Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D475/00—Heterocyclic compounds containing pteridine ring systems
  • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
  • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D475/00—Heterocyclic compounds containing pteridine ring systems
  • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
  • C07D475/10—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with an aromatic or hetero-aromatic ring directly attached in position 2

Definitions

• the present invention relates to compounds which act as mTOR inhibitors, their use and their synthesis.
• Background Growth factor/mitogenic activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway ultimately leads to the key cell cycle and growth control regulator mTOR, the mammalian target of rapamycin (alternatively referred to as FRAP (FKBP 12 and rapamycin associated protein), RAFTl (rapamycin and FKBP12 target 1), RAPTl (rapamycin target 1) - all derived from the interaction with the FK-506-binding protein FKBP 12, and SEP (sirolimus effector protein)).
• FRAP FKBP 12 and rapamycin associated protein
• RAFTl rapamycin and FKBP12 target 1
• RAPTl rapamycin target 1
• SEP sirolimus effector protein
• mTOR is a mammalian serine/threonine kinase of approximately 289 kDa in size and a member of the evolutionary conserved eukaryotic TOR kinases (refs. 1-4).
• the mTOR protein is a member of the PB-kinase like kinase (PIKK) family of proteins due to its C-terminal homology (catalytic domain) with PI3-kinase and the other family members, e.g. DNA-PKcs (DNA dependent protein kinase), ATM (Ataxia- telangiectasia mutated).
• mTOR In addition to a catalytic domain in the C-terminus, mTOR contains a FKBP12/rapamycin complex binding domain (FRB). At the N-terminus up to 20 HEAT (Huntingtin, EF3, alpha regulatory subunit of PP2A and TOR) motifs are found whilst more C-terminal is a FAT (FRAP-ATM-TRRAP) domain, and at the extreme C-terminus of the protein an additional FAT domain is found (FAT-C) (refs. 5,6). TOR has been identified as a central regulator of both cell growth (size) and proliferation, which is in part governed by translation initiation.
• FAT FAT
• S6-kinase S6-kinase
• S6K1 S6-kinase 1
• eIF4E eukaryotic translation initiation factor 4E
• PHAS- I eukaryotic translation initiation factor 4E-BP1
• This modification prevents PHAS-I binding eIF4E, thereby permitting formation of an active eIF4F translation complex (reviewed in refs. 10,11,12).
• Activation of these signalling elements is dependant on insulin, other growth factors and nutrients suggesting a gatekeeper role for mTOR in the control of cell cycle progression only under favourable environmental conditions.
• the PI3K/AKT signalling cascade lies upstream of mTOR and this has been shown to be deregulated in certain cancers and results in growth factor independent activation in, for example, PTEN deficient cells.
• mTOR lies at the axis of control for this pathway and inhibitors of this kinase (e.g. sirolimus (rapamycin or RapamuneTM) and everolimus (RADOOl or CerticanTM)) are already approved for immunosuppression and drug eluting stents (reviewed in refs. 13, 14), and are now receiving particular interest as novel agents for cancer treatment.
• sirolimus rapamycin or RapamuneTM
• RADOOl or CerticanTM everolimus
• Tumour cell growth arises from the deregulation of normal growth control mechanisms such as the loss of tumour suppressor function(s).
• One such tumour suppressor is the phosphatase and tensin homologue deleted from chromosome ten (PTEN).
• PTEN phosphatase and tensin homologue deleted from chromosome ten
• MMAC multiple advanced cancers
• PI3K converts phosphatidylinositol 4,5, bisphosphate (PIP2) to phosphatidylinositol 3,4,5, triphosphate (PIP3) whilst PTEN is responsible for removing the 3' phosphate from PIP3 producing PIP2.
• PIP3-K and PTEN act to maintain an appropriate level of PIP3 which recruits and thus activates AKT (also known as PKB) and the downstream signalling cascade that is then initiated. In the absence of PTEN, there is inappropriate regulation of this cascade, AKT becomes effectively constitutively activated and cell growth is deregulated.
• mTOR rapamycin
• rapamycin potently inhibits proliferation or growth of cells derived from a range of tissue types such as smooth muscle, T-cells as well as cells derived from a diverse range of tumour types including rhabdomyosarcoma, neuroblastoma, glioblastoma and medulloblastoma, small cell lung cancer, osteosarcoma, pancreatic carcinoma and breast and prostate carcinoma (reviewed in ref. 20).
• Rapamycin has been approved and is in clinical use as an immunosuppressant, its prevention of organ rejection being successful and with fewer side effects than previous therapies (refs. 20, 21). Inhibition of mTOR by rapamycin and its analogues (RADOOl, CCI-779) is brought about by the prior interaction of the drug with the FK506 binding protein, FKBP12. Subsequently, the complex of FKBP12/rapamycin then binds to the FRB domain of mTOR and inhibits the downstream signalling from mTOR.
• PI3K, LY294002 and wortmannin also have been shown to inhibit the kinase function of mTOR but act through targeting the catalytic domain of the protein (ref. 21). Further to the inhibition of mTOR function by small molecules targeted to the kinase domain, it has been demonstrated that kinase dead mTOR cannot transmit the upstream activating signals to the downstream effectors of mTOR, PHAS- 1 or p70S6 kinase (ref. 22). It is also shown that not all functions of mTOR are rapamycin sensitive and this may be related to the observation that rapamycin alters the substrate profile of mTOR rather than inhibiting its activity per se (ref. 23).
• mTOR-Rictor complex representing a rapamycin insensitive activity of mTOR (B) (Sarbassov et al Current Biology, 2004, 14, 1296-1302). This activity likely accounts for the discrepancy between kinase dead mTOR and the alteration of mTOR signalling by rapamycin and its derivatives. The discrepancy also identifies the possibility of a therapeutic advantage in inhibiting directly the catalytic activity of mTOR.
• a catalytic inhibitor of mTOR may be a more effective antagonist of cancer cell proliferation and survival and that rapamycin may be more useful in combination with agents that can compensate for its failure to completely disrupt pathway signalling (Choo and Blenis, Cancer Cell, 2006, 9, 77-79; Hay, Cancer Cell, 2005, 8, 179-183). Therefore, it is proposed that a kinase domain directed inhibitor of mTOR may be a more effective inhibitor of mTOR.
• rapamycin and its derivatives have been shown to potentiate the cytotoxicity of a number of chemotherapies including cisplatin, caniptothecin and doxorubicin (reviewed in ref. 20). Potentiation of ionising radiation induced cell killing has also been observed following inhibition of mTOR (ref. 24).
• chemotherapies including cisplatin, caniptothecin and doxorubicin
• pharmacological inhibitors of mTOR kinase should be of therapeutic value for treatment of the various forms of cancer comprising solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies.
• inhibitors of mTOR kinase 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,
• Renal cell carcinoma in particular has been identified as sensitive to the rapamycin derivative CCI-779, resulting from a loss of VHL expression (Thomas et al. Nature Medicine, 2006, 12, 122-127).
• Tumours that have lost the promyelocytic leukaemia (PML) tumour suppressor have also been shown to be sensitive to inhibition of mTOR by rapamycin as a consequence of disruption of the regulation of the mTOR signalling pathway (Bernadi, Nature, 2006, 442, 779-785) and the use of an mTOR kinase inhibitor in these diseases should be of therapeutic value.
• PML promyelocytic leukaemia
• 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).
• Elevated mTOR kinase activity has been associated with cardiac hypertrophy, which is of clinical importance as a major risk factor for heart failure and is a consequence of increased cellular size of cardiomyocytes (Tee & Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37).
• mTOR kinase inhibitors are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer.
• the vast majority of mTOR pharmacology to date has focused on inhibition of mTOR via rapamycin or its analogues.
• the present inventors have identified compounds which are ATP-competitive inhibitors of mTOR, and hence are non-rapamycin like in their mechanism of action.
• the first aspect of the present invention provides a compound of formula I:
• R 7 is selected from halo, OR 01 , SR S1 , NR N1 R N2 , NR N7a C(O)R cl , NR N7b SO 2 R S2a , an optionally substituted 5- to 20-memberedheteroaryl group, or an optionally substituted Cs -20 aryl group, where R 01 and R S1 are selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 1-7 alkyl group; R N1 and R N2 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C 5-20 aryl group or R N1 and R N2 together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms;
• R C1 is selected from H, an optionally substituted C 5-2O aryl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C 1-7 alkyl group or NR N8 R N9 , where R N8 and R N9 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted 5- to 20-memberedheteroaryl group, an optionally substituted C 5-2 o aryl group or R N8 and R N9 together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms;
• R S2a is selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-memberedheteroaryl group, or an optionally substituted Cj -7 alkyl group;
• R N7a and R N7b are selected from H and a Cj -4 alkyl group;
• R 2 is selected from H
• R 7 is selected from halo, OR 01 , SR S1 , NR N1 R N2 , NR N7a C(O)R cl , NR N7b SO 2 R S2a , an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 5-2O aryl group, where R 01 and R S1 are selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 1-7 alkyl group; R N1 and R N2 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C 5-20 aryl group or R N1 and R N2 together with the nitrogen to which they are bound
• R 2 is selected from H, halo, OR 02 , SR S2b , NR N5 R N6 , an optionally substituted 5- to 20- memberedheteroaryl group, and an optionally substituted C 5-20 aryl group, wherein R 02 and R S2b are selected from H, an optionally substituted Cs -20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 1-7 alkyl group; R N5 and R N6 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, and an optionally substituted C 5-20 aryl group, or R N5 and R N6 together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms. According to a third aspect of the present invention there is provided a compound of formula Ia:
• R 7 is selected from halo, OR 01 , SR S1 , NR N1 R N2 , NR N7a C(O)R cl , NR N7b SO 2 R S2a , an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted Cs -20 aryl group, where R 01 and R S1 are selected from H, an optionally substituted C 5-2O aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C ⁇ . ⁇ alkyl group; R N1 and R N2 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C 5-20 aryl group or R N1 and R N2 together with the nitrogen to which they
• R 2 is selected from H, halo, OR 02 , SR S2b , NR N5 R N6 , an optionally substituted 5- to 20- membered heteroaryl group, and an optionally substituted C 5-20 aryl group, wherein R 02 and R S2b are selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 1-7 alkyl group; R N5 and R N6 are independently selected from H, an optionally substituted Ci -7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, and an optionally substituted C 5-20 aryl group, or R N5 and R N6 together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms.
