WO2008032033A1 - Dérivés de 4-benzimidazolyl-2-morpholino-6-pipérazinylpyrimidine utilisés en tant que pi3k et inhibiteurs de mtor destinés au traitement de troubles prolifératifs - Google Patents

Dérivés de 4-benzimidazolyl-2-morpholino-6-pipérazinylpyrimidine utilisés en tant que pi3k et inhibiteurs de mtor destinés au traitement de troubles prolifératifs Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
formula
amino
hydroxy
Prior art date
Application number
PCT/GB2007/003414
Other languages
English (en)
Inventor
Sam Butterworth
Edward Jolyon Griffen
George Beresford Hill
Martin Pass
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2008032033A1 publication Critical patent/WO2008032033A1/fr

Links

Classifications

    • 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

L'invention concerne des dérivés de pyrimidine de formule I dans laquelle p, R1, R2, q, R3, r, R4, X1 et Q1 ont chacun l'une des significations définies dans la description, ainsi que des procédés de préparation de ceux-ci, des compositions pharmaceutiques les contenant et leur utilisation dans un procédé de production d'un effet anti-prolifératif chez un animal à sang chaud tel que l'homme.
PCT/GB2007/003414 2006-09-14 2007-09-12 Dérivés de 4-benzimidazolyl-2-morpholino-6-pipérazinylpyrimidine utilisés en tant que pi3k et inhibiteurs de mtor destinés au traitement de troubles prolifératifs WO2008032033A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US84459606P 2006-09-14 2006-09-14
US60/844,596 2006-09-14

Publications (1)

Publication Number Publication Date
WO2008032033A1 true WO2008032033A1 (fr) 2008-03-20

Family

ID=38783582

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2007/003414 WO2008032033A1 (fr) 2006-09-14 2007-09-12 Dérivés de 4-benzimidazolyl-2-morpholino-6-pipérazinylpyrimidine utilisés en tant que pi3k et inhibiteurs de mtor destinés au traitement de troubles prolifératifs

Country Status (1)

Country Link
WO (1) WO2008032033A1 (fr)

