WO2011078795A1 - Bridged morpholino substituted purines - Google Patents

Bridged morpholino substituted purines Download PDF

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WO2011078795A1
WO2011078795A1 PCT/SG2010/000474 SG2010000474W WO2011078795A1 WO 2011078795 A1 WO2011078795 A1 WO 2011078795A1 SG 2010000474 W SG2010000474 W SG 2010000474W WO 2011078795 A1 WO2011078795 A1 WO 2011078795A1
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optionally substituted
group
cancer
compound according
alkyl
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PCT/SG2010/000474
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French (fr)
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Stéphanie Blanchard
Chen Dizhong
Kumar Mysore Nagaraj Harish
Williams Meredith
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S*Bio Pte Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
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    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to purine compounds that may be useful as kinase inhibitors. More particularly, the invention relates to bridged 2-(morpholin-4-yl), 6- (pyrazin-2-yl) substituted purine derivatives, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of certain medical conditions such as kinase related disorders/conditions.
  • kinases which are alternatively known as phosphotransferases, are enzymes that transfer phosphate groups from high energy donor molecules (for example ATP) to specific target molecules (typically called substrates) in a process termed phosphorylation.
  • high energy donor molecules for example ATP
  • substrates specific target molecules
  • phosphorylation One of the largest groups of kinases is the protein kinases which act on and modify the activity of specific proteins. As a result of this activity these kinases are involved in a number of cellular processes such as in signalling and to prime the cell for biochemical reactions in metabolism.
  • kinases represent an attractive target for medicinal chemists as the provision of kinase inhibitors potentially allows for certain signalling processes to be controlled leading to the control of certain medical conditions.
  • PI3 phosphoinositide 3-kinase family of kinases which are involved in a wide range of cellular events such as cell migration, cell proliferation, oncogenic transformation, cell survival, signal transduction and intracellular trafficking of proteins. This family of kinases has recently been the focus of much research aimed at developing therapies for a range of indications.
  • the phosphoinositide 3-kinase (PI3) family is a group of enzymes that generate phosphatidylinositol 'second messengers'. These lipids are subsequently involved in a wide range of physiological processes.
  • the PI3K signalling pathway is crucial to many aspects of cell growth and survival via its regulation of widely divergent physiological processes that include cell cycle progression, differentiation, transcription, translation and apoptosis. Constitutive activation of the PI3K pathway has been implicated in both the pathogenesis and progression of a large variety of cancers and there is now a rapidly accumulating body of evidence that demonstrates conclusively that PI3K signalling is frequently deregulated in cancer.
  • the deregulation of PI3K signalling is thought to occur in two different ways. The first is an increase in PI3K signalling resulting from activating gene mutations, amplification and over expression of PI3Ks or upstream receptors that activate PI3Ks.
  • the PI3Ka catalytic subunit is amplified and over expressed in ovarian and cervical cancers.
  • upstream receptor tyrosine kinases that activate PI3K are commonly mutated, amplified and over expressed, e.g., EGFR in breast, ovarian and lung cancer.
  • Akt/PKB Protein Kinase B
  • Akt/PKB Protein Kinase B
  • Ras family members which are involved in PI3K activation, are frequently mutated, e.g. in colorectal and pancreatic cancer.
  • the second mechanism of PI3K deregulation involves loss of the tumor suppressor phosphatase PTEN, which occurs in many aggressive brain tumors, endometrial and breast cancers, and melanomas.
  • PI3K phosphatidylinositol 3-kinase
  • Akt phosphatidylinositol 3-kinase
  • RTKs growth factor receptor tyrosine kinases
  • Growth factor RTKs engage the class-la PI3K, which is a heterodimer comprised of the p85 regulatory and p110 catalytic subunits.
  • the small GTPase Ras can also recruit and activate PI3K through direct binding to p110.
  • PI3K catalyzes the production of the lipid second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3). Subsequently, PIP3 recruits other downstream molecules - particularly the serine- threonine kinases Akt and PDK1— via binding to their pleckstrin-homology (PH) domains.
  • Akt is partially activated through phosphorylation at threonine 308 in its activation loop by PDK1. Additional phosphorylation at serine 473 in the C terminus of Akt results in its full activation. This second phosphorylation is carried out by the mammalian target of rapamycin (mTOR).
  • Akt in turn regulates a wide range of target proteins, one of which is mTOR.
  • mTOR thus plays a pivotal role in the signalling downstream of PI3K and Akt and has, as a result, received a lot of attention as a potential therapeutic target for a wide range of indications.
  • the levels of PlP3 in the cell are strictly regulated and several lipid phosphatases act to rapidly remove it. Of particular interest is the phosphatase PTEN, which converts PIP3 back to PIP2 and thus shuts off PI3K signalling.
  • the PI3K-Akt signalling pathway regulates many normal cellular processes including cell proliferation, survival, growth, and motility - processes that are critical for tumorigenesis.
  • PTEN has been identified as a major tumor suppressor in humans and loss-of-function mutations in the PTEN gene are extremely common among sporadic glioblastomas, melanomas, prostate cancers, and endometrial carcinomas, and a significant percentage of breast tumors, lung cancers, and lymphomas also bear PTEN mutations.
  • PI3K signalling a high percentage of human cancers possess activated PI3K signalling.
  • mTOR is important for the oncogenic transformation induced by PI3K and Akt.
  • mice with a constitutively activated p85 regulatory subunit of PI3K progress to malignant lymphoma when crossed with p53-knockout mice.
  • retroviral introduction of Akt and Ras caused glioblastomas in mice provide strong validation for the development of novel anticancer strategies targeted at this pathway.
  • mTOR is a serine/threonine kinase of 289 kDa and is a PI3K-like kinase that links mitogenic stimuli and nutrient status to cell growth and division. mTOR functions as a key enzyme in the PI3K-Akt pathway as discussed above. mTOR was discovered during studies conducted to understand the mechanism of action of rapamycin. Upon entering cells, rapamycin binds to its intracellular target FKBP12 and the complex then binds to and specifically inhibits mTOR. mTOR was, therefore, also named FKBP-RAP associated protein (FRAP), RAP FKBP12 target (RAFT1) and RAP target (RAPT1 ). Cells responsible for organ rejection stop growing due to rapamycin's ability to inhibit the anabolic signals coordinated by mTOR. Since inhibition of cell growth represents a valid target for treating cancer, designing new drugs that inhibit mTOR will potentially have therapeutic value.
  • FKBP-RAP associated protein FRAP
  • mTOR mediates anabolic signals from 2 sources namely nutrients that pass into the cell and activated growth factor receptors. It exists in at least two distinct complexes: a rapamycin-sensitive complex, referred to as mTOR complex 1 (mTORCI ), defined by its interaction with the accessory protein raptor (regulatory-associated protein of mTOR).
  • mTORCI rapamycin-sensitive complex
  • the normal activation of mTOR results in an increase in protein translation because mTORCI phosphorylates and activates the translation regulators eukaryotic initiation factor 4E-binding protein 1 and ribosomal p70 S6 kinase. Therefore, by inhibiting mTOR, rapamycin causes a decrease in phosphorylation of these effectors, and a decrease in protein synthesis, effectively blocking the pro-growth actions of mTOR.
  • mTORC2 The second complex, mTOR complex 2 (mTORC2), is rapamycin- insensitive and is defined by its interaction with rictor (rapamycin-insensitive companion of mTOR).
  • mTORC2 is involved in the regulation of the pro-survival kinase Akt/PKB by phosphorylating it on S473. Together with the phosphorylation of T308 by PDK1 , S473 phosphorylation is necessary for full Akt activation.
  • Recent reports indicate that prolonged treatment with rapamycin in some cells also suppresses the assembly and function of mTORC2 to inhibit Akt and that this property of rapamycin contributes to the anti-apoptotic effects of the drug.
  • mTOR is also one of the main downstream effectors in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and therefore inhibition of mTOR provides a further opportunity to inhibit, at least in part, the PI3K/Akt pathway.
  • PI3K phosphatidylinositol 3-kinase
  • HIF-1 and HIF-2 hypoxia-inducible factor
  • VEGF vascular endothelial growth factor
  • platelet-derived growth factor transforming growth factor
  • TSC1 and TSC2 tuberous sclerosis complex gene products
  • TSC1 and TSC2 function together to inhibit mTOR-mediated downstream signalling. Mutations of these genes occur in tuberous sclerosis and their loss of function yields yet another pathway, which leads to increased activity of mTOR and induces VEGF production. TSC2 also regulates HIF. Thus, studies evaluating the impact of TSC1 and TSC2 mutations demonstrate the connection of increased VEGF and activated mTOR pathways to angiogenesis.
  • Rapamycin also named sirolimus
  • rapamycin inhibits the oncogenic transformation of human cells induced by either PI3K or Akt and has shown metastatic tumor growth inhibition and anti-angiogenic effects in in vivo mouse models.
  • CCI-779 demonstrated anti-tumor activity alone or in combination with cytotoxic agents in a variety of human cancer models such as gliomas, rhabdomyosarcoma, primitive neuroectodermal tumor such as medulloblastoma, head and neck, prostate, pancreatic and breast cancer cells.
  • Treatment of mice with CCI-779 inhibits P70S6K activity and reduces neoplastic proliferation.
  • PTEN-deficient human tumors are more sensitive to CCI-779-mediated growth inhibition than PTEN expressing cells.
  • CCI-779 studies in vitro in a panel of eight human breast cancer cell lines showed that six of eight cancer lines studied were inhibited by CCI-779 with IC50 in the low nanomolar range. Two lines, however, were found to be resistant with ICso>1 ⁇ .
  • the sensitive cell lines were estrogen receptor positive or over-expressed HER-2/Neu, or had lost the tumor suppressor gene product PTEN.
  • the main toxicities of CCI-779 included dermatological toxicities and mild myelosuppression (mainly thrombocytemia).
  • CCI- 779 has been evaluated in a number of clinical trials for a broad range of cancer indications. More recently CCI-779 has received FDA approval for the treatment of advanced renal cell carcinoma (RCC) by intravenous infusion (marketed as TORISELTM). The most common adverse reactions associated with Torisel have been reported as rash, asthenia, mucositis, nausea, edema and anorexia. Further clinical trials are on-going.
  • RAD001 (Everolimus), 40-O-(2-hydroxyethyl)-rapamycin, is another analogue of rapamycin that can be administrated orally. Its anti-neoplastic activity has been evaluated in different human cancer cell lines in vitro and in xenograft models in vivo. p70S6K inhibition and anti-neoplastic effects have been shown in these models. Similarly, RAD001 demonstrated a concentration-dependent antitumor activity in a syngenic rat pancreas carcinoma model with an intermittent dosing schedule. RAD001 has also shown anti-angiogenic activity and inhibits human vascular endothelial cell (HUVEC) proliferation.
  • UAVEC human vascular endothelial cell
  • RAD001 The toxicity reported for RAD001 includes hypercholesterolemia, hypertriglyceridemia, mild leukocytopenia and thrombocytopenia. RAD001 is undergoing evaluation in a broad range of clinical trials both as a single agent and in combination with other therapeutics. As with CCI-779 it has now received FDA approval for use in RCC.
  • rapamycin and its analogues have not shown universal anti-tumor activity in early clinical trials. Response rates vary among cancer types from a low of less than 10% in patients with glioblastomas and advanced renal-cell cancer to a high of around 40% in patients with mantle-cell lymphoma. Knowledge of the status of PTEN and PI3K/Akt/mTOR-linked pathways might help in the selection of tumor types that will respond to mTOR inhibitors. Furthermore, because many tumor types still do not respond to single agent therapy with rapamycin derivatives, it is important to continue the search for factors predictive of resistance or sensitivity to mTOR inhibitors.
  • Akt-dependent kinase inhibitors Of particular interest will be molecules that directly inhibit mTOR kinase activity, the theory being that such molecules will inhibit both mTORCI and mTORC2. Such an inhibitor might be beneficial for treating tumors with elevated Akt phosphorylation and might down-regulate the growth, proliferation and survival effects that are associated with Akt activation. If mTOR- rictor is a crucial activator of Akt-dependent survival processes, such a drug might promote apoptosis in tumor cells that have adapted to Akt-dependent regulatory mechanisms. Considerable effort is now being made to develop mTOR kinase inhibitors and the more advanced compounds, such as OSI-017 and AZD8055, have entered phase 1 clinical trials.
  • mTOR inhibitors have the potential to provide further biologically active compounds that would be expected to have useful, improved pharmaceutical properties in the treatment of kinase related conditions or disorders.
  • mTOR inhibitors may potentially be used in the treatment of a wide range of cancers and related hyper proliferative disorders.
  • recent research implicates mTOR in a number of non-oncology disease areas including inflammation, cardiovascular disease and certain metabolic as well as neurological disorders.
  • R 1 is selected from the group consisting of: H, halogen and optionally substituted CrC 6 alkyl;
  • R 2 is selected from the group consisting of H, halogen, OH, N0 2 , CN, NH 2 , optionally substituted Ci-C- ⁇ alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-C-i2alkynyl, optionally substituted C2-Ci2heteroalkyl, optionally substituted C3-Ci 2 cycloalkyl, optionally substituted C 3 -Ci 2 cycloalkenyl, optionally substituted C2-Ci 2 heterocycloalkyl, optionally substituted C 2 -Ci2heterocycloalkenyl, optionally substituted C6-Ciearyl, optionally substituted Ci-Cieheteroaryl, optionally substituted C C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C2-Ci2alkynyloxy, optionally substituted C2-Ci2heteroalkyl
  • each M is independently N or CR 2a.
  • each R is independently selected from the group consisting of H, halogen,
  • Ci-Ci 2 alkyl optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, optionally substituted C 2 -Ci 2 heteroalkyl, optionally substituted C3-Ci 2 cycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkenyl, optionally substituted C6-C18 aryl, optionally substituted C-i-C-ieheteroaryl, optionally substituted CrCi 2 alkyloxy, optionally substituted C 2 -Ci 2 alkenyloxy, optionally substituted C 2 -Ci 2 alkynyloxy, optionally substituted C 2 -Ci 2 heteroalkyloxy, optionally substituted C3-Ci 2 cycloalkyloxy, optionally substituted C3-Ci 2 cycloalkyloxy, optionally substituted C3-Ci 2
  • r is an integer selected from the group consisting of 1 , 2, and 3;
  • R 3 is selected from the group consisting of H, F, CI, Br, OH, optionally substituted C C 6 alkyl, OR 8 , OCOR 8 , CH 2 OH, NH 2 , NR 8 R 9 , NR 8 COR 9 , and NR 8 S0 2 R 9 ;
  • R 6 is selected from the group consisting of H, OH, OR 8 , OP g °, OCOR 8 , CH 2 OH, NH 2 , NR 8 R 9 , NR 8 P g N , N(P g N ) 2 , NR 8 COR 9 , NR 8 CONR 8 R 9 and NR 8 S0 2 R 9 ;
  • R 7 is selected from the group consisting of H, F, CI, Br, OH, OR 8 , OCOR 8 , CH 2 OH, NH 2 , NR 8 R 9 , NR 8 COR 9 , and NR 8 S0 2 R 9 ;
  • each R 8 and R 9 is independently selected from the group consisting of H, optionally substituted Ci-Ci 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, optionally substituted C 2 -Ci 2 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 3 -Ci 2 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkenyl, optionally substituted Ce-C-iearyl, and optionally substituted Ci-Ci 8 heteroaryl, or
  • R 8 and R 9 when taken together with the atoms to which they are attached form an optionally substituted cyclic moiety
  • P g ° is a protecting group for oxygen
  • each P g N is independently a protecting group for nitrogen
  • each R z is independently selected from the group consisting of Ci-C 6 alkyl, halo-Ci-C 6 alkyl, hydroxyCi-C 6 alkyl, Ci-C 6 alkyloxyCi-C 6 alkyl, cyanoCrC 6 alkyl, aminoCrCealkyl, Ci-C 6 alkylaminoCi-C 6 alkyl, and d C Cealky aminoC-i-Cealkyl;
  • q is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
  • X is a group of formula (CR 10 2 ) m ;
  • each R 10 is independently selected from the group consisting of: H and optionally substituted C-i-Cealkyl;
  • m is an integer selected from the group consisting of 0, 1 , 2, 3 and 4;
  • each R z may be selected from the group consisting of F, CI, Br, methyl, trifluoromethyl, and ethyl.
  • the R z substituent may be attached at any available position on the 7 membered ring. In circumstances where there are multiple R z substituents, each R z substituent is located independently of the others. In some embodiments q is 1 and the R z substituent is located alpha to the ring nitrogen. This provides compounds of formula (la).
  • R 1 , R 2 , R 3 , R 6 , R 7 , R z and X are as defined above.
  • R 1 , R 2 , R 3 , R 6 , R 7 and X are as defined above.
  • R 3 is selected from the group consisting of H, OR 8 , and optionally substituted Ci-C 6 alkyl.
  • R 3 is OR 8 where R 8 is optionally substituted C-i- Cealkyl.
  • R 3 groups of this type include methoxy, trifluoro-methoxy, ethoxy, isopropoxy, propoxy, and butoxy. In some embodiments R 3 is methoxy.
  • R 3 is optionally substituted Ci-C 6 alkyl. Examples of R 3 groups of this type include methyl, trifluoro-methyl, ethyl, propyl, isopropyl, and butyl. In some embodiments R 3 is methyl.
  • R 3 is selected from the group consisting of H, methoxy and methyl. In some embodiments R 3 is H.
  • R 8 is selected from H and Ci-C 6 alkyl. In some embodiments R 8 is methyl. In some embodiments R 8 is H. [0058] In some embodiments of the compounds containing the group R 9 , R 9 is selected from H and C-i-Cealkyl. In some embodiments R 9 is methyl. In some embodiments R 9 is H.
  • X is a group of formula (CR 10 2) m .
  • m is selected from the group consisting of 0, 1 , and 2.
  • m is 0 or 1 .
  • m is 0.
  • m is 1.
  • each R 10 is H.
  • each R 10 is independently an optionally substituted Ci-C6alkyl.
  • one R 10 is H and the other R 10 is H or optionally substituted CrC 6 alkyl.
  • one R 10 is H and the other is CH 3 .
  • R 3 and R 7 are H, m is 1 , q is 0 and one R 10 is H. This provides compounds of the formula (IV):
  • R 1 , R 2 , R 6 and R 10 are as defined above.
  • R 1 is selected from the group consisting of H, fluoro, chloro, bromo, methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
  • R 1 is H.
  • R 6 is selected from the group consisting of H, NH 2 and NR R wherein R B and R are as defined above. In some embodiments R is NH 2 .
  • R 2 is selected from the group consisting of H, cyano, optionally substituted Ci-Ci2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-C 12 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C6-Ciearyl, and optionally substituted Ci-Ci 8 heteroaryl.
  • R 2 is an optionally substituted C6-Ciearyl.
  • the optionally substituted C6-Ci 8 aryl (and hence R 2 ) is a group of the formula:
  • p is an integer selected from the group consisting of 0, 1 , 2, 3, 4, and 5;
  • each R 13 is independently selected from the group consisting of H, halogen, OH, N0 2l CN, NH 2 , optionally substituted Ci-C-i 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C2-Ci 2 alkynyl, optionally substituted C2-Ci 2 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C2-Ci 2 heterocycloalkyl, optionally substituted C 2 -Ci2heterocycloalkenyl, optionally substituted C 6 -Ci8aryl, optionally substituted Ci-Cieheteroaryl, optionally , substituted Ci-C-i2alkyloxy, optionally substituted C 2 -Ci2alkenyloxy, optionally substituted C2-C-i2alkynyloxy, optionally substituted C2-Ci2heteroalkyloxy, optionally substituted C3-
  • any two adjacent R 13 may, when taken together with each other and the carbon atoms to which they are attached form a cyclic moiety; [0078] where R 8 and R 9 are as defined above.
  • the phenyl group may be unsubstituted or may be optionally substituted with one or more suitable substituent groups. If the phenyl group is substituted then there may be 1 , 2, 3, 4 or 5 substituent groups. In some embodiments p is 0, 1 or 2. In some embodiments p is 1. Iii some embodiments p is 2.