• R 7 is selected from halo, OR 01 , SR S1 , NR N1 R N2 , NR N7a C(O)R cl 5 NR N7b SO 2 R S2a , an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 5-20 aryl group, where R 01 and R sl are selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 1-7 alkyl group; R N1 and R N2 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C 5-20 aryl group or R N1 and R N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms; R C1 is selected from H, an optionally substituted C 5-2O ary
• R S2a is selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-memberedheteroaryl group, or an optionally substituted C 1-7 alkyl group;
• R N7a and R N7b are selected from H and a C 1-4 alkyl group;
• R 2 is selected from H, halo, OR 02 , SR S2b , NR N5 R N6 , an optionally substituted 5- to 20- memberedheteroaryl group, and an optionally substituted C 5-20 aryl group, wherein R 02 and R S2b are selected from H, an optionally substituted C 5-2O aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 1-7 alkyl group; R N5 and R N6 are independently selected from H, an optionally substituted Ci -7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, and an optionally substituted C 5-20 aryl group, or R N5 and R N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms.
• R 7 is selected from halo, OR 01 , SR S1 , NR N1 R N2 , NR N7a C(O)R cl , NR N7b SO 2 R S2a , an optionally substituted 5- to 20-memberedheteroaryl group, or an optionally substituted C 5-20 aryl group, where R 01 and R SI are selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 1-7 alkyl group; R N1 and R N2 are independently selected from H, an optionally substituted C L7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C 5-20 aryl group or R N1 and R N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;
• R c ⁇ is selected from H, an optionally substituted C 5-2O aryl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C 1-7 alkyl group or NR N8 R N9 , where R N8 and R N9 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted 5- to 20-memberedheteroaryl group, an optionally substituted C 5-20 aryl group or R N8 and R N9 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;
• R s2a is selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-memberedheteroaryl group, or an optionally substituted C 1-7 alkyl group;
• R N7a and R N7b are selected from H and a C 1-4 alkyl group;
• R 2 is selected from H, halo, OR 02 , SR S2b , NR N5 R N6 , an optionally substituted 5- to 20- membered heteroaryl group, and an optionally substituted C 5-20 aryl group, wherein R 02 and R s2b are selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 1-7 alkyl group; R N5 and R N6 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, and an optionally substituted C 5-20 aryl group, or R N5 and R N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms. According to a further aspect of the present invention there is provided a compound of formula Ia:
• R 7 is selected from halo, OR 01 , SR S1 , NR NI R N2 , NR N7a C(O)R CI , NR N7b SO 2 R S2a , an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 5-20 aryl group, where R O1 and R S1 are selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 1-7 alkyl group; R m and R N2 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C 5-20 aryl group or R NI and R N2 together with the nitrogen to which they are bound form
• R CI is selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C ]-7 alkyl group or NR N8 R N9 , where R N8 and R N9 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted 5- to 20-memberedheteroaryl group, an optionally substituted C 5-20 aryl group or R N8 and R N9 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;
• R S2a is selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-memberedheteroaryl group, or an optionally substituted C 1-7 alkyl group;
• R N7a and R N7b are selected from H and a C 1-4 alkyl group;
• R 2 is selected from H, halo, OR 02 , SR S2b , NR N5 R N6 , an optionally substituted 5- to 20- memberedheteroaryl group, and an optionally substituted C 5-20 aryl group, wherein R° 2 and R S2b are selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C 1-7 alkyl group; R N5 and R N6 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, and an optionally substituted C 5-20 aryl group, or R N5 and R N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms.
• a pharmaceutical composition comprising a compound of of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
• a compound of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body.
• a compound of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease ameliorated by the inhibition of mTOR.
• the compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof have activity as pharmaceuticals, in particular as modulators or inhibitors of mTOR activity, and may be used in the treatment of proliferative and hyperproliferative diseases/conditions, examples of which include the following cancers:
• carcinoma including that of the bladder, brain, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, colon, endometrium, thyroid and skin;
• hematopoietic tumors of lymphoid lineage including acute lymphocytic leukaemia, B-cell lymphoma and Burketts lymphoma
• hematopoietic tumours of myeloid lineage including acute and chronic myelogenous leukaemias and promyelocytic leukaemia
• tumours of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma; and (5) other tumours, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma.
• mTOR inhibitors may also be effective as antifungal agents.
• Another further aspect of the invention provides for the use of a compound of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use as an adjunct in cancer therapy or for potentiating tumour cells for treatment with ionizing radiation or chemotherapeutic agents.
• the compounds of the present invention provide a method for treating cancer characterised by inhibition of mTOR, i.e. the compounds may be used to produce an anticancer effect mediated alone or in part by the inhibition of mTOR.
• a compound of the invention is expected to possess a wide range of anti-cancer properties as activating mutations in mTOR have been observed in many human cancers, including but not limited to, melanoma, papillary thyroid tumours, cholangiocarcinomas, colon, ovarian and lung cancers.
• a compound of the invention will possess anti-cancer activity against these cancers.
• a compound of the present invention will possess activity against a range of leukaemias, lymphoid malignancies and solid tumours such as carcinomas and sarcomas in tissues such as the liver, kidney, bladder, prostate, endometrium, breast and pancreas.
• solid tumours such as carcinomas and sarcomas in tissues such as the liver, kidney, bladder, prostate, endometrium, breast and pancreas.
• such compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the skin, colon, thyroid, lungs, endometrium and ovaries.
• Such compounds of the invention are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with mTOR, especially those tumours which are significantly dependent on mTOR for their growth and spread, including for example, certain tumours of the skin, colon, thyroid, endometrium, lungs and ovaries.
• the compounds of the present invention are useful in the treatment of melanomas and gliomas.
• a method for producing a mTOR inhibitory 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 compound of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein.
• a method for producing an anti-cancer 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 compound of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein.
• a method of treating melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt thereof as defined herein.
• a pharmaceutical composition which comprises a compound of the formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a mTOR inhibitory effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a compound of the formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a compound of the formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a compound of the formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of melanoma, glioma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, endometrium, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as man.
• aromatic ring is used herein in the conventional sense to refer to a cyclic aromatic structure, that is, a structure having delocalised ⁇ -electron orbitals.
• Nitrogen-containing heterocyclic ring having from 3 to 8 ring atoms refers to a 3 to 8 membered heterocylic ring containing at least one nitrogen ring atom.
• N 1 aziridine (C 3 ie 3 membered), azetidine (C 4 ie 4 membered), pyrrolidine (tetrahydropyrrole) (C 5 ie 5 membered), pyrroline (e.g., 3-pyrroline,
• Alkyl refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to
• alkyl includes the sub-classes saturated alkyl, alkenyl, alkynyl, saturated cycloalkyl, cycloalkyenyl, cylcoalkynyl, etc., discussed below. Unless otherwise specified, preferable “alkyl” groups are saturated alkyl or saturated cycloalkyl groups, more preferably saturated alkyl groups.
• the prefixes denote the number of carbon atoms, or range of number of carbon atoms.
• C 1-4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms.
• groups of alkyl groups include C 1-4 alkyl ("lower alkyl"), C 1-7 alkyl, and C 1-20 alkyl.
• the first prefix may vary according to other limitations; for example, for unsaturated alkyl groups, the first prefix must be at least 2; for cyclic alkyl groups, the first prefix must be at least 3; etc.
• saturated alkyl group includes saturated linear alkyl and saturated branched alkyl.
• Examples of (unsubstituted) saturated alkyl groups include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ), butyl (C 4 ), pentyl (C 5 ), hexyl (C 6 ), heptyl (C 7 ), octyl (C 8 ), nonyl (C 9 ), decyl (C 10 ), undecyl (Cn), dodecyl (Ci 2 ), tridecyl (C 13 ), tetradecyl (C 14 ), pentadecyl (C 15 ), and eicodecyl (C 20 ).
• Examples of (unsubstituted) saturated linear alkyl groups include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), n-butyl (C 4 ), n-pentyl (amyl) (C 5 ), n-hexyl (C 6 ), and n-heptyl (C 7 ).
• Examples of (unsubstituted) saturated branched alkyl groups include iso-propyl (C 3 ), iso-butyl (C 4 ), sec-butyl (C 4 ), tert-butyl (C 4 ), iso-pentyl (C 5 ), and neo-pentyl (C 5 ).
• Alkenyl refers to an alkyl group having one or more carbon-carbon double bonds. Examples of groups of alkenyl groups include C 2-4 alkenyl, C 2-7 alkenyl, C 2-20 alkenyl.
• Alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds. Examples of groups of alkynyl groups include C 2-4 alkynyl, C 2-7 alkynyl, C 2-20 alkynyl.
• Examples of (unsubstituted) unsaturated alkynyl groups include, but are not limited to, ethynyl (ethinyl, -C ⁇ CH) and 2-pro ⁇ ynyl (propargyl, -CH 2 -C ⁇ CH).
• Cycloalkyl refers to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated), which moiety has from 3 to 20 carbon atoms (unless otherwise specified), including from 3 to 20 ring atoms.
• cycloalkyl includes the sub-classes saturated cycloalkyl, cycloalkenyl and cycloalkynyl.
• each ring has from 3 to 7 ring atoms.
• groups of cycloalkyl groups include C 3-20 cycloalkyl, C 3-15 cycloalkyl, C 3-10 cycloalkyl, C 3-7 cycloalkyl.
• cycloalkyl groups include, but are not limited to, those derived from: saturated monocyclic hydrocarbon compounds: cyclopropane (C 3 ), cyclobutane (C 4 ), cyclopentane (C 5 ), cyclohexane (C 6 ), cycloheptane (C 7 ), methylcyclopropane (C 4 ), dimethylcyclopropane (C 5 ), methylcyclobutane (C 5 ), dimethylcyclobutane (C 6 ), methylcyclopentane (C 6 ), dimethylcyclopentane (C 7 ), methylcyclohexane (C 7 ), dimethylcyclohexane (C 8 ), menthane (Ci 0 ); unsaturated monocyclic hydrocarbon compounds: cyclopropene (C 3 ), cyclobutene (C 4 ), cyclopentene (C 5 ), cyclohexene (C 6 ), methylcyclopropan
• C 10 bornane (C 10 ), norcarane (C 7 ), norpinane (C 7 ), norbornane (C 7 ), adamantane (C 10 ), decalin (decahydronaphthalene) (C 10 ); unsaturated polycyclic .hydrocarbon compounds: camphene (Cio), limonene (Cjo), pinene (C 10 ); polycyclic hydrocarbon compounds having an aromatic ring: indene (C 9 ), indane
• C 9 2,3-dihydro-lH-indene
• C 10 tetraline (1,2,3,4-tetrahydronaphthalene
• C 12 acenaphthene
• fluorene C 13
• phenalene Ci 3
• acephenanthrene C 15
• aceanthrene C 16
• cholanthrene C 20
• Heterocyclyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified), of which from 1 to 10 are ring heteroatoms.
• each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
• the ring heteroatoms are selected from O, N and S.
• the heterocyclic ring may, unless otherwise specified, be carbon or nitrogen linked, and wherein a -CH 2 - group can optionally be replaced by a -C(O)-, and a ring sulphur atom may be optionally oxidised to form the S-oxides.
• the prefixes e.g. C 3-2 O, C 3-7 , C 5-6 , etc.
