WO2008032041A1 - Dérivés de la pyrimidine à activité inhibitrice contre les enzymes pi3k - Google Patents

Dérivés de la pyrimidine à activité inhibitrice contre les enzymes pi3k Download PDF

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WO2008032041A1
WO2008032041A1 PCT/GB2007/003423 GB2007003423W WO2008032041A1 WO 2008032041 A1 WO2008032041 A1 WO 2008032041A1 GB 2007003423 W GB2007003423 W GB 2007003423W WO 2008032041 A1 WO2008032041 A1 WO 2008032041A1
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alkyl
group
amino
ureido
formula
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PCT/GB2007/003423
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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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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 anti-proliferative 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 PDK such as PDK-I, AKT and mTOR (Blume- Jensen and Hunter, Nature. 2001, 4 ⁇ , 355).
  • PDK lipid kinase
  • lipid kinases including the phosphoinositide 3-kinase (abbreviated hereinafter to PI3K) family that is alternatively known as the ⁇ hosphatidylinositol-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, JJ6: 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.
  • Class II PI3K enzymes phosphorylate both PI and PI 4-phosphate [abbreviated hereinafter to PI(4)P].
  • Class I PI3K enzymes phosphorylate PI, PI(4)P and PI 4,5-bisphos ⁇ hate [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
  • lipid 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
  • 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
  • the regulatory subunit SH2 domains 15 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. Furthermore, the
  • GPCR G-protein coupled receptor
  • tumours such as those of the ovary (Shayesteh et at , Nature Genetics, 1999, 21: 99-102) and cervix (Ma et at, Oncogene. 2000, 19: 2739-2744). More recently, activating mutations within the catalytic site of pi 1 Oa have been associated with various other tumours such as those of the colorectal region and of the breast and lung (Samuels et at , Science, 2004, 304. 554). Tumour-related mutations in p85 ⁇ have also been identified in cancers such as
  • PI3K-mediated pathways include over-expression of the receptor tyrosine kinase Erb2 in a variety of tumours leading to activation of PI3K-mediated pathways (Harari et al, Oncogene, 2000, 19, 6102-6114) and over-expression of the oncogene Ras (Kauffmann-Zeh et al. , Nature, 1997, 385, 544-548).
  • Class Ia PI3Ks may contribute indirectly to tumourigenesis caused by various downstream signalling events.
  • loss of the effect of the PTEN tumour-suppressor phosphatase that catalyses conversion of PI(3,4,5)P3 back to PI(4,5)P2 is associated with a very broad range of tumours via deregulation of PI3K-mediated production of PI(3,4,5)P3 (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41).
  • augmentation of the effects of other PI3K-mediated signalling events is believed to contribute to a variety of cancers, for example by activation of Akt (Nicholson and Anderson, Cellular Signalling. 2002, H, 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 vulva,
  • PBK inhibitors LY294002 and wortmannin. Although use of those compounds may suggest a role for PI3K in a cellular event, they are not sufficiently selective within the PBK family to allow dissection of the individual roles of the family members. For this reason, more potent and selective pharmaceutical PBK inhibitors would be useful to allow a more complete understanding of PBK function and to provide useful therapeutic agents. In addition to tumourigenesis, there is evidence that Class I PBK enzymes play a role in other diseases (Wymann et ah, Trends in Pharmacological Science, 2003, 24, 366-376).
  • Class Ia PBK 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, H, 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 PI3K en2ymes, 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 PI3K enzymes, than against EGF receptor tyrosine kinase or VEGF receptor tyrosine kinase or Src non-receptor tyrosine kinase.
  • Such compounds possess sufficient potency against Class I PI3K enzymes that they may be used in an amount sufficient to inhibit Class I PI3K enzymes, particularly to inhibit Class Ia PI3K 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 IdDa 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 mRNA 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 PDK-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.
  • pharmacological inhibitors of mTOR kinase should be of therapeutic value for treatment of the various forms of the disease of cancer comprising solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies.
  • mTOR kinase plays a role in an array of hamartoma syndromes.
  • tumour suppressor proteins such as TSCl, TSC2, PTEN and LKBl tightly control mTOR kinase signalling. Loss of these tumour suppressor proteins leads to a range of hamartoma conditions as a result of elevated mTOR kinase signalling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37).
  • Syndromes with an established molecular link to dysregulation of mTOR kinase include Koz-Jeghers syndrome (PJS), Cowden disease, Bannayan-Riley- Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and TSC (Inoki et ah, Nature Genetics, 2005, 37, 19-24). Patients with these syndromes characteristically develop benign hamartomatous tumours in multiple organs.
  • Rapamycin has been demonstrated to be a potent immunosuppressant by inhibiting antigen-induced proliferation of T cells, B cells and antibody production (Sehgal, Transplantation Proceedings, 2003, 35_, 7S- 14S) and thus mTOR kinase inhibitors may also be useful immunosuppressives.
  • Inhibition of the kinase activity of mTOR may also be useful in the prevention of restenosis, that is the control of undesired proliferation of normal cells in the vasculature in response to the introduction of stents in the treatment of vasculature disease (Morice et ah, New England Journal of Medicine, 2002, 346, 1773-1780).
  • the Rapamycin analogue, everolimus can reduce the severity and incidence of cardiac allograft vasculopathy (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.
