WO2008032060A1 - Dérivés de 4-benzimidaz0lyl-6-m0rph0lin0-2-pipérazinylpyrimidine utilisés comme inhibiteurs de p13k et mtor dans le traitement de troubles prolifératifs - Google Patents

Dérivés de 4-benzimidaz0lyl-6-m0rph0lin0-2-pipérazinylpyrimidine utilisés comme inhibiteurs de p13k et mtor dans le traitement de troubles prolifératifs Download PDF

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WO2008032060A1
WO2008032060A1 PCT/GB2007/003454 GB2007003454W WO2008032060A1 WO 2008032060 A1 WO2008032060 A1 WO 2008032060A1 GB 2007003454 W GB2007003454 W GB 2007003454W WO 2008032060 A1 WO2008032060 A1 WO 2008032060A1
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alkyl
group
formula
amino
hydroxy
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PCT/GB2007/003454
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Sam Butterworth
Edward Jolyon Griffen
Martin Pass
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Astrazeneca Ab
Astrazeneca Uk Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the invention concerns certain novel pyrimidine derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body.
  • the invention also concerns processes for the manufacture of said 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 antiproliferative effect in a warm-blooded animal such as man.
  • Many of the current treatment regimes for cell proliferation diseases such as cancer and psoriasis utilise compounds which inhibit DNA synthesis. Such compounds are toxic to cells generally but their toxic effect on rapidly dividing cells such as tumour cells can be beneficial.
  • 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, TGF ⁇ , 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.
  • certain 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 downstream of the lipid kinase known as PBK such as PDK-I, AKT and mTOR (Blume- Jensen and Hunter, Nature. 2001, 411, 355).
  • PBK lipid kinase
  • PDK-I lipid kinase
  • AKT kinase
  • mTOR Blume- Jensen and Hunter, Nature. 2001, 411, 355
  • lipid kinases including the phosphoinositide 3-kinase (abbreviated hereinafter to PI3K) family that is alternatively known as the phosphatidylinositol-3 -kinase family.
  • PI3K phosphoinositide 3-kinase
  • oncogenes and tumour-suppressor genes contributes to the formation of malignant tumours, for example by way of increased cell proliferation or increased cell survival.
  • signalling pathways mediated by the PI3K family have a central role in a number of cell processes including proliferation and survival, and deregulation of these pathways is a causative factor in a wide spectrum of human cancers and other diseases (Katso et al. , Annual Rev. Cell Dev. Biol., 2001, 17: 615-617 and Foster et al, J. Cell Science, 2003, 116: 3037-3040).
  • the PI3K family of lipid kinases is a group of enzymes that phosphorylate the 3 -position of the inositol ring of phosphatidylinositol (abbreviated hereinafter to PI).
  • PI phosphatidylinositol
  • Three major groups of PI3K enzymes are known which are classified according to their physiological substrate specificity (Vanhaesebroeck et al , Trends in Biol. Sci., 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 phosphoiylate PI, 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.
  • the single Class Ib enzyme consists of a pi lO ⁇ catalytic subunit that interacts with a pi 01 regulatory subunit.
  • GPCR G-protein coupled receptor
  • Tumour-related mutations in p85 ⁇ have also been identified in cancers such as those of the ovary and colon (Philp et ah, Cancer Research, 2001, 61_, 7426-7429).
  • activation of Class Ia PI3K contributes to tumourigenic events that occur upstream in signalling pathways, for example by way of ligand-dependent or B2007/003454
  • 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, 14, 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). These findings suggest that pharmacological inhibitors of Class I PI3K enzymes 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.
  • 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 vul
  • 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 PBK 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, ⁇ 3_, 206-212). Thus inhibitors of Class I PBK enzymes are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer.
  • 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, insulin-dependent diabetes, diabetic retinopathy and diabetic nephropathy.
  • 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
  • the compounds of the present invention possess potent inhibitory activity against Class I PBK enzymes, particularly against Class Ia PDK 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 PBK 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. It has been noted that at least some of the compounds of the present invention also possess potent inhibitory activity against the Class IV kinase mTOR.
  • 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 family of protein kinases, which includes ATM, ATR, DNA-PK and hSMG-1.
  • PIKK phosphatidylinositol
  • PIKK phosphatidylinositol
  • PIKK phosphatidylinositol
  • mTOR like other PIKK family members, does not possess detectable lipid kinase activity, but instead functions as a serine/threonine kinase.
  • Rapamycin first binds to the 12 kDa immunophilin FK506-binding protein (FKBP 12) and this complex inhibits mTOR signalling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37).
  • 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).
  • 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 niRNA translation.
  • TOP 5 '-terminal oligopyrimidine tract
  • 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, 14, 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 et al. 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. 2007/003454
  • tumour suppressor proteins such as TSCl 5 TSC2, PTEN and LKBl tightly control mTOR kinase signalling.
  • 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, 3_5, 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 (Eisen et al. , New England Journal of Medicine, 2003, 349, 847-858).
  • mTOR kinase inhibitors are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer. It is disclosed in European Patent Application No. 1020462 that certain triazine and pyrimidine derivatives that are substituted with both a 1-benzimidazolyl group and a morpholino group possess anti-tumour activity and are useful in the treatment of cancer. B2007/003454
  • the disclosure focuses on 2,4-diaryl-6-morpholinopyrimidines.
  • the scope of disclosure does not embrace benzimidazolyl substituted pyrimidines.
  • the disclosure focuses on arylamino- and heteroarylamino-substituted pyrimidines.
  • the scope of disclosure does not embrace 4-heteroaryl substituted pyrimidines.
  • compounds such as :- 6-(3-hydroxyphenyl)-2-morpholino-4-[4-(4-nitrophenyl)piperazin-l-yl]pyrimidine (no. 82); 6-(3-hydroxyphenyl)-2-morpholino-4-(4-pyridin-2-ylpiperazin-l-yl)pyrimidine (no. 85); 4-(4-acetylpiperazin-l-yl)-6-(3-hydroxyphenyl)-2-morpholinopyrimidine (no.