  • R 1 is H
  • R 3 is H
  • R 6 is NH 2>
  • R 7 is H
  • X is (CH 2 ) m wherein m is 0, and R 2 is a group of the formula:
  • R 1 is H
  • R 3 is H
  • R 6 is NH 2
  • R 7 is H
  • X is (CR 10 2 ), wherein m is 1
  • R 2 is a group of the formula:
  • R 10 is selected from the group consisting of H, Ci-C 6 haloalkyl, CrCehydroxyalkyl and Ci-C6alkyl. In some embodiments R 10 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and butyl. In some embodiments R 10 is selected from the group consisting of H, methyl and ethyl.
  • R 2 is selected from the group consisting of cyano, optionally substituted Ci-Cealkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, and optionally substituted C2-Ci2heteroalkyl.
  • R 2 is selected from the group consisting of cyano, optionally substituted Ci-Cealkyl, and optionally substituted C2-Ci2heteroalkyl.
  • R 2 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3- dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, hexyl, heptyl, and octyl.
  • R 2 is an optionally substituted methyl group of the
  • R 20 , R 21 and R 22 are each independently selected from the group consisting of H, CI, Br, F, OH, N0 2 , CN, NH 2 , optionally substituted C C 12 alkyl and optionally substituted Ci-Ci 2 heteroalkyl.
  • each R 20 , R 21 and R 22 is independently selected from the group consisting of H, CI, Br, F, OH, N0 2 , CN, NH 2 , methyl, ethyl, propyl, isopropyl, butyl, pentyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 2- ethoxyethyl, 3-ethoxypropyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4- aminobutyl, 5 aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3- methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2- ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethyl
  • R 2 is optionally substituted C 3 -C-i 2 cycloalkyl group. In some embodiments R 2 is selected from the group consisting of optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl and optionally substituted cyclohexyl. In some embodiments R 2 is cyclopropyl.
  • the optionally substituted C 3 -Ci 2 cycloalkyl group is selected from the group consisting of:
  • R is independently selected from the group consisting of H, optionally substituted Ci-Ci 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, optionally substituted C 2 -Ci 2 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 3 -Ci 2 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkenyl, optionally substituted C 6 -Ci 8 aryl, optionally substituted CrCi 8 heteroaryl, optionally substituted CrCi 2 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C 2 -Ci 2 alkynyloxy, optionally substituted C 2 -Ci 0 heteroalkyloxy, optionally substituted C 3 -C 2
  • each R 24 and R 25 is independently selected from the group consisting of H, optionally substituted d-Ci 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -C-
  • the optionally substituted C 3 -C-i 2 cycloalkyl group is selected from the group consisting of:
  • R 2 is a group of the formula:
  • each M is independently N or CR ;
  • each R is independently selected from the group consisting of H, halogen, OH, NO2, CN, NH2, optionally substituted Ci-Ci2alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -Ci 8 aryl, optionally substituted C-i-Cieheteroaryl, optionally substituted Ci-Ci2alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C 2 -Ci 2 alkynyloxy, optionally substituted C2-Ci 2 heteroalkyloxy, optionally substituted, optionally substituted C3-C12 cycl
  • r is an integer selected from the group consisting of 1 , 2, and 3.
  • r is 1 and R is a group of the formula:
  • r is 2 and R 2 is a group of the formula:
  • each M is as defined above.
  • each M is CR .
  • one M group is N and the other M groups are CR 2a
  • R is as defined above; s is an integer selected from the group consisting of 0, 1 , 2, 3 and 4; r is an integer selected from the group consisting of 1 , 2, and 3.
  • each M is CR 2a , r is 1 and R 2 is a group of the
  • each M is CR 2a , r is 2 and R 2 is a group of the formula:
  • R is as defined above.
  • one M is N and the others are CR .
  • R 2 is a group of the formula:
  • R 2a and r are as defined in above.
  • r is selected from the group consisting of 1 , and 2. In some embodiments r is 1. In some embodiments r is 2.
  • Each R substituent may be selected from any suitable optional substituent.
  • each R 2a is independently selected from the group consisting of H, F, CH 3 , CH 2 CH 3 , OCH 3> CN, OCF 3 , C0 2 CH 3 , N0 2 , NH 2) NHCOCH 3 , NHS0 2 CH 3l NHCH 2 CH 3 , and CF 3 .
  • R 2 is optionally substituted C 2 -Ci 2 heterocycloalkyl.
  • R 2 is selected from the group consisting of optionally substituted pyrrolidin-1-yl, optionally substituted pyrrol id in-2-yl, optionally substituted pyrrol id in-3-yl, optionally substituted dioxolane-2-yl, optionally substituted dioxolane- 3-yl, optionally substituted tetrahydrofuran-2-yl, optionally substituted tetrahydrofuran- 3-yl, optionally substituted piperidine-1-yl, optionally substituted piperidine-2-yl, optionally substituted piperidine-3-yl, optionally substituted piperidine-4-yl, optionally substituted morpholine-1-yl, optionally substituted morpholine-2-yl, optionally substituted morpholine-3-yl, optionally substituted 1 ,4,dioxo
  • the optionally substituted C 2 -Ci 2 heterocycloalkyl group is selected from the group consisting of:
  • R is independently selected from the group consisting of H, optionally substituted optionally substituted C 2 -Ci 2 alkynyl, optionally substituted C2-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C3-Ci2cycloalkenyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkenyl, optionally substituted Ce-C-iearyl, optionally substituted Ci-C-ieheteroaryl, optionally substituted Ci-C 12 alkyloxy, optionally substituted C2-Ci2alkenyloxy, optionally substituted C2-Ci2alkynyloxy, optionally substituted C2-Ci 0 heteroalkyloxy, optionally substituted C3-Ci 2 cycloalkyloxy, optionally substituted C 3 -Ci 2 cycloalkenyloxy, optionally substituted
  • each R 27 and R 28 is independently selected from the group consisting of H, optionally substituted Ci-Ci 2 alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C 2 -Ci 0 heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted Cs-C ⁇ cycloalkenyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C2-C 12 heterocycloalkenyl, optionally substituted C 6 -Ci8aryl, and optionally substituted Ci-Ci 8 heteroaryl.
  • the optionally substituted C 2 -Ci2heterocycloalkyl group is selected from the group consisting of:
  • R is as defined above.
  • R is selected from the group consisting of H, COR 27 , and COOR 28 .
  • R 27 is selected from the group consisting of H, optionally substituted Ci-Ci 2 alkyl, optionally substituted C6-Ci 8 aryl, and optionally substituted CrCiaheteroaryl. In some embodiments R 27 is C-i-C 6 alkyl. In some embodiments R 27 is methyl.
  • R 2 is an optionally substituted C 2 -Ci 2 heteroalkyl group.
  • the C 2 -Ci 2 heteroalkyl group is selected from the group consisting of hydroxyC-i-Cealkyl, Ci-Cealkyloxyd-Cealkyl, aminoCi-Cealkyl, C-i- C 6 alkylaminoCi-C 6 alkyl, and di(Ci-C 6 alkyl)aminoC-i-C 6 alkyl.
  • R 2 examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxymethyl, 2-methoxyethyl, 3- methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, aminomethyl, 2-aminoethyl, 3- aminopropyl, 4-aminobutyl, 5 aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl,
  • R 2 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, cyclopropyl, cyclopentyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, hexyl, heptyl, octyl, cyano, methoxymethyl and putoxymethyl.
  • R a , R b , R c and R d are each independently selected from the group consisting of H, C C 2 alkyl, C-i-Ci 2 haloalkyl, C 2 -C 2 alkenyl, C 2 -Ci 2 alkynyl, Ci-C 10 heteroalkyl, C 3 -Ci 2 cycloalkyl, C 3 -C 2 cycloalkenyl, Ci-Ci 2 heterocycloalkyl, C 1 -C 12 heterocycloalkenyl, C 6 -Ci 8 aryl, CrCi 8 heteroaryl, and acyl, or any two or more of R a , R b , R° and R d , when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
  • optionally substituted includes a fused ring such as a cycloalkyl ring, a heterocydoalkyl ring, an aryl ring or a heteroaryl ring.
  • the embodiments disclosed are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.
  • the invention also relates to pharmaceutical compositions including a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention provides a method of inhibiting a protein kinase a fragment or a complex thereof or a functional equivalent thereof, the method including exposing the protein kinase or a fragment or complex thereof or a functional equivalent thereof and/or co-factor(s) thereof to an effective amount of a compound according to formula (I) as described herein.
  • the compounds disclosed herein may act directly and solely on the kinase molecule or a complex or fragment thereof to inhibit biological activity. However, it is understood that the compounds may also act at least partially on co-factors that are involved in the phosphorylation process.
  • co-factors include ionic species (such as zinc and calcium), lipids (such as . phosphatidylserine), and diacylglycerols.
  • the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof.
  • the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof.
  • the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof.
  • the method exposing the one or more protein kinase(s) to the compound includes administering the compound to a mammal containing the one or more protein kinase(s).
  • the invention provides the use of a compound of formula (I) to inhibit one or more protein kinase(s).
  • the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof.
  • the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof.
  • the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof.
  • the invention provides a method of treating or preventing a condition in a mammal in which inhibition of one or more protein kinase(s) or a fragment or a complex thereof or a functional equivalent thereof, prevents, inhibits or ameliorates a pathology or a symptomology of the condition, the method including administration of a therapeutically effective amount of a compound of formula (I).
  • the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof.
  • the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof.
  • the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof.
  • the condition is selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, pancreatitis, multiple sclerosis, autoimmune disorders, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic ovarian syndrome, hamartoma, tuberous sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-dependent diabetes mellitus, obesity, diabetic retinopathy, cardiac hypertrophy, and autosomal dominant polycystic kidney disease.
  • the condition is cancer.
  • the cancer is selected from the group consisting of Hematologic cancer such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplasia syndromes, plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pan
  • the invention provides use of a compound of formula (I) in the preparation of a medicament for treating a condition in an animal in which inhibition of one or more protein kinase(s) or a fragment or a complex thereof or a functional equivalent thereof prevents, inhibits or ameliorates a pathology or a symptomology of the condition.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, N-oxide or prodrug thereof in the treatment of a condition in which inhibition of one or more protein kinase(s) or a fragment or a complex thereof or a functional equivalent thereof prevents, inhibits or ameliorates a pathology or a symptomology of the condition.
  • the present invention provides a method of prevention or treatment of a proliferative condition in a subject, the method including administration of a therapeutically effective amount of a compound of formula (I).
  • the present invention provides the use of a compound of formula (I) in the preparation of a medicament for treating a proliferative condition in a subject.
  • the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof.
  • the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof.
  • the serine/threonine protein kinase is fnTORCI or a fragment or complex thereof or a functional equivalent thereof.
  • the condition is selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, pancreatitis, multiple sclerosis, autoimmune disorders, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic ovarian syndrome, hamartoma, tuberous sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-dependent diabetes mellitus, obesity, diabetic retinopathy, cardiac hypertrophy, and autosomal dominant polycystic kidney disease.
  • the condition is cancer.
  • the cancer is selected from the group consisting of Hematologic cancer such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes, plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer; urinary tract cancer such as prostate
  • R a , R b , R c and R d are each independently selected from the group consisting of H, CrC 12 alkyl, CrC ⁇ haloalkyl, C 2 -C 12 alkenyl, C 2 -Ci 2 alkynyl, C 2 -Ci 0 heteroalkyl, C 3 -Ci 2 cycloalkyl, C 3 -C 2 cycloalkenyl, C 2 -C 12 heterocycloalkyl, C 2 -C 12 heterocycloalkenyl, C 6 -Ci 8 aryl, d-Cieheteroaryl, and acyl, or any two or more of R a , R b , R c and R d , when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
  • Examples of particularly suitable optional substituents include F, CI, Br, I, CH 3) CH 2 CH 3 , OH, OCH 3 , CF 3 , OCF 3> N0 2 , NH 2 , and CN.
  • optionally substituted includes a fused ring such as a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring or a heteroaryl ring.
  • the group may be a terminal group or a bridging group. This is intended to signify that the use of the term is intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety.
  • alkyl alkyl
  • alkylene alkylene
  • examples of acyl include acetyl and benzoyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • "Alkenyl" as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-12 carbon atoms, more preferably 2-10 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain.
  • the group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.
  • the group may be a terminal group or a bridging group.
  • alkenyloxy refers to an alkenyl-O- group in which alkenyl is as defined herein. Preferred alkenyloxy groups are C C 6 alkenyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Alkyl as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a Ci-C-
  • Examples of suitable straight and branched C-i-C 6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like.
  • the group may be a terminal group or a bridging group.
  • Alkylamino includes both mono-alkylamino and dialkylamino, unless specified.
  • Mono-alkylamino means an Alkyl-NH- group, in which alkyl is as defined herein.
  • Dialkylamino means a (alkyl) 2 N- group, in which each alkyl may be the same or different and are each as defined herein for alkyl.
  • the alkyl group is preferably a C1-C6 alkyl group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • Alkyloxy refers to an alkyl-O- group in which alkyl is as defined herein.
  • the alkyloxy is a CrC 6 alkyloxy. Examples include, but are not limited to, methoxy and ethoxy.
  • the group may be a terminal group or a bridging group.
  • Alkyloxyalkyl refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Alkyloxyaryl refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group.
  • the alkyl group is preferably a Ci-C 6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • Alkyloxycycloalkyl refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the cycloalkyl group.
  • Alkyloxyheteroaryl refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroaryl group.
  • Alkyloxyheterocycloalkyl refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyi moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heterocycloalkyi group.
  • the alkyl group is preferably a C1-C6 alkyl group.
  • Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the alkyl group is preferably a d-Cealkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • Alkynyl as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-12 carbon atoms, more preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms in the normal chain.
  • Exemplary structures include, but are not limited to, ethynyl and propynyl.
  • the group may be a terminal group or a bridging group.
  • Alkynyloxy refers to an alkynyl-O- group in which alkynyl is as defined herein.
  • Preferred alkynyloxy groups are Ci-Cealkynyloxy groups.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Aminoalkyl means an Nhb-alkyl- group in which the alkyl group is as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • Aryl as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring.
  • aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C 5-7 cycloalkyl or C5- 7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.
  • the group may be a terminal group or a bridging group.
  • an aryl group is a C6-C18 aryl group.
  • Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein.
  • Exemplary arylalkenyl groups include phenylallyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain a Ci-salkyl moiety.
  • arylalkyl groups include benzyl, phenethyl, 1-naphthalenemethyl and 2- naphthalenemethyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Arylalkyloxy refers to an aryl-alkyl-O- group in which the alkyl and aryl are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Arylamino includes both mono-arylamino and di-arylamino unless specified.
  • Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein, di-arylamino means a group of formula (aryl) 2 N- where each aryl may be the same or different and are each as defined herein for aryl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Arylheteroalkyl means an aryl-heteroalkyl- group in which the aryl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Aryloxy refers to an aryl-O- group in which the aryl is as defined herein.
  • the aryloxy is a Ce-Ciearyloxy, more preferably a Ce-Cioaryloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • a "bond” is a linkage between atoms in a compound or molecule. The bond may be a single bond, a double bond, or a triple bond.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • the cycloalkenyl group may be substituted by one or more substituent groups.
  • a cycloalkenyl group typically is a C3- C 12 alkenyl group.
  • the group may be a terminal group or a bridging group.
  • Cycloalkyi refers to a saturated monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane.
  • a cycloalkyi group typically is a C3-C12 alkyl group. The group may be a terminal group or a bridging group.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyi and alkyl moieties are as defined herein.
  • Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Cycloalkylalkenyl means a cycloalkyl-alkenyl- group in which the cycloalkyi and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Cycloalkylheteroalkyl means a cycloalkyl-heteroalkyl- group in which the cycloalkyi and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group.
  • Cycloalkyloxy refers to a cycloalkyl-O- group in which cycloalkyl is as defined herein.
  • the cycloalkyloxy is a Ci-C6cycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Cycloalkenyloxy refers to a cycloalkenyl-O- group in which the cycloalkenyl is as defined herein.
  • the cycloalkenyloxy is a C Cecycloalkenyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Haloalkyi refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
  • a haloalkyi group typically has the formula CnH(2n+i-m) m wherein each X is independently selected from the group consisting of F, CI, Br and I .
  • n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3.
  • m is typically 1 to 6, more preferably 1 to 3.
  • Examples of haloalkyi include fluoromethyl, difluoromethyl and trifluoromethyl.
  • Haloalkenyl refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.
  • Haloalkynyl refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.
  • Halogen represents chlorine, fluorine, bromine or iodine.
  • Heteroalkyl refers to a straight- or branched-chain alkyl group preferably having from 2 to 12 carbons, more preferably 2 to 6 carbons in the chain, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by a heteroatomic group selected from S, O, P and NR' where R' is selected from the group consisting of H, optionally substituted CrCi 2 alkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted Ce-C-iearyl, and optionally substituted C Ci 8 heteroaryl.
  • heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.
  • heteroalkyl also include hydroxyCi-Cealkyl, Ci-C 6 alkyloxyCi-C6alkyl, aminoCrC 6 alkyl, CrCealkylaminod-Cealkyl, and di(Ci-C 6 alkyl)aminoCi-C 6 alkyl.
  • the group may be a terminal group or a bridging group.
  • Heteroalkyloxy refers to an heteroalkyl-O- group in which heteroalkyl is as defined herein.
  • the heteroalkyloxy is a C2-C 6 heteroalkyloxy.
  • the group may be a terminal group or a bridging group.
  • Heteroaryl either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur.
  • heteroaryl examples include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3- b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,1 ,3,5-triazene, tetrazole, indole, isoindole, 1 H-indazole, benzotriazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, ox
  • a heteroaryl group is typically a C1-C-18 heteroaryl group.
  • the group may be a terminal group or a bridging group.
  • Heteroarylalkyl means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Heteroarylalkenyl means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Heteroarylheteroalkyl means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Heteroaryloxy refers to a heteroaryl-O- group in which the heteroaryl is as defined herein.
  • the heteroaryloxy is a C-iTCieheteroaryloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Heterocyclic refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom.
  • heterocyclic moieties include heterocycloalkyi, heterocycloalkenyl and heteroaryl.
  • Heterocycloalkenyl refers to a heterocycloalkyi group as defined herein but containing at least one double bond.
  • a heterocycloalkenyl group typically is a C 2 - C-I2 heterocycloalkenyl group.
  • the group may be a terminal group or a bridging group.
  • Heterocycloalkyi refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered.
  • heterocycloalkyi substituents examples include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4- oxazepane, and 1 ,4-oxathiapane.
  • a heterocycloalkyl group typically is a C2-C12 heterocycloalkyl group. The group may be a terminal group or a bridging group.
  • Heterocycloalkylalkyl refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as defined herein.
  • exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl,
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Heterocycloalkylalkenyl refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Heterocycloalkylheteroalkyl means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Heterocycloalkyloxy refers to a heterocycloalkyl-O- group in which the heterocycloalkyl is as defined herein.
  • the heterocycloalkyloxy is a Ci- Ceheterocycloalkyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Heterocycloalkenyloxy refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is as defined herein.
  • the Heterocycloalkenyloxy is a Ci- Ce Heterocycloalkenyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Hydroalkyl refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an OH group.
  • a hydroxyalkyl group typically has the formula C n H(2n+ 1-X) (OH) x .
  • n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3.
  • x is typically 1 to 6, more preferably 1 to 3.
  • “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
  • the group may be a terminal group or a bridging group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical isomers in "E” or "Z” configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and/or chemical methods and by those skilled in the art.
  • Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.
  • Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
  • each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995.
  • Prodrug means a compound that undergoes conversion to a compound of formula (I) within a biological system, usually by metabolic means (e.g. by hydrolysis, reduction or oxidation).
  • metabolic means e.g. by hydrolysis, reduction or oxidation
  • an ester prodrug of a compound of formula (I) containing a hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of formula (I) containing a hydroxyl group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, ma!eates, methylene-bis-P-hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • an ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • ester prodrugs are those described by F.J. Leinweber, Drug Metab. Res., 18:379, 1987.
  • an acyl prodrug of a compound of formula (I) containing an amino group may be convertible by hydrolysis in vivo to the parent molecule.
  • prodrugs for these and other functional groups, including amines are described in Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag and J Tilley; Springer, 2007.
  • oxygen protecting group means a group that can prevent the oxygen moiety reacting during further derivatisation of the protected compound and which can be readily removed when desired.
  • the protecting group is removable in the physiological state by natural metabolic processes and in essence the protected compound is acting as a prodrug for the active unprotected species.