  • 2-aryl-4-piperazin-l-ylpyrimidine compounds such as :- 2-(3-chlorophenyl)-6-morpholino-4-[4-(3-trifluoromethylpyridin-2-yl)piperazin-l- yl]pyrimidine and
  • each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, 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, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, JV-(I -6C)alkylcarbamoyl, N,N-di-[(l -6C)alkyl]carbam
  • 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 )CO, 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 o heterocyclyl-(l-6C
  • 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 )C0, 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 (l-8C)alkyl, and Q 3 is aryl, aryl-(l-6C)alkyl,s (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 4 is a direct bond or is selected from O and N(R 8 ), wherein R 8 is hydrogen or (l-8C)alkyl, and R 7 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, mercapto-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylthio-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, (l-6C)alkoxycarbonylamino-(l-6C)alkyl, N-(l-6C)alkylureido
  • 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 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 1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO 2 , N(R 10 ), CO, CH(OR 10
  • R 2 is fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, hydroxy, amino, formamido, (l-6C)alkoxycarbonylamino, (2-6C)alkanoylamino, N-(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 :
  • X 6 is a direct bond or is selected from O and N(R 12 ), wherein R 12 is hydrogen or s (l-8C)alkyl, and R 11 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl,
  • X 1 is a direct bond or is selected from CO, N(R 13 )CO, CON(R 13 ), N(R 13 )CON(R 13 ), N(R 13 )COC(R 13 ) 2 O, N(R 13 )COC(R 13 ) 2 S, N(R 13 )COC(R 13 ) 2 N(R 13 ) and s N(R l3 )COC(R 13 ) 2 N(R 13 )CO, wherein R 13 is hydrogen or (l-8C)alkyl; and
  • Q 1 is (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, mercapto-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)alkylthio-(l-6C)alkyl, (l-6C)alkylsulphinyl-(l-6C)alkyl, o (l-6C)alkylsulphonyl-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, iV-(l-6
  • X 7 is a direct bond or is selected from O and N(R 15 ), wherein R 15 is hydrogen or
  • 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
  • each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l- ⁇ C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l- ⁇ C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, JV-(I -6C)alkylcarbam
  • 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, s (3-8C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C
  • 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 )C0, 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
  • R 6 is hydrogen or (l-8C)alkyl
  • Q 3 is aryl, aryl-(l-6C)alkyl
  • X 4 is a direct bond or is selected from O and N(R 8 ), wherein R 8 is hydrogen or (l-8C)alkyl, and R 7 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, merca ⁇ to-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylthio-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, (l-6C)alkoxycarbonylamino-(l-6C)alkyl, N-(l-6C)alkylureid
  • 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 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 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 1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO 2 , N(R 10 ), CO, CH(OR 10
  • R 2 is fluoromethyl, difiuoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, hydroxy, amino, formamido, (l-6C)alkoxycarbonylamino, (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 : -X 6 -R u wherein X 6 is a direct bond or is selected from O and N(R 12 ), wherein R 12 is hydrogen or
  • X 1 is selected from CO, N(R 13 )CO, CON(R 13 ), N(R I3 )CON(R 13 ), N(R 13 )COC(R 13 ) 2 O, N(R 13 )COC(R 13 ) 2 S, N(R 13 )COC(R 13 ) 2 N(R 13 ) and N(R 13 )COC(R 13 ) 2 N(R 13 )CO, wherein R 13 is hydrogen or (l-8C)alkyl; and
  • Q 1 is (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, mercapto-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, ( 1 -6C)alkylthio-( 1 -6C)alkyl, ( 1 -6C)alkylsulphinyl-( 1 -6C)alkyl, (l-6C)alkylsulphonyl-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl,
  • X 7 is a direct bond or is selected from O and N(R 15 ), wherein R 15 is hydrogen or (l-8C)alkyl 9 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- [( 1 -6C)alky 1] amino-( 1 -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-SC)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 )C0, CON(R
  • (l-8C)alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-bvfiyl, and also
  • (3-8C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and also (3-6C)cycloalkyl-(l-2C)alkyl groups such as cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl and 2-cyclohexylethyl.
  • references to individual alkyl groups such as "propyl” are specific for the straight-chain version only
  • references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only
  • references to individual cycloalkyl groups such as “cyclopentyl” are specific for that 5-membered ring only.
  • (l-6C)alkoxy includes (3-6C)cycloalkyloxy groups and (3-5C)cycloalkyl-(l-2C)alkoxy groups, for example methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, 2-cyclopropylethoxy, cyclobutylmethoxy, 2-cyclobutylethoxy and cyclopentylmethoxy;
  • (l-6C)alkylamino includes (3-6C)cycloalkylamino groups and (3-5C)cycloalkyl- (l-2C)alkylamino groups, for example methylamino, ethylamino, propylamino, cyclopropylamino, cyclobutylamino, cyclohexylamino, cyclopropyl
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • tautomerism may affect 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-SC)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[3.1.1 ]hept-6-yl, 6-oxa-3 -azabicyclo [3.1.1 ]hept-3 -yl, 3-oxa-8-azabicyclo[3.2.1]oct-8-yl or 8-oxa-3-azabicyclo[3.2.1]oct-3-yl group.
  • there is a single R group. More conveniently, no R group is present (q 0).
  • any R 4 group that may be present on the heterocyclyl group that is located at the 2-position on the pyrimidine ring may be located at any available position on said heterocyclyl 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 position on said piperidine or tetrahydropyridine group.
  • s and t is 2, a piperidin-1-yl ring is formed.
  • a suitable group so formed is, for example, a 3 -azabicyclo [3. l.l]hept-3-yl, 6-azabicyclo[3.1.1]hept-6-yl, 2-azabicyclo[2.2.1]hept-2-yl, 2-azabicyclo[2.2.2]oct-2-yl, 3-azabicyclo[3.2.1]oct-3-yl or 8-azabicyclo[3.2.1]oct-8-yl group.
  • s is 1 and t is 2, a pyrrolidin-1-yl ring is formed.
  • a suitable group so formed is, for example, a 3 -azabicyclo [2.1.l]hex-2-yl group.
  • Suitable values for the generic radicals referred to above include those set out below.
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 5 ) when it is aryl or for the aryl group within a 'Q' group is, for example, phenyl or naphthyl, preferably phenyl.
  • 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,
  • a suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxooxazolidinyl, 2-oxothiazolidinyl, 2-oxopiperidinyl, 4-oxo-l,4-dihydropyridinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
  • a suitable value for a 'Q' group when it is heteroaryl-(l-6C)alkyl is, for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl.
  • the invention comprises corresponding suitable values for 'Q' groups when, for example, rather than a heteroaryl-(l-6C)alkyl group, an aryl-(l-6C)alkyl, (3-8C)cycloalkyl-(l-6C)alkyl, (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; or (2-6C)alkenyloxy: vinyloxy
  • 3-hydroxypropyl is for mercapto-(l-6C)alkyl: mercaptomethyl, 2-mercaptoethyl, 1-mercaptoethyl and 3-mercaptopropyl; for (l-6C)alkoxy-(l-6C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxy ethyl,
  • amino-(l-6C)alkyl aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl and 5-aminopropyl; for (l-6C)alkylamino-(l-6C)alkyl: methylaminomethyl, ethylaminomethyl,
  • a suitable value for (R*)p when it is a (l-3C)alkylenedioxy group is, for example, methylenedioxy, ethylidenedioxy, isopropylidenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.
