohexyl-N-ethylamino, N-cyclopropylmethyl-N-methylamino, iV-(2-cyclopropylethyl)- iV-methylamino and iV-cyclopentylmethyl-iV-methylamino.
  • optically active or racemic forms by virtue of one or more asymmetric carbon atoms
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • tautomerism may affect heterocyclic groups within the R 1 and Q 1 groups that bear 1 or 2 oxo or thioxo substituents.
  • present invention includes in its definition any such tautomeric form, or a mixture thereof, which possesses the above-mentioned activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings or named in the Examples.
  • any R 1 group that is present on the phenyl group that is located at the 2-position on the pyrimidine ring may be located at any available position on said phenyl group.
  • the R 1 groups may be the same or different.
  • any R 3 group that may be present on the morpholinyl group that is located at the 6-position on the pyrimidine ring may be located at any available position on said morpholinyl group.
  • any R 4 group that may be present on the piperidine or tetrahydropyridine group that is located at the 4-position on the pyrimidine ring may be located at any available position on said piperidine or tetrahydropyridine group, including at the 4-position of any such 4-piperidinyl ring.
  • the R 4 group is a
  • any two such groups may be located at the same ring position on said piperidine or tetrahydropyridine group.
  • there is a single R 4 group. More conveniently, no R 4 group is present (r 0).
  • 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 5 ) when it is aryl or for the aryl group within a 'Q' group is, for example, phenyl or naphthyl, preferably phenyl.
  • (3-8C)cycloalkyl or for the (3-8C)cycloalkyl group within a 'Q' group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl or cyclooctyl and a suitable value for any one of the 'Q' groups (Q 1 to Q 3 ) when it is
  • (3-8C)cycloalkenyl or for the (3-8C)cycloalkenyl group within a '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 5 ) when it is heteroaryl or for the heteroaryl group within a '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, benzoxazolyl, benzimidazolyl, be
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 5 ) when it is heterocyclyl or for the heterocyclyl group within a '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, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, oxazolidine, thiazolidine, 2-azabicyclo[2.2.1]heptyl, quinuclidinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl,
  • tetrahydropyrimidinyl or tetrahydropyridazine preferably tetrahydrofuranyl
  • tetrahydropyranyl pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl.
  • 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-oxooxazolidinyl, 2-oxothiazolidinyl, 2-oxopiperidinyl, 4-oxo-l,4-dihydropyridinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
  • a suitable value for a '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,
  • Suitable values for any of the 'R' groups (R 1 to R 17 ), or for various groups within an R 1 , R 3 or R 4 substituent, or for Q 1 , or for various groups within Q 1 include:- for halogeno fluoro, chloro, bromo and iodo;
  • (l-8C)alkyl methyl, ethyl, propyl, isopropyl, f ⁇ rt-butyl,
  • (2-8C)alkenyl vinyl, isopropenyl, allyl and but-2-enyl;
  • (2-8C)alkynyl ethynyl, 2-propynyl and but-2-ynyl;
  • (2-6C)alkynyloxy ethynyloxy and 2-propynyloxy
  • for (l-6C)alkylthio methylthio, ethylthio and propylthio
  • (l-6C)alkylsulphinyl methylsulphinyl and ethylsulphinyl;
  • JV,JV-di-[(l-6C)alkyl]carbamoyl JV.JV-dimethylcarbamoyl, JV-ethyl- JV-methylcarbamoyl and JV,JV-diethylcarbamoyl, for (2-6C)alkanoyl: acetyl, propionyl and isobutyryl;
  • (2-6C)alkanoylamino acetamido and propionamido
  • JV-(I -6C)alkyl-(3-6C)alkynoylamino JV-methylpropiolamido
  • JV-(I -6C)alkylureido JV'-methylureido and JV'-ethylureido;
  • JV-(I -6C)alkylsulphamoyl JV-methylsulphamoyl and JV-ethylsulphamoyl;
  • halogeno-(l-6C)alkyl chloromethyl, 2-fluoroethyl, 2-chloroethyl,
  • hydroxy-(l-6C)alkyl hydroxymethyl, 2-hydroxyethyl, 1 -hydroxy ethyl and
  • mercapto-(l-6C)alkyl mercaptomethyl, 2-mercaptoethyl, 1-mercaptoethyl io and 3-mercaptopropyl;
  • JV'-(l-6C)aIkylureido-(l-6C)alkyl N'-methylureidomethyl, 2-(iV'-methylureido)ethyl and l-(iV'-methylureido)ethyl;
  • N-(I -6C)alkylureido-(l -6C)alkyl iV-methylureidomethyl, 2-(N-methylureido)ethyl and
  • N ⁇ '-di-[(l-6C)alkyl]ureido-(l-6C)alkyl N,iV'-dimethylureidomethyl
  • a suitable value for (R 1 ) p when it is a (l-3C)alkylenedioxy 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 2 -X 2 - and, 5 for example, X 2 is a OC(R 5 ) 2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R 5 ) 2 linking group which is attached to the phenyl ring and the oxygen atom is attached to the Q 2 group.
  • a CH 3 group within a R 1 substituent bears a group of the formula -X 3 -Q 3 and, for example, X 3 is a C(R 6 ) 2 O linking group, it is the carbon atom, not the oxygen atom, of the C(R 6 ) 2 O linking group which is attached to the CH 3 group and the
  • adjacent carbon atoms in any (2-6C)alkylene chain within a R 1 substituent may be optionally separated by the insertion into the chain of a group such as O, CON(R 10 ) or C ⁇ C.
  • a group such as O, CON(R 10 ) or 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, for
  • 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 substituent 5 optionally bears on each said CH, CH 2 or CH 3 group a substituent as defined hereinbefore
  • suitable R 1 substituents 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
  • 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] amino-(2-6C)alkoxy groups such as 3-dimethylamino-2-hydroxypropoxy
  • hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino- 2-hydroxypropoxy
  • 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
  • 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-substituted di-[(l-6C)alkyl]amino-(2-6C)alkylammo groups such as
  • 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 a substituent as defined hereinbefore, such an optional substituent may be present on a CH 5 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 substituent.
  • R 1 includes an aryl or heteroaryl group that is substituted by a (l-8C)alkyl group
  • the (l-8C)alkyl group may be optionally substituted on a CH, CH 2 or CH 3 group therein by one of the hereinbefore defined substituents therefor.
  • R 1 includes a heteroaryl group that is substituted by, for example, a (l-6C)alkylamino-(l-6C)alkyl group
  • (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 group may be a heteroaryl group such as a thienyl group that is substituted by a N-(2-methylsulphonylethyl)aminomethyl group such that R 1 is, for example, a 5-[iV-(2-methylsulphonylethyl)aminomethyl]thien-2-yl group.
  • R 1 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 group may be a
  • suitable Q 1 groups so formed include, for example, hydroxy-substituted amino-(l-6C)alkyl groups such as l-amino-2-hydroxyethyl or l-amino-2-hydroxypropyl, an (l- ⁇ C)alkoxy-substituted amino-(l-6C)alkyl groups such as l-amino-2-methoxyethyl, a (l-6C)alkylamino-(l-6C)alkyl-substituted heteroaryl group such as a
  • (3-8C)cycloalkenyl, heteroaryl or heterocyclyl group within the Q 1 group may optionally bear 1, 2 or 3 substituents. Any such substituent may be present on any available position on said Q 1 group.
  • substituents may be present on any available position on said Q 1 group.
  • a substituent may be present on any available position, including at the atom from which the (3-8C)cycloalkyl,
  • (3-8C)cycloalkenyl or heterocyclyl group is linked to the remainder of the chemical structure.
  • a (3-8C)cycloalkyl group within the Q 1 group such as a cyclopropyl group that bears an amino substituent may thereby form a 1-aminocycloprop-l-yl group and a
  • heterocyclyl group within the Q 1 group such as a piperidin-4-yl group that bears a hydroxy substituent may thereby form a 4-hydroxypiperidin-4-yl group.
  • a suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • a further suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, a salt formed within the human or animal body after administration of a compound of the Formula I.
  • a suitable pharmaceutically-acceptable solvate of a compound of the Formula I also forms an aspect of the present invention.
  • a suitable pharmaceutically-acceptable solvate is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate or an alternative quantity thereof.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I also forms an aspect of the present invention.
  • the compounds of the invention may be administered in the form of a pro-drug, that is a compound that is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • pro-drugs examples include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula I and in vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula I.
