WO2008032033A1 - 4-benzimidazolyl-2-morpholino-6-piperazinylpyrimidine derivatives as pi3k and mtor inhibitors for the treatment of proliferative disorders - Google Patents

4-benzimidazolyl-2-morpholino-6-piperazinylpyrimidine derivatives as pi3k and mtor inhibitors for the treatment of proliferative disorders Download PDF

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WO2008032033A1
WO2008032033A1 PCT/GB2007/003414 GB2007003414W WO2008032033A1 WO 2008032033 A1 WO2008032033 A1 WO 2008032033A1 GB 2007003414 W GB2007003414 W GB 2007003414W WO 2008032033 A1 WO2008032033 A1 WO 2008032033A1
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alkyl
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amino
hydroxy
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Sam Butterworth
Edward Jolyon Griffen
George Beresford Hill
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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the invention concerns certain novel pyrimidine derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body.
  • the invention also concerns processes for the manufacture of said pyrimidine derivatives, pharmaceutical compositions containing them and their use in therapeutic methods, for example in the manufacture of medicaments for use in the production of an antiproliferative effect in a warm-blooded animal such as man.
  • Many of the current treatment regimes for cell proliferation diseases such as cancer and psoriasis utilise compounds which inhibit DNA synthesis. Such compounds are toxic to cells generally but their toxic effect on rapidly dividing cells such as tumour cells can be beneficial.
  • Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication. They are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation.
  • EGF epidermal growth factor
  • Various classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based on families of growth factors which bind to different receptor tyrosine kinases. The classification includes Class I receptor tyrosine kinases comprising the EGF family of receptor tyrosine kinases such as the EGF, TGF ⁇ , Neu and erbB receptors.
  • tyrosine kinases belong to the class of non-receptor tyrosine kinases which are located intracellularly and are involved in the transmission of biochemical signals such as those that influence tumour cell motility, dissemination and invasiveness and subsequently metastatic tumour growth.
  • Various classes of non-receptor tyrosine kinases are known including the Src family such as the Src, Lyn, Fyn and Yes tyrosine kinases.
  • 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 PI3K such as PDK-I, AKT and mTOR (Blume- Jensen and Hunter, Nature. 2001, 411, 355).
  • lipid kinases that belong to the class of lipid kinases are located intracellularly and are also involved in the transmission of biochemical signals such as those that influence tumour cell growth and invasiveness.
  • Various classes of lipid kinases are known including the phosphoinositide 3 -kinase (abbreviated hereinafter to PI3K) family that is alternatively known as the phosphatidylinositol-3 -kinase family.
  • PI3K phosphoinositide 3 -kinase
  • 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. ScL, 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-bisphosphate [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].
  • Class IV kinases such as mTOR and DNA-dependent kinase that phosphorylate serine/threonine residues within protein substrates.
  • the most studied and understood of these lipid kinases are the Class I PI3K enzymes.
  • Class I PI3K is a heterodimer consisting of a pi 10 catalytic subunit and a regulatory subunit, and the family is further divided into Class Ia and Class Ib enzymes on the basis of regulatory partners and mechanism of regulation.
  • Class Ia enzymes consist of three distinct catalytic subunits (pi 10a, pi lO ⁇ and pi lO ⁇ ) that dimerise with five distinct regulatory subunits (p85 ⁇ , p55 ⁇ , p50 ⁇ , p85 ⁇ and p55 ⁇ ), with all catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers.
  • Class Ia PI3K are generally activated in response to growth factor-stimulation of receptor tyrosine kinases, via interaction of the regulatory subunit SH2 domains with specific phospho-tyrosine residues of the activated receptor or adaptor proteins such as IRS-I. Both pllO ⁇ and pi lO ⁇ are constitutively expressed in all cell types, whereas pi lO ⁇ expression is more restricted to leukocyte populations and some epithelial cells. In contrast, the single Class Ib enzyme consists of a pi lO ⁇ catalytic subunit that interacts with a pi 01 regulatory subunit. Furthermore, the Class Ib enzyme is activated in response to G-protein coupled receptor (GPCR) systems and its expression appears to be limited to leucocytes.
  • GPCR G-protein coupled receptor
  • Tumour-related mutations in p85 ⁇ have also been identified in cancers such as those of the ovary and colon (Philp et al, Cancer Research. 2001, 61, 7426-7429).
  • activation of Class Ia PI3K contributes to tumourigenic events that occur upstream in signalling pathways, for example by way of ligand-dependent or ligand-independent activation of receptor tyrosine kinases, GPCR systems or integrins (Vara et al, Cancer Treatment Reviews, 2004, 30, 193-204).
  • upstream signalling pathways examples include over-expression of the receptor tyrosine kinase Erb2 in a variety of tumours leading to activation of PI3K-mediated pathways (Harari et al, Oncogene, 2000, 19, 6102-6114) and over-expression of the oncogene Ras (Kauffmann-Zeh et 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, 14, 381-395).
  • Class Ia PI3K enzymes will also contribute to tumourigenesis via its function in tumour-associated stromal cells.
  • PI3K signalling is known to play an important role in mediating angiogenic events in endothelial cells in response to pro-angiogenic factors such as VEGF (Abid et al. , Arterioscler. Thromb. Vase. Biol. 2004, 24, 294-300).
  • VEGF vascular endothelial cells
  • VEGF vascular endothelial growth factor
  • PI3K inhibitors should provide therapeutic benefit via inhibition of tumour cell invasion and metastasis.
  • Class I PI3K enzymes play an important role in the regulation of immune cells with PI3K activity contributing to pro-tumourigenic effects of inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867). These findings suggest that pharmacological inhibitors of Class I PI3K enzymes should be of therapeutic value for treatment of the various forms of the disease of cancer comprising solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies.
  • inhibitors of Class I PI3K enzymes should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
  • cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva,
  • 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, L3, 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 enzymes, whilst possessing less potent inhibitory activity against tyrosine kinase enzymes such as the receptor tyrosine kinases, for example EGF receptor tyrosine kinase and/or VEGF receptor tyrosine kinase, or against non-receptor tyrosine kinases such as Src.
  • the receptor tyrosine kinases for example EGF receptor tyrosine kinase and/or VEGF receptor tyrosine kinase
  • non-receptor tyrosine kinases such as Src.
  • certain compounds of the present invention possess substantially better potency against Class I PI3K enzymes, particularly against Class Ia 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 kDa immunophilin FK506-binding protein (FKBP 12) and this complex inhibits mTOR signalling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37).
  • mTOR protein consists of a catalytic kinase domain, an FKBP12-Rapamycin binding (FRB) domain, a putative repressor domain near the C-terminus and up to 20 tandemly-repeated HEAT motifs at the iV-terminus, as well as FRAP-ATM-TRRAP (FAT) and FAT C-terminus domain (Huang and Houghton, Current Opinion in Pharmacology, 2003, 3, 371-377).
  • mTOR kinase is a key regulator of cell growth and has been shown to regulate a wide range of cellular functions including translation, transcription, niRNA 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 PI3K-Akt-mTOR signalling pathway (Dancey, Expert Opinion on Investigational Drugs, 2005, 14, 313-328).
  • VEGF vascular endothelial cell growth factor
  • mTOR kinase signalling is believed to partially control VEGF synthesis through effects on the expression of hypoxia- inducible factor- l ⁇ (HIF- l ⁇ ) (Hudson et al , Molecular and Cellular Biology. 2002, 22, 7004- 7014).
  • tumour angiogenesis may depend on mTOR kinase signalling in two ways, through hypoxia-induced synthesis of VEGF by tumour and stromal cells, and through VEGF stimulation of endothelial proliferation and survival through PI3K-Akt-mTOR signalling.
  • 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 al., 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 al., 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.
  • the disclosure focuses on arylamino- and heteroarylamino-substituted pyrimidines.
  • the scope of disclosure does not embrace 4-heteroaryl substituted pyrimidines.
  • compounds such as :- 6-(3-hydroxyphenyl)-2-morpholino-4-[4-(4-nitrophenyl)piperazin-l-yl]pyrimidine (no. 82); 6-(3-hydroxyphenyl)-2-morpholino-4-(4-pyridin-2-ylpiperazin-l-yl)pyrimidine (no. 85); 4-(4-acetylpiperazin-l-yl)-6-(3-hydroxyphenyl)-2-morpholinopyrimidine (no.
  • 2-piperazin-l-ylpyriniidine compounds such as :- 4-(2-fluoro ⁇ henyl)-6-morpholino-2-(4-pyridin-2-ylpiperazin-l-yl)pyrimidine (no. 87); and also of 2-aryl-4-piperazin-l-ylpyrimidine compounds such as :-
  • each R 1 group which may be the same or different, is selected from halogeno, 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-6C)alkylsulphinyl,
  • X 2 is a direct bond or is selected from O, S, SO, SO 2 , N(R 5 ), CO, CH(OR 5 ), CON(R 5 ), N(R 5 )C0, N(R 5 )CON(R 5 ), SO 2 N(R 5 ), N(R 5 )SO 2 , OC(R 5 ) 2 , SC(R 5 ) 2 and N(R 5 )C(R 5 ) 2 , wherein R 5 is hydrogen or (l-8C)alkyl, and Q 2 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l -6C)alkyl, (3-8C)cycloalkenyl, (3-8C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-( 1 -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 )CO, N(R 6 )CON(R 6 ), SO 2 N(R 6 ), N(R 6 )SO 2 , C(R 6 ) 2 O, C(R 6 ) 2 S and C(R 6 ) 2 N(R 6 ), wherein R 6 is hydrogen or (l-8C)alkyl, and Q 3 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-6C)alkyl, (3-8C)cycloalkenyl, (3-8C)cycloalkenyl- (l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and
  • 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, 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 : A K wherein X 6 is a direct bond or is selected from O and N(R 12 ), wherein R 12 is hydrogen or (l-8C)alkyl, and R 11
  • X 7 is a direct bond or is selected from O and N(R 15 ), wherein R 15 is hydrogen or (l-8C)alkyl, and R 14 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl or di-[(l-6C)alkyl]amino-(l-6C)alkyl, or from a group of the formula :
  • X 8 is a direct bond or is selected from O, CO and N(R 17 ), wherein R 17 is hydrogen or (l-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 )CO, CON(R 16
  • (l-8C)alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-8C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and also (3-6C)cycloalkyl-(l-2C)alkyl groups such as cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl,
  • (l-6C)alkoxy includes (3-6C)cycloalkyloxy groups and (3-5C)cycloalkyl-(l-2C)alkoxy groups, for example methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, 2-cyclopropylethoxy, cyclobutylmethoxy, 2-cyclobutylethoxy and cyclopentylmethoxy;
  • (l- ⁇ C)alkylamino includes (3-6C)cycloalkylamino groups and (3-5C)cycloalkyl- (l-2C)alkylamino groups, for example methylamino, ethylamino, propylamino, cyclopropylamino, cyclobutylamino, cyclohexylamino, cyclopropy
  • 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. It is to be understood that certain compounds of Formula I defined above may exhibit the phenomenon of tautomerism.
  • 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 2-position on the pyrimidine ring may be located at any available position on said morpholinyl group.
  • the R 3 group is a (l-8C)alkyl group such as a methyl group, up to four such groups are present. Any two such groups may be located at the same ring position on said morpholinyl group.
  • a suitable group so formed is, for example, a 3-oxa-6-azabicyclo[3.1.1]hept-6-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl,
  • any R 4 group that may be present on the piperazinyl group that is located at the 6-position on the pyrimidine ring may be located at any available position on said piperazinyl group.
  • the R 4 group is a (l-8C)alkyl group such as a methyl group, up to four such groups are present. Any two such groups may be located at the same ring position on said piperazinyl group.
  • a suitable group so formed is, for example, a 3,6-diazabicyclo[3.1.1]hept-3-yl, 3,6-diazabicyclo[3.1.1]hept-6-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.2]oct-2-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl or 3,8-diazabicyclo[3.2.1]oct-8-yl group.
  • there is a single R group. More conveniently, no R group is present (r 0).
  • Suitable values for the generic radicals referred to above include those set out below.
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 5 ) when it is aryl or for the aryl group within a 'Q' group is, for example, phenyl or naphthyl, preferably phenyl.
  • 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- ⁇ C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C)alkenyloxy:
  • TV-(I -6C)alkylureido TV'-methylureido and TV'-ethylureido; for TV',TV'-di-[(l -6C)alkyl]ureido: TV',TV'-dimethylureido and TV'-methyl-TV'-ethylureido; for TV-(I -6C)alkylureido: TV-methylureido and TV-ethylureido; for TV,TV'-di-[(l-6C)alkyl]ureido: TV 5 TV' -dimethylureido, TV-methyl-TV'-ethylureido and
  • TV-methyl-TV' ,TV' -diethy lureido TV-methyl-TV' ,TV' -diethy lureido ; for TV-(I -6C)alkylsulphamoyl: TV-methylsulphamoyl and TV-ethylsulphamoyl; for TV,TV-di-[(l-6C)alkyl]sulphamoyl: TV 5 TV-dimethylsulphamoyl;
  • amino-(l-6C)alkyl aminomethyl, 2-aminoethyl, 1-aminoethyl,
  • N'-(l-6C)alkylureido-(l-6C)alkyl N'-methylureidomethyl, 2-(N'-methylureido)ethyl and l-(iV'-methylureido)ethyl; or ⁇ N'-di-[(l-6C)alkyl]ureido-(l-6C)alkyl: iV',N'-dimethylureidomethyl, 2-(N',iV'-dimethylureido)ethyl and
  • N-(l-6C)alkylureido-(l-6C)alkyl iV-methylureidomethyl, 2-(JV-methylureido)ethyl and
  • a suitable value for (R 1 ) p when it is a (l-3C)alkylenedioxy group is, for example, methylenedioxy, ethylidenedioxy, isopropylidenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.
  • an R 1 group forms a group of the formula Q 2 -X 2 - and, 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 2 group.
  • a CH 3 group within a R 1 substituent bears a group of the formula -X 3 -Q 3 and, for example, X 3 is a C(R 6 ) 2 O linking group, it is the carbon atom, not the oxygen atom, of the C(R 6 ) 2 O linking group which is attached to the CH 3 group and the oxygen atom is linked to the Q 3 group.
  • adjacent carbon atoms in any (2-6C)alkylene chain within a R 1 substituent may be optionally separated by the insertion into the chain of a group such as O, CON(R 10 ) or C ⁇ C.
  • insertion of an O atom into the alkylene chain within a 4-methoxybutoxy group gives rise to, for example, a 2-(2-methoxyethoxy)ethoxy group
  • insertion of a C ⁇ C group into the ethylene chain within a 2-hydroxyethoxy group gives rise to a 4-hydroxybut-2-ynyloxy group
  • insertion of a CONH group into the ethylene chain within a 3-methoxypropoxy group gives rise to, for example, a 2-(2-methoxyacetamido)ethoxy group.
  • any CH, CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH, CH 2 or CH 3 group one or more halogeno or (l-8C)alkyl substituents, there is suitably 1 halogeno or (l- ⁇ C)alkyl substituent present on each said CH group, there are suitably 1 or 2 such substituents present on each said CH 2 group and there are suitably 1, 2 or 3 such substituents present on each said CH 3 group.
  • R 1 substituents so formed include, for example, hydroxy-substituted (l-8C)alkyl groups such as hydroxymethyl, 1 -hydroxy ethyl and 2-hydroxy ethyl, hydroxy-substituted (l-6C)alkoxy groups such as 2-hydroxypropoxy and 3-hydroxypropoxy, (l-6C)alkoxy-substituted (l-6C)alkoxy groups such as 2-methoxyethoxy and 3-ethoxypropoxy, hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino- 2-hydroxypropoxy, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkoxy groups such as
  • 2-hydroxy-3-methylaminopro ⁇ oxy hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkoxy groups such as 3-dimethylamino-2-hydroxypropoxy, hydroxy-substituted amino-(2-6C)alkylamino groups such as 3-amino-2-hydroxypropylamino, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkylamino groups such as 2-hydroxy-3-methylaminopropylamino and hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkylarnino groups such as 3-dimethylamino-2-hydroxypropylamino.
  • any CH, CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH, CH 2 or CH 3 group a substituent as defined hereinbefore, such an optional substituent may be present on a CH 5 CH 2 or CH 3 group within the hereinbefore defined substituents that may be present on an aryl, heteroaryl or heterocyclyl group within a R 1 substituent.
  • R 1 includes an aryl or heteroaryl group that is substituted by a (l-8C)alkyl group
  • the (l-8C)alkyl group may be optionally substituted on a CH, CH 2 or CH 3 group therein by one of the hereinbefore defined substituents therefor.
  • R 1 includes a heteroaryl group that is substituted by, for example, a (l-6C)alkylamino-(l-6C)alkyl group
  • the terminal CH 3 group of the (1 -6C)alkylamino group may be further substituted by, for example, a (1 -6C)alkyIsulphonyl group or a (2-6C)alkanoyl group.
  • the R 1 group may be a heteroaryl group such as a thienyl group that is substituted by a N-(2-methylsulphonylethyl)aminomethyl group such that R 1 is, for example, a 5-[JV-(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 N-(2-dimethylaminoacetyl)piperidin-4-yl group or a4-(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 -hydroxy ethyl or l-amino-2-hydroxypropyl, an (1 -6C)alkoxy-substituted amino-( 1 -6C)alkyl groups such as 1 -amino-2-methoxy ethyl, a (l-6C)alkylamino-(l-6C)alkyl-substituted heteroaryl group such as a 5-[iV-(2-methylsulphonylethyl)aminomethyl]thien-2-yl group, and a (2-6C)alkan
  • (3-8C)cycloalkenyl, heteroaryl or heterocyclyl group within the Q 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.
  • a further suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, a salt formed within the human or animal body after administration of a compound of the Formula I.
  • a suitable pharmaceutically-acceptable solvate of a compound of the Formula I also forms an aspect of the present invention.
  • a suitable pharmaceutically-acceptable solvate is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate or an alternative quantity thereof.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I also forms an aspect of the present invention.
  • the compounds of the invention may be administered in the form of a pro-drug, that is a compound that is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • pro-drugs examples include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula I and in vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula I.
  • the present invention includes those compounds of the Formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I may be a synthetically -produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkyl esters such as methyl, ethyl and tert-butyl, (l-6C)alkoxymethyl esters such as methoxymethyl esters, (l-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo- 1 ,3 -dioxolenylmethyl esters such as 5 -methyl-2-oxo- 1 ,3 -dioxolen-4-ylmethyl esters and (l-6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1 -methoxycarbonyloxy
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the Formula I containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include (l-lOC)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N,iV-[di-(l-4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxy acetyl groups.
  • (l-lOC)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups
  • (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N,iV-[di-(l-4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxy acetyl groups.
  • Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (l-4C)alkylamine such as methylamine, a di-(l-4C)alkylamine such as dimethylamine, JV-ethyl-JV-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, JV-ethyl-JV-methylamine or diethyl
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (l-lOC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, iV-alkylaminomethyl, ⁇ N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l -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 , X 1 and Q 1 has any of the meanings defined hereinbefore or in paragraphs (a) to (iii) 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 T -(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(I -6C)alkyl-(2-6C
  • X 2 is a direct bond or is selected from O, S, N(R 5 ), CO, wherein R 5 is hydrogen or (1 -8C)alkyl
  • Q 2 is aryl, aryl-(l -6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l -6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or (R*) p is (1-3 C)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-SC)alkyl substituents and/or a substituent selected from hydroxy, mercapto, amino, cyano, carboxy, carbamoyl, ureido,
  • each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoylamino and N-(I -6C)alkyl-(2-6C)alkanoylamino, and wherein any CH, CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH, CH 2 or CH 3 group 1, 2 or 3 halogeno or (l-8C)alkyl substituents and/or a substituent selected from hydroxy, amino, cyano, carboxy,
  • each R 1 group which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, carboxy, carbamoyl, ureido, methyl, ethyl, propyl, vinyl, allyl, ethynyl, 2-propynyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methoxycarbonyl, ethoxycarbonyl, acetamido, propionamido, N-methylacetamido, N-methylpropionamido, hydroxymethyl, 1 -hydroxy ethyl, 1 -hydroxy- 1-methylethyl, 2-hydroxy ethyl, 2-hydroxy- 1-methylethyl, 2-hydroxypropyl, l,l-d
  • p is 0 or p is 1 and the R 1 group is located at the A-, 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,
  • JV-methylacetamido methylamino, ethylamino, dimethylamino, diethylamino, hydroxymethyl or methoxy methyl;
  • R 2 is fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido, acetamido or hydroxymethyl;
  • R 2 is difluoromethyl, trifluoromethyl, amino, formamido, acetamido or hydroxymethyl;
  • R 2 is difluoromethyl; (1) q is 0 or q is 1, 2 or 3 and each R 3 group, which may be the same or different, is methyl, ethyl or propyl;
  • (m) q is 2 and the two R 3 groups together form a methylene or ethylene group
  • each R group which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl,
  • (p) r is 0 or r is 1, 2, 3 or 4 and each R 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, SO 2 , CON(R 13 ), COC(R 13 ) 2 O, COC(R 13 ) 2 S, COC(R 13 ) 2 N(R 13 ) and COC(R 13 ) 2 N(R 13 )CO, wherein R 13 is hydrogen or (l-8C)alkyl;
  • X 1 is selected from CO, SO 2 , CONH, COCH 2 O, COCH 2 NH and COCH 2 NHCO;
  • X 1 is selected from CO, SO 2 , CONH, CON(Me), COCH 2 O 5 COCH 2 NH and COCH 2 NHCO;
  • (y) 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,
  • any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q 1 group optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl,
  • X 7 is a direct bond or is selected from O and N(R 15 ), wherein R 15 is hydrogen or (l-8C)alkyl, and R 14 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl or di-[(l-6C)alkyl]amino-(l-6C)alkyl, and wherein any heter ⁇ cyclyl group within the Q 1 group optionally bears 1 or 2 oxo or thioxo substituents;
  • Q 1 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)alkylthio-(l-6C)alkyl or (2-6C)alkanoylamino-(l-6C)alkyl, or Q 1 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH, CH 2 or CH 3 group within the Q 1 group optionally bears on each
  • any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q 1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (l- ⁇ C)alkoxy, (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 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 3 group within the Q 1 group optionally
  • Q 1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopen ⁇ yl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl, 2-imidazolylethyl, pyrazolylmethyl, thiazolylmethyl, triazolylmethyl, oxadiazolylmethyl
  • Q 1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl, thienylmethyl, imidazolylmethyl, thiazolylmethyl, thiadiazolylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperid
  • any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q 1 group optionally bears a substituent selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, methoxy, methylamino and dimethylamino and any such aryl,
  • Q 1 is aminomethyl, 1-aminoethyl, 1 -amino- 1-methylethyl, methylaminomethyl,
  • the X ⁇ Q 1 group is a naturally-occurring ⁇ -amino carbonyl group;
  • the X ⁇ Q 1 group is selected from glycyl, sarcosyl, iV-ethylglycyl, JV,N-dimethylglycyl, glycylglycyl, L-alanyl, 2-methylalanyl, iV-methylalanyl, ⁇ -alanyl, (2S)-2-aminobutanoyl,
  • L-valyl N-methyl-L-valyl, 2-aminopent-4-ynoyl, 2-aminopentanoyl, L-isoleucyl, L-leucyl,
  • X 1 is a direct bond and Q 1 is (1 -8C)alkyl, (2-8C)alkenyl or (2-8C)alkynyl;
  • X 1 is a direct bond and Q 1 is methyl, ethyl, propyl, isopropyl, butyl, pentyl or allyl; (11) the 5-position on the pyrimidine ring may bear a methyl group;
  • (nn) p is 0 or p is 1 and the R 1 group is located at the 4-position on the benzimidazolyl group and is methoxy;
  • (oo) p is 1 and the R 1 group is located at the 4-position on the benzimidazolyl group and is (1- 6C)alkoxy (such as methoxy);
  • R 2 is difluoromethyl or trifluoromethyl
  • (ss) q is 0; (tt) q is 1 and the R 3 group is (l- ⁇ C)alkyl (such as methyl); (uu) r is 0, or r is 1 or 2 and each R 4 group, which may be the same or different, is a (1- 44CC))aallkkyyll ggrroouupp,, oorr rr is 2 and the two R groups together form a methylene, ethylene or trimethylene group;
  • each R 4 group which may be the same or different, is a (l-4C)alkyl group (especially a methyl group), or r is 2 and the two R 4 groups together form an ethylene group;
  • each R 4 group which may be the same or different, is a (l-4C)alkyl group
  • (yy) X 1 is a direct bond or is selected from CO, CON(R 13 ), COC(R 13 ) 2 N(R 13 ) and
  • (yy) X 1 is a direct bond or is selected from CO, CON(R 13 ) and COC(R 13 ) 2 N(R 13 )CO, wherein
  • R 13 is hydrogen or (l-2C)alkyl (such as methyl); (zz) X 1 is a direct bond or is selected from CO, CONH, COCH 2 NH and COCH 2 NHCO;
  • (zz) X 1 is a direct bond or is selected from CO, CONH and COCH 2 NHCO;
  • X 1 is selected from CO, CONH, COCH 2 NH and COCH 2 NHCO (especially CO and
  • X 1 is selected from CO, CONH and COCH 2 NHCO (especially CO and COCH 2 NHCO);
  • Q 1 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, amino-(l-
  • 6C)alkyl carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, JV-(I- 6C)alkyl-(2-6C)alkanoylamino, iV'-(l-6C)alkylureido, N',iV'-di-[(l-6C)alkyi]ureido, TV-(I-
  • 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 )C0, CON(R
  • Q 1 is hydrogen, hydroxymethyl, aminomethyl, 2-aminoethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl, and wherein any CH or CH 2 or group within the Q 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, iV-methylcarbamoyl, N-ethylcarbamoyl, N- isopropylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, acetyl, propionyl, butyryl, pivaloyl, acetamido, propionamido and N-methylacetamido, 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, carb
  • Q 1 is hydrogen, hydroxymethyl, aminomethyl, 2-aminoethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl (especially hydroxymethyl, 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 methylamino, ethylamino, dimethylamino and diethylamino (especially methylamino);
  • (fff) X 1 is a direct bond and Q 1 is hydroxy-(l-6C)alkyl or amino-(l-6C)alkyl;
  • X 1 is CO ⁇ H and Q 1 is amino-(l-6C)alkyl (such as aminomethyl or 2-aminoethyl);
  • X 1 is COCH 2 NHCO and Q 1 is heterocyclyl (such as pyrrolidinyl or piperidinyl, especially pyrrolidinyl); and
  • X 1 is CO and Q 1 is amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl (such as 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.
  • Me herein represents methyl.