  • 2-piperazin-l-ylpyrimidine compounds such as :- 4-(2-fluorophenyl)-6-morpholino-2-(4-pyridin-2-ylpiperazin-l-yl)pyrimidine (no. 87); and also of 2-aryl-4-piperazin-l-ylpyrimidine compounds such as :-
  • each R 1 group which may be the same or different, is selected from halogeno, trifiuoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl,
  • X 2 is a direct bond or is selected from O, S, SO, SO 2 , N(R 5 ), CO, CH(OR 5 ), CON(R 5 ), N(R 5 )C0, N(R 5 )CON(R 5 ), SO 2 N(R 5 ), N(R 5 )SO 2 , OC(R 5 ) 2 , SC(R 5 ) 2 and N(R 5 )C(R 5 ) 2 , wherein R 5 is hydrogen or (l-8C)alkyl, and Q 2 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)alky
  • any CH, CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH, CH 2 or CH 3 group one or more halogeno or (l-8C)alkyl substituents and/or a substituent selected from hydroxy, mercapto, amino, cyano, carboxy, carbamoyl, ureido, (1 -6C)alkoxy, (1 -6C)alkylthio, (1 -6C)alkylsulphinyl, (1 -6C)alkylsulphonyl, (1 -6C)alkylamino, di-[(l-6C)alkyl]amino, (l- ⁇ C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyi]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyl, (2-6C)alkanoyl, (2-6C)alkano
  • X 3 is a direct bond or is selected from O, S, SO, SO 2 , N(R 6 ), CO, CH(OR 6 ), CON(R 6 ), N(R 6 )CO, N(R 6 )CON(R 6 ), SO 2 N(R 6 ), N(R 6 )SO 2 , C(R 6 ) 2 O, C(R 6 ) 2 S and C(R 6 ) 2 N(R 6 ), wherein R 6 is hydrogen or (1 -8C)alkyl, and Q 3 is aryl, aryl-(l -6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-6C)alkyl, (3-8C)cycloalkenyl, (3-8C)cycloalkenyl- (l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(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
  • Q 4 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl I 0 or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, hydroxy, (l-8C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo or thioxo substituents, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R substituent is are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO 2 , N(R 10 ), CO, CH(
  • R 2 is fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, hydroxy, amino, formamido, (l-6C)alkoxycarbonylamino, 20 (2-6C)alkanoylamino, iV-(l-6C)alkyl-(2-6C)alkanoylamino, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, hydroxy-(l-6C)alkyl or (l-6C)alkoxy-(l-6C)alkyl; q is 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 :
  • R 11 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l- ⁇ C)alkylamino- (l- ⁇ C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl or (2-6C)alkanoylamino-(l-6C)alkyl, 30 or two R 3 groups together form a methylene, ethylene or trimethylene group; r is O, 1, 2, 3 or 4; each R 4 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro,
  • N-(l-6C)alkylureido iV 5 N'-di-[(l-6C)alkyl]ureido, N,N',iV'-tri-[(l-6C)alkyl]ureido,
  • 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 di ⁇ [(l-6C)alkyl]amino-(l-6C)alkyl, or from a group of the formula :
  • X 8 is a direct bond or is selected from O, CO and N(R 17 ), wherein R 17 is hydrogen or (l-8C)alkyl
  • Q 5 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, and wherein any heterocyclyl group within the Q 1 group optionally bears 1 or 2 oxo or thioxo substituents, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within the Q 1 group are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO 2 , B2007/003454
  • N(R 16 ), N(R 16 )CO, CON(R 16 ), N(R l6 )CON(R 16 ), CO, CH(OR 16 ), N(R 16 )SO 2 , SO 2 N(R 16 ), CH CH and C ⁇ C wherein R 16 is hydrogen or (l-8C)alkyl; and wherein the 5-position on the pyrimidine ring may optionally bear a (l-8C)alkyl group; or a pharmaceutically-acceptable salt thereof.
  • (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,
  • (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, propylamine, cyclopropylamino, cyclobutylamino, cyclohexylamino, cyclopropylmethyl
  • 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 2007/003454
  • tautomerism may affect the benzimidazolyl group when R 2 is a hydroxy or amino group or tautomerism may affect heterocyclic groups within the R 1 and Q 1 groups that bear 1 or 2 oxo or thioxo substituents.
  • the present invention includes in its definition any such tautomeric form, or a mixture thereof, which possesses the above-mentioned activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings or named in the Examples.
  • any R 1 group that is present on the phenyl ring portion of the benzimidazolyl group that is located at the 4-position on the pyrimidine ring may be located at any available position on said phenyl ring.
  • the R 1 groups may be the same or different.
  • a single R 1 group is located at the 4-, 5- or 6-position on said benzimidazolyl group.
  • a single R 1 group is located at the 4-position on said benzimidazolyl group.
  • 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.
  • the R 3 group is a (l-8C)alkyl group such as a methyl group, up to four such groups are present. Any two such groups may be located at the same ring position on said morpholinyl group.
  • a suitable group so formed is, for example, a 3-oxa-6-azabicyclo[3.1. l]hept-6-yl, 6-oxa-3-azabicyclo[3.1. l]hept-3-yl,
  • any R 4 group that may be present on the piperazinyl group that is located at the 2-position on the pyrimidine ring may be located at any available position on said piperazinyl group.
  • the R 4 group is a (l-8C)alkyl group such as a methyl group, up to four such groups are present. Any two such groups may be located at the same ring position on said piperazinyl group.
  • a suitable group so formed is, for example, a 3,6-diazabicyclo[3.1.l]hept-3-yl, 3,6-diazabicyclo[3.1. l]hept-6-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.2]oct-2-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl or 3,8-diazabicyclo[3.2.1]oct-8-yl 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 5 Q' group is, for example, phenyl or naphthyl, preferably phenyl.
  • 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,
  • 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-dioxo ⁇ iperidinyl.
  • 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, (3-8C)cycloalkenyl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group is present.
  • 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; for (l-8C)alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, cyclohexylmethyl and 2-cyclopropylethyl; for (2-8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy
  • (l-6C)alkoxycarbonylammo methoxycarbonylamino, ethoxycarbonylamino and tert-bxitoxy carbony lamino ; or iV-(l-6C)alkylcarbamoyl: JV-methylcarbamoyl, iV-ethylcarbamoyl and iV-propylcarbamoyl; or N,iV-di-[(l-6C)alkyl]carbamoyl: N ⁇ V-dimethylcarbamoyl, JV-ethyl-
  • hydroxy-(l-6C)alkyl hydroxymethyl, 2-hydroxyethyl, 1 -hydroxy ethyl and
  • amino-(l-6C)alkyl aminomethyl, 2-aminoethyl, 1-aminoethyl,
  • N-methylmethanesulphonylaminomethyl 2-(N-methylmethanesulphonylamino)ethyl and l-(N-methylmethanesulphonylamino)ethyl.
  • a suitable value for (R 1 ⁇ 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, 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 benzimidazolyl ring and the oxygen atom is B2007/003454
  • a CH 3 group within a R 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 oxygen atom is linked to the Q 3 group.
  • 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.
  • insertion of an O atom into the alkylene chain within a 4-methoxybutoxy group gives rise to, for example, a 2-(2-methoxyethoxy)ethoxy group
  • insertion of a C ⁇ C group into the ethylene chain within a 2-hydroxyethoxy group gives rise to a 4-hydroxybut-2-ynyloxy group
  • insertion of a CONH group into the ethylene chain within a 3-methoxypropoxy group gives rise to, for example, a 2-(2-methoxyacetamido)ethoxy group.
  • any CH, CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH, CH 2 or CH 3 group one or more halogeno or (l-8C)alkyl substituents, there is suitably 1 halogeno or (l-8C)alkyl substituent present on each said CH group, there are suitably 1 or 2 such substituents present on each said CH 2 group and there are suitably 1, 2 or 3 such substituents present on each said CH 3 group.