  • the present invention includes those compounds of the Formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following
  • a suitable pharmaceutically-acceptable pro-drag of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically-acceptable esters for carboxy include
  • (l-6C)alkyl esters such as methyl, ethyl and tert-butyl, (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
  • 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
  • a suitable pharmaceutically-acceptable pro-drag of a compound of the Formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the Formula I containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include (l-lOC)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, iV,iV-[di-(l-4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and
  • 2-carboxyacetyl groups examples include aminomethyl, iV-alkylaminomethyl, ⁇ yV-dialkylaminomethyl,
  • Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (l ⁇ 4C)alkylamine such as methylamine, a di-(l-4C)alkylamine such as dimethylamine, iV-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, iV-ethyl-N-methylamine or dieth
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (l-lOC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl,
  • the in vivo effects of a compound of the Formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula I. As stated hereinbefore, the in vivo effects of a compound of the Formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • Particular novel compounds of the invention include, for example, pyrimidine derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of p, R 1 , R 2 , q, R 3 , r, R 4 , X 1 and Q 1 has any of the meanings defined hereinbefore or in paragraphs (a) to (gg) hereinafter :- (a) p is 1, 2 or 3, and each R 1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, hydroxy, mercapto, amino, carboxy, carbamoyl, ureido, (l-SC)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l- ⁇ C)alkoxy, (2-6C)alkenyloxy,
  • Q 2 -X 2 - wherein X is a direct bond or is selected from O, S, N(R ), CO, wherein R is hydrogen or (l-8C)alkyl, and Q 2 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl 5 (3-8C)cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or (R J ) P is
  • 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, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo or thioxo
  • each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoylamino and N-(l-6C)alkyl-(2-6C)alkanoylamino,
  • 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 1, 2 or 3 halogeno or (l-SC)alkyl substituents and/or a substituent selected from hydroxy, amino, cyano, carboxy, carbamoyl, ureido, (l-6C)alkoxy,
  • (l-6C)alkylamino di-[(l-6C)alkyl] amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino and N-(l-6C)alkyl- (2-6C)alkanoylamino;
  • each R 1 group which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, carboxy, carbamoyl, ureido, methyl, ethyl, propyl, vinyl, allyl, ethynyl, 2-propynyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methoxycarbonyl, ethoxycarbonyl, acetamido, propionamido, N-methylacetamido, N-methylpropionamido, hydroxymethyl, 1-hydroxyethyl, 1 -hydroxy- 1-methylethyl, 2-hydroxyethyl, 2-hydroxy- 1-methylethyl, 2-hydroxypropyl, l,l-dimethyl-2-hydroxyethyl,
  • a first R 1 group is selected from hydroxy, amino, carboxy, carbamoyl, methylamino, ethylamino, dimethylamino, diethylamino, methoxycarbonyl, ethoxycarbonyl, acetamido, propionamido, N-methylacetamido, iV-methylpropionamido, hydroxymethyl, 1-hydroxyethyl, 1 -hydroxy- 1-methylethyl, aminomethyl, 1-aminoethyl, 1-amino- 1-methylethyl, methylaminomethyl, 1-methylaminoethyl, 1-methylamino- 1-methylethyl, acetamidomethyl, 1-acetamidoethyl and 1-acetamido- 1-methylethyl, and the optional second R 1 group is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, methyl, ethyl
  • p is 1 or 2
  • a first R 1 group is selected from hydroxy, carbamoyl, acetamido, propionamido, iV-methylacetamido, iV-methylpropionamido, hydroxymethyl, 1-hydroxyethyl and 1 -hydroxy- 1-methylethyl
  • the optional second R 1 group is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy;
  • p is 1 and the R group is located at the 3- or 4-position on the phenyl group and is selected from hydroxy, carbamoyl, acetamido, hydroxymethyl, 1-hydroxyethyl and 1-hydroxy- 1-methylethyl;
  • (g) p is 1 and the R 1 group is located at the 3-position on the phenyl group and is a hydroxymethyl group;
  • R 2 is hydrogen, methyl, ethyl or propyl
  • R 2 is hydrogen or methyl
  • R 2 is hydrogen
  • each R 3 group which may be the same or different, is methyl, ethyl or propyl; (m) q is 1 and the R 3 group is methyl;
  • each R group which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,
  • (r) r is 0 or r is 1 and the R 4 group is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, methoxy, methylamino and dimethylamino;
  • (s) r is 0 or r is 1 and the R 4 group is selected from fluoro, chloro and methyl;
  • X 1 is selected from CO, SO 2 , CON(R 13 ), COC(R 13 ) 2 O, COC(R 13 ) 2 S and
  • X 1 is selected from CO, SO 2 , CONH 5 COCH 2 O and COCH 2 NHCO;
  • X 1 is selected from CO 5 SO 2 , CONH 5 CON(Me), COCH 2 O and COCH 2 NHCO;
  • Q 1 is (l-8C)alkyl, (2-8C)alkenyl 5 (2-8C)alkynyl, halogeno-(l -6C)alkyl,
  • hydroxy-(l-6C)alkyl 5 mercapto-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl 5 (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl,
  • Q 1 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-6C)alkyl,
  • heteroaryl heteroaryl, heteroaryl-( 1 -6C)alkyl, heterocyclyl or heterocyclyl-( 1 -6C)alkyl,
  • any CH, CH 2 or CH 3 group within the Q 1 group optionally bears on each said CH, CH 2 or CH 3 group one or more halogeno or (l-8C)alkyl substituents and/or a substituent selected from hydroxy, amino, cyano, carboxy, carbamoyl, ureido, (l-6C)alkoxy,
  • any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q 1 group optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl,
  • X 7 is a direct bond or is selected from O and N(R 15 ), wherein R 15 is hydrogen or (l-8C)alkyl, and R 14 is 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 the Q 1 group optionally bears 1 or 2 oxo or thioxo substituents;
  • Q 1 is (l-8C)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, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)alkylthio-(l-6C)alkyl or (2-6C)alkanoylamino-(l-6C)alkyl, or Q 1 is aryl,
  • heteroaryl-(l-6C)alkyl heterocyclyl or heterocyclyl-(l-6C)alkyl
  • any CH, CH 2 or CH 3 group within the Q 1 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, carboxy, carbamoyl, ureido, (l-6C)alkoxy,
  • JV-(I -6C)alkylcarbamoyl N,iV-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino and iV-(l-6C)alkyl-(2-6C)alkanoylamino,
  • any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q 1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (l- ⁇ C)alkoxy,
  • X 7 is a direct bond and R 14 is 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
  • Q 1 is (l-SC)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, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)alkylsulphonyl-(l-6C)alkyl or (2-6C)alkanoylamino-(l-6C)alkyl, or Q 1 is aryl, aryl-(l-6C)alkyl 5 (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl,
  • any CH, CH 2 or CH 3 group within the Q 1 group optionally bears on each said CH, CH 2 or CH 3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, (l-6C)alkoxy, (l-6C)alkylsul ⁇ honyl, (l-6C)alkylamino 5 di-[(l-6C)alkyl] amino,
  • any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q 1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-SC)alkyl, (l- ⁇ C)alkoxy,
  • (l-6C)alkylamino di-[(l-6C)alkyl]amino, hydroxy-(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 and heterocyclyl-( 1 -6C)alkyl;
  • Q 1 is methyl, ethyl, propyl, isopropyl, butyl, pentyl, allyl, 2-hydroxyethyl,
  • 5-cyanopentyl aminomethyl, 2-aminoethyl, 3-aminopro ⁇ yl, 4-aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaniinopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminopropyl,
  • dimethylaminomethyl 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylammobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl, 5-diethylaminopentyl, 2-methylsulphonylethyl,