  • a particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R 1 group is located at the 4-, 5- or 6-position on the benzimidazolyl group and is selected from fluoro, chloro, hydroxy, amino, methoxy, ethoxy, methylamino, ethylamino and acetamido;
  • R 2 is fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido, acetamido or hydroxymethyl; q is 0 or q is 1 or 2 and each R 3 group is methyl; r is 0, or r is 1 , 2, 3 or 4 and each R group, which may be the same or different, is methyl, ethyl or propyl; or r is 2 and the two R 4 groups together form a methylene or ethylene group;
  • X 1 is selected from CO, SO 2 , CONH, CON(Me), COCH 2 O, COCH 2 NH and COCH 2 NHCO;
  • Q 1 is 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 1-cyano-l-methylethyl, 4-cyanobutyl, 5-cyanopentyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylamino
  • Q 1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl, 2-imidazolylethyl, pyrazolylmethyl, thiazolylmethyl, triazolylmethyl, oxadiazolylmethyl
  • 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 methoxy and ethoxy (especially methoxy); R 2 is difluoromethyl or trifluoromethyl; q is 0 or q is 1 and the R 3 group is methyl; r is 0, or r is 1 or 2 and each R 4 group, which may be the same or different, is methyl, ethyl or propyl (especially methyl), or r is 2 and the two R 4 groups together form an ethylene group;
  • X 1 is a direct bond or is selected from CO, CO ⁇ H, COCH 2 NH and COCH 2 NHCO (especially X 1 is a direct bond or is selected from CO, CONH and COCH 2 NHCO);
  • Q 1 is hydrogen, hydroxymethyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2- ethoxy ethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 1 -cyano- 1- methylethyl, 4-cyanobutyl, 5-cyanopentyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4- aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3- ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2- dimethylaminoethyl, 3-di
  • Q 1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl, 2-imidazolylethyl, pyrazolylmethyl, thiazolylmethyl, triazolylmethyl, oxadiazolylmethyl
  • 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 methoxy; R 2 is difluoromethyl or trifluoromethyl; q is 0 or q is 1 and the R 3 group is methyl; r is 0, or r is 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form an ethylene group;
  • X 1 is a direct bond or is selected from CO, CONH, COCH 2 NH and COCH 2 NHCO (especially X 1 is a direct bond or is selected from CO, CONH and COCH 2 NHCO, more especially X 1 is selected from CO and COCH 2 NHCO); and
  • Q 1 is hydrogen, hydroxymethyl, 2-hydroxy ethyl, 2-methoxy ethyl, 3-methoxypropyl, 2- ethoxyethyl, 3-ethoxypropyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5- aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4- methylaminobutyl, 5-methylaminopentyl, ethylarninomethyl, 2-ethylaminoethyl, 3- ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2- dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylamin
  • R 2 is difluoromethyl or trifluoromethyl (especially difluoromethyl); q is 0 or q is 1 and the R 3 group is methyl; o r is 0, or r is 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form an ethylene group;
  • X 1 is a direct bond or is selected from CO, CONH, COCH 2 NH and COCH 2 NHCO (especially X 1 is a direct bond or is selected from CO, CONH and COCH 2 NHCO, more especially X 1 is selected from CO and COCH 2 NHCO); and s Q 1 is hydrogen, hydroxymethyl, 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 methylamino and dimethylamino (especially methylamino), 0 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
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :-0 p is 0 or p is 1 and the R 1 group is located at the 4-, 5- or 6-position on the benzimidazolyl group and is selected from fluoro, chloro, hydroxy, amino, methoxy, ethoxy, methylamino, ethylamino and acetamido; R 2 is fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido, acetamido or hydroxymethyl; q is 0 or q is 1 or 2 and each R 3 group is methyl; 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 groups together form a methylene or ethylene group; and the X l -Q [ group is selected from glycyl, sar
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R 1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy; R 2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form a methylene or ethylene group;
  • X 1 is CO; and Q 1 is 2-ethoxyethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, aminomethyl,
  • 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
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R 1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy; R 2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form a methylene or ethylene group; X 1 is CO; and Q 1 is hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-methylethyl, 1-hydroxy- 1-methylethyl, 1 -hydroxy- 1-trifluoromethylethyl, methoxymethyl, 2-methoxy ethyl, methylsulphonylmethyl, 2-methylsulphonylethyl, methoxycarbonylmethyl, fert-butoxycarbonylmethyl, N,N-dimethylcarbamoylmethyl, 2-(iV,
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R 1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy; R 2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form a methylene or ethylene group; and the X ⁇ Q 1 group is glycyl, sarcosyl, iV-acetylglycyl, JV,iV-dimethylglycyl, 2-methylalanyl, iV-acetylalanyl, ⁇ -alanyl, D-valyl, L-seryl, iV-methyl-L-seryl, JV-acetylseryl, L-homoseryl, glycyglycyl, N
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R 1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy;
  • R 2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form a methylene or ethylene group;
  • X 1 is CO; and Q 1 is hydroxymethyl, 2-hydroxy-2-methylethyl, methoxymethyl, cyclopropyl, 1-hydroxycycloprop-l-yl, tetrahydropyran-4-yl, morpholin-2-yl, morpholin-3-yl, tetrahydro-l,4-thiazin-3-yl, azetidin-2-yl, pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, tetrahydropyran-4-ylmethyl, pyrrolidin-2-ylmethyl, piperidin-3-ylmethyl, piperazin-1-ylmethyl, phenyl, 3-carbamoylphenyl, 3-aminophenyl, 4-aminophenyl,
  • 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; and the X ⁇ Q 1 group is glycyl, sarcosyl, iV-acetylglycyl, iV,iV-dimethylglycyl, iV-acetylalanyl,
  • 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;
  • X 1 is CO; and 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; and the 5-position on the pyrimidine ring is unsubstituted;
  • a further particular compound of the invention is a pyrimidine derivative of the
  • R 2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R 4 group is methyl;
  • X 1 is CO
  • Q 1 is hydroxymethyl, 2-hydroxy-2-methylethyl, cyclopropyl, 1-hydroxycycloprop-l-yl, 1-aminocycloprop-l-yl, 1-aminocyclobut-l-yl, tetrahydropyran-4-yl, morpholin-2-yl, morpholin-3-yl, tetrahydro-l,4 ⁇ thiazin-3-yl, azetidin-2-yl, pyrrolidin-2-yl, pipei ⁇ din-3-yl, l-aminopiperidin-3-yl, piperidin-4-yl, l-aminopiperidin-4-yl, piperazin-2-yl, tetrahy dropyran-4-ylmethyl, pyrrolidin-2-ylmethyl, piperidin-3 -ylmethyl, piperazin-1-ylmethyl, 3-aminophenyl, 4-aminophenyl, 3-aminomethylphenyl, 4-amin
  • R 2 is difluoromethyl; q is 0; r is 0;
  • X 1 is CO; and Q 1 is 1-aminocycloprop-l-yl, 1-aminocyclobut-l-yl, morpholin-2-yl, morpholin-3-yl, pyrrolidin-2-yl, l-aminopiperidin-3-yl, piperazin-2-yl, 3-aminophenyl or 4-aminophenyl; and the 5 -position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrimidine derivative of the
  • R 2 is difluoromethyl; q is 0; r is 0; and the X ⁇ Q 1 group is glycyl or sarcosyl; 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 or trifluoromethyl (especially difluoromethyl); q is 0 or q is 1 and the R 3 group is methyl; r is 0, or r is 2 and each R 4 group is methyl, or r is 2 and the two R 4 groups together form an ethylene group; X 1 is CO; and
  • Q 1 is amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl (such as 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, 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 pyrimidine ring is unsubstituted
  • a further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0; R is difluoromethyl; q is O; r is 0;
  • X 1 is COCH 2 NHCO
  • Q 1 is heterocyclyl (such as pyrrolidinyl or piperidinyl, especially pyrrolidinyl); and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
  • a particular compound of the invention is, for example, a pyrimidine derivative of the Formula I that is disclosed hereinafter as Example 1 , or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is, for example, a pyrimidine derivative of the Formula I that is disclosed hereinafter as Example 2, 3, 4, 5, 6, 7, 8, 9 or 10, or a pharmaceutically-acceptable salt thereof.
  • a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically- related compounds. Such processes, when used to prepare a pyrimidine derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, p, R 1 , R 2 , q, R 3 , r, R 4 , X 1 and 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 and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. (a) The reaction, conveniently in the presence of a suitable base, of a pyrimidine of the Formula II
  • 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 fert-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 fert-butoxide, or, for example, an alkali metal amide,
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran, 1,4-dioxan or 1 ,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol.
  • a suitable inert solvent or diluent for example an ether such as tetrahydrofuran, 1,4-dioxan or 1 ,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol.
  • a dipolar aprotic solvent such as iVjN ' -dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.
  • the reaction is carried out at a temperature in the range, for example, 10 to 25O 0 C, preferably in the range 40 to 150°C.
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods.
  • Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • protecting groups are given below for the sake of convenience, in which "lower”, as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.
  • a carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy- lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and
  • aryl-lower alkyl groups for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl
  • tri(lower alkyl)silyl groups for example trimethylsilyl and fert-butyldimethylsilyl
  • tri(lower alkyl)silyl-lower alkyl groups for example trimethylsilylethyl
  • (2-6C)alkenyl groups for example allyl.
  • hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for example trimethylsilyl and fer ⁇ -butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups.
  • lower alkyl groups for example tert-butyl
  • lower alkenyl groups for example allyl
  • lower alkanoyl groups for example acetyl
  • amino protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisymiethyl and furylmethyl groups; lower alkoxycarbonyl (for example fer/-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.
  • aryl-lower alkyl groups for example
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as 2-nitrobenzyloxycarbonyl.
  • groups such as 2-nitrobenzyloxycarbonyl
  • hydrogenation for groups such as benzyl
  • photolytically for groups such as 2-nitrobenzyloxycarbonyl.
  • the reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents and to Protective Groups in Organic Synthesis, 2 nd Edition, by T. Green et al. , also published by John Wiley & Son, for general guidance on protecting groups.
  • Pyrimidine starting materials of the Formula II may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter.
  • a pyrimidine of the Formula XII may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter.
  • a pyrimidine of the Formula XII may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter.
  • 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.
  • 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 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, (b)
  • a suitable acid such as hydrochloric acid or trifluoroacetic acid
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine, diisopropylethylamine, iV-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine, diisopropylethylamine, iV-methylmorpho
  • a suitable reactive derivative of a carboxylic acid of the Formula V is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid with an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid with a chloroformate such as isoburyl chloroformate; an active ester, for example an ester formed by the reaction of the acid with a phenol such as pentafluorophenol, with an ester such as pentafluorophenyl trifluoroacetate or with an alcohol such as methanol, ethanol, isopropanol, butanol or JV-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid with an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid with a cyanide such as dieth
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene.
  • a dipolar aprotic solvent such as iV,A/-dimethylformamide,
  • Pyrimidine starting materials of the Formula IV may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter.
  • a pyrimidine of the Formula XIV may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter.
  • a pyrimidine of the Formula XIV may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter.
  • L is a displaceable group as defined hereinbefore and p
  • R 1 , R 2 , r and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a morpholine of the Formula VII
  • L is a displaceable group as defined hereinbefore and q, R 3 , r and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a benzimidazole of the Formula XI
  • r and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
  • a pyrimidine of the Formula XX a pyrimidine of the Formula XX
  • R1 XX wherein p, R 1 , R 2 , q, R 3 , r and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted under conditions suitable for affecting a ring closure reaction, for example by reaction in the presence of a suitable acid (such as hydrochloric acid or trifluoroacetic acid), whereafter any protecting group that is present is removed by conventional means.
  • a suitable acid such as hydrochloric acid or trifluoroacetic acid
  • compounds of the Formula I wherein X 1 is a COC(R 13 )2 ⁇ , COC(R 13 ) 2 S, COC(R 13 ) 2 N(R 13 ) or COC(R 13 ) 2 N(R 13 )CO, wherein R 13 is hydrogen or (l-8C)alkyl may also be prepared by the acylation of a pyrimidine of the Formula IV with the appropriate carboxylic acid selected from the formulae :-
  • a two-step procedure may be employed whereby a pyrimidine of the Formula IV is reacted with an acetic acid, or reactive derivative thereof, that is substituted at the 2-position with a leaving group as defined hereinbefore.
  • a suitable such acetic acid derivative is, for example, 2-chloroacetyl chloride.
  • the product so obtained is reacted with a appropriate alcohol, thiol or amine selected from the formulae :-
  • L is a displaceable group as defined hereinbefore and p, R 1 , R 2 , r, R 4 , X 1 and Q 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a morpholine compound of the Formula VII
  • reaction may conveniently be carried out in the presence of a suitable acid or in the presence of a suitable base.
  • a suitable acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, iV-rnethylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, iV-rnethylmorpholine or diazabicyclo[5.4.0]undec
  • 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 N,iV-dimethylformamide, iV,iV-dimethylacetamide, iV-methylpyrrolidin-2-one or dimethylsulphoxide.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such
  • the pyrimidine of the Formula VI may be reacted with a morpholine of the Formula VII in the presence of an aprotic solvent such as A ⁇ N-dimethylformamide or iV,JV-dimethylacetamide, conveniently in the presence of a suitable base, for example potassium carbonate or sodium hexamethyldisilazane, and at a temperature in the range, for example, 0 to 200°C, preferably in the range, for example, 25 to 15O 0 C.
  • an aprotic solvent such as A ⁇ N-dimethylformamide or iV,JV-dimethylacetamide
  • a suitable base for example potassium carbonate or sodium hexamethyldisilazane
  • Pyrimidine starting materials of the Formula VI may be obtained by conventional procedures analogous to those disclosed in the Examples that are set out hereinafter.
  • a pyrimidine of the Formula XIII may be obtained by conventional procedures analogous to those disclosed in the Examples that are set out hereinafter.
  • a pyrimidine of the Formula XIII may be obtained by conventional procedures analogous to those disclosed in the Examples that are set out hereinafter.
  • L is a displaceable group as defined hereinbefore and p
  • R 1 and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a piperazine of the Formula III
  • L is a suitable displaceable group as defined hereinbefore.
  • a suitable displaceable group L is, for example, an alkoxy, aryloxy or sulphonyloxy group, for example a methoxy, phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • a suitable chemical equivalent of phosgene is a carbonate derivative such as disuccinimido carbonate.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 to 12O 0 C, preferably at or near ambient temperature.
  • 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 12O 0 C, preferably at or near ambient temperature.
  • a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 to 12O 0 C, preferably at or near ambient temperature.
  • a suitable reactive derivative of a sulphonic acid of the Formula IX is, for example, a sulphonyl halide, for example a sulphonyl chloride formed by the reaction of the sulphonic acid with an inorganic acid chloride, for example thionyl chloride.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 to 12O 0 C, preferably at or near ambient temperature.
  • a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 to 12O 0 C, preferably at or near ambient temperature.
  • L is a displaceable group as defined hereinbefore and q, R 3 , r, R 4 , X 1 and Q 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a benzimidazole of the Formula XI
  • 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 t ⁇ r/-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 t ⁇ r/-butoxide, or, for example, an alkali metal
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran, 1,4-dioxan or 1,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol.
  • a suitable inert solvent or diluent for example an ether such as tetrahydrofuran, 1,4-dioxan or 1,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol.
  • the reaction is carried out in the presence of a dipolar aprotic solvent such as N,iV-dimethylformamide, N,iV-dimethylacetamide, JV-methylpyrrolidin-2-one or dimethylsulphoxide.
  • the reaction is carried out at a temperature in the range,
  • Pyrimidine starting materials of the Formula X may be obtained by conventional procedures analogous to those disclosed in the Examples that are set out hereinafter.
  • L is a displaceable group as defined hereinbefore and q, R 3 , r and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be acylated, conveniently in the presence of a suitable base as defined hereinbefore, with a carboxylic acid of the Formula V
  • the pyrimidine derivative of the Formula I may be obtained from the process variants described hereinbefore in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of the formula H-L wherein L has the meaning defined hereinbefore.
  • the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • a pharmaceutically-acceptable salt of a pyrimidine derivative of the Formula I is required, for example an acid-addition salt, it may be obtained by, for example, reaction of said pyr
  • a pharmaceutically-acceptable pro-drug of a pyrimidine derivative of the Formula I When a pharmaceutically-acceptable pro-drug of a pyrimidine derivative of the Formula I is required, it may be obtained using a conventional procedure.
  • an in vivo cleavable ester of a pyrimidine derivative of the Formula I may be obtained by, for example, reaction of a compound of the Formula I containing a carboxy group with a pharmaceutically-acceptable alcohol or by reaction of a compound of the Formula I containing a hydroxy group with a pharmaceutically-acceptable carboxylic acid.
  • an in vivo cleavable amide of a pyrimidine derivative of the Formula I may be obtained by, for example, reaction of a compound of the Formula I containing a carboxy group with a pharmaceutically-acceptable amine or by reaction of a compound of the Formula I containing an amino group with a pharmaceutically-acceptable carboxylic acid.
  • the following assays can be used to measure the effects of the compounds of the present invention as PB kinase inhibitors, as mTOR PI kinase-related kinase inhibitors, as inhibitors in vitro of the activation of PB kinase signalling pathways, as inhibitors in vitro of the activation of PB kinase signalling pathways, as inhibitors in vitro of the proliferation of MDA-MB-468 human breast adenocarcinoma cells, and as inhibitors in vivo of the growth in nude mice of xenografts of MDA-MB-468 carcinoma tissue, (a) In Vitro PBK Enzyme Assay The assay used AlphaScreen technology (Gray et al. , Analytical Biochemistry, 2003,
  • test compounds to inhibit phosphorylation by recombinant Type I PBK enzymes of the lipid PI(4,5)P2.
  • DNA fragments encoding human PBK catalytic and regulatory subunits were isolated from cDNA libraries using standard molecular biology and PCR cloning techniques. The selected DNA fragments were used to generate baculovirus expression vectors.
  • full length DNA of each of the pi 10a, pi lO ⁇ and pi 105 Type Ia human PBK pi 10 isoforms (EMBL Accession Nos. HSU79143, S67334, Y10055 for pl lO ⁇ , pl lO ⁇ and pl lO ⁇ respectively) were sub-cloned into a pDESTIO vector (Invitrogen Limited, Fountain Drive, Paisley, UK).
  • the vector is a Gateway-adapted version of Fastbacl containing a 6-His epitope tag.
  • Type Ib human PI3K pi 10 ⁇ 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.
  • 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 white polystyrene plate
  • adenosine triphosphate (ATP; 4 ⁇ M) and a buffer solution [comprising Tris-HCl pH7.6 buffer (40 mM, 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 mM, 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 enzyme were created by adding wortmannin (6 ⁇ M; Calbiochem / Merck Bioscience, Padge Road, Beeston, Nottingham, UK, Catalogue No. 681675) instead of test compound.
  • wortmannin (6 ⁇ M; Calbiochem / Merck Bioscience, Padge Road, Beeston, Nottingham, UK, Catalogue No. 681675) instead of test compound.
  • 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
  • the donor bead : acceptor bead complex produces a signal that can be measured.
  • PI3K enzme activity to form PI(3,4,5)P3 and subsequent competition with biotinylated PI(3,4,5)P3 results in a reduced signal.
  • signal strength is recovered.
  • PI3K enzyme inhibition for a given test compound was expressed as an IC 50 value.
  • inhibitory properties of compounds of formula (I) against PI3K enzymes such as the Class Ia PI3K enzymes (e.g. POKalpha, PBKbeta and PBKdelta) and the Class Ib
  • PI3K enzyme (PDKgamma) may be demonstrated.
  • 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 niM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 ⁇ l) of each compound dilution were placed into a well of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one).
  • LV low volume
  • 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-LyS-GIu-NH 2 ; Bachem UK Ltd), ATP (20 ⁇ M) and a buffer solution [comprising Tris-HCl pH7.4 buffer (50 niM), EGTA (0.1 niM), bovine serum albumin (0.5 mg/ml), DTT (1.25 raM) 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-Le
  • Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound.
  • Control wells that produced a minimum signal corresponding to fully inhibited enzyme were created by adding EDTA (83 mM) instead of test compound. These assay solutions were incubated for 2 hours at room temperature.
  • Phosphorylated biotinylated peptide is formed in situ as a result of mTOR mediated phosphorylation.
  • the phosphorylated biotinylated peptide that is associated with AlphaScreen Streptavidin donor beads forms a complex with the p70 S6 Kinase (T389) 1 A5 Monoclonal Antibody that is associated with Alphascreen Protein A acceptor beads.
  • the donor bead : acceptor bead complex produces a signal that can be measured. Accordingly, the presence of mTOR kinase activity results in an assay signal. In the presence of an mTOR kinase inhibitor, signal strength is reduced.
  • mTOR enzyme inhibition for a given test compound was expressed as an IC 50 value.
  • a MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Teddington, Middlesex, UK, Catalogue No. HTB- 132) was routinely maintained at 37°C with
  • Test compounds were prepared as
  • each plate contained wells having a final concentration of 30 ⁇ M LY294002 (Calbiochem, Beeston, UK, Catalogue No. 440202).
  • test compounds contained 0.5% DMSO instead of test compound.
  • DMSO methyl methacrylate
  • 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).
  • 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°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., Catalogue No. 3598). Aliquots (100 ⁇ l) per well of growth medium were added to some wells to provide blank values for the colorometric measurement. The cells were incubated overnight at 37°C with 5% CO 2 to allow them to adhere. Sufficient phenazine ethosulphate (PES, Sigma Catalogue No. P4544) was added to a
  • Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted with growth medium to give a range of test concentrations. An aliquot (50 ⁇ l) of each compound dilution was placed in a well in the 96-well plates. Each plate contained control wells without test compound. With the exception of wells containing the plate blanks, the outer wells on each 96-well plate were not used. The cells were incubated for 72 hours at 37 0 C with 5% CO 2 . An aliquot (30 ⁇ l) of the MTS/PES solution was added to each well and the cells were incubated for 2 hours at 37 0 C with 5% CO 2 . The optical density was measured on a plate reader using a wavelength of 492nm.
  • This test measures the ability of compounds to inhibit the growth of MDA-MB-468 human breast adenocarcinoma cells grown as a tumour in athymic nude mice (Alderley Park nu/nu strain).
  • a total of about 5 x 10 6 MDA-MB-468 cells in matrigel (Beckton Dickinson Catalogue No. 40234) are injected subcutaneously into the left flank of each test mouse and the resultant tumours are allowed to grow for about 14 days. Tumour size is measured twice weekly using callipers and a theoretical volume is calculated. Animals are selected to provide control and treatment groups of approximately equal average tumour volume.
  • Test compounds are prepared as a ball-milled suspension in 1% polysorbate vehicle and dosed orally once daily for a period of about 28 days. The effect on tumour growth is assessed.
  • the pyrimidine compound disclosed within Example 1 possesses activity in Test (a) with an IC 50 versus pi 10a Type Ia human PI3K of approximately 0.4 ⁇ M, and in Test (c) with an ICs 0 of approximately 0.1 ⁇ M.
  • the pyrimidine compound disclosed within Example 4 possesses activity in Test (a) with an IC 50 versus pi 10a Type Ia human PI3K of approximately 1.2 ⁇ 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.
  • PBK enzymes contribute to tumourigenesis by one or more of the effects of mediating proliferation of cancer and other cells, mediating angiogenic events and mediating the motility, migration and invasiveness of cancer cells.
  • the pyrimidine derivatives of the present invention possess potent anti-tumour activity which it is believed is obtained by way of inhibition of one or more of the Class I 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 rumour 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.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by inhibition of PI3K enzymes such as the Class Ia PI3K enzymes and the Class Ib PI3K enzyme, i.e. the compounds may be used to produce a PI3K enzyme inhibitory effect in a warm-blooded animal in need of such treatment.
  • inhibitors of PI3K enzymes should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias [including acute lymphoctic leukaemia (ALL) and chronic myelogenous leukaemia (CML)], multiple myeloma and lymphomas.
  • ALL acute lymphoctic leukaemia
  • CML chronic myelogenous leukaemia
  • a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore 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 5 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.
  • PB K enzymes such as the Class Ia enzymes and/or the Class Ib PBK enzyme
  • a mTOR kinase such as a mTOR PI kinase-related kinase
  • PI3K enzymes such as the Class Ia enzymes and/or the Class Ib PDK enzyme
  • a mTOR kinase such as a mTOR PI kinase-related kinase
  • tumours which are sensitive to inhibition of PBK enzymes (such as the Class Ia enzymes and/or the Class Ib PDK enzyme) and/or a mTOR kinase (such as a mTOR PI kinase-related kinase) that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells
  • PBK enzymes such as the Class Ia enzymes and/or the Class Ib PDK enzyme
  • a mTOR kinase such as a mTOR PI kinase-related kinase
  • 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 signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
  • PDK enzymes such as the Class Ia enzymes and/or the Class Ib PDK enzyme
  • a mTOR kinase such as a mTOR PI kinase-related kinase
  • a PDK enzyme inhibitory effect such as a Class Ia PDK enzyme or Class Ib PDK enzyme inhibitory effect
  • a mTOR kinase inhibitory effect such as a mTOR PI kinase-related kinase inhibitory effect
  • a PDK enzyme inhibitory effect such as a Class Ia PDK enzyme or Class Ib PDK enzyme inhibitory effect
  • a mTOR kinase inhibitory effect such as a mTOR PI kinase-related kinase inhibitory effect
  • a method for providing a PBK enzyme inhibitory effect such as a Class Ia PBK enzyme or Class Ib PI3K enzyme inhibitory effect
  • a mTOR kinase inhibitory effect such as a mTOR PI kinase-related kinase inhibitory effect
  • a pyrimidine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for providing a PBK enzyme inhibitory effect (such as a Class Ia PBK enzyme or Class Ib PBK enzyme inhibitory effect) and/or a mTOR kinase inhibitory effect (such as a mTOR PI kinase-related kinase inhibitory effect).
  • a PBK enzyme inhibitory effect such as a Class Ia PBK enzyme or Class Ib PBK enzyme inhibitory effect
  • a mTOR kinase inhibitory effect such as a mTOR PI kinase-related kinase inhibitory effect
  • certain compounds of the present invention possess substantially better potency against Class Ia PBK enzymes or against the Class Ib PBK enzyme than against EGF receptor tyrosine kinase, VEGF receptor tyrosine kinase or Src non-receptor tyrosine kinase enzymes.
  • Such compounds possess sufficient potency against Class Ia PBK enzymes or the Class Ib PBK enzyme that they may be used in an amount sufficient to inhibit PBK enzymes whilst demonstrating little activity against EGF receptor tyrosine kinase, VEGF receptor tyrosine kinase or Src non-receptor tyrosine kinase enzymes.
  • Such compounds are likely to be useful for the selective inhibition of PBK enzymes and are likely to be useful for the effective treatment of, for example Class Ia PBK enzyme driven tumours.
  • a pyrimidine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a selective PBK enzyme inhibitory effect.
  • a method for providing a selective PBK enzyme inhibitory effect which comprises administering an effective amount of a pyrimidine derivative of the Formula I, 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 5 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.
  • 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];
  • c-Src kinase family inhibitors like 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran- 4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and bosutinib (SKI-606),
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies [for example the anti-erbB2 antibody trastuzumab and the anti-erbBl antibodies cetuximab (C225) and panitumumab]; such inhibitors also include, for example, tyrosine kinase inhibitors [for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib (ZDl 839), erlotinib (OSI-774) and CI 1033, and erbB2 tyrosine kinase inhibitors such as lapatinib), inhibitors of the hepatocyte growth factor family, inhibitors of the insulin growth factor receptor, inhibitors of the platelet-derived growth factor family and/or bcr/abl kinase such as imatinib, dasatinib (BMS-354825) and nilotinib
  • 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
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapy approaches including for example ex- vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • a pharmaceutical product comprising a pyrimidine derivative of the formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer.
  • the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of PI3K enzymes. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • Solvents A, B and C respectively to a 95:5 mixture of Solvents B and C;
  • Method A2 Phenomenex 'Gemini' RP 1 IOA column (5 microns silica, 2 mm diameter, 50 mm length) using a Solvent C comprising 0.1% aqueous ammonium hydroxide
  • Method Bl Phenomenex Synergi MAX-RP 8 ⁇ A column (4 microns silica, 2.1 mm diameter, 50 mm length) using a Solvent C comprising a 1:1 mixture of water and acetonitrile (the mixture containing 1% formic acid) and a solvent gradient over 4 minutes from a 90:5:5 mixture of Solvents A, B and C respectively to a 95:5 mixture of Solvents B and C;
  • Method B2 Phenomenex Synergi MAX-RP 8 ⁇ A column (4 microns silica, 2.1 mm diameter, 50 mm length) using a Solvent C comprising a 1 :1 mixture of water and acetonitrile (the mixture containing 1% formic acid) and a solvent gradient over 4 minutes from a 95:5 mixture of Solvents A and C to a 58:37:5 mixture of Solvents A, B and C respectively; 5 (xii) where certain compounds were obtained as an acid-addition salt, for
  • the 6-chloro-4-(2-difluoromethylbenzimidazol-l-yl)-2-morpholinopyrimidine used as a starting material was prepared as follows :- Under an atmosphere of nitrogen, a solution of morpholine (13.06 ml) in methylene chloride (100 ml) was added dropwise over 15 minutes to a stirred mixture of 2,4,6-trichloropyrimidine (27.52 g), triethylamine (22.1 ml) and methylene chloride (200 ml) that was cooled to a temperature between 5°C and 15 0 C. The resultant mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The mixture was washed with an aqueous brine solution.
  • the l-(iV-tert-butoxycarbonylglycyl)piperazine used as a starting material was prepared as follows :-
  • the organic extract was washed with distilled water, saturated sodium chloride and then dried with anhydrous sodium sulphate, filtered and evaporated.
  • the crude product was purified by column chromatography using a gradient of 100% dichloromethane to 20% ethyl acetate/dichloromethane as eluent.
  • the 2-(difluoromethyl)- 1 -(2-moipholin-4-yl-6-piperazin- 1 -yl-pyrimidin-4- yl)benzoimidazole used as a starting material was prepared as follows :- A mixture of l-(6-chloro-2-morpholm-4-yl-pyrimidin-4-yl)-2-
  • (difluoromethyl)benzoimidazole used as a starting material was prepared as follows:- A mixture of l-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-2- (difluoromethyl)benzoimidazole (0.147 g), tert-bv ⁇ yl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.090 g), sodium bicarbonate (0.222 g) and DMF (2 ml) was heated under nitrogen to 90°C for 15 minutes and then at 105°C for 1 hour. The resultant mixture was cooled, filtered and evaporated.

Abstract

The invention concerns pyrimidine derivatives of Formula (I): wherein each of p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in a method for producing an anti-proliferative effect in a warm blooded animal such as man.

