WO2009093981A1

WO2009093981A1 - Triazine compounds as kinase inhibitors

Info

Publication number: WO2009093981A1
Application number: PCT/SG2009/000030
Authority: WO
Inventors: Cheng Hsia Angeline Lee; Harish Kumar Mysore Nagaraj; Anthony Deodaunia William; Meredith Williams; Zhengchang Xiong
Original assignee: S Bio Pte Ltd
Priority date: 2008-01-23
Filing date: 2009-01-22
Publication date: 2009-07-30

Abstract

The present invention relates to triazine compounds that are useful as kinase inhibitors. More particularly, the present invention relates to morpholino substituted triazines, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative disorders including tumours and cancers as well as other disorders or conditions related to or associated with mTOR kinases or PI3 kinases. The compounds are of the formula (I).

Description

TRIAZINE COMPOUNDS AS KINASE INHIBITORS

FIELD

[0001] The present invention relates to triazine compounds that may be useful as kinase inhibitors. More particularly, the present invention relates to 2-(morpholin-4-yl) substituted triazine derivatives, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of certain kinase related disorders.

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.

[0003] 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.

[0004] 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 such as proliferative diseases, for example cancer, immune and inflammatory diseases, diseases supported by excessive neovascularization and transplant rejection.

[0005] 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. In mammalian cells, the large PI3K family has been categorized into three classes, referred to as I, II, and III, each of which has its own characteristics in terms of molecular structure and substrate specificity. Class I PI3K preferred in vivo substrate is phosphatidylinositol-4,5 bisphosphate, which is phosphorylated to yield phosphatidylinositol-3,4,5 trisphosphate. These are further subdivided into Class IA and IB PI3Ks. Class IA enzymes consist of any one of the 'catalytic' subunits (p110α, p110β, or p110δ) complexed with any one of the 'regulatory' subunits (p85α, p85β or p55γ). Only one Class IB PI3K enzyme exists, and is made up of the p110γ catalytic and the p101 regulatory subunit. There are also three Class Il PI3Ks (Cllα, Cllβ, and Cllγ) and one Class III PI3K (Vps34).

[0006] The class I PI3Ks are the best understood members of this family and are key players of multiple intracellular signalling networks that integrate a variety of signals initiated by many growth factors. The Class IA enzymes are activated by tyrosine kinases (e.g. growth factor receptors), antigen receptors, and cytokine receptors, whilst the Class IB enzyme is activated by 'G Protein Coupled Receptors' (GPCRs). In response to activation, the PI3Ks generate lipid second messengers, which bind to, and activate, specific proteins in distinct signal transduction pathways. The signal transduction pathways remain active until phosphatase enzymes, in particular the oncogene PTEN, dephosphorylate the PI3K lipid second messengers.

[0007] 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 PI3Kα 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.

[0008] 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.

[0009] 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-IA 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. Akt in turn regulates a wide range of target proteins, one of which is the mammalian target of Rapamycin (commonly known as mTOR). The levels of PIP3 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.

[0010] 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.

[0011] In addition to the compelling correlative data presented above, direct proof of the involvement of deregulated PI3K signalling in 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 PI3Ks. Indeed recent interest in PI3K inhibitors has been intense with a number of compounds now in development having demonstrated anti-tumor activity in animal models. The most advanced compounds are now undergoing evaluation in phase I clinical trials. Accordingly compounds that are PI3K inhibitors would be expected to show interesting biological activity as PI3K inhibitors have the potential to block the PI3K/Akt signalling pathway and thereby form the basis of therapy in disease involving deregulation of this pathway.

[0012] In addition, Pl 3-kinase isoforms p110δ and p110γ regulate different aspects of immune and inflammatory responses. Hence there is great interest in the role of Pl 3-kinase signalling in a range of immune and inflammatory diseases as well as in transplant rejection.

[0013] Another area that has received attention has been the serine/threonine kinases. One serine/threonine kinase that has attracted significant interest is mTOR.

[0014] 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 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.

[0015] 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.

[0016] 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 T0RC2 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/AM pathway.

[0017] An additional pathway influenced by mTOR that appears to be particularly important in renal cell carcinoma involves the hypoxia-inducible factor (HlF). 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.

[0018] 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.

[0019] So far, four mTOR inhibitors have been tested in clinical trials: the prototype rapamycin and three rapamycin derivatives, CCI-779 (temsirolimus), RAD001 (everolimus) and AP23573. 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.

[0020] 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, a more water-soluble ester derivative of rapamycin was identified by investigators at Wyeth Ayerst as a non- cytotoxic agent that delayed tumor cell proliferation. At several non-toxic doses, 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 IC₅Q in the low nanomolar range. Two lines, however, were found to be resistant with IC₅o>1μM. 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).