  • R 1 substituents so formed include, for example, hydroxy-substituted (l-8C)alkyl groups such as hydroxymethyl, 1 -hydroxy ethyl and 2-hydroxy ethyl, hydroxy-substituted (l- ⁇ C)alkoxy groups such as 2-hydroxypropoxy and 3-hydroxypropoxy, (l-6C)alkoxy-substituted (l-6C)alkoxy groups such as 2-methoxyethoxy and 3-ethoxypropoxy, hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino- 2-hydroxypropoxy, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkoxy groups such as
  • 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, 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
  • the terminal CH 3 group of the (l-6C)alkylamino group may be further substituted by, for example, a (l-6C)alkylsulphonyl group or a (2-6C)alkanoyl group.
  • the R 1 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-[N-(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 iV-(2-dimethylaminoacetyl)piperidin-4-yl group or a 4-(2-dimethylaminoacetyl)piperazin-l-yl group. Similar considerations apply to the attachments and substitutions within the -X ⁇ Q 1 group.
  • 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-6C)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 5-[iV-(2-methylsulphonylethyl)aminomethyl]thien-2-yl group, and a (2-6C)alkanoyl- substituted heterocyclic group such as a iV-(2-dimethylaminoace
  • (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.
  • 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, trifiuoroacetic, 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 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 T/GB2007/003454
  • the present invention includes those compounds of the Formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkyl esters such as methyl, ethyl and tert-butyl, (l- ⁇ C)alkoxy methyl esters such as methoxymethyl esters, (l-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-l,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and (l-6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxy ethyl esters
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the Formula I containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include (l-lOC)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N, N- [di-(l-4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • (l-lOC)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups
  • (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N, N- [di-(l-4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • 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-iV-methylamine or diethylamine, a (l-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, aphenyl-(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-iV-methylamine or diethy
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (l-lOC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, iV-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)allcylpi ⁇ erazin-l-ylmethyl.
  • the in vivo effects of a compound of the Formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula I. As stated hereinbefore, the in vivo effects of a compound of the Formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • 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 (jjj) hereinafter :-
  • each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, hydroxy, mercapto, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, iV,7V-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, JV-(I -6C)alkyl-(2-6
  • X 2 is a direct bond or is selected from O, S, N(R 5 ), CO, wherein R 5 is hydrogen or (l-8C)alkyl
  • Q 2 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or (R*) p is (1-3 C)alky lenedioxy , and wherein any CH, CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH, CH 2 or CH 3 group one or more halogeno or (l-8C)alkyl substituents and/or a substituent selected from hydroxy, mercapto, amino, cyano, carboxy, carbamoyl, ureido,
  • 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- ⁇ C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoylamino and N-(l-6C)alkyl-(2-6C)alkanoylamino, and wherein any CH, CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH, CH 2 or CH 3 group 1, 2 or 3 halogeno or (l-8C)alkyl substituents and/or a substituent selected from hydroxy, amino, cyano, carboxy,
  • 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, iV-methylpropionaniido, hydroxymethyl, 1 -hydroxy ethyl, 1 -hydroxy- 1-methylethyl, 2 -hydroxy ethyl, 2-hydroxy- 1-methylethyl, 2-hydroxypropyl, l
  • p is 0 or p is 1 and the R 1 group is located at the 4-, 5- or 6-position on the benzimidazolyl group and is selected from fluoro, chloro, hydroxy, amino, methoxy, ethoxy, methylamino, ethylamino and acetamido;
  • p is 0 or p is 1 and the R 1 group is located at the 4-position on the benzimidazolyl group and is selected from fluoro, chloro, hydroxy, amino, methoxy, methylamino and acetamido;
  • R 2 is fiuoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
  • R 2 is fiuoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido, acetamido or hydroxymethyl;
  • R 2 is difluoromethyl, trifluoromethyl, amino, formamido, acetamido or hydroxymethyl;
  • R 2 is difluoromethyl; (1) q is 0 or q is 1, 2 or 3 and each R 3 group, which may be the same or different, is methyl, ethyl or propyl;
  • (m) q is 2 and the two R 3 groups together form a methylene or ethylene group
  • each R 4 group which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl,
  • (p) r is 0 or r is 1, 2, 3 or 4 and each R 4 group, which may be the same or different, is methyl, ethyl or propyl;
  • (r) r is 0 or r is 1, 2, 3 or 4 and each R 4 group is methyl; B2007/003454
  • (s) X 1 is selected from CO, SO 2 , CON(R 13 ), COC(R 13 ) 2 O, COC(R 13 ) 2 S, COC(R 13 ) 2 N(R 13 ) and COC(R 13 ) 2 N(R 13 )CO, wherein R 13 is hydrogen or (l-8C)alkyl;
  • X 1 is selected from CO, SO 2 , CONH, COCH 2 O, COCH 2 NH and COCH 2 NHCO;
  • X 1 is selected from CO, SO 2 , CONH, CON(Me) 5 COCH 2 O, COCH 2 NH and s COCH 2 NHCO;
  • (y) Q 1 is (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, halogeno-(l-6C)alkyl, o hydroxy-(l-6C)alkyl, mercapto-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l -6C)alkyl, (1 -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, s heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein 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- ⁇ C)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, selecteds 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 oro (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 hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l -6C)alkyl, (1 -6C)alkylamino-(l -6C)alkyl, di-[(l -6C)alkyl]amino-(l -6C)alkyl, (1 -6C)alkylthio-(l -6C)alkyl or (2-6C)alkanoylamino-(l -6C)alkyl, or Q 1 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH, CH 2 or CH 3 group within the Q 1 group
  • 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 di-[(l-6C)alkyl]amino-(l-6C)alkyl;
  • Q 1 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l -6C)alkyl, (1 -6C)alkylamino-(l -6C)alkyl, di-[(l -6C)alkyl]amino-(l -6C)alkyl,
  • (l-6C)alkylsul ⁇ honyl-(l-6C)alkyl or (2-6C)alkanoylamino-(l-6C)alkyl, or Q 1 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-
  • 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,
  • Q 1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl, 2-imidazolylethyl, pyrazolylmethyl, thiazolylmethyl, triazolylmethyl, oxadiazolylmethyl