  • an R 1 group forms a group of the formula Q 2 -X 2 - and, 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 attached to the Q group.
  • X 3 is a C(R 6 ) 2 O linking group
  • it is the carbon atom, not the oxygen atom, of the C(R ) 2 O linking group which is attached to the CH 3 group and the oxygen atom is linked to the Q 3 group.
  • 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 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-hydroxyethyl and 2-hydroxy ethyl, hydroxy-substituted (l- ⁇ C)alkoxy groups such as 2-hydroxypropoxy and 3-hydroxypropoxy, (l- ⁇ C)alkoxy-substituted (l-6C)alkoxy groups such as 2-methoxyethoxy and 3-ethoxypropoxy, hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino- 2-hydroxypropoxy, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkoxy groups such as 2-hydroxy-3-methylaminopropoxy, hydroxy-substituted di-[(l-8C)alkyl groups such as hydroxymethyl, 1-hydroxyethyl and 2-hydroxy ethyl, hydroxy-substituted (l- ⁇ C)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-SC)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 iV-(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.
  • suitable Q 1 groups so formed include, for example, hydroxy-substituted amino-(l-6C)alkyl groups such as l-amino-2-hydroxyethyl or l-amino-2-hydroxypropyl, an (l- ⁇ C)alkoxy-substituted amino-(l-6C)alkyl groups such as l-amino-2-methoxyethyl, a (l-6C)alkylamino-(l-6C)alkyl-substituted heteroaryl group such as a 5-[N-(2-methylsulphonylethyl)aminomethyl]thien-2-yl group, and a (2-6C)alkanoyl- substitute
  • any aryl, (3-8C)cycloalkyl, (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, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an acid-addition salt of a compound of the Formula I for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid
  • a further suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, a salt formed within the human or animal body after administration of a compound of the Formula I. It is further to be understood that a suitable pharmaceutically-acceptable solvate of a compound of the Formula I also forms an aspect of the present invention.
  • a suitable pharmaceutically-acceptable solvate is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate or an alternative quantity thereof. It is further to be understood that a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I also forms an aspect of the present invention.
  • the compounds of the invention may be administered in the form of a pro-drug, that is a compound that is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula I and in vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula I.
  • 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-drags", 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)alkoxymethyl esters such as methoxymethyl esters, (l-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxy ethyl esters, 2-oxo-l,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dio
  • a suitable pharmaceutically-acceptable pro-drag of a compound of the Formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the Formula I containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include (l-lOC)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, iV,N-[di-(l-4C)alkyl]carbamoyl, 2-dialkylaminoacetyl and
  • 2-carboxyacetyl groups examples include aminomethyl, iV-alkylaminomethyl, JV,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)alkylpiperazin-l-ylmethyl.
  • Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (l-4C)alkylamine such as methylamine, a di-(l-4C)alkylamine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a (l-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(l-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a (l-4C)alkylamine such as methylamine
  • a di-(l-4C)alkylamine such as dimethylamine
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (l-lOC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, ⁇ N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-( 1 -4C)alkylpiperazin- 1 -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 , s, t, 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- ⁇ C)alkoxycarbonyl, iV-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(I -6C)alkyl-(2-6C)al
  • 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 is ( 1 -3 C)alkylenedioxy , 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, (l-6C)alkoxy, (l-6
  • 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, JV-methylacetamido, JV-methylpropionamido, hydroxymethyl, 1-hydroxyethyl, 1 -hydroxy- 1-methylethyl, 2-hydroxyethyl, 2-hydroxy- 1-methylethyl, 2-hydroxypropyl, l,l-dimethyl
  • 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 fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, hydroxy, amino, formamido, acetamido, propionamido, iV-methylacetamido, methylamino, ethylamino, dimethylamino, diethylamino, hydroxymethyl or methoxymethyl; (i) R 2 is fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido or acetamido;
  • R is difluoromethyl, trifluoromethyl, amino, formamido or acetamido
  • R 2 is difluoromethyl
  • 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
  • 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;
  • X 1 is selected from CO, N(R 13 )CO, CON(R 13 ), N(R 13 )CON(R 13 ), N(R 13 )COC(R 13 ) 2 O,
  • (x) X 1 is selected from CO, NHCO, N(Me)CO, CONH and CON(Me);
  • (aa) X 1 is CO;
  • Q 1 is (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, merca ⁇ to-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl,
  • X 7 is a direct bond or is selected from O and N(R 15 ), wherein R 15 is hydrogen or (l-8C)alkyl, and R 14 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl or di-[(l-6C)alkyl]amino-(l-6C)alkyl, and wherein any heterocyclyl group within the Q 1 group optionally bears 1 or 2 oxo or thioxo substituents; (cc) Q 1 is (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (cc) Q 1 is (l-8
  • any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q 1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino, or from a group of the formula :
  • 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 (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)alkylsulphonyl-(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
  • Q 1 is aminomethyl, 1-aminoethyl, 1 -amino- 1-methylethyl, methylaminomethyl, 1-methylaminoethyl, 1 -methylamino- 1-methylethyl, acetamidomethyl, 1-acetamidoethyl or 1 -acetamido- 1 -methylethyl;
  • the X'-Q 1 group is an ⁇ -amino carbonyl group
  • the X'-Q 1 group is selected from glycyl, sarcosyl, iV-ethylglycyl, ⁇ N-dimethylglycyl, glycylglycyl, L-alanyl, 2-methylalanyl, N-methylalanyl, ⁇ -alanyl, (2S)-2-aminobutanoyl, L-valyl, iV-methyl-L-valyl, 2-aminopent-4-ynoyl, 2-aminopentanoyl, L-isoleucyl, L-leucyl, 2-methyl-L-leucyl, iV-methyl-L-leucyl, seryl, O-methyl-L-seryl, JV-methyl ⁇ L-seryl, O-methyl-L-homoseryl, L-threonyl, S-methyl-L-cysteinyl, S-methyl-L-homo
  • the X ⁇ Q 1 group is an ⁇ -amino carboxamido group
  • the X ⁇ Q 1 group is a naturally-occurring ⁇ -amino carboxamido group; (nn) the X ⁇ Q 1 group is selected from glycylamino, sarcosylamino,
  • L-isoleucylamino L-leucylamino, 2-methyl-L-leucylamino, (N-methyl-L-leucyi)amino, serylamino, (O-methyl-L-seryl)amino, (N-methyl-L-seryi)amino,
  • 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;
  • (tt) r is 0, or r is 2 and 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; (uu) r is 0;
  • each R 4 group which may be the same or different, is a (l-4C)alkyl group
  • (ww) 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, N(R 13 )CO, CON(R 13 ) and N(R 13 )COC(R 13 ) 2 N(R 13 )CO, wherein R 13 is hydrogen or (l-2C)alkyl (such as methyl);