[0021] RAD001 , 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 with IC50 ranging from 5 to 180OnM. p70S6K inhibition and anti-neoplastic effects have been shown in these models, with an optimal effect being achieved with 2.5 mg/kg/day in melanoma, lung, pancreas and colon carcinoma. Similarly, RAD001 demonstrated a concentration-dependent anti-tumor 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. In a phase I trial performed in patients with advanced cancer, RAD001 displayed a good safety profile with mild to moderate skin and mucous toxicity up to 30 mg weekly. Preliminary efficacy results showed an objective response in a patient with non-small cell lung carcinoma.

[0022] AP23573 is the latest rapamycin analog to be reported in clinical development. It is a phosphorus-containing compound synthesized with the aid of computational modelling studies. AP23573 was found to be stable in organic solvents, aqueous solutions at a variety of pHs and in plasma and whole blood, both in vitro and in vivo and has shown potent inhibition of diverse human tumor cell lines in vitro and as xenografts implanted into nude mice, alone or in combination with cytotoxic or targeted^' agents. In phase I trials, AP23573 was administered intravenously daily for 5 days every 2 weeks. Dose-limiting toxicity is severe grade 3 oral mucositis occurring during the first cycle. Other side effects seem to be moderate, including minor to moderate episodes of mucositis, fatigue, nausea, rash, anaemia, neutropenia, diarrhoea, hyperlipidemias and thrombocytopenia. Preliminary anti-tumor activity is observed at all dose levels.

[0023] 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 assumption 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.

[0024] In addition mTOR inhibitors have been shown to be very effective in preventing organ rejection after transplantation through an effect on immune responses, demonstrating a potential for treatment of autoimmune and inflammatory diseases as well as cancer.

[0025] Through the role of PI3K isoforms as key components of the down stream signaling pathways of angiogenic growth factors such as VEGF, FGF and PDGF as well angiogenic cytokines and because of the role of mTOR in the regulation of vascular endothelial growth factor (VEGF), PI3K and mTOR inhibitors also have potential to treat diseases supported by pathological neovascularization. This occurs during tumorigenesis, inflammatory conditions such as rheumatoid arthritis and ocular neovascular diseases e.g., age-related macular degeneration (AMD), retinal vascular diseases (vein occlusion and diabetic retinopathy) and other possible proliferative vascular disorders.

[0026] mTOR and PI3 have been identified as protein kinases that are involved in a number of disorders, and compounds that target one or more of these kinases should display useful biological activity. Accordingly, compounds that are mTOR and/or PI3K inhibitors have the potential to provide further biologically active compounds that would be expected to have useful, improved pharmaceutical properties in the treatment of proliferative disorders such as cancer, immune and inflammatory diseases, diseases supported by excessive neovascularisation and organ transplant rejection.

[0027] Compounds that inhibit both mTOR and PI3K simultaneously may be expected to provide powerful anti-proliferative, anti-angiogenic and antitumor activity since these compounds act at multiple points in the PI3K/Akt/mTOR pathway. A number of inhibitors of this type are now being investigated in a clinical setting for the first time (e.g. BEZ235, XL765, GDC0941 , PX866, SF1126). SUMMARY

[0028] The present invention provides compounds of formula (I):

Formula (I)

[0029] wherein:

[0030] A is selected from the group consisting of N and CR⁴;

[0031] B is selected from the group consisting of N and CR⁵;

[0032] D is selected from the group consisting of N and CR⁶;

[0033] X is selected from the group consisting of N and CR¹;

[0034] R¹ is selected from the group consisting of: H, F, Cl, Br, I, OH, NO₂, CN, NH₂, optionally substituted Ci-Ci₂alkyl, optionally substituted C₂-Ci₂alkenyl, optionally substituted Ci-C₆fluoroalkyl, 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 Cβ-Ciaaryl, optionally substituted Ci-Ciβheteroaryl, optionally substituted C₆-Ci₈arylCi-C6alkyl, OR⁸, SR⁸, CO₂R⁹, (CH₂)_VCO₂R⁹, (CH₂)_VCONR⁸R⁹, CONR⁸R⁹, NR⁸R⁹; optionally substituted CrCi₂alkyloxy, optionally substituted C₂-Ci ₂alkenyloxy, optionally substituted C₂-Ci₂alkynyloxy, optionally substituted C₂-Cioheteroalkyloxy, optionally substituted C₃-Ci₂cycloalkyloxy, optionally substituted C₃-Ci₂cycloalkenyloxy, optionally substituted C₂-Ci₂heterocycloalkyloxy, optionally substituted C₂- Ci₂heterocycloalkenyloxy, optionally substituted C₆-Ci₈aryloxy, optionally substituted Ci-C-|₈heteroaryloxy, optionally substituted Ci-Ci₂alkylamino, SR¹², SO₃H, SO₂NR¹²R¹³, SO₂R¹², SONR¹²R¹³, SOR¹², COR¹², COOH, NR¹²COR¹³, NR¹²COOR¹³, NR¹²SO₂R¹³, NR¹²CONR¹³R¹⁴, NR¹²R¹³, (CH₂)_VNR¹²R¹³, and acyl,