  • Q 1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl, thienylmethyl, imidazolylmethyl, thiazolylmethyl, thiadiazolylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperid
  • Q 1 is aminomethyl, 1-aminoethyl, 1 -amino- 1-methylethyl, methylaminomethyl,
  • the X'-Q 1 group is a naturally-occurring ⁇ -amino carbonyl group;
  • the X ⁇ Q 1 group is selected from glycyl, sarcosyl, iV-ethylglycyl, N,iV-diinethylglycyl, glycylglycyl, L-alanyl, 2-methylalanyl, iV-methylalanyl, ⁇ -alanyl, (2S)-2-aminobutanoyl,
  • X 1 is a direct bond and Q 1 is (1 -8C)alkyl, (2-8C)alkenyl or (2-8C)alkynyl;
  • X 1 is a direct bond and Q 1 is methyl, ethyl, propyl, isopropyl, butyl, pentyl or allyl;
  • Q 1 is methyl, ethyl, propyl, isopropyl, butyl, pentyl or allyl;
  • U the 5-position on the pyrimidine ring may bear a methyl group;
  • each R 4 group which may be the same or different, is a (1- 4C)alkyl group, or r is 2 and the two R 4 groups together form a methylene, ethylene or trimethylene group;
  • each R 4 group which may be the same or different, is a (l-4C)alkyl group (especially a methyl group), or r is 2 and the two R 4 groups together form an ethylene group; (rr) r is 0;
  • each R 4 group which may be the same or different, is a (l-4C)alkyl group
  • (tt) r is 2 and the two R 4 groups together form an ethylene group
  • X 1 is a direct bond or is selected from CO, CON(R 13 ), COC(R 13 ) 2 N(R 13 ) and
  • (vv) X 1 is a direct bond or is selected from CO, CON(R 13 ) and COC(R 13 ) 2 N(R 13 )CO, wherein R 13 is hydrogen or (l-2C)alkyl (such as methyl);
  • X 1 is a direct bond or is selected from CO, CONH, COCH 2 NH and COCH 2 NHCO;
  • X 1 is a direct bond or is selected from CO, CONH and COCH 2 NHCO;
  • X 1 is selected from CO, CONH, COCH 2 NH and COCH 2 NHCO (especially CO, COCH 2 NH and COCH 2 NHCO, more especially CO and COCH 2 NHCO);
  • Q 1 is hydrogen, (l-8C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l- 6C)alkyl]amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl (especially amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl), and wherein any CH or 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, mercapto, amino, cyano, carboxy, carbamoyl, ureido, (1- 6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkyl
  • X 7 is a direct bond or is selected from O and N(R 15 ), wherein R 15 is hydrogen or (1- 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 di-[(l-6C)alkyl]amino-(l-6C)alkyl, or from a group of the formula :
  • X 8 is a direct bond or is selected from O, CO and N(R 17 ), wherein R 17 is hydrogen or (l-8C)alkyl
  • Q 5 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, hydroxy, (l-8C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within the Q 1 group optionally bears 1 or 2 oxo or thioxo substituents, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within the Q 1 group are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO 2 , N(R 16 ), N(R 16 )CO, CON(R 16
  • any phenyl, pyrrolidinyl or piperidinyl 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, 2-methoxyethyl, cyanomethyl, 2-cyanoethyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2- methyla
  • Q 1 is aminomethyl, 2-aminoethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl (especially aminomethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl), and wherein any CH or CH 2 group within the Q 1 group optionally bears on each said CH or CH 2 group a substituent selected from methylamino, ethylamino, dimethylamino and diethylamino (especially methylamino);
  • X 1 is CONH and Q 1 is amino-(l-6C)alkyl (especially amino-(l-2C)alkyl such as 2- aminoethyl);
  • X 1 is COCH 2 NHCO and Q 1 is heterocyclyl (especially pyrrolidinyl or piperidinyl, more especially pyrrolidinyl);
  • X 1 is CO and Q 1 is amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl (especially aminomethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl), and wherein any CH or CH 2 group within the Q 1 group optionally bears on each said CH or CH 2 group a methylamino substiruent; and
  • (jjj) X 1 is a direct bond and Q 1 is amino-(l-6C)alkyl (especially amino-(l-2C)alkyl such as 2- aminoethyl).
  • Me herein represents methyl.
  • a particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R 1 group is located at the 4-, 5- or 6-position on the benzimidazolyl group and is selected from fluoro, chloro, hydroxy, amino, methoxy, ethoxy, methylamino, ethylamino and acetamido; R 2 is fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido, acetamido or hydroxymethyl; q is 0 or q is 1 or 2 and each R 3 group is methyl; B2007/003454
  • r is 0, or r is 1, 2, 3 or 4 and each R 4 group, which may be the same or different, is methyl, ethyl or propyl; or r is 2 and the two R 4 groups together form a methylene or ethylene group;
  • X 1 is selected from CO, SO 2 , CONH, CON(Me), COCH 2 O 5 COCH 2 NH and COCH 2 NHCO;
  • Q 1 is 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 1-cyano-l-methylethyl, 4-cyanobutyl, 5-cyanopentyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminopropyl,
  • Q 1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, furyl, thienyl, oxazolyl, isoxazolyl,
  • 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, 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, methoxymethyl, cyanomethyl, aminoniethyl,
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is O;
  • R 2 is difluoromethyl; q is 0 or q is 1 or 2 and each R 3 group is methyl; r is 0, or r is lor 2 and each R 4 group, which may be the same or different, is methyl, ethyl or propyl (especially each R 4 group is methyl); or r is 2 and the two R 4 groups together form an ethylene group;
  • X 1 is a direct bond or is selected from CO, CONH, COCH 2 NH and COCH 2 NHCO (especially X 1 is CO, COCH 2 NH or COCH 2 NHCO, more especially CO or COCH 2 NHCO); and
  • Q 1 is hydrogen, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 1-cyano-l-methylethyl, 4-cyanobutyl, 5- cyanopentyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethyl
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is O;
  • R 2 is difluoromethyl; q is 0 or q is 1 or 2 and each R 3 group is methyl; r is 0, or r is lor 2 and each R 4 group, which may be the same or different, is methyl, ethyl or propyl (especially each R 4 group is methyl); or r is 2 and the two R 4 groups together form an ethylene group;
  • X 1 is a direct bond or is selected from CO, CONH, COCH 2 NH and COCH 2 NHCO (especially X 1 is CO, COCH 2 NH or COCH 2 NHCO, more especially CO or COCH 2 NHCO); and
  • Q 1 is hydrogen, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5- aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4- methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3- ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2- dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl, 5- diethylaminopentyl, or
  • Q 1 is benzyl, 2-phenylethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, indolinyl or isoindolinyl, and wherein 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, iV-ethylcarb
  • any aryl 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, methoxy, methylamino and dimethylamino and any such aryl or heterocyclyl group within the Q 1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrimidine derivative of the Formula