Cited By (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010044401A1 (fr) 2008-10-14 2010-04-22 第一三共株式会社 Dérivé de morpholinopurine
WO2010092962A1 (fr) 2009-02-12 2010-08-19 アステラス製薬株式会社 Dérivé d'hétérocycle
WO2011058025A1 (fr) 2009-11-12 2011-05-19 F. Hoffmann-La Roche Ag Composés de pyrazolopyrimidine et de purine n-7-substitués, compositions et procédés d'utilisation correspondants
WO2011058027A2 (fr) 2009-11-12 2011-05-19 F. Hoffmann-La Roche Ag Composés de purine n-9-substitués, compositions et procédés d'utilisation
WO2011041399A3 (fr) * 2009-09-29 2011-08-18 Tyrogenex, Inc. Inhibiteurs sélectifs de la pi3k (delta)
WO2011114275A1 (fr) 2010-03-15 2011-09-22 University Of Basel Composés spirocycliques et leur utilisation comme agents thérapeutiques et sondes de diagnostic
CN102209714A (zh) * 2008-11-10 2011-10-05 巴塞尔大学 三嗪、嘧啶和吡啶类似物和它们作为治疗剂和诊断探针的应用
WO2011135520A1 (fr) 2010-04-30 2011-11-03 University Of Basel Pipérazinotriazines comme inhibiteurs de pi3k pour une utilisation dans le traitement de troubles antiprolifératifs
WO2012020762A1 (fr) 2010-08-10 2012-02-16 アステラス製薬株式会社 Composé hétérocyclique
US8163763B2 (en) 2008-07-31 2012-04-24 Genentech, Inc. Pyrimidine compounds, compositions and methods of use
WO2012135009A1 (fr) * 2011-03-25 2012-10-04 Incyte Corporation Dérivés de pyrimidine-4,6-diamine en tant qu'inhibiteurs de pi3k
US8362241B2 (en) 2009-04-28 2013-01-29 Amgen Inc. Inhibitors of PI3 kinase and/or mTOR
WO2013019927A1 (fr) 2011-08-03 2013-02-07 Signal Pharmaceuticals, Llc Identification d'un profil d'expression génique à titre de biomarqueur prédictif de l'état lkb1
US8461158B2 (en) 2009-03-27 2013-06-11 Pathway Therapeutics Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
US8486939B2 (en) 2009-07-07 2013-07-16 Pathway Therapeutics Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy
WO2013174794A1 (fr) 2012-05-23 2013-11-28 F. Hoffmann-La Roche Ag Compositions et procédés d'obtention et d'utilisation de cellules endodermiques et d'hépatocytes
WO2014005182A1 (fr) * 2012-07-04 2014-01-09 Monash University Inhibiteurs de phosphoinositide 3-kinase (pi3k)
US8680108B2 (en) 2009-12-18 2014-03-25 Incyte Corporation Substituted fused aryl and heteroaryl derivatives as PI3K inhibitors
EP2762142A1 (fr) 2009-10-30 2014-08-06 ARIAD Pharmaceuticals, Inc. Compositions pour le traitement du cancer
WO2014164942A1 (fr) * 2013-03-13 2014-10-09 The Regents Of The University Of Michigan Inhibiteurs doubles de mek/pi3k et procédés thérapeutiques les utilisant
US8940752B2 (en) 2009-06-29 2015-01-27 Incyte Corporation Pyrimidinones as PI3K inhibitors
US9056852B2 (en) 2011-03-28 2015-06-16 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US9062055B2 (en) 2010-06-21 2015-06-23 Incyte Corporation Fused pyrrole derivatives as PI3K inhibitors
US9096600B2 (en) 2010-12-20 2015-08-04 Incyte Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9108984B2 (en) 2011-03-14 2015-08-18 Incyte Corporation Substituted diamino-pyrimidine and diamino-pyridine derivatives as PI3K inhibitors
US9155736B2 (en) 2012-10-18 2015-10-13 Signal Pharmaceuticals, Llc Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity
US9193721B2 (en) 2010-04-14 2015-11-24 Incyte Holdings Corporation Fused derivatives as PI3Kδ inhibitors
US9199982B2 (en) 2011-09-02 2015-12-01 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
EP2992878A1 (fr) 2010-02-03 2016-03-09 Signal Pharmaceuticals, LLC Identification d'une mutation lkb1 comme biomarqueur prédictif de la sensibilité aux inhibiteurs de la kinase tor
US9309251B2 (en) 2012-04-02 2016-04-12 Incyte Holdings Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
US9359364B2 (en) 2013-04-17 2016-06-07 Signal Pharmaceuticals, Llc Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b] pyrazin-2(1H)-one
US9358232B2 (en) 2013-04-17 2016-06-07 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
US9403847B2 (en) 2009-12-18 2016-08-02 Incyte Holdings Corporation Substituted heteroaryl fused derivatives as P13K inhibitors
US9416134B2 (en) 2014-04-16 2016-08-16 Signal Pharmaceuticals, Llc Solid forms of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, as TOR kinase inhibitors
US9474757B2 (en) 2013-04-17 2016-10-25 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
US9505764B2 (en) 2013-04-17 2016-11-29 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
US9512129B2 (en) 2014-04-16 2016-12-06 Signal Pharmaceuticals, Llc Solid forms comprising 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one and a coformer
US9604939B2 (en) 2013-05-29 2017-03-28 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-YL)pyridin-3-YL)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-B]pyrazin-2(1H)-one, a solid form thereof and methods of their use
KR20170036109A (ko) * 2014-08-21 2017-03-31 화이자 인코포레이티드 Jak 억제제로서의 아미노피리미디닐 화합물
US9630966B2 (en) 2013-04-17 2017-04-25 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
US9732097B2 (en) 2015-05-11 2017-08-15 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor
US9782427B2 (en) 2013-04-17 2017-10-10 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
US9937169B2 (en) 2013-04-17 2018-04-10 Signal Pharmaceuticals, Llc Methods for treating cancer using dihydropyrazino-pyrazine compound combination therapy
US9988401B2 (en) 2015-05-11 2018-06-05 Incyte Corporation Crystalline forms of a PI3K inhibitor
US10077277B2 (en) 2014-06-11 2018-09-18 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US10214519B2 (en) 2016-09-23 2019-02-26 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10227350B2 (en) 2016-09-23 2019-03-12 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10336759B2 (en) 2015-02-27 2019-07-02 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US10479770B2 (en) 2016-09-23 2019-11-19 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US11096940B2 (en) 2017-06-22 2021-08-24 Celgene Corporation Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection
US11304953B2 (en) 2017-05-23 2022-04-19 Mei Pharma, Inc. Combination therapy
US11351176B2 (en) 2017-08-14 2022-06-07 Mei Pharma, Inc. Combination therapy