Description

4-BENZIMIDAZ0LYL-2-M0RPH0LIN0-e-PIPERAZINYLPYRIMIDINE DERIVATIVES
AS PI3K AND MTOR INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISORDERS
The invention concerns certain novel pyrimidine derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body. The invention also concerns processes for the manufacture of said pyrimidine derivatives, pharmaceutical compositions containing them and their use in therapeutic methods, for example in the manufacture of medicaments for use in the production of an antiproliferative effect in a warm-blooded animal such as man. Many of the current treatment regimes for cell proliferation diseases such as cancer and psoriasis utilise compounds which inhibit DNA synthesis. Such compounds are toxic to cells generally but their toxic effect on rapidly dividing cells such as tumour cells can be beneficial. Alternative approaches to anti-tumour agents which act by mechanisms other than the inhibition of DNA synthesis have the potential to display enhanced selectivity of action. In recent years it has been discovered that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene, that is a gene which, on activation, leads to the formation of malignant tumour cells (Bradshaw, Mutagenesis. 1986, 1, 91). Several such oncogenes give rise to the production of peptides which are receptors for growth factors. Activation of the growth factor receptor complex subsequently leads to an increase in cell proliferation. It is known, for example, that several oncogenes encode tyrosine kinase enzymes and that certain growth factor receptors are also tyrosine kinase enzymes (Yarden et ah, Ann. Rev. Biochem.. 1988, 57, 443; Larsen et ah, Ann. Reports in Med. Chem., 1989, Chpt. 13). The first group of tyrosine kinases to be identified arose from such viral oncogenes, for example pp60v"Src tyrosine kinase (otherwise known as v-Src), and the corresponding tyrosine kinases in normal cells, for example pp60c~Src tyrosine kinase (otherwise known as c-Src).
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. 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, TGFα, Neu and erbB receptors.
It is also known that certain 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.
It is also known that 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. Such serine/threonine signalling pathways include the Raf-MEK-ERK cascade and those downstream of the lipid kinase known as PI3K such as PDK-I, AKT and mTOR (Blume- Jensen and Hunter, Nature. 2001, 411, 355). It is also known that certain kinases that belong to the class of lipid kinases are located intracellularly and are also involved in the transmission of biochemical signals such as those that influence tumour cell growth and invasiveness. Various classes of lipid kinases are known including the phosphoinositide 3 -kinase (abbreviated hereinafter to PI3K) family that is alternatively known as the phosphatidylinositol-3 -kinase family. It is now well understood that deregulation of oncogenes and tumour-suppressor genes contributes to the formation of malignant tumours, for example by way of increased cell proliferation or increased cell survival. It is also now known that 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 ah, Annual Rev. Cell Dev. Biol., 2001, 17: 615-617 and Foster et al, J. Cell Science, 2003, 116: 3037-3040).
The PI3K family of lipid kinases is a group of enzymes that phosphorylate the 3-position of the inositol ring of phosphatidylinositol (abbreviated hereinafter to PI). Three major groups of PI3K enzymes are known which are classified according to their physiological substrate specificity (Vanhaesebroeck et al, Trends in Biol. ScL, 1997, 22, 267). Class III
PI3K enzymes phosphorylate PI alone. In contrast, Class II PI3K enzymes phosphorylate both PI and PI 4-phosphate [abbreviated hereinafter to PI(4)P]. Class I PI3K enzymes phosphorylate PI, PI(4)P and PI 4,5-bisphosphate [abbreviated hereinafter to PI(4,5)P2], although only PI(4,5)P2 is believed to be the physiological cellular substrate. Phosphorylation of PI(4,5)P2 produces the lipid second messenger PI 3,4,5-triphosphate [abbreviated hereinafter to PI(3,4,5)P3]. More distantly related members of this superfamily are Class IV kinases such as mTOR and DNA-dependent kinase that phosphorylate serine/threonine residues within protein substrates. The most studied and understood of these lipid kinases are the Class I PI3K enzymes.
Class I PI3K is a heterodimer consisting of a pi 10 catalytic subunit and a regulatory subunit, and the family is further divided into Class Ia and Class Ib enzymes on the basis of regulatory partners and mechanism of regulation. Class Ia enzymes consist of three distinct catalytic subunits (pi 10a, pi lOβ and pi lOδ) that dimerise with five distinct regulatory subunits (p85α, p55α, p50α, p85β and p55γ), with all catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers. Class Ia PI3K are generally activated in response to growth factor-stimulation of receptor tyrosine kinases, via interaction of the regulatory subunit SH2 domains with specific phospho-tyrosine residues of the activated receptor or adaptor proteins such as IRS-I. Both pllOα and pi lOβ are constitutively expressed in all cell types, whereas pi lOδ expression is more restricted to leukocyte populations and some epithelial cells. In contrast, the single Class Ib enzyme consists of a pi lOγ catalytic subunit that interacts with a pi 01 regulatory subunit. Furthermore, the Class Ib enzyme is activated in response to G-protein coupled receptor (GPCR) systems and its expression appears to be limited to leucocytes.
There is now considerable evidence indicating that Class Ia PI3K enzymes contribute to tumourigenesis in a wide variety of human cancers, either directly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, the pi 10a subunit is amplified in some tumours such as those of the ovary (Shayesteh et al, Nature Genetics, 1999, 21: 99-102) and cervix (Ma et al, 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 al, Science, 2004, 304, 554). Tumour-related mutations in p85α have also been identified in cancers such as those of the ovary and colon (Philp et al, Cancer Research. 2001, 61, 7426-7429). In addition to direct effects, it is believed that activation of Class Ia PI3K contributes to tumourigenic events that occur upstream in signalling pathways, for example by way of ligand-dependent or ligand-independent activation of receptor tyrosine kinases, GPCR systems or integrins (Vara et al, Cancer Treatment Reviews, 2004, 30, 193-204). Examples of such upstream signalling 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). In addition, Class Ia PI3Ks may contribute indirectly to tumourigenesis caused by various downstream signalling events. For example, 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). Furthermore, augmentation of the effects of other PI3K-mediated signalling events is believed to contribute to a variety of cancers, for example by activation of Akt (Nicholson and Anderson, Cellular Signalling, 2002, 14, 381-395).
In addition to a role in mediating proliferative and survival signalling in tumour cells, there is also good evidence that Class Ia PI3K enzymes will also contribute to tumourigenesis via its function in tumour-associated stromal cells. For example, 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). As Class I PI3K enzymes are also involved in motility and migration (Sawyer, Expert Opinion Investig. Drugs, 2004, 13, 1 - 19), PI3K inhibitors should provide therapeutic benefit via inhibition of tumour cell invasion and metastasis.
In addition, 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. In particular, 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.
Generally, investigators have explored the physiological and pathological roles of the PDK enzyme family using the 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 al, Trends in Pharmacological Science, 2003, 24, 366-376). Both 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, L3, 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.
We have now found that surprisingly certain pyrimidine derivatives possess potent anti-tumour activity, being useful in inhibiting the uncontrolled cellular proliferation which arises from malignant disease. Without wishing to imply that the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds provide an anti-tumour effect by way of inhibition of Class I PBK enzymes, particularly by way of inhibition of the Class Ia PBK enzymes and/or the Class Ib PBK enzyme, more particularly by way of inhibition of the Class Ia PBK enzymes.
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.
Generally, the compounds of the present invention possess potent inhibitory activity against Class I PBK enzymes, particularly against Class Ia PI3K enzymes, whilst possessing less potent inhibitory activity against tyrosine kinase enzymes such as the receptor tyrosine kinases, for example EGF receptor tyrosine kinase and/or VEGF receptor tyrosine kinase, or against non-receptor tyrosine kinases such as Src. Furthermore, 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 (sirolimus) 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. mTOR, like other PIKK family members, does not possess detectable lipid kinase activity, but instead functions as a serine/threonine kinase. Much of the knowledge of mTOR signalling is based upon the use of Rapamycin. Rapamycin first binds to the 12 kDa immunophilin FK506-binding protein (FKBP 12) and this complex inhibits mTOR signalling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). mTOR protein consists of a catalytic kinase domain, an FKBP12-Rapamycin binding (FRB) domain, a putative repressor domain near the C-terminus and up to 20 tandemly-repeated HEAT motifs at the iV-terminus, as well as FRAP-ATM-TRRAP (FAT) and FAT C-terminus domain (Huang and Houghton, Current Opinion in Pharmacology, 2003, 3, 371-377). mTOR kinase is a key regulator of cell growth and has been shown to regulate a wide range of cellular functions including translation, transcription, niRNA 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. mTOR kinase is activated by growth factors through the PDK-Alct pathway. 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.
Generally, investigators have explored the physiological and pathological roles of mTOR using inhibition with Rapamycin and related Rapamycin analogues based on their specificity for mTOR as an intracellular target. However, recent data suggests that Rapamycin displays variable inhibitory actions on mTOR signalling functions and suggest that direct inhibition of the mTOR kinase domain may display substantially broader anti-cancer activities than that achieved by Rapamycin (Edinger et al, Cancer Research. 2003, 63, 8451-8460). For this reason, potent and selective inhibitors of mTOR kinase activity would be useful to allow a more complete understanding of mTOR kinase function and to provide useful therapeutic agents.
There is now considerable evidence indicating that the pathways upstream of mTOR are frequently activated in cancer (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489- 501; Bjornsti and Houghton, Nature Reviews Cancer, 2004, 4, 335-348; Inoki et al. Nature Genetics, 2005, 37, 19-24). For example, 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.
In addition there is evidence that endothelial cell proliferation may also be dependent upon mTOR signalling. Endothelial cell proliferation is stimulated by vascular endothelial cell growth factor (VEGF) activation of the PI3K-Akt-mTOR signalling pathway (Dancey, Expert Opinion on Investigational Drugs, 2005, 14, 313-328). Moreover, mTOR kinase signalling is believed to partially control VEGF synthesis through effects on the expression of hypoxia- inducible factor- lα (HIF- lα) (Hudson et al , Molecular and Cellular Biology. 2002, 22, 7004- 7014). Therefore, 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. These findings suggest that 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. In addition to tumourigenesis, there is evidence that mTOR kinase plays a role in an array of hamartoma syndromes. Recent studies have shown that the 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 Peutz-Jeghers syndrome (PJS), Cowden disease, Bannayan-Riley- Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and TSC (Inoki et al., Nature Genetics, 2005, 37, 19-24). Patients with these syndromes characteristically develop benign hamartomatous tumours in multiple organs.
Recent studies have revealed a role for mTOR kinase in other diseases (Easton & Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551-564). 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 al., New England Journal of Medicine. 2002, 346, 1773-1780). Furthermore, 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). Elevated mTOR kinase activity has been associated with cardiac hypertrophy, which is of clinical importance as a major risk factor for heart failure and is a consequence of increased cellular size of cardiomyocytes (Tee & Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). Thus 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. There is the disclosure of a single pyrimidine substituted by each of a benzimidazol-1-yl group, a morpholino group and a piperazin-1-yl group, namely 2-benzimidazol-l-yl- 4-morpholino-6-piperazin-l-ylpyrimidine (compound 24).
It is disclosed in International Patent Application WO 00/043385 that certain further 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. There is the disclosure of a single triazine substituted by each of a benzimidazol-1-yl group, a morpholino group and a 4-(morpholinocarbonyl)piperazin-l-yl group, namely 2-benzimidazol- 1 -yl-4-morpholino-6- [4-(morpholinocarbonyl)piperazin- 1 -yl]triazine. There is no specific disclosure of any pyrimidines that are substituted by each of a benzimidazol-1-yl group, a morpholino group and a piperazin-1-yl group.
It is disclosed in European Patent Application No. 1389617 that certain further 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. The scope of disclosure does not embrace any triazines or pyrimidines that are substituted by each of a benzimidazol-1-yl group, a morpholino group and a piperazin-1-yl group.
It is disclosed in European Patent Application No. 1557415 that certain further 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. The scope of disclosure does not embrace any triazines or pyrimidines that are substituted by each of a benzimidazol-1-yl group, a morpholino group and a piperazin-1-yl group.
It is disclosed in International Patent Application WO 2005/095389 that certain further 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. The scope of disclosure does not embrace any triazines or pyrimidines that are substituted by each of a benzimidazol-1-yl group, a morpholino group and a piperazin-1-yl group.
It is disclosed in International Patent Application WO 2006/005914 that certain pyrimidine derivatives possess PI3K enzyme inhibitory activity and are useful in the treatment of cancer. The disclosure focuses on 2,4-diaryl-6-morpholinopyrimidines. The scope of disclosure does not embrace benzimidazolyl substituted pyrimidines.
It is disclosed in International Patent Application WO 2006/005918 that certain pyrimidine derivatives possess PI3K enzyme inhibitory activity and are useful in the treatment of cancer. The disclosure focuses on 2,4-diaryl-6-morpholinopyrimidines. The scope of disclosure does not embrace benzimidazolyl substituted pyrimidines.
It is disclosed in International Patent Application WO 2006/005915 that certain pyrimidine derivatives possess PI3K enzyme inhibitory activity and are useful in the treatment of cancer. The disclosure focuses on 4-heteroaryl-6-morpholinopyrirnidines and there is also the disclosure of certain 2-heteroaryl-6-morpholinopyrimidines. There is the disclosure of a 2-(lif-benzimidazol-4-yl)-6-morpholinopyrimidine. There is no specific disclosure of any benzimidazol-1-yl substituted pyrimidines.
It is disclosed in European Patent Application 1277738 that a variety of structures possess PI3K enzyme inhibitory activity and are useful in the treatment of cancer. The disclosure includes mention of 4-morpholino-substituted bicyclic heteroaryl compounds such as quinazoline and pyrido[3,2-cf]pyrmiidme derivatives and 4-morpholino-substituted tricyclic heteroaryl compounds such as compounds described as pyrido[3\2':4,5]furo[3,2-^pyrimidine derivatives. The scope of disclosure does not embrace monocyclic pyrimidine derivatives. It is disclosed in International Patent Application WO 2004/048365 that certain pyrimidine derivatives possess PI3K enzyme inhibitory activity and are useful in the treatment of cancer. The disclosure focuses on arylamino- and heteroarylamino-substituted pyrimidines. The scope of disclosure does not embrace 4-heteroaryl substituted pyrimidines. There is the disclosure of compounds such as :- 6-(3-hydroxyphenyl)-2-morpholino-4-[4-(4-nitrophenyl)piperazin-l-yl]pyrimidine (no. 82); 6-(3-hydroxyphenyl)-2-morpholino-4-(4-pyridin-2-ylpiperazin-l-yl)pyrimidine (no. 85); 4-(4-acetylpiperazin-l-yl)-6-(3-hydroxyphenyl)-2-morpholinopyrimidine (no. 86) and 6-(3 -hydroxyphenyl)-2-morpholino-4- [4-(2-dimethylaminoethyl)piperazin- 1 -yl]ρyrimidine (no. 128). It is disclosed in International Patent Application WO 2005/007648 that certain pyridine, pyrimidine and triazine derivatives that are substituted with a 4-arylpiperazin-l-yl group or with a 4-heteroarylpiperazin-l-yl group are useful in the treatment of acute or chronic pain. For example, there is the disclosure of many 2-piperazin-l-ylpyriniidine compounds such as :- 4-(2-fluoroρhenyl)-6-morpholino-2-(4-pyridin-2-ylpiperazin-l-yl)pyrimidine (no. 87); and also of 2-aryl-4-piperazin-l-ylpyrimidine compounds such as :-
2-(3-chlorophenyl)-6-niorpholino-4-[4-(3-trifluoromethylpyridin-2-yl)piperazin-l- yl]pyrimidine and 4-[4-(3-chloropyridin-2-yl)-2-methylpiperazin-l-yl]-2-(3,4-difluorophenyl)- 6-morpholinopyrimidine (no. 92).
According to one aspect of the invention there is provided a pyrimidine derivative of the Formula I
Figure imgf000012_0001
wherein p is 0, 1, 2 or 3; each R1 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-όC)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, N-(l-6C)alkylcarbamoyl, iV,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, 7V-( 1 -6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(I -6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N'-(l-6C)alkylureido, N',N'-di-[(l-6C)alkyl]ureido, iV-(l-6C)alkylureido, iV,iV'-di-[(l-6C)alkyl]ureido, iV,iV',iV'-tri-[(l-6C)alkyl]ureido, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and iV-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
Q2-X2- wherein X2 is a direct bond or is selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)C0, N(R5)CON(R5), SO2N(R5), N(R5)SO2, OC(R5)2, SC(R5)2 and N(R5)C(R5)2, wherein R5 is hydrogen or (l-8C)alkyl, and Q2 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l -6C)alkyl, (3-8C)cycloalkenyl, (3-8C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-( 1 -6C)alkyl, or (R')P is (l-3C)alkylenedioxy, and wherein any CH, CH2 or CH3 group within a R1 substituent optionally bears on each said CH, CH2 or CH3 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-6C)alkylthio, (l-6C)alkylsulphinyl, (l-όC)alky Sulphonyl, (l-όC)alkylamino, di- [( 1 -6C)alkyl] amino, ( 1 -6C)alkoxycarbonyl, N-(I -6C)alkylcarbamoyl, N, N-di-[(l-6C)alkyl] carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, JV-(I -6C)alkyl-(2-6C)alkanoylamino, N-( 1 -6C)alkylureido, N'-( 1 -6C)alkylureido, 7V',N'-di-[(l-6C)alkyl]ureido, N,N'-di-[(l-6C)alkyl]ureido, N,N',iV'-tri-[(l-6C)alkyl]ureido, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
-X3-Q3 wherein X3 is a direct bond or is selected from O, S, SO, SO2, N(R6), CO, CH(OR6), CON(R6), N(R6)CO, N(R6)CON(R6), SO2N(R6), N(R6)SO2, C(R6)2O, C(R6)2S and C(R6)2N(R6), wherein R6 is hydrogen or (l-8C)alkyl, and Q3 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-6C)alkyl, (3-8C)cycloalkenyl, (3-8C)cycloalkenyl- (l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulρhinyl, (l-όC)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-όC)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, TV-(I -6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, N-(I -6C)alkyl-(2-6C)alkanoylamino, N-(I -6C)alkylureido, N'-(l -6C)alkylureido, N',iV'-di-[(l -6C)alkyl]ureido, N,N'-di-[(l -6C)alkyl]ureido, ΛζN',N'-tri-[(l-6C)alkyl]ureido, N-(l-6C)alkylsulphamoyl, N,iV-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(I -6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula : • -X4-R7 wherein X4 is a direct bond or is selected from O and N(R8), wherein R8 is hydrogen or (l-8C)alkyl, and R7 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, mercapto-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl5 (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-(l-6C)alkyl, iV'-(l-6C)alkylureido-(l-6C)alkyl, N\N'-di-[(l-6C)alkyl]ureido-(l-6C)alkyl, N,iV'-di-[(l-6C)alkyl]ureido-(l-6C)alkyl or N,N',N'-tri-[(l-6C)alkyl]ureido-(l-6C)alkyl, or from a group of the formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, CO and N(R9), wherein R9 is hydrogen or (l-8C)alkyl, and Q4 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-όC)alkoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R10), CO, CH(OR10), CON(R10), N(R10)CO, N(R10)CON(R10), SO2N(R10), N(R10)SO2, CH=CH and C≡C wherein R10 is hydrogen or (l-8C)alkyl;
R2 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 R3 group, which may be the same or different, is (l-8C)alkyl or a group of the formula : A K wherein X6 is a direct bond or is selected from O and N(R12), wherein R12 is hydrogen or (l-8C)alkyl, and R11 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-όC)alkylamino- (l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl or (2-6C)alkanoylamino-(l-6C)alkyl, or two R3 groups together form a methylene, ethylene or trimethylene group; r is O, 1, 2, 3 or 4; each R group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, mercapto, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-όC)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, iV-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl- (2-6C)alkanoylamino, N' -(I -6C)alkylureido, N',N'-di-[(l -6C)alkyl]ureido, N-(l-6C)alkylureido, iV,iV'-di-[(l-6C)alkyl]ureido, N,iV',N'-tri-[(l-6C)alkyl]ui-eido, iV-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or two R groups together form a methylene, ethylene or trimethylene group; X1 is a direct bond or is selected from CO, S, SO, SO2, CON(R13), COC(R13)2O, COC(R13)2S, COC(RI3)2N(R13) and COC(R13)2N(R13)CO, wherein R13 is hydrogen or (l-8C)alkyl; and Q1 is hydrogen, (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, (l-6C)alkylsulphonyl-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, N-(l-6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl, (l-6C)alkoxycarbonylamino-(l-6C)alkyl, N-(l-6C)alkylureido-(l-6C)alkyl, iV'-(l-6C)alkylureido-(l-6C)alkyl, N',iV'-di-[(l-6C)alkyl]ureido-(l-6C)alkyl, N,iV'-di-[(l-6C)alkyl]ureido-(l-6C)alkyl, N,N',iV'-tri-[(l-6C)alkyl]ureido-(l-6C)alkyl, (l-6C)alkanesulphonylamino-(l-6C)alkyl or N-(I -6C)alkyl-(l -6C)alkanesulphonylamino-(l -6C)alkyl, or Q1 is aryl, aryl-(l -6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l -6C)alkyl,
(3-8C)cycloalkenyl, (3-8C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 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-6C)alkylthio, (l-6C)alkylsulphinyl, (l-όC)alkylsulphonyl, (l-6C)alkylamino, di- [( 1 -6C)alkyl]amino, ( 1 -6C)alkoxy carbonyl, N-(I -6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, iV-(l-6C)alkyl-(2-6C)alkanoylamino, iV'-(l-6C)alkylureido, iV',N'-di-[(l-6C)alkyl]ureido, iV-(l-6C)alkylureido, N,N'-di-[(l-6C)alkyl]ureido, iV,N',N'-tri-[(l-6C)alkyl]ureido, iV-(l-6C)alkylsulphamoyl, iV,iV-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, and wherein any aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-όC)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, (2-6C)alkanoyl, (2-6C)alkanoyloxy, iV-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, N'-(l-6C)alkylureido, N',iV'-di-[(l-6C)alkyl]ureido, iV-(l-6C)alkylureido, iV5iV'-di-[(l-6C)alkyl]ureido, N,N',N'-tri-[(l-6C)alkyl]ureido, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulρhamoyl, (l-6C)alkanesulphonylamino and N-(I -6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
-X7-R14 wherein X7 is a direct bond or is selected from O and N(R15), wherein R15 is hydrogen or (l-8C)alkyl, and R14 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 :
-X8-Q5 wherein X8 is a direct bond or is selected from O, CO and N(R17), wherein R17 is hydrogen or (l-SC)alkyl, and Q5 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 Q1 group optionally bears 1 or 2 oxo or thioxo substituents, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within the Q1 group are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R16), N(R16)CO, CON(R16), N(R16)CON(R16), CO, CH(OR16), N(R16)SO2, SO2N(R16), CH=CH and C≡C wherein R16 is hydrogen or (l-8C)alkyl; and wherein the 5-position on the pyrimidine ring may optionally bear a (l-8C)alkyl group; or a pharmaceutically-acceptable salt thereof.
In this specification the generic term "(l-8C)alkyl" includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-8C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and also (3-6C)cycloalkyl-(l-2C)alkyl groups such as cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl,
2-cyclopentylethyl, cyclohexylmethyl and 2-cyclohexylethyl. However 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 and references to individual cycloalkyl groups such as "cyclopentyl" are specific for that 5-membered ring only. An analogous convention applies to other generic terms, for example (l-6C)alkoxy includes (3-6C)cycloalkyloxy groups and (3-5C)cycloalkyl-(l-2C)alkoxy groups, for example methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, 2-cyclopropylethoxy, cyclobutylmethoxy, 2-cyclobutylethoxy and cyclopentylmethoxy; (l-θC)alkylamino includes (3-6C)cycloalkylamino groups and (3-5C)cycloalkyl- (l-2C)alkylamino groups, for example methylamino, ethylamino, propylamino, cyclopropylamino, cyclobutylamino, cyclohexylamino, cyclopropyhnethylamino, 2-cyclopropylethylamino, cyclobutylmethylamino, 2-cyclobutylethylamino and cyclopentylmethylamino; and di-[(l-6Calkyl]amino includes di-[(3-6C)cycloalkyl]amino groups and di-[(3-5C)cycloalkyl-(l-2C)alkyl]amino groups, for example dimethylamino, diethylamino, dipropylamino, N-cyclopropyl-TV-methylarnino, iV-cyclobutyl-N-methylamino, iV-cyclohexyl-N-ethylamino, N-cyclopropylmethyl-N-methylamino, N-(2-cyclopropylethyl)- iV-methylamino and N-cyclopentylmethyl-N-methylamino.
It is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter. It is to be understood that certain compounds of Formula I defined above may exhibit the phenomenon of tautomerism. In particular, tautomerism may affect the benzimidazolyl group when R2 is a hydroxy or amino group or tautomerism may affect heterocyclic groups within the R1 and Q1 groups that bear 1 or 2 oxo or thioxo substituents. It is to be understood that 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.
It is to be understood that any R1 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. When multiple R1 groups are present, the R1 groups may be the same or different. Conveniently, no R1 group is present (p=0) or there is a single R1 group (p=l). Conveniently, a single R1 group is located at the 4-, 5- or 6-position on said benzimidazolyl group. Conveniently, a single R1 group is located at the 4-position on said benzimidazolyl group.
It is further to be understood that any R3 group that may be present on the morpholinyl group that is located at the 2-position on the pyrimidine ring may be located at any available position on said morpholinyl group. Conveniently, when the R3 group is a (l-8C)alkyl group such as a methyl group, up to four such groups are present. Any two such groups may be located at the same ring position on said morpholinyl group. When two R3 groups together form a methylene, ethylene or trimethylene 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. Conveniently, there is a single R3 group. More conveniently, no R3 group is present (q=0).
It is further to be understood that any R4 group that may be present on the piperazinyl group that is located at the 6-position on the pyrimidine ring may be located at any available position on said piperazinyl group. Conveniently, when the R4 group is a (l-8C)alkyl group such as a methyl group, up to four such groups are present. Any two such groups may be located at the same ring position on said piperazinyl group. When two R4 groups together form a methylene, ethylene or trimethylene group, a suitable group so formed is, for example, a 3,6-diazabicyclo[3.1.1]hept-3-yl, 3,6-diazabicyclo[3.1.1]hept-6-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.2]oct-2-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl or 3,8-diazabicyclo[3.2.1]oct-8-yl group. Conveniently, there is a single R group. More conveniently, no R group is present (r=0).
Suitable values for the generic radicals referred to above include those set out below. A suitable value for any one of the 'Q' groups (Q1 to Q5) 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 (Q1 to Q3) when it is (3-8C)cycloalkyl or for the (3-8C)cycloalkyl group within a 'Q' group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl or cyclooctyl and a suitable value for any one of the 'Q' groups (Q1 to Q3) when it is (3-8C)cycloalkenyl or for the (3-8C)cycloalkenyl group within a 'Q' group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl. A suitable value for any one of the 'Q' groups (Q1 to Q5) 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, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl.
A suitable value for any one of the 'Q' groups (Q1 to Q5) when it is heterocyclyl or for the heterocyclyl group within a 'Q' group is, for example, a non-aromatic saturated or partially saturated 3 to 10 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, 1,1 -dioxotetrahydro- 1 ,4-thiazinyl, piperidinyl, homopiperidiny 1, piperazinyl, homopiperazinyl, oxazolidine, thiazolidine, 2-azabicyclo[2.2.1]heptyl, quinuclidinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl or tetrahydropyridazine, preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl. A suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxooxazolidinyl, 2-oxothiazolidinyl, 2-oxopiperidinyl, 4-oxo-l,4-dihydropyridinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
A suitable value for a 'Q' group when it is heteroaryl-(l-6C)alkyl is, for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl. The invention comprises corresponding suitable values for 'Q' groups when, for example, rather than a heteroaryl-(l-6C)alkyl group, an aryl-(l-6C)alkyl, (3-8C)cycloalkyl-(l-6C)alkyl, (3-8C)cycloalkenyl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group is present.