  • Q 1 is aminomethyl, 2-aminoethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl (especially arninomethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl), and wherein 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 methylamino and dimethylaminoo (especially methylamino) and wherein any aryl 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, methoxy, methylamino and dimethylamino and any such aryl or heterocyclyl group within the Q 1 group optionally bears a substituent selected from5 hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylamin
  • a further particular compound of the invention is a pyrimidine derivative of the 0 Formula I wherein :- p is 0 or p is 1 and the R 1 group is located at the 4-, 5- or 6-position on the benzimidazolyl group and is selected from fluoro, chloro, hydroxy, amino, methoxy, ethoxy, methylamino, ethylammo and acetamido;
  • R 2 is fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido,5 acetamido or hydroxymethyl; q is 0 or q is 1 or 2 and each R 3 group is methyl; r is 0, or r is 1, 2, 3 or 4 and each R 4 group, which may be the same or different, is methyl, ethyl or propyl; or r is 2 and the two R 4 groups together form a methylene or ethylene group; and o the X ⁇ Q 1 group is selected from glycyl, sarcosyl, N-ethylglycyl, N,N-dimethylglycyl, glycylglycyl, L-alanyl, 2-methylalanyl, iV-methylalanyl, ⁇ -alanyl, (2S)-2-aminobutanoyl 5 L-valyl, iV-methyl-L-valyl, 2-amino ⁇
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R 1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy;
  • R 2 is difluoromethyl; qis O; r is 0, or r is 1 or 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form a methylene or ethylene group; X 1 is CO; and
  • Q 1 is 2-ethoxyethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, aminomethyl, 2-aminoethyl, methylarninornethyl, 2-methylaminoethyl, ethylaminomethyl, 2-ethylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl, 4-dimethylaminobutyl, 2-methylsulphonylethyl or acetamidomethyl, or 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
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R 1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy;
  • R 2 is difluoromethyl; q is 0; r is 0, or r is 1 or 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form a methylene or ethylene group;
  • X 1 is CO
  • Q 1 is hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-methylethyl, 1-hydroxy- 1-methylethyl, 1 -hydroxy- 1-trifluoromethylethyl, methoxymethyl, 2 -methoxy ethyl, methylsulphonylmethyl, 2-methylsulphonylethyl, methoxycarbonylmethyl, f ⁇ t-butoxycarbonylmethyl, N,N-dimethylcarbamoylmethyl, 2-(JV,N-dimethylcarbamoyl)ethyl, cyclopropyl, 1-hydroxycycloprop-l-yl, 1-aminocycloprop-l-yl, cyclobutyl, 1-hydroxycyclobut-l-yl, 1-aminocyclobut-l-yl, cyclopentyl, 1-hydroxycyclopent-l-yl, 7 003454
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R 1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy;
  • R 2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form a methylene or ethylene group; and the X ⁇ Q 1 group is glycyl, sarcosyl, iV-acetylglycyl, JV,N-dimethylglycyl, 2-methylalanyl,
  • a further particular compound of the invention is a pyrimidine derivative of the
  • R 2 is difluoromethyl; q is 0; r is 0, or r is 1 or 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form a methylene or ethylene group;
  • X 1 is CO
  • Q 1 is hydroxymethyl, 2-hydroxy-2-methylethyl, methoxy methyl, cyclopropyl, 1 -hydroxycycloprop- 1 -yl, tetrahydropyran-4-yl, morpholin-2-yl, morpholin-3-yl, tetrahydro-l,4-thiazin-3-yl, azetidin-2-yl, pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, tetrahydropyran-4-ylmethyl, pyrrolidin-2-ylmethyl, piperidin-3-ylmethyl, piperazin-1-ylmethyl, phenyl, 3-carbamoylphenyl, 3-aminophenyl, 4-aminophenyl, 3-aminomethylphenyl, 4-aminomethylphenyl, 3-hydroxybenzyl, 2-furyl, 2-thienyl, 2-pyrrolyl,
  • a further particular compound of the invention is a pyrimidine derivative of the
  • R 2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R 4 group is methyl; and the X ⁇ Q 1 group is glycyl, sarcosyl, N-acetylglycyl, iV,iV-dimethylglycyl, N-acetylalanyl, 2-methylalanyl, ⁇ -alanyl, D-valyl, L-seryl, iV-methyl-L-seryl, JV-acetylseryl, L-homoseryl or JV-(4-toluoyl)glycyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R 1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy;
  • R 2 is difluoromethyl; qis O; r is 0, or r is 1 or 2 and each R 4 group is methyl;
  • X 1 is CO; and Q 1 is aminomethyl, 1-aminoethyl, 1 -amino- 1-methylethyl, methylaminomethyl,
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R 1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy; 7 003454
  • R 2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R 4 group is methyl;
  • X 1 is CO; and Q 1 is hydroxymethyl, 2-hydroxy-2-methylethyl, cyclopropyl, l-hydroxycycloprop-l-yl,
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is O; R 2 is difluoromethyl; q is O; r is 0;
  • X 1 is CO
  • Q 1 is 1-aminocycloprop-l-yl, 1-aminocyclobut-l-yl, morpholin-2-yl, morpholin-3-yl, pyrrolidin-2-yl, l-aminopiperidin-3-yl, piperazin-2-yl, 3-aminophenyl or 4-aminophenyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0;
  • R 2 is difluoromethyl; q is O; r is 0; and the X l -Q* group is glycyl or sarcosyl; and the 5-position on the pyri ⁇ nidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrimidine derivative of the Formula
  • R 2 is difluoromethyl; q is 0 or q is 2 and each R 3 group is methyl; r is 0, or r is 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form an ethylene group;
  • X 1 is CO
  • Q 1 is amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl (such as aminomethyl, 2- phenylethyl, pyrrolidinyl or piperidinyl, especially aminomethyl, 2-phenylethyl, pyrrolidin-2- yl or piperdin-2-yl), and wherein any CH or CH 2 group within the Q 1 group optionally bears on each said CH or CH 2 group a rnethylamino substituent, and wherein any aryl 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, methoxy, methylamino and dimethylarnino and any such aryl or heterocyclyl group within the Q 1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is O;
  • R is difluoromethyl; q is 0; r is O;
  • X 1 is COCH 2 NHCO
  • Q 1 is amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl (especially heterocyclyl, such as pyrrolidinyl or piperidinyl, for example pyrrolidin-2-yl or piperdin-2-yl), and wherein any CH or CH 2 group within the Q 1 group optionally bears on each said CH or CH 2 group a methylamino substituent, and wherein any aryl 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, methoxy, methylamino and dimethylamino and any such aryl or heterocyclyl group within the Q 1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; and the 5 -
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0;
  • R 2 is difluoromethyl; q is 0 or q is 2 and each R 3 group is methyl; r is 0, or r is 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form an ethylene group; X 1 is a direct bond; and
  • Q 1 is amino-(l-6C)alkyl (such as aminomethyl or 2-aminoethyl), and the 5 -position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is O;
  • R 2 is difluoromethyl; q is 0 or q is 2 and each R 3 group is methyl; r is 0, or r is 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form an ethylene group;
  • X 1 is CONH
  • Q 1 is amino-(l-6C)alkyl (such as aminomethyl or 2-aminoethyl), and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
  • a particular compound of the invention is, for example, a pyrimidine derivative of the
  • Example 1 Formula I that is disclosed hereinafter as Example 1, or a pharmaceutically-acceptable salt thereof.