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1020462A1 (fr) * 1997-07-24 2000-07-19 Zenyaku Kogyo Kabushiki Kaisha Composes heterocycliques et agent antitumoral contenant lesdits composes utilises comme ingredients actifs
WO2004048365A1 (fr) * 2002-11-21 2004-06-10 Chiron Corporation Pyrimidines 2,4,6-trisubstitutees utilisees comme inhibiteurs de phosphotidylinositol (pi) 3-kinase et leur utilisation dans le traitement du cancer
EP1557415A1 (fr) * 2002-10-25 2005-07-27 Zenyaku Kogyo Kabushikikaisha Composes heterocycliques et medicaments antitumoraux contenant ces derniers en tant qu'ingredient actif

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1020462A1 (fr) * 1997-07-24 2000-07-19 Zenyaku Kogyo Kabushiki Kaisha Composes heterocycliques et agent antitumoral contenant lesdits composes utilises comme ingredients actifs
EP1557415A1 (fr) * 2002-10-25 2005-07-27 Zenyaku Kogyo Kabushikikaisha Composes heterocycliques et medicaments antitumoraux contenant ces derniers en tant qu'ingredient actif
WO2004048365A1 (fr) * 2002-11-21 2004-06-10 Chiron Corporation Pyrimidines 2,4,6-trisubstitutees utilisees comme inhibiteurs de phosphotidylinositol (pi) 3-kinase et leur utilisation dans le traitement du cancer