  • (yy) X 1 is a direct bond or is selected from CO, NHCO, CONH and NHCOCH 2 NHCO;
  • (zz) X 1 is a direct bond or is NHCO; (aaa) X 1 is a direct bond;
  • Q 1 is (l-8C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-
  • Q 1 is amino-(l-2C)alkyl, aryl-(l-2C)alkyl or heterocyclyl, and wherein any CH or CH 2 group within the Q 1 group optionally bears on each said CH or CH 2 group one or more (1-
  • Q 1 is aminomethyl, 2-aminoethyl, 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 hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, ethylamino, dimethylamino, diethylamino, methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl, iV-ethylcarbamoyl, JV- isopropylcarbamoyl, JV,JV-dimethylcarbamoyl, JV,JV-diethylcarbamoyl, acetyl, propionyl, butyryl, pivaloyl, acetamido, propionamido and
  • (fff) X 1 is NHCO 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 substituent;
  • (ggg) X 1 is a direct bond and Q 1 is amino-(l-6C)alkyl (especially amino-(l-2C)alkyl, such as 2-aminoethyl);
  • X 1 is CONH and Q 1 is amino-(l-6C)alkyl (especially amino-(l-2C)alkyl, such as 2- aminoethyl);
  • X 1 is NHCOCH 2 NHCO and Q 1 is heterocyclyl (especially pyrrolidinyl or piperidinyl); (jjj) 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 substituent.
  • Q "Me” herein represents methyl.
  • a particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is O 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,s methylamino, ethylamino and acetamido;
  • R 2 is fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido or acetamido;
  • q is O 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, isQ methyl, ethyl or propyl; or r is 2 and the two R 4 groups together form a methylene or ethylene group;
  • s is 2 and t is 2, or s is 1 and t is 3;
  • X 1 is selected from CO, NHCO, N(Me)CO, CONH and CON(Me);
  • Q 1 is methyl, ethyl, propyl, isopropyl, butyl, pentyl, allyl, 2-methoxyethyl, 5 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, Q dimethyla
  • 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 1 and the 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; s is 2 and t is 2; X 1 is a direct bond or is selected from CO, NHCO, CONH and NHCOCH 2 NHCO
  • Q 1 is methyl, ethyl, propyl, isopropyl, butyl, pentyl, allyl, 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, dimethylamino
  • 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 1 and the 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; s is 2 and t is 2; X 1 is a direct bond or is selected from CO, NHCO, CONH and NHCOCH 2 NHCO
  • Q 1 is aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5- methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminopropyl, A- ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3- dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2- diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl or 5-diethylaminopentyl, or Q 1 is benzyl, 2-
  • 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 and the R group is methyl; r is O; s is 2 and t is 2;
  • X 1 is a direct bond or is NHCO; and Q 1 is aminomethyl, 2-aminoethyl, 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 dimethylamino (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 from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; and the 5-position on the
  • 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-, 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 or acetamido; 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; s is 2 and t is 2, or s is 1 and t is 3; and the X'-Q 1 group is selected from glycylamino, sarcosylamino, (iV,iV-dimethylglycyl)amino, glycylglycylamino, L-alanylamino, 2-methylalanylamino, (JV-methylalanyl)amino, (2S)-2-aminobutanoylamino, L-valyla
  • 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; s is 2 and t is 2, or s is 1 and t is 3; X 1 is CO, CONH or CON(Me); and
  • Q 1 is methyl, ethyl, propyl, isopropyl, 2-ethoxy ethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-methylaminoethyl, ethylaminomethyl, 2-ethylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl,
  • Q 1 is phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrazol-3-yl, thiazol-5-yl, l,2,3-triazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-2-yl
  • 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; s is 2 and t is 2, or s is 1 and t is 3;
  • X 1 is CONH or CON(Me); and Q 1 is methyl, ethyl, propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl,
  • 2-hydroxy-2-methylethyl 1 -hydroxy- 1 -methylethyl, 1 -hydroxy- 1 -trifluoromethylethyl, methoxymethyl, 2-methoxyethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, methylsulphonylmethyl, 2-methylsulphonylethyl, methoxycarbonylmethyl, fert-butoxycarbonylmethyl, N-methylcarbamoylmethyl, iV-ethylcarbamoylmethyl, iV-isopropylcarbamoylmethyl, iV,iV-dimethylcarbamoylmethyl,
  • 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; s is 2 and t is 2, or s is 1 and t is 3;
  • X 1 is CO; and Q 1 is methyl, ethyl, isopropyl, hydroxymethyl, 2-hydroxy-2-methylethyl, methoxymethyl, cyclopropyl, 1-hydroxycycloprop-l-yl, tetrahydropyran-4-yl, azetidin-1-yl, azetidin-2-yl, pyrrolidin-1-yl, 3-diniethylaminopyrrolidin-l-yl, 2-carbamoylpyrrolidin-l-yl, 2-(2-methoxyethyl)pyrrolidin-l-yl, pyrrolidin-2-yl, morpholino, morpholin-2-yl, morpholin-3-yl, tetrahydro-l,4-thiazin-4-yl, tetrahydro-l,4-thiazin-3-yl, piperidino, 4-aminopiperidino, 3-fluoropiperidino,
  • 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; s is 2 and t is 2, or s is 1 and t is 3;
  • X 1 is CONH or CON(Me);
  • Q 1 is methyl, ethyl, isopropyl, allyl, hydroxymethyl, 2-hydroxy-2-methylethyl, methoxymethyl, 4-aminobutyl, N-isopropylcarbamoylmethyl, cyclopropyl, 1-hydroxycycloprop-l-yl, cyclopropylmethyl, 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, tetrahydrofuran-2-ylmethyl, tetrahydropyran-4-ylmethyl, pyrrolidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperazin-1-ylmethyl, phenyl,
  • 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; s is 2 and t is 2, or s is 1 and t is 3;
  • X 1 is CO; and Q ! is pyrrolidin- 1 -yl, 3 -dimethylaminopyrrolidin- 1 -yl, 2-carbamoylpyrrolidin- 1 -yl, morpholino, tetrahydro-l,4-thiazin-4-yl, piperidino, 4-aminopiperidino, 4-fluoropiperidino, 3-cyanomethylpiperidino, piperazin-1-yl or 3-oxopiperazin-l-yl; 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
  • R 2 is difluoromethyl; q is 0; r is 0, or r is 1 or 2 and each R 4 group is methyl; s is 2; t is 2;
  • X 1 is CONH; and Q 1 is methyl, ethyl, allyl, 4-aminobutyl, iV-isopropylcarbamoylmethyl, 2-aminobenzyl,
  • 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; s is 2; t is 2;
  • X 1 is CO
  • Q 1 is 3-dimethylaminopyrrolidin-l-yl, morpholino, piperidino, 4-aminopiperidino or 4-fluoropiperidino ; 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 0; r is 0; s is 2 and t is 2;
  • X 1 is a direct bond; and Q 1 is amino-(l-6C)alkyl (such as aminomethyl or 2-aminoethyl, especially 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 1 and the R 3 group is methyl; r is 0; s is 2 and t is 2;
  • X 1 is NHCO; and Q 1 is amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl (such as 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 and dimethylamino (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, trifluoromefhyl, hydroxy, amino, carbamoyl, methyl, methoxy, methylamino and dimethylamino and any such aryl or heterocyclyl group within the Q 1 group optional
  • a particular compound of the invention is, for example, the pyrimidine derivative ; 4-(2-difluoromethylbenzimidazol-l-yl)-
  • 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 , s, t, X 1 and Q 1 have any of the meanings defined hereinbefore.
  • Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist, (a) The reaction, conveniently in the presence of a suitable base, of a pyrimidine of the Formula II
  • L is a displaceable group as defined hereinafter and p, R 1 , R 2 , R 3 and q have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a heterocyclic compound of the Formula III
  • r, R 4 , s, t, X 1 and Q 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
  • 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, or a dipolar aprotic solvent such as N,N-dimethylformamide, JV,iV-dimethylacetamide, iV-methylpyrrolidin-2-one or dimethylsulphoxide, and the reaction is conveniently carried out at a temperature in the range, for example, 10 to 250°C, preferably in the range 40 to 12O 0 C.
  • 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
  • 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 alkoxy carbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl,
  • hydroxy protecting groups include lower alkyl groups (for example tert-bvLtyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example fert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for example trimethylsilyl and /er/-butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups.
  • lower alkyl groups for example tert-bvLtyl
  • lower alkenyl groups for example allyl
  • lower alkanoyl groups for example acety
  • amino protecting groups include formyl, aiyl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyl and fert-butyldimethylsilyl); alkylidene (for example methylidene) and benzylidene and substituted benzylidene groups.
  • lower alkoxycarbonyl for example tert-
  • 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.
  • 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 X
  • 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
  • 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.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine,
  • 2,6-lutidine collidine, 4-dimethylaminopyridine, triethylamme, morpholine, diisopropylethylamine, 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 alkali or alkaline earth metal carbonate or hydroxide for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide
  • an alkali metal amide for example sodium hexamethyldisilazane
  • an alkali metal hydride for example sodium hydride.
  • a suitable reactive derivative of a carboxylic acid of the Formula IV 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 iV-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
  • the reaction is conveniently earned 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 iV,iV-dimethyl
  • L is a displaceable group as defined hereinbefore and p, R 1 , R 2 , R 3 and q have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a heterocyclic compound of the Formula XIII
  • r, R 4 , s and t have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
  • L is a displaceable group as defined hereinbefore and p
  • R 1 , R 2 , r, R 4 , s and t 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 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.
  • L is a displaceable group as defined hereinbefore and q, R 3 , r, R 4 , s and t 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 X
  • 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, (d)
  • 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, (d)
  • L is a displaceable group as defined hereinbefore and p, R 1 , R 2 , r, R 4 , s, t, 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
  • a suitable acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, 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.
  • 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 ⁇ yV-dimethylformamide, ⁇ iV-dimethylacetamide, iV-methylpyriOlidin-2-one or dimethylsulphoxide.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as
  • 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 iV,N-dimethylformamide or iV,iV-dimethylacetamide 5 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 15O 0 C.
  • an aprotic solvent such as iV,N-dimethylformamide or iV,iV-dimethylacetamide 5 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 15O 0 C.
  • Pyrimidine starting materials of the Formula VI may be obtained by conventional procedures.
  • a pyrimidine of the Formula XII of the Formula XII
  • 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 heterocyclic compound of the Formula III wherein r, R 4 , s, t, X 1 and Q 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
  • a suitable chemical equivalent of phosgene is, for example, a compound of the Formula XIV
  • L is a suitable displaceable group as defined hereinbefore.
  • a suitable displaceable group L is, for example, an alkoxy, aryloxy or sulphonyloxy group, for example a methoxy, phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • a suitable chemical equivalent of phosgene is a carbonate derivative such as disuccinimido carbonate.
  • 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 0 C, preferably at or near ambient temperature.
  • Pyrimidine starting materials of the Formula VIII may be obtained by conventional procedures.
  • L is a displaceable group as defined hereinbefore and p, R 1 , R 2 , R 3 and q have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a heterocyclic ring of the Formula XV
  • r, R 4 , s, t and R 13 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
  • L is a displaceable group as defined hereinbefore and q, R 3 , r, R 4 , s, t and R 13 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 X
  • R 13 NH - Q 1 v wherein 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.
  • 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.
  • L is a displaceable group as defined hereinbefore and q, R 3 , r, R 4 , s, t, X 1 and Q 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a benzimidazole of the Formula X
  • 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 fe/Y-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 fe/Y-butoxide, or, for example, an alkali
  • 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-dimethoxy ethane, 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-dimethoxy ethane, 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, JV,JV-dimethylacetamide, iV-methylpyrrolidin-2-one or dimethylsulphoxide.
  • the reaction is carried out at a
  • Pyrimidine stalling materials of the Formula IX may be obtained by conventional procedures. For example, for the production of those compounds of the Formula IX wherein X 1 is
  • 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.