  • Q 1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
  • any CH, CH 2 or CH 3 group within the Q 1 group optionally bears on each said CH 5 CH 2 or CH 3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, ethylamino, dimethylamino, diethylamino, methoxycarbonyl, ethoxycarbonyl, iV-methylcarbamoyl, JV-ethylcarbamoyl,
  • iV-isopropylcarbamoyl i ⁇ yV-dimethylcarbamoyl, 7V,7V-diethylcarbamoyl, acetyl, propionyl, butyryl, pivaloyl, acetamido, propionamido and JV-methylacetamido,
  • any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q 1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino, hydroxymethyl, 2-hydroxyethyl, methoxymethyl,
  • methylaminomethyl 2-methylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl, pyrrolidinylmethyl, morpholinylmethyl, piperidinylmethyl, homopiperidinylmethyl, piperazinylmethyl and homopiperazinylmethyl;
  • Q 1 is methyl, ethyl, propyl, isopropyl, butyl, pentyl, allyl, 2-methoxyethyl,
  • tetrahydropyranyl tetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, indolinyl, isoindolinyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl,
  • any CH 5 CH 2 or CH 3 group within the Q 1 group optionally bears on each said CH, CH 2 or CH 3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, dimethylamino, methoxycarbonyl, ethoxycarbonyl, iV-methylcarbamoyl, 7V-ethylcarbamoyl, JV-isopropylcarbamoyl,
  • any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, methoxy, methylamino and dimethylamino and any such aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q 1 group optionally bears a substituent selected from hydroxymethyl,
  • the X*-Q group is an ⁇ -amino carbonyl group
  • the X ⁇ Q 1 group is a naturally-occurring ⁇ -amino carbonyl group; and (gg) the X ⁇ Q 1 group is selected from glycyl, sarcosyl, ⁇ ,./V-dimethylglycyl, glycylglycyl, L-alanyl, 2-methylalanyl, iV-methylalanyl, (2S)-2-aminobutanoyl, L-valyl,
  • a particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 1 or 2, and a first R 1 group is selected from hydroxy, carbamoyl, acetamido, propionamido, JV-methylacetamido, VV-methylpropionamido, hydroxymethyl, 1 -hydroxy ethyl and 1 -hydroxy- 1-methylethyl, and the optional second R 1 group is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy;
  • R 2 is hydrogen or methyl
  • q is 0 or q is 1 and the R 3 group is methyl
  • r is 0 or r is 1 and the R 4 group is selected from fluoro, chloro and methyl;
  • X 1 is selected from CO, SO 2 , CONH, CON(Me), COCH 2 O and COCH 2 NHCO; and Q 1 is methyl, ethyl, propyl, isopropyl, butyl, pentyl, allyl, 2-methoxyethyl,
  • Q 1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl,
  • tetrahydropyranyl tetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, indolinyl, isoindolinyl, tetrahydrofiiranylmethyl, tetrahydropyranylmethyl,
  • any CH, CH 2 or CH 3 group within the Q 1 group optionally bears on each said CH, CH 2 or CH 3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, dimethylamino, methoxycarbonyl, ethoxycarbonyl, iV-methylcarbamoyl, 7V-ethylcarbamoyl, N-isopropylcarbamoyl,
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 1 or 2, and a first R 1 group is selected from hydroxy, carbamoyl, acetamido, propionamido, iV-methylacetamido, iV-methylpropionamido, hydroxymethyl, 1 -hydroxy ethyl and 1 -hydroxy- 1 -methyl ethyl, and the optional second R 1 group is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy;
  • R 2 is hydrogen or methyl
  • q is 0 or q is 1 and the R 3 group is methyl
  • the X ⁇ Q 1 group is located at the 3-position and is selected from glycyl, sarcosyl, JV,iV-dimethylglycyl, glycylglycyl, L-alanyl, 2-methylalanyl, JV-methylalanyl,
  • a further particular compound of the invention is a pyrimidine derivative of the
  • R 2 is hydrogen
  • X 1 is CO or SO 2 ;
  • Q 1 is methyl, ethyl, propyl, isopropyl, 2-ethoxyethyl, 3-ethoxypropyl, cyanomethyl,
  • Q 1 is phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrazol-3-yl, thiazol-5-yl, l,2,3-triazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-2-yl
  • imidazol-1-ylmethyl imidazol-2-ylmethyl, 2-imidazol-l-ylethyl, 2-imidazol-2-yl ethyl, 2-imidazol-4-ylethyl, pyrazol-1-ylmethyl, pyrazol-3-ylmethyl, 1,2,3-triazol-l-ylmethyl, l,2,3-triazol-4-ylmethyl, l,2,4-oxadiazol-3-ylmethyl, l,2,3-thiadiazol-3-ylmethyl,
  • any CH, CH 2 or CH 3 group within the Q group optionally bears on each said CH, CH 2 or CH 3 group a substituent selected from hydroxy, carbamoyl, methoxycarbonyl, ethoxycarbonyl, JV-methylcarbamoyl, JV-ethylcarbamoyl, JV-isopropylcarbamoyl,
  • any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q 1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, amino, carbamoyl, methyl, methylamino, dimethylamino,
  • R 2 is hydrogen
  • X 1 is CO
  • Q 1 is methyl, ethyl, propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl,
  • 2-hydroxy-2-methylethyl 1 -hydroxy- 1-methylethyl, 1 -hydroxy- 1-trifluoromethylethyl, methoxymethyl, 2-methoxyethyl, methylsulphonylmethyl, 2-methylsulphonylethyl, methoxycarbonylmethyl, tert-butoxycarbonylmethyl, ⁇ ,iV-dimethylcarbamoylmethyl, 2-(N,N ⁇ dimethylcarbamoyl)ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, l-hydroxycycloprop-l-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, morpholin-2-yl, morpholin-3-yl, tetrahydro-l,4-thiazin-3-yl, azetidin-2-yl, pyrrolidin-2-yl, pyr
  • piperidin-4-ylmethyl piperazin-1-ylmethyl, 2-oxo-l,3-oxazolidin-3-ylmethyl,
  • a further particular compound of the invention is apyrimidine derivative of the
  • the X ⁇ Q 1 group is glycyl, JV-acetylglycyl, ⁇ iV-dimethylglycyl, 2-methylalanyl,
  • JV-acetylalanyl D-valyl, L-seryl, iV-methyl-L-seryl, iV-acetylseryl, L-homoseryl, glycyglycyl, iV-benzoylglycyl, N-(4-toluoyl)glycyl or iV-(2-furoyl)glycyl;
  • a further particular compound of the invention is a pyrimidine derivative of the
  • R 2 is hydrogen
  • r 0;
  • X 1 is CO
  • Q 1 is methyl, ethyl, isopropyl, hydroxymethyl, 2-hydroxy-2-methylethyl,
  • a further particular compound of the invention is a pyrimidine derivative of the
  • R 2 is hydrogen; q is O;
  • the X ⁇ Q 1 group is glycyl, JV-acetylglycyl, iVJV-dimethylglycyl, JV-acetylalanyl, 2-methylalanyl, D-valyl, L-seryl, iV-methyl-L-seryl, iV-acetylseryl, L-homoseryl,
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 1 and R 1 is a hydroxymethyl group that is located at the 3-position;
  • R 2 is hydrogen
  • X 1 is CO
  • Q 1 is isopropyl, hydroxymethyl, methoxymethyl, morpholin-2-yl, morpholin-3-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, phenyl, 3-carbamoylphenyl,
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 1 and R 1 is a hydroxymethyl group that is located at the 3-position;
  • R is hydrogen
  • the X ⁇ Q 1 group is glycyl, JV-methylglycyl, JV-ethylglycyl, L-alanyl, JV-methyl-L-alanyl, 2-methylalanyl, JV-methyl-2-methylalanyl, iV-methyl-L-leucyl, L-valyl, iV-methyl-L-valyl, D-valyl, 7V-methyl-D-valyl, L-leucyl, iV-methyl-L-leucyl, L-isoleucyl, N-methyl-L-isoleucyl, L-seryl, L-homoseryl, L-phenylalanyl, (25)-azetidin-2-ylcarbonyl,
  • a further particular compound of the invention is a pyrimidine derivative of the
  • R" is hydrogen
  • the X ⁇ Q 1 group is glycyl, 2-methylalanyl, D-valyl, L-seryl, L-homoseryl,
  • a particular compound of the invention is, for example, a pyrimidine derivative of the
  • Example 5 8, 9, 10, 17, 18, 19, 20, 22, 27, 31, 34, 37, 40, 46, 49, 51 or 52 within Example 5; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is, for example, a pyrimidine derivative of the Formula I selected from :-
  • a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically- related compounds. Such processes, when used to prepare a pyrimidine derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, p, R 1 , R 2 , q, R 3 , r, R 4 , X 1 and Q have any of the meanings defined hereinbefore.
  • Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • L is a displaceable group and R 2 , q, R 3 , r, R 4 , X 1 and Q 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an organoboron reagent of the Formula III
  • each of L and L which may be the same or different, is a suitable ligand and p and R 1 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 by conventional means.