  • Further particular compounds of the invention are, for example, a pyrimidine derivative of the Formula I that is disclosed hereinafter as Example 2, 3, 4, 5, 6, 7 or 8, or a pharmaceutically-acceptable salt thereof.
  • 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
  • a suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • the reaction 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-dioxan or 1 ,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol.
  • a suitable inert solvent or diluent for example an ether such as tetrahydrofuran, 1,4-dioxan or 1 ,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol.
  • the reaction is carried out in the presence of a dipolar aprotic solvent such as iV,N-dimethylformamide, iV,JV-dimethylacetamide, JV-methylpyrrolidin-2-one or dimethylsulphoxide.
  • the reaction is carried out at
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • protecting groups are given below for the sake of convenience, in which "lower”, as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.
  • a carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy- lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxy ethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl,
  • hydroxy protecting groups include lower alkyl groups (for example tert-buty ⁇ ), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxy carbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example ally loxy carbonyl); aryl-lower alkoxy carbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzy loxy carbonyl); tri(lower alkyl)silyl (for example trimethylsilyl and f ⁇ rt-butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups.
  • lower alkyl groups for example tert-buty ⁇
  • lower alkenyl groups for example allyl
  • lower alkanoyl groups for example acetyl
  • 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 alkoxy carbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example ally loxy carbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 7 003454
  • 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.
  • L is a displaceable group as defined hereinbefore and q and R 3 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 base as defined hereinbefore, with a benzimidazole of the Formula XI
  • L is a displaceable group as defined hereinbefore and p
  • R 1 and R 2 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 p
  • R 1 , R 2 , q and R 3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted under conditions suitable for affecting a ring closure reaction, for example by reaction with a suitable acid (such as hydrochloric acid or trifluoroacetic acid), whereafter any protecting group that is present is removed by conventional means,
  • a suitable acid such as hydrochloric acid or trifluoroacetic acid
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, diisopropylethylamine, iV-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, diisopropylethylamine, iV-methylmorpho
  • 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 JV-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid with an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid with a cyanide such as die
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1 ,4-dioxan, an aromatic solvent such as toluene.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1 ,4-dioxan, an aromatic solvent such as toluene.
  • a dipolar aprotic solvent such as ⁇ N-dimethylformamide,
  • 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.
  • a pyrimidine of the Formula XIV may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter.
  • a pyrimidine of the Formula XIV 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 4 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 q, R 3 , r and R have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a benzimidazole of the Formula XI
  • L is a displaceable group as defined hereinbefore and p, R 1 , R 2 , q and R 3 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 base as defined hereinbefore, with a piperazine of the Formula XVII
  • r and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
  • pyrimidine starting materials of the Formula IV may be prepared by the reaction of a pyrimidine of the Formula XVIII
  • p, R 1 , 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 under conditions suitable for affecting a ring closure reaction, for example by reaction with a suitable acid (such as hydrochloric acid or trifluoroacetic acid), whereafter any protecting group that is present is removed by conventional means.
  • a suitable acid such as hydrochloric acid or trifluoroacetic acid
  • compounds of the Formula I wherein X 1 is a COC(R 13 ) 2 O, COC(R 13 ) 2 S, COC(R 13 ) 2 N(R 13 ) or COC(R 13 ) 2 N(R 13 )CO, wherein R 13 is hydrogen or (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 :- HO 2 C-C(R 1S ) 2 O- Q 1 HO 2 C-C(R 13 ) 2 S — Q 1 HO 2 C —C(R 1S ) 2 N(R 13 )— Q 1
  • a two-step procedure may be employed whereby a pyrimidine of the Formula IV is reacted with an acetic acid, or reactive derivative thereof, that is substituted at the 2-position with a leaving group as defined hereinbefore.
  • a suitable such acetic acid derivative is, for example, 2-chloroacetyl chloride.
  • the product so obtained is reacted with a appropriate alcohol, thiol or amine 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 morpholine compound of the Formula VII wherein q and R 3 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 conveniently be carried out in the presence of a suitable acid or in the presence of a suitable base.
  • a suitable acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, coUidine, 4-dimethylaminopyridine, triethylamine, morpholine, JV-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • an organic amine base such as, for example, pyridine, 2,6-lutidine, coUidine, 4-dimethylaminopyridine, triethylamine, morpholine, JV-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as ⁇ iV-dimethylformamide, iV,iV-dimethylacetamide, iV-methylpyrrolidin-2-one or dimethylsulphoxide.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such
  • 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 ⁇ N-dimethylformamide or ⁇ iV-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 0 C, preferably in the range, for example, 25 to 150°C.
  • an aprotic solvent such as ⁇ N-dimethylformamide or ⁇ iV-dimethylacetamide
  • a suitable base for example potassium carbonate or sodium hexamethyldisilazane
  • Pyrimidine starting materials of the Formula VI may be obtained by conventional procedures analogous to those disclosed in the Examples that are set out hereinafter. 7 003454
  • L is a displaceable group as defined hereinbefore and p
  • R 1 and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a piperazine of the Formula III
  • a suitable chemical equivalent of phosgene is, for example, a compound of the 5 Formula XVI
  • 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 io 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 120°C, preferably at or near ambient temperature.
  • R 13 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 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 120°C, preferably at or near ambient temperature.
  • a suitable reactive derivative of a sulphonic acid of the Formula IX 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.
  • R 1 and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed 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-dioxan or 1,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol.
  • a suitable inert solvent or diluent for example an ether such as tetrahydrofuran, 1,4-dioxan or 1,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol.
  • the reaction is carried out in the presence of a dipolar aprotic solvent such as JV,N-dimethylformamide, iV,N-dimethylacetamide, JV-methylpyrrolidin-2-one or dimethylsulphoxide.
  • the reaction is carried out at a temperature in the range
  • Pyrimidine starting materials of the Formula X may be obtained by conventional procedures analogous to those disclosed in the Examples that are set out hereinafter.
  • a pyrimidine of the Formula XV wherein L is a displaceable group as defined hereinbefore and q, R 3 , r and R 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
  • 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 hereinbefore.
  • the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylarninopyridine, triethylamine, morpholine, iV-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • a suitable base for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylarninopyridine, triethylamine, morpholine, iV-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene
  • an alkali or alkaline earth metal carbonate or hydroxide for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydrox
  • 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.
  • a pharmaceutically-acceptable pro-drug of a pyrimidine derivative of the Formula I When a pharmaceutically-acceptable pro-drug of a pyrimidine derivative of the 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 2007/003454
  • 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 pharmaceutically-acceptable amine or by reaction of a compound of the Formula I containing an amino group with a pharmaceutically-acceptable carboxylic acid.
  • the following assays can be used to measure the effects of the compounds of the present invention as PB kinase inhibitors, as mTOR PI kinase-related kinase inhibitors, as inhibitors in vitro of the activation of PI3 kinase signalling pathways, 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, (a) In Vitro PBK Enzyme Assay
  • 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 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 baculo virus 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 pi 1 Oa, pl lO ⁇ and pl lO ⁇ respectively) were sub-cloned into a pDESTIO vector (Invitrogen Limited, Fountain Drive, Paisley, UK).