  • a carboxylic acid of the Formula XVI or a reactive derivative thereof as defined hereinbefore wherein L is a displaceable group as defined hereinbefore and q, R 3 , r, R 4 , s and t have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be coupled, conveniently in the presence of a suitable base as defined hereinbefore, with the NH-containing heterocyclyl group Q 1 where any functional group (other than the reacting NH group) is protected if necessary, whereafter any protecting group that is present is removed by conventional means, (h)
  • the coupling conveniently in the presence of a suitable base, of a pyrimidine
  • 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
  • the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, iV-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline
  • a suitable base for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, iV-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline
  • I 0 earth metal carbonate or hydroxide for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • a pharmaceutically-acceptable salt of a pyrimidine derivative of the Formula I for example an acid-addition salt, it may be obtained by, for example, reaction of said pyrimidine derivative with a suitable acid using a conventional procedure.
  • Formula I is required, it may be obtained using a conventional procedure.
  • an in vivo cleavable ester of a pyrimidine derivative of the Formula I may be obtained by, for example, reaction of a compound of the Formula I containing a carboxy group with a pharmaceutically-acceptable alcohol or by reaction of a compound of the Formula I containing
  • 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.
  • 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 PI3K 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 PI3K enzymes of the lipid PI(4,5)P2.
  • DNA fragments encoding human PI3K catalytic and regulatory subunits were isolated from cDNA libraries using standard molecular biology and PCR cloning techniques. The selected DNA fragments were used to generate baculovirus expression vectors.
  • full length DNA of each of the pi 10a, pi lO ⁇ and pi 105 Type Ia human PI3K pi 10 isoforms (EMBL Accession Nos. HSU79143, S67334, Y10055 for pi 10a, pi lO ⁇ and pi 105 respectively) were sub-cloned into apDESTIO 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 PI3K 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. HSP13KIN) 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.
  • DNA corresponding to amino acids 263 to 380 of human general receptor for phosphoinositides (Grpl) PH domain was isolated from a cDNA library using standard molecular biology and PCR cloning techniques. The resultant DNA fragment was sub-cloned into a pGEX 4Tl E. coli expression vector containing a GST epitope tag (Amersham Pharmacia Biotech, Rainham, Essex, UK) as described by Gray et al. , Analytical
  • Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 ⁇ l) of each compound dilution were placed into a well of a Greiner 384- well low volume (LV) white polystyrene plate (Greiner Bio-one, Brunei Way, Stonehouse, Gloucestershire, UK Catalogue No. 784075). A mixture of each selected recombinant purified PI3K enzyme (15 ng), DiC8-PI(4,5)P2 substrate (40 ⁇ M; Cell Signals Inc., Kinnear Road, Columbus, USA, Catalogue No.
  • LV low volume
  • adenosine triphosphate (ATP; 4 ⁇ M) and a buffer solution [comprising Tris-HCl pH7.6 buffer (40 niM, 10 ⁇ l), 3-[(3-cholamidopropyl)dimethylammonio]- 1-propanesulphonate (CHAPS; 0.04%), dithiothreitol (DTT; 2 mM) and magnesium chloride (10 mM)] was agitated at room temperature for 20 minutes.
  • Tris-HCl pH7.6 buffer 40 niM, 10 ⁇ l
  • CHAPS 3-[(3-cholamidopropyl)dimethylammonio]- 1-propanesulphonate
  • DTT dithiothreitol
  • magnesium chloride 10 mM
  • Control wells that produced a minimum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound.
  • Control wells that produced a maximum signal corresponding to fully inhibited en ⁇ yme 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) and AlphaScreen Anti-GST donor and acceptor beads (100 ng; Packard Bioscience Limited, Station Road, Pangbourne, Berkshire, UK, Catalogue No. 6760603M) were added and the assay plates were left for about 5 to 20 hours at room temperature in the dark. 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 PI3K 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. Accordingly, PI3K enzme activity to form PI(3,4,5)P3 and subsequent competition with biotinylated PI(3,4,5)P3 results in a reduced signal. In the presence of a PI3K enzyme inhibitor, signal strength is recovered.
  • PI3K enzyme inhibition for a given test compound was expressed as an IC 50 value.
  • the inhibitory properties of compounds of formula (I) against PI3K enzymes such as the Class Ia PI3K enzymes (e.g. PBKalpha, PBKbeta and PDKdelta) and the Class Ib PI3K enzyme (PBKgamma) may be demonstrated.
  • PBKalpha, PBKbeta and PDKdelta the Class Ib PI3K enzyme
  • PBKgamma Class Ib PI3K enzyme
  • the assay used AlphaScreen technology (Gray et at , 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- VaI-Ly S-GIu-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-G
  • 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.
  • EDTA 83 mM
  • These assay solutions were incubated for 2 hours at room temperature. Each reaction was stopped by the addition of 10 ⁇ l of a mixture of EDTA (50 mM), bovine serum albumin (BSA; 0.5 mg/ml) and Tris-HCl pH7.4 buffer (50 mM) containing p70 S6 Kinase (T389) 1A5 Monoclonal Antibody (Cell Signalling Technology, Catalogue No.
  • the phosphorylated biotinylated peptide that is associated with AlphaScreen Streptavidin donor beads forms a complex with the p70 S 6 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 5O 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-glutamine.
  • the cells were detached from the culture flask using 'Accutase' (Innovative Cell Technologies Inc., San Diego, CA, USA; Catalogue No. ATI 04) using standard tissue culture methods and resuspended in media to give 5.5x10 4 cells per ml. Aliquots (90 ⁇ l) were seeded into each of the inner 60 wells of a black 'Costar' 96-well plate (Corning Inc., NY, USA; Catalogue No. 3904) to give a density of -5000 cells per well.
  • Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required with DMSO and with growth media to give a range of concentrations that were 10-fold the required final test concentrations. Aliquots (10 ⁇ l) of each compound dilution were placed in duplicate wells to give the final required concentrations. As a minimum response control, each plate contained wells having a final concentration of 30 ⁇ M LY294002 (Calbiochem, Beeston, UK, Catalogue No. 440202). As a maximum response control, wells contained 0.5% DMSO instead of test compound. [An alternative cell treatment procedure involved the transfer of test compounds to the wells using an 'Echo 550' liquid dispenser (Labcyte Inc., Sunnyvale, CA 94089, USA).