Suitable values for any of the 'R' groups (R1 to R17), or for various groups within an R1, R3 or R4 substituent, or for Q1, or for various groups within Q1 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-όC)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for ( 1 -6C)alkylthio : methylthio, ethylthio and propylthio; for (l-όC)alkylsulphinyl: methylsulphinyl and ethylsulphinyl; for (l-6C)alkylsulphonyl: methylsulphonyl and ethylsulphonyl; for (l-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-[(l-6C)alkyl]amino: dimethylamino, diethylamino, iV-ethyl-N-methylamino and diisopropylamino; for (l-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for (l-6C)alkoxycarbonylamino: methoxycarbonylamino, ethoxycarbonylamino and ter t-butoxy carbonylamino ; for JV-(I -6C)alkylcarbamoyl: iV-methylcarbamoyl, TV-ethylcarbamoyl and TV-propylcarbamoyl; for TV,TV-di-[(l-6C)alkyl]carbamoyl: TV,TV~dimethylcarbamoyl, TV-ethyl- TV-methylcarbamoyl and TV5TV-diethylcarbamoyl; for (2-6C)alkanoyl: acetyl, propionyl and isobutyryl; for (2-6C)alkanoyloxy: acetoxy and propionyloxy; for (2-6C)alkanoylamino: acetamido and propionamido;
IQ for TV-(I -6C)alkyl-(2-6C)alkanoylamino: iV-methylacetamido and JV-methylpropionamido; for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; for TV-(I -6C)alkyl-(3-6C)alkenoylamino: TV-methylacrylamido and TV-methylcrotonamido; for (3-6C)alkynoylamino: propiolamido; for TV-(l-6C)alkyl-(3-6C)alkynoylamino: TV-methylpropiolamido;
15 for TV-(I -6C)alkylureido: TV'-methylureido and TV'-ethylureido; for TV',TV'-di-[(l -6C)alkyl]ureido: TV',TV'-dimethylureido and TV'-methyl-TV'-ethylureido; for TV-(I -6C)alkylureido: TV-methylureido and TV-ethylureido; for TV,TV'-di-[(l-6C)alkyl]ureido: TV5TV' -dimethylureido, TV-methyl-TV'-ethylureido and
TV-ethyl-TV' -methylureido;
20 for TV5TV' ,TV'-di-[(l -6C)alkyl]ureido: TV5TV' ,TV' -trimethylureido,
TV-ethyl-N',N' -dimethylureido and
TV-methyl-TV' ,TV' -diethy lureido ; for TV-(I -6C)alkylsulphamoyl: TV-methylsulphamoyl and TV-ethylsulphamoyl; for TV,TV-di-[(l-6C)alkyl]sulphamoyl: TV5TV-dimethylsulphamoyl;
25 for (l-6C)alkanesulphonylamino: methanesulphonylamino and ethanesulphonylamino; for TV-( 1 -6C)alkyl-( 1 -6C)alkanesulphonylamino : TV-methylmethanesulphonylamino and
TV-methylethanesulphonylamino ; for halogeno-(l-6C)alkyl: chloromethyl, 2-fluoroethyl, 2-chloroethyl,
1-chloroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
30 3-fluoropropyl, 3-chloropropyl, 3,3-difluoropropyl and 3,3,3-trifluoropropyl; for hydroxy-(l-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1 -hydroxy ethyl and
3 -hydroxypropyl; for mercapto-(l-6C)alkyl: mercaptomethyl, 2-mercaptoethyl, 1-mercaptoethyl and 3-mercaptopropyl; 5 for (l-6C)alkoxy-(l-6C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl,
2-methoxyethyl, 2-ethoxyethyl and
3-methoxypropyl; for (l-6C)alkylthio-(l-6C)alkyl: methylthiomethyl, ethylthiomethyl,
2-methylthioethyl, 1-methylthioethyl and io 3-methylthiopropyl; for (l-6C)alkylsulphinyl-(l-6C)alkyl: methylsulphinylmethyl, ethylsulphinylmethyl,
2-methylsulphinylethyl, 1-methylsulphinylethyl and
3 -methylsulphinylpropyl; for (l-6C)alkylsulphonyl-(l-6C)alkyl: methylsulphonylmethyl, ethylsulphonylmethyl, I5 2-methylsulphonylethyl, 1-methylsulphonylethyl and
3 -methylsulphonylpropyl; for cyano-(l-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and
3-cyanopropyl; for amino-(l-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl,
20 3-aminopropyl, 1-aminopropyl and 5-aminopropyl; for (l-6C)alkylamino-(l-6C)alkyl: methylaminomethyl, ethylaminomethyl,
1 -methylaminoethyl, 2-inethylaminoethyl,
2-ethylaminoethyl and 3-methylaminopropyl; for di-[(l-6C)alkyl]amino-(l-6C)alkyl: dimethylaminomethyl, diethylaminomethyl, 25 1-dimethylaminoethyl, 2-dimethylaminoethyl and
3 -dimethylaminopropyl; for (2-6C)alkanoylamino-(l-6C)alkyl: acetamidomethyl, propionamidomethyl,
2-acetamidoethyl and 1-acetamidoethyl; for N-(l-6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl: 30 N-methylacetamidomethyl,
N-methylpropionamidomethyl, 2-(iV-methylacetamido)ethyl and 1 -(iV-methylacetamido)ethyl; or (l-6C)alkoxycarbonylamino-(l-6C)alkyl: methoxycarbonylaminometliyl, ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and
2-methoxycarbonylaminoethyl; or N'-(l-6C)alkylureido-(l-6C)alkyl: N'-methylureidomethyl, 2-(N'-methylureido)ethyl and l-(iV'-methylureido)ethyl; or Λ^N'-di-[(l-6C)alkyl]ureido-(l-6C)alkyl: iV',N'-dimethylureidomethyl, 2-(N',iV'-dimethylureido)ethyl and
1 -(AT,N'-dimethylureido)ethyl; for N-(l-6C)alkylureido-(l-6C)alkyl: iV-methylureidomethyl, 2-(JV-methylureido)ethyl and
1 -(iV-methylureido)ethyl; for N,N'-di-[(l-6C)alkyl]ureido-(l-6C)alkyl: MN'-dimethylureidomethyl, 2-(N,Λ/"-dimethylureido)ethyl and
1 -(N,N''-dimeth.ylureido)ethyl; for N,N',iV'-di-[(l-6C)alkyl]ureido-(l-6C)alkyl: iV,N',N'-trimethylureidomethyl,
2-(N,iV',N'-trimetliylureido)ethyl and l-(iV,iV',N'-trimethylureido)ethyl; for (l-6C)alkanesulphonylamino-(l-6C)alkyl: methanesulphonylaminomethyl,
2-(methanesulphonylamino)ethyl and 1 -(methanesulphonylamino)ethyl; and forN-(l-6C)alkyl-(l-6C)alkanesulphonylamino-(l-6C)alkyl:
N-methylmethanesulphonylaminomethyl, 2-(N-methylmethanesulphonylamino)ethyl and l-(iV-methylmethanesulphonylamino)etb.yl.
A suitable value for (R1 )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. When, as defined hereinbefore, an R1 group forms a group of the formula Q2-X2- and, for example, X2 is a OC(R5)2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R5)2 linking group which is attached to the benzimidazolyl ring and the oxygen atom is attached to the Q2 group. Similarly, when, for example a CH3 group within a R1 substituent bears a group of the formula -X3-Q3 and, for example, X3 is a C(R6)2O linking group, it is the carbon atom, not the oxygen atom, of the C(R6)2O linking group which is attached to the CH3 group and the oxygen atom is linked to the Q3 group. As defined hereinbefore, adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent may be optionally separated by the insertion into the chain of a group such as O, CON(R10) or C≡C. For example, insertion of an O atom into the alkylene chain within a 4-methoxybutoxy group gives rise to, for example, a 2-(2-methoxyethoxy)ethoxy group, for example, insertion of a C≡C group into the ethylene chain within a 2-hydroxyethoxy group gives rise to a 4-hydroxybut-2-ynyloxy group and, for example, 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.
When, as defined hereinbefore, any CH, CH2 or CH3 group within a R1 substituent optionally bears on each said CH, CH2 or CH3 group one or more halogeno or (l-8C)alkyl substituents, there is suitably 1 halogeno or (l-δC)alkyl substituent present on each said CH group, there are suitably 1 or 2 such substituents present on each said CH2 group and there are suitably 1, 2 or 3 such substituents present on each said CH3 group.
When, as defined hereinbefore, any CH, CH2 or CH3 group within a R1 substituent optionally bears on each said CH, CH2 or CH3 group a substituent as defined hereinbefore, suitable R1 substituents so formed include, for example, hydroxy-substituted (l-8C)alkyl groups such as hydroxymethyl, 1 -hydroxy ethyl and 2-hydroxy ethyl, hydroxy-substituted (l-6C)alkoxy groups such as 2-hydroxypropoxy and 3-hydroxypropoxy, (l-6C)alkoxy-substituted (l-6C)alkoxy groups such as 2-methoxyethoxy and 3-ethoxypropoxy, hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino- 2-hydroxypropoxy, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkoxy groups such as
2-hydroxy-3-methylaminoproρoxy, hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkoxy groups such as 3-dimethylamino-2-hydroxypropoxy, hydroxy-substituted amino-(2-6C)alkylamino groups such as 3-amino-2-hydroxypropylamino, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkylamino groups such as 2-hydroxy-3-methylaminopropylamino and hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkylarnino groups such as 3-dimethylamino-2-hydroxypropylamino. It is further to be understood that when, as defined hereinbefore, any CH, CH2 or CH3 group within a R1 substituent optionally bears on each said CH, CH2 or CH3 group a substituent as defined hereinbefore, such an optional substituent may be present on a CH5 CH2 or CH3 group within the hereinbefore defined substituents that may be present on an aryl, heteroaryl or heterocyclyl group within a R1 substituent. For example, if R1 includes an aryl or heteroaryl group that is substituted by a (l-8C)alkyl group, the (l-8C)alkyl group may be optionally substituted on a CH, CH2 or CH3 group therein by one of the hereinbefore defined substituents therefor. For example, if R1 includes a heteroaryl group that is substituted by, for example, a (l-6C)alkylamino-(l-6C)alkyl group, the terminal CH3 group of the (1 -6C)alkylamino group may be further substituted by, for example, a (1 -6C)alkyIsulphonyl group or a (2-6C)alkanoyl group. For example, the R1 group may be a heteroaryl group such as a thienyl group that is substituted by a N-(2-methylsulphonylethyl)aminomethyl group such that R1 is, for example, a 5-[JV-(2-methylsulphonylethyl)aminomethyl]thien-2-yl group. Further, for example, if R1 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 CH3 group of the (2-6C)alkanoyl group may be further substituted by, for example, a di-[(l-6C)alkyl]amino group. For example, the R1 group may be a N-(2-dimethylaminoacetyl)piperidin-4-yl group or a4-(2-dimethylaminoacetyl)piperazin-l-yl group. Similar considerations apply to the attachments and substitutions within the -X1 -Q1 group. For example, when, as defined hereinbefore, any CH, CH2 or CH3 group within a Q1 group optionally bears on each said CH, CH2 or CH3 group a substituent as defined hereinbefore, suitable Q1 groups so formed include, for example, hydroxy-substituted amino-(l-6C)alkyl groups such as l-amino-2 -hydroxy ethyl or l-amino-2-hydroxypropyl, an (1 -6C)alkoxy-substituted amino-( 1 -6C)alkyl groups such as 1 -amino-2-methoxy ethyl, a (l-6C)alkylamino-(l-6C)alkyl-substituted heteroaryl group such as a 5-[iV-(2-methylsulphonylethyl)aminomethyl]thien-2-yl group, and a (2-6C)alkanoyl- substituted heterocyclic group such as a N-(2-dimethylaminoacetyl)piperidin-4-yl group or a 4-(2-dimethylaminoacetyl)piperazin-l -yl group. Further, for example, it is defined hereinbefore that any aryl, (3-8C)cycloalkyl,
(3-8C)cycloalkenyl, heteroaryl or heterocyclyl group within the Q group may optionally bear 1, 2 or 3 substituents. Any such substituent may be present on any available position on said Q1 group. For example, it is to be understood that, when there is a (3-8C)cycloalkyl, ' (3-8C)cycloalkenyl or heterocyclyl group within the Q1 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. For example, a (3-8C)cycloalkyl group within the Q1 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 Q1 group such as a piperidin-4-yl group that bears a hydroxy substituent may thereby form a 4-hydroxypiperidin-4-yl group.
A suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. A further suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, a salt formed within the human or animal body after administration of a compound of the Formula I.
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. Accordingly, the compounds of the invention may be administered in the form of a pro-drug, that is a compound that is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula 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.
Accordingly, 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.
Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al, Chem. Pharm. Bull.. 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium
Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987. 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-6C)alkoxymethyl esters such as methoxymethyl esters, (l-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo- 1 ,3 -dioxolenylmethyl esters such as 5 -methyl-2-oxo- 1 ,3 -dioxolen-4-ylmethyl esters and (l-6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1 -methoxycarbonyloxy ethyl esters.
A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the Formula I containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include (l-lOC)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N,iV-[di-(l-4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxy acetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, iV-alkylaminomethyl, ΛζN-dialkylaminomethyl, morpholinomethy 1, piperazin- 1 -ylmethyl and 4-( 1 -4C)alky lpiperazin- 1 -y lmethyl . Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include α-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, JV-ethyl-JV-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.
A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (l-lOC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, iV-alkylaminomethyl, Λζ N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l -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). Particular novel compounds of the invention include, for example, pyrimidine derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of p, R1, R2, q, R3, r, R4, X1 and Q1 has any of the meanings defined hereinbefore or in paragraphs (a) to (iii) hereinafter :-
(a) p is 0 or p is 1, 2 or 3, and each R1 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-βC)alkoxycarbonyl, iVT-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(I -6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-( 1 -6C)alkyl-(3 -6C)alkenoylamino, (3 -6C)alkynoylamino, iV-(l-6C)alkyl-(3-6C)alkynoylamino, iV-(l-6C)alkylsurphamoyl,
N,iV-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and JV-(I -6C)alkyl~ (l-6C)alkanesulphonylamino, or from a group of the formula :
Q2-X2- wherein X2 is a direct bond or is selected from O, S, N(R5), CO, wherein R5 is hydrogen or (1 -8C)alkyl, and Q2 is aryl, aryl-(l -6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l -6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or (R*)p is (1-3 C)alkylenedioxy , and wherein any CH, CH2 or CH3 group within a R1 substituent optionally bears on each said CH, CH2 or CH3 group one or more halogeno or (l-SC)alkyl substituents and/or a substituent selected from hydroxy, mercapto, amino, cyano, carboxy, carbamoyl, ureido,
(l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-βC)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-όC)alkoxycarbonyl, JV-(I -6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(I -6C)alkyl-(2-6C)alkanoylamino, JV-( 1 -6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl- ( 1 -6C)alkanesulphonylamino, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-βC)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents;
(b) p is 0 or p is 1 or 2, and each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoylamino and N-(I -6C)alkyl-(2-6C)alkanoylamino, and wherein any CH, CH2 or CH3 group within a R1 substituent optionally bears on each said CH, CH2 or CH3 group 1, 2 or 3 halogeno or (l-8C)alkyl substituents and/or a substituent selected from hydroxy, amino, cyano, carboxy, carbamoyl, ureido, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-όC)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[( 1 -6C)alkyl]carbamoyl, (2-6C)alkanoylamino and TV-(I -6C)alkyl- (2-6C)alkanoylamino;
(c) p is 0 or p is 1 or 2, and each R1 group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, carboxy, carbamoyl, ureido, methyl, ethyl, propyl, vinyl, allyl, ethynyl, 2-propynyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methoxycarbonyl, ethoxycarbonyl, acetamido, propionamido, N-methylacetamido, N-methylpropionamido, hydroxymethyl, 1 -hydroxy ethyl, 1 -hydroxy- 1-methylethyl, 2-hydroxy ethyl, 2-hydroxy- 1-methylethyl, 2-hydroxypropyl, l,l-dimethyl-2-hydroxy ethyl, 2-hydroxy-2-methylpropyl, aminomethyl, 1-aminoethyl, 1 -amino- 1-methylethyl, 2-aminoethyl, 2-amino- 1-methylethyl, 2-aminopropyl, 2-amino- 1 , 1 -dimethylethyl, 2-amino-2-methylpropyl, methylaminomethyl, 1-methylaminoethyl, 1 -methylamino- 1-methylethyl, 2-methylaminoethyl, 2-methylamino- 1-methylethyl, 2-methylaminopropyl, 2-methylamino- 1,1 -dimethylethyl, 2-methylamino- 2-methylpropyl, acetamidomethyl, 1-acetamidoethyl, 1-acetamido-l-methylethyl, 2-acetamidoethyl, 2-acetamido-l-metliylethyl, 2-acetamidopropyl, 2-acetamido- 1,1-dimethylethyl and 2-acetamido-2-methylpropyl;
(d) p is 0 or p is 1 and the R1 group is located at the A-, 5- or 6-position on the benzimidazolyl group and is selected from fluoro, chloro, hydroxy, amino, methoxy, ethoxy, methylamino, ethylamino and acetamido;
(e) p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is selected from fluoro, chloro, hydroxy, amino, methoxy, methylamino and acetamido;
(f) p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy;
(g) p is 0;
(h) R2 is fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, hydroxy, amino, formamido, acetamido, propionamido,
JV-methylacetamido, methylamino, ethylamino, dimethylamino, diethylamino, hydroxymethyl or methoxy methyl;
(i) R2 is fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido, acetamido or hydroxymethyl;
(J) R2 is difluoromethyl, trifluoromethyl, amino, formamido, acetamido or hydroxymethyl;
(k) R2 is difluoromethyl; (1) q is 0 or q is 1, 2 or 3 and each R3 group, which may be the same or different, is methyl, ethyl or propyl;
(m) q is 2 and the two R3 groups together form a methylene or ethylene group;
(n) q is 0 or q is 1 or 2 and each R group is methyl;
(o) r is 0 or r is 1, 2, 3 or 4 and each R group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoylamino and N-(l-6C)alkyl-(2-6C)alkanoylamino, or two R4 groups together form a methylene or ethylene group;
(p) r is 0 or r is 1, 2, 3 or 4 and each R group, which may be the same or different, is methyl, ethyl or propyl;
(q) r is 2 and the two R4 groups together form a methylene or ethylene group;
(r) r is 0 or r is 1, 2, 3 or 4 and each R4 group is methyl; (s) X1 is selected from CO, SO2, CON(R13), COC(R13)2O, COC(R13)2S, COC(R13)2N(R13) and COC(R13)2N(R13)CO, wherein R13 is hydrogen or (l-8C)alkyl;
(t) X1 is selected from CO, SO2, CONH, COCH2O, COCH2NH and COCH2NHCO;
(u) X1 is selected from CO, SO2, CONH, CON(Me), COCH2O5 COCH2NH and COCH2NHCO;
(v) X1 is CONH or CON(Me);
(w) X1 Is CO;
(x) X1 is SO2;
(y) Q1 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,
(l-6C)alkylsulphonyl-(l-6C)alkyl or (2-6C)alkanoylamino-(l-6C)alkyl, or Q1 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, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group one or more halogeno or (l-8C)alkyl substituents and/or a substituent selected from hydroxy, amino, cyano, carboxy, carbamoyl, ureido, (l-6C)alkoxy,
(l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulρhonyl, (l-6C)alkylamino, di- [( 1 -6C)alky 1] amino, ( 1 -6C)alkoxycarbonyl, N-(I -6C)alkylcarbamoyl,
N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino and Λ/-(l-6C)alkyl-
(2-6C)alkanoylamino, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino, or from a group of the formula :
-X7-R14 wherein X7 is a direct bond or is selected from O and N(R15), wherein R15 is hydrogen or (l-8C)alkyl, and R14 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 heterόcyclyl group within the Q1 group optionally bears 1 or 2 oxo or thioxo substituents;
(z) Q1 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, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)alkylthio-(l-6C)alkyl or (2-6C)alkanoylamino-(l-6C)alkyl, or Q1 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, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group 1, 2 or 3 halogeno or (l-8C)alkyl substituents and/or a substituent selected from hydroxy, amino, cyano, carboxy, carbamoyl, ureido, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, JV-(I -6C)alkylcarbamoyl, N,iV-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino and
ΪV-(l-6C)alkyl-(2-6C)alkanoylamino, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 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-όC)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino, or from a group of the formula :
-X7-R14 wherein X7 is a direct bond and R14 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;
(aa) Q1 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, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)alkylsulphonyl-(l-6C)alkyl or (2-6C)alkanoylamino-(l-6C)alkyl, or Q1 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, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, (l-6C)alkoxy, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-όC)alkoxycarbonyl, iV-(l-6C)alkylcarbamoyl, iV,iV-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoylamino and JV-(I -6C)alkyl-(2-6C)alkanoylamino, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l-όC)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, hydroxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyl]amino-(l-6C)alkyl; (bb) Q1 is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxy ethyl, 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, 1 -isopropyl- 1 -methylaminomethyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl, 5-diethylaminopentyl, 2-methylsulphonylethyl, 3-methylsulphonylpropyl, acetamidomethyl or 1-acetamidoethyl, or Q1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furylmethyl, 2-furylethyl, thienylmethyl, 2-thienylethyl, oxazolylmethyl, 2-oxazolylethyl, isoxazolylmethyl, 2-isoxazolylethyl, imidazolylmethyl, 2-imidazolylethyl, pyrazolylmethyl, 2-pyrazolylethyl, thiazolylmethyl, 2-thiazolylethyl, triazolylmethyl, 2-triazolylethyl, oxadiazolylmethyl, 2-oxadiazolylethyl, thiadiazolylmethyl, 2-thiadiazolylethyl, tetrazolylmethyl, 2-tetrazolylethyl, pyridylmethyl, 2-pyridylethyl, pyrazinylmethyl, 2-pyrazinylethyl, pyridazinylmethyl, 2-pyridazinylethyl, pyrimidinylmethyl,
2-pyrimidinylethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclo[2.2.1]heptyl, indolinyl, isoindolinyl, dihydropyridinyl, tetrahydrofuranylmethyl, tetrahydropyrariylmethyl, tetrahydrothiopyranylmethyl, 1,3-dioxolanylmethyl, 1,4-dioxanylmethyl, pyrrolinylmethyl, 2-(pyrrolinyl)ethyl, pyrrolidinylmethyl, 2-(pyrrolidinyl)ethyl, imidazolidinylmethyl, pyrazolidinylmethyl, morpholinylmethyl, 2-(morpholinyl)ethyl, tetrahydro-1 ,4-thiazinylmethyl, 2-(tetrahydro-l ,4-thiazinyl)ethyl, piperidinylmethyl, 2-(piperidinyl)ethyl5 homopiperidinylmethyl, 2-(homopiperidinyl)ethyl, piperazinylmethyl, 2-(piperazinyl)ethyl, homopiperazinylmethyl, 2-(homopiperazinyl)ethyl or 2-azabicy clo [2.2.1 ]heptylmethyl, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, ethylamino, dimethylamino, diethylamino, methoxycarbonyl, ethoxycarbonyl, 7V-methylcarbamoyl, iV-ethylcarbamoyl, iV-isopropylcarbamoyl, iV,iV-dimethylcarbamoyl, iV,N-diethylcarbamoyl, acetyl, propionyl, butyryl, pivaloyl, acetamido, propionamido and JV-methylacetamido, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2 -methoxy ethyl, cyanomethyl, 2-cyanoethyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl and 2-dimethylaminoethyl; (cc) Q1 is 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 1 -cyano- 1-methylethyl, 4-cyanobutyl, 5-cyanopentyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl, 5-diethylaminopentyl, 2-methylsulphonylethyl or acetamidomethyl, or
Q1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopenτyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl, 2-imidazolylethyl, pyrazolylmethyl, thiazolylmethyl, triazolylmethyl, oxadiazolylmethyl, thiadiazolylmethyl, tetrazolylmethyl, pyridylmethyl, 2-pyridylethyl, pyrazinylmethyl, 2-pyrazinylethyl, pyridazinylmethyl, 2-pyridazinylethyl, pyrimidinylmethyl, 2-pyrimidinylethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, indolinyl, isoindolinyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, 1,3-dioxolanylmethyl, 1 ,4-dioxanylmethyl, pyrrolidinylmethyl, 2-(pyrrolidinyl)ethyl, morpholinylmethyl, 2-(morpholinyl)ethyl, piperidinylmethyl, 2-(piperidinyl)ethyl, homopiperidinylmethyl, piperazinylmethyl, 2-(piperazinyl)ethyl or homopiperazinylmethyl, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, dimethylamino, methoxycarbonyl, ethoxycarbonyl, iV-methylcarbamoyl, iV-ethylcarbamoyl, N-isopropylcarbamoyl, iVjiV-dimethylcarbamoyl, acetyl, propionyl, pivaloyl, acetamido and iV-methylacetamido, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, methoxy, methylamino and dimethylamino and any such aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; (dd) Q1 is aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl,
5-methylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl or 5-dimethylaminopentyl, or Q1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl, thienylmethyl, imidazolylmethyl, thiazolylmethyl, thiadiazolylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, indolinyl, isoindolinyl, pyrrolidinylmethyl, 2-(pyrrolidinyl)ethyl, morpholinylmethyl, 2-(morpholinyl)ethyl, piperidinylmethyl, 2-(piperidinyl)ethyl, homopiperidinylmethyl, piperazinylmethyl, 2-(piperazinyl)ethyl, homopiperazinylmethyl or 2-azabicyclo[2.2. ljheptylmethyl, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears a substituent selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, methoxy, methylamino and dimethylamino and any such aryl,
(3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears a further substituent selected from aminomethyl, methylaminomethyl and dimethylaminomethyl; (ee) Q1 is aminomethyl, 1-aminoethyl, 1 -amino- 1-methylethyl, methylaminomethyl,
1-methylaminoethyl, 1 -methylamino- 1-methylethyl, acetamidomethyl, 1-acetamidoethyl or
1 -acetamido- 1 -methylethy 1 ;
(ff) the X^Q1 group is an α-amino carbonyl group;
(gg) the X^Q1 group is a naturally-occurring α-amino carbonyl group; (hh) the X^Q1 group is selected from glycyl, sarcosyl, iV-ethylglycyl, JV,N-dimethylglycyl, glycylglycyl, L-alanyl, 2-methylalanyl, iV-methylalanyl, β-alanyl, (2S)-2-aminobutanoyl,
L-valyl, N-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, iV-methyl-L-seryl,
O-methyl-L-homoseryl, L-threonyl, S-methyl-L-cysteinyl, S-methyl-L-homocysteinyl, L-methionyl, iV-methyl-L-lysyl, iV-methyl-L-ornithyl, D-asparaginyl, D-glutaminyl,
L-tyrosyl, prolyl and histidyl;
(ii) X1 is a direct bond and Q1 is hydrogen;
Gj) X1 is a direct bond and Q1 is (1 -8C)alkyl, (2-8C)alkenyl or (2-8C)alkynyl;
(kk) X1 is a direct bond and Q1 is methyl, ethyl, propyl, isopropyl, butyl, pentyl or allyl; (11) the 5-position on the pyrimidine ring may bear a methyl group;
(mm) the 5-position on the pyrimidine ring is unsubstiruted;
(nn) p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is methoxy;
(oo) p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is (1- 6C)alkoxy (such as methoxy);
(pp) R2 is difluoromethyl or trifluoromethyl;
(qq) R2 is trifluoromethyl;
(rr) q is 0 or q is 1 and the R3 group is methyl;
(ss) q is 0; (tt) q is 1 and the R3 group is (l-όC)alkyl (such as methyl); (uu) r is 0, or r is 1 or 2 and each R4 group, which may be the same or different, is a (1- 44CC))aallkkyyll ggrroouupp,, oorr rr is 2 and the two R groups together form a methylene, ethylene or trimethylene group;
(vv) r is 0, or r is 2 and each R4 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 R4 groups together form an ethylene group;
(ww) r is 0;
(xx) r is 2 and each R4 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 R4 groups together form a methylene, ethylene or trimethylene group (especially an ethylene group);
(yy) X1 is a direct bond or is selected from CO, CON(R13), COC(R13)2N(R13) and
COC(R13)2N(R13)CO, wherein R13 is hydrogen or (l-2C)alkyl (such as methyl);
(yy) X1 is a direct bond or is selected from CO, CON(R13) and COC(R13)2N(R13)CO, wherein
R13 is hydrogen or (l-2C)alkyl (such as methyl); (zz) X1 is a direct bond or is selected from CO, CONH, COCH2NH and COCH2NHCO;
(zz) X1 is a direct bond or is selected from CO, CONH and COCH2NHCO;
(aaa) X1 is selected from CO, CONH, COCH2NH and COCH2NHCO (especially CO and
COCH2NHCO);
(aaa) X1 is selected from CO, CONH and COCH2NHCO (especially CO and COCH2NHCO); (bbb) Q1 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, amino-(l-
6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl (especially hydroxy-(l-6C)alkyl, amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl), and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group one or more halogeno or (l-8C)alkyl substituents and/or a substituent selected from hydroxy, mercapto, amino, cyano, carboxy, carbamoyl, ureido, (1-
6C)alkoxy, (l-όC)alkylthio, (l-6C)alkylsulphinyl, (l-όC)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, iV-(l-6C)alkylcarbamoyl, JV,iV-di-[(l-
6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, JV-(I- 6C)alkyl-(2-6C)alkanoylamino, iV'-(l-6C)alkylureido, N',iV'-di-[(l-6C)alkyi]ureido, TV-(I-