  • a suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • a suitable value for the ligands L 1 and L 2 which are present on the boron atom of the aryl-boron reagent include, for example, a hydroxy, (l-4C)alkoxy or (l- ⁇ C)alkyl ligand, for example a hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methyl, ethyl, propyl, isopropyl or butyl ligand.
  • the ligands L 1 and L 2 may be linked such that, together with the boron atom to which they are attached, they form a ring.
  • L 1 and L 2 together may define an oxy-(2-4C)alkylene-oxy group, for example an oxyethyleneoxy, oxytrimethyleneoxy group or -O-C(CH 3 ) 2 C(CH 3 ) 2 -O- group such that, together with the boron atom to which they are attached, they form a cyclic boronic acid ester group.
  • an oxy-(2-4C)alkylene-oxy group for example an oxyethyleneoxy, oxytrimethyleneoxy group or -O-C(CH 3 ) 2 C(CH 3 ) 2 -O- group such that, together with the boron atom to which they are attached, they form a cyclic boronic acid ester group.
  • organoboron reagents include, for example, compounds wherein each of L 1 and L 2 is a hydroxy, a isopropoxy or an ethyl group or L 1 and L 2 together define a group of formula -O-C(CH 3 ) 2 C(CH 3 ) 2 -O-.
  • a suitable catalyst for the reaction includes, for example, a metallic catalyst such as a palladium(O), palladium(II), nickel(O) or nickel(II) catalyst, for example
  • a free radical initiator may conveniently be added, for example an azo compound such as
  • the reaction may be carried out in the presence of a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, caesium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal alkoxide, for example sodium tert-butoxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, caesium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal alkoxide, for example sodium tert-butoxide, or, for example, an alkali metal amide,
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol, and the reaction is conveniently carried out at a temperature in the range, for example, 10 to 250°C, preferably in the range 40 to 120°C.
  • a suitable inert solvent or diluent for example an ether such as tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol
  • Aryl-boron reagents of the Formula III may be obtained by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist, for example by the reaction of an aryl-metal reagent where the metal is, for example, lithium or the
  • the magnesium halide portion of a Grignard reagent with an organoboron compound of the formula L-B(L 1 XL 2 ) wherein L is a displaceable group as defined hereinbefore.
  • an organoboron compound of the formula L-B(L 1 XL 2 ) wherein L is a displaceable group as defined hereinbefore.
  • the compound of the formula L-B(L 1 XL 2 ) is, for example, boric acid or a tri-(l-4C)alkyl borate such as tri-isopropyl borate.
  • the aryl-boron reagent of the Formula III may be replaced with an organometallic compound of the formula aryl-M wherein M is a metal atom or a metallic group (that is a metal atom bearing suitable ligands).
  • M is a metal atom or a metallic group (that is a metal atom bearing suitable ligands).
  • Suitable values for the metal atom include, for example, lithium and copper.
  • Suitable values for the metallic group include, for example, groups which contain a tin, silicon, zirconium, aluminium, magnesium, mercury or zinc atom.
  • Suitable ligands within such a metallic group include, for example, hydroxy groups, (l-6C)alkyl groups such as methyl, ethyl, propyl, isopropyl and butyl groups, halogeno groups such as chloro, bromo and iodo groups, and (l-6C)alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups.
  • a particular organometallic compound of the formula aryl-M is, for example, an organotin compound such as a compound of the formula aryl-SnBu 3 , an organosilicon compound such as a compound of the formula aryl-Si(Me)F 2 , an organozirconium compound such as a compound of the formula aryl-ZrCl 3 , an organotin compound such as a compound of the formula aryl-SnBu 3 , an organosilicon compound such as a compound of the formula aryl-Si(Me)F 2 , an organozirconium compound such as a compound of the formula aryl-ZrCl 3 , an organotin compound such as a compound of the formula aryl-SnBu 3 , an organosilicon compound such as a compound of the formula aryl-Si(Me)F 2 , an organozirconium compound such as a compound of the formula aryl-ZrCl
  • organoaluminium compound such as a compound of the formula aryl- AlEt 2 , an
  • organomagnesium compound such as a compound of the formula aryl-MgBr, an
  • organomercury compound such as a compound of the formula aryl-HgBr, or an organozinc compound such as a compound of the formula aryl-ZnBr.
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • protecting groups are given below for the sake of convenience, in which "lower”, as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.
  • a carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • Examples of carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, and tert-buty ⁇ );
  • lower alkoxy- lower alkyl groups for example methoxymethyl, ethoxymethyl and
  • acyloxy-lower alkyl groups for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl
  • lower acyloxy-lower alkyl groups for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl
  • alkoxycarbonyloxy-lower alkyl groups for example 1-methoxycarbonyloxyethyl and
  • aryl-lower alkyl groups for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl
  • tri(lower alkyl)silyl groups for example trimethylsilyl and tert-butyldimethylsilyl
  • tri(lower alkyl)silyl-lower alkyl groups for example trimethylsilylethyl
  • (2-6C)alkenyl groups for example allyl.
  • alkenyloxycarbonyl groups for example allyloxycarbonyl
  • aryl-lower alkoxycarbonyl groups for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl
  • tri(lower alkyl)silyl for example trimethylsilyl and fert-butyldimethylsilyl
  • aryl-lower alkyl for example benzyl
  • amino protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and
  • 2,4-dimethoxybenzyl, and triphenylmethyl di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example fert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example methylidene) and benzylidene and substituted benzylidene groups.
  • lower alkoxycarbonyl for example fert-butoxycarbonyl
  • lower alkenyloxycarbonyl for example allyloxycarbonyl
  • aryl-lower alkoxycarbonyl groups for example benzyloxycarbonyl
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as
  • Pyrimidine starting materials of the Formula II may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter.
  • X 1 is CO
  • L, R ⁇ , q, R ⁇ , r and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be acylated, conveniently in the presence of a suitable base as defined hereinbefore, with a carboxylic acid of the Formula V
  • a suitable base is, for example, an organic amine base such as, for example, pyridine,
  • 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.
  • a suitable reactive derivative of a carboxylic acid of the Formula V is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid with an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid with a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid with a phenol such as pentafluorophenol, with an ester such as pentafluorophenyl trifluoroacetate or with an alcohol such as methanol, ethanol, isopropanol, butanol or N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid with an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid with a cyanide such as dieth
  • 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 iV,N-dimethylformamide, iV,7V-dimethylacetamide, JV-methylpyrrolidin-2-one or dimethylsulphoxide.
  • a dipolar aprotic solvent such as iV,N-dimethylformamide, iV,7V-dimethylacetamide, JV-methylpyrrolidin-2-one or dimethylsulphoxide.
  • the reaction is conveniently carried out at a temperature in the range, for example, 0 to 120°C, preferably at or near ambient temperature.
  • Pyrimidine starting materials of the Formula IV may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter.
  • L is a displaceable group as defined hereinbefore and p, R 1 , R 2 , r and R have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a morpholine of the Formula VII
  • L is a displaceable group as defined hereinbefore and R 2 , q, R 3 , r and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted, conveniently in the presence of a suitable catalyst as defined hereinbefore, with an organoboron reagent of the Formula III
  • each of L 1 and L 2 which may be the same or different, is a suitable ligand as defined hereinbefore and p and R 1 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 by conventional means.
  • (l-8C)alkyl may also be prepared by the acylation of a pyrimidine of the Formula IV with the appropriate carboxylic acid selected from the formulae :-
  • L is a displaceable group as defined hereinbefore and p, R 1 , R 2 , r, R 4 , X 1 and Q 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a niorpholine compound of the Formula VII
  • 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, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec ⁇ 7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • 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 ⁇ ,N-dimethylformamide, A ⁇ iV-dimethylacetamide,
  • 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
  • the reaction is conveniently carried out at a temperature in the range, for example, 0 to 250°C, preferably in the range 25 to 150 0 C.
  • the pyrimidine of the Formula VI may be reacted with a morpholine of the Formula VII in the presence of an aprotic solvent such as NJV-dimethylformamide or
  • a ⁇ V-dimethylacetamide conveniently in the presence of a suitable base, for example potassium carbonate or sodium hexamethyldisilazane, and at a temperature in the range, for example, 0 to 200°C, preferably in the range, for example, 25 to 15O 0 C.