  • oxygen protecting groups include acyl groups (such as acetyl), ethers (such as methoxy methyl ether (MOM), B-methoxy ethoxy methyl ether (MEM), p- methoxy benzyl ether (PMB), methylthio methyl ether, Pivaloyl (Piv), Tetrahydropyran (THP)), andsilyl ethers (such as Trimethylsilyl (TMS) tert-butyl dimethyl silyl (TBDMS) and tri i sop ropy Isi lyl (TIPS).
  • acyl groups such as acetyl
  • ethers such as methoxy methyl ether (MOM), B-methoxy ethoxy methyl ether (MEM), p- methoxy benzyl ether (PMB), methylthio methyl ether, Pivaloyl (Piv), Tetrahydropyran (THP)
  • sil ethers such as
  • nitrogen protecting group means a group that can prevent the nitrogen moiety reacting during further derivatisation of the protected compound and which can be readily removed when desired.
  • the protecting group is removable in the physiological state by natural metabolic processes and in essence the protected compound is acting as a prodrug for the active unprotected species.
  • nitrogen protecting groups examples include formyl, trityl, phthalimidoacetyl, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl; urethane-type blocking groups such as benzyloxycarbonyl ('CBz'), 4- phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2- chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t- butoxycarbonyl ('tBoc'), 2-(4-xen
  • the actual nitrogen protecting group employed is not critical so long as the derivatised nitrogen group is stable to the condition of subsequent reaction(s) and can be selectively removed as required without substantially disrupting the remainder of the molecule including any other nitrogen protecting group(s).
  • Further examples of these groups are found in: Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, Second edition; Wiley-lnterscience: 1991 ; Chapter 7; McOmie, J. F. W. (ed.), Protective Groups in Organic Chemistry, Plenum Press, 1973; and Kocienski, p. J., Protecting Groups, Second Edition, Theime Medical Pub., 2000.
  • terapéuticaally effective amount or "effective amount” is an amount sufficient to effect beneficial or desired clinical results.
  • An effective amount can be administered in one or more administrations.
  • An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
  • kinases may have isoforms, such that while the primary, secondary, tertiary or quaternary structure of a given kinase isoform is different to the protoypical kinase, the molecule maintains biological activity as a protein kinase. Isoforms may arise from normal allelic variation within a population and include mutations such as amino acid substitution, deletion, addition, truncation, or duplication. Also included within the term “functional equivalent” are variants generated at the level of transcription. Other functional equivalents include kinases having altered post-translational modification such as glycosylation.
  • the compounds have the ability to inhibit the activity of certain protein kinases.
  • the ability to inhibit kinase activity may be a result of the compounds acting directly and solely on the kinase molecule to inhibit biological activity. However, it is understood that the compounds may also act at least partially on co-factors of the kinase in question that are involved in the phosphorylation process.
  • the compounds may have activity against certain serine/threonine kinases such as mTOR or a fragment or complex or functional equivalent thereof.
  • the inhibition of the protein kinase may be carried out in any of a number of well known ways in the art. For example if inhibition of the protein kinase in vitro is desired an appropriate amount of the compound may be added to a solution containing the kinase. In circumstances where it is desired to inhibit the activity of the kinase in a mammal the inhibition of the kinase typically involves administering the compound to a mammal containing the kinase.
  • the compounds may find a multiple number of applications in which their ability to inhibit protein kinases of the type mentioned above can be utilised.
  • the compounds may be used to inhibit serine/threonine protein kinases.
  • the compounds may also be used in treating or preventing a condition in a mammal in which inhibition of a protein kinase and/or co-factor thereof prevents, inhibits or ameliorates a pathology or a symptomology of the condition.
  • the compounds of the invention will be useful in treating a wide range of conditions related to mTOR kinase including conditions selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, pancreatitis, multiple sclerosis, autoimmune disorders, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic ovarian syndrome, hamartoma, tuberous sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-dependent diabetes mellitus, obesity, diabetic retinopathy, cardiac hypertrophy, autosomal dominant polycystic kidney disease.
  • conditions related to mTOR kinase including conditions selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, pancreatitis, multiple s
  • the compounds of the invention will be useful in treating various cancers including but not limited to bone cancers, brain and CNS tumours, breast cancers, colorectal cancers, endocrine cancers including adrenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, gastrointestinal cancers, Liver cancer, extra hepatic bile duct cancer, gastrointestinal carcinoid tumour, gall bladder cancer, genitourinary cancers, gynaecological cancers, head and neck cancers, leukemias, myelomas, hematological disorders, lung cancers, lymphomas, eye cancers, skin cancers, soft tissue sarcomas, adult soft tissue sarcoma, Kaposi's sarcoma, urinary system cancers.
  • various cancers including but not limited to bone cancers, brain and CNS tumours, breast cancers, colorectal cancers, endocrine cancers including adrenocort
  • Exemplary cancers that may be treated by compounds of this invention include Hematologic cancer such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes, plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer; urinary tract
  • the compounds may also be used the preparation of a medicament for treating a condition in an animal in which inhibition of a protein kinase can prevent, inhibit or ameliorate the pathology or symptomolpgy of the condition.
  • the compounds may also be used in the preparation of a medicament for the treatment or prevention of a kinase-related disorder.
  • Administration of compounds of formula (I) to humans can be by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion.
  • the active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose.
  • the inhibitor compound may be selectively toxic or more toxic to rapidly proliferating cells, e.g. cancerous tumours, than to normal cells.
  • In using the compounds they can be administered in any form or mode which makes the compound bioavailable.
  • the compounds can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutically acceptable carrier diluent or excipient.
  • the compounds, while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.
  • compositions which are formulated depending on the desired mode of administration.
  • a pharmaceutical composition including a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compositions are prepared in manners well known in the art.
  • kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions.
  • a pack or kit can be found a container having a unit dosage of the agent(s).
  • the kits can include a composition comprising an effective agent either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the concentration of use, where the vials may include one or more dosages.
  • single dosages can be provided in sterile vials so that the physician can employ the vials directly, where the vials will have the desired amount and concentration of agent(s).
  • Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the compounds may be used or administered in combination with one or more additional drug(s) for the treatment of the disorder/diseases mentioned.
  • the components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds may be administered sequentially or simultaneously with the other drug(s).
  • the compounds may be used in a combination therapy. When this is done the compounds are typically administered in combination with each other. Thus one or more of the compounds may be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result.
  • compositions of the present teaching for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.
  • the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Dosage forms for topical administration of a compound of this invention include powders, patches, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • the amount of compound administered will preferably treat and reduce or alleviate the condition.
  • a therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.
  • a preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day.
  • a more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day.
  • a suitable dose can be administered in multiple sub-doses per day.
  • the agents of the various embodiments may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available.
  • the preparation of particular compounds of the embodiments is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various embodiments.
  • the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.
  • a list of suitable protecting groups in organic synthesis can be found in T.W. Greene's Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, 1991.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the various embodiments.
  • Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.
  • a wide range of trisubstituted purines can be prepared in a straightforward three step procedure starting from 2,6-dichloropurine which is commercially available from a number of sources or may be prepared from purine-2,6-dione or xanthine itself using, for example, phosphorylchloride (Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 23; 12; 1984; 1286 - 1288).
  • the general representative procedure is shown in scheme 1,
  • the R substituent may be varied either by using an 8-substituted dichloropurine as starting material (Scheme 1) or can be introduced later in the synthetic sequence (Scheme 2).
  • Scheme 1 an 8-substituted dichloropurine as starting material
  • Scheme 2 can be introduced later in the synthetic sequence
  • chemistry may be carried out on the 8- position after completion of the sequence illustrated in scheme 1 above.
  • the 8-position of 4 may be brominated to give 5.
  • the bromide may then be displaced by, for example, an organometallic agent, such as an organozinc, to install R 1 as in 6.
  • Scheme 3 depicts three variations on the three step procedure in which different conditions are used in the first step so as to introduce diverse substituents at the 9-position of the purine scaffold.
  • a skilled addressee could modify the general reaction scheme shown in scheme one where the nitrogen moiety at the 9 position of the purine may be reacted with a moiety containing a suitable leaving group (such as a halide) in a reaction whereby the nitrogen displaces the leaving group to form the compound in which the nitrogen at the 9 position is then functionalised with the moiety.
  • a suitable leaving group such as a halide
  • Suitable leaving groups for use in reactions of this type which can be displaced by nitrogen in such reactions are known in the art and in general the synthesis of moieties containing leaving groups of this type for use in these types of reactions are also well known to a skilled worker in the field.
  • the three simplest routes to the compounds of the invention involve reaction of the dichloropurine with either an arylalkyl halide (such as benzyl halide) or a heteroarylalkyi halide to introduce an aryl or heteroaryl substituted methyl group at the 9 position, an alcohol (to introduce a di-substituted methyl group at the 9 position) or an aryl or heteroaryl boronic acid (to introduce an aryl or heteroaryl group directly.
  • an arylalkyl halide such as benzyl halide
  • a heteroarylalkyi halide to introduce an aryl or heteroaryl substituted methyl group at the 9 position
  • an alcohol to introduce a di-substi
  • THF Tetrahydrofuran
  • DMF ⁇ , ⁇ -dimethylformamide
  • TLC plates were visualized by UV absorption or with a p-anisaldehyde spray reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20 wt% in ethanol) which was activated with heat, or by staining in an iodine chamber. Workups were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume (unless otherwise indicated). Product solutions were dried over anhydrous sodium sulfate prior to filtration, and evaporation of the solvents was under reduced pressure on a rotary evaporator and noted as solvents removed in vacuo.
  • a p-anisaldehyde spray reagent or a phosphomolybdic acid reagent Aldrich Chemical, 20 wt% in ethanol
  • Flash column chromatography [Still et a/, J. Org. Chem., 43, 2923 (1978)] was conducted using E Merck-grade flash silica gel (40-63 ⁇ ) and a silica crude material ratio of about 20:1 to 50:1 , unless otherwise stated. Hydrogenolysis was done at the pressure indicated or at ambient pressure.
  • NMR spectra were recorded on a Bruker instrument operating at 400 MHz, and 13 C-NMR spectra was recorded operating at 100 MHz. NMR spectra were obtained as CDCI3 solutions (reported in ppm), using chloroform as the reference standard (7.27 ppm and 77.00 ppm) or CD 3 OD (3.4 and 4.8 ppm and 49.3 ppm), or an internal tetramethylsilane standard (0.00 ppm) when appropriate. Other NMR solvents were used as needed.
  • 2,6-Dichloropurine (1 eq), the alcohol (1-3 eq) and triphenylphosphine (1-2 eq) are dissolved in a suitable organic solvent (e.g. THF) to a concentration of 0.1-0.2 M.
  • a suitable organic solvent e.g. THF
  • reaction mixture was then stirred on an oil bath maintained at 80°C for 3 h. Conversion was monitored by LC/MS for the disappearance of the starting purine.
  • the reaction mixture was cooled to room temperature and the solvents removed under reduced pressure. The residue was taken up in ethyl acetate and water. The organic phase was separated and the aqueous layer further extracted with 3x200 ml portions of ethyl acetate. The organics were dried over sodium sulfate and the solvents removed under vacuum to give 5-[2-chloro-9alkyl-9H-purin-6-yl]- pyrazin-2-ylamine.
  • Phosphorylation assays were initially performed in a final volume of 20 pL in 384-well polypropylene plate (Greiner). Compounds were typically tested over the range from 100 ⁇ to 0.006 ⁇ , in 8 step dilutions, in duplicate.
  • 10 pUwell of 2X Enzyme-Substrate solution (1.5 pg/mL mTOR, 40pg/ml_ 4eBP1 in 1X assay buffer: 10 mM Hepes pH 7.5, 50 mM NaCI and 10 mM MnCI 2 ) were first added to the sample plate containing 1 pUwell of test compound in neat DMSO.
  • the reaction was initiated by adding 10 pUwell of 20 ⁇ ATP solution (final assay concentration 10 ⁇ ATP and 0.4 pCi/well of [Y ⁇ PJ-ATP). After 1 hour incubation at room temperature, the reaction was terminated with 40 pUwell of 20 mM EDTA/1 mM ATP solution.

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Abstract

The present invention relates to purine compounds that are useful as kinase inhibitors. More particularly, the present invention relates to purine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative conditions or disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative conditions or disorders including tumours and cancers as well as other disorders or conditions related to or associated with PI3K and/or mTOR kinases.

Description

BRIDGED ORPHOLINO SUBSTITUTED PURINES
FIELD
[0001] The invention relates to purine compounds that may be useful as kinase inhibitors. More particularly, the invention relates to bridged 2-(morpholin-4-yl), 6- (pyrazin-2-yl) substituted purine derivatives, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of certain medical conditions such as kinase related disorders/conditions.
BACKGROUND
[0002] The search for kinase inhibitors has proven to be a fruitful area for the development of useful pharmaceutically active substances. Kinases, which are alternatively known as phosphotransferases, are enzymes that transfer phosphate groups from high energy donor molecules (for example ATP) to specific target molecules (typically called substrates) in a process termed phosphorylation. One of the largest groups of kinases is the protein kinases which act on and modify the activity of specific proteins. As a result of this activity these kinases are involved in a number of cellular processes such as in signalling and to prime the cell for biochemical reactions in metabolism. Certain cellular signalling processes have been implicated as important in a number of medical conditions and the effective inhibition of certain cell signalling processes therefore provides the potential to stop these conditions developing. Accordingly, kinases represent an attractive target for medicinal chemists as the provision of kinase inhibitors potentially allows for certain signalling processes to be controlled leading to the control of certain medical conditions.
[0003] One family of kinases associated with undesirable medical conditions in the body are the phosphoinositide 3-kinase (PI3) family of kinases which are involved in a wide range of cellular events such as cell migration, cell proliferation, oncogenic transformation, cell survival, signal transduction and intracellular trafficking of proteins. This family of kinases has recently been the focus of much research aimed at developing therapies for a range of indications. [0004] The phosphoinositide 3-kinase (PI3) family is a group of enzymes that generate phosphatidylinositol 'second messengers'. These lipids are subsequently involved in a wide range of physiological processes. The PI3K signalling pathway is crucial to many aspects of cell growth and survival via its regulation of widely divergent physiological processes that include cell cycle progression, differentiation, transcription, translation and apoptosis. Constitutive activation of the PI3K pathway has been implicated in both the pathogenesis and progression of a large variety of cancers and there is now a rapidly accumulating body of evidence that demonstrates conclusively that PI3K signalling is frequently deregulated in cancer. The deregulation of PI3K signalling is thought to occur in two different ways. The first is an increase in PI3K signalling resulting from activating gene mutations, amplification and over expression of PI3Ks or upstream receptors that activate PI3Ks. For example, the PI3Ka catalytic subunit is amplified and over expressed in ovarian and cervical cancers. Similarly, upstream receptor tyrosine kinases that activate PI3K are commonly mutated, amplified and over expressed, e.g., EGFR in breast, ovarian and lung cancer.
[0005] In addition, activation of the effectors downstream of PI3K can also contribute to deregulation of the PI3K pathway, e.g., Akt/PKB (Protein Kinase B) is over expressed and activated in breast, pancreatic and ovarian cancers among others. Also, the Ras family members, which are involved in PI3K activation, are frequently mutated, e.g. in colorectal and pancreatic cancer. The second mechanism of PI3K deregulation involves loss of the tumor suppressor phosphatase PTEN, which occurs in many aggressive brain tumors, endometrial and breast cancers, and melanomas.
[0006] One specific cell signalling pathway mediated by the PI3 family of kinases is the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. This pathway is critically involved in the mediation of cell survival and is a major signalling component downstream of growth factor receptor tyrosine kinases (RTKs). Growth factor RTKs engage the class-la PI3K, which is a heterodimer comprised of the p85 regulatory and p110 catalytic subunits. The small GTPase Ras can also recruit and activate PI3K through direct binding to p110. At the cell membrane, PI3K catalyzes the production of the lipid second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3). Subsequently, PIP3 recruits other downstream molecules - particularly the serine- threonine kinases Akt and PDK1— via binding to their pleckstrin-homology (PH) domains. At the membrane, Akt is partially activated through phosphorylation at threonine 308 in its activation loop by PDK1. Additional phosphorylation at serine 473 in the C terminus of Akt results in its full activation. This second phosphorylation is carried out by the mammalian target of rapamycin (mTOR). Akt in turn regulates a wide range of target proteins, one of which is mTOR. mTOR thus plays a pivotal role in the signalling downstream of PI3K and Akt and has, as a result, received a lot of attention as a potential therapeutic target for a wide range of indications. The levels of PlP3 in the cell are strictly regulated and several lipid phosphatases act to rapidly remove it. Of particular interest is the phosphatase PTEN, which converts PIP3 back to PIP2 and thus shuts off PI3K signalling. The PI3K-Akt signalling pathway regulates many normal cellular processes including cell proliferation, survival, growth, and motility - processes that are critical for tumorigenesis.
[0007] The role of the PI3K/Akt pathway in oncogenesis has also been extensively investigated and mutations or altered expression of most of the pathway's components have been widely implicated in many cancers. Gene amplification of p110 occurs in some cases of human ovarian cancer, and amplification of Akt is found in ovarian, breast, and colon cancer. In addition, activating mutations in p85 have been identified in ovarian and colon cancer. Most importantly PTEN has been identified as a major tumor suppressor in humans and loss-of-function mutations in the PTEN gene are extremely common among sporadic glioblastomas, melanomas, prostate cancers, and endometrial carcinomas, and a significant percentage of breast tumors, lung cancers, and lymphomas also bear PTEN mutations. Thus, through a variety of mechanisms, a high percentage of human cancers possess activated PI3K signalling. Significantly, it has been shown that (mTOR) is important for the oncogenic transformation induced by PI3K and Akt. [0008] In addition to the compelling correlative data presented above, direct proof of the involvement of deregulated PI3K signalling in1 cancer comes from mouse genetic models. For example, mice with a constitutively activated p85 regulatory subunit of PI3K progress to malignant lymphoma when crossed with p53-knockout mice. Further, retroviral introduction of Akt and Ras caused glioblastomas in mice. Taken together, all these data provide strong validation for the development of novel anticancer strategies targeted at this pathway.
[0009] mTOR is a serine/threonine kinase of 289 kDa and is a PI3K-like kinase that links mitogenic stimuli and nutrient status to cell growth and division. mTOR functions as a key enzyme in the PI3K-Akt pathway as discussed above. mTOR was discovered during studies conducted to understand the mechanism of action of rapamycin. Upon entering cells, rapamycin binds to its intracellular target FKBP12 and the complex then binds to and specifically inhibits mTOR. mTOR was, therefore, also named FKBP-RAP associated protein (FRAP), RAP FKBP12 target (RAFT1) and RAP target (RAPT1 ). Cells responsible for organ rejection stop growing due to rapamycin's ability to inhibit the anabolic signals coordinated by mTOR. Since inhibition of cell growth represents a valid target for treating cancer, designing new drugs that inhibit mTOR will potentially have therapeutic value.
[0010] In humans, mTOR mediates anabolic signals from 2 sources namely nutrients that pass into the cell and activated growth factor receptors. It exists in at least two distinct complexes: a rapamycin-sensitive complex, referred to as mTOR complex 1 (mTORCI ), defined by its interaction with the accessory protein raptor (regulatory-associated protein of mTOR). The normal activation of mTOR results in an increase in protein translation because mTORCI phosphorylates and activates the translation regulators eukaryotic initiation factor 4E-binding protein 1 and ribosomal p70 S6 kinase. Therefore, by inhibiting mTOR, rapamycin causes a decrease in phosphorylation of these effectors, and a decrease in protein synthesis, effectively blocking the pro-growth actions of mTOR.
[0011] The second complex, mTOR complex 2 (mTORC2), is rapamycin- insensitive and is defined by its interaction with rictor (rapamycin-insensitive companion of mTOR). mTORC2 is involved in the regulation of the pro-survival kinase Akt/PKB by phosphorylating it on S473. Together with the phosphorylation of T308 by PDK1 , S473 phosphorylation is necessary for full Akt activation. Recent reports indicate that prolonged treatment with rapamycin in some cells also suppresses the assembly and function of mTORC2 to inhibit Akt and that this property of rapamycin contributes to the anti-apoptotic effects of the drug. mTOR is also one of the main downstream effectors in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and therefore inhibition of mTOR provides a further opportunity to inhibit, at least in part, the PI3K/Akt pathway.