  • 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 II' pipettor (Matrix Technologies Corporation, Handforth SK9 3LP, UK).
  • the permeabilsation/blocking buffer caused the cell wall to be partially degraded to allow immunostaining to proceed whilst blocking non-specific binding sites.
  • the buffer was removed and the cells were incubated for 16 hours at 4 0 C with rabbit anti-phospho-Akt (Ser473) antibody solution (50 ⁇ l per well; Cell Signaling Technology Inc., Hitchin, Herts, U.K., Catalogue No. 3787) that had been diluted 1:500 in 'blocking' buffer consisting of a mixture of PBS, 0.5% Tween-20 and 5% dried skimmed milk. Cells were washed three times in a mixture of PBS and 0.05% Tween- 20.
  • This assay determines the ability of test compounds to inhibit cell proliferation, as assessed by the extent of metabolism by living cells of a tetrazolium dye.
  • a MDA-MB-468 human breast carcinoma cell line (ATCC, Catalogue No. HTB- 132) was routinely maintained as described in Biological Assay (c) hereinbefore except that the growth medium did not contain phenol red.
  • the cells were detached from the culture flask using '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.,
  • 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.
  • Test (e) - activity in the range, for example, 1-200 mg/kg/day.
  • the pyrimidine compound disclosed within Example 1 possesses activity in Test (a) with an IC 50 versus pi 10a Type Ia human PBK of approximately 0.2 ⁇ M, and in Test (c) with an IC 50 of approximately 0.01 ⁇ M.
  • the pyrimidine compound disclosed within Example 2 possesses activity in Test (a) with an IC 50 versus pi 10a Type Ia human PI3K of approximately 0.6 ⁇ M, and in Test (c) with an IC 50 of approximately 0.2 ⁇ 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 pharmaceutically-acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder), 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 elix
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 1 mg to 1 g of active agent (more suitably from 1 to 250 mg, for example from 1 to 100 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range, for example, 1 mg/kg to
  • 100 mg/kg body weight is received, given if required in divided doses.
  • lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, 1 mg/kg to 25 mg/kg body weight will generally be used.
  • a dose in the range for example, 1 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration is however preferred, particularly in tablet form.
  • unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention.
  • PI3K 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 PI3K enzymes (such as the Class Ia PI3K enzymes and/or the Class Ib PI3K 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 PI3K enzymes such as the Class Ia PI3K enzymes and/or the Class Ib PI3K enzyme
  • a mTOR kinase such as a mTOR PI
  • the derivatives of the present invention are of value as anti-tumour agents, in particular as selective inhibitors of the proliferation, survival, motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of tumour growth and survival and to inhibition of metastatic tumour growth.
  • the pyrimidine derivatives of the present invention are of value as anti-proliferative and anti-invasive agents in the containment and/or treatment of solid tumour disease.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of one or more of the multiple PI3K enzymes such as the Class Ia PI3K enzymes and the Class Ib 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. Further, 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 PBK enzymes and the Class Ib PI3K enzyme, i.e.
  • 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 broncliioalveolar 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 use as a medicament in a warm-blooded animal such as man.
  • a pyrimidine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for the production of an anti-proliferative effect in a warm-blooded animal such as man.
  • a pyrimidine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore 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 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, 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, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a pyrimidine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.
  • a method for the prevention or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a pyrimidine derivative of the Formula I 5 or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.
  • PDK 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
  • PDK enzymes such as the Class Ia enzymes and/or the Class Ib PDK enzyme
  • a mTOR kinase such as a mTOR is PI kinase-related kinase
  • tumours which are sensitive to inhibition of PDK enzymes (such as the Class Ia enzymes and/or the Class Ib PDK enzyme) and/or a mTOR
  • kinase such as a mTOR PI kinase-related kinase
  • kinase that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells
  • administering comprises administering to said animal an effective amount of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a 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 PDK enzyme) and/or a mTOR kinase (such as a mTOR PI kinase-related kinase) that are involved in the PDK enzymes (such as the Class Ia enzymes and/or the Class Ib PDK enzyme) and/or a mTOR kinase (such as a mTOR PI kinase-related kinase) that are involved in the PDK enzymes (such as the Class Ia enzymes and/or the Class Ib PDK enzyme) and/or a mTOR kinase (such as a mTOR PI kinase-related kinase) that are involved in the PDK enzymes (such as the Class
  • a PBK enzyme inhibitory effect such as a Class Ia PI3K enzyme or Class Ib PI3K enzyme inhibitory effect
  • a mTOR kinase inhibitory effect such as a mTOR PI kinase-related kinase inhibitory effect
  • a PI3K enzyme inhibitory effect such as a Class Ia PI3K enzyme or Class Ib PI3K enzyme inhibitory effect
  • a mTOR kinase inhibitory effect such as a mTOR PI kinase-related kinase inhibitory effect
  • a method for providing a PI3K enzyme inhibitory effect (such as a Class Ia PI3K enzyme or Class Ib PI3K 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, 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 providing a PI3K enzyme inhibitory effect (such as a Class Ia PI3K enzyme or Class Ib PI3K enzyme inhibitory effect) and/or a mTOR kinase inhibitory effect (such as a mTOR PI kinase-related kinase inhibitory effect).
  • a PI3K enzyme inhibitory effect such as a Class Ia PI3K enzyme or Class Ib PI3K enzyme inhibitory effect
  • a 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 PI3K enzymes or against the Class Ib PI3K 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 PI3K enzymes or the Class Ib PI3K enzyme that they may be used in an amount sufficient to inhibit PI3K 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 PI3K enzymes and are likely to be useful for the effective treatment of, for example Class Ia PI3K enzyme driven tumours.
  • a pyrimidine derivative of the Formula I 5 or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in providing a selective PI3K enzyme inhibitory effect is provided.
  • a method for providing a selective PI3K enzyme inhibitory effect which comprises administering an effective amount of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a selective PI3K enzyme inhibitory effect is meant that the pyrimidine derivatives of the Formula I are more potent against PI3K enzymes than against other kinase enzymes.
  • some of the compounds according to the invention are more potent against PI3K enzymes than against other kinases such as receptor or non-receptor tyrosine kinases or serine/threonine kinases.
  • a selective PI3K 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 PI3K enzymes than against other kinases.