• groups of heterocyclyl groups include C 3-20 heterocyclyl (ie 3 to 20 membered heterocyclyl), C 5-20 heterocyclyl (ie 5 to 20 membered heterocyclyl), C 3-15 heterocyclyl (ie 3 to 15 membered heterocyclyl), C 5-15 heterocyclyl (ie 5 to 15 membered heterocyclyl), C 3-I2 heterocyclyl (ie 3 to 12 membered heterocyclyl), C 5-12 heterocyclyl (ie 5 to 12 membered heterocyclyl), C 3-10 heterocyclyl (ie 3 to 10 membered heterocyclyl), C 5 , 10 heterocyclyl (ie 5 to 10 membered heterocyclyl), C 3-7 heterocyclyl (ie 3 to 7 membered heterocyclyl), C 5-7 heterocyclyl (ie 5 to 7 membered heterocyclyl), and C 5-6 heterocyclyl (ie 5 to 6 membered heterocyclyl).
• monocyclic heterocyclyl groups include, but are not limited to, those derived from: N 1 : aziridine (C 3 ie 3 memberd), azetidine (C 4 ie 4 membered), pyrrolidine
• pyrroline e.g., 3-pyrroline
• 2,5-dihydropyrrole (C 5 ie 5 membered), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C 5 ie 5 membered), piperidine (C 6 ie 6 membered), dihydropyridine (C 6 ie 6 membered), tetrahydropyridine (C 6 ie 6 membered), azepine (C 7 ie 7 membered);
• O 2 dioxolane (C 5 ie 5 membered), dioxane (C 6 ie 6 membered), and dioxepane (C 7 ie membered);
• O 3 trioxane (C 6 ie 6 membered);
• N 2 imidazolidine (C 5 ie 5 membered), pyrazolidine (diazolidine) (C 5 ie 5 membered), imidazoline (C 5 ie 5 membered), pyrazoline (dihydropyrazole) (C 5 ie 5 membered), piperazine (C 6 ie ⁇ membered);
• N 1 O 1 tetrahydrooxazole (C 5 ie 5 membered), dihydrooxazole (C 5 ie 5 membered), tetrahydroisoxazole (C 5 ie 5 membered), dihydroisoxazole (C 5 ie 5 membered), morpholine (C 6 ie 6 membered), tetrahydrooxazine (C 6 ie 6 membered), dihydrooxazine (C 6 ie 6 membered), oxazine (C 6 ie 6 membered);
• N 1 S 1 thiazoline (C 5 ie 5 membered), thiazolidine (C 5 ie 5 membered), thiomorpholine (C 6 ie 6 membered); N 2 O 1 : oxadiazine (C 6 ie 6 membered);
• NiOiS 1 oxathiazine (C 6 ie 6 membered).
• substituted (non-aromatic) monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, furanoses (C 5 ie 5 membered), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C 6 ie 6 membered), such as allopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose.
• furanoses C 5 ie 5 membered
• pyranoses C 6 ie 6 membered
• allopyranose altropyranose
• glucopyranose glucopyranose
• mannopyranose gulopyranose
• idopyranose idopyranose
• galactopyranose
• Spiro-C 3 - 7 cycloalkyl or heterocyclyl refers to a C 3-7 cycloalkyl or C 3-7 heterocyclyl ring (3 to 7 membered) joined to another ring by a single atom common to both rings.
• C 5-20 aryl The term "C 5-2 O aryl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a C 5-20 aromatic compound, said compound having one ring, or two or more rings (e.g., fused), and having from 5 to 20 ring atoms, and wherein at least one of said ring(s) is an aromatic ring.
• each ring has from 5 to 7 ring atoms.
• the ring atoms may be all carbon atoms, as in "carboaryl groups” in which case the group may conveniently be referred to as a “Cs -20 carboaryl” group.
• C 5-20 aryl groups which do not have ring heteroatoms include, but are not limited to, those derived from benzene (i.e. phenyl) (C O ), naphthalene (C 10 ), anthracene (C 14 ), phenanthrene (C 14 ), and pyrene (C 16 ).
• the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur, as in “heteroaryl groups".
• the group may conveniently be referred to as a “C 5-2O heteroaryl” group, wherein “C 5-20 " denotes ring atoms, whether carbon atoms or heteroatoms (or otherwise referred to as a 5 to membered heteroaryl group).
• each ring has from 5 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
• heteroatoms are selected from oxygen, nitrogen or sulphur.
• C 5-20 heteroaryl groups include, but are not limited to, C 5 heteroaryl groups (5 membered heteroaryl groups) derived from furan (oxole), thiophene (thiole), pyrrole (azole), imidazole (1,3-diazole), pyrazole (1,2-diazole), triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole and oxatriazole; and C 6 heteroaryl groups (6 membered heteroaryl groups) derived from isoxazine, pyridine (azine), pyridazine (1,2-diazine), pyrimidine (1,3-diazine; e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) and triazine.
• C 5 heteroaryl groups (5 membered heteroaryl
• the heteroaryl group may be bonded via a carbon or hetero ring atom.
• C 5-2O heteroaryl groups which comprise fused rings include, but are not limited to, C 9 heteroaryl groups (9 membered heteroaryl groups) derived from benzofuran, isobenzofuran, benzothiophene, indole, isoindole; C 10 heteroaryl groups (10 membered heteroaryl groups) derived from quinoline, isoquinoline, benzodiazine, pyridopyridine; C 14 heteroaryl groups (14 membered heteroaryl groups) derived from acridine and xanthene.
• Halo -F, -Cl, -Br, and -I.
• Ether -OR, wherein R is an ether substituent, for example, a C 1-7 alkyl group (also referred to as a C 1-7 alkoxy group), a C 3-20 heterocyclyl group (also referred to as a C 3-20 heterocyclyloxy group), or a C 5-20 aryl group (also referred to as a C 5-20 aryloxy group), preferably a C 1-7 alkyl group.
• R is an ether substituent, for example, a C 1-7 alkyl group (also referred to as a C 1-7 alkoxy group), a C 3-20 heterocyclyl group (also referred to as a C 3-20 heterocyclyloxy group), or a C 5-20 aryl group (also referred to as a C 5-20 aryloxy group), preferably a C 1-7 alkyl group.
• R is an acyl substituent, for example, H, a C 1-7 alkyl group (also referred to as C 1-7 alkylacyl or C 1-7 alkanoyl), a C 3-20 heterocyclyl group (also referred to as C 3-20 heterocyclylacyl), or a C 5-20 aryl group (also referred to as C 5-20 arylacyl), preferably a C 1-7 alkyl group.
• R is an acyl substituent, for example, H, a C 1-7 alkyl group (also referred to as C 1-7 alkylacyl or C 1-7 alkanoyl), a C 3-20 heterocyclyl group (also referred to as C 3-20 heterocyclylacyl), or a C 5-20 aryl group (also referred to as C 5-20 arylacyl), preferably a C 1-7 alkyl group.
• Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C(O)NR 1 R 2 , wherein
• R 1 and R 2 are independently amino substituents, as defined for amino groups.
• amido groups include, but are not limited to, -C(O)NH 2 , -C(O)NHCH 3 , -C(O)N(CH 3 ) 2 , -C(O)NHCH 2 CH 3 , and -C(O)N(CH 2 CH 3 ) 2 , as well as amido groups in which R 1 and R 2 , together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinylcarbonyl.
• R and R are independently amino substituents, for example, hydrogen, a C 1-7 alkyl group (also referred to as C 1-7 alkylamino or di-C 1-7 alkylamino), a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably H or a C 1-7 alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
• amino groups include, but are not limited to, -NH 2 , -NHCH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , and -NHPh.
• cyclic amino groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, perhydrodiazepinyl, morpholino, and thiomorpholino.
• the cylic amino groups may be substituted on their ring by any of the substituents defined here, for example carboxy, carboxylate and amido.
• Aminosulfonyl -S( 1 O) 2 NR 1 R 2 wherein R 1 and R 2 each independently is an amino substituent, as defined for amino groups.
• R 1 is an amide substituent, for example, hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably H or a C 1-7 alkyl group, most preferably H
• R 2 is an acyl substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
• R 1 and R 2 may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl:
• R 2 and R 3 are independently amino substituents, as defined for amino groups, and Rl is a ureido substituent, for example, hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably hydrogen or a C 1-7 alkyl group.
• Acyloxy (reverse ester): -0C( 0)R, wherein R is an acyloxy substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
• R is an acyloxy substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
• Thiol : -SH.
• C 1-7 alkylthio groups include, but are not limited to, -SCH 3 and -SCH 2 CH 3 .
• R is a sulfoxide substituent, for example, a Ci- 7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
• Sulfonyl (sulfone): -S( O) 2 R, wherein R is a sulfone substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-2O aryl group, preferably a C 1-7 alkyl group.
• R is a sulfone substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-2O aryl group, preferably a C 1-7 alkyl group.
• Thioamido (thiocarbamyl): -Q S)NR 1 R 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups.
• R 1 is an amino substituent, as defined for amino groups
• R is a sulfonamino substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
• two or more adjacent substituents may be linked such that together with the atoms to which they are attached from a C 3-7 cycloalkyl, C 3-20 heterocyclyl or C 5-20 aryl ring.
• the groups that form the above listed substituent groups e.g. C 1-7 alkyl, C 3-20 heterocyclyl and C 5-2O aryl, may themselves be substituted.
• the above definitions cover substituent groups which are substituted.
• R 7 is halo, OR 01 , SR SI , NR N1 R N2 , NR N7a C(-O)R cl , NR N7b SO 2 R S2a , a C 5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 5-2 oaryl, C 5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl
• R N1 and R N2 are independently H, a C 1-7 alkyl group, a C 5-20 heteroaryl group, a C 5-20 aryl group or R N1 and R N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, where each C 1-7 alkyl, C 5-20 heteroaryl, C 5-20 aryl or heterocyclic is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 5-2 oaryl, C 5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sul
• R S2a is H, a C 5-20 aryl group, a C 5-20 heteroaryl group, or a C 1-7 alkyl group where each Ci- 7 alkyl, C 5-20 heteroaryl or C 5-20 aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or Ci -7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 Cy cloalkyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 5-20 aryl, C 5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro,
• R N7a and R N7b are H or a C 1-4 alkyl group
• R 2 is H, halo, OR 02 , SR S2b , NR N5 R N6 , a C 5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or Q ⁇ alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C3- 7 cycloalkyl, C 3-7 cycloalkenyl, C 3-2 oheterocyclyl ?