6C)alkylureido, 7V,/V'-di-[(l-6C)alkyl]ureido, N,iV',JV'-tri-[(l-6C)alkyl]ureido, N-(I- 6C)alkylsulphamoyl, iV,iV-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylaniino and iV-(l- 6C)alkyl-( 1 -6C)alkanesulphonylamino5 and wherein any aryl or heterocyclyl group within the Q1 group optionally bears I5 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2- 8C)alkynyl, (l-θC)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (1- 6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (1- 6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, N-(l-6C)alkylcarbamoyl, JV,N-di-[(l- 6C)alkyl]carbamoyl, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, N'-(l- 6C)alkylureido, N',N'-di-[(l-6C)alkyl]ureido, N-(l-6C)alkylureido, JV,iV'-di-[(l-
6C)alkyl]ureido, N,N',iV'-tri-[(l-6C)alkyl]ureido, TV-(I -6C)alkylsulphamoyl, N,N-di-[(l- 6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l- 6C)alkanesulphonylamino, or from a group of the formula :
-X7-R14 wherein X7 is a direct bond or is selected from O and N(R15), wherein R15 is hydrogen or
(l-8C)alkyl, and R14 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 :
-X8 -Q5 wherein X8 is a direct bond or is selected from O, CO and N(R17), wherein R17 is hydrogen or (l-8C)alkyl, and Q5 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 Q1 group optionally bears 1 or 2 oxo or thioxo substituents, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within the Q1 group are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R16), N(R16)C0, CON(R16), N(R16)CON(R16), CO, CH(OR16), N(R16)SO2, SO2N(R16), CH=CH and C=C wherein R16 is hydrogen or (l-8C)alkyl; (ccc) Q1 is hydrogen, hydroxy-(l-6C)alkyl, amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl (especially hydroxy-(l-6C)alkyl, amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl), and wherein any CH or CH2 group within the Q1 group optionally bears on each said CH or CH2 group one or more (l-6C)alkylamino substituents;
(ddd) Q1 is hydrogen, hydroxymethyl, aminomethyl, 2-aminoethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl, and wherein any CH or CH2 or group within the Q group optionally bears on each said
CH or CH2 group a substituent selected from hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, ethylamino, dimethylamino, diethylamino, methoxycarbonyl, ethoxycarbonyl, iV-methylcarbamoyl, N-ethylcarbamoyl, N- isopropylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, acetyl, propionyl, butyryl, pivaloyl, acetamido, propionamido and N-methylacetamido, and wherein any aryl or heterocyclyl group within the Q1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-methoxy ethyl, cyanomethyl, 2-cyanoethyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl and 2-dimethylaminoethyl;
(eee) Q1 is hydrogen, hydroxymethyl, aminomethyl, 2-aminoethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl (especially hydroxymethyl, aminomethyl, 2-aminoethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl), and wherein any CH or CH2 group within the Q1 group optionally bears on each said CH or CH2 group a substituent selected from methylamino, ethylamino, dimethylamino and diethylamino (especially methylamino);
(fff) X1 is a direct bond and Q1 is hydroxy-(l-6C)alkyl or amino-(l-6C)alkyl;
(ggg) X1 is COΝH and Q1 is amino-(l-6C)alkyl (such as aminomethyl or 2-aminoethyl); (hhh) X1 is COCH2NHCO and Q1 is heterocyclyl (such as pyrrolidinyl or piperidinyl, especially pyrrolidinyl); and
(iii) X1 is CO and Q1 is amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl (such as aminomethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl), and wherein any CH or CH2 group within the Q1 group optionally bears on each said CH or CH2 group a methylamino substituent. "Me" herein represents methyl. A particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R1 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;
R2 is fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido, acetamido or hydroxymethyl; q is 0 or q is 1 or 2 and each R3 group is methyl; r is 0, or r is 1 , 2, 3 or 4 and each R group, which may be the same or different, is methyl, ethyl or propyl; or r is 2 and the two R4 groups together form a methylene or ethylene group;
X1 is selected from CO, SO2, CONH, CON(Me), COCH2O, COCH2NH and COCH2NHCO; and
Q1 is 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 1-cyano-l-methylethyl, 4-cyanobutyl, 5-cyanopentyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl, 5-diethylaminopentyl, 2-methylsulphonylethyl or acetamidomethyl, or
Q1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl, 2-imidazolylethyl, pyrazolylmethyl, thiazolylmethyl, triazolylmethyl, oxadiazolylmethyl, thiadiazolylmethyl, tetrazolylmethyl, pyridylmethyl, 2-pyridylethyl, pyrazinylmethyl, 2-pyrazinylethyl, pyridazinylmethyl, 2-pyridazinylethyl, pyrimidinylmethyl, 2-pyrimidinylethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, indolinyl, isoindolinyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, 1,3-dioxolanylmethyl, 1,4-dioxanylmethyl, pyrrolidinylmethyl, 2-(pyrrolidinyl)ethyl, morpholinylmethyl, 2-(morpholinyl)ethyl, piperidinylmethyl, 2-(piperidinyl)ethyl, liomopiperidinylmethyl, piperazinylmethyl, 2-(piperazinyl)ethyl or homopiperazinylmethyl, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, dimethylamino, methoxycarbonyl, ethoxycarbonyl, iV-methylcarbamoyl, iV-ethylcarbamoyl, N-isopropylcarbamoyl, ΛζN-dimethylcarbamoyl, acetyl, propionyl, pivaloyl, acetamido and JV-methylacetamido, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, methoxy, methylamino and dimethylamino and any such aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R1 group is located at the 4-, 5- or 6-position on the benzimidazolyl group and is selected from methoxy and ethoxy (especially methoxy); R2 is difluoromethyl or trifluoromethyl; q is 0 or q is 1 and the R3 group is methyl; r is 0, or r is 1 or 2 and each R4 group, which may be the same or different, is methyl, ethyl or propyl (especially methyl), or r is 2 and the two R4 groups together form an ethylene group;
X1 is a direct bond or is selected from CO, COΝH, COCH2NH and COCH2NHCO (especially X1 is a direct bond or is selected from CO, CONH and COCH2NHCO); and
Q1 is hydrogen, hydroxymethyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2- ethoxy ethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 1 -cyano- 1- methylethyl, 4-cyanobutyl, 5-cyanopentyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4- aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3- ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2- dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl, 5- diethylaminopentyl, 2-methylsulphonylethyl or acetamidomethyl, or
Q1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl, 2-imidazolylethyl, pyrazolylmethyl, thiazolylmethyl, triazolylmethyl, oxadiazolylmethyl, thiadiazolylmethyl, tetrazolylmethyl, pyridylmethyl, 2-pyridylethyl, pyrazinylmethyl, 2-pyrazinylethyl, pyridazinylmethyl, 2-pyridazinylethyl, pyrimidinylmethyl, 2-pyrimidinylethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, indolinyl, isoindolinyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, 1,3-dioxolanylmethyl, 1,4-dioxanylmethyl, pyrrolidinylmethyl, 2-(pyrrolidinyl)ethyl, morpholinylmethyl, 2-(morpholinyl)ethyl, piperidinylmethyl, 2-(piperidinyl)ethyl, homopiperidinylmethyl, piperazinylmethyl, 2-(piperazinyl)ethyl or homopiperazinylmethyl, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, dimethylarnino, methoxycarbonyl, ethoxycarbonyl, iV-methylcarbamoyl, N-ethylcarbamoyl, iV-isopropylcarbamoyl, iV,JV-dimethylcarbamoyl, acetyl, propionyl, pivaloyl, acetamido and iV-methylacetamido, and wherein any aryl, (3-8C)cycloalkyl, heteroaiyl or heterocyclyl group within the Q1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, methoxy, methylamino and dimethylamino and any such aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof. A further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R1 group is located at the 4-, 5- or 6-position on the benzimidazolyl group and is methoxy; R2 is difluoromethyl or trifluoromethyl; q is 0 or q is 1 and the R3 group is methyl; r is 0, or r is 2 and each R4 group is methyl, or r is 2 and the two R4 groups together form an ethylene group;
X1 is a direct bond or is selected from CO, CONH, COCH2NH and COCH2NHCO (especially X1 is a direct bond or is selected from CO, CONH and COCH2NHCO, more especially X1 is selected from CO and COCH2NHCO); and
Q1 is hydrogen, hydroxymethyl, 2-hydroxy ethyl, 2-methoxy ethyl, 3-methoxypropyl, 2- ethoxyethyl, 3-ethoxypropyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5- aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4- methylaminobutyl, 5-methylaminopentyl, ethylarninomethyl, 2-ethylaminoethyl, 3- ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2- dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl or 5- diethylaminopentyl, or Q1 is benzyl, 2-phenylethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, indolinyl or isoindolinyl, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, dimethylamino, methoxycarbonyl, ethoxycarbonyl, iV-methylcarbamoyl, iV-ethylcarbamoyl, JV-isopropylcarbamoyl, Λζ,N-dimethylcarbamoyl, acetyl, propionyl, pivaloyl, acetamido and iV-methylacetamido, and wherein any aryl or heterocyclyl group within the Q1 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 Q1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; and the 5 -position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof. s A further particular compound of the invention is a pyrimidine derivative of the Formula
I wherein :- p is 0;
R2 is difluoromethyl or trifluoromethyl (especially difluoromethyl); q is 0 or q is 1 and the R3 group is methyl; o r is 0, or r is 2 and each R4 group is methyl, or r is 2 and the two R4 groups together form an ethylene group;
X1 is a direct bond or is selected from CO, CONH, COCH2NH and COCH2NHCO (especially X1 is a direct bond or is selected from CO, CONH and COCH2NHCO, more especially X1 is selected from CO and COCH2NHCO); and s Q1 is hydrogen, hydroxymethyl, aminomethyl, 2-aminoethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl, and wherein any CH or CH2 group within the Q1 group optionally bears on each said CH or CH2 group a substituent selected from methylamino and dimethylamino (especially methylamino), 0 and wherein any aryl or heterocyclyl group within the Q1 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 Q1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and S dimethylaminomethyl; and the 5 -position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :-0 p is 0 or p is 1 and the R1 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; R2 is fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido, acetamido or hydroxymethyl; q is 0 or q is 1 or 2 and each R3 group is methyl; r is 0, or r is 1, 2, 3 or 4 and each R4 group, which may be the same or different, is methyl, ethyl or propyl; or r is 2 and the two R groups together form a methylene or ethylene group; and the Xl-Q[ group is selected from glycyl, sarcosyl, JV-ethylglycyl, N,iV-dimethylglycyl, glycylglycyl, L-alanyl, 2-methylalanyl, N-methylalanyl, β-alanyl, (2S)-2-aminobutanoyl, L-valyl, N-methyl-L-valyl, 2-aminopent-4-ynoyl, 2-aminopentanoyl, L-isoleucyl, L-leucyl, 2-methyl-L-leucyl, N-methyl-L-leucyl, seryl, O-methyl-L-seryl, iV-methyl-L-seryl, O-methyl-L-homoseryl, L-threonyl, S-methyl-L-cysteinyl, S-methyl-L-homocysteinyl, L-methionyl, iV-methyl-L-lysyl, iV-methyl-L-ornithyl, D-asparaginyl, D-glutaminyl, L-tyrosyl, prolyl and histidyl; and the 5 -position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy; R2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R4 group is methyl, or r is 2 and the two R4 groups together form a methylene or ethylene group;
X1 is CO; and Q1 is 2-ethoxyethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, aminomethyl,
2-aminoethyl, methylaminoniethyl, 2-methylaminoethyl, ethylaminomethyl, 2-ethylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl, 4-dimethylaminobutyl, 2-methylsulphonylethyl or acetamidomethyl, or Q1 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-4-yl, thien-3-ylmethyl, oxazol-4-ylmethyl, isoxazol-3-ylmethyl, isoxazol-4-ylmethyl, imidazol-1-ylmethyl, imidazol-2-ylmethyl, 2-iniidazol-l-ylethyl, 2-imidazol-2-ylethyl, 2-imidazol-4-ylethyl, pyrazol-1-ylmethyl, pyrazol-3-ylmethyl, 1,2,3-triazol-l-ylmethyl, 1 ,2,3-triazol-4-ylmethyl, 1 ,2,4-oxadiazol-3-ylmethyl, 1 ,2,3-thiadiazol-3-ylmethyl, tetrazol-1-ylmethyl, tetrazol-5-ylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, 2-pyridin-2-ylethyl, 2-pyridin-3-ylethyl, 2-pyridin-4-ylethyl, pyrazin-2-ylmethyl, 2-pyrazin-2-ylethyl, pyridazin-4-ylmethyl, 2-pyridazin-4-ylethyl, pyrimidin-2-ylmethyl, pyrimidin-4-ylmethyl, 2-pyrimidin-2-ylethyl, 2-pyrimidin-4-ylethyl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, azetidin-2-yl, 3-pyrrolin-2-yl, pyrrolidiii-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, morpholino, morpholin-2-yl, morpholin-3-yl, piperidino, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, isoindolin-1-yl, tetrahydrofuran-2-ylmethyl, tetrahydropyran-4-ylmethyl, l,3-dioxolan-2-ylmethyl, l,4-dioxan-2-ylmethyl, pyrrolidin-2-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, 2-(piperidin-4-yl)ethyl, piperidin-4-yloxymethyl, piperazin- 1 -y lmethy 1 or 2-(piperazin- 1 -y l)ethy 1, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group a substituent selected from hydroxy, carbamoyl, methoxycarbonyl, ethoxycarbonyl, iV-methylcarbamoyl, iV-ethylcarbamoyl, N-isopropylcarbamoyl, N,JV-dimethylcarbamoyl, acetyl, propionyl, pivaloyl, acetamido and iV-methylacetamido, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, amino, carbamoyl, methyl, methylamino, dimethylamino, hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy; R2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R4 group is methyl, or r is 2 and the two R4 groups together form a methylene or ethylene group; X1 is CO; and Q1 is hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-methylethyl, 1-hydroxy- 1-methylethyl, 1 -hydroxy- 1-trifluoromethylethyl, methoxymethyl, 2-methoxy ethyl, methylsulphonylmethyl, 2-methylsulphonylethyl, methoxycarbonylmethyl, fert-butoxycarbonylmethyl, N,N-dimethylcarbamoylmethyl, 2-(iV,iV-dimethylcarbamoyl)ethyl, cyclopropyl, 1-hydroxycycloprop-l-yl, 1-aminocycloprop-l-yl, cyclobutyl, 1-hydroxycyclobut-l-yl, 1-aminocyclobut-l-yl, cyclopentyl, 1-hydroxycyclopent-l-yl, 1-aminocyclopent-l-yl, cyclohexyl, 1-hydroxycyclohex-l-yl, 1-aminocyclohex-l-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, morpholino, morpholin-2-yl, morpholin-3-yl, tetrahydro-l,4-thiazin-3-yl, azetidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, 5-aminopyrrolidin-2-yl, pyrrolidin-3-yl, iV-methylpyrrolidin-3-yl, l-aminopyrrolidin-3-yl, piperidino, piperidin-3-yl, iV-methyrpiperidin-3-yl, 3-aminopiperidin-3-yl, piperidin-4-yl, iV-methylpiperidin-4-yl, 1 -aminopiperidin-4-yl, piperazin- 1 -yl, 4-methylpiperazin- 1 -yl, piperazin-2-yl, 1 ,4-dimethylpiperazin-2-yl, 2-oxo-l ,3-thiazolidin-4-yl, 6-oxo-l,4,5,6-tetrahydropyridazin-3-yl, tetrahydrofuran-3 -ylmethyl, tetrahydropyran-4-ylmethyl, pyrrolidin-2-ylmethyl, piperidin-3 -ylmethy 1, piperidin-4-ylmethyl, piperazin- 1 -y lmethyl, 2-oxo-l ,3 -oxazolidin-3 -ylmethyl, 2-oxo- 1 ,2-dihy dropyridin- 1 -ylmethyl, phenyl, 2-aminophenyl, 3 -aminophenyl,
4-aminophenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 3-carbamoylphenyl, 3-aminomethylphenyl, 4-aminomethylphenyl, benzyl, 3-hydroxybenzyl, 4-mesylbenzyl, 1-formamido-l-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 3-(4-methoxyphenyl)propyl, l-hydroxy-3-phenylpropyl, 2-furyl, 3-furyl, 3-methylfuran-2-yl, 5-methylfuran-3-yl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 2-imidazolyl, iV-methylimidazol-2-yl, 3-pyrazolyl,
1 -methyl- lH-pyrazol-3-yl, 4-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 2-methyloxazol-4-yl, 5-oxazolyl, 3-isoxazolyl, 5-methylisoxazol-3-yl, 4-isoxazolyl, 3-methylisoxazol-4-yl, 5-methylisoxazol-4-yl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 4-methylthiazol-5-yl, 1 H- 1 ,2,3-triazol-5-yl, AH- 1 ,2,4-triazol-3-yl, 3 -amino- 1 H- 1 ,2,4-triazol-5 -yl, 5-hydroxy-4H-l,2,4-triazol-3-yl, l,2,3-thiadiazol-4-yl, 2,l,3-thiadiazol-4-yl, 5-tetra'zolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyridazinyl, 2-pyrazinyl, 3-aminopyrazin-2-yl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-hydroxy-4-methylpyrimidin-5-yl, 3-thienylmethyl, 2-imidazolylniethyl, 4-imidazolylmethyl, 5-methyl-lϋ/-imidazol-4-ylmethyl, 1 if-pyrazol- 1 -y lmethyl, 1 /f-pyrazol-3 -y lmethyl, 3 , 5 -dimethyl- 1 H-pyrazol- 1 -ylmethyl, 4-oxazolylmethyl, 3-isoxazolylmethyl, 5 -isoxazo Iy lmethyl, 1 H- 1,2,4-triazol-l -ylmethyl, 1 H-tetrazol- 1 -ylmethyl, 1 H-tetrazol-5 -ylmethyl, 2-( lH-pyrazol- 1 -yl)ethyl, 2-(3-methyl-lH-pyrazol-l-yl)ethyl, 2-(lH-l,2,4-triazol-l-yl)ethyl, 2-pyridylmethyl, 3 -pyridy lmethyl, 4-pyridy lmethyl, 4-pyridaziny lmethyl, 4-pyrimidiny lmethyl, 2-pyrazinylmethyl, 2-pyridin-3-ylethyl, 2-pyrimidin-4-ylethyl, 2-pyridazin-4-ylethyl, phenoxymethyl, 2-tolyloxymethyl or piperidin-4-yloxymethyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy; R2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R4 group is methyl, or r is 2 and the two R4 groups together form a methylene or ethylene group; and the X^Q1 group is glycyl, sarcosyl, iV-acetylglycyl, JV,iV-dimethylglycyl, 2-methylalanyl, iV-acetylalanyl, β-alanyl, D-valyl, L-seryl, iV-methyl-L-seryl, JV-acetylseryl, L-homoseryl, glycyglycyl, N-benzoylglycyl or 7V-(4-toluoyl)glycyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy;
R2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R4 group is methyl, or r is 2 and the two R4 groups together form a methylene or ethylene group;
X1 is CO; and Q1 is hydroxymethyl, 2-hydroxy-2-methylethyl, methoxymethyl, cyclopropyl, 1-hydroxycycloprop-l-yl, tetrahydropyran-4-yl, morpholin-2-yl, morpholin-3-yl, tetrahydro-l,4-thiazin-3-yl, azetidin-2-yl, pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, tetrahydropyran-4-ylmethyl, pyrrolidin-2-ylmethyl, piperidin-3-ylmethyl, piperazin-1-ylmethyl, phenyl, 3-carbamoylphenyl, 3-aminophenyl, 4-aminophenyl,
3-aminomethylphenyl, 4-aminomethylphenyl, 3-hydroxybenzyl, 2-furyl, 2-thienyl, 2-pyrrolyl, JV-methylimidazol-2-yl, 3-pyrazolyl, l-methyl-lH-pyrazol-3-yl, 4-pyrazolyl, 2-methyloxazol- 4-yl, 5-isoxazolyl, lH-l,2,3-triazol-5-yl, l,2,3-thiadiazol-4-yl, 3-pyridyl, 4-pyridazinyl, 3-thienylmethyl, lH-l,2,4-triazol-l-ylmethyl, lH-tetrazol-1-ylmethyl, lH-tetrazol-5-ylmethyl, 2-pyridin-3-ylethyl, 2-pyridazin-4-ylethyl, 2-tolyloxymethyl or piperidin-4-yloxymethyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy;
R2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R4 group is methyl; and the X^Q1 group is glycyl, sarcosyl, iV-acetylglycyl, iV,iV-dimethylglycyl, iV-acetylalanyl,
2-methylalanyl, β-alanyl, D-valyl, L-seryl, iV-methyl-L-seryl, iV-acetylseryl, L-homoseryl or JV-(4-toluoyl)glycyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof. A further particular compound of the invention is a pyrimidine derivative of the
Formula I wherein :- p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy;
R2 is difluoromethyl; q is 0; r is 0, or r is 1 or 2 and each R4 group is methyl;
X1 is CO; and Q1 is aminomethyl, 1-aminoethyl, 1 -amino- 1-methylethyl, methylaminomethyl, 1-methylaminoethyl, 1-methylamino- 1-methylethyl, acetamidomethyl, 1-acetamidoethyl or 1 -acetamido- 1 -methylethyl; and the 5-position on the pyrimidine ring is unsubstituted; 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 R1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy;
R2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R4 group is methyl;
X1 is CO; and
Q1 is hydroxymethyl, 2-hydroxy-2-methylethyl, cyclopropyl, 1-hydroxycycloprop-l-yl, 1-aminocycloprop-l-yl, 1-aminocyclobut-l-yl, tetrahydropyran-4-yl, morpholin-2-yl, morpholin-3-yl, tetrahydro-l,4~thiazin-3-yl, azetidin-2-yl, pyrrolidin-2-yl, pipeiϊdin-3-yl, l-aminopiperidin-3-yl, piperidin-4-yl, l-aminopiperidin-4-yl, piperazin-2-yl, tetrahy dropyran-4-ylmethyl, pyrrolidin-2-ylmethyl, piperidin-3 -ylmethyl, piperazin-1-ylmethyl, 3-aminophenyl, 4-aminophenyl, 3-aminomethylphenyl, 4-aminomethylphenyl, iV-methylimidazol-2-yl, 1 -methyl-l/J-pyrazol-3-yl, 2-methyloxazol-4-yl, lH-l,2,3-triazol-5-yl, l,2,3-thiadiazol-4-yl, 3-pyridyl, 4-pyridazinyl, IH- 1 ,2,4-triazol- 1 -ylmethyl, lH-tetrazol-1 -ylmethyl, 1 H-tetrazol- 5 -ylmethyl, 2-pyridin-3-ylethyl, 2-pyridazin-4-ylethyl or piperidin-4-yloxymethyl; 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;
R2 is difluoromethyl; q is 0; r is 0;
X1 is CO; and Q1 is 1-aminocycloprop-l-yl, 1-aminocyclobut-l-yl, morpholin-2-yl, morpholin-3-yl, pyrrolidin-2-yl, l-aminopiperidin-3-yl, piperazin-2-yl, 3-aminophenyl or 4-aminophenyl; and the 5 -position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof. A further particular compound of the invention is a pyrimidine derivative of the
Formula I wherein :- p is 0;
R2 is difluoromethyl; q is 0; r is 0; and the X^Q1 group is glycyl or sarcosyl; 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;
R2 is difluoromethyl or trifluoromethyl (especially difluoromethyl); q is 0 or q is 1 and the R3 group is methyl; r is 0, or r is 2 and each R4 group is methyl, or r is 2 and the two R4 groups together form an ethylene group; X1 is CO; and
Q1 is amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl (such as aminomethyl, 2- phenylethyl, pyrrolidinyl or piperidinyl), and wherein any CH or CH2 group within the Q1 group optionally bears on each said CH or CH2 group a methylamino substituent, and wherein any aryl or heterocyclyl group within the Q1 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 Q1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
A further particular compound of the invention is a pyrimidine derivative of the Formula I wherein :- p is 0; R is difluoromethyl; q is O; r is 0;
X1 is COCH2NHCO; and
Q1 is heterocyclyl (such as pyrrolidinyl or piperidinyl, especially pyrrolidinyl); and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
A particular compound of the invention is, for example, a pyrimidine derivative of the Formula I that is disclosed hereinafter as Example 1 , or a pharmaceutically-acceptable salt thereof. A further particular compound of the invention is, for example, a pyrimidine derivative of the Formula I that is disclosed hereinafter as Example 2, 3, 4, 5, 6, 7, 8, 9 or 10, or a pharmaceutically-acceptable salt thereof.
A pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically- related compounds. Such processes, when used to prepare a pyrimidine derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. (a) The reaction, conveniently in the presence of a suitable base, of a pyrimidine of the Formula II
Figure imgf000054_0001
wherein p, R1, R2, q and R3, r and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a piperazine of the Formula III
Figure imgf000054_0002
III wherein r, R4, X1 and Q1 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.
Conveniently, 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 fert-butoxide, 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 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. Conveniently, the reaction is carried out in the presence of a dipolar aprotic solvent such as iVjN'-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide. Conveniently, the reaction is carried out at a temperature in the range, for example, 10 to 25O0C, preferably in the range 40 to 150°C. 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.
Specific examples of protecting groups are given below for the sake of convenience, in which "lower", as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.
A carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy- lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and
1-ethoxycarbonyloxy ethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and fert-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups (for example trimethylsilylethyl); and (2-6C)alkenyl groups (for example allyl). Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed cleavage. Examples of hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for example trimethylsilyl and fer^-butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups.
Examples of amino protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisymiethyl and furylmethyl groups; lower alkoxycarbonyl (for example fer/-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.
Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as 2-nitrobenzyloxycarbonyl. The reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents and to Protective Groups in Organic Synthesis, 2nd Edition, by T. Green et al. , also published by John Wiley & Son, for general guidance on protecting groups.
Pyrimidine starting materials of the Formula II may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter. For example, a pyrimidine of the Formula XII
Figure imgf000056_0001
XII wherein L is a displaceable group as defined hereinbefore and q and R3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted, conveniently in the presence of a suitable base as defined hereinbefore, with a benzimidazole of the Formula XI
Figure imgf000057_0001
wherein p, R1 and R2 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.
Alternatively, a pyrimidine of the Formula XIII
Figure imgf000057_0002
wherein L is a displaceable group as defined hereinbefore and p, R1 and R2 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
Figure imgf000057_0003
wherein q and R3 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. Alternatively, a pyrimidine of the Formula XVII
Figure imgf000058_0001
wherein L is a displaceable group as defined hereinbefore and p, R1, R2, q and R 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, (b) For the production of those compounds of the Formula I wherein X1 is CO, the acylation, conveniently in the presence of a suitable base, of a pyrimidine of the Formula IV
Figure imgf000058_0002
wherein p, R1, R2, q, R3, r and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a carboxylic acid of the Formula V
HO2C - QJ v
or a reactive derivative thereof, wherein Q1 has 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, triethylamine, moφholine, diisopropylethylamine, iV-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
A suitable reactive derivative of a carboxylic acid of the Formula V is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid with an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid with a chloroformate such as isoburyl chloroformate; an active ester, for example an ester formed by the reaction of the acid with a phenol such as pentafluorophenol, with an ester such as pentafluorophenyl trifluoroacetate or with an alcohol such as methanol, ethanol, isopropanol, butanol or JV-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid with an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid with a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid with a carbodiimide such as dicyclohexylcarbodiimide or with a uronium compound such as 2-(7-azabenzotriazol- 1 -yl)- 1,1,3 ,3 -tetramethyluronium hexafluorophosphate(V). 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. Conveniently, the reaction is carried out in the presence of a dipolar aprotic solvent such as iV,A/-dimethylformamide, iV,iV-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide. The reaction is conveniently carried out at a temperature in the range, for example, 0 to 1200C, preferably at or near ambient temperature.
Pyrimidine starting materials of the Formula IV may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter. For example, a pyrimidine of the Formula XIV
Figure imgf000060_0001
wherein L is a displaceable group as defined hereinbefore and p, R1, R2, r and R4 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
Figure imgf000060_0002
wherein q and R3 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.
10 Alternatively, a pyrimidine of the Formula XV
Figure imgf000060_0003
wherein L is a displaceable group as defined hereinbefore and q, R3, r and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a benzimidazole of the Formula XI
Figure imgf000060_0004
I5 XI wherein p, R1 and R2 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. As the skilled person would appreciate, the free -NH group in the heterocyclic group of the pyrimidine of the Formula XV typically would be protected by a suitable protecting group prior to reaction with the benzimidazole of the Formula XL Alternatively, a pyrimidine of the Formula XVIII
Figure imgf000061_0001
XVIII wherein L is a displaceable group as defined hereinbefore and p, R1, R3, q and R2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a piperazine of the Formula XIX
Figure imgf000061_0002
wherein r and R4 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. Alternatively, a pyrimidine of the Formula XX
)r
(R1
Figure imgf000061_0003
XX wherein p, R1, R2, q, R3, r and R4 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 in the presence of a suitable acid (such as hydrochloric acid or trifluoroacetic acid), whereafter any protecting group that is present is removed by conventional means.