  • a suitable base for example potassium carbonate or sodium hexamethyldisilazane
  • Pyrimidine starting materials of the Formula VI may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter.
  • L is a displaceable group as defined hereinbefore and R 2 , r, R 4 , X 1 and Q 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted, conveniently in the presence of a suitable catalyst as defined hereinbefore, with an organoboron reagent of the Formula III
  • each of L and L which may be the same or different, is a suitable ligand as defined hereinbefore and p and R 1 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 by conventional means,
  • a suitable chemical equivalent of phosgene is, for example, a compound of the
  • L is a suitable displaceable group as defined hereinbefore.
  • a suitable displaceable group L is, for example, an alkoxy, aryloxy or sulphonyloxy group, for example a methoxy, phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • a suitable chemical equivalent of phosgene is a carbonate derivative such as disuccinimido carbonate.
  • 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, 0 to 12O 0 C, preferably at or near ambient temperature.
  • each of L 1 and L 2 which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and r, R 4 , X 1 and Q 1 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 by conventional means.
  • the reaction may be carried out in the presence of a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, caesium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal alkoxide, for example sodium tert-butoxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, caesium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal alkoxide, for example sodium tert-butoxide, or, for example, an alkali metal amide,
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol, and the reaction is conveniently carried out at a temperature in the range, for example, 10 to 250°C, preferably in the range 40 to 15O 0 C.
  • a suitable inert solvent or diluent for example an ether such as tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol
  • Alkenyl-boron reagents of the Formula IX may be obtained by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist, for example by the reaction of an aryl-metal reagent where the metal is, for example, lithium or the
  • the magnesium halide portion of a Grignard reagent with an organoboron compound of the formula L-B(L 1 XL 2 ) wherein L is a displaceable group as defined hereinbefore.
  • the compound of the formula L-B(L 1 XL 2 ) is, for example, boric acid or a tri-(l-4C)alkyl borate such as tri-isopropyl borate.
  • the alkenyl-boron reagent of the Formula IX may be replaced with an organometallic compound of the formula alkenyl-M wherein M is a metal atom or a metallic group (that is a metal atom bearing suitable ligands).
  • Suitable values for the metal atom include, for example, lithium and copper.
  • Suitable values for the metallic group include, for example, groups which contain a tin, silicon, zirconium, aluminium, magnesium, mercury or zinc atom.
  • Suitable ligands within such a metallic group include, for example, hydroxy groups, (l- ⁇ C)alkyl groups such as methyl, ethyl, propyl, isopropyl and butyl groups, halogeno groups such as chloro, bromo and iodo groups, and (l-6C)alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups.
  • a particular organometallic compound of the formula alkenyl-M is, for example, an organotin compound such as a compound of the formula alkenyl-SnBu 3 , an organosilicon compound such as a compound of the formula alkenyl-Si(Me)F 2 , an organozirconium compound such as a compound of the formula alkeny 1-ZrCl 3 , an organoaluminium compound such as a compound of the formula alkenyl- AlEt 2 , an organomagnesium compound such as a compound of the formula
  • alkenyl-MgBr an organomercury compound such as a compound of the formula
  • alkenyl-HgBr or an organozinc compound such as a compound of the formula alkenyl -ZnBr.
  • Pyrimidine starting materials of the Formula VIII may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter,
  • a suitable reactive derivative of a sulphonic acid of the Formula X is, for example, a sulphonyl halide, for example a sulphonyl chloride formed by the reaction of the sulphonic acid with an inorganic acid chloride, for example thionyl chloride.
  • 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, 0 to 12O 0 C, preferably at or near ambient temperature.
  • the pyrimidine derivative of the Formula I may be obtained from the process variants described hereinbefore 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
  • 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,
  • 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 pharmaceutically-acceptable salt of a pyrimidine derivative of the Formula I for example an acid-addition salt, it may be obtained by, for example, reaction of said pyrimidine derivative with a suitable acid using a conventional procedure.
  • Formula I is required, it may be obtained using a conventional procedure.
  • an in vivo cleavable ester of a pyrimidine derivative of the Formula I may be obtained by, for example, reaction of a compound of the Formula I containing a carboxy group with a pharmaceutically-acceptable alcohol or by reaction of a compound of the Formula I containing a hydroxy group with a pharmaceutically-acceptable carboxylic acid.
  • an in vivo cleavable amide of a pyrimidine derivative of the Formula I may be obtained by, for example, reaction of a compound of the Formula I containing a carboxy group with a
  • the following assays can be used to measure the effects of the compounds of the present invention as PB kinase inhibitors, as mTOR PI kinase-related kinase inhibitors, as inhibitors in vitro of the activation of PB kinase signalling pathways, as inhibitors in vitro of the proliferation of MDA-MB-468 human breast adenocarcinoma cells, and as inhibitors in vivo of the growth in nude mice of xenografts of MDA-MB-468 carcinoma tissue.
  • the assay used AlphaScreen technology (Gray et ah, Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant Type I PBK enzymes of the lipid PI(4,5)P2.
  • DNA fragments encoding human PBK catalytic and regulatory subunits were isolated from cDNA libraries using standard molecular biology and PCR cloning techniques. The selected DNA fragments were used to generate baculovirus expression vectors.
  • full length DNA of each of the pi 10a, pi lO ⁇ and pi lO ⁇ Type Ia human PBK pi 10 isoforms (EMBL Accession Nos. HSU79143, S67334, Y10055 for pl l ⁇ , pl l ⁇ and pl lO ⁇
  • phosphoinositides (Grpl) PH domain was isolated from a cDNA library using standard molecular biology and PCR cloning techniques. The resultant DNA fragment was sub-cloned into a pGEX 4Tl E. coli expression vector containing a GST epitope tag (Amersham
  • Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 ⁇ l) of each compound dilution were placed into a well of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one, Brunei Way, Stonehouse, Gloucestershire, UK Catalogue No. 784075). A mixture of each selected recombinant purified PI3K enzyme (15 ng), DiC8-PI(4,5)P2 substrate (40 ⁇ M; Cell Signals Inc., Kinnear Road, Columbus, USA,
  • Control wells that produced a minimum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound.
  • Control wells that produced a maximum signal corresponding to fully inhibited enzyme were created by adding wortmannin (6 ⁇ M; Calbiochem / Merck Bioscience, Padge Road, Beeston, Nottingham, UK, Catalogue No. 681675) instead of test compound. These assay solutions were also agitated for 20 minutes at room temperature.
  • PI(3,4,5)P3 is formed in situ as a result of PI3K mediated phosphorylation of PI(4 5 5)P2.
  • the GST-Grpl PH domain protein that is associated with AlphaScreen Anti-GST donor beads forms a complex with the biotinylated PI(3,4,5)P3 that is associated with Alphascreen
  • Streptavidn acceptor beads The enymatically-produced PI(3,4,5)P3 competes with biotinylated PI(3,4,5)P3 for binding to the PH domain protein. Upon laser light excitation at 680 nm, the donor bead : acceptor bead complex produces a signal that can be measured. Accordingly, PI3K enzme activity to form PI(3,4,5)P3 and subsequent competition with biotinylated PI(3,4,5)P3 results in a reduced signal. In the presence of a PI3K enzyme inhibitor, signal strength is recovered.
  • PI3K enzyme inhibition for a given test compound was expressed as an IC 50 value.
  • the inhibitory properties of compounds of formula (I) against PI3K enzymes such as the Class Ia PI3K enzymes (e.g. PBKalpha, PDKbeta and PBKdelta) and the Class Ib PI3K enzyme (PDKgamma) may be demonstrated,
  • the assay used AlphaScreen technology (Gray et al, Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant mTOR.
  • a C-terminal truncation of mTOR encompassing amino acid residues 1362 to 2549 of mTOR was stably expressed as a FLAG-tagged fusion in HEK293 cells as described by Vilella-Bach et al, Journal of Biochemistry. 1999, 274, 4266- 4272.
  • the HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely maintained at 37°C with 5% CO 2 up to a confluency of 70-90% in Dulbecco's modified Eagle's growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalogue No.
  • DMEM Dulbecco's modified Eagle's growth medium
  • Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 ⁇ l) of each compound dilution were placed into a well of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one).
  • LV low volume
  • Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound.
  • Control wells that produced a minimum signal corresponding to fully inhibited enzyme were created by adding EDTA (83 mM) instead of test compound. These assay solutions were incubated for 2 hours at room temperature.