Cited By (106)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8163763B2 (en) 2008-07-31 2012-04-24 Genentech, Inc. Pyrimidine compounds, compositions and methods of use
US8309546B2 (en) 2008-10-14 2012-11-13 Daiichi Sankyo Company, Limited Morpholinopurine derivatives
WO2010044401A1 (fr) 2008-10-14 2010-04-22 第一三共株式会社 Dérivé de morpholinopurine
US8097622B2 (en) 2008-10-14 2012-01-17 Daiichi Sankyo Company, Limited Morpholinopurine derivatives
CN102209714A (zh) * 2008-11-10 2011-10-05 巴塞尔大学 三嗪、嘧啶和吡啶类似物和它们作为治疗剂和诊断探针的应用
WO2010092962A1 (fr) 2009-02-12 2010-08-19 アステラス製薬株式会社 Dérivé d'hétérocycle
US9108980B2 (en) 2009-03-27 2015-08-18 Vetdc, Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
US8772287B2 (en) 2009-03-27 2014-07-08 Vetdc, Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
US8461158B2 (en) 2009-03-27 2013-06-11 Pathway Therapeutics Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
US8772480B2 (en) 2009-04-28 2014-07-08 Amgen Inc. Inhibitors of PI3 kinase and/or mTOR
US8362241B2 (en) 2009-04-28 2013-01-29 Amgen Inc. Inhibitors of PI3 kinase and/or mTOR
US9434746B2 (en) 2009-06-29 2016-09-06 Incyte Corporation Pyrimidinones as PI3K inhibitors
US8940752B2 (en) 2009-06-29 2015-01-27 Incyte Corporation Pyrimidinones as PI3K inhibitors
US11401280B2 (en) 2009-06-29 2022-08-02 Incyte Holdings Corporation Pyrimidinones as PI3K inhibitors
US10829502B2 (en) 2009-06-29 2020-11-10 Incyte Corporation Pyrimidinones as PI3K inhibitors
US10428087B2 (en) 2009-06-29 2019-10-01 Incyte Corporation Pyrimidinones as PI3K inhibitors
US9975907B2 (en) 2009-06-29 2018-05-22 Incyte Holdings Corporation Pyrimidinones as PI3K inhibitors
US8486939B2 (en) 2009-07-07 2013-07-16 Pathway Therapeutics Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy
JP2013505965A (ja) * 2009-09-29 2013-02-21 エックスカバリー ホールディング カンパニー エルエルシー Ｐｉ３ｋ（デルタ）選択的阻害剤
CN102741253A (zh) * 2009-09-29 2012-10-17 艾科睿控股公司 PI3K(δ)选择性抑制剂
WO2011041399A3 (fr) * 2009-09-29 2011-08-18 Tyrogenex, Inc. Inhibiteurs sélectifs de la pi3k (delta)
US8569296B2 (en) 2009-09-29 2013-10-29 Xcovery Holding Company, Llc PI3K (delta) selective inhibitors
EP2762142A1 (fr) 2009-10-30 2014-08-06 ARIAD Pharmaceuticals, Inc. Compositions pour le traitement du cancer
US8288381B2 (en) 2009-11-12 2012-10-16 Genentech, Inc. N-9 substituted purine compounds, compositions and methods of use
WO2011058025A1 (fr) 2009-11-12 2011-05-19 F. Hoffmann-La Roche Ag Composés de pyrazolopyrimidine et de purine n-7-substitués, compositions et procédés d'utilisation correspondants
US8828990B2 (en) 2009-11-12 2014-09-09 Genentech, Inc. N-7 substituted purine and pyrazolopyrimine compounds, compositions and methods of use
WO2011058027A2 (fr) 2009-11-12 2011-05-19 F. Hoffmann-La Roche Ag Composés de purine n-9-substitués, compositions et procédés d'utilisation
US8680108B2 (en) 2009-12-18 2014-03-25 Incyte Corporation Substituted fused aryl and heteroaryl derivatives as PI3K inhibitors
US9403847B2 (en) 2009-12-18 2016-08-02 Incyte Holdings Corporation Substituted heteroaryl fused derivatives as P13K inhibitors
US9555033B2 (en) 2010-02-03 2017-01-31 Signal Pharmaceuticals, Llc Identification of LKB1 mutation as a predictive biomarker for sensitivity to TOR kinase inhibitors
EP2992878A1 (fr) 2010-02-03 2016-03-09 Signal Pharmaceuticals, LLC Identification d'une mutation lkb1 comme biomarqueur prédictif de la sensibilité aux inhibiteurs de la kinase tor
WO2011114275A1 (fr) 2010-03-15 2011-09-22 University Of Basel Composés spirocycliques et leur utilisation comme agents thérapeutiques et sondes de diagnostic
US9193721B2 (en) 2010-04-14 2015-11-24 Incyte Holdings Corporation Fused derivatives as PI3Kδ inhibitors
WO2011135520A1 (fr) 2010-04-30 2011-11-03 University Of Basel Pipérazinotriazines comme inhibiteurs de pi3k pour une utilisation dans le traitement de troubles antiprolifératifs
JP2013525419A (ja) * 2010-04-30 2013-06-20 ユニバーシティ・オブ・バーゼル 抗増殖性障害の処置における使用のためのｐｉ３ｋ阻害剤としてのピペラジノトリアジン
US9062055B2 (en) 2010-06-21 2015-06-23 Incyte Corporation Fused pyrrole derivatives as PI3K inhibitors
US8912180B2 (en) 2010-08-10 2014-12-16 Astellas Pharma Inc. Heterocyclic compound
WO2012020762A1 (fr) 2010-08-10 2012-02-16 アステラス製薬株式会社 Composé hétérocyclique
JP5765342B2 (ja) * 2010-08-10 2015-08-19 アステラス製薬株式会社 へテロ環化合物
EA023931B1 (ru) * 2010-08-10 2016-07-29 Астеллас Фарма Инк. Гетероциклическое соединение
JPWO2012020762A1 (ja) * 2010-08-10 2013-10-28 アステラス製薬株式会社 へテロ環化合物
US9096600B2 (en) 2010-12-20 2015-08-04 Incyte Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9527848B2 (en) 2010-12-20 2016-12-27 Incyte Holdings Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9815839B2 (en) 2010-12-20 2017-11-14 Incyte Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9108984B2 (en) 2011-03-14 2015-08-18 Incyte Corporation Substituted diamino-pyrimidine and diamino-pyridine derivatives as PI3K inhibitors
WO2012135009A1 (fr) * 2011-03-25 2012-10-04 Incyte Corporation Dérivés de pyrimidine-4,6-diamine en tant qu'inhibiteurs de pi3k
US9126948B2 (en) 2011-03-25 2015-09-08 Incyte Holdings Corporation Pyrimidine-4,6-diamine derivatives as PI3K inhibitors
US10064868B2 (en) 2011-03-28 2018-09-04 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US10335415B2 (en) 2011-03-28 2019-07-02 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US11400097B2 (en) 2011-03-28 2022-08-02 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US10603324B2 (en) 2011-03-28 2020-03-31 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US9056852B2 (en) 2011-03-28 2015-06-16 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
WO2013019927A1 (fr) 2011-08-03 2013-02-07 Signal Pharmaceuticals, Llc Identification d'un profil d'expression génique à titre de biomarqueur prédictif de l'état lkb1
US10646492B2 (en) 2011-09-02 2020-05-12 Incyte Corporation Heterocyclylamines as PI3K inhibitors