It is also to be understood that compounds of the Formula I wherein X1 is a COC(R13)2θ, COC(R13)2S, COC(R13)2N(R13) or COC(R13)2N(R13)CO, wherein R13 is hydrogen or (l-8C)alkyl, may also be prepared by the acylation of a pyrimidine of the Formula IV with the appropriate carboxylic acid selected from the formulae :-
HO2C - C(R13)2O — Q1
HO2C- C(R13)2S — Q1 HO2C — C(R13)2N(R13) — Q1
HO2C — C(R13)2N(R13)CO — QJ or a reactive derivative thereof, wherein Q1 and R13 have any of the meanings defined hereinbefore except that any functional group is protected if necessary. Alternatively, a two-step procedure may be employed whereby a pyrimidine of the Formula IV is reacted with an acetic acid, or reactive derivative thereof, that is substituted at the 2-position with a leaving group as defined hereinbefore. A suitable such acetic acid derivative is, for example, 2-chloroacetyl chloride. In the second step, the product so obtained is reacted with a appropriate alcohol, thiol or amine selected from the formulae :-
HO — Q1
HS - Q1
HN(R13) - Q1 wherein Q1 and R13 have any of the meanings defined hereinbefore except that any functional group is protected if necessary. Examples of such a two-step procedure when X is a COC(RI3)2NH group are disclosed in the Examples that are set out hereinafter. (c) The reaction of a pyrimidine of the Formula VI
Figure imgf000063_0001
wherein L is a displaceable group as defined hereinbefore and p, R1, R2, r, R4, X1 and Q1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a morpholine compound of the Formula VII
Figure imgf000063_0002
wherein q and R3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means. The reaction may conveniently be carried out in the presence of a suitable acid or in the presence of a suitable base. A suitable acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, iV-rnethylmorpholine 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 N,iV-dimethylformamide, iV,iV-dimethylacetamide, iV-methylpyrrolidin-2-one or dimethylsulphoxide. The reaction is conveniently carried out at a temperature in the range, for example, 0 to 25O0C, preferably in the range 25 to 150°C.
Typically, 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 AζN-dimethylformamide or iV,JV-dimethylacetamide, conveniently in the presence of a suitable base, for example potassium carbonate or sodium hexamethyldisilazane, and at a temperature in the range, for example, 0 to 200°C, preferably in the range, for example, 25 to 15O0C.
Pyrimidine starting materials of the Formula VI may be obtained by conventional procedures analogous to those disclosed in the Examples that are set out hereinafter. For example, a pyrimidine of the Formula XIII
Figure imgf000064_0001
wherein L is a displaceable group as defined hereinbefore and p, R1 and R2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a piperazine of the Formula III
Figure imgf000064_0002
111 wherein r, R4, X1 and Q1 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.
(d) For the production of those compounds of the Formula I wherein X1 is CO and Q is a heterocyclyl group that contains an NH group, the coupling, conveniently in the presence of a suitable base as defined hereinbefore, of phosgene, or a chemical equivalent thereof, with the NH-containing heterocyclyl group where any functional group (other than the reacting NH group) is protected if necessary and with a pyrimidine of the Formula IV
Figure imgf000065_0001
wherein p, R1, R2, q, R3, r and R4 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 XVI
L - CO - L xvi wherein L is a suitable displaceable group as defined hereinbefore. For example, 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. Alternatively, 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 12O0C, preferably at or near ambient temperature.
(e) For the production of those compounds of the Formula I wherein X1 is CON(R13), the coupling, conveniently in the presence of a suitable base as defined hereinbefore, of phosgene, or a chemical equivalent thereof as defined hereinbefore, with a pyrimidine of the Formula IV
Figure imgf000065_0002
IV wherein p, R1, R2, q, R3, r and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, and with an amine of the Formula VIII
R13NH - Q1 vm
wherein R13 and Q1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 to 12O0C, preferably at or near ambient temperature. (f) For the production of those compounds of the Formula I wherein X1 is SO2, the reaction, conveniently in the presence of a suitable base, of a pyrimidine of the Formula IV
Figure imgf000066_0001
wherein p, R1, R2, q, R3, r and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a sulphonic acid of the Formula IX
HO3S - Q1 Iχ
or a reactive derivative thereof, wherein Q1 has 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 reactive derivative of a sulphonic acid of the Formula IX is, for example, a sulphonyl halide, for example a sulphonyl chloride formed by the reaction of the sulphonic acid with an inorganic acid chloride, for example thionyl chloride.
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 12O0C, preferably at or near ambient temperature. (g) The reaction of a pyrimidine of the Formula X
Figure imgf000067_0001
wherein L is a displaceable group as defined hereinbefore and q, R3, r, R4, X1 and Q1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a benzimidazole of the Formula XI
Figure imgf000067_0002
wherein p, R1 and R2 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. Conveniently, 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 tβr/-butoxide, 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 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. Conveniently, the reaction is carried out in the presence of a dipolar aprotic solvent such as N,iV-dimethylformamide, N,iV-dimethylacetamide, JV-methylpyrrolidin-2-one or dimethylsulphoxide. Conveniently, the reaction is carried out at a temperature in the range, for example 10 to 250°C, preferably in the range 40 to 1500C.
Pyrimidine starting materials of the Formula X may be obtained by conventional procedures analogous to those disclosed in the Examples that are set out hereinafter.
For example, for the production of those compounds of the Formula X wherein X1 is CO, a pyrimidine of the Formula XV
Figure imgf000068_0001
wherein L is a displaceable group as defined hereinbefore and q, R3, r and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be acylated, conveniently in the presence of a suitable base as defined hereinbefore, with a carboxylic acid of the Formula V
HO2C - Q1 v
or a reactive derivative thereof as defined hereinafter, wherein Q1 has 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 pyrimidine derivative of the Formula I may be obtained from the process variants described hereinbefore in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of the formula H-L wherein L has the meaning defined hereinbefore. When it is desired to obtain the free base from the salt, the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. When a pharmaceutically-acceptable salt of a pyrimidine derivative of the Formula I is required, 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.
When a pharmaceutically-acceptable pro-drug of a pyrimidine derivative of the Formula I is required, it may be obtained using a conventional procedure. For example, an in vivo cleavable ester of a pyrimidine derivative of the Formula I may be obtained by, for example, reaction of a compound of the Formula I containing a carboxy group with a pharmaceutically-acceptable alcohol or by reaction of a compound of the Formula I containing a hydroxy group with a pharmaceutically-acceptable carboxylic acid. For example, 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.
Many of the intermediates defined herein are novel and these are provided as a further feature of the invention. For example, compounds of the Formulae VI are novel compounds. For example, many compounds of the Formulae IV and X also are novel compounds. Biological Assays
The following assays can be used to measure the effects of the compounds of the present invention as PB kinase inhibitors, as mTOR PI kinase-related kinase inhibitors, as inhibitors in vitro of the activation of PB kinase signalling pathways, as inhibitors in vitro of the activation of PB kinase signalling pathways, as inhibitors in vitro of the proliferation of MDA-MB-468 human breast adenocarcinoma cells, and as inhibitors in vivo of the growth in nude mice of xenografts of MDA-MB-468 carcinoma tissue, (a) In Vitro PBK Enzyme Assay The assay used AlphaScreen technology (Gray et al. , Analytical Biochemistry, 2003,
313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant Type I PBK enzymes of the lipid PI(4,5)P2.
DNA fragments encoding human PBK catalytic and regulatory subunits were isolated from cDNA libraries using standard molecular biology and PCR cloning techniques. The selected DNA fragments were used to generate baculovirus expression vectors. In particular, full length DNA of each of the pi 10a, pi lOβ and pi 105 Type Ia human PBK pi 10 isoforms (EMBL Accession Nos. HSU79143, S67334, Y10055 for pl lOα, pl lOβ and pl lOδ respectively) were sub-cloned into a pDESTIO vector (Invitrogen Limited, Fountain Drive, Paisley, UK). The vector is a Gateway-adapted version of Fastbacl containing a 6-His epitope tag. A truncated form of Type Ib human PI3K pi 10γ isoform corresponding to amino acid residues 144-1102 (EMBL Accession No. X8336A) and the full length human p85α 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 p85α regulatory subunit. Following expression in the baculovirus system using standard baculovirus expression techniques, 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 Biochemistry. 2003, 3_13: 234-245). The GST-tagged Grpl PH domain was expressed and purified using standard 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 μl) 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 μM; Cell Signals Inc., Kinnear Road, Columbus, USA, Catalogue No. 901), adenosine triphosphate (ATP; 4 μM) and a buffer solution [comprising Tris-HCl pH7.6 buffer (40 mM, 10 μl), 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.
Control wells that produced a minimum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound. Control wells that produced a maximum signal corresponding to fully inhibited enzyme were created by adding wortmannin (6 μM; 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.
Each reaction was stopped by the addition of 10 μl of a mixture of EDTA (100 mM), bovine serum albumin (BSA, 0.045 %) and Tris-HCl pH7.6 buffer (40 mM). 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 run 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. Upon laser light excitation at
680 nm, the donor bead : acceptor bead complex produces a signal that can be measured.
Accordingly, PI3K enzme activity to form PI(3,4,5)P3 and subsequent competition with biotinylated PI(3,4,5)P3 results in a reduced signal. In the presence of a PI3K enzyme inhibitor, signal strength is recovered. PI3K enzyme inhibition for a given test compound was expressed as an IC50 value.
Thereby, the inhibitory properties of compounds of formula (I) against PI3K enzymes, such as the Class Ia PI3K enzymes (e.g. POKalpha, PBKbeta and PBKdelta) and the Class Ib
PI3K enzyme (PDKgamma) may be demonstrated.
(b) In Vitro mTOR PI kinase-related Kinase 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 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% CO2 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 niM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 μl) 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 μl mixture of recombinant purified mTOR enzyme, 1 μM 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-LyS-GIu-NH2; Bachem UK Ltd), ATP (20 μM) and a buffer solution [comprising Tris-HCl pH7.4 buffer (50 niM), EGTA (0.1 niM), bovine serum albumin (0.5 mg/ml), DTT (1.25 raM) and manganese chloride (10 mM)] was agitated at room temperature for 90 minutes.
Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound. Control wells that produced a minimum signal corresponding to fully inhibited enzyme were created by adding EDTA (83 mM) instead of test compound. These assay solutions were incubated for 2 hours at room temperature.
Each reaction was stopped by the addition of 10 μl 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. 9206B) and AlphaScreen Streptavidin donor and Protein A acceptor beads (200 ng; Perkin Elmer, Catalogue No. 6760002B and 6760137R respectively) were added and the assay plates were left for about 20 hours at room temperature in the dark. The resultant signals arising from laser light excitation at 680 nm were read using a Packard Envision instrument.
Phosphorylated biotinylated peptide is formed in situ as a result of mTOR mediated phosphorylation. The phosphorylated biotinylated peptide that is associated with AlphaScreen Streptavidin donor beads forms a complex with the p70 S6 Kinase (T389) 1 A5 Monoclonal Antibody that is associated with Alphascreen Protein A acceptor beads. Upon laser light excitation at 680 nm, 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 IC50 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,
Royston, Herts, SG8 6EE, UK), a plate reader that can be used to rapidly quantitate features of images generated by laser-scanning.
A MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Teddington, Middlesex, UK, Catalogue No. HTB- 132) was routinely maintained at 37°C with
5% CO2 up to a confluency of 70-90% in DMEM containing 10% FCS and 1% L-glutamine. For the assay, the cells were detached from the culture flask using 'Accutase'
(Innovative Cell Technologies Inc., San Diego, CA, USA; Catalogue No. AT104) using standard tissue culture methods and resuspended in media to give 5.5x104 cells per ml. Aliquots (90 μl) 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.
Aliquots (90 μl) of culture media were placed in the outer wells to prevent edge effects. [An alternative cell handling procedure involved the maintenance of the cells in a 'SelecT' robotic device (The Automation Partnership, Royston, Herts SG8 5WY, UK). Cells were resuspended in media to give 5 xlO4 cells per ml. Aliquots (100 μl) were seeded into the wells of a black
'Costar' 96-well plate.] The cells were incubated overnight at 37°C with 5% CO2 to allow them to adhere.
On day 2, the cells were treated with test compounds. Test compounds were prepared as
10 niM 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 μl) 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 μM 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 μl) of each compound were dispensed into one well of a quadrant of wells within a 384-well plate (Labcyte Inc., Catalogue No. P-05525-CV1). Four concentrations of each compound were prepared in each quadrant of wells in the 384-well plate using a 'Hydra IF pipettor (Matrix Technologies Corporation, Handforth SK9 3LP, UK). Using a 'Quadra Tower' liquid pipetting system (Tomtec Inc., Hamden, CT 06514, USA) and the 'Echo 550' liquid dispenser, the required concentration of each compound was placed in specific wells in duplicate.] The treated cells were incubated for 2 hours at 370C with 5% CO2.
Following incubation, the contents of the plates were fixed by treatment with a 1.6% aqueous formaldehyde solution (Sigma, Poole, Dorset, UK, Catalogue No. F 1635) at room temperature for 30 minutes.
All subsequent aspiration and washing steps were carried out using a Tecan 96-well plate washer (aspiration speed 10 mm/sec). The fixing solution was removed and the contents of the plates were washed with phosphate-buffered saline (PBS; 50 μl; such as that available from Gibco, Catalogue No. 10010015). The contents of the plates were treated at room temperature for 1 hour with an aliquot (50 μl) of a cell permeabilisation/blocking buffer consisting of a mixture of PBS, 0.5% Tween-20 and 5% dried skimmed milk ['Marvel' (registered trade mark); Premier Beverages, Stafford, GB]. 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°C with rabbit anti-phospho-Akt (Ser473) antibody solution (50 μl 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. Subsequently, cells were incubated for 1 hour at 4°C with Alexafluor488 labelled goat anti-rabbit IgG (50 μl per well; Molecular Probes, Invitrogen Limited, Paisley, UK, Catalogue No. Al 1008) that had been diluted 1 :500 in 'blocking' buffer. Cells were washed 3 times with a mixture of PBS and 0.05% Tween-20. An aliquot of PBS containing 1.6% aqueous formaldehyde (50 μl) was added to each well. After 15 minutes, the formaldehyde was removed and each of the wells was washed with PBS (100 μl). An aliquot of PBS (50 μl) was added to each well and the plates were sealed with black plate sealers and the fluorescence signal was detected and analysed. Fluorescence dose response data obtained with each compound were analysed and the degree of inhibition of Serine 473 in Akt was expressed as an IC50 value, (d) In Vitro MDA-MB-468 human breast adenocarcinoma Proliferation Assay
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.
For the proliferation assay, the cells were detached from the culture flask using 'Accutase' and, at a density of 4000 cells per well in 100 μl of complete growth medium, the cells were placed in wells in a 'Costar' 96-well tissue culture-treated plate (Corning Inc., Catalogue No. 3598). Aliquots (100 μl) per well of growth medium were added to some wells to provide blank values for the colorometric measurement. The cells were incubated overnight at 37°C with 5% CO2 to allow them to adhere. Sufficient phenazine ethosulphate (PES, Sigma Catalogue No. P4544) was added to a
1.9 mg/ml solution of 3-(4, 5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)- 2-(4-sulphophenyl)-2i/-tetrazolium salt (MTS; Promega UK, Southampton SO16 7NS, UK; Catalogue No. Gl 111) to give a 0.3 mM PES solution. An aliquot (20 μl) of the resultant MTS/PES solution was added to each well of one plate. The cells were incubated for 2 hours at 370C with 5% CO2 and the optical density was measured on a plate reader using a wavelength of 492nm. The relative cell number at the commencement of the assay was thereby measured.
Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted with growth medium to give a range of test concentrations. An aliquot (50 μl) of each compound dilution was placed in a well in the 96-well plates. Each plate contained control wells without test compound. With the exception of wells containing the plate blanks, the outer wells on each 96-well plate were not used. The cells were incubated for 72 hours at 370C with 5% CO2. An aliquot (30 μl) of the MTS/PES solution was added to each well and the cells were incubated for 2 hours at 370C with 5% CO2. The optical density was measured on a plate reader using a wavelength of 492nm.
Dose response data were obtained for each test compound and the degree of inhibition of MDA-MB-468 cell growth was expressed as an ICs0 value. (e) In Vivo MDA-MB-468 Xenograft Growth Assay
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 106 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.
Although the pharmacological properties of the compounds of the Formula I vary with structural change as expected, in general activity possessed by compounds of the Formula I, may be demonstrated at the following concentrations or doses in one or more of the above tests (a), (b), (c), (d) and (e) :- Test (a):- IC50 versus pi 1 Oa Type Ia human PI3K in the range, for example,
0.01 - 5 μM; Test (b):- IC50 versus mTOR PI kinase-related kinase in the range, for example,
0.1 - 10 μM;
Test (c):- IC50 in the range, for example, 0.01 - 5 μM; Test (d):- IC50 in the range, for example, 0.05 - 20 μM;
Test (e):- activity in the range, for example, 1-200 mg/kg/day.
For example, the pyrimidine compound disclosed within Example 1 possesses activity in Test (a) with an IC50 versus pi 10a Type Ia human PI3K of approximately 0.4 μM, and in Test (c) with an ICs0 of approximately 0.1 μM. For example, the pyrimidine compound disclosed within Example 4 possesses activity in Test (a) with an IC50 versus pi 10a Type Ia human PI3K of approximately 1.2 μM, and in Test (c) with an IC50 of approximately 0.2 μM.
No untoward toxicological effects are expected when a compound of Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore is administered at the dosage ranges defined hereinafter. According to a further aspect of the invention there is provided 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.
The 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).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, 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. For example, 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.
In using a compound of the Formula I for therapeutic or prophylactic purposes it will generally be administered so that 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. In general, lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 1 mg/kg to 25 mg/kg body weight will generally be used. Similarly, for administration by inhalation, 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. Typically, unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention.
As stated above, it is known that PBK enzymes contribute to tumourigenesis by one or more of the effects of mediating proliferation of cancer and other cells, mediating angiogenic events and mediating the motility, migration and invasiveness of cancer cells. We have found that 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 rumour cells and the invasiveness and migratory ability of metastasising tumour cells.
Accordingly, 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. Particularly, 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. Particularly, 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 PI3K enzymes and the Class Ib PI3K enzyme, i.e. the compounds may be used to produce a PI3K enzyme inhibitory effect in a warm-blooded animal in need of such treatment.
As stated hereinbefore, inhibitors of PI3K enzymes should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias [including acute lymphoctic leukaemia (ALL) and chronic myelogenous leukaemia (CML)], multiple myeloma and lymphomas.
According to a further aspect of the invention there is provided 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.
According to a further aspect of the invention, there is provided a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in the production of an antiproliferative effect in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is provided a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore 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.
According to a further feature of this aspect of the invention, there is provided the use of 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.
According to a further feature of this aspect of the invention there is provided the use of 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.
According to a further feature of this aspect of the invention there is provided the use of 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. According to a further feature of this aspect of the invention there is provided the use of a pyrimidine derivative of the Formula I5 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. According to a further feature of this aspect of the invention there is provided 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.
According to a further feature of this aspect of the invention there is provided 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.
According to a further aspect of the invention there is provided the use of 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.
According to a further feature of this aspect of the invention there is provided 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.
According to a further feature of this aspect of the invention there is provided a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is provided the use of a pyrimidine derivative of the Formula I, 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. According to a further aspect of the invention there is provided a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in the prevention or treatment of those tumours which are sensitive to inhibition of PB K enzymes (such as the Class Ia enzymes and/or the Class Ib PBK enzyme) and/or a mTOR kinase (such as a mTOR PI kinase-related kinase) that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells. According to a further feature of this aspect of the invention there is provided the use of 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 those tumours which are sensitive to inhibition of PI3K 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 signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
According to a further feature of this aspect of the invention there is provided a method for the prevention or treatment of those tumours which are sensitive to inhibition of PBK 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 signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells 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.
According to a further feature of this aspect of the invention there is provided the use of 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 signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
According to a further aspect of the invention there is provided a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in providing a PDK enzyme inhibitory effect (such as a Class Ia PDK enzyme or Class Ib PDK enzyme inhibitory effect) and/or a mTOR kinase inhibitory effect (such as a mTOR PI kinase-related kinase inhibitory effect).
According to a further feature of this aspect of the invention there is provided the use of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a PDK enzyme inhibitory effect (such as a Class Ia PDK enzyme or Class Ib PDK enzyme inhibitory effect) and/or a mTOR kinase inhibitory effect (such as a mTOR PI kinase-related kinase inhibitory effect).
According to a further feature of this aspect of the invention there is also provided a method for providing a PBK enzyme inhibitory effect (such as a Class Ia PBK 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.
According to a further feature of this aspect of the invention there is provided the use of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for providing a PBK enzyme inhibitory effect (such as a Class Ia PBK enzyme or Class Ib PBK enzyme inhibitory effect) and/or a mTOR kinase inhibitory effect (such as a mTOR PI kinase-related kinase inhibitory effect).
As stated hereinbefore, certain compounds of the present invention possess substantially better potency against Class Ia PBK enzymes or against the Class Ib PBK enzyme than against EGF receptor tyrosine kinase, VEGF receptor tyrosine kinase or Src non-receptor tyrosine kinase enzymes. Such compounds possess sufficient potency against Class Ia PBK enzymes or the Class Ib PBK enzyme that they may be used in an amount sufficient to inhibit PBK enzymes whilst demonstrating little activity against EGF receptor tyrosine kinase, VEGF receptor tyrosine kinase or Src non-receptor tyrosine kinase enzymes. Such compounds are likely to be useful for the selective inhibition of PBK enzymes and are likely to be useful for the effective treatment of, for example Class Ia PBK enzyme driven tumours.
According to this aspect of the invention there is provided a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in providing a selective PBK enzyme inhibitory effect.
According to a further feature of this aspect of the invention there is provided the use of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a selective PBK enzyme inhibitory effect. According to a further feature of this aspect of the invention there is also provided a method for providing a selective PBK 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.
According to a further feature of this aspect of the invention there is provided the use of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for providing a selective PB K enzyme inhibitory effect.
By "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. In particular, 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. For example 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.
According to a further feature of the invention there is provided a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore 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.
According to a further feature of this aspect of the invention there is provided a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in the treatment 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.
According to a further feature of this aspect of the invention there is provided the use of 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.
According to a further feature of this aspect of the invention there is provided the use of 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 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.
According to a further feature of this aspect of the invention there is provided 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.
According to a further feature of this aspect of the invention there is provided 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.
According to a further feature of this aspect of the invention there is provided the use of a pyrimidine derivative of the Formula I5 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. According to a further feature of this aspect of the invention there is provided the use of a pyrimidine derivative of the Formula I5 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. As stated hereinbefore, the in vivo effects of a compound of the Formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula I.
The anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the pyrimidine derivative of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents :- (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine, taxoids like taxol and taxotere, and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(ii) 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 5α-reductase such as finasteride;
(iii) 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];
(iv) 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 factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib (ZDl 839), erlotinib (OSI-774) and CI 1033, and erbB2 tyrosine kinase inhibitors such as lapatinib), inhibitors of the hepatocyte growth factor family, inhibitors of the insulin growth factor receptor, inhibitors of the platelet-derived growth factor family and/or bcr/abl kinase such as imatinib, dasatinib (BMS-354825) and nilotinib (AMNl 07), inhibitors of cell signalling through MEK, AKT, PI3, c-kit, and/or aurora kinases]; such inhibitors also include cyclin dependent kinase inhibitors including CDK2 and CDK4 inhibitors; and such inhibitors also include, for example, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (Rl 15777) and lonafarnib (SCH66336); (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SUl 1248) and 4-(4-fluoro-2-methylindol-5-yloxy)- 6-methoxy-7-(3-pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin)];
(vi) 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; (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) 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
(ix) 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.
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. According to this aspect of the invention there is provided 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.
Although 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 will now be illustrated in the following Examples in which, generally : (i) operations were 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;
(ii) reactions conducted under microwave radiation were 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;
(iii) in general, the course of reactions was followed by thin layer chromatography (TLC) and/or analytical high pressure liquid chromatography (HPLC); the reaction times that are given are not necessarily the minimum attainable; (iv) when necessary, organic solutions were dried over anhydrous magnesium sulphate, work-up procedures were carried out after removal of residual solids by filtration, evaporations
1 were carried out by rotary evaporation in vacuo;
(v) yields, where present, are not necessarily the maximum attainable, and, when necessary, reactions were repeated if a larger amount of the reaction product was required; (vi) in general, the structures of the end-products of the Formula I were 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;
(vii) unless stated otherwise compounds containing an asymmetric carbon and/or sulphur atom were not resolved; (viii) intermediates were not necessarily fully purified but their structures and purity were assessed by TLC, analytical HPLC, infra-red (IR) and/or NMR analysis;
(ix) unless otherwise stated, column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica
(Art. 9385); (x) preparative HPLC was performed on Cl 8 reversed-phase silica, for example on a
Waters 'Xterra' preparative reversed-phase column (5 microns silica, 19 mm diameter,
100 mm length) using decreasingly polar mixtures as eluent, for example decreasingly polar mixtures of water (containing 1% acetic acid or 1% aqueous ammonium hydroxide (d=0.88) and acetonitrile; (xi) analytical HPLC methods selected from those listed below were used; in general, reversed-phase silica was used with a flow rate of about ImI per minute and detection was by
Electrospray Mass Spectrometry and by UV absorbance using a diode array detector over a wavelength of 220 to 300 nm; for each method Solvent A: was water and Solvent B was acetonitrile :- Method Al : Phenomenex Synergi MAX-RP 8θA column (4 microns silica, 2.1 mm diameter, 50 mm length) using a Solvent C comprising 0.1% aqueous ammonium hydroxide
(d=0.88) in deionised water and a solvent gradient over 4 minutes from a 90:5:5 mixture of
Solvents A, B and C respectively to a 95:5 mixture of Solvents B and C;
Method A2 : Phenomenex 'Gemini' RP 1 IOA column (5 microns silica, 2 mm diameter, 50 mm length) using a Solvent C comprising 0.1% aqueous ammonium hydroxide
(d=0.88)) and a solvent gradient over 4 minutes from a 5:95 mixture of Solvents B and C to a
95:5 mixture of Solvents B and C;
Method Bl : Phenomenex Synergi MAX-RP 8θA column (4 microns silica, 2.1 mm diameter, 50 mm length) using a Solvent C comprising a 1:1 mixture of water and acetonitrile (the mixture containing 1% formic acid) and a solvent gradient over 4 minutes from a 90:5:5 mixture of Solvents A, B and C respectively to a 95:5 mixture of Solvents B and C; Method B2 : Phenomenex Synergi MAX-RP 8θA 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; 5 (xii) where certain compounds were obtained as an acid-addition salt, for example a mono-hydrochloiϊde salt or a di-hydrochloride salt, the stoichiometry of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the salt was generally not determined, for example by means of elemental analysis data;
(xiii) one or more of the following abbreviations have been used : - io DMSO dimethylsulphoxide
THF tetrahydrofuran DMF Aζ,N-dimethylformamide DMA iV,iV-dimethylacetamide NMP iV-methylpyrrolidin-2-one
I5
Example 1
4-(2-difluoromethylbenzimidazol-l-yI)-6-(4-glycylpiperazin-l-yl)-
2-morphoIinopyrimidine
A mixture of 6-chloro-4-(2-difluoromethylbenzimidazol-l-yl)-2-morpholinopyrimidine 20 (0.081 g), l-(N-tert-butoxycarbonylglycyl)piperazine (0.081 g), sodium bicarbonate (0.093 g) and DMF (1 ml) was heated to 110°C under nitrogen in a sealed vessel in a microwave oven for 25 minutes. The reaction mixture was cooled to ambient temperature. Ethyl acetate (5 ml) was added and the mixture was washed with water, dried over magnesium sulphate and evaporated. The reaction product was purified by column chromatography on silica using 25 increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 6- [4-(iV-fert-butόxycarbonylgly cyl)piperazin- 1 -yl] -4-(2-difluoromethylbenzimidazol- l-yl)-2-morpholinopyrimidine (0.1 g); ΝMR Spectrum: (DMSOd6) 1.4 (s, 9H), 3.18 (d, 2H), 3.58 (s, 4H), 3.66-3.71 (m, 10H), 3.86 (d, 2H), 6.46 (s, IH), 6.77 (t, IH), 7.41-7.49 (m, 2H), 7.54 (t, IH), 7.77 (d, IH), 7.86 (d, IH).