• R N1 and R N2 are independently H, a C 1-7 alkyl group, a C 5 . 2 oheteroaryl group, a C 5-20 aryl group or R N1 and R N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, where each C 1-7 alkyl, C 5-2 oheteroaryl, C 5-2O aTyI or heterocyclic is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2- 7alkynyl, C 3 _ 7 cycloalkyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 5-20 aryl, C 5-2 oheteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido,
• R C1 is H, a C 5-20 aryl group, a C 5-2O heteroaryl group, a Ci -7 alkyl group or NR N8 R N9 where R N8 and R N9 are independently selected from H, a Ci -7 alkyl group, a C 5-20 heteroaryl group, a C 5-20 aryl group or R N8 and R N9 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, where each Ci -7 alkyl, C 5- 20 heteroaryl, C
• R S2a is H, a C 5-20 aryl group, a C 5-20 heteroaryl group, or a C 1-7 alkyl group where each C 1- 7 alkyl, C 5-20 heteroaryl or C 5-20 aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 5-2 oaryl, C 5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro
• R N7a and R N7b are H or a C 1-4 alkyl group;
• R 2 is H, halo, OR 02 , SR S2b , NR N5 R N6 , a C 5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-2 oheterocyclyl, C 5-20 aryl, C 5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo,
• R° 2 and R S2b are H, a C 5-20 aryl group, a C 5-20 heteroaryl group, or a C 1-7 alkyl group where each C 1-7 alkyl, C 5-20 heteroaryl or Cs -2 oaryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C 1-7 alkyl, C 2 - 7 alkenyl, C 2 - 7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-2 oheterocyclyl, C 5-2 oaryl, C 5-20 heteroaryl
• R S2a is H, a C 5-20 aryl group, a C 5-20 heteroaryl group, or a C 1-7 alkyl group where each C 1- 7 alkyl, C 5-20 heteroaryl or C 5-2 oaryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C ⁇ alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-2 oheterocyclyl, C 5 , 20 aryl, Cs ⁇ oheteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from hal
• R N7a and R N7b are H or a C 1-4 alkyl group;
• R 2 is H, halo, OR 02 , SR S2b , NR N5 R N6 , a C 5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or Ci.
• R NS and R N6 are independently H, a C 1-7 alkyl group, a C 5-20 heteroaryl group, a C 5-20 aryl group, or R N5 and R N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms where each Ci -7 alkyl, Cs ⁇ oheteroaryl, C 5-2 oaryl or heterocyclic ring is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or Ci -7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-2 oheterocyclyl, C 5-20 aryl, C 5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether,
• X 5 and X 8 are N.
• X 5 , X 6 and X 8 are N. More preferably one of X 5 and X 8 is N, and most preferably X 8 is N.
• R 7 is preferably selected from an optionally substituted C 5-20 aryl group, OR 01 , SR S1 ,
• R S2a are as previously defined. It is further preferred that R 7 is preferably selected from an optionally substituted C 5-20 aryl group, OR 01 , NR N1 R N2 , NR N7a C(O)R cl and NR N7b SO 2 R s2a .
• R 7 is OR 01 , then preferably R o1 is a C 1-7 alkyl group, which may be substituted.
• R N2 is selected from H and C 1-4 alkyl (e.g. methyl) and more preferably is H. If R N1 is C 1-7 alkyl, it is preferably selected from C 3-7 cycloalkyl. If
• R Nl is C 5-20 aryl, it is preferably selected from C 5-10 aryl (e.g. phenyl, pyrrolyl, pyridyl, pyrazolyl, furanyl, thiophenyl, pyrazinyl, pyrimidinyl, tetrazolyl, thiazolyl, indazolyl, imidazolyl, triazolyl, oxadiazolyl) and more preferably C 5-6 aryl (e.g.
• Particularly preferred groups include furyl, phenyl, pyridyl, pyrrolyl, pyrazolyl and thiophenyl.
• the aforementioned groups are optionally substituted, and in some embodiments are preferably substituted.
• Substituent groups may include, but are not limited to, C 1-7 alkyl, C 3-20 heterocyclyl, C 5-20 aryl, carboxy, ester, ether (eg Ci -7 alkoxy), hydroxy, aryloxy, cyano, halo, nitro, amido, sulfonyl, sulfonylamino, amino sulfonyl and amino.
• R N7a is preferably H.
• R cl may be an optionally substituted C 5-20 aryl group (e.g. phenyl, imadazolyl, quinoxalinyl), C 3-20 heterocyclyl, C 1-7 alkyl (e.g. propenyl, methyl (substituted with thiophenyl)) or NR N8 R N9 .
• R N8 is preferably hydrogen
• R N9 is preferably C 1-7 alkyl (e.g. ethyl).
• R N7b is preferably H.
• R S2a is preferably C 1-7 alkyl (e.g. methyl).
• R 7 is a C 5-20 aryl group, it is preferably an optionally substituted C 5-10 aryl and more preferably an optionally substituted C 5-6 aryl group. Most preferably it is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from halo, hydroxyl, C 1-7 alkyl, C 1-7 alkoxy, C 5-6 arylamino and C[ -7 alkylamino and wherein the susbtitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C 1-7 alkyl, C 1-7 alkoxy, C 5 ⁇ aTyI, C 5-6 arylamino and C ⁇ alkylamino.
• R 7 is a 5 to 20 membered heteroaryl group, it is preferably an optionally substituted 5 to 10 membered heteroaryl and more preferably an optionally substituted 5 or 6 memebered heteroaryl group.
• R 7 is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from halo, hydroxyl, cyano, C 1-7 alkyl, C 1-7 alkoxy, amino (for example -NH 2, C 5-6 arylamino, C 1-7 alkylamino, and di-(C 1 .
• R 7 is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from fluoro, hydroxyl, cyano, nitro, methyl, methoxy, -OCH 2 CH 3 , -NH 2 , -NHSO 2 CH 3 , -CH 2 NHSO 2 CH 3 , -OCHF 2 , -CH 2 OH, -CO 2 H -CONH 2 , -CONHMe, -CONHEt, -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 F, -CONHCH 2 CHF 2 , -CONHCH 2 CH 2 OH, -CONMeEt, -CONMe 2 , N-methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl.
• the optional substituents are preferably selected from fluoro, hydroxyl, cyano, nitro, methyl, methoxy, -OCH 2 CH 3 , -NH 2 ,
• R 7 is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from fluoro, hydroxyl, cyano, nitro, methyl, methoxy, -CH 2 OH, -CO 2 H 1 -CONH 25 -CONHMe, -CONHEt, -CONHCH 2 CH 2 F, -CONHCH 2 CHF 2 , -CONHCH 2 CH 2 OH, -CONMeEt, -CONMe 2 , N-methylpiperazinylcarbonyl and 4- hydroxypiperidinylcarbonyl.
• the optional substituents are preferably selected from fluoro, hydroxyl, cyano, nitro, methyl, methoxy, -CH 2 OH, -CO 2 H 1 -CONH 25 -CONHMe, -CONHEt, -CONHCH 2 CH 2 F, -CONHCH 2 CHF 2 , -CONHCH 2 CH 2 OH, -CONMeEt,
• R 7 is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from methoxy, -OCH 2 CH 3 , -NH 2 , -NHSO 2 CH 3 , -CH 2 NHSO 2 CH 3 , -OCHF 2 , -CH 2 OH, -CONH 2 , -CONHMe and -CONHCH(CH 3 ) 2 .
• R 7 is an optionally substituted 5 or 6 memebered nitrogen containing heteroaryl group such as a pyridine group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C 1-7 alkyl, C 1-7 alkoxy, amino (for example -NH 2 , C 5-6 arylamino, C 1-7 alkylamino, and di-(C 1-7 alkyl)amino), and amido (for example -CO 2 NH 2 , -CO 2 NHC 1-7 alkyl, -CO 2 N(C 1-7 alky I) 2 and -CONHheterocycyl) and wherein the susbtitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C 1-7 alkyl, C 1-7 alkoxy, C 5-6 aryl, C 5 .
• the optional substituents are selected from halo, hydroxyl, cyan
• R is a pyridinyl group optionally substituted halo, hydroxyl, cyano, C 1-7 alkyl, C 1-7 alkoxy, amino (for example -NH 2 , C 5-6 arylamino, C 1-7 alkylamino, and di-(C 1-7 alkyl)amino), and amido (for example -CO 2 NH 2 , -CO 2 NHC i -7 alkyl, -CO 2 N(C 1-7 alkyl) 2 and -CONHheterocycyl) and wherein the susbtitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C 1-7 alkyl, C 1-7 alkoxy, C 5-6 aryl, C 5-6 arylamino, di-(C
• R 7 is a pyridinyl group optionally substituted with NH 2 .
• R 7 is an optionally substituted phenyl group selected from
• Z is H, F or OR 03 ;
• R° 3 is selected from hydrogen or an optionally substituted C 1-6 alkyl group
• R N1 ° is selected from hydrogen, C(O)R 02 , C(S)R 03 , SO 2 R S3 , an optionally substituted C 5-20 heterocyclyl group, an optionally substituted C 5-20 aryl group, or an optionally substituted C 1- 10 alkyl group
• R 02 and R 03 are selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted C 5-20 heterocyclyl group, an optionally substituted C 1-7 alkyl group or NR N11 R N12 , where R N ⁇ and R N12 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted C 5-20 heterocyclyl group, an optionally substituted C 5-20 aryl group or R NU and R N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms
• R S3 is selected from H,
• R 7 is an optionally substituted phenyl group selected from
• R ,03 is selected from hydrogen or an optionally substituted C 1-6 alkyl group
• R ,N N l i O ⁇ is selected from C(O)R >C2 , C(S)R >C3 , SO 2 R S ⁇ 3 ⁇ an optionally substituted C 5-20 heteroaryl group, an optionally substituted C 5-20 aryl group, or an optionally substituted Cj -10 alkyl group
• R C2 and R 03 are selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted C 5-20 heteroaryl group, an optionally substituted C 1-7 alkyl group or NR N11 R N12 , where R NU and R N12 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted C 5-20 heteroaryl group, an optionally substituted C 5-20 aryl group or R NU and R NI2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms; and R S3 is selected from H, an optionally substituted C 5-20 aryl group,
• Z is H, F or OR 03 ;
• R N1 ° is selected from hydrogen, C(O)R 02 , an optionally substituted C 5-20 heteroaryl group, an optionally substituted C 5-20 aryl group, or an optionally substituted Ci -10 alkyl group
• R C2 are selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted C 5-20 heterocyclyl group, an optionally substituted C 1-7 alkyl group or NR Nn R N12 , where R NU and R N12 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted C 5-20 heterocycly group, an optionally substituted C 5-20 aryl group or R N11 and R N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;
• R N1Oa is selected from hydrogen or an optionally substituted C 1-10 alkyl group; or
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms.