  • Phosphorylated biotinylated peptide is formed in situ as a result of mTOR mediated phosphorylation.
  • the phosphorylated biotinylated peptide that is associated with AlphaScreen Streptavidin donor beads forms a complex with the p70 S6 Kinase (T389) 1 A5 Monoclonal Antibody that is associated with Alphascreen Protein A acceptor beads.
  • the donor bead : acceptor bead complex produces a signal that can be measured. Accordingly, the presence of mTOR kinase activity results in an assay signal. In the presence of an mTOR kinase inhibitor, signal strength is reduced.
  • This assay determines the ability of test compounds to inhibit phosphorylation of Serine 473 in Akt as assessed using Acumen Explorer technology (TTP LabTech Limited, Royston, Herts, SG8 6EE, UK), a plate reader that can be used to rapidly quantitate features of images generated by laser-scanning.
  • a MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem,
  • the cells were detached from the culture flask using 'Accutase'
  • Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required with DMSO and with growtho media to give a range of concentrations that were 10-fold the required final test concentrations.
  • each plate contained wells having a final concentration of 30 ⁇ M LY294002 (Calbiochem, Beeston, UK, Catalogue No. 440202).
  • wells contained 0.5% DMSO instead of test compound.
  • Test compounds were prepared as 1OmM stock solutions in DMSO and aliquots (40 ⁇ l) of each compound were dispensed into one well of a quadrant of wells within a 384-well plate (Labcyte Inc., Catalogue No. P-05525-CV1). Four concentrations of each compound were prepared in each quadrant of0 wells in the 384-well plate using a 'Hydra IF pipettor (Matrix Technologies Corporation, Handforth SK9 3LP, UK).
  • the permeabilsation/blocking buffer caused the cell wall to be partially degraded to allow immunostaining to proceed whilst blocking non-specific binding sites.
  • the buffer was removed and the cells were incubated for 16 hours at 4 0 C with rabbit anti-phospho-Akt (Ser473) antibody solution (50 ⁇ l per well; Cell Signaling Technology Inc., Hitchin, Herts, U.K., Catalogue No. 3787) that had been diluted 1:500 in 'blocking' buffer consisting of a mixture of PBS, 0.5% Tween-20 and 5% dried skimmed milk. Cells were washed three times in a mixture of PBS and 0.05% Tween- 20.
  • This assay determines the ability of test compounds to inhibit cell proliferation, as assessed by the extent of metabolism by living cells of a tetrazolium dye.
  • a MDA-MB-468 human breast carcinoma cell line (ATCC, Catalogue No. HTB-132) was routinely maintained as described in Biological Assay (c) hereinbefore except that the growth medium did not contain phenol red.
  • the cells were detached from the culture flask using
  • PES phenazine ethosulphate
  • MTS 3-(4, 5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)- 2-(4-sulpho ⁇ henyl)-2#-tetrazolium salt
  • MTS PromegaUK, Southampton SO16 7NS, UK; Catalogue No. Gl 111
  • An aliquot (20 ⁇ l) of the resultant MTS/PES solution was added to each well of one plate. The cells were incubated for 2 hours at 37°C with 5% CO 2 and the optical density was measured on a plate reader using a wavelength of 492nm. The relative cell number at the commencement of the assay was thereby measured.
  • Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted with growth medium to give a range of test concentrations. An aliquot (50 ⁇ l) of each compound dilution was placed in a well in the 96-well plates. Each plate contained control wells without test compound. With the exception of wells containing the plate blanks, the outer wells on each 96-well plate were not used. The cells were incubated for 72 hours at 37°C with 5% CO 2 . An aliquot (30 ⁇ l) of the MTS/PES solution was added to each well and the cells were incubated for 2 hours at 37 0 C with 5% CO 2 . The optical density was measured on a plate reader using a wavelength of 492nm.
  • MDA-MB-468 cell growth was expressed as an IC 50 value
  • This test measures the ability of compounds to inhibit the growth of MDA-MB-468 human breast adenocarcinoma cells grown as a tumour in athymic nude mice (Alderley Park nu/nu strain).
  • a total of about 5 x 10 6 MDA-MB-468 cells in matrigel (Beckton Dickinson Catalogue No. 40234) are injected subcutaneously into the left flank of each test mouse and the resultant tumours are allowed to grow for about 14 days. Tumour size is measured twice weekly using callipers and a theoretical volume is calculated. Animals are selected to provide control and treatment groups of approximately equal average tumour volume.
  • Test compounds are prepared as a ball-milled suspension in 1% polysorbate vehicle and dosed orally once daily for a period of about 28 days. The effect on tumour growth is assessed.
  • the pyrimidine compound disclosed within Example 1 possesses activity in Test (a) with an IC 50 versus pllO ⁇ Type Ia human PBK of approximately 0.5 ⁇ M, and in Test (c) with an IC 50 of approximately 2 ⁇ M;
  • the pyrimidine compound disclosed within Example 3 possesses activity in Test (a) with an IC 5O of approximately 1 ⁇ M, and in Test (c)o with an IC 50 of approximately 1.2 ⁇ M;
  • the pyrimidine compound disclosed within Example 4 possesses activity in Test (a) with an IC 50 of approximately 0.5 ⁇ M, and in Test (c) with an IC 50 of approximately 0.5 ⁇ M;
  • the pyrimidine compound disclosed as Compound No. 1 within Example 5 possesses activity in Test (a) with an IC 50 of approximately 1 ⁇ M, and in Test (c) with an IC 50 of approximately 1 ⁇ M.
  • a pharmaceutical composition which comprises a pyrimidine derivative of the Formula I, or a
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels,5 or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intraperitoneal or intramuscular dosing) or for rectal administration (for example as a suppository).
  • oral use for example as 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.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range, for example, 1 mg/kg to
  • 100 mg/kg body weight is received, given if required in divided doses.
  • lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, 1 mg/kg to 25 mg/kg body weight will generally be used.
  • a dose in the range for example, 1 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration is however preferred, particularly in tablet form.
  • unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention.
  • PBK enzymes contribute to tumourigenesis by one or more of the effects of mediating proliferation of cancer and other cells, mediating angiogenic events and mediating the motility, migration and invasiveness of cancer cells.
  • the pyrimidine derivatives of the present invention possess potent anti-tumour activity which it is believed is obtained by way of inhibition of one or more of the Class I PDK enzymes (such as the Class Ia PBK enzymes and/or the Class Ib PBK enzyme) and/or a mTOR kinase (such as a mTOR PI kinase-related kinase) that are involved in the signal transduction steps which lead to the proliferation and survival of tumour cells and the invasiveness and migratory ability of metastasising tumour cells.
  • the Class I PDK enzymes such as the Class Ia PBK enzymes and/or the Class Ib PBK enzyme
  • a mTOR kinase such as a mTOR PI kinase-related
  • the derivatives of the present invention are of value as anti-tumour agents, in particular as selective inhibitors of the proliferation, survival, motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of tumour growth and survival and to inhibition of metastatic tumour growth.
  • the pyrimidine derivatives of the present invention are of value as anti-proliferative and anti-invasive agents in the containment and/or treatment of solid tumour disease.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of one or more of the multiple PI3K enzymes such as the Class Ia PI3K enzymes and the Class Ib PBK enzyme that are involved in the signal transduction steps which lead to the proliferation and survival of tumour cells and the migratory ability and invasiveness of metastasising tumour cells.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by inhibition of PBK enzymes such as the Class Ia PBK enzymes and the Class Ib PBK enzyme, i.e. the compounds may be used to produce a PBK enzyme inhibitory effect in a warm-blooded animal in need of such treatment.
  • inhibitors of PBK enzymes should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias [including acute lymphoctic leukaemia (ALL) and chronic myelogenous leukaemia (CML)], multiple myeloma and lymphomas.
  • ALL acute lymphoctic leukaemia
  • CML chronic myelogenous leukaemia
  • a pyrimidine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for the production of an anti-proliferative effect in a warm-blooded animal such as man.
  • a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
  • a method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pyrimidine derivative of the Formula I 5 or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a pyrimidine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.