  • the vector is a Gateway-adapted version of Fastbacl containing a 6-His epitope tag.
  • Type Ib human PBK pi lO ⁇ isoform corresponding to amino acid residues 144-1102 (EMBL Accession No. X8336A) and the full length human p85 ⁇ regulatory subunit (EMBL Accession No. HSP13KTN) were also sub-cloned into pFastBacl vector containing a 6-His epitope tag.
  • the Type Ia pi 10 constructs were co-expressed with the p85 ⁇ regulatory subunit.
  • expressed proteins were purified using the His epitope tag using standard purification techniques.
  • 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.
  • Biotinylated-DiC8-PI(3,4,5)P3 50 nM; Cell Signals Inc., Catalogue No. 107
  • recombinant purified GST-Grpl PH protein 2.5 nM
  • AlphaScreen Anti-GST donor and acceptor beads 100 ng; Packard Bioscience Limited, Station Road, Pangbourne, Berkshire, UK, Catalogue No. 6760603M
  • the resultant signals arising from laser light excitation at 680 nm were read using a Packard AlphaQuest instrument.
  • PI(3,4,5)P3 is formed in situ as a result of PDK mediated phosphorylation of PI(4,5)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.
  • the donor bead : acceptor bead complex produces a signal that can be measured.
  • 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.
  • signal strength is recovered.
  • PI3K enzyme inhibition for a given test compound was expressed as an IC50 value.
  • the inhibitory properties of compounds of formula (I) against PI3K enzymes such as the Class Ia PI3K enzymes (e.g. PBKalpha, PBKbeta and PBKdelta) and the Class Ib PI3K enzyme (PBKgamma) may be demonstrated,
  • PBKalpha, PBKbeta and PBKdelta the Class Ib PI3K enzyme
  • PBKgamma Class Ib PI3K enzyme
  • 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 mTOR.
  • a C-terminal truncation of mTOR encompassing amino acid residues 1362 to 2549 of mTOR (EMBL Accession No. L34075) 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. 41966-029) containing 10% heat-inactivated foetal calf serum (FCS; Sigma, Poole, Dorset, UK, Catalogue No. F0392), 1% L-glutamine (Gibco, Catalogue No. 25030-024) and 2 mg/ml Geneticin (G418 sulphate; Invitrogen Limited, UK Catalogue No. 10131-027). Following expression in the mammalian HEK293 cell line, expressed protein was purified using the FLAG epitope tag using standard purification techniques.
  • 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).
  • a 30 ⁇ l mixture of recombinant purified mTOR enzyme, 1 ⁇ M biotinylated peptide substrate (Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly- Phe-Thr-Tyr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH 2 ; Bachem UK Ltd), ATP (20 ⁇ M) and a buffer solution [comprising Tris-HCl pH7.4 buffer (50 mM), EGTA (0.1 mM), bovine serum albumin (0.5 mg/ml), DTT (1.25 mM) and manganese chloride (10 mM)] was agitated at room temperature for 90 minutes.
  • biotinylated peptide substrate Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-
  • 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.
  • 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.
  • mTOR enzyme inhibition for a given test compound was expressed as an IC 50 value, (c) In Vitro phospho-Ser473 Akt assay
  • 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,
  • a MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Teddington, Middlesex, UK, Catalogue No. HTB-132) was routinely maintained at 37 0 C with 5% CO 2 up to a confluency of 70-90% in DMEM containing 10% FCS and 1% L-glutarnine.
  • the cells were detached from the culture flask using ' Accutase' (Innovative Cell Technologies Inc., San Diego, CA, USA; Catalogue No. AT104) using standard tissue culture methods and resuspended in media to give 5.5xlO 4 cells per ml.
  • Test compounds were prepared as
  • 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 of 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 proliferation assay the cells were detached from the culture flask using 'Accutase' and, at a density of 4000 cells per well in 100 ⁇ l of complete growth medium, the cells were placed in wells in a 'Costar' 96-well tissue culture-treated plate (Corning Inc., Catalogue No. 3598). Aliquots (100 ⁇ l) per well of growth medium were added to some wells to provide blank values for the colorometric measurement. The cells were incubated overnight at 37 0 C with 5% CO 2 to allow them to adhere.
  • PES phenazine ethosulphate
  • MTS 3-(4, 5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)- 2-(4-sulphophenyl)-2H-tetrazolium salt
  • MTS 3-(4, 5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)- 2-(4-sulphophenyl)-2H-tetrazolium salt
  • MTS 3-(4, 5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)- 2-(4-sulphophenyl)-2H-tetrazolium salt
  • 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 0 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°C with 5% CO 2 . The optical density was measured on a plate reader using a wavelength of 492nm.
  • 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 ins Test (a) with an IC 50 versus pi 10a Type Ia human PDK of approximately 0.1 ⁇ M, and in Test (c) with an IC 50 of approximately 0.1 ⁇ M.
  • the pyrimidine compound disclosed within Example 5 possesses activity in Test (a) with an IC 50 versus pi 10a Type Ia human PDK of approximately 0.2 ⁇ M, and in Test (c) with an IC 50 of approximately 0.6 ⁇ M.
  • a pharmaceutical composition which comprises a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in association with a 5 pharmaceutically-acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a0 finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder), 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 e
  • 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.
  • PDK 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 PBK 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 PBK 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 antiproliferative 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 PI3K 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 PI3K enzymes such as the Class Ia PI3K enzymes and the Class Ib PI3K enzyme, i.e. the compounds may be used to produce a PI3K enzyme inhibitory effect in a warm-blooded animal in need of such treatment.
  • inhibitors of 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 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 5 or a pharmaceutically-acceptable salt thereof, as defined hereinbefore as an anti-invasive agent in the containment and/or treatment of solid tumour disease in a warm-blooded animal such as man.
  • a pyrimidine derivative of the Formula I 5 or a pharmaceutically-acceptable salt thereof as defined hereinbefore in the manufacture of a medicament for use in 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 5 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 5 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.
  • PI3K 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
  • 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
  • a method for the prevention or treatment of those tumours which are sensitive to inhibition of PI3K enzymes (such as the Class Ia enzymes and/or the Class Ib PI3K enzyme) and/or a mTOR 454
  • PI3K enzymes such as the Class Ia enzymes and/or the Class Ib PI3K enzyme
  • kinase such as a mTOR PI kinase-related kinase
  • a pyrimidine derivative of the Formula I 5 or a pharmaceutically-acceptable salt thereof, as defined hereinbefore 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 for the prevention or treatment of those tumours which are sensitive to inhibition of PDK 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.