30 A mixture of the material so obtained, trifluoroacetic acid (0.5 ml) and methylene chloride (1.5 ml) was stirred at ambient temperature for 25 minutes. An aqueous sodium carbonate solution (IM, 5 ml) was added dropwise, followed by methanol (0.5 ml). The layers were separated and the aqueous solution was washed with methylene chloride (5 ml). The combined organic solutions were dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of a 1.75 M methanolic ammonia solution and methylene chloride as eluent. There was thus obtained the title compound as a solid (0.058 g); NMR Spectrum: (DMSOd6) 3.4 (s, 2H), 3.52 (s, 2H), 3.61 (s, 2H), 3.66-3.71 (m, 12H), 6.45 (s, IH), 7.42-7.48 (m, 2H), 7.54 (t, IH), 7.78 (d, IH), 7.87 (d, IH); Mass Spectrum: M+H+ 473.
The 6-chloro-4-(2-difluoromethylbenzimidazol-l-yl)-2-morpholinopyrimidine used as a starting material was prepared as follows :- Under an atmosphere of nitrogen, a solution of morpholine (13.06 ml) in methylene chloride (100 ml) was added dropwise over 15 minutes to a stirred mixture of 2,4,6-trichloropyrimidine (27.52 g), triethylamine (22.1 ml) and methylene chloride (200 ml) that was cooled to a temperature between 5°C and 150C. The resultant mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The mixture was washed with an aqueous brine solution. The organic solution was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasing proportions of ethyl acetate added to a 1 :1 mixture of isohexane and methylene chloride as eluent. There was thus obtained 4,6-dichloro-2-morpholinopyrimidine (6.82 g); NMR Spectrum: (DMSOd6) 3.64-3.71 (m, 8H), 6.97 (s, IH); Mass Spectrum: M+H+ 234. A mixture of 2-difluoromethyl-lH-benzimidazole (0.168 g), 4,6-dichloro-
2-morpholinopyrimidine (0.233 g), sodium bicarbonate (0.168 g) and DMA (5 ml) was stirred under nitrogen and heated to 9O0C for 20 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate in methylene chloride as eluent. The solid so obtained was washed with a 1 : 1 mixture of isohexane and diethyl ether. There was thus obtained 6-chloro-4-(2-difluoromethylbenzimidazol- 1 -yl)-2-morpholinopyrimidine (0.075 g); NMR Spectrum: (DMSOd6) 3.7 (m, 4H), 3.78 (m, 4H), 7.2 (s, IH), 7.39-7.72 (m, 3H), 7.84 (d, IH), 7.9 (d, IH); Mass Spectrum: M+H+ 366.
The l-(iV-tert-butoxycarbonylglycyl)piperazine used as a starting material was prepared as follows :-
A
Figure imgf000090_0001
(2.45 g), 2-(7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (V) (5.31 g) and DMA (60 ml) was stirred at ambient temperature for 20 minutes. Piperazine (3 g) was added and the resultant solution was stirred at ambient temperature for 17 hours. The reaction mixture was evaporated and the residue was dissolved in acetonitrile (35 ml). A 7M solution of ammonia in methanol (20 ml) was added. The resultant mixture was filtered to remove a precipitate and the filtrate was evaporated to give an oil which was purified by column chromatography on silica using a 5 : 1 mixture of methylene chloride and methanol as eluent. There was thus obtained l-(Λ/-tert-butoxycarbonylglycyl)piperazine (2.23 g); NMR Spectrum: (DMSOd6) 1.4 (s, 9H), 3.06 (d, 4H), 3.6 (s, 4H), 3.83 (d, 2H), 6.8 (t, IH), 8.35 (s, IH); Mass Spectrum: M+H+ 244. The 2-difluoromethyl-lH-benzimidazole used as a starting material was prepared as follows :-
A mixture of 1 ,2-phenylenediamine (54.1 g), ethyl difluoroacetate (57.8 ml) and toluene (350 ml) was stirred under an atmosphere of nitrogen and heated to 87°C for 41 hours. The resultant mixture was filtered whilst hot. The filtrate was evaporated. A mixture of methylene chloride (200 ml) and THF (200 ml) was added to the residue and the solution was purified by filtration through silica (30 g). Evaporation of the solvent gave a solid which was washed with a 2:1 mixture of isohexane and methylene chloride. There was thus obtained 2-difluoromethyl-lH-benzimidazole (64.8 g); NMR Spectrum: (DMSOd6) 7.28 (t, IH), 7.29-7.34 (m, 2H), 7.66-7.68 (m, 2H), 13.3 (s, IH); Mass Spectrum: M+H* 169.
Example 2
2-Amino-l-[4-[2-morpholin-4-yl-6-[2-(trifluoromethyl)benzoimidazol-l-yl]pyrimidin-4- yl]piperazin-l-yl]ethanone
A mixture of l-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-2- (trifluoromethyl)benzoimidazole (0.100 g), fert-butyl N-(2-oxo-2-piperazin-l-yl- ethyl)carbamate (0.071 g) and sodium bicarbonate (0.158 g) in dry dimethylformamide (3.0 ml) was stirred and heated under nitrogen at 9O0C for 6 hours. The resultant reaction mixture was concentrated and the residue dissolved in water and ethyl acetate and the layers partitioned and separated. The organic extract was washed with l.OM phosphate buffer (pH 5), water and saturated sodium chloride and then dried with anhydrous sodium sulphate, filtered and evaporated. The residue was dissolved and stirred in dichloromethane (3.0 ml). Trifluoroacetic acid (1.0 m) was then added and the solution stirred at ambient temperature for 3 hours. The resultant reaction mixture was diluted with more dichloromethane and the solution loaded onto an Isolute SCX-3 cation exchange cartridge (1O g, International Sorbent Technology Limited, Mid Glamorgan, UK) pre-equilibrated with methanol. The column was washed with methanol, then with 2.0M ammonia/Methanol to elute the product. The crude, product was purified by HPLC using a "Xbridge" preparative reverse- phase column (5
5 microns silica, 19mm diameter, 100mm length) using decreasingly polar mixtures of of water [containing 1% aqueous ammonium hydroxide (density 0.88 )] and aceonitile as eluent. There was thus obtained the title compound as a solid (0.070 g); NMR Spectrum: (DMSOd6) 3.53 (s, 2H), 3.55 (m, 14H), 6.5 (s, IH), 7.5 (m, 2H), 7.7 (d, IH), 7.93 (d, IH); Mass spectrum: M+H+ 491. io The 1 -(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-2-(trifluoromethyl)benzoimidazole used as a starting material was prepared as follows :-
A mixture of 4,6-dichloro-2-morpholin-4-yl-pyrimidine (2.8 g), 1,2-phenylenediamine (2.59 g) in dry dimethylacetamide (36 ml) was stirred and heated under nitrogen at 1000C for 18 hours. The resultant mixture was evaporated and the residue dissolved in water and ethyl
I5 acetate and the layers partitioned and separated. The organic extract was washed with water (twice), saturated sodium chloride and then dried with anhydrous sodium sulphate, filtered and evaporated. The crude product was purified by column chromatography using a gradient of 100% dichloromethane to 50% ethylacetate/dichloromethane as eluent. There was thus obtained N'-(6-chloro-2-moφholin-4-yl-pyrimidin-4-yl)benzene-l,2-diamine (2.2Ig); NMR
20 Spectrum: (DMSOdfi) 3.6 (s, 8H), 4.9 (s, 2H), 5.73 (s, IH), 6.58 (t, IH), 6.77 (d, IH), 6.95 (t, IH), 7.13 (d, IH), 8.57 (s, IH); Mass spectrum: M+H+ 306.
A stirred solution of N'-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)benzene-l,2- diamine (2.2 g) in dry pyridine (50 mL) at 0°C was treated with trifluoroacetic anhydride (1.1 ml). The resultant reaction mixture was stirred at 0°C for 10 minutes and then at ambient
25 temperature for 18 hours. Water (0.5 ml) was added and the solution evaporated. The residue was treated with distilled water and the resultant solid filtered, washed with water and dried. There was thus obtained N- [2- [(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)amino]pheny I]- 2,2,2-trifluoro-acetamide (2.62g); NMR Spectrum: (DMSOd6) 3.6 (s, 8H), 6.05 (s, IH), 7.23 (t, IH), 7.44 (d, IH), 7.65 (d, IH), 9.03 (s, IH), 10.7 (s, IH); Mass spectrum: M+H+402.
30 A solution of N-[2-[(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)amino]phenyl]-2,2,2- trifluoro-acetamide (2.62 g) in a mixture of 4M hydrogen chloride in dioxane (16 ml) and dioxane (34 ml) was stirred and heated at 1000C for 18 hours. A further portion of 4M hydrogen chloride in dioxane (16 ml) was added and the resultant reaction mixture stirred and heated at 100°C for 18 hours. The reaction mixture was then evaporated and the residue suspended in distilled water and excess saturated sodium bicarbonate added. Ethyl acetate was then added and the layers partitioned and separated. The organic extract was washed with distilled water, saturated sodium chloride and then dried with anhydrous sodium sulphate, filtered and evaporated. The crude product was purified by column chromatography using a gradient of 100% dichloromethane to 20% ethyl acetate/dichloromethane as eluent. There was thus obtained l-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-2- (trifluoromethyl)benzoimidazole (1.19 g); H NMR Spectrum: (DMSOd6) 3.7 (s, 4H), 3.77 (s, 4H), 7.26 (s, IH), 7.53 (t, IH), 7.58 (t, IH), 7.77 (d, IH), 7.98 (d, IH); Mass spectrum: M+H+ 384.
Example 3
(2S)-N-[2-[4-[6-[2-(difluoromethyl)benzoimidazol-l-yl]-2-morphoIin-4-yl-pyrimidin-4- yI]piperazin-l-yl]-2-oxo-ethyl]pyrrolidine-2-carboxamide
A mixture of 2- [[(2S)- 1 - [(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2- carbonyl]amino]acetic acid (0.109 g), 2-(7-Azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (0.153 g), triethylamine (0.168 ml) and DMF (0.55 ml) was shaken at ambient temperature for 15 minutes. A mixture of 2-(difluoromethyl)-l-(2-morpholin-4-yl-6- piperazin-l-yl-pyrimidin-4-yl)benzoimidazole (0.104 g) and DMF (0.5ml) was added and the resultant reaction mixture was shaken at ambient temperature for 18 hours. The resultant mixture was then evaporated and the residue was taken into dichloromethane (1 ml) and trifluoroacetic acid (1 ml), stirred at ambient temperature for 1 hour, and evaporated. The residue was dissolved in methanol (5 ml), filtered and added to an Isolute SCX-3 cation exchange cartridge (5 g), followed by methanol (30 ml). The product was then eluted by addition of a 7M solution of ammonia in methanol (15 ml) and after evaporation was further purified by HPLC using a Waters "Xbridge" preparative reversed-phase column (5 microns silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water [containing 1% aqueous ammonium hydroxide (d=0.88)] and acetonitrile as eluent. There was thus obtained the title compound as a gum (0.091 g); NMR Spectrum: (DMSOd6) 1.58-1.62 (m, 2H), 1.68-1.74 (m, IH), 1.93-1.96 (m, IH), 2.74-2.80 (m, IH), 2.87-2.93 (m, IH), 3.57- 3.60 (m, 5H), 3.67-3.72 (m, 10H), 3.75 (s, 2H), 4.02-4.04 (m, 2H), 6.45 (s, IH), 7.41-7.50 (m, 2H), 7.54 (t, IH), 7.78 (d, IH), 7.87 (d, IH), 8.21 (t, IH). Mass Spectrum: M+H+ 570.
The 2-(difluoromethyl)- 1 -(2-moipholin-4-yl-6-piperazin- 1 -yl-pyrimidin-4- yl)benzoimidazole used as a starting material was prepared as follows :- A mixture of l-(6-chloro-2-morpholm-4-yl-pyrimidin-4-yl)-2-
(difluoromethyl)benzoimidazole (0.48 g), piperazine (1.10 g), sodium bicarbonate (0.72 g) and DMF (10 ml) was heated to 14O0C for 1 minute, cooled and diluted with water (30ml). The mixture was washed twice with ethyl acetate (30 ml; 150 ml) and the combined organic solution washed with water (4 x 10 ml) and brine (10 ml), dried over magnesium sulphate and evaporated. The residue was taken into THF and evaporated onto silica (3 g) before purification by chromatography on silica eluting with increasing amounts of a 10:1 mixture of methanol and aqueous ammonia [d=0.88] in dichloromethane. There was thus obtained (2S)- N-[2-[4-[6-[2-(difluoromethyl)benzoimidazol-l-yl]-2-morpholin-4-yl-pyrimidin-4- yl]piperazin-l-yl]-2-oxo-ethyl]pyrrolidine-2-carboxamide (0.552 g); NMR Spectrum: (DMSOd6) 2.77 (t, 4H), 3.59-3.67 (m, 12H), 6.38 (s, IH), 7.41-7.49 (m, 2H), 7.53 (t, IH), 7.75 (d, IH), 7.86 (d, IH). Mass Spectrum: M+H+ 416.
Examples 4 to 6
Using analogous procedures to those described in Example 3, 2-(difluoromethyl)-l-(2- morpholin-4-yl-6-piperazin-l -yl-pyrimidin-4-yl)benzoimidazole (0.104 g) was reacted with the appropriate JV-tert-butoxycarbonyl protected carboxylic acid and the N-fert-butoxycarbonyl group subsequently removed by treatment with trifluoroacetic acid as described within Example 3 to give the compounds described in Table I.
Each required carboxylic acid was commercially available. The products were purified using a Waters 'Xbridge' preparative reversed-phase column
(5 microns silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water [containing 1% aqueous ammonium hydroxide (d=0.88)] and acetonitrile as eluent, except for Example 6 for which an 'Xterra' column was used. Table I
Figure imgf000095_0001
Figure imgf000095_0002
Notes After amide formation and removal of the protecting group, the products gave the characterising data shown below.
[1] [4-[6-[2-(difluoromethyl)benzoimidazol-l-yl]-2-morpholin-4-yl-pyrimidin-4- yl]piperazin-l-yl]-[(2S)-2-piperidyl]methanone
(2S)-l-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-2-carboxylic acid was used as the required carboxylic acid. NMR Spectrum: (DMSOd6) 1.26- 1.32 (m, 2H), 1.42- 1.51 (m, 2H), 1.62-1.65 (m, IH), 1.82 (m, IH), 2.55 (m, 2H), 2.98 (m, IH), 3.54-3.58 (m, 2H), 3.62- 3.67 (s, 7H), 3.71 (s, 7H), 6.44 (s, IH), 7.41-7.49 (m, 2H), 7.54 (t, IH), 7.77-7.79 (m, IH), 7.86-7.88 (m, IH). Mass Spectrum: M+H+ 527.
[2] (2R)-l-[4-[6-[2-(difluoromethyl)benzoimidazol-l-yl]-2-morpholin-4-yl-pyrimidin- 4-yl]piperazin-l-yI]-2-methylamino-3-phenyl-propan-l-one
(2R)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-phenyl-propanoic acid was used as the required carboxylic acid. NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.77 (m, IH), 2.80 (m, IH), 3.54-3.68 (m, 15H), 3.79 (t, 2H), 6.38 (s, IH), 7.18-7.28 (m, 5H), 7.42-7.48 (m, 2H), 7.53 (t, IH)5 7.76 (d, IH), 7.87 (d, IH). Mass Spectrum: M+H+ 577. [3] [4-[6-[2-(difluoromethyl)benzoimidazol-l-yl]-2-morpholin-4-yl-pyrimidin-4- yl] piperazin-1-yl] -[(2S)-pyrrolidin-2-yl] methanone
(2S)-l-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid was used as the required carboxylic acid. NMR Spectrum: (DMSOd6) 1.55-1.72 (m, 3H), 1.99-2.03 (m, 5 IH), 2.62-2.68 (m, IH), 2.97-3.01 (m, IH), 3.60-3.75 (m, 16H), 3.85-3.89 (m, IH), 6.46 (s, IH), 7.40-7.50 (m, 2H), 7.54 (t, IH), 7.78 (d, IH), 7.87 (d, IH). Mass Spectrum: M+Y? 513.
Example 7
2-amino-l-[3-[6-[2-(difluoromethyI)benzoimidazol-l-yl]-2-morphoIin-4-yl-pyrimidin-4- i o yl] -3,8-diazabicy do [3.2.1] oct-8-yl] ethanone l-[6-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-morpholin-4-yl-pyrimidin-4-yl]-2- (difluoromethyl)benzoimidazole (0.133 g) was added to a stirred mixture of N-fert- butoxycarbonylglycine (0.079 g), 2-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (0.172 g), triethylamine (0.189 ml) and DMF (1.5 ml) and the resultant is reaction mixture was stirred at ambient temperature under nitrogen for 18 hours. The resultant reaction mixture was then evaporated and the residue was taken into dichloromethane (1.0 ml) and trifluoroacetic acid (1.0 ml) and the resultant mixture was stirred at ambient temperature for 30 minutes. IM aqueous sodium carbonate (5 ml) was added dropwise, followed by methanol (0.5 ml). The layers were separated and the organic layer was washed twice with
20 dichloromethane (5 ml), dried over magnesium sulfate and evaporated. The residue was dissolved in methanol (5 ml), filtered and added to an Isolute SCX-3 cation exchange cartridge (5 g), followed by methanol (30 ml). The product was then eluted by addition of a 7M solution of ammonia in methanol (10 ml) and after evaporation was further purified by HPLC using a Waters "Xterra" preparative reversed-phase column (5 microns silica, 19 mm
25 diameter, 100 mm length) using decreasingly polar mixtures of water [containing 1% aqueous ammonium hydroxide (d=0.88)] and acetonitrile as eluent. There was thus obtained the title compound as a gum (0.056 g); NMR Spectrum: (DMSOd6) 1.63-1.85 (m, 3H), 1.95 (m, IH), 3.02-3.44 (m, 6H), 3.67-3.69 (m, 8H), 4.40 (m, IH), 4.64 (m, IH), 6.37 (s, IH), 7.40-7.49 (m, 2H), 7.54 (t, IH), 7.78 (d, IH), 7.86 (d, IH). Mass Spectrum: M+H+ 499.
30 The l-[6-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-morpholin-4-yl-pyrimidin-4-yl]-2-
(difluoromethyl)benzoimidazole used as a starting material was prepared as follows:- A mixture of l-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-2- (difluoromethyl)benzoimidazole (0.147 g), tert-bvάyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.090 g), sodium bicarbonate (0.222 g) and DMF (2 ml) was heated under nitrogen to 90°C for 15 minutes and then at 105°C for 1 hour. The resultant mixture was cooled, filtered and evaporated. The residue was taken into dichloromethane (1.0 ml) and trifluoroacetic acid (1.0 ml), shaken at ambient temperature for 1 hour and evaporated. The residue was dissolved in methanol (5 ml), filtered and added to an Isolute SCX-3 cation exchange cartridge (5 g), followed by methanol (30 ml). The product was then eluted by addition of a 7M solution of ammonia in methanol (10 ml) and the eluent evaporated. There was thus obtained l-[6-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-morpholin-4-yl-pyrimidin-4-yl]-2- (difluoromethyl)benzoimidazole (0.15Og); Mass Spectrum: M+H+ 422. HPLC: method Al, Retention Time 2.11 minutes.
Example 8 2-amino-l-[(2S,6R)-4-[6-[2-(difluoromethyl)benzoimidazol-l-yl]-2-morpholin-4-yl- pyrimidin-4-yI]-2,6-dimethyl-piperazin-l-yl]ethanone
Using an analogous procedure to that described in Example 7, 2-(difluoromethyl)-l-[6- [(3S,5R)-3,5-dimethylpiperazin-l-yl]-2-morpholin-4-yl-pyrimidin-4-yl]benzoimidazole (0.147 g) was reacted with N-tert-butoxycarbonylglycine followed by deprotection with trifluoroacetic acid. There was thus obtained the title compound (0.062 g); NMR Spectrum: (DMSOd6) 1.23 (m, 6H), 3.20-3.35 (m, 6H), 3.67-3.69 (m, 8H)5 4.40 (m, IH)5 4.55 (m, IH), 6.54 (s, IH), 7.41-7.49 (m, 2H), 7.54 (t, IH), 7.71 (d, IH), 7.86 (d, IH). Mass Spectrum: M+H+ 501.
The 2-(difluoromethyl)-l-[6-[(3S,5R)-3,5-dimethylpiperazin-l-yl]-2-morpholin-4-yl- pyrimidin-4-yl]benzoimidazole used as a starting material was prepared as follows :-
A mixture of l-(6-chloro-2-moφholin-4-yl-pyrimidin-4-yl)-2-
(difluoromethyl)benzoimidazole (0.121 g), (2S,6R)-2,6-dimethylpiperazine (0.040 g), sodium bicarbonate (0.183 g) and DMF (1 ml) was heated under nitrogen to 90°C for 15 minutes, cooled, filtered and evaporated. There was thus obtained 2-(difluoromethyl)-l-[6-[(3S,5R)- 3 ,5-dimethylpiperazin- 1 -yl]-2-morpholin-4-yl-pyrimidin-4-yl]benzoimidazole (0.15Og); Mass Spectrum: M+H4" 444. HPLC: method Al, Retention Time 2.16 minutes. Example 9
2-amino-l-[4-[6-[2-(difluoromethyI)benzoimidazol-l-yI]-2-morpholin-4-yl-pyrimidin-4- yl]-2,2-dimethyI-piperazin-l-yl]ethanone
Using an analogous procedure to that described in Example 7, 2-(difluoromethyl)-l-[6- (3 ,3 -dimethylpiperazin- 1 -yl)-2-morpholin-4-yl-pyπmidin-4-yl]benzoimidazole (77% purity, 0.147 g) was reacted withN-ført-butoxycarbonylglycine, followed by deprotection with trifluoroacetic acid. There was thus obtained the title compound as a gum (0.077 g); NMR Spectrum: (DMSOd6) 1.45 (s, 6H), 3.33 (s, 2H), 3.67-3.72 (m, 14H), 3.95 (s, IH), 6.11-6.54 (m, IH), 7.40-7.49 (m, 2H), 7.54 (t, IH), 7.75-7.91 (m, 2H). Mass Spectrum: M+H* 501. The 2-(difluoromethyl)- 1 - [6-(3 ,3 -dimethylpiperazin- 1 -yl)-2-morpholin-4-yl-pyrimidin-4- yl]benzoimidazole used as a starting material was prepared as follows :-
A mixture of l-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-2- (difluorornethyl)benzoimidazole (0.121 g), 2,2-dimethylpiperazine (0.040 g), sodium bicarbonate (0.183 g) and DMF (1 ml) was heated under nitrogen to 90°C for 45 minutes, cooled, filtered and evaporated. There was thus obtained 2-(difluoromethyl)-l-[6-[(3S,5R)- 3,5-dimethylpiperazin-l-yl]-2-morpholin-4-yl-pyrimidin-4-yl]benzoimidazole (77% pure by HPLC, 0.150g); Mass Spectrum: M+H+ 444. HPLC: method Al, Retention Time 2.12 minutes.
Example 10
2-Amino-l-[4-[6-[2-(difluoromethyl)benzoimidazol-l-yl]-2-[(3S)-3-methylmorpholin-4- yl]pyrimidin-4-yl]piperazm-l-yl]ethanone
A solution of l-[6-chloro-2-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]-2- (difluoromethyl)benzoimidazole (0.085 g), tert-butyl N-(2-oxo-2-piperazin-l-yl- ethyl)carbamate (0.08 g) and sodium carbonate (0.105 g) in DMA (3 ml) was heated by microwave to 100°C for 30 minutes. The resultant mixture was cooled and the treated with 4M HCl (4 ml). The resultant mixture was stirred at ambient temperature for 16 hours before being concentrated, redissolved in methanol and loaded onto an Isolute SCX column (10 g). The column was washed with methanol (50 ml), then the product eluted in 3M ammonia/methanol (50 ml) and the product-containing fraction concentrated and purified by HPLC using a Waters 'Xterra' preparative reversed-phase column (5 microns silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water [containing 1% aqueous ammonium hydroxide (d=0.88)] and acetonitrile as eluent. There was thus obtained the title compound as a solid (0.067 g): NMR Spectrum: (DMSOd6) 1.22 (d, 3H), 3.33 - 3.40 (m, 3H), 3.42 - 3.46 (m, 2H), 3.49 - 3.64 (m, 4H), 3.66 - 3.77 (m, 4H), 3.93 (s, IH), 4.07 (q, IH), 4.21 - 4.27 (m, IH), 4.55 - 4.62 (m, IH), 6.43 (s, IH), 7.40 - 7.49 (m, 2H), 7.52 (t, IH), 7.77 (d, IH), 7.86 (d, IH); Mass Spectrum: M+H+ 487.
The l-[6-chloro-2-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]-2- (difluoromethyl)benzoimidazole used as a starting material was prepared as follows :-
A stirred solution of N-[2-[(2,6-dichloropyrimidin-4-yl)amino]phenyl]-2,2-difluoro- acetamide (1.0 g) and (3S)-3-methylmorpholine (0.60 g) in DMA (10 ml) was heated by microwave to 80°C for 1.5 hour, and then to 100 0C for 20 minutes. The resultant reaction mixture was poured onto ethyl acetate (40 ml), washed with water (40 ml), dried over magnesium sulphate and concentrated onto silica before being purified by chromatography on silica eluting with increasing proportions of a 10:1 mixture of methanol and concentrated aqueous ammonia in dichloromethane. There was thus obtained N-[2-[[6-chloro-2-[(3S)-3- methylmorpholin-4-yl]pyrimidin-4-yl]amino]phenyl]-2,2-difluoro-acetamide (0.59 g); Mass Spectrum: M+H+ 398; HPLC: method Bl, Retention Time 2.36 minutes.
A solution of N- [2- [[6-chloro-2- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-4- yl]amino]phenyl]-2,2-difluoro-acetamide (0.59 g) in dioxane (6 ml) and 4M HCl in dioxane (3.8 ml) was heated by microwave to 110°C for 1 hour. The resultant mixture was concentrated onto silica and purified by chromatography on silica eluting with increasing proportions of ethyl acetate in iso-hexane. There was thus obtained l-[6-chloro-2-[(3S)-3- methylmorpholin-4-yl]pyrimidin-4-yl]-2-(difluoromethyl)benzoimidazole (0.34 g); Mass Spectrum: M+H+ 380; HPLC: method Bl, Retention Time 2.62 minutes.