US10376513B2 (en) 2011-09-02 2019-08-13 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US10092570B2 (en) 2011-09-02 2018-10-09 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US11819505B2 (en) 2011-09-02 2023-11-21 Incyte Corporation Heterocyclylamines as PI3K inhibitors
US9730939B2 (en) 2011-09-02 2017-08-15 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US11433071B2 (en) 2011-09-02 2022-09-06 Incyte Corporation Heterocyclylamines as PI3K inhibitors
US9199982B2 (en) 2011-09-02 2015-12-01 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US9707233B2 (en) 2011-09-02 2017-07-18 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US9309251B2 (en) 2012-04-02 2016-04-12 Incyte Holdings Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
US10259818B2 (en) 2012-04-02 2019-04-16 Incyte Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
US9944646B2 (en) 2012-04-02 2018-04-17 Incyte Holdings Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
WO2013174794A1 (fr) 2012-05-23 2013-11-28 F. Hoffmann-La Roche Ag Compositions et procédés d'obtention et d'utilisation de cellules endodermiques et d'hépatocytes
WO2014005182A1 (fr) * 2012-07-04 2014-01-09 Monash University Inhibiteurs de phosphoinositide 3-kinase (pi3k)
US9155736B2 (en) 2012-10-18 2015-10-13 Signal Pharmaceuticals, Llc Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity
US9557338B2 (en) 2012-10-18 2017-01-31 Signal Pharmaceuticals, Llc Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for tor kinase inhibitory activity
WO2014164942A1 (fr) * 2013-03-13 2014-10-09 The Regents Of The University Of Michigan Inhibiteurs doubles de mek/pi3k et procédés thérapeutiques les utilisant
JP2016516702A (ja) * 2013-03-13 2016-06-09 ザ リージェンツ オブ ザ ユニバーシティー オブ ミシガン Ｍｅｋ／ｐｉ３ｋ二重阻害剤および該阻害剤を使用する治療方法
US9474757B2 (en) 2013-04-17 2016-10-25 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
US10183019B2 (en) 2013-04-17 2019-01-22 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
US9359364B2 (en) 2013-04-17 2016-06-07 Signal Pharmaceuticals, Llc Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b] pyrazin-2(1H)-one
US9358232B2 (en) 2013-04-17 2016-06-07 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
US9980963B2 (en) 2013-04-17 2018-05-29 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
US9505764B2 (en) 2013-04-17 2016-11-29 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
US9630966B2 (en) 2013-04-17 2017-04-25 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
US10391092B2 (en) 2013-04-17 2019-08-27 Signal Pharmaceuticals, Llc Methods for treating cancer using dihydropyrazino-pyrazine compound combination therapy
US10052322B2 (en) 2013-04-17 2018-08-21 Signal Pharmaceuticals, Llc Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one
US9937169B2 (en) 2013-04-17 2018-04-10 Signal Pharmaceuticals, Llc Methods for treating cancer using dihydropyrazino-pyrazine compound combination therapy
US9782427B2 (en) 2013-04-17 2017-10-10 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
US9827243B2 (en) 2013-04-17 2017-11-28 Signal Pharmaceuticals, Llc Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one
US9604939B2 (en) 2013-05-29 2017-03-28 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-YL)pyridin-3-YL)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-B]pyrazin-2(1H)-one, a solid form thereof and methods of their use
US9974786B2 (en) 2013-05-29 2018-05-22 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3- B]pyrazin-2(1H)-one, a solid form there of and methods of their use
US9795603B2 (en) 2013-05-29 2017-10-24 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-B]pyrazin-2(1H)-one, a solid form thereof and methods of their use
US10052323B2 (en) 2013-05-29 2018-08-21 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1H)-one, a solid form thereof and methods of their use
US9975898B2 (en) 2014-04-16 2018-05-22 Signal Pharmaceuticals, Llc Solid forms of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-YL)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1H)-one as tor kinase inhibitors
US9981971B2 (en) 2014-04-16 2018-05-29 Signal Pharmaceuticals, Llc Solid forms of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one as TOR kinase inhibitors
US9416134B2 (en) 2014-04-16 2016-08-16 Signal Pharmaceuticals, Llc Solid forms of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, as TOR kinase inhibitors
US9512129B2 (en) 2014-04-16 2016-12-06 Signal Pharmaceuticals, Llc Solid forms comprising 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one and a coformer
US11130767B2 (en) 2014-06-11 2021-09-28 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US10077277B2 (en) 2014-06-11 2018-09-18 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US10479803B2 (en) 2014-06-11 2019-11-19 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
KR101877189B1 (ko) * 2014-08-21 2018-07-10 화이자 인코포레이티드 Jak 억제제로서의 아미노피리미디닐 화합물
KR20170036109A (ko) * 2014-08-21 2017-03-31 화이자 인코포레이티드 Jak 억제제로서의 아미노피리미디닐 화합물
US11084822B2 (en) 2015-02-27 2021-08-10 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US10336759B2 (en) 2015-02-27 2019-07-02 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US10125150B2 (en) 2015-05-11 2018-11-13 Incyte Corporation Crystalline forms of a PI3K inhibitor
US9988401B2 (en) 2015-05-11 2018-06-05 Incyte Corporation Crystalline forms of a PI3K inhibitor
US9732097B2 (en) 2015-05-11 2017-08-15 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor
US10479770B2 (en) 2016-09-23 2019-11-19 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10227350B2 (en) 2016-09-23 2019-03-12 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10214519B2 (en) 2016-09-23 2019-02-26 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US11304953B2 (en) 2017-05-23 2022-04-19 Mei Pharma, Inc. Combination therapy
US11096940B2 (en) 2017-06-22 2021-08-24 Celgene Corporation Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection
US11351176B2 (en) 2017-08-14 2022-06-07 Mei Pharma, Inc. Combination therapy