  • a method for the prevention or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • PBK enzymes such as the Class Ia enzymes and/or the Class Ib PI3K enzyme
  • a mTOR kinase such as a mTOR PI kinase-related kinase
  • PI3K enzymes such as the Class Ia enzymes and/or the Class Ib PBK enzyme
  • a mTOR kinase such as a mTOR PI kinase-related kinase
  • tumours which are sensitive to inhibition of PBK enzymes (such as the Class Ia enzymes and/or the Class Ib PBK enzyme) and/or a mTOR kinase (such as a mTOR PI kinase-related kinase) that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells
  • PBK enzymes such as the Class Ia enzymes and/or the Class Ib PBK enzyme
  • a mTOR kinase such as a mTOR PI kinase-related kinase
  • a PBK enzyme inhibitory effect such as a Class Ia PBK enzyme or Class Ib PBK enzyme inhibitory effect
  • a mTOR kinase inhibitory effect such as a mTOR PI kinase-related kinase inhibitory effect
  • apyrimidine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a PBK enzyme inhibitory effect (such as a Class Ia PBK enzyme or Class Ib PBK enzyme inhibitory effect) and/or a mTOR kinase inhibitory effect (such as a mTOR PI kinase-related kinase inhibitory effect).
  • a PBK enzyme inhibitory effect such as a Class Ia PBK enzyme or Class Ib PBK enzyme inhibitory effect
  • a mTOR kinase inhibitory effect such as a mTOR PI kinase-related kinase inhibitory effect
  • a method for providing a PDK enzyme inhibitory effect such as a Class Ia PBK enzyme or Class Ib PBK enzyme inhibitory effect
  • a mTOR kinase inhibitory effect such as a mTOR PI kinase- related kinase inhibitory effect
  • administering an effective amount of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • certain compounds of the present invention possess better potency against Class Ia PBK enzymes than against the Class Ib PBK enzyme or against EGF receptor tyrosine kinase, VEGF receptor tyrosine kinase or Src non-receptor tyrosine kinase enzymes.
  • Such compounds possess sufficient potency against Class Ia PBK enzymes that they may be used in an amount sufficient to inhibit Class Ia PBK enzymes whilst
  • Such compounds are likely to be useful for the selective inhibition of Class Ia PBK enzymes and are likely to be useful for the effective treatment of, for example Class Ia PBK enzyme driven tumours.
  • a method for providing a selective Class Ia PBK enzyme inhibitory effect which comprises administering an effective amount of a pyrimidine derivative of the Formula I, or a
  • a selective Class Ia PBK enzyme inhibitory effect is meant that the pyrimidine derivatives of the Formula I are more potent against Class Ia PBK enzymes than against other kinase enzymes.
  • some of the compounds according to the invention are more potent against Class Ia PBK enzymes than against other kinases such as receptor or non-receptor tyrosine kinases or serine/threonine kinases.
  • a selective Class Ia PBK enzyme inhibitor according to the invention is at least 5 times more potent, preferably at least 10 times more potent, more preferably at least 100 times more potent, against Class Ia
  • leukaemias including ALL and CML
  • a pyrimidine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate.
  • ALL and CML multiple myeloma and lymphomas.
  • a method for treating cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a method for treating cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • the in vivo effects of a compound of the Formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula I.
  • the anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the pyrimidine derivative of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such 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, m ' trogen 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, epirubicin, idarubicin, mitomycin-C, dactinomycin and
  • mithramycin for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine, taxoids like taxol and taxotere, and polokinase inhibitors
  • antimitotic agents for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine, taxoids like taxol and taxotere, and polokinase 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 (ZD1839), 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, inhibitors of the platelet-derived growth factor family and/or bcr/abl kinase such as imatinib, dasatinib (BMS-354825) and nilotinib (BMS-354825) and
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SUl 1248) and 4-(4-fluoro-2-methylindol-5-yloxy)- 6-methoxy-7-(3-pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SUl 1248) and 4-(4
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669,
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRC A2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • a pharmaceutical product comprising a pyrimidine derivative of the formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer.
  • the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of PI3K 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.
  • Method A3 Waters 'Xterra' reversed-phase column (5 microns silica, 2 mm diameter, 50 mm length) using a Solvent C comprising a 10 mM aqueous ammonium bicarbonate solution (adjusted to pHIO by the addition of ammonia) and a solvent gradient over 4 minutes from a 1:99 mixture of Solvents B and C to 100% Solvent B;
  • Solvent C comprising a 10 mM aqueous ammonium bicarbonate solution (adjusted to pHIO by the addition of ammonia) and a solvent gradient over 4 minutes from a 1:99 mixture of Solvents B and C to 100% Solvent B;
  • Method A4 Phenomenex 'Gemini' RP 1 IOA column (5 microns silica, 2 mm diameter, 50 mm length) using a Solvent C comprising 0.1% aqueous ammonium hydroxide (d ⁇ O. ⁇ S)) and a solvent gradient over 4 minutes from a 5:95 mixture of Solvents B and C to a 95:5 mixture of Solvents B and C;
  • Solvent C comprising 0.1% aqueous ammonium hydroxide (d ⁇ O. ⁇ S)
  • Method Bl Phenomenex Synergi MAX-RP 8 ⁇ A column (4 microns silica, 2.1 mm diameter, 50 mm length) using a Solvent C comprising a 1:1 mixture of water and acetonitrile (the mixture containing 1% formic acid) and a solvent gradient over 4 minutes from a 90:5:5 mixture of Solvents A, B and C respectively to a 95:5 mixture of Solvents B and C;
  • Method B2 Phenomenex Synergi MAX-RP 8 ⁇ A column (4 microns silica, 2.1 mm diameter, 50 mm length) using a Solvent C comprising a 1:1 mixture of water and acetonitrile (the mixture containing 1% formic acid) and a solvent gradient over 4 minutes from a 95:5 mixture of Solvents A and C to a 58:37:5 mixture of Solvents A, B and C respectively;
  • Method B3 Phenomenex Synergi MAX-RP 8 ⁇ A column (4 microns silica, 2.1 mm diameter, 50 mm length) using a Solvent C comprising a 1:1 mixture of water and acetonitrile (the mixture containing 1% formic acid) and a solvent gradient over 4 minutes from a 35:60:5 mixture of Solvents A, B and C respectively to a 95:5 mixture of Solvents B and C;
  • Method B4 Phenomenex 'Gemini' RP IIOA column (5 microns silica, 2 mm diameter, 50 mm length) using a Solvent C comprising a 1:1 mixture of water and acetonitrile (the mixture containing 1% formic acid) and a solvent gradient over 4 minutes from a 95:0:5 mixture of Solvents A, B and C respectively to a 0:95:5 mixture of Solvents A, B and C (Solvent C being constant at 5%);
  • the resultant reaction mixture was heated to 140 0 C for 15 minutes in a microwave reactor. This reaction was repeated ten times and the resultant reaction mixtures were combined and the solvent was evaporated. The residue was partitioned between methylene chloride and water. The aqueous layer was washed with methylene chloride. The organic solutions were combined, washed with a saturated aqueous brine solution, dried over magnesium sulphate and evaporated. The resultant material was purified by column chromatography on silica using an increasingly polar gradient from 0% to 50% ethyl acetate in methylene chloride as eluent.
  • the resultant solution was purified by HPLC using a Waters 'Xterra' preparative reversed-phase column (5 microns silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water
  • tert-Butyl piperazine-1-carboxylate 0.037 g
  • diisopropylethylamine 0.172 ml
  • a solution of bis(trichloromethyl) carbonate 0.018 g
  • methylene chloride 8 ml
  • a suspension of 2-(3-hydroxymethylphenyl)-6-morpholino-4-(l,2,3,6-tetrahydropyridin- 4-yl) ⁇ yrimidine 0.071 g) in methylene chloride (1 ml) was added and the resultant solution was stirred at ambient temperature for 16 hours.
  • 6-morpholino-4-(l ,2,3,6-tetrahydropyridin-4-yl)pyrimidine was reacted with the appropriate carboxylic acid to give the compounds described in Table II.
  • carboxylic acid carried a primary or secondary amino group which was not connected to a carbonyl group or a secondary amino group which was not a ring member in a heteroaryl ring, said primary or secondary amino group was protected by a JV-tert-butoxycarbonyl group which was subsequently removed by treatment with
  • 6-morpholinopyrimidine as a viscous oil (2.3 g) that crystallised on standing; NMR Spectrum: (CDCl 3 ) 0.05 (s, 6H), 0.85 (t, 9H), 1.38 (s, 9H), 2.48-2.53 (m, 2H), 3.54 (t, 2H), 3.60-3.65 (m, 4H), 3.69-3.72 (m, 4H) 5 4.05 (d, 2H), 4.72 (s, 2H), 6.26 (s, IH), 6.84-6.88 (m, IH), 7.27-7.28 (m, IH), 8.19-8.22 (m, IH), 8.3 (d, IH); ); Mass Spectrum: M+H + 567; HPLC: method Bl, Retention Time 3.87 minutes ..