• R 7 is
• Z is H, F or OR 03 ;
• R N1 ° is selected from hydrogen, C(O)R 02 , an optionally substituted C 5-6 heteroaryl group, an optionally substituted C 6 aryl group, or an optionally substituted C 1-10 alkyl group where R C2 are selected from CH 3 or CH 2 OH; R N1Oa is selected from hydrogen or an optionally substituted C 1-10 alkyl group; or
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms; and where the optional subtsituents are selected from cyano, halo, hydroxyl, C 1-7 alkyloxy,
• R 7 is
• Z is H, F or OR 03 ;
• R N1 ° is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -CH(CH 3 ) 2 , -CH 2 CH 2 OMe, -CH 2 C(CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 2 , -CH(CH 3 )CH 2 C(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , cycloproyl, cyclopentyl, cyclohexyl, cycloheptyl, -Ctbcyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, -CH 2 imidazole ; R N1Oa is hydrogen; or
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms; and where the optional subtsituents are selected from halo, hydroxyl, C 1-7 alkyloxy.
• R 7 is selected from
• R 2 is OR 02 where R° 2 is an optionally substituted C 1-7 alkyl group.
• R 2 is OR 02 where R° 2 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , or -CH(CH 3 )CH 2 N(CH 3 ) 2 .
• R 2 is NR N5 R N6 , where R N5 and R N6 are as previously defined, and more preferably R N5 and R N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, which may optionally be substituted.
• the ring preferably has from 5 to 7 ring atoms.
• Preferred optionally substituted groups include, but are not limited, to imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N- substiruted) and pyrrolidinyl.
• Preferred C-substituents for the groups include Ci -4 alkyl, preferably methyl.
• the groups may bear one or more substituents, for example one or two substituents;
• Preferred C-substituents for the groups include phenyl, ester, amide and Ci -4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxy ethyl,.
• the groups may bear one or more substituents, for example one or two substituents.
• R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound form a heterocyclic ring containing 5 to 7 ring atoms which may be optionally be substituted, wherein the optional substituents are selected from amino, cyano, halo, hydroxyl, ester, a C 3-7 cycloalkyl ring, a C 6 carboaryl ring, a heterocyclic ring containing 5 to 7 ring atoms and C 1-7 saturated alkyl and C 1-7 saturated alkoxy (wherein the heterocyclic ring, the cycloalkyl ring, the carboaryl ring, the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C 1-7 alkoxy, amino and C 5-6 aryl)
• R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 5 to 7 ring atoms which may be optionally be substituted, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C 1-7 saturated alkyl and C 1-7 saturated alkoxy (wherein the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C 1-7 alkoxy, amino and C 5-6 aryl)
• R 2 is NR N5 R N6 , where R N5 is an optionally substituted C 1-7 alkyl group or an optionally substituted phenyl group, and R N6 is hydrogen.
• R 2 is NR N5 R N6 , where R N5 is -CH(CH 3 )CH 2 OCH 3 , cyclopentyl or a phenyl group, and R N6 is hydrogen.
• Preferred R 2 groups are pyrrolidinyl, morpholino, piperadinyl and homopiperadinyl groups. More preferred groups are morpholino and piperadinyl. These are preferably substituted with one or more alkyl substituents, for example methyl or ethyl substituents. More preferably these are substituted with one or two methyl substituents. If these groups bear two methyl substituents, these are preferably on separate carbon atoms.
• the alkyl substituents may also be optionally substituted. Examples of optional substituents of the alkyl substitutents include halo, hydroxy, ether or amino. Particularly preferred groups include methylmorpholino groups, dimethylmorpholino groups and methyl piperidinyl groups, for example:
• More preferred groups are morpholino and piperadinyl. These are preferably substituted with one or more alkyl substituents, for example methyl or ethyl substituents. More preferably these are substituted with one or two methyl substituents. If these groups bear two methyl substituents, these are preferably on separate carbon atoms. Particularly preferred groups include methylniorpholino groups, dimethylmorpholino groups and methyl piperidinyl groups, for example:
• R groups are pyrrolidinyl, morpho>lino, pipe 1 radinyl and homopiperadinyl groups. More preferred groups are morpholino and piperadinyl. These are preferably substituted with one or more alkyl substituents, for example methyl or ethyl substituents.
• alkyl substituents may also be optionally substituted.
• optional substituents of the alkyl substitutents include halo, hydroxy, ether or amino.
• Particularly preferred groups include methylmorpholino groups, dimethylmorpholino groups and methyl piperidinyl groups, for example:
• R 2 groups are optionally substituted pyrrolidinyl, morpholino, piperadinyl and homopiperadinyl wherein the optional substituents are selected from hydroxyl, C 1-7 alkyl, C 1-7 alkoxy, amino (for example -NH 2, C 5-6 arylamino, C 1-7 alkylamino, and di-(C 1-7 alkyl)amino), amido (for example -CONH 2 , -CONHC 1-7 alkyl, -CON(C i -7 alkyl) 2 ), ester (for example -CO 2 C 1-7 alkyl), C 6 aryl and 3 to 7 membered heterocyclyl group and wherein the susbtitutent alkyl, alkoxy, aryl or heterocyclyl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C 1-7 alkyl, C 1-7 alkoxy, -NH 2 , di-(C 1-7 alkyl)a
• More preferred groups are morpholino, piperadinyl and homopiperadinyl which may be optionally substited by one or more groups selected from hydroxy., methyl, ethyl, -CO 2 Me, -CO 2 Et, -CH 2 OH, -CH 2 0me, -CH 2 NMe 2 , -CONH 2 , -CONHMe, -CONMe 2 , phenyl, pyrrolidinyl, morpholino and piperadinyl.
• R 2 is selected from
• R 2 is selected from
• R 2 is selected from OR 02 , NR N5 R N6 , an optionally substituted C 5-20 heteroaryl group, and an optionally substituted C 5-2 O aryl group.
• R 7 is an optionally substituted C 5-6 aryl group or an optionally substituted 5 or 6 membered heteraryl group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C 1-7 alkyl, C 1-7 alkoxy, amino (for example -NH 2 , C 5-6 arylamino, Ci.
• R 2 is selected from OR 02 , NR N5 R N6 , an optionally substituted C 5-6 heteroaryl group, and an optionally substituted C 6 aryl group.
• R 2 is selected from OR 02 , NR N5 R N6 , an optionally substituted C 5-6 heteroaryl group, and an optionally substituted C 6 aryl group.
• R 7 is an optionally substituted C 5-6 aryl group or an optionally substituted 5 or 6 membered heteraryl group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C 1-7 alkyl, C 1-7 alkoxy, amino (for example -NH 2, Cs ⁇ arylamino, C 1-7 alkylamino, and di-(C 1-7 alkyl)amino), and amido (for example -CONH 2 ,
• R 7 is an optionally substituted C 5-6 aryl group or an optionally substituted 5 or 6 membered heteraryl group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C 1-7 alkyl, C 1-7 alkoxy, amino (for example -NH 2 , C 5-6 arylamino, C 1-7 alkylamino, and di-(C 1-7 alkyl)amino), and amido (for example -CONH 2 ,
• C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C 1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.
• compounds of formula (I), (Ia) or (Ib), and pharmaceutically acceptable salts thereof in which: only one of X 5 , X 6 and X 8 is N;
• R 2 is selected from OR 02 , NR N5 R N6 , an optionally substituted C 5-20 heteroaryl group, and an optionally substituted C 5-20 aryl group.
• R 2 is selected from OR 02 , NR N5 R N6 , an optionally substituted C 5-20 heteroaryl group, and an optionally substituted C 5-20 aryl group.
• R 7 is an optionally substituted C 5-6 aryl group or an optionally substituted 5 or 6 membered heteraryl group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C 1-7 alkyl, C 1-7 alkoxy, amino (for example -NH 2 , C 5-6 arylamino, C 1-7 alkylamino, and di-(C 1 _ 7 alkyl)amino), and amido (for example -CONH 2 , -CONHC 1-7 alkyl, -CON(C 1-7 alkyl) 2 and -CONHheterocycyl) and wherein the susbtitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C 1-7 alkyl, C 1-7 alkoxy, C 5-6 aryl,
• R 2 is selected from OR 02 , NR N5 R N6 , an optionally substituted C 5-6 heteroaryl group, and an optionally substituted C 6 aryl group.
• R 2 is selected from OR 02 , NR N5 R N6 , an optionally substituted C 5-6 heteroaryl group, and an optionally substituted C 6 aryl group.
• R 7 is an optionally substituted C 5-6 aryl group or an optionally substituted 5 or 6 membered heteraryl group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C 1-7 alkyl, C 1-7 alkoxy, amino (for example -NH 2j C 5-6 arylamino, C 1-7 alkylamino, and di-(C 1-7 alkyl)amino), and amido (for example -CONH 2 ,
• R 7 is an optionally substituted C 5-6 aryl group or an optionally substituted 5 or 6 membered heteraryl group, wherein the optional substituents are selected from halo, hydroxy 1, cyano, C 1-7 alkyl, C 1-7 alkoxy, amino (for example -NH 2j C 5-6 arylamino, Ci -7 alkylamino, and di-(C 1-7 alkyl)amino), and amido (for example -CONH 2 ,
• C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C 1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.
• X 5 and X 6 are each CH; X 8 is N; R 7 is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from fluoro, hydroxyl, cyano, nitro, methyl, methoxy, -OCH 2 CH 3 , -NH 2 , -NHSO 2 CH 3 , -CH 2 NHSO 2 CH 3 , -OCHF 2 , -CH 2 OH, -CO 2 H -CONH 2 , -CONHMe, -CONHEt, -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 F, -CONHCH 2 CHF 2 , -CONHCH 2 CH 2 OH, -CONMeEt, -CONMe 2 , N- methylpiperazinylcarbonyl and 4-
• X 5 and X 6 are each CH;
• X 8 is N;
• R 7 is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from fluoro, hydroxyl, cyano, nitro, methyl, methoxy, -OCH 2 CH 3 , -NH 2 , -NHSO 2 CH 3 , -CH 2 NHSO 2 CH 3 , -OCHF 2 , -CH 2 OH, -CO 2 H -CONH 2 , -CONHMe, -CONHEt, -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 F, -CONHCH 2 CHF 2 , -CONHCH 2 CH 2 OH, -CONMeEt, -CONMe 2 , N- methylpiperazinylcarbon
• C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C 1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.
• X 5 and X 6 are each CH; X 8 is N; R 7 is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from -NH 2 , fluoro, hydroxyl, cyano, nitro, methyl, methoxy, -CH 2 OH 5 -CO 2 H -CONH 2 , -CONHMe, -CONHEt, -CONHCH 2 CH 2 F, -CONHCH 2 CHF 25 -CONHCH 2 CH 2 OH, -CONMeEt, -CONMe 2 , N- methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl; and R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound form an optionally substituted imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadi
• N-substituted) or pyrrolidinyl wherein optional N-substituents on the piperazinyl and homopiperazinyl groups include C 1-7 alkyl groups or esters, in particular, esters bearing a C 1-7 alkyl group as an ester substituent, e.g.
• C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C 1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.
• X 8 is N
• R 7 is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from -NH 2 , fluoro, hydroxyl, cyano, nitro, methyl, methoxy, -CH 2 OH, -CO 2 H -CONH 2 , -CONHMe, -CONHEt, -CONHCH 2 CH 2 F, -CONHCH 2 CHF 2 , -CONHCH 2 CH 2 OH, -CONMeEt, -CONMe 2 , N- methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl; and R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound form an optionally substituted imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-
• optional C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and Ci -4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.