[0012] An additional pathway influenced by mTOR that appears to be particularly important in renal cell carcinoma involves the hypoxia-inducible factor (HIF). With loss of Von Hippel-Lindau (VHL) gene function commonly seen in clear cell renal cell cancer, there is accumulation of the oxygen-sensitive transcription factors HIF-1 and HIF-2. An accumulation of these factors yields increased stimulation of vascular endothelial growth factor (VEGF), platelet-derived growth factor, and transforming growth factor. This effect is augmented by the activation of mTOR, which stimulates both a protein stabilization function and a protein translational function and, thus, increases HIF- 1 activity.
[0013] It has also been determined that tuberous sclerosis complex gene products, TSC1 and TSC2, function together to inhibit mTOR-mediated downstream signalling. Mutations of these genes occur in tuberous sclerosis and their loss of function yields yet another pathway, which leads to increased activity of mTOR and induces VEGF production. TSC2 also regulates HIF. Thus, studies evaluating the impact of TSC1 and TSC2 mutations demonstrate the connection of increased VEGF and activated mTOR pathways to angiogenesis.
[0014] Rapamycin, also named sirolimus, is a natural antibiotic produced by Streptomyces hygroscopicus. It was developed initially as an anti-fungal drug directed against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. Later, rapamycin was developed as an immunosuppressive agent and those studies helped in understanding the mechanism of action of this agent. As an anti-cancer agent, rapamycin was shown to inhibit the growth of several murine and human cancer cell lines in a concentration-dependent manner, both in tissue culture and xenograft models. In the sixty tumor cell lines screened at the National Cancer Institute in the USA, general sensitivity to the drug was seen at doses under 2000 ng/ml, more evident in leukemia, ovarian, breast, central nervous system and small cell lung cancer cell lines. In addition, rapamycin inhibits the oncogenic transformation of human cells induced by either PI3K or Akt and has shown metastatic tumor growth inhibition and anti-angiogenic effects in in vivo mouse models.
[0015] Based on these pre-clinical results, clinical trials with rapamycin as an anticancer drug were carried out and rapamycin analogues with more favourable pharmaceutical properties were developed. CCI-779 (Temsirolimus), a more water- soluble ester derivative of rapamycin was identified by investigators at Wyeth Ayerst as a non-cytotoxic agent that inhibited tumor cell proliferation in vitro. At several nontoxic doses in animals, CCI-779 demonstrated anti-tumor activity alone or in combination with cytotoxic agents in a variety of human cancer models such as gliomas, rhabdomyosarcoma, primitive neuroectodermal tumor such as medulloblastoma, head and neck, prostate, pancreatic and breast cancer cells. Treatment of mice with CCI-779 inhibits P70S6K activity and reduces neoplastic proliferation. As with rapamycin, PTEN-deficient human tumors are more sensitive to CCI-779-mediated growth inhibition than PTEN expressing cells. Specifically, studies in vitro in a panel of eight human breast cancer cell lines showed that six of eight cancer lines studied were inhibited by CCI-779 with IC50 in the low nanomolar range. Two lines, however, were found to be resistant with ICso>1 μΜ. The sensitive cell lines were estrogen receptor positive or over-expressed HER-2/Neu, or had lost the tumor suppressor gene product PTEN. The main toxicities of CCI-779 included dermatological toxicities and mild myelosuppression (mainly thrombocytemia). CCI- 779 has been evaluated in a number of clinical trials for a broad range of cancer indications. More recently CCI-779 has received FDA approval for the treatment of advanced renal cell carcinoma (RCC) by intravenous infusion (marketed as TORISEL™). The most common adverse reactions associated with Torisel have been reported as rash, asthenia, mucositis, nausea, edema and anorexia. Further clinical trials are on-going.
[0016] RAD001 (Everolimus), 40-O-(2-hydroxyethyl)-rapamycin, is another analogue of rapamycin that can be administrated orally. Its anti-neoplastic activity has been evaluated in different human cancer cell lines in vitro and in xenograft models in vivo. p70S6K inhibition and anti-neoplastic effects have been shown in these models. Similarly, RAD001 demonstrated a concentration-dependent antitumor activity in a syngenic rat pancreas carcinoma model with an intermittent dosing schedule. RAD001 has also shown anti-angiogenic activity and inhibits human vascular endothelial cell (HUVEC) proliferation. The toxicity reported for RAD001 includes hypercholesterolemia, hypertriglyceridemia, mild leukocytopenia and thrombocytopenia. RAD001 is undergoing evaluation in a broad range of clinical trials both as a single agent and in combination with other therapeutics. As with CCI-779 it has now received FDA approval for use in RCC.
[0017] There is thus a plethora of studies that demonstrate that mTOR inhibitors can improve cancer patient survival. However, rapamycin and its analogues have not shown universal anti-tumor activity in early clinical trials. Response rates vary among cancer types from a low of less than 10% in patients with glioblastomas and advanced renal-cell cancer to a high of around 40% in patients with mantle-cell lymphoma. Knowledge of the status of PTEN and PI3K/Akt/mTOR-linked pathways might help in the selection of tumor types that will respond to mTOR inhibitors. Furthermore, because many tumor types still do not respond to single agent therapy with rapamycin derivatives, it is important to continue the search for factors predictive of resistance or sensitivity to mTOR inhibitors. Of particular interest will be molecules that directly inhibit mTOR kinase activity, the theory being that such molecules will inhibit both mTORCI and mTORC2. Such an inhibitor might be beneficial for treating tumors with elevated Akt phosphorylation and might down-regulate the growth, proliferation and survival effects that are associated with Akt activation. If mTOR- rictor is a crucial activator of Akt-dependent survival processes, such a drug might promote apoptosis in tumor cells that have adapted to Akt-dependent regulatory mechanisms. Considerable effort is now being made to develop mTOR kinase inhibitors and the more advanced compounds, such as OSI-017 and AZD8055, have entered phase 1 clinical trials.
[0018] Thus mTOR inhibitors have the potential to provide further biologically active compounds that would be expected to have useful, improved pharmaceutical properties in the treatment of kinase related conditions or disorders. In particular mTOR inhibitors may potentially be used in the treatment of a wide range of cancers and related hyper proliferative disorders. Furthermore, recent research implicates mTOR in a number of non-oncology disease areas including inflammation, cardiovascular disease and certain metabolic as well as neurological disorders. SUMMARY
[0019] The invention provides compounds of formula (I):
Figure imgf000009_0001
Formula (I)
[0020] wherein:
[0021] R1 is selected from the group consisting of: H, halogen and optionally substituted CrC6alkyl;
[0022] R2 is selected from the group consisting of H, halogen, OH, N02, CN, NH2, optionally substituted Ci-C-^alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-C-i2alkynyl, optionally substituted C2-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C3-Ci2cycloalkenyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C2-Ci2heterocycloalkenyl, optionally substituted C6-Ciearyl, optionally substituted Ci-Cieheteroaryl, optionally substituted C C12alkyloxy, optionally substituted C2-C12alkenyloxy, optionally substituted C2-Ci2alkynyloxy, optionally substituted C2-Ci2heteroalkyloxy, optionally substituted C3-Ci2cycloalkyloxy, optionally substituted C3-Ci2cycloalkenyloxy, optionally substituted C2-Ci2heterocycloalkyloxy, optionally substituted C2- Ci2heterocycloalkenyloxy, optionally substituted C6-Ci8aryloxy, optionally substituted C-i-C-ieheteroaryloxy, optionally substituted CrC^alkylamino, SR8, S03H, S02NR8R9, S02R8, SONR8R9, SOR8, COR8, COOH, COOR8, CONR8R9, NR8COR9, NR8COOR9, NR8S02R9, NR8CONR8R9, NR8R9, and acyl, [0023] or R is a group of the formula:
Figure imgf000010_0001
[0024] wherein each M is independently N or CR 2a.
[0025] each R is independently selected from the group consisting of H, halogen,
OH, N02, CN, NH2, optionally substituted Ci-Ci2alkyl, optionally substituted C2-Ci2 alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C2-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C2-Ci2heterocycloalkenyl, optionally substituted C6-C18 aryl, optionally substituted C-i-C-ieheteroaryl, optionally substituted CrCi2alkyloxy, optionally substituted C2-Ci2alkenyloxy, optionally substituted C2-Ci2alkynyloxy, optionally substituted C2-Ci2heteroalkyloxy, optionally substituted C3-Ci2 cycloalkyloxy, optionally substituted C3-Ci2cycloalkenyloxy, optionally substituted C Ci2heterocycloalkyloxy, optionally substituted C2-Ci2heterocycloalkenyloxy, optionally substituted C6-Ciearyloxy, optionally substituted Ci-Ci8heteroaryloxy, optionally substituted C1-C12 alkylamino, SR8, S03H, S02NH2, S02R8, SONH2, SOR8, COR8, COOH, COOR8, CONR8R9, NR8COR9, NR8COOR9, NR8S02R9, NR8CONR8R9, NR8R9, and acyl;
[0026] r is an integer selected from the group consisting of 1 , 2, and 3;
[0027] R3 is selected from the group consisting of H, F, CI, Br, OH, optionally substituted C C6alkyl, OR8, OCOR8, CH2OH, NH2, NR8R9, NR8COR9, and NR8S02R9;
[0028] R6 is selected from the group consisting of H, OH, OR8, OPg°, OCOR8, CH2OH, NH2, NR8R9, NR8Pg N, N(Pg N)2, NR8COR9, NR8CONR8R9 and NR8S02R9; [0029] R7 is selected from the group consisting of H, F, CI, Br, OH, OR8, OCOR8, CH2OH, NH2, NR8R9, NR8COR9, and NR8S02R9;
[0030] each R8 and R9 is independently selected from the group consisting of H, optionally substituted Ci-Ci2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C2-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C3-Ci2cycloalkenyl, optionally substituted C2-C12heterocycloalkyl, optionally substituted C2-Ci2heterocycloalkenyl, optionally substituted Ce-C-iearyl, and optionally substituted Ci-Ci8heteroaryl, or
[0031] R8 and R9 when taken together with the atoms to which they are attached form an optionally substituted cyclic moiety;
[0032] Pg° is a protecting group for oxygen;
[0033] each Pg N is independently a protecting group for nitrogen;
[0034] each Rz is independently selected from the group consisting of Ci-C6alkyl, halo-Ci-C6alkyl, hydroxyCi-C6alkyl, Ci-C6alkyloxyCi-C6alkyl, cyanoCrC6alkyl, aminoCrCealkyl, Ci-C6alkylaminoCi-C6alkyl, and d C Cealky aminoC-i-Cealkyl;
[0035] q is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
[0036] X is a group of formula (CR10 2)m;
[0037] each R10 is independently selected from the group consisting of: H and optionally substituted C-i-Cealkyl;
[0038] m is an integer selected from the group consisting of 0, 1 , 2, 3 and 4;
[0039] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof. [0040] As with any group of structurally related compounds which possess a particular utility, certain embodiments of variables of the compounds of the formula (I), are particularly useful in their end use application. [0041] In various embodiments q is an integer selected from the group consisting of 0, 1 , 2, 3, and 4. In some embodiments q is 4. In some embodiments q is 3. In some embodiments q is 2. In some embodiments q is 1. In some embodiments q is 0. [0042] In some embodiments wherein q is other than 0, each Rz may be selected from the group consisting of F, CI, Br, methyl, trifluoromethyl, and ethyl. The Rz substituent may be attached at any available position on the 7 membered ring. In circumstances where there are multiple Rz substituents, each Rz substituent is located independently of the others. In some embodiments q is 1 and the Rz substituent is located alpha to the ring nitrogen. This provides compounds of formula (la).
Figure imgf000012_0001
Formula (la)
[0043] or a pharmaceutically acceptable salt or prodrug thereof,
[0044] wherein R1, R2, R3, R6, R7, Rz and X are as defined above.
[0045] In some embodiments q is 0. This provides compounds of formula (lb):
Figure imgf000013_0001
Formula (lb)
[0046] or a pharmaceutically acceptable salt or prodrug thereof,
[0047] wherein R1, R2, R3, R6, R7 and X are as defined above.
[0048] In some embodiments R3 is selected from the group consisting of H, OR8, and optionally substituted Ci-C6alkyl.
[0049] In some embodiments R3 is OR8 where R8 is optionally substituted C-i- Cealkyl. Examples of R3 groups of this type include methoxy, trifluoro-methoxy, ethoxy, isopropoxy, propoxy, and butoxy. In some embodiments R3 is methoxy. [0050] In some embodiments R3 is optionally substituted Ci-C6alkyl. Examples of R3 groups of this type include methyl, trifluoro-methyl, ethyl, propyl, isopropyl, and butyl. In some embodiments R3 is methyl.
[0051] In some embodiments R3 is selected from the group consisting of H, methoxy and methyl. In some embodiments R3 is H.
[0052] In some embodiments R7 is selected from the group consisting of H, F, CI, Br, OH and NH2. In some embodiments R7 is H. [0053] In some embodiments R3 and R7 are both H. [0054] In some embodiments q = 0, R3 is H and R7 is H. This provides compounds of formula (lc
Figure imgf000014_0001
Formula (lc)
[0055] or a pharmaceutically acceptable salt or prodrug thereof, [0056] wherein R1, R2, R6, and X are as defined above.
[0057] In some embodiments of compounds containing the group R8, R8 is selected from H and Ci-C6alkyl. In some embodiments R8 is methyl. In some embodiments R8 is H. [0058] In some embodiments of the compounds containing the group R9, R9 is selected from H and C-i-Cealkyl. In some embodiments R9 is methyl. In some embodiments R9 is H.
[0059] As stated previously X is a group of formula (CR102)m. In some embodiments m is selected from the group consisting of 0, 1 , and 2. In some embodiments m is 0 or 1 . In some embodiments m is 0. In some embodiments m is 1.
[0060] In some embodiments q = 0, R3 is H, R7 is H and m is o. This provides compounds of formula (II):
Figure imgf000015_0001
Formula (II)
[0061] or a pharmaceutically acceptable salt or prodrug thereof, [0062] wherein R1, R2, and R6 are as defined above.
[0063] In some embodiments q = 0, R3 is H, R7 is H and m is 1. This provides compounds of formula (III):
Figure imgf000015_0002
Formula (III)
[0064] or a pharmaceutically acceptable salt or prodrug thereof, [0065] wherein R1 , R2, R6 and R10 are as defined above. [0066] In some embodiments of the compounds of formula (I), (la), (lb), (Ic) and (III) each R10 is H. In some embodiments each R10 is independently an optionally substituted Ci-C6alkyl. In some embodiments one R10 is H and the other R10 is H or optionally substituted CrC6alkyl. In some embodiments one R10 is H and the other is CH3.
[0067] In some embodiments of the compounds of formula (I), (la), (lb), (Ic) and (III) m is 1 , one R10 is H and X is therefore a group of the formula:
Figure imgf000016_0001
[0068] In some embodiments R3 and R7 are H, m is 1 , q is 0 and one R10 is H. This provides compounds of the formula (IV):
Figure imgf000016_0002
ormu a
[0069] or a pharmaceutically acceptable salt or prodrug thereof,
[0070] wherein R1, R2, R6 and R10 are as defined above.
[0071] In some embodiments R1 is selected from the group consisting of H, fluoro, chloro, bromo, methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl. In some embodiments R1 is H.
[0072] In some embodiments R6 is selected from the group consisting of H, NH2 and NR R wherein RB and R are as defined above. In some embodiments R is NH2.
[0073] In some embodiments R2 is selected from the group consisting of H, cyano, optionally substituted Ci-Ci2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-C12heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C6-Ciearyl, and optionally substituted Ci-Ci8heteroaryl.
[0074] In some embodiments R2 is an optionally substituted C6-Ciearyl. In some embodiments of R2 the optionally substituted C6-Ci8aryl (and hence R2) is a group of the formula:
Figure imgf000017_0001
[0075] wherein p is an integer selected from the group consisting of 0, 1 , 2, 3, 4, and 5;
[0076] each R13 is independently selected from the group consisting of H, halogen, OH, N02l CN, NH2, optionally substituted Ci-C-i2alkyl, optionally substituted C2-Ci2 alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C2-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C2-Ci2heterocycloalkenyl, optionally substituted C6-Ci8aryl, optionally substituted Ci-Cieheteroaryl, optionally , substituted Ci-C-i2alkyloxy, optionally substituted C2-Ci2alkenyloxy, optionally substituted C2-C-i2alkynyloxy, optionally substituted C2-Ci2heteroalkyloxy, optionally substituted C3- Ci2cycloalkyloxy, optionally substituted C3-Ci2cycloalkenyloxy, optionally substituted C2-C12heterocycloalkyloxy, optionally substituted C2-Ci2heterocycloalkenyloxy, optionally substituted C6-Ci8 aryloxy, optionally substituted Ci-Ci8heteroaryloxy, optionally substituted C1-C12 alkylamino, SR8, SO3H, S02NH2, S02R8, SONH2, SOR8, COR8, COOH, COOR8, CONR8R9, NR8COR9, NR8COOR9, NR8S02R9, NR8CONR8R9, NR8R9, and acyl, or
[0077] any two adjacent R13 may, when taken together with each other and the carbon atoms to which they are attached form a cyclic moiety; [0078] where R8 and R9 are as defined above.
[0079] The phenyl group may be unsubstituted or may be optionally substituted with one or more suitable substituent groups. If the phenyl group is substituted then there may be 1 , 2, 3, 4 or 5 substituent groups. In some embodiments p is 0, 1 or 2. In some embodiments p is 1. Iii some embodiments p is 2.
[0080] In some embodiments R1 is H, R3 is H, R6 is NH2> R7 is H, X is (CH2)m wherein m is 0, and R2 is a group of the formula:
Figure imgf000018_0001
[0081] This provides compounds of formula (V):
Figure imgf000019_0001
Formula (V)
[0082] or a pharmaceutically acceptable salt or prodrug thereof,
[0083] wherein R13 and p are as defined above.
[0084] In some embodiments R1 is H, R3 is H, R6 is NH2, R7 is H, X is (CR10 2), wherein m is 1 , and R2 is a group of the formula:
Figure imgf000019_0002
[0085] This provides compounds of formula (Va):
Figure imgf000020_0001
Formula (Va)
[0086] or a pharmaceutically acceptable salt or prodrug thereof,
[0087] wherein R10, R13 and p are as defined above.
[0088] In some embodiments of the compounds containing R10, R10 is selected from the group consisting of H, Ci-C6haloalkyl, CrCehydroxyalkyl and Ci-C6alkyl. In some embodiments R10 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and butyl. In some embodiments R10 is selected from the group consisting of H, methyl and ethyl.
[0089] In some embodiments R2 is selected from the group consisting of cyano, optionally substituted Ci-Cealkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, and optionally substituted C2-Ci2heteroalkyl.
[0090] In some embodiments R2 is selected from the group consisting of cyano, optionally substituted Ci-Cealkyl, and optionally substituted C2-Ci2heteroalkyl.
[0091] In some embodiments R2 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3- dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, hexyl, heptyl, and octyl. In some embodiments R2 is an optionally substituted methyl group of the
Figure imgf000021_0001
[0093] wherein R20, R21 and R22 are each independently selected from the group consisting of H, CI, Br, F, OH, N02, CN, NH2, optionally substituted C C12alkyl and optionally substituted Ci-Ci2heteroalkyl.
[0094] In some embodiments each R20, R21 and R22 is independently selected from the group consisting of H, CI, Br, F, OH, N02, CN, NH2, methyl, ethyl, propyl, isopropyl, butyl, pentyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 2- ethoxyethyl, 3-ethoxypropyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4- aminobutyl, 5 aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3- methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2- ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4- dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl and 5-diethylaminopentyl.
[0095] In some embodiments R2 is optionally substituted C3-C-i2cycloalkyl group. In some embodiments R2 is selected from the group consisting of optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl and optionally substituted cyclohexyl. In some embodiments R2 is cyclopropyl.