  • PDK 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
  • 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 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) which comprises administering 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 5 or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for providing a PBK enzyme inhibitory effect (such as a Class Ia PBK 454
  • mTOR kinase inhibitory effect such as a mTOR PI kinase-related kinase inhibitory effect
  • certain compounds of the present invention possess substantially better potency against Class Ia PBK enzymes or against the Class Ib PBK enzyme than 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 or the Class Ib PBK enzyme that they may be used in an amount sufficient to inhibit PBK enzymes whilst demonstrating little activity against EGF receptor tyrosine kinase, VEGF receptor tyrosine kinase or Src non-receptor tyrosine kinase enzymes.
  • Such compounds are likely to be useful for the selective inhibition of PBK enzymes and are likely to be useful for the effective treatment of, for example Class Ia PBK enzyme driven tumours.
  • a pyrimidine derivative of the Formula I 9 or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in providing a selective PBK enzyme inhibitory effect According to a further feature of this aspect of the invention there is provided the use of a pyrimidine derivative of the Formula I 9 or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for- use in providing a selective PBK enzyme inhibitory effect.
  • a method for providing a selective PBK enzyme inhibitory effect which comprises administering an effective amount of a pyrimidine derivative of the Formula I 9 or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a selective PBK enzyme inhibitory effect is meant that the pyrimidine derivatives of the Formula I are more potent against PBK enzymes than against other kinase enzymes.
  • some of the compounds according to the invention are more potent against PBK enzymes than against other kinases such as receptor or non-receptor tyrosine kinases or serine/threonine kinases.
  • a selective 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 PBK enzymes than against other kinases. 454
  • 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.
  • leukaemias including ALL and CML
  • 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 03454
  • a pyrimidine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for treating cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate.
  • a pyrimidine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore 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.
  • 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 :- (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin
  • inhibitors of growth factor function for example such inhibitors include c-Src kinase family inhibitors like 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin- 1 -yl)ethoxy]-5-tetrahydropyran- 4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function]; (iv) inhibitors of growth factor function: for example such inhibitors include
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • a 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 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;
  • 6-morpholinopyrimidine (11.7 g), sodium bicarbonate (21 g) and DMF (100 ml) was stirred under nitrogen and heated to 110°C for 20 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and methylene chloride as eluent. The solid so obtained was a mixture of major and minor isomeric products. The solid was washed with a mixture of isohexane (400 ml) and diethyl ether (400 ml). The washings were evaporated to give a Residue [A].
  • the washed solid was recrystallised from warm methylene chloride (30 ml) by the addition of isohexane (120 ml).
  • the resultant crystalline solid was isolated and washed with a mixture of diethyl ether (300 ml) and isohexane (300 ml) and the washings were again evaporated to give a Residue [B].
  • the l-(7V-te7't-butoxycarbonylglycyl)piperazine used as a starting material was prepared as follows :- A mixture of iV-t ⁇ /'t-butoxycarbonylglycine (2.45 g), 2-(7-azabenzotriazol-l-yl)-
  • the 2-difluoromethyl-lH-benzimidazole used as a starting material was prepared as follows :- s A mixture of 1,2-phenylenediamine (54.1 g), ethyl difluoroacetate (57.8 ml) and toluene
  • the 2-(difluoromethyl)-l -[2-[(3R,5 S)-3 ,5-dimethylpiperazin- 1 -yl]-6-morpholin-4-yl- pyrimidin-4-yl]benzoimidazole used as a starting material was prepared as follows :- A mixture of l-(2-chloro-6-morpholin-4-yl-pyrimidin-4-yl)-2- (difluoromethyl)benzoimidazole (0.100 g), (2R,6S)-2,6-dimethylpiperazine (0.039 g) sodium carbonate (0.036 g) and DMF (2 mL) was heated in a sealed vessel in a microwave at 100°C for 40 minutes.
  • the 2-(difluoromethyi)- 1 -[2-(3 ,3 -dimethy lpiperazin- 1 -yl)-6-morpholin-4-yl-pyrimidin-4- yljbenzoimidazole used as starting material was prepared as follows :-0 Using analogous procedures to those described in Example 2, l-(2-chloro-6-morpholin-4- yl-pyrimidin-4-yl)-2-(difluoromethyl)benzoimidazole was reacted with 2,2-dimethylpiperazine 454
  • Solution A was added to a mixture of 2-(difluoromethyl)-l-(6- morpholin-4-yl-2-pi ⁇ erazin-l-yl-pyrimidin-4-yl)benzoimidazole (0.089 g) and DMF (0.5ml). After stirring at ambient temperature under nitrogen for 30 minutes, a second Solution A was prepared and added to the reaction mixture. The resultant reaction mixture was stirred at ambient temperature for 15 minutes and the mixture was evaporated in a centrifugal evaporator. The residue was taken into dichloromethane (1 ml) and trifluoroacetic acid (1 ml), stirred at ambient temperature for 1 hour, treated with more trifluoroacetic acid (1 ml), and evaporated.
  • the mixture was taken into dichloromethane (0.5 ml) and trifluoroacetic acid (0.5 ml), stirred for 30 minutes at ambient temperature under nitrogen, treated with more trifluoroacetic acid (1 ml), and stirred at ambient temperature for a further hour.
  • the resultant reaction mixture was stirred while sodium carbonate solution (2M, 5 ml) was added dropwise, then the organic layer was separated and the aqueous layer washed three times with dichloromethane (5 ml).
  • the dichloromethane solutions were combined, dried over magnesium sulfate, and evaporated.
  • the resultant mixture was evaporated at 3O 0 C and the residue was taken into ethyl acetate (100 ml), filtered and the filtrate evaporated.
  • Theo resultant residue was purified by chromatography on silica eluting with a gradient from isohexane:dichloromethane:ethyl acetate 50:50:2 to dichloromethane:ethyl acetate 5:1.
  • Solution A was then added to a mixture of 2-(difluoromethy I)-I- [6- [(3 S)-3 -methylmorpholin-4-yl] -2-piperazin- 1 -yl-pyrimidin-4-yl]benzoimidazole (61 % purity, 0.084 g) and DMF (0.5ml). The resultant reaction mixture was stirred at ambient temperature under nitrogen for 30 minutes. A second Solution A was prepared and added to the reaction mixture. The resultant reaction mixture was stirred for a further 15 minutes at ambient temperature the reaction mixture was evaporated in a centrifugal evaporator.

Abstract

L'invention concerne des dérivés de pyrimidine représentés par la formule (I) dans laquelle chaque élément parmi p, R1, R2, q, R3, r, R4, X1 et Q1 sont tels que définis dans la description, leurs procédés de préparation, des compositions pharmaceutiques contenant ceux-ci et leur utilisation dans une méthode destinée à induire un effet anti-prolifératif chez un animal à sang chaud, par exemple l'homme.
PCT/GB2007/003454 2006-09-14 2007-09-12 Dérivés de 4-benzimidaz0lyl-6-m0rph0lin0-2-pipérazinylpyrimidine utilisés comme inhibiteurs de p13k et mtor dans le traitement de troubles prolifératifs WO2008032060A1 (fr)

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