Similar Documents

Publication Publication Date Title
US20090270390A1 (en) Pyrimidine derivatives
WO2008032033A1 (fr) Dérivés de 4-benzimidazolyl-2-morpholino-6-pipérazinylpyrimidine utilisés en tant que pi3k et inhibiteurs de mtor destinés au traitement de troubles prolifératifs
US20090233926A1 (en) 2-benzimidazolyl-6-morpholino-4-piperidin-4-ylpyrimidine derivatives as pi3k and mtor inhibitors for the treatment of proliferative disorders
US7893063B2 (en) 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in the treatment of cancer
US20100022534A1 (en) 2-benzimidazolyl-6-morpholino-4- (azetidine, pyrrolidine, piperidine or azepine) pyrimidine derivatives as pi3k and mtor inhibitors for the treatment of proliferative disorders
EP1768978B1 (fr) Pyrimidines a substitution triple aux positions 2, 4, 6 utilises en tant qu'inhibiteurs de phosphotidylinositol (pi) 3-kinase et utilisations de celles-ci pour traiter un cancer
US20090325954A1 (en) 2-benzimidazolyl-6-morpholino-4-phenylpyrimidine derivatives as pi3k and mtor inhibitors for the treatment of proliferative disorders
WO2008032060A1 (fr) Dérivés de 4-benzimidaz0lyl-6-m0rph0lin0-2-pipérazinylpyrimidine utilisés comme inhibiteurs de p13k et mtor dans le traitement de troubles prolifératifs
WO2008032036A1 (fr) Dérivés de 6-benzimidazolyl-2-morpholino-4-(azétidine, pyrrolidine, piperidine ou azépine) pyrimidine comme inhibiteurs de pi3k et mtor pour le traitement de troubles prolifératifs
WO2008032091A1 (fr) Dérivés de pyrimidine
WO2007066099A1 (fr) Derives de pyrimidine
WO2008032077A1 (fr) Dérivés de pyrimidine
WO2007066102A1 (fr) Derives de pyrimidine
WO2008032089A1 (fr) Dérivés de 4-benzimidaz0lyl-2-m0rph0lin0-6-piperidin-4-ylpyrimidine utilisés comme inhibiteurs de p13k et de mtor pour le traitement de troubles prolifératifs
WO2008032027A1 (fr) Dérivés de pyrimidine
US20080051401A1 (en) 2,4,6-Trisubstituted Pyrimidines as Phosphotidylinositol (Pi) 3-Kinase Inhibitors and Their Use in the Treatment of Cancer
US20090118336A1 (en) Pyrazole derivatives and their use as pi3k inhibitors
WO2007066103A1 (fr) Dérivés de pyrimidine utilisés comme inhibiteurs de la pi3k de classe i
US20090076009A1 (en) Thiazole derivatives and their use as anti-tumour agents
WO2008032041A1 (fr) Dérivés de la pyrimidine à activité inhibitrice contre les enzymes pi3k
KR20070032064A (ko) 포스포티딜이노시톨(ｐｉ) 3-키나제 저해제로서의2,4,6-삼치환 피리미딘 및 암 치료에 있어서의 이의 용도

Legal Events

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

Ref document number: 07804212

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07804212

Country of ref document: EP

Kind code of ref document: A1