[0096] In some embodiments the optionally substituted C3-Ci2cycloalkyl group is selected from the group consisting of:
Figure imgf000021_0002
[0097] wherein R is independently selected from the group consisting of H, optionally substituted Ci-Ci2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C2-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C3-Ci2cycloalkenyl, optionally substituted C2-C12heterocycloalkyl, optionally substituted C2-Ci2heterocycloalkenyl, optionally substituted C6-Ci8aryl, optionally substituted CrCi8heteroaryl, optionally substituted CrCi2alkyloxy, optionally substituted C2-C12alkenyloxy, optionally substituted C2-Ci2alkynyloxy, optionally substituted C2-Ci0heteroalkyloxy, optionally substituted C3-C 2cycloalkyloxy, optionally substituted C3-Ci2cycloalkenyloxy, optionally substituted C2-Ci2heterocycloalkyloxy, optionally substituted C2-Ci2 heterocycloalkenyloxy, optionally substituted C6-Ci8aryloxy, optionally substituted C Cieheteroaryloxy, optionally substituted Ci-C 2alkylamino, S02NR24R25, SOR24, S02R24, SONR2 R25, SOR24, COR24, COOH, COOR24, and CONR24R25;
[0098] each R24 and R25 is independently selected from the group consisting of H, optionally substituted d-Ci2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-C-|2alkynyl, optionally substituted C2-Ci0heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C3-Ci2cycloalkenyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C2-C12heterocycloalkenyl, optionally substituted C6-Ci8aryl, and optionally substituted C C18heteroaryl.
[0099] In some embodiments the optionally substituted C3-C-i2cycloalkyl group is selected from the group consisting of:
Figure imgf000023_0001
Figure imgf000023_0002
[0100] where R is as defined above.
[0101] In some embodiments R2 is a group of the formula:
Figure imgf000023_0003
[0102] wherein each M is independently N or CR ;
[0103] each R is independently selected from the group consisting of H, halogen, OH, NO2, CN, NH2, optionally substituted Ci-Ci2alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C2-C12heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C2-C12heterocycloalkenyl, optionally substituted C6-Ci8 aryl, optionally substituted C-i-Cieheteroaryl, optionally substituted Ci-Ci2alkyloxy, optionally substituted C2-C12alkenyloxy, optionally substituted C2-Ci2alkynyloxy, optionally substituted C2-Ci2heteroalkyloxy, optionally substituted, optionally substituted C3-C12 cycloalkyloxy, optionally substituted C3-Ci2cycloalkenyloxy, optionally substituted Ci-Ci2heterocycloalkyloxy, optionally substituted C2- Ci2heterocycloalkenyloxy, optionally substituted C6-C 8aryloxy, optionally substituted Ci-Ci8heteroaryloxy, optionally substituted C1-C12 alkylamino, SR8, SOaH, SO2NH2, S02R8, SONH2) SOR8, COR8, COOH, COOR8, CONR8R9, NR8COR9, NR8COOR9, NR8S02R9, NR8CONR8R9, NR8R9, and acyl;
[0104]: where R8 and R9 are as defined above;
[0105] r is an integer selected from the group consisting of 1 , 2, and 3.
[0106] In some embodiments r is 1 and R is a group of the formula:
Figure imgf000024_0001
[0107] where each m is as described above.
[0108] In some embodiments r is 2 and R2 is a group of the formula:
Figure imgf000024_0002
[0109] wherein each M is as defined above. [0110] In some embodiments each M is CR . In some embodiments one M group is N and the other M groups are CR 2a
In some embodiments of R is a group of the formula:
Figure imgf000024_0003
wherein R is as defined above; s is an integer selected from the group consisting of 0, 1 , 2, 3 and 4; r is an integer selected from the group consisting of 1 , 2, and 3.
In some embodiments each M is CR2a, r is 1 and R2 is a group of the
Figure imgf000025_0001
[0116] wherein R is as defined above
[0117] In some embodiments each M is CR2a, r is 2 and R2 is a group of the formula:
Figure imgf000025_0002
wherein R is as defined above. [0119] In some embodiments one M is N and the others are CR . In one embodiment R2 is a group of the formula:
Figure imgf000026_0001
[0120] wherein R2a and r are as defined in above. [0121] In some embodiments r is selected from the group consisting of 1 , and 2. In some embodiments r is 1. In some embodiments r is 2.
[0122] Each R substituent may be selected from any suitable optional substituent. In some embodiments each R2a is independently selected from the group consisting of H, F, CH3, CH2CH3, OCH3> CN, OCF3, C02CH3, N02, NH2) NHCOCH3, NHS02CH3l NHCH2CH3, and CF3.
[0123] In some embodiments R2 is optionally substituted C2-Ci2heterocycloalkyl. [0124] In some embodiments R2 is selected from the group consisting of optionally substituted pyrrolidin-1-yl, optionally substituted pyrrol id in-2-yl, optionally substituted pyrrol id in-3-yl, optionally substituted dioxolane-2-yl, optionally substituted dioxolane- 3-yl, optionally substituted tetrahydrofuran-2-yl, optionally substituted tetrahydrofuran- 3-yl, optionally substituted piperidine-1-yl, optionally substituted piperidine-2-yl, optionally substituted piperidine-3-yl, optionally substituted piperidine-4-yl, optionally substituted morpholine-1-yl, optionally substituted morpholine-2-yl, optionally substituted morpholine-3-yl, optionally substituted 1 ,4,dioxolane-2-yl, optionally substituted thiomorpholine-1-yl, optionally substituted thiomorpholine-2-yl, optionally substituted thiomorpholine-3-yl, optionally substituted thiomorpholine-4-yl,optionally substituted piperazine-1-yl and optionally substituted piperazine-2-yl.
[0125] In some embodiments the optionally substituted C2-Ci2heterocycloalkyl group is selected from the group consisting of:
Figure imgf000027_0001
[0126] wherein R is independently selected from the group consisting of H, optionally substituted
Figure imgf000027_0002
optionally substituted C2-Ci2alkynyl, optionally substituted C2-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C3-Ci2cycloalkenyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C2-Ci2heterocycloalkenyl, optionally substituted Ce-C-iearyl, optionally substituted Ci-C-ieheteroaryl, optionally substituted Ci-C12alkyloxy, optionally substituted C2-Ci2alkenyloxy, optionally substituted C2-Ci2alkynyloxy, optionally substituted C2-Ci0heteroalkyloxy, optionally substituted C3-Ci2cycloalkyloxy, optionally substituted C3-Ci2cycloalkenyloxy, optionally substituted C2-Ci2heterocycloalkyloxy, optionally substituted C2-C12 heterocycloalkenyloxy, optionally substituted C6-Ci8aryloxy, optionally substituted C Cieheteroaryloxy, optionally substituted Ci-Ci2alkylamino, S02NR27R28, SOR27, S02R27, SONR27R28, SOR27, COR27, COOH, COOR27, and CONR27R28;
[0127] each R27 and R28 is independently selected from the group consisting of H, optionally substituted Ci-Ci2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C2-Ci0heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted Cs-C^cycloalkenyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C2-C12heterocycloalkenyl, optionally substituted C6-Ci8aryl, and optionally substituted Ci-Ci8heteroaryl.
[0128] In some embodiments the optionally substituted C2-Ci2heterocycloalkyl group is selected from the group consisting of:
Figure imgf000027_0003
[0129] wherein R is as defined above. [0130] In some embodiments R is selected from the group consisting of H, COR27, and COOR28.
[0131] In some embodiments R27 is selected from the group consisting of H, optionally substituted Ci-Ci2alkyl, optionally substituted C6-Ci8aryl, and optionally substituted CrCiaheteroaryl. In some embodiments R27 is C-i-C6 alkyl. In some embodiments R27 is methyl.
[0132] In some embodiments R2 is an optionally substituted C2-Ci2heteroalkyl group. In some embodiments the C2-Ci2heteroalkyl group is selected from the group consisting of hydroxyC-i-Cealkyl, Ci-Cealkyloxyd-Cealkyl, aminoCi-Cealkyl, C-i- C6alkylaminoCi-C6alkyl, and di(Ci-C6alkyl)aminoC-i-C6alkyl. Examples of possible values of R2 as C2-Ci2heteroalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxymethyl, 2-methoxyethyl, 3- methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, aminomethyl, 2-aminoethyl, 3- aminopropyl, 4-aminobutyl, 5 aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl,
2- ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4- dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl,
3- diethylaminopropyl, 4-diethylaminobutyl and 5-diethylaminopentyl.
[0133] In some embodiments R2 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, cyclopropyl, cyclopentyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, hexyl, heptyl, octyl, cyano, methoxymethyl and putoxymethyl.
[0134] Many if not all of the variables discussed above may be optionally substituted. If the variable is optionally substituted then in some embodiments each optional substituent is independently selected from the group consisting of halogen, =0, =S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterdcycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkyi heteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyi, alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -C(=0)OH, -C(=0)Ra, -C(=0)ORa, C(=0)NRaRb, C(=NOH)Ra, C(=NRa)NRbR°, NRaRb, NRaC(=0)Rb, NRaC(=0)ORb, NRaC(=0)NRbRc, N RaC(= N Rb)N R°Rd , NRaS02Rb,-SRa, S02NRaRb, -ORa, OC(=0)NRaRb, OC(=0)Ra and acyl,
[0135] wherein Ra, Rb, Rc and Rd are each independently selected from the group consisting of H, C C 2alkyl, C-i-Ci2haloalkyl, C2-C 2alkenyl, C2-Ci2alkynyl, Ci-C10 heteroalkyl, C3-Ci2cycloalkyl, C3-C 2cycloalkenyl, Ci-Ci2heterocycloalkyl, C1-C12 heterocycloalkenyl, C6-Ci8aryl, CrCi8heteroaryl, and acyl, or any two or more of Ra, Rb, R° and Rd, when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
[0136] In some embodiments each optional substituent is independently selected from the group consisting of: F, CI, Br, =0, =S, -CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyi, alkynyl, aryl, cycloalkyi, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyi, alkoxy, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C(0)ORa, COOH, SH, and acyl.
[0137] In some embodiments each optional substituent is independently selected from the group consisting of: F, Br, CI, =0, =S, -CN methyl, trifluoro-methyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH2, -N02, phenoxy, hydroxy, methoxy, trifluoro-methoxy, ethoxy, and methylenedioxy.
[0138] Alternatively, two optional substituents on the same moiety when taken together may be joined to form a fused cyclic substituent attached to the moiety that is optionally substituted. Accordingly the term optionally substituted includes a fused ring such as a cycloalkyl ring, a heterocydoalkyl ring, an aryl ring or a heteroaryl ring.
[0139] In addition to compounds of formula I, the embodiments disclosed are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.
[0140] The invention also relates to pharmaceutical compositions including a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
[0141] In a further aspect the invention provides a method of inhibiting a protein kinase a fragment or a complex thereof or a functional equivalent thereof, the method including exposing the protein kinase or a fragment or complex thereof or a functional equivalent thereof and/or co-factor(s) thereof to an effective amount of a compound according to formula (I) as described herein.
[0142] The compounds disclosed herein may act directly and solely on the kinase molecule or a complex or fragment thereof to inhibit biological activity. However, it is understood that the compounds may also act at least partially on co-factors that are involved in the phosphorylation process. Known kinase co-factors include ionic species (such as zinc and calcium), lipids (such as . phosphatidylserine), and diacylglycerols.
[0143] In some embodiments the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof. In some embodiments the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof. In some embodiments the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof. [0144] In one embodiment of the method exposing the one or more protein kinase(s) to the compound includes administering the compound to a mammal containing the one or more protein kinase(s). [0145] In an even further aspect the invention provides the use of a compound of formula (I) to inhibit one or more protein kinase(s).
[0146] In some embodiments the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof. In some embodiments the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof. In some embodiments the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof. [0147] In an even further aspect the invention provides a method of treating or preventing a condition in a mammal in which inhibition of one or more protein kinase(s) or a fragment or a complex thereof or a functional equivalent thereof, prevents, inhibits or ameliorates a pathology or a symptomology of the condition, the method including administration of a therapeutically effective amount of a compound of formula (I).
[0148] In some embodiments the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof. In some embodiments the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof. In some embodiments the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof.
[0149] In some embodiments the condition is selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, pancreatitis, multiple sclerosis, autoimmune disorders, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic ovarian syndrome, hamartoma, tuberous sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-dependent diabetes mellitus, obesity, diabetic retinopathy, cardiac hypertrophy, and autosomal dominant polycystic kidney disease.
[0150] In some embodiments the condition is cancer. In some embodiments the cancer is selected from the group consisting of Hematologic cancer such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplasia syndromes, plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer; urinary tract cancer such as prostate cancer, kidney and renal cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer such as melanoma; brain tumour such as glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stem gliomas, medulloblastoma, menigiomas, astrocytoma, oligodendroglioma; head and neck cancer such as nasopharyngeal carcinoma, laryngeal carcinoma; respiratory tract cancer such as lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease such as retinoblastoma; musculo- skeleton diseases such as osteosarcoma, musculoskeleletal neoplasm; Squamous cell carcinoma and fibroid tumour.
[0151] In an even further aspect the invention provides use of a compound of formula (I) in the preparation of a medicament for treating a condition in an animal in which inhibition of one or more protein kinase(s) or a fragment or a complex thereof or a functional equivalent thereof prevents, inhibits or ameliorates a pathology or a symptomology of the condition. [0152] In another aspect the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, N-oxide or prodrug thereof in the treatment of a condition in which inhibition of one or more protein kinase(s) or a fragment or a complex thereof or a functional equivalent thereof prevents, inhibits or ameliorates a pathology or a symptomology of the condition. [0153] In another aspect the present invention provides a method of prevention or treatment of a proliferative condition in a subject, the method including administration of a therapeutically effective amount of a compound of formula (I).
[0154] In another aspect the present invention provides the use of a compound of formula (I) in the preparation of a medicament for treating a proliferative condition in a subject. [0155] In some embodiments the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof. In some embodiments the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof. In some embodiments the serine/threonine protein kinase is fnTORCI or a fragment or complex thereof or a functional equivalent thereof.
[0156] In some embodiments the condition is selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, pancreatitis, multiple sclerosis, autoimmune disorders, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic ovarian syndrome, hamartoma, tuberous sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-dependent diabetes mellitus, obesity, diabetic retinopathy, cardiac hypertrophy, and autosomal dominant polycystic kidney disease. [0157] In some embodiments the condition is cancer. In some embodiments the cancer is selected from the group consisting of Hematologic cancer such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes, plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer; urinary tract cancer such as prostate cancer, kidney and renal cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer such as melanoma; brain tumor such as glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stem gliomas, medulloblastoma, menigiomas, astrocytoma, oligodendroglioma; head and neck cancer such as nasopharyngeal carcinoma, laryngeal carcinoma; respiratory tract cancer such as lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease such as retinoblastoma; musculo- skeleton diseases such as osteosarcoma, musculoskeleletal neoplasm; Squamous cell carcinoma and fibroid tumour.
[0158] These and other features of the present teachings are set forth herein.
DETAILED DESCRIPTION
[0159] In this specification a number of terms are used which are well known to a skilled addressee. Nevertheless for the purposes of clarity a number of terms will be defined.
[0160] As used herein, the term "unsubstituted" means that there is no substituent or that the only substituents are hydrogen.
[0161] The term "optionally substituted" as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system), with one or more non-hydrogen substituent groups. In certain embodiments the substituent groups are one or more groups independently selected from the group consisting of halogen, =0, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyi, arylamino, sulfonylamino, sulfinylamino, suifonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyi, aryisuifinyi, aminosulfinylaminoalkyl, -C(=0)OH, -C(=0)Ra, -C(=0)ORa, C(=0)NRaRb, C(=NOH)Ra, C(=NRa)NRbRc, NRaRb, NRaC(=0)Rb, NRaC(=0)ORb, NRaC(=0)NRbRc, N RaC(= N Rb) N R°Rd , NRaS02Rb,-SRa, S02NRaRb, -ORa, OC(=0)NRaRb, OC(=0)Ra and acyl,
[0162] wherein Ra, Rb, Rc and Rd are each independently selected from the group consisting of H, CrC12alkyl, CrC^haloalkyl, C2-C12alkenyl, C2-Ci2alkynyl, C2-Ci0 heteroalkyl, C3-Ci2cycloalkyl, C3-C 2cycloalkenyl, C2-C12heterocycloalkyl, C2-C12 heterocycloalkenyl, C6-Ci8aryl, d-Cieheteroaryl, and acyl, or any two or more of Ra, Rb, Rc and Rd, when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
[0163] In some embodiments each optional substituent is independently selected from the group consisting of: halogen, =0, =S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyioxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyi, arylamino, suifonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyi, -COOH, -SH, and acyl.
[0164] Examples of particularly suitable optional substituents include F, CI, Br, I, CH3) CH2CH3, OH, OCH3, CF3, OCF3> N02, NH2, and CN.
[0165] Alternatively, two optional substituents on the same moiety when taken together may be joined to form a fused cyclic substituent attached to the moiety that is optionally substituted. Accordingly the term optionally substituted includes a fused ring such as a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring or a heteroaryl ring.
[0166] In the definitions of a number of substituents below it is stated that "the group may be a terminal group or a bridging group". This is intended to signify that the use of the term is intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety. Using the term alkyl as an example, some publications would use the term "alkylene" for a bridging group and hence in these other publications there is a distinction between the terms "alkyl" (terminal group) and "alkylene" (bridging group). In the present application no such distinction is made and most groups may be either a bridging group or a terminal group.
[0167] "Acyl" means an R-C(=0)- group in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as defined herein. Examples of acyl include acetyl and benzoyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon. [0168] "Acylamino" means an R-C(=0)-NH- group in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom. [0169] "Alkenyl" as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-12 carbon atoms, more preferably 2-10 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain. The group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. The group may be a terminal group or a bridging group.
[0170] "Alkenyloxy" refers to an alkenyl-O- group in which alkenyl is as defined herein. Preferred alkenyloxy groups are C C6 alkenyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom. [0171] "Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a Ci-C-|2 alkyl, more preferably a C-1-C10 alkyl, most preferably C1-C6 unless otherwise noted. Examples of suitable straight and branched C-i-C6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like. The group may be a terminal group or a bridging group.
[0172] "Alkylamino" includes both mono-alkylamino and dialkylamino, unless specified. "Mono-alkylamino" means an Alkyl-NH- group, in which alkyl is as defined herein. "Dialkylamino" means a (alkyl)2N- group, in which each alkyl may be the same or different and are each as defined herein for alkyl. The alkyl group is preferably a C1-C6 alkyl group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
[0173] "Alkylaminocarbonyl" refers to a group of the formula (Alkyl)x(H)yNC(=0)- in which alkyl is as defined herein, x is 1 or 2, and the sum of X+Y =2. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
[0174] "Alkyloxy" refers to an alkyl-O- group in which alkyl is as defined herein. Preferably the alkyloxy is a CrC6alkyloxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group. [0175] "Alkyloxyalkyl" refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group. [0176] "Alkyloxyaryl" refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group. [0177] "Alkyloxycarbonyl" refers to an alkyl-0-C(=0)- group in which alkyl is as defined herein. The alkyl group is preferably a Ci-C6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
[0178] "Alkyloxycycloalkyl" refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the cycloalkyl group.
[0179] "Alkyloxyheteroaryl" refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroaryl group.
[0180] "Alkyloxyheterocycloalkyl" refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyi moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heterocycloalkyi group.
[0181] "Alkylsulfinyl" means an alkyl-S-(=0)- group in which alkyl is as defined herein.. The alkyl group is preferably a C1-C6 alkyl group. Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
[0182] "Alkylsulfonyl" refers to an alkyl-S(=0)2- group in which alkyl is as defined above. The alkyl group is preferably a d-Cealkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom. [0183] "Alkynyl" as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-12 carbon atoms, more preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl. The group may be a terminal group or a bridging group.
[0184] "Alkynyloxy" refers to an alkynyl-O- group in which alkynyl is as defined herein. Preferred alkynyloxy groups are Ci-Cealkynyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
[0185] "Aminoalkyl" means an Nhb-alkyl- group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
[0186] "Aminosulfonyl" means an NH2-S(=0)2- group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
[0187] "Aryl" as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C5-7 cycloalkyl or C5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The group may be a terminal group or a bridging group. Typically an aryl group is a C6-C18 aryl group.