• X 5 and X 6 are each CH; X 8 is N;
• R 7 is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from fluoro, hydroxyl, cyano, nitro, methyl, methoxy, -OCH 2 CH 3 , -NH 2 , -NHSO 2 CH 3 , -CH 2 NHSO 2 CH 3 , -OCHF 2 , -CH 2 OH, -CO 2 H -CONH 2 , -CONHMe, -CONHEt, -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 F, -CONHCH 2 CHF 2 , -CONHCH 2 CH 2 OH, -CONMeEt, -CONMe 2 , N- methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl; and R 2 is a group selected from
• R 7 is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from -NH 2 , fluoro, hydroxyl, cyano, nitro, methyl, methoxy, -CH 2 OH, -CO 2 H -CONH 2 , -CONHMe, -CONHEt, -CONHCH 2 CH 2 F,
• R 2 is a group selected from
• X 8 is N;
• R 7 is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from -NH 2 , fluoro, hydroxyl, cyano, nitro, methyl, methoxy, -CH 2 OH, -CO 2 H -CONH 2 , -CONHMe, -CONHEt, -CONHCH 2 CH 2 F, -CONHCH 2 CHF 25 -CONHCH 2 CH 2 OH, -CONMeEt, -CONMe 2 , N- methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl; and R 2 is a group selected from
• X 8 is N
• R 7 is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3 -hydroxy methy 1-4- methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3- hydroxyphenyl or a 3-hydroxymethylphenyl group; and R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound
• X 5 and X 6 are each CH; X 8 is N;
• R 7 is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4- methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3- hydroxyphenyl or a 3-hydroxymethylphenyl group; and R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound
• R 7 is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4- methoxy -phenyl, 3,5 ⁇ dimethoxy ⁇ 4-hydroxyphenyl, 4-hydroxyphenyl, 3- hydroxyphenyl or a 3-hydroxymethylphenyl group; and R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound
• X 8 is N
• R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound form a
• R N1 ° is selected from hydrogen, C(O)R 02 , an optionally substituted C 5-20 heteroaryl group, an optionally substituted C 5-20 aryl group, or an optionally substituted Ci -10 alkyl group where R 02 are selected from H, an optionally substituted Cs -20 aryl group, an optionally substituted C 5-20 heterocyclyl group, an optionally substituted C 1-7 alkyl group or NR N11 R N12 , where R N11 and R NI2 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted C 5-2O heterocycly group, an optionally substituted C 5-2O aryl group or R N ⁇ and R N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;
• R N1Oa is selected from hydrogen or an optionally substituted C 1-I0 alkyl group; or R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms;
• R° 3 is an optionally substituted C 1-6 alkyl group
• R 2 is selected from NR N5 R N6 , an optionally substituted C 5-20 heteroaryl group, and an optionally substituted C 5-20 aryl group.
• R 2 is selected from NR N5 R N6 , an optionally substituted C 5-20 heteroaryl group, and an optionally substituted C 5-20 aryl group.
• Z is H, F or OR 03
• R 02 are selected from CH 3 or CH 2 OH where the optional subtsituents are selected from cyano, halo, hydroxyl, C 1-7 alkyloxy, C 1-7 alkylamino and di-C 1-7 alkylamino;
• R N1Oa is selected from hydrogen or an optionally substituted C 1-10 alkyl group where the optional subtsituents are selected from cyano, halo, hydroxyl, Ci -7 alkyloxy,
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms, where the optional subtsituents are selected from cyano, halo, hydroxyl, Ci -7 alkyloxy,
• R° 3 is an unsubstituted C 1-3 alkyl group
• R 2 is selected from NR N5 R N6 , an optionally substituted C 5-6 heteroaryl group, and an optionally substituted C 6 aryl group.
• Z is H, F or OR 03 R N1 ° is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH, -CH 3 , -CH 2 CH 3 ,
• R N1Oa is hydrogen
• R NI ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional subtsituents are selected from halo, hydroxyl, C 1-7 alkyloxy;
• R° 3 is a methyl group
• R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 5 to 7 ring atoms which may be optionally be substituted, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C 1-7 saturated alkyl and C 1-7 saturated alkoxy (wherein the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, Ci -7 alkoxy, amino and C 5-6 aryl).
• Z is H, F or OR 03
• R N1 ° is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH, -CH 3 , -CH 2 CH 3 ,
• R N1Oa is hydrogen
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional subtsituents are selected from halo, hydroxyl, C ⁇ alkyloxy;
• R 03 is a methyl group
• R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound form an optionally substituted imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably
• C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C 1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.
• X 8 is N
• Z is H, F or OR 03
• R N1 ° is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH, -CH 3 , -CH 2 CH 3 ,
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional subtsituents are selected from halo, hydroxyl, C 1-7 alkyloxy; R 03 is a methyl group; and
• R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound form an optionally substituted morpholino, thiomorpholino, piperidinyl, homopiperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably
• saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C 1-7 alkoxy, amino and C 5-6 aryl).
• X 8 is N
• Z is H, F or OR 03
• R N1 ° is a R N1 ° is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH, -CH 3 , -CH 2 CH 3 ,
• R N1Oa is hydrogen
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional subtsituents are selected from halo, hydroxyl, C 1-7 alkyloxy;
• R 03 is a methyl group
• R 2 is a group selected from
• Z is H, F or OR 03
• R N1 ° is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -CH(CH 3 ) 2 , -CH 2 CH 2 OMe, -CH 2 C(CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 2 , -CH(CH 3 )CH 2 C(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , cycloproyl, cyclopentyl, cyclohexyl, cycloheptyl, -CH 2 cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, -CH 2 imidazole ; R N1Oa is hydrogen; or
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional subtsituents are selected from halo, hydroxyl, C 1-7 alkyloxy;
• R 03 is a methyl group; and
• R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound
• X 8 is N
• Z is H, F or OR 03 R Nl ° is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH, -CH 3 , -CH 2 CH 3 ,
• R N1Oa is hydrogen
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional subtsituents are selected from halo, hydroxyl, C ⁇ alkyloxy;
• R 03 is a methyl group
• R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound
• R N1 ° is selected from hydrogen, C(O)R 02 , an optionally substituted C 5-20 heteroaryl group, an optionally substituted C 5-20 aryl group, or an optionally substituted C 1-10 alkyl group where R 02 are selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted C 5-20 heterocyclyl group, an optionally substituted C 1-7 alkyl group or NR N11 R N12 , where R NU and R N12 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted C 5-20 heterocycly group, an optionally substituted C 5-20 aryl group or R N ⁇ and R N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms; j ⁇ Ni o a j ⁇ s se i
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms;
• R 03 is an optionally substituted C 1-6 alkyl group
• R 2 is selected from NR N5 R N6 , an optionally substituted C 5-20 heteroaryl group, and an optionally substituted C 5-20 aryl group.
• R N1 ° is selected from hydrogen, C(O)R 02 , an optionally substituted C 5-6 heteroaryl group, an optionally substituted C 6 aryl group, or an optionally substituted C 1-I o alkyl group where R C2 are selected from CH 3 or CH 2 OH where the optional subtsituents are selected from cyano, halo, hydroxyl, C 1-7 alkyloxy, C 1-7 alkylamino and di-C 1-7 alky lamino ; ⁇ Ni o a j s se i ec t e( j f rom hydrogen or an optionally substituted C 1-I0 alkyl group where the optional subtsituents are selected from
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms, where the optional subtsituents are selected from cyano, halo, hydroxyl, Ci -7 alkyloxy,
• R 03 is an unsubstituted C 1-3 alkyl group
• R 2 is selected from NR N5 R N6 , an optionally substituted C 5-6 heteroaryl group, and an optionally substituted C 6 aryl group.
• Z is H, F or OR 03
• R N1 ° is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -CH(CH 3 ) 2 , -CH 2 CH 2 OMe, -CH 2 C(CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 2 , -CH(CH 3 )CH 2 C(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , cycloproyl, cyclopentyl, cyclohexyl, cycloheptyl, -CH 2 cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, -CH 2 imidazole ; R N1Oa is hydrogen; or
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional subtsituents are selected from halo, hydroxyl, C ⁇ alkyloxy;
• R is a methyl group
• R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 5 to 7 ring atoms which may be optionally be substituted, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C 1-7 saturated alkyl and C 1-7 saturated alkoxy (wherein the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C 1-7 alkoxy, amino and C 5-6 aryl).
• Z is H, F or OR 03
• R N1 ° is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -CH(CH 3 ) 2 , -CH 2 CH 2 OMe, -CH 2 C(CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 2 , -CH(CH 3 )CH 2 C(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , cycloproyl, cyclopentyl, cyclohexyl, cycloheptyl, -CH 2 cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, -CH 2 imidazole ; R N1Oa is hydrogen; or R N1 ° and R N 1Oa together with the nitrogen to which they are bound form
• C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C 1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional subtsituents are selected from halo, hydroxyl, Ci.
• R 03 is a methyl group
• R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound form an optionally substituted morpholino, thiomorpholino, piperidinyl, homopiperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group, wherein the optional substituents are selected from cyano, halo, hydroxyl, and Ci -7 saturated alkyl and C 1-7 saturated alkoxy (wherein the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, Ci -7 alkoxy, amino and C 5-6 aryl).
• R ,N m 10 ⁇ is a R )N m 10 ⁇ is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -CH(CH 3 ) 2 , -CH 2 CH 2 OMe, -CH 2 C(CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 2 , -CH(CH 3 )CH 2 C(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , cycloproyl, cyclopentyl, cyclohexyl, cycloheptyl, -CH 2 cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, -CH 2 imidazole ;
• R N1Oa is hydrogen; or
• Z is H, F or OR 03
• R N1 ° is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH 3 -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -CH(CH 3 ) 2 , -CH 2 CH 2 OMe, -CH 2 C(CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 2 , -CH(CH 3 )CH 2 C(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , cycloproyl, cyclopentyl, cyclohexyl, cycloheptyl, -CH 2 cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, -CH 2 imidazole ; R N1Oa is hydrogen; or
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional subtsituents are selected from halo, hydroxyl, C 1-7 alkyloxy; R° 3 is a methyl group; and R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound
• X 5 and X 6 are each CH;
• X 8 is N
• Z is H, F or OR 03 R N1 ° is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH, -CH 3 , -CH 2 CH 3 ,
• R N1Oa is hydrogen
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional subtsituents are selected from halo, hydroxyl, C 1-7 alkyloxy;
• R 03 is a methyl group; and R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound
• R N1 ° is selected from hydrogen, -C(O)CH 3 , -C(O)CH 2 OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -CH(CH 3 ) 2 , -CH 2 CH 2 OMe, -CH 2 C(CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 2 , -CH(CH 3 )CH 2 C(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , cycloproyl, cyclopentyl, cyclohexyl, cycloheptyl, -CH 2 cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, -CH 2 imidazole ;
• R N1Oa is hydrogen
• R N1 ° and R N1Oa together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional subtsituents are selected from halo, hydroxyl, C 1-7 alkyloxy; R° 3 is a methyl group; and
• R 2 is NR N5 R N6 where R N5 and R N6 together with the nitrogen to which they are bound
• a compound, or a pharmaceutical salt thereof selected from any one of the Examples.