Claims

1. A pyrimidine derivative of the Formula I
Figure imgf000100_0001
wherein p is 0, 1, 2 or 3; each R1 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-όC)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulρhinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, -V-(I -6C)alkylcarbamoyl, 7V,7V-di- [( 1 -6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(I -6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, JV-(I -6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, JV-(I -6C)alkyl-(3-6C)alkynoylamino, JV-(I -6C)alkylureido, 7V',JV-di-[( 1 -6C)alkyl]ureido, JV-(l-6C)alkylureido, 7V,JV'-di-[(l-6C)alkyl]ureido, N,JV',JV'-tri-[(l-6C)alkyl]ureido,
JV-(I -6C)alkylsulphamoyl, iV,iV-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and JV-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
Q2 -X2- wherein X2 is a direct bond or is selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)CO, N(R5)CON(R5), SO2N(R5), N(R5)SO2, OC(R5)2, SC(R5)2 and N(R5)C(R5)2, wherein R5 is hydrogen or (l-8C)alkyl, and Q2 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 heterocy clyl-( 1 -6C)alky 1, or (R1 )p is (l-3C)alkylenedioxy, and wherein any CH, CH2 or CH3 group within a R1 substituent optionally bears on each said CH, CH2 or CH3 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-όC)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulρhonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, iV-(l-6C)alkylcarbamoyl,
JV,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, N-(l-6C)alkylureido, iV'-(l-6C)alkylureido, N',N'-di-[(l-6C)alkyl]ureido, iV,iV'-di-[(l-6C)alkyl]ureido, iV,iV',N'-tri-[(l-6C)alkyl]ureido, TV-(I -6C)alkylsulphamoyl, Λζ,iV-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and iV-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
-X3-Q3 wherein X3 is a direct bond or is selected from O, S, SO, SO2, N(R6), CO, CH(OR6), CON(R6), N(R6)CO, N(R6)CON(R6), SO2N(R6), N(R6)SO2, C(R6)2O, C(R6)2S and C(R6)2N(R6), wherein R6 is hydrogen or (l-8C)alkyl, and Q3 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l -6C)alkyl, (3-8C)cycloalkenyl, (3-8C)cycloalkenyl- (l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (1 -8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1 -6C)alkoxy , (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulρhonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, iV-(l-6C)alkylcarbamoyl, iV,iV-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, TV-(I -6C)alkyl-(2-6C)alkanoylamino, JV-(I -6C)alkylureido, JV-(I -6C)alkylureido, TV', TV' -di- [(I -6C)alkyl]ureido, TV,TV'-di-[(l -6C)alkyl]ureido, iV,N',iV'-tri-[(l-6C)alkyl]ureido, N-(l-6C)alkylsulphamoyl, iV,N-di-[(l-6C)alkyl]sulρhamoyl, (l-6C)alkanesulphonylamino and TV-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
-X4-R7 wherein X4 is a direct bond or is selected from O and N(R8), wherein R8 is hydrogen or (l-8C)alkyl, and R7 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, mercapto-(l-6C)alkyl, (1 -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, iV-(l-6C)alkylui-eido-(l-6C)alkyl, iV'-(l-6C)alkylureido-(l-6C)alkyl5 N',N'-di-[(l-6C)alkyl]ureido-(l-6C)alkyl, iV,N'-di-[(l-6C)alkyl]ureido-(l-6C)alkyl or N,N' ,N'-tri-[(l-6C)alkyl]ureido-(l-6C)alkyl, or from a group of the formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, CO and N(R9), wherein R9 is hydrogen or (l-8C)alkyl, and Q4 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 R1 optionally bears 1 or 2 oxo or thioxo substituents, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R10), CO, CH(OR10), CON(R10), N(R10)CO, N(R10)CON(R10), SO2N(R10), N(R10)SO2, CH-CH and C≡C wherein R10 is hydrogen or (l-8C)alkyl;
R2 is fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, hydroxy, amino, formamido, (l-6C)alkoxycarbonylamino, (2-6C)alkanoylamino, TV-(I -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 0, 1, 2, 3 or 4; each R3 group, which may be the same or different, is (l-SC)alkyl or a group of the formula :
-X6-Rn wherein X6 is a direct bond or is selected from O and N(R12), wherein R12 is hydrogen or
(l-8C)alkyl, and R11 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, di-[(l-6C)alkyl]amino-(l-6C)alkyl or (2-6C)alkanoylamino-(l-6C)alkyl,> or two R3 groups together form a methylene, ethylene or trimethylene group; r is 0, 1, 2, 3 or 4; each R4 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, mercapto, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-όC)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, ( 1 -6C)alkoxycarbonyl, N-( 1 -6C)alkylcarbamoyl, N,N-di- [( 1 -6C)alkyl] carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino3 N-(l-6C)alkyl- (2-6C)alkanoylamino, N'-(l-6C)alkylureido, N',N'-di-[(l-6C)alkyl]ureido,
N-(l-6C)alkylureido, N,iV'-di-[(l-6C)alkyl]ureido, iV,Nr,N'-tri-[(l-6C)alkyl]ureido, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(I -6C)alkyl-( 1 -6C)alkanesulphonylamino, or two R4 groups together form a methylene, ethylene or trimethylene group; X1 is a direct bond or is selected from CO, S, SO, SO2, CON(R13), COC(Rl3)2O,
COC(R13)2S, COC(R13)2N(R13) and COC(R13)2N(R13)CO, wherein R13 is hydrogen or (l-8C)alkyl; and
Q1 is hydrogen, (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, (l-6C)alkylsulphonyl-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, N-(l-6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl, (l-6C)alkoxycarbonylamino-(l-6C)alkyl, N-(I -6C)alkylureido-( 1 -6C)alkyl, N'-( 1 -6C)alkylureido-( 1 -6C)alkyl, N',N'-di-[(l-6C)alkyl]ureido-(l-6C)alkyl, N,N'-di-[(l-6C)alkyl]ureido-(l-6C)alkyl,
N,N',N'-tri-[(l -6C)alkyl]ureido-(l -6C)alkyl, (1 -6C)alkanesulphonylamino-(l -6C)alkyl or
N-(l-6C)alkyl-(l-6C)alkanesulρhonylamino-(l-6C)alkyl, or Q1 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-6C)alkyl,
(3-8C)cycloalkenyl, (3-8C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 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-6C)alkylthio, (l-όC)alkylsulphinyl, (l-6C)alkylsulρhonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl,
N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, N'-(l-6C)alkylureido, iV',N'-di-[(l-6C)alkyl]ureido, N-(I -6C)alkylureido, N,N'-di-[(l -6C)alkyl]ureido, N,N',N'-tri-[(l -6C)alkyl]ureido,
N-(l-6C)alkylsulphamoyl, iV,iV-di-[(l-6C)alkyl]sulphaπioyl,
( 1 -6C)alkanesulphonylamino and N-(I -6C)alkyl-( 1 -6C)alkanesulphonylamino, and wherein any aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-βC)alkylsulphinyl, (l-6C)alkylsulρhonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, iV-(l-6C)alkylcarbamoyl, N,N-di-[(l -6C)alkyl] carbamoyl, (2-6C)alkanoylamino, N-(I -6C)alkyl-(2-6C)alkanoylamino, N'-(l -6C)alkylureido, N',N'-di- [(l-6C)alkyl]ureido, N-(I -6C)alkylureido, N,N'-di-[(l -6C)alkyl]ureido, N,N',7V"-tri-[(l-6C)alkyl]ureido, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
-X7-R14 wherein X7 is a direct bond or is selected from O and N(R15), wherein R15 is hydrogen or (l-8C)alkyl, and R14 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 :
-X8-Q5 wherein X8 is a direct bond or is selected from O, CO and N(R17), wherein R17 is hydrogen or (l-8C)alkyl, and Q5 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-όC)alkoxy, and wherein any heterocyclyl group within the Q1 group optionally bears 1 or 2 oxo or thioxo substituents, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within the Q1 group are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R16), N(RI6)CO, CON(R16), N(R16)CON(R16), CO, CH(OR16), N(R16)SO2, SO2N(R16), CH=CH and C≡C wherein R16 is hydrogen or (l-8C)alkyl; and wherein the 5-position on the pyrimidine ring may optionally bear a (l-8C)alkyl group; or a pharmaceutically-acceptable salt thereof.
2. A pyrimidine derivative of the Formula I according to claim 1 wherein :- p is 0 or p is 1 and the R1 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;
R2 is fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido, acetamido or hydroxymethyl; q is 0 or q is 1 or 2 and each R3 group is methyl; r is 0, or r is 1, 2, 3 or 4 and each R4 group, which may be the same or different, is methyl, ethyl or propyl; or r is 2 and the two R4 groups together form a methylene or ethylene group; X1 is selected from CO, SO2, CONH, CON(Me), COCH2O, COCH2NH and
COCH2NHCO; and
Q1 is 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 1-cyano-l-methylethyl, 4-cyanobutyl, 5-cyanopentyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminoρentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl, 5-diethylaminopentyl, 2-methylsulphonylethyl or acetamidomethyl, or
Q1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl, 2-imidazolylethyl, pyrazolylmethyl, thiazolylmethyl, triazolylmethyl, oxadiazolylmethyl, thiadiazolylmethyl, tetrazolylmethyl, pyridylmethyl, 2-pyridylethyl, pyrazinylmethyl, 2-pyrazinylethyl, pyridazinylmethyl, 2-pyridazinylethyl, pyrimidinylmethyl, 2-pyrimidinylethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, indolinyl, isoindolinyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, 1,3-dioxolanylmethyl, 1,4-dioxanylmethyl, pyrrolidinylmethyl, 2-(pyrrolidinyl)ethyl, morpholinylmethyl, 2-(morpholinyl)ethyl, piperidinylmethyl, 2-(piperidinyl)ethyl, homopiperidinylmethyl, piperazinylmethyl, 2-(piperazinyl)ethyl or homopiperazinylmethyl, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, dimethylamino, methoxycarbonyl, ethoxycarbonyl, iV-methylcarbamoyl, iV-ethylcarbamoyl, iV-isopropylcarbamoyl, N,N-dimethylcarbamoyl, acetyl, propionyl, pivaloyl, acetamido and iV-methylacetamido, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, methoxy, methylamino and dimethylamino and any such aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; and the 5 -position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
3. A pyrimidine derivative of the Formula I according to claim 1 wherein :- p is 0 or p is 1 and the R1 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;
R2 is fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, amino, formamido, acetamido or hydroxymethyl; q is 0 or q is 1 or 2 and each R3 group is methyl; r is 0, or r is 1, 2, 3 or 4 and each R4 group, which may be the same or different, is methyl, ethyl or propyl; or r is 2 and the two R4 groups together form a methylene or ethylene group; and the X^Q1 group is selected from glycyl, sarcosyl, iV-ethylglycyl, N,N-dimethylglycyl, glycylglycyl, L-alanyl, 2-methylalanyl, iV-methylalanyl, β-alanyl, (2S)-2-aminobutanoyl, L-valyl, iV-methyl-L-valyl, 2-aminopent-4-ynoyl, 2-aminopentanoyl, L-isoleucyl, L-leucyl, 2-methyl-L-leucyl, JV-methyl-L-leucyl, seryl, O-methyl-L-seryl, N-methyl-L-seryl, 5 O-methyl-L-homoseryl, L-threonyl, iS-methyl-L-cysteinyl, S-methyl-L-homocysteinyl, L-methionyl, iV-methyl-L-lysyl, iV-methyl-L-ornithyl, D-asparaginyl, D-glutaminyl, L-tyrosyl, prolyl and histidyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof. Q
4. A pyrimidine derivative of the Formula I according to claim 1 wherein :- p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy;
R2 is difluoromethyl; s q is 0; r is 0, or r is 1 or 2 and each R4 group is methyl, or r is 2 and the two R groups together form a methylene or ethylene group;
X1 is CO; and
Q1 is 2-ethoxyethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, aminomethyl,Q 2-aminoethyl, methylaminomethyl, 2-methylarninoethyl, ethylaminomethyl,
2-ethylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl, 4-dimethylaminobutyl, 2-methylsulphonylethyl or acetamidomethyl, or Q1 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,5 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-4-yl, thien-3-ylmethyl, oxazol-4-ylmethyl, isoxazol-3-ylmethyl, isoxazol-4-ylmethyl, imidazol-1-ylmethyl, imidazol-2-ylmethyl, 2-imidazol-l-ylethyl, 2-imidazol-2-ylethyl, 2-imidazol-4-ylethyl, pyrazol-1-ylmethyl, pyrazol-3-ylmethyl, 1,2,3-triazol-l-ylmethyl,0 l,2,3-triazol-4-ylmethyl, l,2,4-oxadiazol-3-ylmethyl, l,2,3-thiadiazol-3-ylmethyl, tetrazol-1-ylmethyl, tetrazol-5-ylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, 2-pyridin-2-ylethyl, 2-pyridin-3-ylethyl, 2-pyridin-4-ylethyl, pyrazin-2-ylmethyl, 2-pyrazin-2-ylethyl, pyridazin-4-ylmethyl, 2-pyridazin-4-ylethyl5 pyrimidin-2-ylmethyl, pyrimidin-4-ylmethyl, 2-pyrimidiii-2-ylethyl, 2-pyrimidin-4-ylethyl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, azetidin-2-yl, 3-pyrrolin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, morpholino, morpholin-2-yl, morpholin-3 -yl, piperidino, piperidin-2-yl, piperidin-3 -yl, piperidin-4-yl, piperazin- 1 -yl, piperazin-2-yl, isoindolin-1-yl, tetrahydrofuran-2-ylmethyl, tetrahydropyran-4-ylniethyl, l,3-dioxolan-2-ylmethyl, l,4-dioxan-2-ylmethyl, pyrrolidin-2-ylmethyl, piperidin-2-ylmethyl, piperidin-3 -ylmethyl, piperidin-4-ylmethyl, 2-(piperidin-4-yl)ethyl, piperidin-4-yloxymethyl, piperazin- 1-ylmethyl or 2-(piperazin-l-yl)ethyl, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group a substituent selected from hydroxy, carbamoyl, methoxycarbonyl, ethoxycarbonyl, iV-methylcarbamoyl, JV-ethylcarbamoyl, iV-isopropylcarbamoyl, N,iV-dimethylcarbamoyl, acetyl, propionyl, pivaloyl, acetamido and iV-methylacetamido, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, amino, carbamoyl, methyl, methylamino, dimethylamino, hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; and the 5 -position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
5. A pyrimidine derivative of the Formula I according to claim 1 wherein :- p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy; R2 is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R4 group is methyl; and the X^Q1 group is glycyl, sarcosyl, iV-acetylglycyl, ΛζN-dimethylglycyl, iV-acetylalanyl, 2-methylalanyl, β-alanyl, D-valyl, L-seryl, iV-methyl-L-seryl, JV-acetylseryl, L-homoseryl or iV-(4-toluoyl)glycyl; and the 5 -position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
6. A pyrimidine derivative of the Formula I according to claim 1 wherein :- p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is selected from hydroxy and methoxy; 5 R is difluoromethyl; q is O; r is 0, or r is 1 or 2 and each R4 group is methyl; X1 is CO; and
Q1 is hydroxymethyl, 2-hydroxy-2-methylethyl, cyclopropyl, 1-hydroxycycloprop-l-yl, io 1-aminocycloprop-l-yl, 1-aminocyclobut-l-yl, tetrahydropyran-4-yl, morpholin-2-yl, morpholin-3-yl, tetrahydro-l,4-thiazin-3-yl, azetidin-2-yl, pyrrolidin-2-yl, piperidin-3-yl, l-aminopiperidin-3-yl, piperidin-4-yl, l-arninopiperidin-4-yl, piperazin-2-yl, tetrahydropyran-4-ylmethyl, pyrrolidin-2-ylmethyl, piperidin-3 -y lmethyl, piperazin-1-ylmethyl, 3-aminophenyl, 4-aminophenyl, 3-aminomethylphenyl, I5 4-aminomethylphenyl, iV-methylimidazol-2-yl, l-methyl-lH-pyrazol-3-yl,
2-methyloxazol-4-yl, l/f-l,2,3-triazol-5-yl, l,2,3-thiadiazol-4-yl, 3-pyridyl, 4-pyridazinyl, 1 H- 1,2,4-triazol-l-y lmethyl, lH-tetrazol-1-ylmethyl, 1/f-tetrazol- 5 -y lmethyl, 2-pyridin-3-ylethyl, 2-pyridazin-4-ylethyl or piperidin-4-yloxymethyl; and the 5-position on the pyrimidine ring is unsubstituted; 20 or a pharmaceutically-acceptable salt thereof.
7. A pyrimidine derivative of the Formula I according to claim 1 wherein :- p is 0 or p is 1 and the R1 group is located at the 4-, 5- or 6-position on the benzimidazolyl group and is selected from methoxy and ethoxy; 25 R2 is difluoromethyl or trifluoromethyl; q is 0 or q is 1 and the R3 group is methyl; r is 0, or r is 1 or 2 and each R4 group, which may be the same or different, is methyl, ethyl or propyl; or r is 2 and the two R4 groups together form an ethylene group;
X1 is a direct bond or is selected from CO, CONΗ, COCH2NH and COCH2NHCO; and 30 Q1 is hydrogen, hydroxymethyl, 2 -hydroxy ethyl, 2-methoxy ethyl, 3-methoxypropyl, 2- ethoxy ethyl, 3-ethoxypropyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 1-cyano-l- methylethyl, 4-cyanobutyl, 5-cyanopentyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4- aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3- ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2- dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl, 5- diethylaminopentyl, 2-methylsulphonylethyl or acetamidomethyl, or Q1 is phenyl, benzyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl, 2-imidazolylethyl, pyrazolylmethyl, thiazolylmethyl, triazolylmethyl, oxadiazolylmethyl, thiadiazolylmethyl, tetrazolylmethyl, pyridylmethyl, 2-pyridylethyl, pyrazinylmethyl, 2-pyrazinylethyl, pyridazinylmethyl, 2-pyridazinylethyl, pyrimidinylmethyl, 2-pyrimidinylethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, liomopiperidinyl, piperazinyl, homopiperazinyl, indolinyl, isoindolinyl, tetrahydrofuranylmetliyl, tetrahydropyranylmethyl, 1,3-dioxolanylmethyl, 1,4-dioxanylmethyl, pyrrolidinylmethyl, 2-(pyrrolidinyl)ethyl, moφholinylmethyl, 2-(morpholinyl)ethyl, piperidinylmethyl, 2-(piperidinyl)ethyl, homopiperidinylmethyl, piperazinylmethyl, 2-(piperazinyl)ethyl or homopiperazinylmethyl, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, dimethylamino, methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl, JV-ethylcarbamoyl, iV-isopropylcarbamoyl, JV,iV-dimethylcarbamoyl, acetyl, propionyl, pivaloyl, acetamido and 7V-methylacetamido, and wherein any aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, methoxy, methylamino and dimethylamino and any such aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl group within the Q1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; and the 5 -position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
8. A pyrimidine derivative of the Formula I according to claim 1 wherein :- p is 0 or p is 1 and the R1 group is located at the 4-, 5- or 6-position on the benzimidazolyl group and is methoxy;
R2 is difluoromethyl or trifiuoromethyl; q is 0 or q is 1 and the R3 group is methyl; r is 0, or r is 2 and each R4 group is methyl, or r is 2 and the two R4 groups together form an ethylene group; X1 is a direct bond or is selected from CO, CONH, COCH2NH and COCH2NHCO; and
Q1 is hydrogen, hydroxymethyl, 2 -hydroxy ethyl, 2-methoxy ethyl, 3-methoxypropyl, 2- ethoxyethyl, 3-ethoxypropyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5- aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4- methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3- ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2- dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl or 5- diethylaminopentyl, or
Q1 is benzyl, 2-phenylethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, moφholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, indolinyl or isoindolinyl, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group a substituent selected from hydroxy, amino, cyano, carbamoyl, methoxy, ethoxy, methylsulphonyl, methylamino, dimethylamino, methoxycarbonyl, ethoxycarbonyl, iV-methylcarbamoyl, JV-ethylcarbamoyl, N-isopropylcarbamoyl,
ΛζiV-dimethylcarbamoyl, acetyl, propionyl, pivaloyl, acetamido and N-methylacetamido, and wherein any aryl or heterocyclyl group within the Q1 group optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifiuoromethyl, hydroxy, amino, carbamoyl, methyl, methoxy, methylamino and dimethylamino and any such aryl or heterocyclyl group within the Q1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminomethyl; and the 5 -position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
9. A pyrimidine derivative of the Formula I according to claim 1 wherein :- p is 0;
R2 is difluoromethyl or trifluoromethyl; q is 0 or q is 1 and the R3 group is methyl; r is 0, or r is 2 and each R4 group is methyl, or r is 2 and the two R4 groups together form an ethylene group; X1 is a direct bond or is selected from CO5 CONH, COCH2NH and COCH2NHCO; and
Q1 is hydrogen, hydroxymethyl, aminomethyl, 2-aminoethyl, 2-phenylethyl, pyrrolidinyl or piperidinyl, and wherein any CH or CH2 group within the Q1 group optionally bears on each said CH or CH2 group a substituent selected from methylamino and dimethylamino, and wherein any aryl or heterocyclyl group within the Q1 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 Q1 group optionally bears a substituent selected from hydroxymethyl, methoxymethyl, cyanomethyl, aminomethyl, methylaminomethyl and dimethylaminoniethyl; and the 5-position on the pyrimidine ring is unsubstituted; or a pharmaceutically-acceptable salt thereof.
10. A pyrimidine derivative of the Formula I according to any one or more of claims 1 to 8, wherein p is 0 or p is 1 and the R1 group is located at the 4-position on the benzimidazolyl group and is methoxy; or a pharmaceutically-acceptable salt thereof.
I L A pyrimidine derivative of the Formula I according to any one or more of claims 1 to 3, wherein R2 is difluoromethyl; or a pharmaceutically-acceptable salt thereof.
12. A pyrimidine derivative of the Formula I according to any one or more of claims 1 to 3, wherein q is 0 or q is 1 and the R3 group is methyl; or a pharmaceutically-acceptable salt thereof.
13. A pyrimidine derivative of the Formula I according to any one or more of claims 1 to 4, wherein r is 0, or r is 2 and the R4 group is methyl, or r is 2 and the two R4 groups together form an ethylene group; or a pharmaceutically-acceptable salt thereof.
14. A pyrimidine derivative of the Formula I according to claim 1, wherein X1 is a direct bond or is selected from CO, CON(R13), COC(RI3)2N(R13) and COC(R13)2N(R13)CO, wherein R13 is hydrogen or (l-2C)alkyl; or a pharmaceutically-acceptable salt thereof.
15. A pyrimidine derivative of the Formula I according to claim 1 or 14, wherein Q1 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, aryl-(l-6C)alkyl or heterocyclyl, and wherein any CH, CH2 or CH3 group within the Q1 group optionally bears on each said CH, CH2 or CH3 group one or more halogeno or (l-8C)alkyl substituents and/or a substituent selected from hydroxy, mercapto, amino, cyano, carboxy, carbamoyl, ureido, (1- 6C)alkoxy, (l-6C)alkylthio, (l-όC)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-όC)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, iV-(l-6C)alkylcarbamoyl, N,N-di-[(l- 6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(I- 6C)alkyl-(2-6C)alkanoylamino, N'-(l-6C)alkylureido, N',N'-di-[(l-6C)alkyl]ureido, N-(I- 6C)alkylureido, N,N'-di-[(l-6C)alkyl]ureido, N,N',N'-tri-[(l-6C)alkyl]ureido, N-(I- 6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(I- 6C)alky l-( 1 -6C)alkanesulphonylamino, and wherein any aryl or heterocyclyl group within the Q1 group optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2- 8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (1- 6C)alkylsulphinyl, (l-6C)alkylsulρhonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (1- 6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, N-(l-6C)alkylcarbamoyl, N,N-di-[(l- 6C)alkyl]carbamoyl, (2-6C)alkanoylamino, JV-(I -6C)alkyl-(2-6C)alkanoylamino, iV'-(l- 6C)alkylureido, iV',N'-di-[(l-6C)alkyl]ureido, JV-(I -6C)alkylureido, N,N'-άi-[(\- 6C)alkyl]ureido, N,N',N'-tri-[(l-6C)alkyl]ureido, JV-(I -6C)alkylsulphamoyl, iV,N-di-[(l- 6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and iV-(l-6C)alkyl-(l- 6C)alkanesulρhonylamino, or from a group of the formula :
-X7-R14 wherein X7 is a direct bond or is selected from O and N(R15), wherein R15 is hydrogen or (l-8C)alkyl, and R14 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 :
-X8 -Q5 wherein X8 is a direct bond or is selected from O, CO and N(R17), wherein R17 is hydrogen or (l-8C)alkyl, and Q5 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 Q1 group optionally bears 1 or 2 oxo or thioxo substituents, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within the Q1 group are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R16), N(R16)CO, CON(R16), N(R16)CON(R16), CO, CH(OR16), N(R16)SO2, SO2N(R16), CH=CH and C≡C wherein R16 is hydrogen or (l-8C)alkyl; or a pharmaceutically-acceptable salt thereof.
16. The pyrimidine derivative of the Formula I according to claim 1 that is disclosed as Example 1, or a pharmaceutically-acceptable salt thereof.
17. A pyrimidine derivative of the Formula I selected from one or more of the following: 4-(2-difluoromethylbenzimidazol- 1 -yl)-6-(4-glycylpiperazin- 1 -yl)- 2-morpholinopyrimidine ; 2-amino- 1 -[4- [2-morpholin-4-yl-6- [2-(trifluoromethyl)benzoimidazol- 1 -yl]pyrimidin-4- yl]piperazin-l -yl]ethanone; (2S)-N-[2-[4-[6-[2-(difluoromethyl)benzoimidazol-l-yl]-2-morpholin-4-yl-pyrimidin-4- yl]piperazin-l-yl]-2-oxo-ethyl]pyrrolidine-2-carboxamide;
[4- [6- [2-(difluoromethy l)benzoimidazol- 1 -yl] -2-morpholin-4-y l-pyrimidin-4-yl]piperazin- 1 - yl]-[(2S)-2-piperidyl]methanone;
(2R)-l-[4-[6-[2-(difluoromethyl)benzoimidazol-l-yl]-2-niorpholin-4-yl-pyrimidin-4- y l]piperazin- 1 -yl] -2-methy lamino-3 -phenyl-propan- 1 -one ;
[4- [6- [2-(difluoromethy l)benzoimidazol- 1 -yl]-2-moφholin-4-yl-pyrimidin-4-yl]piperazin- 1 - yl]-[(2S)-pyrrolidin-2-yl]methanone;
2-amino- 1 - [3 - [6- [2-(difluoromethyl)benzoimidazol- 1 -yl] -2-morpholin-4-y l-pyrimidin-4-yl] -
10 3,8-diazabicyclo[3.2.1]oct-8-yl]ethanone;
2-amino-l-[(2S,6R)-4-[6-[2-(difluoromethyl)benzoiniidazol-l-yl]-2-niorpholm-4-yl- pyrimidin-4-yl]-2,6-dimethyl-piperazin- 1 -yl]ethanone;
2-amino-l-[4-[6-[2-(difluoromethyl)benzoimidazol-l-yl]-2-morpholin-4-yl-pyrimidin-4-yl]-
2,2-dimethyl-piperazin- 1 -yl]etlianone; and
I5 2-amino- 1 - [4- [6- [2-(difluoromethyl)benzoimidazol- 1 -yl] -2-[(3 S)-3 -methylmorpholin-4- yl]pyrimidin-4-yl]piperazin- 1 -yl]ethanone; or a pharmaceutically-acceptable salt thereof.
18. A process for the preparation of a pyrimidine derivative of the Formula I, or a 20 pharmaceutically-acceptable salt thereof, according to claim 1 which comprises :- (a) the reaction of a pyrimidine of the Formula II
Figure imgf000115_0001
wherein p, R1, R2, q and R3 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a piperazine of the Formula III
Figure imgf000116_0001
III wherein r, R4, X1 and Q1 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, whereafter any protecting group that is present is removed; (b) for the production of those compounds of the Formula I wherein X1 is CO, the acylation of a pyrimidine of the Formula IV
Figure imgf000116_0002
wherein p, R1, R2, q, R3, r and R4 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a carboxylic acid of the Formula V
HO2C - Q1 v v or a reactive derivative thereof, wherein Q1 has any of the meanings defined in claim 1 except that any functional group is protected if necessary, whereafter any protecting group that is present is removed;
(c) the reaction of a pyrimidine of the Formula VI
Figure imgf000116_0003
VI wherein L is a displaceable group and p, R1, R2, r, R4, X1 and Q1 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a morpholine compound of the Formula VII
Figure imgf000117_0001
wherein q and R3 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, whereafter any protecting group that is present is removed; (d) for the production of those compounds of the Formula I wherein X1 is CO and Q1 is a heterocyclyl group that contains an NH group, the coupling of phosgene, or a chemical equivalent thereof, with the NH-containing heterocyclyl group where any functional group (other than the reacting NH group) is protected if necessary and with a pyrimidine of the Formula IV
Figure imgf000117_0002
wherein p, R1, R2, q, R3, r and R4 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, whereafter any protecting group that is present is removed;
(e) for the production of those compounds of the Formula I wherein X1 is CON(R13), the coupling of phosgene, or a chemical equivalent thereof, with a pyrimidine of the Formula IV
Figure imgf000118_0001
wherein p, R1, R , q, R3, r and R4 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, and with an amine of the Formula VIII
R13NH - Q1 viπ
wherein R13 and Q1 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, whereafter any protecting group that is present is removed; (f) for the production of those compounds of the Formula I wherein X1 is SO2, the reaction of a pyrimidine of the Formula IV
Figure imgf000118_0002
wherein p, R1, Rz, q, RJ, r and R4 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a sulphonic acid of the Formula IX
HO3S - Qi Iχ
or a reactive derivative thereof, wherein Q1 has any of the meanings defined in claim 1 except that any functional group is protected if necessary, whereafter any protecting group that is—. ~ present is removed; or (g) the reaction of a pyrimidine of the Formula X
Figure imgf000119_0001
wherein L is a displaceable group and q, R3, r, R4, X1 and Q1 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a benzimidazole of the Formula XI
Figure imgf000119_0002
wherein p, R1 and R2 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, whereafter any protecting group that is present is removed; and when a pharmaceutically-acceptable salt of a pyrimidine derivative of the Formula I is required such as an acid-addition salt, it may be obtained by reaction of said pyrimidine derivative with a suitable acid.
19. A pharmaceutical composition which comprises a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 in association with a pharmaceutically-acceptable diluent or carrier.
20. A pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 for use as a medicament.
21. 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, according to claim 1.
22. 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, according to claim 1.
23. A method for the prevention or treatment of those tumours which are sensitive to inhibition of PI3K enzymes and/or a mTOR kinase that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells which comprises administering to said animal an effective amount of a pyrimidine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1.
24. A method for treating cancer of the breast, colorectum, lung 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, according to claim 1.
25. 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, 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, according to claim 1.
PCT/GB2007/003414 2006-09-14 2007-09-12 4-benzimidazolyl-2-morpholino-6-piperazinylpyrimidine derivatives as pi3k and mtor inhibitors for the treatment of proliferative disorders WO2008032033A1 (en)

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