[0188] "Arylalkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein. Exemplary arylalkenyl groups include phenylallyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group. [0189] "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain a Ci-salkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl, 1-naphthalenemethyl and 2- naphthalenemethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
[0190] "Arylalkyloxy" refers to an aryl-alkyl-O- group in which the alkyl and aryl are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
[0191] "Arylamino" includes both mono-arylamino and di-arylamino unless specified. Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein, di-arylamino means a group of formula (aryl)2N- where each aryl may be the same or different and are each as defined herein for aryl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
[0192] "Arylheteroalkyl" means an aryl-heteroalkyl- group in which the aryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
[0193] "Aryloxy" refers to an aryl-O- group in which the aryl is as defined herein. Preferably the aryloxy is a Ce-Ciearyloxy, more preferably a Ce-Cioaryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
[0194] "Arylsulfonyl" means an aryl-S(=0)2- group in which the aryl group is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom. [0195] A "bond" is a linkage between atoms in a compound or molecule. The bond may be a single bond, a double bond, or a triple bond. [0196] "Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituent groups. A cycloalkenyl group typically is a C3- C12 alkenyl group. The group may be a terminal group or a bridging group.
[0197] "Cycloalkyi" refers to a saturated monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. A cycloalkyi group typically is a C3-C12 alkyl group. The group may be a terminal group or a bridging group.
[0198] "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyi and alkyl moieties are as defined herein. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group. [0199] "Cycloalkylalkenyl" means a cycloalkyl-alkenyl- group in which the cycloalkyi and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group. [0200] "Cycloalkylheteroalkyl" means a cycloalkyl-heteroalkyl- group in which the cycloalkyi and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group. [0201] "Cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined herein. Preferably the cycloalkyloxy is a Ci-C6cycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
[0202] "Cycloalkenyloxy" refers to a cycloalkenyl-O- group in which the cycloalkenyl is as defined herein. Preferably the cycloalkenyloxy is a C Cecycloalkenyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
[0203] "Haloalkyi" refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine. A haloalkyi group typically has the formula CnH(2n+i-m) m wherein each X is independently selected from the group consisting of F, CI, Br and I . In groups of this type n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3. m is typically 1 to 6, more preferably 1 to 3. Examples of haloalkyi include fluoromethyl, difluoromethyl and trifluoromethyl.
[0204] "Haloalkenyl" refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.
[0205] "Haloalkynyl" refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I. [0206] "Halogen" represents chlorine, fluorine, bromine or iodine.
[0207] "Heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having from 2 to 12 carbons, more preferably 2 to 6 carbons in the chain, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by a heteroatomic group selected from S, O, P and NR' where R' is selected from the group consisting of H, optionally substituted CrCi2alkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted Ce-C-iearyl, and optionally substituted C Ci8heteroaryl. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. Examples of heteroalkyl also include hydroxyCi-Cealkyl, Ci-C6alkyloxyCi-C6alkyl, aminoCrC6alkyl, CrCealkylaminod-Cealkyl, and di(Ci-C6alkyl)aminoCi-C6alkyl. The group may be a terminal group or a bridging group. [0208] "Heteroalkyloxy" refers to an heteroalkyl-O- group in which heteroalkyl is as defined herein. Preferably the heteroalkyloxy is a C2-C6heteroalkyloxy. The group may be a terminal group or a bridging group.
[0209] "Heteroaryl" either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3- b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,1 ,3,5-triazene, tetrazole, indole, isoindole, 1 H-indazole, benzotriazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole,1 ,2,3-oxadiazole, 1 ,2,4- oxadiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, 1 ,2,4-thiadiazole, 1 ,3,4-thiadiazole, furazane, phenoxazine, 2-, 3- or 4- pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1-, 3-, 4-, or 5- isoquinolinyl 1-, 2-, or 3- indolyl, and 2-, or 3-thienyl. A heteroaryl group is typically a C1-C-18 heteroaryl group. The group may be a terminal group or a bridging group. [0210] "Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group. [0211] "Heteroarylalkenyl" means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
[0212] "Heteroarylheteroalkyl" means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
[0213] "Heteroaryloxy" refers to a heteroaryl-O- group in which the heteroaryl is as defined herein. Preferably the heteroaryloxy is a C-iTCieheteroaryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
[0214] "Heterocyclic" refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom. Examples of heterocyclic moieties include heterocycloalkyi, heterocycloalkenyl and heteroaryl.
[0215] "Heterocycloalkenyl" refers to a heterocycloalkyi group as defined herein but containing at least one double bond. A heterocycloalkenyl group typically is a C2- C-I2 heterocycloalkenyl group. The group may be a terminal group or a bridging group.
[0216] "Heterocycloalkyi" refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyi substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4- oxazepane, and 1 ,4-oxathiapane. A heterocycloalkyl group typically is a C2-C12 heterocycloalkyl group. The group may be a terminal group or a bridging group.
[0217] "Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as defined herein. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl,
(2-tetrahydrothiofuranyl) methyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
[0218] "Heterocycloalkylalkenyl" refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
[0219] "Heterocycloalkylheteroalkyl" means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
[0220] "Heterocycloalkyloxy" refers to a heterocycloalkyl-O- group in which the heterocycloalkyl is as defined herein. Preferably the heterocycloalkyloxy is a Ci- Ceheterocycloalkyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
[0221] "Heterocycloalkenyloxy" refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is as defined herein. Preferably the Heterocycloalkenyloxy is a Ci- Ce Heterocycloalkenyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
[0222] "Hydroxyalkyl" refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an OH group. A hydroxyalkyl group typically has the formula CnH(2n+1-X)(OH)x. In groups of this type n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3. x is typically 1 to 6, more preferably 1 to 3. [0223] "Lower alkyl" as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl). The group may be a terminal group or a bridging group.
[0224] "Sulfinyl" means an R-S(=0)- group in which the R group may be OH, alkyl, cycloalkyi, heterocycloalkyi; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
[0225] "Sulfinylamino" means an R-S(=0)-NH- group in which the R group may be OH, alkyl, cycloalkyi, heterocycloalkyi; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
[0226] "Sulfonyl" means an R-S(=0)2- group in which the R group may be OH, alkyl, cycloalkyi, heterocycloalkyi; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
[0227] "Sulfonylamino" means an R-S(=0)2-NH- group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom. [0228] It is understood that included in the family of compounds of Formula (I) are isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical isomers in "E" or "Z" configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and/or chemical methods and by those skilled in the art.
[0229] Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.
[0230] Additionally, Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
[0231] The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae. [0232] "Prodrug" means a compound that undergoes conversion to a compound of formula (I) within a biological system, usually by metabolic means (e.g. by hydrolysis, reduction or oxidation). For example an ester prodrug of a compound of formula (I) containing a hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of formula (I) containing a hydroxyl group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, ma!eates, methylene-bis-P-hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. As another example an ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. (Examples of ester prodrugs are those described by F.J. Leinweber, Drug Metab. Res., 18:379, 1987). Similarly, an acyl prodrug of a compound of formula (I) containing an amino group may be convertible by hydrolysis in vivo to the parent molecule. (Many examples of prodrugs for these and other functional groups, including amines, are described in Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag and J Tilley; Springer, 2007.)
[0233] The term "oxygen protecting group" means a group that can prevent the oxygen moiety reacting during further derivatisation of the protected compound and which can be readily removed when desired. In one embodiment the protecting group is removable in the physiological state by natural metabolic processes and in essence the protected compound is acting as a prodrug for the active unprotected species. Examples of oxygen protecting groups include acyl groups (such as acetyl), ethers (such as methoxy methyl ether (MOM), B-methoxy ethoxy methyl ether (MEM), p- methoxy benzyl ether (PMB), methylthio methyl ether, Pivaloyl (Piv), Tetrahydropyran (THP)), andsilyl ethers (such as Trimethylsilyl (TMS) tert-butyl dimethyl silyl (TBDMS) and tri i sop ropy Isi lyl (TIPS).
[0234] The term "nitrogen protecting group" means a group that can prevent the nitrogen moiety reacting during further derivatisation of the protected compound and which can be readily removed when desired. In one embodiment the protecting group is removable in the physiological state by natural metabolic processes and in essence the protected compound is acting as a prodrug for the active unprotected species. Examples of suitable nitrogen protecting groups that may be used include formyl, trityl, phthalimidoacetyl, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl; urethane-type blocking groups such as benzyloxycarbonyl ('CBz'), 4- phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2- chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t- butoxycarbonyl ('tBoc'), 2-(4-xenyl)-isopropoxycarbonyl, 1 ,1-diphenyleth-1- yloxycarbonyl, 1,1-diphenylprop-l-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p- toluyl)-prop-2-yloxy-carbonyl, cyclo-pentanyloxy-carbonyl, 1- methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1- methylcyclohexanyloxycarbonyl 2-methylcyclohexanyloxycarbonyl, 2-(4- toluylsulfono)-ethoxycarbonyl, 2-(methylsulfono)ethoxycarbonyl, 2- (triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxycarbonyl ("FMOC"), 2- (trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1- enyloxycarbonyl, 5-benzisoxalymethoxy carbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, oyclopropylmethoxycarbonyl, 4- (decycloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonlyl and the like; benzoylmethylsulfono group, 2-nitrophenylsulfenyl, diphenylphosphine oxide, and the like. The actual nitrogen protecting group employed is not critical so long as the derivatised nitrogen group is stable to the condition of subsequent reaction(s) and can be selectively removed as required without substantially disrupting the remainder of the molecule including any other nitrogen protecting group(s). Further examples of these groups are found in: Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, Second edition; Wiley-lnterscience: 1991 ; Chapter 7; McOmie, J. F. W. (ed.), Protective Groups in Organic Chemistry, Plenum Press, 1973; and Kocienski, p. J., Protecting Groups, Second Edition, Theime Medical Pub., 2000.
[0235] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
[0236] The term "functional equivalent" is intended to include variants of the specific protein kinase species described herein. It will be understood that kinases may have isoforms, such that while the primary, secondary, tertiary or quaternary structure of a given kinase isoform is different to the protoypical kinase, the molecule maintains biological activity as a protein kinase. Isoforms may arise from normal allelic variation within a population and include mutations such as amino acid substitution, deletion, addition, truncation, or duplication. Also included within the term "functional equivalent" are variants generated at the level of transcription. Other functional equivalents include kinases having altered post-translational modification such as glycosylation.
[0237] Specific compounds of the invention include the following:
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
[0238] or a pharmaceutically acceptable salt or prodrug thereof.
[0239] The compounds have the ability to inhibit the activity of certain protein kinases. The ability to inhibit kinase activity may be a result of the compounds acting directly and solely on the kinase molecule to inhibit biological activity. However, it is understood that the compounds may also act at least partially on co-factors of the kinase in question that are involved in the phosphorylation process.
[0240] The compounds may have activity against certain serine/threonine kinases such as mTOR or a fragment or complex or functional equivalent thereof. [0241] The inhibition of the protein kinase may be carried out in any of a number of well known ways in the art. For example if inhibition of the protein kinase in vitro is desired an appropriate amount of the compound may be added to a solution containing the kinase. In circumstances where it is desired to inhibit the activity of the kinase in a mammal the inhibition of the kinase typically involves administering the compound to a mammal containing the kinase.
[0242] Accordingly the compounds may find a multiple number of applications in which their ability to inhibit protein kinases of the type mentioned above can be utilised. For example the compounds may be used to inhibit serine/threonine protein kinases. The compounds may also be used in treating or preventing a condition in a mammal in which inhibition of a protein kinase and/or co-factor thereof prevents, inhibits or ameliorates a pathology or a symptomology of the condition. [0243] It is anticipated that the compounds of the invention will be useful in treating a wide range of conditions related to mTOR kinase including conditions selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, pancreatitis, multiple sclerosis, autoimmune disorders, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic ovarian syndrome, hamartoma, tuberous sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-dependent diabetes mellitus, obesity, diabetic retinopathy, cardiac hypertrophy, autosomal dominant polycystic kidney disease. [0244] It is anticipated that the compounds of the invention will be useful in treating various cancers including but not limited to bone cancers, brain and CNS tumours, breast cancers, colorectal cancers, endocrine cancers including adrenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, gastrointestinal cancers, Liver cancer, extra hepatic bile duct cancer, gastrointestinal carcinoid tumour, gall bladder cancer, genitourinary cancers, gynaecological cancers, head and neck cancers, leukemias, myelomas, hematological disorders, lung cancers, lymphomas, eye cancers, skin cancers, soft tissue sarcomas, adult soft tissue sarcoma, Kaposi's sarcoma, urinary system cancers. [0245] Exemplary cancers that may be treated by compounds of this invention include Hematologic cancer such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes, plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer; urinary tract cancer such as prostate cancer, kidney and renal cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer such as melanoma; brain tumour such as glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stem gliomas, medulloblastoma, menigiomas, astrocytoma, oligodendroglioma; head and neck cancer such as nasopharyngeal carcinoma, laryngeal carcinoma; respiratory tract cancer such as lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease such as retinoblastoma; musculo-skeleton diseases such as osteosarcoma, musculoskeleletal neoplasm; Squamous cell carcinoma and fibroid tumour.
[0246] The compounds may also be used the preparation of a medicament for treating a condition in an animal in which inhibition of a protein kinase can prevent, inhibit or ameliorate the pathology or symptomolpgy of the condition. The compounds may also be used in the preparation of a medicament for the treatment or prevention of a kinase-related disorder.
[0247] Administration of compounds of formula (I) to humans can be by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion. The active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose. In various embodiments the inhibitor compound may be selectively toxic or more toxic to rapidly proliferating cells, e.g. cancerous tumours, than to normal cells. [0248] In using the compounds they can be administered in any form or mode which makes the compound bioavailable. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19th edition, Mack Publishing Co. (1995) for further information. [0249] The compounds can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. The compounds, while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.
[0250] The compounds are, however, typically used in the form of pharmaceutical compositions which are formulated depending on the desired mode of administration. As such in some embodiments there is provided a pharmaceutical composition including a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. The compositions are prepared in manners well known in the art.
[0251] The present teachings in other embodiments provide a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions. In such a pack or kit can be found a container having a unit dosage of the agent(s). The kits can include a composition comprising an effective agent either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the concentration of use, where the vials may include one or more dosages. Conveniently, in the kits, single dosages can be provided in sterile vials so that the physician can employ the vials directly, where the vials will have the desired amount and concentration of agent(s). Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
[0252] The compounds may be used or administered in combination with one or more additional drug(s) for the treatment of the disorder/diseases mentioned. The components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds may be administered sequentially or simultaneously with the other drug(s). [0253] In addition to being able to be administered in combination with one or more additional drugs, the compounds may be used in a combination therapy. When this is done the compounds are typically administered in combination with each other. Thus one or more of the compounds may be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result.
[0254] Pharmaceutical compositions of the present teaching for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[0255] These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.
[0256] If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
[0257] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
[0258] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[0259] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
[0260] The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
[0261] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
[0262] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
[0263] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[0264] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof.
[0265] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
[0266] Dosage forms for topical administration of a compound of this invention include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
[0267] The amount of compound administered will preferably treat and reduce or alleviate the condition. A therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances. [0268] A preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day. A more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day. A suitable dose can be administered in multiple sub-doses per day.
SYNTHESIS OF COMPOUNDS OF THE INVENTION
[0269] The agents of the various embodiments may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available. The preparation of particular compounds of the embodiments is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various embodiments. For example, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. A list of suitable protecting groups in organic synthesis can be found in T.W. Greene's Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1991. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the various embodiments.
[0270] Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.
GENERAL SYNTHETIC SCHEME
[0271] A wide range of trisubstituted purines can be prepared in a straightforward three step procedure starting from 2,6-dichloropurine which is commercially available from a number of sources or may be prepared from purine-2,6-dione or xanthine itself using, for example, phosphorylchloride (Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 23; 12; 1984; 1286 - 1288). The general representative procedure is shown in scheme 1,
Scheme 1
Figure imgf000061_0001
[0272] As shown, initial reaction of 2,6-dichloropurine with an alkyl halide results in alkylation predominately at the 9 position (Nucleosides & Nucleotides 2001, 20(4-7), 1067). In a typical procedure an alcohol may be reacted with the 2,6-dichloropurine in the presence of a phosphine and an activating agent, such as diethylazodicarboxylate. Alternatively an alkyl halide may be reacted with the starting purine in the presence of a suitable base such as potassium carbonate , so as to effect a similar alkylation (Bioorganic & Medicinal Chemistry Letters 2004,14(1 1 ), 2955). Subsequent palladium catalysed coupling of 2 with a suitable aryl boronic acid or ester then delivers intermediate 3 (Tetrahedron Letters 1995, 36, 1 1 , 1945, Collect. Czech. Chem. Commun. 2002, 67, 325). Addition of 8-oxa-3-aza-bicyclo[3.2.1]octane (Organic Process Research & Development 2010, 14, 459) can then be carried out at elevated temperature or using microwave irradiation, in a suitable solvent such as DMA, NMP, DMF or THF, to give the desired trisubstituted purine.
Scheme 2
Figure imgf000062_0001
[0273] The R substituent may be varied either by using an 8-substituted dichloropurine as starting material (Scheme 1) or can be introduced later in the synthetic sequence (Scheme 2). For example chemistry may be carried out on the 8- position after completion of the sequence illustrated in scheme 1 above. For example, the 8-position of 4 may be brominated to give 5. The bromide may then be displaced by, for example, an organometallic agent, such as an organozinc, to install R1 as in 6.
[0274] Scheme 3 depicts three variations on the three step procedure in which different conditions are used in the first step so as to introduce diverse substituents at the 9-position of the purine scaffold. In principle, however, a skilled addressee could modify the general reaction scheme shown in scheme one where the nitrogen moiety at the 9 position of the purine may be reacted with a moiety containing a suitable leaving group (such as a halide) in a reaction whereby the nitrogen displaces the leaving group to form the compound in which the nitrogen at the 9 position is then functionalised with the moiety. Suitable leaving groups for use in reactions of this type which can be displaced by nitrogen in such reactions are known in the art and in general the synthesis of moieties containing leaving groups of this type for use in these types of reactions are also well known to a skilled worker in the field. As shown in Scheme 3 the three simplest routes to the compounds of the invention involve reaction of the dichloropurine with either an arylalkyl halide (such as benzyl halide) or a heteroarylalkyi halide to introduce an aryl or heteroaryl substituted methyl group at the 9 position, an alcohol (to introduce a di-substituted methyl group at the 9 position) or an aryl or heteroaryl boronic acid (to introduce an aryl or heteroaryl group directly.
Scheme 3
Aryl boronic acid
Figure imgf000064_0001
EXAMPLES
[0275] In the examples described below, unless otherwise indicated, all temperatures in the following description are in degrees Celsius and all parts and percentages are by weight, unless indicated otherwise.
[0276] Various starting materials and other reagents were purchased from commercial suppliers, such as Aldrich Chemical Company or Lancaster Synthesis Ltd., and used without further purification, unless otherwise indicated. Tetrahydrofuran (THF) and Ν,Ν-dimethylformamide (DMF) were purchased from Aldrich in SureSeal bottles and used as received. All solvents were purified by using standard methods in the art, unless otherwise indicated.
[0277] The reactions set forth below were performed under a positive pressure of nitrogen, argon or with a drying tube, at ambient temperature (unless otherwise stated), in anhydrous solvents, and the reaction flasks are fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven-dried and/or heat-dried. Analytical thin-layer chromatography was performed on glass- backed silica gel 60 F 254 plates (E Merck (0.25 mm)) and eluted with the appropriate solvent ratios (v/v). The reactions were assayed by TLC and terminated as judged by the consumption of starting material.
[0278] The TLC plates were visualized by UV absorption or with a p-anisaldehyde spray reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20 wt% in ethanol) which was activated with heat, or by staining in an iodine chamber. Workups were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume (unless otherwise indicated). Product solutions were dried over anhydrous sodium sulfate prior to filtration, and evaporation of the solvents was under reduced pressure on a rotary evaporator and noted as solvents removed in vacuo. Flash column chromatography [Still et a/, J. Org. Chem., 43, 2923 (1978)] was conducted using E Merck-grade flash silica gel (40-63 μιτι) and a silica gekcrude material ratio of about 20:1 to 50:1 , unless otherwise stated. Hydrogenolysis was done at the pressure indicated or at ambient pressure.
[0279] 1H NMR spectra were recorded on a Bruker instrument operating at 400 MHz, and 13C-NMR spectra was recorded operating at 100 MHz. NMR spectra were obtained as CDCI3 solutions (reported in ppm), using chloroform as the reference standard (7.27 ppm and 77.00 ppm) or CD3OD (3.4 and 4.8 ppm and 49.3 ppm), or an internal tetramethylsilane standard (0.00 ppm) when appropriate. Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplets. Coupling constants, when given, are reported in Hertz.