Abstract

L'invention concerne des dérivés de pyrimidine de formule (I), dans laquelle p, R1, R2, q, R3, r, R4, X1 et Q1 ont chacun l'une des significations définies dans la description, ainsi que des procédés pour les préparer et des compositions pharmaceutiques les contenant qui sont utiles pour produire un effet anti-prolifératif chez un animal à sang chaud tel que l'homme.
PCT/GB2006/004554 2005-12-09 2006-12-06 Dérivés de pyrimidine utilisés comme inhibiteurs de la pi3k de classe i WO2007066103A1 (fr)

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009093981A1 (fr) * 2008-01-23 2009-07-30 S Bio Pte Ltd Composés de triazine comme inhibiteurs de la kinase
US7696204B2 (en) 2005-10-11 2010-04-13 Ludwig Institute For Cancer Research Pharmaceutical compounds
US7750003B2 (en) 2006-08-24 2010-07-06 Astrazeneca Ab Compounds-943
WO2011114275A1 (fr) 2010-03-15 2011-09-22 University Of Basel Composés spirocycliques et leur utilisation comme agents thérapeutiques et sondes de diagnostic
US8097622B2 (en) 2008-10-14 2012-01-17 Daiichi Sankyo Company, Limited Morpholinopurine derivatives
US8138183B2 (en) 2007-07-09 2012-03-20 Astrazeneca Ab Morpholino pyrimidine derivatives used in diseases linked to mTOR kinase and/or PI3K
US8252802B2 (en) 2010-06-11 2012-08-28 Astrazeneca Ab Chemical compounds
WO2013019927A1 (fr) 2011-08-03 2013-02-07 Signal Pharmaceuticals, Llc Identification d'un profil d'expression génique à titre de biomarqueur prédictif de l'état lkb1
US8461158B2 (en) 2009-03-27 2013-06-11 Pathway Therapeutics Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
US8486939B2 (en) 2009-07-07 2013-07-16 Pathway Therapeutics Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy
US9056852B2 (en) 2011-03-28 2015-06-16 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
EP2992878A1 (fr) 2010-02-03 2016-03-09 Signal Pharmaceuticals, LLC Identification d'une mutation lkb1 comme biomarqueur prédictif de la sensibilité aux inhibiteurs de la kinase tor
CN109942562A (zh) * 2019-02-27 2019-06-28 江西科技师范大学 含芳基结构的五元杂环联三嗪类化合物及其制备方法和应用
US11096940B2 (en) 2017-06-22 2021-08-24 Celgene Corporation Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection
US11304953B2 (en) 2017-05-23 2022-04-19 Mei Pharma, Inc. Combination therapy
US11351176B2 (en) 2017-08-14 2022-06-07 Mei Pharma, Inc. Combination therapy

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1277738A1 (fr) * 2000-04-27 2003-01-22 Yamanouchi Pharmaceutical Co. Ltd. Derives d'heteroaryle condenses
WO2004048365A1 (fr) * 2002-11-21 2004-06-10 Chiron Corporation Pyrimidines 2,4,6-trisubstitutees utilisees comme inhibiteurs de phosphotidylinositol (pi) 3-kinase et leur utilisation dans le traitement du cancer
WO2006005918A1 (fr) * 2004-07-09 2006-01-19 Astrazeneca Ab Pyrimidines 2,4,6-trisubstitutees utilisees comme inhibiteurs de phosphotidylinositol (pi) 3-kinase et leur utilisation dans le traitement du cancer
WO2006005914A1 (fr) * 2004-07-09 2006-01-19 Astrazeneca Ab Pyrimidines a substitution triple aux positions 2, 4, 6 utilises en tant qu'inhibiteurs de phosphotidylinositol (pi) 3-kinase et utilisations de celles-ci pour traiter un cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1277738A1 (fr) * 2000-04-27 2003-01-22 Yamanouchi Pharmaceutical Co. Ltd. Derives d'heteroaryle condenses
WO2004048365A1 (fr) * 2002-11-21 2004-06-10 Chiron Corporation Pyrimidines 2,4,6-trisubstitutees utilisees comme inhibiteurs de phosphotidylinositol (pi) 3-kinase et leur utilisation dans le traitement du cancer
WO2006005918A1 (fr) * 2004-07-09 2006-01-19 Astrazeneca Ab Pyrimidines 2,4,6-trisubstitutees utilisees comme inhibiteurs de phosphotidylinositol (pi) 3-kinase et leur utilisation dans le traitement du cancer
WO2006005914A1 (fr) * 2004-07-09 2006-01-19 Astrazeneca Ab Pyrimidines a substitution triple aux positions 2, 4, 6 utilises en tant qu'inhibiteurs de phosphotidylinositol (pi) 3-kinase et utilisations de celles-ci pour traiter un cancer

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7696204B2 (en) 2005-10-11 2010-04-13 Ludwig Institute For Cancer Research Pharmaceutical compounds
US7750003B2 (en) 2006-08-24 2010-07-06 Astrazeneca Ab Compounds-943
US8138183B2 (en) 2007-07-09 2012-03-20 Astrazeneca Ab Morpholino pyrimidine derivatives used in diseases linked to mTOR kinase and/or PI3K
WO2009093981A1 (fr) * 2008-01-23 2009-07-30 S Bio Pte Ltd Composés de triazine comme inhibiteurs de la kinase
US8097622B2 (en) 2008-10-14 2012-01-17 Daiichi Sankyo Company, Limited Morpholinopurine derivatives
US8309546B2 (en) 2008-10-14 2012-11-13 Daiichi Sankyo Company, Limited Morpholinopurine derivatives
US9108980B2 (en) 2009-03-27 2015-08-18 Vetdc, Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
US8772287B2 (en) 2009-03-27 2014-07-08 Vetdc, Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
US8461158B2 (en) 2009-03-27 2013-06-11 Pathway Therapeutics Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
US8486939B2 (en) 2009-07-07 2013-07-16 Pathway Therapeutics Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy
US9555033B2 (en) 2010-02-03 2017-01-31 Signal Pharmaceuticals, Llc Identification of LKB1 mutation as a predictive biomarker for sensitivity to TOR kinase inhibitors
EP2992878A1 (fr) 2010-02-03 2016-03-09 Signal Pharmaceuticals, LLC Identification d'une mutation lkb1 comme biomarqueur prédictif de la sensibilité aux inhibiteurs de la kinase tor
WO2011114275A1 (fr) 2010-03-15 2011-09-22 University Of Basel Composés spirocycliques et leur utilisation comme agents thérapeutiques et sondes de diagnostic
CN102939292A (zh) * 2010-03-15 2013-02-20 巴塞尔大学 螺环化合物及其作为治疗剂和诊断探针的用途
US8999997B2 (en) 2010-06-11 2015-04-07 Astrazeneca Ab Chemical compounds
US9421213B2 (en) 2010-06-11 2016-08-23 Astrazeneca Ab Chemical compounds
US8552004B2 (en) 2010-06-11 2013-10-08 Astrazeneca Ab Chemical compounds
US9155742B2 (en) 2010-06-11 2015-10-13 Astrazeneca Ab Chemical compounds
US8252802B2 (en) 2010-06-11 2012-08-28 Astrazeneca Ab Chemical compounds
US10603324B2 (en) 2011-03-28 2020-03-31 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US10064868B2 (en) 2011-03-28 2018-09-04 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US10335415B2 (en) 2011-03-28 2019-07-02 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US9056852B2 (en) 2011-03-28 2015-06-16 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US11400097B2 (en) 2011-03-28 2022-08-02 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
WO2013019927A1 (fr) 2011-08-03 2013-02-07 Signal Pharmaceuticals, Llc Identification d'un profil d'expression génique à titre de biomarqueur prédictif de l'état lkb1
US11304953B2 (en) 2017-05-23 2022-04-19 Mei Pharma, Inc. Combination therapy
US11096940B2 (en) 2017-06-22 2021-08-24 Celgene Corporation Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection
US11351176B2 (en) 2017-08-14 2022-06-07 Mei Pharma, Inc. Combination therapy
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