• a compound, or a pharmaceutical salt thereof selected from Examples lbu, Ice, 12b, 18de, 18dg, 18j, lar, 19e, 19h, 19i, 191, 19m, 19n, 19o, 18n, 18o, 18z, 18aa, 18ag, 18ai, 18al, Iv, 18az, lah, 7e, 7i, 7j, 5d, 5f, 4v, 4ab, 4aj, 5t, 5u, 5w, 5x, 5y, 5z, 3f, 3g, 18bp, 18bs, 18bv, 18by, 18cb, 18cv, law, 3u, lbf, 18ct, 19q, 19s, 19u, 19v, 19w, lau, 5r, 4t, 18dj, IcI, 2d, 2e
• a compound, or a pharmaceutical salt thereof selected from Examples lbo, lbp, Ij, lbx, lby, lcf, lei, lcj, 4an, 4ap, 4av, 12d, 18dh, 18di, 6a, In, Ip, Iq, 18e, 18h, 19b, 19c, 19f, 19k, 18p, lbd, 18w, 18ab, 18af, 18aj, 18aq, 18as, 18av, 18ay, 18bb, 18bc, 18bf, 18bl, lab, 4 ⁇ , 9a, lav, 3a, 5b, 5c, 5e, 5g, 4aa, 4ad, 4ah, 5 v, 3e, 18bq, 18bt, 18bz, 18ca, 18cd, 18cg, 18ci, 18bx, 5n, lam, lao, 18cn
• a compound, or a pharmaceutical salt thereof selected from Examples Ib, Ia, Ic, Id, IbI, lbm, If, Ii, Ig, Ih, lbr, lbs, lbv, Ie, lbz, Ice, Ik, leg, 11, 4al, 4am, 4ao, 4aq, 4as, 4at, 4au, 4aw, 4ax, 4ay, 4az, 4ba, 4bb, 4bc, 4bd, 4be, 4bf, 12c, 12a, 18a, las, Is, 18c, 18d, 18f, 18g, 18i, 18k, 19j, 18m, 18q, 18r, 18s, 18t, 18u,
• a compound, or a pharmaceutical salt thereof selected from Examples Ia, Iu, IaI, lap, lat, laz, lco, lde, ldg, ldh, ldk, IdI, ldp, ldq, ldr, Ids, ldt, ldu, ldy, lee, lee, 12d, 14b, 18dn and 18do.
• a compound, or a pharmaceutical salt thereof selected from Examples Ia, Iu, IaI, lap, lat, laz, lco, lde, ldg, ldh, ldk, IdI, ldp, ldq, ldr, Ids, ldt, ldu, ldy, lee, lee, 12d, 14b, 18dn and 18do.
• a reference to carboxylic acid also includes the anionic (carboxylate) form (-COO " ), a salt or solvate thereof, as well as conventional protected forms.
• a reference to an amino group includes the protonated form (-N + HR 1 R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
• a reference to a hydroxyl group also includes the anionic form (-0 " ), a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group.
• Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, /-, and r-forms; endo- and ex ⁇ -forms; R-, S-, and «?e,ro-forms; D- and Z-forms; d- and /-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal- forms; ⁇ - and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
• Example Ia was isolated as Form A: 2-Theta° 6.9 (46%), 8.53 (100%), 10.1 (21%), 10.86 (24%), 11.65 (11%), 13.31 (14%), 13.75 (7%), 14.37 (54%), 15.21 (5%), 16.19 (13%), 16.81 (39%), 17.19 (40%), 17.97 (21%), 18.41 (65%), 18.78 (80%), 20.66 (8%), 21.07 (89%), 22.05 (19%), 22.36 (42%), 24 (7%), 24.36 (33%), 25.25 (31%), 25.54 (16%), 26.92 (18%), 27.26 (8%), 28.03 (8%), 28.39 (21%), 29 (8%), 29.91 (13%), 30.62 (23%), 31.48 (9%), 32.72 (5%), 33.27 (11%), 34.88 (4%), 35.48 (5%), 36.16 (4%), 36.88 (4%), 37.37 (4%), 37.91 (6%
• Form B 5 has also been isolated from water / THF: 2-Theta° 3.67 (7%), 7.28 (7%), 8.52 (7%), 9.22 (30%), 11.42 (78%), 12.69 (24%), 13 (15%), 13.41 (44%), 13.6 (26%), 14.51 (19%), 15.56 (13%), 16.25 (9%), 17.11 (13%), 17.55 (18%), 18.24 (64%), 18.59 (56%), 19.51 (33%), 19.85 (26%), 20.32 (13%), 21.49 (17%), 21.79 (13%), 22.23 (18%), 22.84 (26%), 23.72 (23%), 25.46 (74%), 26.1 (100%), 26.72 (43%), 27.94 (16%), 28.35 (8%), 34.74 (10%), 35.34 (6%), 36.72 (9%) and 38.55 (4%).
• isomers are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
• a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
• a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta- chlorophenyl.
• a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C 1-7 alkyl includes n-propyl and /_? ⁇ -propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para- methoxypheny 1) .
• keto-, enol-, and enolate-forms as in, for example, the following tautomeric pairs: keto/enol, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N- nitroso/hyroxyazo, and nitro/aci-nitro.
• H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
• a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof. Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g. fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner. Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below, as well as its different polymorphic forms.
• a corresponding salt of the active compound for example, a pharmaceutically-acceptable salt.
• a pharmaceutically-acceptable salt examples are discussed in ref. 25.
• a salt may be formed with a suitable cation.
• suitable inorganic cations include, but are not limited to, alkali metal ions such as Na and K , alkaline earth cations such as Ca and Mg , and other cations such as Al .
• suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
• Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
• An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
• a salt may be formed with a suitable anion.
• suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
• Suitable organic anions include, but are not limited to, those derived from the following organic acids: acetic, propionic, succinic, gycolic, stearic, palmitic, lactic, malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, aspartic, benzoic, cinnamic, pyruvic, salicyclic, sulfanilic, 2-acetyoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, isethionic, valeric, and gluconic.
• Suitable polymeric anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. It may be convenient or desirable to prepare, purify, and/or handle a corresponding, solvate of the active compound.
• solvate is used herein in the conventional sense to refer to a complex of solute (e.g. active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
• chemically protected form pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
• a protected or protecting group also known as a masked or masking group or a blocked or blocking group.
• the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
• an amine group may be protected, for example, as an amide or a urethane, for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHC0- OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2- propoxy amide (-NHCO-OC(CH 3 ) 2 C 6 H 4 C 6 H 5 , -NH-Bpoc), as a 9-fluorenylmethoxy amide (- NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (- NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NHCO-
• a carboxylic acid group may be protected as an ester for example, as: an C 1-7 alkyl ester (e.g. a methyl ester; a t-butyl ester); a C 1-7 haloalkyl ester (e.g. a C 1-7 trihaloalkyl ester); a MC 1-7 alkylsilyl-Ci -7 alkyl ester; or a C 5-20 aryl-C 1-7 alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
• an C 1-7 alkyl ester e.g. a methyl ester; a t-butyl ester
• a C 1-7 haloalkyl ester e.g. a C 1-7 trihaloalkyl ester
• a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH 2 NHC(O)CH 3 ).
• a thioether for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH 2 NHC(O)CH 3 ).
• prodrug refers to a compound which, when metabolised (e.g. in vivo), yields the desired active compound.
• the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties.
• some prodrugs are esters of the active compound (e.g. a physiologically acceptable metabolically labile ester).
• Examples of such metabolically labile esters include those wherein R is C 1-20 alkyl (e.g. -Me, -Et); C 1-7 aminoalkyl (e.g.
• acyloxy-C 1-7 alkyl e.g. acyloxymethyl; acyloxyethyl; e.g.
• pivaloyloxymethyl acetoxymethyl; acetoxymethyl; 1-acetoxyethyl; l-(l-methoxy-l- methyl)ethyl-carbonxyloxy ethyl; 1 -(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1 -isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1 -cyclohexyl- carbonyloxy ethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4- tetrahydropyranyloxy) carbonyloxymethyl; l-(4-tetrahydropyranyloxy)carbonyloxyethyl; (4- tetrahydropyranyl)carbonyloxymethyl; and 1 -(4-tetrahydropyranyl)carbonyloxyethy
• prodrug forms include phosphonate and glycolate salts.
• hydroxy groups (-OH)
• Such a group can be cleared by phosphotase enzymes during metabolism to yield the active drug with the hydroxy group.
• prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
• the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
• R 4 represents
• R 7 When R 7 is NR N1 R N2 , this is by reaction with R 7 H. When R 7 is an amide, urea or sulfonamide group, this is by reaction with ammonia followed by reaction of the resulting primary amide with the appropriate acid chloride, isocyanate or sulfonyl chloride. When R 7 is OR 01 or SR S1 , this is by reaction with potassium carbonate in the appropriate alcohol or thiol solvent. When R 7 is an optionally substituted C 3-20 heterocyclyl group or C 5-20 aryl group, this is by reaction with R 7 B(OAIk) 2 , where each AIk is independently C 1-7 alkyl or together with the oxygen to which they are attached form a C 5-7 heterocyclyl group.
• Compounds of Formula 2 can be synthesised from compounds of Formula 3 : Formula 3
• Compounds of Formula 5 can be synthesised from compounds of Formula 6, for example by reaction with liquid ammonia followed by reaction with thionyl chloride and ammonia gas:
• R 7 When R 7 is NR N1 R N2 , this is by reaction with R 7 H. When R 7 is an amide, urea or sulfonamide group, this is by reaction with ammonia followed by reaction of the resulting primary amide with the appropriate acid chloride, isocyanate or sulfonyl chloride. When R 7 is OR 01 or SR S1 , this is by reaction with potassium carbonate in the appropriate alcohol or thiol solvent. When R 7 is an optionally substituted C 3-20 heterocyclyl group or C 5-20 aryl group, this is by reaction with R 7 B(OAIk) 2 , where each AIk is independently C 1-7 alkyl or together with the oxygen to which they are attached form a C 5-7 heterocyclyl group.
• Compounds of Formula 8 can be synthesised from compounds of Formula 3:
• Lv is a leaving group, such as a halogen, for example chlorine, or a OSO 2 group, where R is alkyl or aryl, such as methyl, by reaction with R N10 NH 2 .