[0280] Mass spectra were obtained using LC/MS either in ESI or APCI. All melting points are uncorrected. [0281] Reactions requiring microwave irradiation were carried out in a CEM Discover S-Class reactor.
[0282] All final products had greater than 90% purity (by HPLC at wavelengths of 220 nm and 254 nm).
[0283] The following examples are intended to illustrate the embodiments disclosed and are not to be construed as being limitations thereto. Additional compounds, other than those described below, may be prepared using the following described reaction scheme or appropriate variations or modifications thereof.
General Procedure
[0284] Dichloropurine Alkylation
Figure imgf000066_0001
[0285] 2,6-Dichloropurine (1 eq), the alcohol (1-3 eq) and triphenylphosphine (1-2 eq) are dissolved in a suitable organic solvent (e.g. THF) to a concentration of 0.1-0.2 M.
[0286] To this solution is added drop-wise dialkylazodicarboxylate (1-2 eq), or an equivalent coupling agent, at room temperature over a period of about 30 minutes. The reaction mixture is stirred at ambient to 60°C for approximately 12-24 h. Conversion is monitored by TLC and/or LC/MS. The reaction mixture is then quenched with ice-cold water. Extraction of the aqueous layer with an organic solvent such as ethyl acetate or diclhoromethane, affords the crude product. Purification can then be carried out on a silica gel column using a suitable solvent system to afford the A/-substituted dichloropurine Suzuki Coupling
Figure imgf000067_0001
[0287] The /V-substituted dichloropurine (1 eq), 5-aminopyrazine-2-boronic acid pinacol ester (1 eq) and a palladium (II) catalyst complex (5-10 mol%) are taken up in peroxide free organic solvent (0.05-0.1 M), such as dioxane, DME or THF. Following addition of a 2M aqueous solution of sodium or potassium carbonate (4 eq), the reaction mixture was degassed and purged with nitrogen. This reaction mixture is then stirred on an oil bath maintained at 60-100°C for 1-5 h. Conversion is monitored by LC/MS for the disappearance of the starting purine. The reaction mixture is cooled to room temperature and the solvents removed under reduced pressure. The residue is partitioned between ethyl acetate and water, the organic phase was separated and the aqueous layer further extracted with portions of ethyl acetate. The combined organic layers are dried over sodium sulfate and the solvents removed under vacuum to give 5-[2-chloro-alkyl-9H-purin-6-yl)-pyrazin-2-ylamine. The crude material is taken up to the next stage without further purification.
8-Oxa-3-aza-bicyclo[3.2.1 ]octane Addition
Figure imgf000067_0002
[0288] 5-[2-Chloro-9-alkyl-9H-purin-6-yl)-pyrazin-2-ylamine (1 eq), 8-oxa-3aza- bicyclo[3.2.1] octane hydrochloride salt (5-10 eq) and triethylamine (5-10 eq) in a suitable polar microwave active solvent, such as NMP, DMA or DMF, (0.05-1 M) are heated in a sealed vial using a microwave irradiation at 150-180°C for 20-40 min. Conversion may be monitored by LCMS for the formation of the product. The crude material is purified by chromatography to afford the desired trisubstitituted purine.
Example 1, Compound 6
[0289] Synthesis of 2,6-Dichloro-9-(1-ethyl-propyl)-9H-purine
Figure imgf000068_0001
[0290] 2,6-Dichloropurine (10.58 mmol, 1 eq), 3-pentanol (15.87 mmol, 1.5 eq) and triphenylphosphine (15.87 mmol, 1.5 eq) were dissolved in 80 ml anhydrous tetrahydrofuran, to which was added drop-wise di/'sopropylazodicarboxylate (15.87 mmol, 1.5 eq) at room temperature over a period of 30 minutes. The reaction mixture was stirred at room temperature for 24 h. Conversion was monitored by TLC or LC/MS. The reaction mixture was poured into a beaker containing ice-cold water. Extraction of the aqueous layer, using 3x100 ml portions of ethyl acetate, afforded the crude product. This was purified on the silica gel column (5-60% ethyl acetate in petroleum ether, gradient elution) to give the desired compound in a yield of 75%
(2.4g). 1H NMR CDCI3 (ppm): 8.12 (s, 1 H); 4.46 (m, 1H); 2.05 (m, 4H); 0.96 (t, 6H). [0291] Synthesis of 5-[2-Chloro-9-(1 -ethyl-propyl)-9H-purin-6-yl]-pyrazin-2- ylamine
Figure imgf000069_0001
[0292] To a solution of 2,6-dichloro-9-(1-ethyl-propyl)-9H-purine (1 mmol, 1 eq), 5- aminopyrazine-2-boronic acid pinacol ester (1 mmol, 1 eq) and 1 ,1'-bis(diphenyl phosphino) ferrocene palladium (II) chloride, complexed with dichloromethane, (0.1 mmol, 10mol%) in peroxide free dioxane (20 ml) was added 2M aqueous solution of sodium carbonate (4 mmol, 4 eq). The reaction mixture was degassed and purged with nitrogen. This reaction mixture was then stirred on an oil bath maintained at 80°C for 3 h. Conversion was monitored by LC/MS for the disappearance of the starting purine. The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure. The residue was taken up in ethyl acetate and water. The organic phase was separated and the aqueous layer further extracted with 3x200 ml portions of ethyl acetate. The organics were dried over sodium sulfate and the solvents removed under vacuum to give 5-[2-chloro-9alkyl-9H-purin-6-yl]- pyrazin-2-ylamine.
[0293] Synthesis of 5-[9-(1-Ethyl-propyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3yl)- 9H-purin-6-yl]-pyrazin-2-ylamine (6)
Figure imgf000070_0001
[0294] 5-[2-Chloro-9-(1-ethyl-propyl)-9H-purin-6-yl)-pyrazin-2-ylamine (0.163 mmol, 1 eq), 8-oxa-3aza-bicyclo[3.2.1]octane hydrochloride salt (0.817 mmol, 5 eq) and tnethylamine (1.14 mmol, 7 eq) in 3 ml of NMP were heated in a sealed vial using a microwave irradiation at 165°C for 25 min. The contents were allowed to cool down to room temperature and the conversion was monitored by LCMS for the formation of the product. After 25 mins the reaction was complete with minimum or no decomposition. The crude material was purified by reverse phase HPLC to give the desired compound of 98-99% purity (14% yield). 1H NMR DMSO-d6 (ppm): 9.17 (s, 1H), 9.00 (bs, 1H), 8.10 (s, 1H), 7.32 (bs, 2H), 4.47^.34 (m, 5H), 3.20-3.1 (m, 2H), 2.10-1.90 (m, 4H), 1.80 (m, 2H), 1.70 (m, 2H), 0.65 (t, 6H). m/z: 395.21 [MH+].
Example 2, Compound 10
[0295] Synthesis of 4-(2,6-Dichloro-purin-9-yl)-piperidine-1 -carboxylic acid fert-butyl ester
Figure imgf000070_0002
[0296] 2,6-Dichloropurine (2.0 mmol, 1 eq), 4-hydroxy-piperidine-1-carboxylic acid iert-butyl ester (1.3 mmol, 0.65 eq) and triphenylphosphine (2.4 mmol, 1.2 eq) were dissolved in 16 ml anhydrous tetrahydrofuran to which was added drop-wise diethylazodicarboxylate (2.2 mmol, 1.1 eq) at room temperature over a period of 30 min. The reaction mixture was stirred at 60-70°C for 24 h. The reaction mixture was poured into a beaker containing ice-cold water. Extraction of the aqueous layer, using 3x25 ml portions of ethyl acetate, afforded the crude product. This was purified on the silica gel column (20-50% ethyl acetate in petroleum ether, gradient elution) to give the 4-(2,6-dichloro-purin-9-yl)-piperidine-1-carboxylic acid ferf-butyl ester.
[0297] Synthesis of 4-[6-(5-Amino-pyrazin-2-yl)-2-chloro-purin-9-yl]-piperidine- 1-carboxylic acid ferf-butyl ester
Figure imgf000071_0001
[0298] To a solution of 2,6-dichloro-9-(1-ethyl-propyl)-9H-purine (0.83 mmol, 1 eq), 5-aminopyrazine-2-boronic acid pinacol ester (1.25 mmol, 1.5 eq) and 1 ,1'- bis(diphenylphosphino) ferrocene palladium (II) chloride, complexed with dichloromethane, (8 mol%, 0.07 mmol) in peroxide free dioxane (20 ml) was added 2M aqueous solution of potassium carbonate (2.49 mmol, 3 eq). The reaction mixture was degassed and purged with nitrogen. This reaction mixture was then stirred on an oil bath maintained at 80°C for 3 h. Conversion was monitored by LC/MS for the disappearance of the starting purine. The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure. The residue was taken up in ethyl acetate and water. The organic phase was separated and the aqueous layer further extracted with 3x200 ml portions of ethyl acetate. The organics were dried over sodium sulfate and the solvents removed under vacuum to give 4-[6- (5-amino-pyrazin-2-yl)-2-ehloro-purin-9-yl]-piperidine-1-carboxylic acid ferf-butyl ester. The crude material was purified by chromatography on silica gel using ethyl acetate in petroleum ether to yield the desired product (38 mg). [0299] Synthesis of 4-[6-(5-Amino-pyrazin-2-yl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct- 3-yl)-purin-9-yl]-piperidine-1-carboxylic acid iert-butyl ester (10)
Figure imgf000072_0001
[0300] 4-[6-(5-Amino-pyrazin-2-yl)-2-chloro-purin-9-yl]-piperidine-1-carboxylic acid te/t-butyl ester (0.07 mmol, 1 eq), 8-oxa-3aza-bicyclo[3.2.1]octane hydrochloride salt (0.70 mmol, 10 eq) and triethylamine (0.35 mmol, 5 eq) in 2 ml of DMA were heated on an oil bath at 150°C for 12 h. The contents were allowed to cool down to room temperature and the conversion was monitored by LCMS for the formation of the product. The crude material was purified by reverse phase HPLC to give the desired product (1.16 mg). 1H NMR MeOD (ppm): 9.30 (s, 1H), 9.10 (s, 1 H), 8.15 (s, 1H), 4.95 (m, 1H), 4.55-4.45 (m, 4H), 4.30 (d, 2H), 3.35-3.30 (m, 2H), 3.15-3.00 (m, 2H), 2.30-2.15 (m, 4H), 2.05-1.95 (m, 2H), 1.80-1.70 (m, 2H), 1.52 (s, 9H). m/z: 508.27
[MH+]. 11
Example 3, Compound 11
[0301] Synthesis of 2,6-dichloro-9-/sopropyl-9H-purine
Figure imgf000073_0001
[0302] To a solution of 2,6-dichloro-9H-purine (1.00 g, 5.29 mmol) dissolved in 40 mL of DMSO was added 2-iodopropane (1.62 g, 9.52 mmol) and K2C03 (1.32 g, 9.52 mmol). The solution was stirred at room temperature under a nitrogen atmosphere for 1 day. The reaction mixture was diluted in H20 and ethyl acetate, the organic layer was separated and the aqueous layer extracted twice with ethyl acetate. Purification by flush column chromatography (silica gel, hexane/ethyl acetate 1 :3) afforded 2,6-dichloro-9-/'sopropyl-9H-purine (45% yield) as a white solid. 1H NMR CDCI3 (ppm): 8.17 (d, 1H), 4.86-4.97 (septet, 1 H),1.64-1.66 (d, 6H). m/z: 231 [MH+] [0303] Synthesis of 5-(2-chloro-9-;sopropyl-9H-purin-6-yl)-pyrazin-2-ylamine
Figure imgf000073_0002
[0304] To a solution of 216-dichloro-9-/'sopropyl-9H-purine (0.50 g, 2.16 mmol) dissolved in 15 mL of anhydrous dioxane was added 5-amino-boronic acid pinacol ester (0.48 g, 2.28 mmol) and 1,1'-bis(diphenyl phosphino) ferrocene palladium (II) chloride, complexed with dichloromethane (0.18 g, 0.22 mmol). Aqueous saturated K2CO3 (0.60 g, 4.33 mmol) was subsequently added to the solution. The solution was stirred at 90"C for 4 hours. After cooling the solvent was evaporated and the reaction mixture was dissolved in H2O and DCM. The organic layer was separated and the aqueous phase extracted twice with DCM. Purification by flush column chromatography (silica gel, 2% of methanol in DCM) afforded 5-(2-chloro-9-/sopropyl- 9H-purin-6-yl)-pyrazin-2-ylamine (41% yield) as a white solid. 1H NMR CDCI3 (ppm): 9.48 (s, 1H), 8.27 (d, 1 H), 8.21 (s, 1 H), 5.03 (s, 2H), 4.94-5.03 (septet, 1 H), 1.65-1.66 (d, 6H). m/z: 290 [MH+]
[0305] Synthesis of 5-[9-/sopropyl-2-(8-oxa-3-aza-bicyclo[3.2.1 ]oct-3-yl)-9H- purin-6-yl]-pyrazin-2-ylamine (11)
Figure imgf000074_0001
[0306] To a solution of 5-(2-chloro-9-/sopropyl-9H-purin-6-yl)-pyrazin-2-ylamine (0.46 g, 1.60 mmol) dissolved in 15 ml. of DMA was added 8-oxa-3-aza- bicyclo[3.2.1]octane (0.81 g, 7.19 mmol) and 7 mL of triethyamine. The brown solution was heated using microwave irradiation for 30 minutes. The reaction mixture was dissolved in H2O and ethyl acetate and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. Purification by flush column chromatography (silica gel, 2% of methanol in DCM) afforded 5-[9-/sopropyl-2-(8-oxa- 3-aza-bicyclo[3.2.1]oct-3-yl)-9H-purin-6-yl]-pyrazin-2-ylamine (51% yield) as a brown solid. 1H NMR CDCI3 (ppm): 9.21 (d, 1H), 8.25 (d, 1H), 7.88 (s, 1H), 4.84 (s, 2H), 4.74-4.82 (septet, 1H), 4.51 (m, 2H), 3.26-3.30 (dd, 4H), 1.87-1.97 (m, 4H), 1.59-1.60 (d, 6H). m/z: 367.22 [MH+] Example 4, Compound 19
[0307] Synthesis of 5-[8-Bromo-9-/sopropyl-2(8-oxa-3-aza-bicyclo[3.2.1] oct-3- yl)-9H-purin-6-yl]pyrazin-2-ylamine (19)
Figure imgf000075_0001
[0308] To a solution of 5-[9-/sopropyl-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-9H- purin-6-yl]-pyrazin-2-ylamine (11) (0.32 g, 0.86 mmol) dissolved in 15ml_ of chloroform was added slowly N-bromosuccinimide (0.18 g, 1.03 mmol) at 5°Ό. The brown solution was stirred at this temperature for 2 hours. After that, the reaction mixture was dissolved in DCM and H2O and the organic layer was separated. The aqueous layer was extracted twice with DCM. Purification by preparative HPLC afforded 5-[8-bromo-9- sopropyl-2(8-oxa-3-aza-bicyclo[3.2.1 ]oct-3-yl)-9H-purin-6-yl] pyrazin-2-ylamine (23% yield) as a brown solid. 1H NMR MeOD (ppm): 9.18 (s, 1 H), 9.01 (s, 1H), 4.90 (m, 1H), 4.36 (m, 4H), 3.28 (m, 1 H), 3.13 (m, 1H), 1.88 (m, 2H), 1.72 (m, 2H), 1.58 (d, 6H); m/z: 445/447 [MH+]
Example 5, Compound 20
[0309] Synthesis of 5-[8-Bromo-9-(1 -ethyl-propyl)-2-(8-oxa-3-aza-bicyclo[3.2.1] oct-3-yl)-9H-purin-6-yl]-pyrazin-2-ylamine (20)
Figure imgf000075_0002
[0310] To a solution of 5-[9-(1-ethyl-propyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3yl)- 9H-purin-6-yl]-pyrazin-2-ylamine (6) (40mg, O.lmmol) dissolved in 10mL of chloroform was added slowly N-bromosuccinimide (20mg, 0.12mmol) at 5*C. The brown solution was stirred at this temperature for 2 hours. After that, the reaction mixture was dissolved in DCM and l-½0 and the organic layer was separated. The aqueous layer was extracted twice with DCM. Purification by preparative HPLC afforded 5-[8-bromo- 9-(1-ethyl-propyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-9H-purin-6-yl]-pyrazin-2- ylamine (18mg, 38% yield) as a brown solid. 1H NMR MeOD (ppm): 9.11 (s, 1H), 9.03 (s, 1H), 4.52 (m, 1H), 4.46 (m, 4H), 3.25 (m, 2H), 2.12 (m, 4H), 1.98 (m, 2H), 1.80 (m, 2H), 0.86 (m, 6H); m/z: 473/475 [MH+]
Example 6, Compound 9
[0311] Synthesis of 9-benzyl-2,6-dichloro-9H-purine
Figure imgf000076_0001
[0312] To a stirred solution of 2,6-dichloropurine (5.30 mmol, 1 eq) in 10 ml anhydrous DMSO at room temperature was added anhydrous potassium carbonate (6.34 mmol, 1.2 eq) and benzyl bromide (6.34 mmol, 1.2 eq). The reaction mixture was maintained at this temperature for 20 h. The reaction can be monitored using either TLC or LC/MS. The reaction mixture was poured into a beaker containing ice- cold water. The aqueous layer was acidified to pH 5-6. Extraction of the aqueous layer, using 3x75 ml portions of ethyl acetate, afforded the crude product. This was purified on the silica gel column (10-70% ethyl acetate in petroleum ether, step- gradient), to give the desired compound in a yield of 56%. [0313] Synthesis of 5-(9-Benzyl-2-chloro-9H-purin-6-yl)-pyrazin-2-yl-amine
Figure imgf000077_0001
[0314] 9-Benzyl-2,6-dichloro-9H-purine (0.159 mmol, 1 eq), 5-aminopyrazine-2- boronic acid pinacol ester (0.159 mmol, 1 eq) and 1,1'-bis(diphenylphosphino) ferrocene palladium (II) chloride, complexed with dichloromethane, (0.015 mmol, 10 mol%) were taken up in a mixture of peroxide free dioxane (4 ml) and 2M aqueous solution of sodium carbonate (0.636 mmol, 4 eq) added. The reaction mixture was degassed and purged with nitrogen. This reaction mixture was then stirred on an oil bath maintained at 70-75°C for 3 h. The reaction was monitored by LC/MS for the disappearance of the starting purine. The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure. The residue was taken up in ethyl acetate-water mixture. The organic phase was separated and the aqueous layer further extracted with 3x50 ml portions of ethyl acetate. The combined ethyl acetate layers were washed once with brine solution (10 ml). The organics were dried over sodium sulfate and the solvents removed under vacuum to give 5-(9- benzyl-2-chloro-9H-purin-6-yl)-pyrazin-2-yl-amine. This material was taken to the next stage without further purification.
[0315] Synthesis of 5-[9-Benzyl-2-(8-oxa-3-aza-bicyclo[3.2.1]ocy-3-yl)-9H- purin-6-yl]-pyrazin-2-yl-amine (9)
Figure imgf000078_0001
[0316] 5-(9-Benzyl-2-chloro-9H-purin-6-yl)-pyrazin-2-yl-amine (0.1 mmol, 1 eq), 8- oxa-3aza-bicyclo[3.2.1]octane hydrochloride salt (0.5 mmol, 5 eq) and triethylamine (0.7 mmol, 7 eq) in 3 ml of NMP were heated in a sealed vial using a microwave irradiation at 165°C for 25 min. The contents were allowed to cool down to room temperature and the conversion was monitored by LCMS for the formation of the product. After 25 min the reaction was complete with no observed decomposition. The crude material was purified by reverse phase HPLC to give 5-[9-benzyl-2-(8-oxa- 3-aza-bicyclo[3.2.1]ocy-3-yl)-9H-purin-6-yl]-pyrazin-2-yl-amine of 98% purity (16% yield). 1H NMR CDCI3 (ppm): 9.76 (d, 1H), 8.38 (s, 1H), 8.30 (s, 1 H), 7.76 (s, 1 H), 7.46-7.30 (m, 4H), 7.37 (bs, 2H), 5.39 (m, 2H), 4.56 (m, 2H), 4.34 (d, 2H), 3.34 (d, 2H), 2.11 -1.85 (m, 4H), m/z: 415.20 [MH+].