  • 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 effective amount of a pyrimidine derivative of the Formula I, 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 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.
  • anti-cancer treatment 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.
  • 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,
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran- 4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function];
  • inhibitors of growth factor function for example such inhibitors include growth factor antibodies and growth factor receptor antibodies [for example the anti-erbB2 antibody trastuzumab and the anti-erbBl antibodies cetuximab (C225) and panitumumab]; such inhibitors also include, for example, tyrosine kinase inhibitors [for example inhibitors of the epidermal growth
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-ma
  • 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.
  • the invention may be illustrated by representative Examples in which, generally : (i) operations may be carried out at ambient temperature, i.e. in the range 17 to 25°C and under an atmosphere of an inert gas such as nitrogen or argon unless otherwise stated;
  • reactions conducted under microwave radiation may be performed using an instrument such as a 'Smith Synthesiser' (300 KWatts) on either the normal or high setting, which instrument makes use of a temperature probe to adjust the microwave power ouput automatically in order to maintain the required temperature; alternatively an 'Emrys Optimizer' microwave instrument may be used;
  • the structures of the end-products of the Formula I may be confirmed by nuclear magnetic resonance (NMR) and/or mass spectral techniques; electrospray mass spectral data were obtained using a Waters ZMD or Waters ZQ LC/mass spectrometer acquiring both positive and negative ion data, generally, only ions relating to the parent structure are reported; proton NMR chemical shift values were measured on the delta scale using either a Bruker Spectrospin DPX300 spectrometer operating at a field strength of 300 MHz or a Bruker Avance spectrometer operating at a field strength of 400 MHz; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad;
  • Method Bl Phenomenex Synergi MAX-RP 8 ⁇ A column (4 microns silica, 2.1 mm diameter, 50 mm length
  • 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;
  • the washed solid was recrystallised from dichloromethane (30 ml) by addition of iso- 5 hexane (120 ml) and the crystalline solid was filtered off, washed with a mixture of diethyl ether (300 ml) and iso-hexane (300 ml) and the washings were again evaporated to a residue, [B].
  • 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 at ambient temperature for a further 15 minutes and the reaction mixture was evaporated in a centrifugal evaporator.
  • the residue was taken into dichloromethane (1 ml) and trifluoroacetic0 acid (1 ml), the resultant mixture stirred at ambient temperature for 1 hour, treated with more trifluoroacetic acid (1 ml), and evaporated.
  • the residue was dissolved in methanol (5 ml) and added to an Isolute SCX-3 cation exchange cartridge (5 g), followed by methanol (30 ml).

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Abstract

L'invention concerne des dérivés de la pyrimidine de la formule (I), dans laquelle chacun des p, R1, R2, q, R3, s, t, X1 et Q1 a n'importe laquelle des significations définies dans le descriptif, leurs processus de préparation, les compositions pharmaceutiques les contenant et leur utilisation dans un procédé de production d'un effet anti-prolifératif chez un animal à sang chaud, par exemple un humain.
PCT/GB2007/003423 2006-09-14 2007-09-12 Dérivés de la pyrimidine à activité inhibitrice contre les enzymes pi3k WO2008032041A1 (fr)

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WO2010092962A1 (fr) 2009-02-12 2010-08-19 アステラス製薬株式会社 Dérivé d'hétérocycle
WO2012020762A1 (fr) 2010-08-10 2012-02-16 アステラス製薬株式会社 Composé hétérocyclique
EP2453294A2 (fr) 2010-11-15 2012-05-16 U2T Photonics UK Limited Modulateur de polarisation de guide d'ondes électro-optique et procédé de modulation
US8362241B2 (en) 2009-04-28 2013-01-29 Amgen Inc. Inhibitors of PI3 kinase and/or mTOR
US8461158B2 (en) 2009-03-27 2013-06-11 Pathway Therapeutics Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
US8486939B2 (en) 2009-07-07 2013-07-16 Pathway Therapeutics Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy
WO2013174794A1 (fr) 2012-05-23 2013-11-28 F. Hoffmann-La Roche Ag Compositions et procédés d'obtention et d'utilisation de cellules endodermiques et d'hépatocytes
EP2762142A1 (fr) 2009-10-30 2014-08-06 ARIAD Pharmaceuticals, Inc. Compositions pour le traitement du cancer
US9056852B2 (en) 2011-03-28 2015-06-16 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US11304953B2 (en) 2017-05-23 2022-04-19 Mei Pharma, Inc. Combination therapy
US11351176B2 (en) 2017-08-14 2022-06-07 Mei Pharma, Inc. Combination therapy

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WO2010092962A1 (fr) 2009-02-12 2010-08-19 アステラス製薬株式会社 Dérivé d'hétérocycle
US8772287B2 (en) 2009-03-27 2014-07-08 Vetdc, Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
US9108980B2 (en) 2009-03-27 2015-08-18 Vetdc, Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
US8461158B2 (en) 2009-03-27 2013-06-11 Pathway Therapeutics Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
US8362241B2 (en) 2009-04-28 2013-01-29 Amgen Inc. Inhibitors of PI3 kinase and/or mTOR
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US8486939B2 (en) 2009-07-07 2013-07-16 Pathway Therapeutics Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy
EP2762142A1 (fr) 2009-10-30 2014-08-06 ARIAD Pharmaceuticals, Inc. Compositions pour le traitement du cancer
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EP2453294A2 (fr) 2010-11-15 2012-05-16 U2T Photonics UK Limited Modulateur de polarisation de guide d'ondes électro-optique et procédé de modulation
US10064868B2 (en) 2011-03-28 2018-09-04 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US9056852B2 (en) 2011-03-28 2015-06-16 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US10335415B2 (en) 2011-03-28 2019-07-02 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US10603324B2 (en) 2011-03-28 2020-03-31 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US11400097B2 (en) 2011-03-28 2022-08-02 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US12059422B2 (en) 2011-03-28 2024-08-13 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
WO2013174794A1 (fr) 2012-05-23 2013-11-28 F. Hoffmann-La Roche Ag Compositions et procédés d'obtention et d'utilisation de cellules endodermiques et d'hépatocytes
US11304953B2 (en) 2017-05-23 2022-04-19 Mei Pharma, Inc. Combination therapy
US11351176B2 (en) 2017-08-14 2022-06-07 Mei Pharma, Inc. Combination therapy

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