• Lv is a leaving group, such as a halogen, for example chlorine, or a OSO 2 group, where R is alkyl or aryl, such as methyl, by reaction with R N10 NH 2 .
• R 4 represents and
• Compounds of Formula Ib can be prepared by reaction with R 7 B(OAIk) 2 , where each AIk is independently C 1-7 alkyl or together with the oxygen to which they are attached form a C 5-7 heterocyclyl group.
• the present invention provides active compounds, specifically, active in inhibiting the activity of mTOR.
• active refers to compounds which are capable of inhibiting mTOR activity, and specifically includes both compounds with intrinsic activity (drugs) as well as prodrugs of such compounds, which prodrugs may themselves exhibit little or no intrinsic activity.
• the present invention further provides a method of inhibiting the activity of mTOR in a cell, comprising contacting said cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable composition.
• a method may be practised in vitro or in vivo.
• a sample of cells may be grown in vitro and an active compound brought into contact with said cells, and the effect of the compound on those cells observed.
• effect the inhibition of cellular growth in a certain time or the accumulation of cells in the Gl phase of the cell cycle over a certain time may be determined.
• the active compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.
• treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.
• Treatment as a prophylactic measure i.e. prophylaxis is also included.
• adjunct anti-cancer agents that could be combined with compounds from the invention include, but are not limited to, the following: alkylating agents: nitrogen mustards, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil: Nitrosoureas: carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), ethylenimine/methylmelamine, thriethylenemelamine (TEM), triethylene thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine): Alkyl sufonates; busulfan; Triazines, dacarbazine (DTIC): Antimetabolites; folic acid analogs, methotrex
• Adrenocortical suppressant mitotane (c ⁇ '-DDD), aminoglutethimide: Cytokines; interferon
• Active compounds may also be used as cell culture additives to inhibit mTOR, for example, in order to sensitize cells to known chemotherapeutic agents or ionising radiation treatments in vitro.
• Active compounds may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
• the present invention provides active compounds which are anticancer agents or adjuncts for treating cancer.
• active compounds which are anticancer agents or adjuncts for treating cancer.
• One of ordinary skill in the art is readily able to determine whether or not a candidate compound treats a cancerous condition for any particular cell type, either alone or in combination.
• cancers include, but are not limited to, lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma and leukemias.
• Any type of cell may be treated, including but not limited to, lung, gastrointestinal
• kidney (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney
• anti cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
• Such chemotherapy may include one or more of the following categories of anti-tumour agents:-
• antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis platin, oxaliplatin, 5 carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,
• alkylating agents for example cis platin, oxaliplatin, 5 carboplatin, cyclophosphamide,
• dactinomycin and mithramycin dactinomycin and mithramycin
• antimitotic agents for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors
• topoisomerase inhibitors for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin
• cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant,
• toremifene, raloxifene, droloxifene and iodoxyfene antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5* -reductase such as finasteride;
• 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
• 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 N-(2- chloro-6-methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-l-yl]-2-methylpyrimidin-4- ylamino ⁇ thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-
• c-Src kinase family inhibitors like 4-(6- chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran-
• metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;
• inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti erbBl
• inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amme (gefitinib, ZDl 839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI 774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-
• antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the ami vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as 4- (4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy- 7-(3-pyrrolidin-l-ylpro ⁇ oxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications WO97/22596, WO
• vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
• antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
• gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy; and
• immunotherapy approaches including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using anti idiotypic antibodies.
• Administration The active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g.
• the subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent
• a guinea pig e.g. a guinea pig, a hamster, a rat, a mouse
• murine e.g. a mouse
• canine e.g. a dog
• feline e.g. a cat
• equine e.g. a horse
• primate e.g. a monkey or ape
• monkey e.g. marmoset, baboon
• an ape e.g. gorilla, chimpanzee, orangutang, gibbon
• compositions comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
• the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilisers, or other materials, as described herein.
• pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• a subject e.g. human
• Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, refs. 27 to 29.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
• Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.
• Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
• a tablet may be made by conventional means, e.g. compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
• Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
• Formulations suitable for topical administration e.g. transdermal, intranasal, ocular, buccal, and sublingual
• a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active compounds and optionally one or more excipients or diluents.
• Formulations suitable for topical administration in the mouth include losenges comprising the active compound in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid carrier.
• Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.
• Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
• Suitable formulations wherein the carrier is a liquid for administration as, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser include aqueous or oily solutions of the active compound.
• Formulations suitable for administration by inhalation include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as diclilorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
• a suitable propellant such as diclilorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
• Formulations suitable for topical administration via the skin include ointments, creams, and emulsions.
• the active compound When formulated in an ointment, the active compound may optionally be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active compounds may be formulated in a cream with an oil-in- water cream base.
• the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane- 1 ,3 -diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
• the topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
• the oily phase may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
• an emulsifier otherwise known as an emulgent
• a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
• the emulsif ⁇ er(s) with or without stabiliser(s) make up the so-called emulsifying wax
• the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
• Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
• the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
• the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
• Straight or branched chain, mono- or dibasic alkyl esters such as di- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
• Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
• Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate.
• Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain antioxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
• Suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
• concentration of the active compound in the solution is from about 1 ng/ml to about 10 ⁇ g/ml, for example from about 10 ng/ml to about 1 ⁇ g/ml.
• the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
• Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs. Dosage
• appropriate dosages of the active compounds, and compositions comprising the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention.
• the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
• the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
• Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
• a suitable dose of the active compound is in the range of about 100 ⁇ g to about 250 mg per kilogram body weight of the subject per day.
• the active compound is a salt, an ester, prodrug, or the like
• the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
• the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of mTor in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
• Mass spectra were recorded on a Waters ZQ instrument in Electrospray ionisation mode.
• Mobile phase A - 0.1 % aqueous formic acid.
• Mobile phase B - 0.1 % Formic acid in acetonitrile; Flowrate 2 ml/min; Gradient - starting at 100 % A/0 % B for 1 minute, rising to 95 % B after 7 minutes and holding for 2 minutes before returning to the starting conditions.
• Mass spectra were recorded on a Waters ZQ instrument in Electrospray ionisation mode.
• Mobile phase A - 0.1 % aqueous formic acid.
• Mobile phase B - 0.1 % Formic acid in acetonitrile; Flowrate 2 ml/min; Gradient - starting at 95 % A/5 % B, rising to 95 % B after 20 minutes and holding for 3 minutes before returning to the starting conditions.
• Mass spectra were recorded on a Waters ZQ instrument in Electrospray ionisation mode.
• Mobile phase A - 0.1 % aqueous formic acid.
• Mobile phase B - 0.1 % Formic acid in acetonitrile; Flowrate 2 ml/min; Gradient - starting at 95 % A/5 % B, rising to 95 % B after 5 minutes and holding for 5 minutes before returning to the starting conditions.
• Mass spectra were recorded on a Waters ZQ instrument in Electrospray ionisation mode.
• Mobile phase A 0.1 % aqueous formic acid.
• Mobile phase B 0.1 % Formic acid in acetonitrile; Flowrate 2 ml/min; Gradient - starting at 100 % A/0 % B for 1 minute, rising to 10 95 % B after 20 minutes and holding for 5 minutes before returning to the starting conditions.
• Example Ik 25 of Example Ik were analysed using the QC Method QC2-Long.
• Examples 18p and lbd were analysed using the QC Method QC3-AQ-Long.
• Reactions were carried out using a Personal ChemistryTM Emrys Optimiser microwave synthesis unit with robotic arm.
• Power range between. 0-300 W at 2.45 GHz.
• Pressure range between 0-20 bar; temperature increase between 2-5°C/sec; temp range 60-250 0 C.
• the residue was purified by reverse phase column using a gradient from 5 % to 20 % acetonitrile in 0.1 % formic acid/water solution, yielding the desired product.
• the aqueous phase was further extracted with EtOAc and the combined organic phases dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was sonicated in EtOAc, the suspension was filtered onto a sintered funnel and the collected grey solid was dried and used without further purification.
• the aqueous phase was further extracted with CH 2 Cl 2 MeOH.
• the combined organic phases were dried (MgSO 4 ), filtered and concentrated in vacuo.
• the residue was sonicated in hexane/ CH 2 Cl 2 , filtered, sonicated in CH 2 Cl 2 and filtered to yield the desired product.
• 4-Bromo-2-bromomethyl-benzoic acid methyl ester was prepared according to literature. A solution of 4-bromo-2-bromomethyl-benzoic acid methyl ester (1 equiv) in a 1:1 THF/MeOH mixture was treated by gentle bubbling of ammonia gas for 4 hours at room temperature. The reaction mixture was concentrated in vacuo. The residue was sonicated in water, filtered, then sonicated in diethylether and filtered to give the desired product as a white solid.
• the aqueous phase was further extracted with EtOAc and the combined organic phases dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was dissolved in CH 2 Cl 2 and hexane was added. The resulting suspension was filtered and the collected brown powder was dried and used without further purification.
• R 2 (S)-3-methyl-morpholine or cis-dimethylmorpholine or 2-Ethyl-piperidine or morpholine or thiomorpholine or 4-methylpiperazine
• R 7 aryl or heteroaryl
• Conditions A The appropriate chloro-substrate (1 equiv) was dissolved in a toluene/ethanol (1:1) solution (0.02 M). Sodium carbonate (2 equiv) and the appropriate pinacolate boron ester or boronic acid (1 equiv) were then added followed by tetrakis(triphenylphosphine) palladium 0 (0.1 equiv). The reaction vessel was sealed and the mixture exposed to microwave radiation (140 0 C, medium absorption setting) for 30 minutes. Upon completion the samples were filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products. Conditions B:
• Conditions H A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and tetrakis(triphenylphosphine) palladium 0 (0.05 equiv) in acetonitrile/water (0.1 M of chloro- substrate) was stirred at 100 0 C for 8 hours. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product. Conditions I:
• Conditions I were similar to conditions H apart form the heating method: 100 0 C for 2 hours.
• Conditions J were similar to conditions H apart form the heating method: 100 0 C for 2 hours.
• Conditions Q A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and tetrakis(triphenylphosphine) palladium 0 (0.05 equiv) were dissolved in r ⁇ -butanol (0.056 M of chloro-substrate).
• the reaction vessel was sealed and exposed to microwave radiation (150 0 C, medium absorption setting) for 30 minutes. Upon completion the samples were filtered through a silica cartridge, washed with CH 2 Cl 2 and methanol and then concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with ethyl acetate and then 5 % MeOH in CH 2 Cl 2 to give the desired product.
• Conditions R A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), the appropriate pinacol
• 2-Difluoromethoxy-N-methyl-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide was prepared in a similar way as 2-Difluoromethoxy-5-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide using 5-bromo-2-difluoromethoxy- N-methyl- benzamide as the starting material.
• 2-Difluoromethoxy-N-methyl-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzamide (100 % yield, crude taken forward without further analysis)

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