Example 7, Compound 27
[0317] Synthesis of 5-(2-Chloro-9-/'sopropyl-8-methyl-9H-purin-6-yl)-pyrazin-2- ylamine
Figure imgf000078_0002
[0318] 2,6-Dichloro-9-/'sopropyl-8-methyl-9H-purine was purchased from and converted to 5-(2-chloro-9-/sopropyl-8-methyl-9H-purin-6-yl)-pyrazin-2-ylamine using an identical procedure as outlined for 5-(2-chloro-9-/sopropyl-9H-purin-6-yl)-pyrazin-2- ylamine above. The crude product was taken into the next step without purification.
[0319] Synthesis of 5-[9-/sopropyl-8-methyl-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3- yl)-9H-purin-6-yl]-pyrazin-2-ylamine (27)
Figure imgf000079_0001
[0320] 5-(2-Chloro-9-/'sopropyl-8-methyl-9H-purin-6-yl)-pyrazin-2-ylamine was converted to 5-[9-/'sopropyl-8-methyl-2-(8-oxa-3-aza-bicyclo[3.2.1 ]oct-3-yl)-9H-purin- 6-yl]-pyrazin-2-ylamine (27) using an identical procedure as outlined for 5-[9- /sopropyl-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-9H-purin-6-yl]-pyrazin-2-ylamine (11) above. 5-[9-/sopropyl-8-methyl-2-(8-oxa-3-aza-bicyclo[3.2.1 ]oct-3-yl)-9H-purin-6-yl]- pyrazin-2-ylamine was isolated, after chromatography on silca gel, with a yield of 22% over the two steps starting from the commercially available 2,6-dichloro-9-/'sopropyl-8- methyl-9H-purine. H NMR d6-DMSO (ppm): 9.01 (s, 1 H); 8.09 (s, 1H); 7.42 (bs, 2H); 4.81 (q, 1H); 4.45 (m, 2H), 4.35 (m, 2H), 3.18 (m, 2H), 2.83 (s, 3H), 1.83 (m, 2H), 1.70 (m, 2H), 1.63 (s, 6H), 1.60 (s, 6H); m/z: 381.18 [MH+]
[0321] The compounds outlined in Table 1 were synthesized following the procedures outlined above or variations thereof. Table 1 S nthesised compounds
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
BIOLOGICAL TESTING
[0323] mTOR Assay
[0324] Full-length mTOR kinase and His-tagged 4eBP1 were produced in-house. [^PJ-ATP was purchased from Amersham (GE Healthcare). All chemicals, unless otherwise stated, were from Sigma-Aldrich.
[0325] Phosphorylation assays were initially performed in a final volume of 20 pL in 384-well polypropylene plate (Greiner). Compounds were typically tested over the range from 100 μΜ to 0.006 μΜ, in 8 step dilutions, in duplicate. 10 pUwell of 2X Enzyme-Substrate solution (1.5 pg/mL mTOR, 40pg/ml_ 4eBP1 in 1X assay buffer: 10 mM Hepes pH 7.5, 50 mM NaCI and 10 mM MnCI2) were first added to the sample plate containing 1 pUwell of test compound in neat DMSO. The reaction was initiated by adding 10 pUwell of 20 μΜ ATP solution (final assay concentration 10 μΜ ATP and 0.4 pCi/well of [Y^PJ-ATP). After 1 hour incubation at room temperature, the reaction was terminated with 40 pUwell of 20 mM EDTA/1 mM ATP solution.
[0326] 50 pUwell of the stopped reaction mix was then transferred to 384-well MUltiScreenHTS-PH filter plate (Millipore) pre-added with 50 pUwell of 1 % phosphoric acid. The plate was washed 4 times with 120 pUwell of 0.5 % phosphoric acid via vacuum filtration. Finally, 10 pUwell of Optiphase™ SuperMix liquid scintillation cocktail (Perkin Elmer) was added. After minimum 1 hour of incubation, counting was performed in a Wallac MicroBeta TriLux scintillation counter using coincidence counting mode with crosstalk correction. IC50 is defined as the concentration of compound required for 50% inhibition of kinase enzyme activity. IC50 data are shown in Table 2 below.
[0327] Table 2- In vitro mTOR inhibition activity assay IC50
Figure imgf000088_0001
*+++ <0.1 μΜ
++ 0.1 μΜ-1 μΜ
+ >1μΜ
[0328] The details of specific embodiments described in this invention are not to be construed as limitations. Various equivalents and modifications may be made without departing from the essence and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.

Claims

What is claimed is:
1. A compound of formula (I):
Figure imgf000089_0001
Formula (I)
wherein:
R is selected from the group consisting of: H, halogen and optionally substituted CrC6 alkyl;
R2 is selected from the group consisting of H, halogen, OH, NO2, CN, NH2, optionally substituted C Ci2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C2-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C3-Ci2cycloalkenyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C2-Ci2heterocycloalkenyl, optionally substituted C6-C18aryl, optionally substituted Ci-Ci8heteroaryl, optionally substituted C-i-C^alkyloxy, optionally substituted C2-Ci2alkenyloxy, optionally substituted C2-C-i2alkynyloxy, optionally substituted C2-Cioheteroalkyloxy, optionally substituted C3-Ci2cycloalkyloxy, optionally substituted C3-Ci2cycloalkenyloxy, optionally substituted C2-C12heterocycloalkyloxy, optionally substituted C2-C12 heterocycloalkenyloxy, optionally substituted Ce-Ciearyloxy, optionally substituted Ci- Ci2heteroaryloxy, optionally substituted Ci-Ci2alkylamino, SR8, S03H, S02NR8R9, S02R8, SONR8R9, SOR8, COR8, COOH, COOR8, CONR8R9, NR8COR9, NR8COOR9, NR8S02R9, NR8CONR8R9, NR8R9, and acyl, or R2 is a group of the formula:
Figure imgf000090_0001
wherein each M is independently N or CR , each R2a is independently selected from the group consisting of H, halogen, OH, 02, CN, NH2, optionally substituted d-C^alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C2-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C2-Ci2heterocycloalkenyl, optionally substituted C6-C18 aryl, optionally substituted Ci-Cieheteroaryl, optionally substituted Ci-C-|2alkyloxy, optionally substituted C2-C-i2alkenyloxy, optionally substituted C2-Ci2alkynyloxy, optionally substituted C2-C12heteroalkyloxy, optionally substituted C3-C12 cycloalkyloxy, optionally substituted C3-Ci2cycloalkenyloxy, optionally substituted Cr Ci2heterocycloalkyloxy, optionally substituted C2-Ci2heterocycloalkenyloxy, optionally substituted Ce-Ciearyloxy, optionally substituted C-i-Cieheteroaryloxy, optionally substituted C C12 alkylamino, SR8, S03H, S02NH2, S02R8, SONH2, SOR8, COR8, COOH, COOR8, CONR8R9, NR8COR9, NR8COOR9, NR8S02R9, NR8CONR8R9, NR8R9, and acyl; r is an integer selected from the group consisting of 1 , 2, and 3;
R3 is selected from the group consisting of H, F, CI, Br, OH, optionally substituted Ci-C6 alkyl, OR8, OCOR8, CH2OH, NH2, NR8R9, NR8COR9, and NR8S02R9;
R6 is selected from the group consisting of H, OH, OR8, OPg°, OCOR8, CH2OH, NH2, NR8R9, NR8Pg N, N(Pg N)2, NR8COR9, NR8CONR8R9, and NR8S02R9; R7 is selected from the group consisting of H, F, CI, Br, OH, OR8, OCOR8,
CH2OH, NH2, NR8R9, NR8COR9, and NR8S02R9; each R8 and R9 is independently selected from the group consisting of H, optionally substituted Ci-Ci2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C2-C-ioheteroalkyl, optionally substituted Ca-C^cycloalkyl, optionally substituted C3-Ci2cycloalkenyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C2-Ci2heterocycloa!kenyl, optionally substituted C6-Ci8aryl, and optionally substituted Ci-Ci8heteroaryl, or
R8 and R9 when taken together with the atoms to which they are attached form an optionally substituted cyclic moiety;
: Pg° is a protecting group for oxygen; each Pg N is independently a protecting group for nitrogen; each Rz is independently selected from the group consisting of Ci-C6alkyl, halo-CrC6alkyl, hydroxyCi-C6alkyl, Ci-C6alkyloxyCi-C6alkyl, cyanoCrC6alkyl, aminoCi-C6alkyl, C CealkylaminoC Cealkyl, and di(Ci-C6alkyl)aminoCi-C6alkyl; q is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
X is a group of formula (CR10 2)m; each R10 is independently selected from the group consisting of: H and optionally substituted C1-C6 alkyl; m is an integer selected from the group consisting of 0, 1 , 2, 3 and 4; or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof.
2. A compound according to claim 1 wherein q is 0.
3. A compound according to claim 1 or 2 wherein R3 is selected from the group consisting of H, OR8, and optionally substituted d-C6alkyl, wherein R8 is as defined in claim 1.
4. A compound according to any one of claims 1 to 3 wherein R3 is H.
5. A compound according to any one of claims 1 to 4 wherein R7 is H.
6. A compound according to any one of claims 1 to 5 wherein m is selected from the group consisting of 0, 1 , and 2.
7. A compound according to any one of claims 1 to 6 wherein m is 0 or 1.
8. A compound according to any one of claims 1 to 7 wherein m is 0.
9. A compound according to any one of claims 1 to 7 wherein m is 1.
10. A compound according to claim 9 wherein one R10 is H and X is a group of the formula:
Figure imgf000092_0001
wherein R10 is as defined in claim 1.
11. A compound according to claim 1 wherein the compound is a compound of the formula:
Figure imgf000093_0001
wherein R1, R2, R6 and R10 are as defined in claim 1.
12. A compound according to claim 10 or 1 1 wherein R10 is selected from the group consisting of H, C-i-Cehaloalkyl, d-Cehydroxy alkyl and CrC6alkyl.
13. A compound according to any one of claims 10 to 12 wherein R10 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, and butyl.
14. A compound according to any one of claims 10 to 13 wherein R10 is selected from the group consisting of H, methyl and ethyl.
15. A compound according to any one of claims 1 to 14 wherein R1 is H.
16. A compound according to any one of claims 1 to 15 wherein R6 is selected from the group consisting of NH2 and NR8R9 wherein R8 and R9 are as defined in claim 1.
17. A compound according to any one of claims 1 to 16 wherein R6 is NH2.
18. A compound according to any one of claims 1 to 17 wherein R2 is selected from the group consisting of H, cyano, optionally substituted Ci-C-i2alkyl, optionally substituted C2-Ci2alkenyl, optionally substituted C2-C12heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C6-Ci8aryl, and optionally substituted C-i-deheteroaryl.
19. A compound according to any one of claims 1 to 17 wherein R2 is a group of the formula:
Figure imgf000094_0001
wherein each M is independently N or CR' each R is independently selected from the group consisting of H, halogen, OH, N02, CN, NH2, optionally substituted CrC^alkyl, optionally substituted C2-Ci2 alkenyl, optionally substituted C2-Ci2alkynyl, optionally substituted C2-Ci2heteroalkyl, optionally substituted C3-C-i2cycloalkyl, optionally substituted C2-Ci2heterocycloalkyl, optionally substituted C2-Ci2heterocycloalkenyl, optionally substituted C6-C18 aryl, optionally substituted C-i-Cieheteroaryl, optionally substituted C Ci2alkyloxy, optionally substituted C2-C-i2alkenyloxy, optionally substituted C2-C-|2alkynyloxy, optionally substituted C2-Ci2heteroalkyloxy, optionally substituted, optionally substituted C3-Ci2 cycloalkyloxy, optionally substituted C3-C 2cycloalkenyloxy, optionally substituted C-i-Ci2heterocycloalkyloxy, optionally substituted C2- Ci2heterocycloalkenyloxy, optionally substituted C6-Ci8aryloxy, optionally substituted CrC-ieheteroaryloxy, optionally substituted Ci-Ci2 alkylamino, SR8, S03H, S02NH2, S02R8, SONH2, SOR8, COR8, COOH, COOR8, CONR8R9, NR8COR9, NR8COOR9, NR8S02R9, NR8CONR8R9, NR8R9, and acyl; where R8 and R9 are as defined in claim 1 ; r is an integer selected from the group consisting of 1 , 2, and 3.
20. A compound according to claim 19 wherein r is 1 or 2.
21. A compound according to claim 19 wherein the compound is of the formula:
Figure imgf000095_0001
wherein R and r are as defined in claim 19.
22. A compound according to any one of claims 19 to 21 wherein each R2a is independently selected from the group consisting of H, F, OCH3, CN, OCF3, C02CH3, N02, NH2, NHCOCH3, NHSO2CH3, NHCH2CH3, CH3, and CF3.
23. A compound according to claim 18 wherein R2 is selected from the group consisting of cyano, optionally substituted Ci-Ci2alkyl, optionally substituted C3-C12 cycloalkyi, optionally substituted C2-Ci2heterocycloalkyf, and optionally substituted C2- Ci2heteroalkyl.
24. A compound according to claim 23 wherein R2 is an optionally substituted Ci- Ci2alkyl group of the formula:
Figure imgf000095_0002
wherein R20, R21 and R22 are each independently selected from the group consisting of H, CI, Br, F, OH, N02, CN, NH2, optionally substituted C C12alkyl, optionally substituted C2-Ci2heteroalkyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C2-C 2heterocycloalkyl, optionally substituted C6-Ci8aryl, and optionally substituted Ci-Ci8heteroaryl; or any two or more of R20, R21 and R22 when taken together with the carbon atom to which they are attached form a cyclic moiety.
25. A compound according to claim 24 wherein each R20, R21 and R22 is independently selected from the group consisting of H, CI, Br, F, OH, N02) CN, NH2, methyl, ethyl, propyl, isopropyl, butyl, pentyl, methoxymethyl, 2-methoxyethyl, 3- methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, aminomethyl, 2-aminoethyl, 3- aminopropyl, 4-aminobutyl, 5 aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl. 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl,
2- ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4- dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl,
3- diethylaminopropyl, 4-diethylaminobutyl and 5-diethylaminopentyl.
26. A compound according to claim 23 wherein R2 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, cyclopropyl, cyclopentyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2- methyl, pentyl, pent-4-enyl, hexyl, heptyl, octyl, cyano, methoxymethyl and butoxymethyl.
27. A compound according to any one of claims 1 to 26 wherein the optional substituent is selected from the group consisting of: F, Br, CI, =0, =S, -CN methyl, trifluoro-methyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3- dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl- pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH2, -N02, phenoxy, hydroxy, methoxy, trifluoro-methoxy, ethoxy, and methylenedioxy.
28. A compound according to claim 1 selected from the group consisting of:
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
or a pharmaceutically acceptable salt or prodrug thereof.
29. A pharmaceutical composition including a compound according to any one of claims 1 to 28 and a pharmaceutically acceptable diluent, excipient or carrier.
30. A method of inhibiting a protein kinase, the method including exposing the protein kinase or a fragment or complex thereof or a functional equivalent thereof and/or co-factor(s) thereof to an effective amount of a compound according to any one of claims 1 to 28.
31. A method according to claim 30 wherein the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof.
32. A method according to claim 31 wherein the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof.
33. A method according to claim 31 or 32 wherein the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof.
34. Use of a compound according to any one of claims 1 to 28 to inhibit one or more protein kinase(s).
35. A use according to claim 34 wherein the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof.
36. A use according to claim 35 wherein the serine/threonine protein kinase or a 5 fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof.
37. A use according to claim 35 or 36 wherein the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof.
[0
38. A method of treating or preventing a condition in a mammal in which inhibition of one or more protein kinase(s) or a fragment or a complex thereof or a functional equivalent thereof, prevents, inhibits or ameliorates a pathology or a symptomology of the condition, the method including administration of as therapeutically effective amount of a compound according to any one of claims 1 to 28.
39. A method according to claim 38 wherein the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional 0 equivalent thereof.
40. A method according to claim 39 wherein the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof.
5
41. A method according to claim 39 or 40 wherein the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof.
30 42. A method according to any one of claims 38 to 41 wherein the condition is selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, pancreatitis, multiple sclerosis, autoimmune disorders, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic ovarian syndrome, hamartoma, tuberous sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin- dependent diabetes mellitus, obesity, diabetic retinopathy, cardiac hypertrophy, and autosomal dominant polycystic kidney disease.
43. A method according to any one of claims 38 to 41 wherein the condition is cancer.
44. A method according to claim 43 wherein the cancer is selected from the group consisting of Hematologic cancer such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes, plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer; urinary tract cancer such as prostate cancer, kidney and renal cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer such as melanoma; brain tumour such as glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stem gliomas, medulloblastoma, menigiomas, astrocytoma, oligodendroglioma; head and neck cancer such as nasopharyngeal carcinoma, laryngeal carcinoma; respiratory tract cancer such as lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease such as retinoblastoma; musculo-skeleton diseases such as osteosarcoma, musculoskeletal neoplasm; Squamous cell carcinoma and fibroid tumour.
45. Use of a compound according to any one of claims 1 to 28 in the preparation of a medicament for treating a condition in an animal in which inhibition of one or more protein kinase(s) or a fragment or a complex thereof or a functional equivalent thereof, prevents, inhibits or ameliorates a pathology or a symptomology of the condition.
46. Use of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt, N-oxide or prodrug thereof in the treatment of a condition in which inhibition of one or more protein kinase(s) or a complex thereof or a functional equivalent thereof, prevents, inhibits or ameliorates a pathology or a symptomology of the condition.
47. A use according to claim 45 or 46 wherein the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof.
48. A use according to claim 47 wherein the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof.
49. A use according to claim 47 or 48 wherein the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof.
50. A use according to any one of claims 45 to 49 wherein the condition is selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, pancreatitis, multiple sclerosis, autoimmune disorders, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic ovarian syndrome, hamartoma, tuberous sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin- dependent diabetes mellitus, obesity, diabetic retinopathy, cardiac hypertrophy, and autosomal dominant polycystic kidney disease.
51. A use according to any one of claims 45 to 49 wherein the condition is cancer.
52. A use according to claim 51 wherein the cancer is selected from the group consisting of Hematologic cancer such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes, plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer; urinary tract cancer such as prostate cancer, kidney and renal cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer such as melanoma; brain tumour such as glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stem gliomas, medulloblastoma, menigiomas, astrocytoma, oligodendroglioma; head and neck cancer such as nasopharyngeal carcinoma, laryngeal carcinoma; respiratory tract cancer such as lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease such as retinoblastoma; musculo-skeleton diseases such as osteosarcoma, musculoskeleletal neoplasm; Squamous cell carcinoma and fibroid tumour.
53. A method of prevention or treatment of a proliferative condition in a subject, the method including administration of a therapeutically effective amount of a compound according to any one of claims 1 to 28 to the subject.
54. A method according to claim 53 wherein the condition is cancer.
55. A method according to claim 54 wherein the cancer is selected from the group consisting of Hematologic cancer such as myeloproliferative disorders
(idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes, plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer; urinary tract cancer such as prostate cancer, kidney and renal cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer such as melanoma; brain tumour such as glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stem gliomas, medulloblastoma, menigiomas, astrocytoma, oligodendroglioma; head and neck cancer such as nasopharyngeal carcinoma, laryngeal carcinoma; respiratory tract cancer such as lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease such as retinoblastoma; musculo-skeleton diseases such as osteosarcoma, musculoskeletal neoplasm; Squamous cell carcinoma and fibroid tumour.
56. Use of a compound according to any one of claims 1 to 28 in the preparation of a medicament for treating a proliferative condition in a subject.
57. A use according to claim 56 wherein the condition is cancer.
58. A use according to claim 57 wherein the cancer is selected from the group consisting of Hematologic cancer such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonoc tic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes, plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer; urinary tract cancer such as prostate cancer, kidney and renal cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer such as melanoma; brain tumour such as glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stem gliomas, medulloblastoma, menigiomas, astrocytoma, oligodendroglioma; head and neck cancer such as nasopharyngeal carcinoma, laryngeal carcinoma; respiratory tract cancer such as lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease such as retinoblastoma; musculo-skeleton diseases such as osteosarcoma, musculoskeletal neoplasm; Squamous cell carcinoma and fibroid tumour.
59. A compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt, N-oxide or prodrug thereof in the treatment of a proliferative condition.
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