[0035] R², R³, R⁴, R⁵, and R⁶, are each independently selected from the group consisting of H, F, Cl, Br, CN, optionally substituted d-C^alkyl, OR¹⁰, OCOR¹⁰, CH₂OR¹⁰, CH₂NR¹⁰R¹¹, CH₂SO₂R¹⁰, NR¹⁰R¹¹, NR¹⁰COR¹¹, and NR¹⁰SO₂R¹¹, or

[0036] R⁴, when taken together with one of R² and R⁵, and the carbon atoms to which they are attached, forms an optionally substituted ring which may be an unsaturated, partially unsaturated, or saturated ring, the ring being fused to the six membered ring;

[0037] X¹, X² and X³ are each independently selected from the group consisting of N and CR⁷;

[0038] each R⁷ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NO₂, CN, NH₂, optionally substituted Ci-C-i₂alkyl, optionally substituted d- C₆fluoroalkyl, optionally substituted C₂-C-|₂alkenyl, 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 Ci-Ci₈heteroaryl, optionally substituted Ci-Ci₂alkyloxy, 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-Ci₂heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionally substituted Ci-Ci₈heteroaryloxy, optionally substituted C_rC₁₂alkylamino, SR¹², SO₃H, SO₂NR¹²R¹³, SO₂R¹², SONR¹²R¹³, SOR¹², COR¹², COOH, COOR¹², CONR¹²R¹³, NR¹²COR¹³, NR¹²COOR¹³, NR¹²SO₂R¹³, NR¹²CONR¹³R¹⁴, NR¹²R¹³, (CH₂)_VNR¹²R¹³ and acyl, or [0039] any two R⁷ on adjacent carbon atoms when taken together with the carbon atoms to which they are attached form an optionally substituted ring which may be an unsaturated, partially unsaturated, or saturated ring, the ring being fused to the five membered ring;

[0040] each R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is independently selected from the group consisting of H, optionally substituted Ci-Ci₂alkyl, optionally substituted Cz- 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-Ci₈aryl, and optionally substituted d-Ciaheteroaryl, or

[0041] any two R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ when taken together with the atoms to which they are attached may form a cyclic moiety;

[0042] v is an integer selected from the group consisting of 1 , 2, 3, and 4;

[0043] each R^z is independently selected from the group consisting of CrC₆alkyl, halo-Ci-C₆alkyl, hydroxyCi-C₆alkyl, Ci-C₆alkyloxyCi-C₆alkyl, cyanoCi-C₆alkyl, aminoCi-C₆alkyl, C_rC₆alkylaminoCi-C₆alkyl, and di(CrC₆alkyl)aminoCrC6alkyl;

[0044] q is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;

[0045] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof.

[0046] 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.

[0047] In some embodiments X is CR¹. This provides compounds of formula (Ia):

Formula (Ia)

[0048] or a pharmaceutically acceptable salt, N-oxide or prodrug thereof;

[0049] wherein R j1¹, F Dc2, R π3^J, R nz^z, A Λ, B D, D rv, X v1¹, X v%2 X v3^d a , nd q are as defined above.

[0050] In some embodiments X is N. This provides compounds of formula (Ib):

Formula (Ib)

[0051] or a pharmaceutically acceptable salt, N-oxide or prodrug thereof;

[0052] wherein R², R³, R^z, A, B, D, X¹, X², X³ and q are as defined above.

[0053] In the present invention 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.

[0054] In some embodiments wherein q is other than 0 each R^z may be selected from the group consisting of F, Cl, Br, methyl, trifluoromethyl, and ethyl. The R^z substituent may be attached at the 2, 3, 5 or 6 position of the morpholine ring and in circumstances where there are multiple R^z substltuents each R^z substituent is located independently of the others such that where there are multiple R^z substituents then two of the R^z substituents may be located on the same carbon on the morpholine ring or each substituent may be located on a different carbon.

[0055] In some embodiments q is 1 , X is CR¹ and the R^z substituent is located at the 3 position of the morpholine ring. This provides compounds of formula (laa).

Formula (laa)

[0056] or a pharmaceutically acceptable salt, N-oxide or prodrug thereof;

[0057] wherein R¹, R², R³, A, B, D, X¹, X², X³ and R^z are as defined above.

[0058] In some embodiments q is 0 and X is CR¹. This provides compounds of formula (lab).

Formula (lab)

[0059] or a pharmaceutically acceptable salt, N-oxide or prodrug thereof; [0060] wherein R¹, R , R , A, B, D, X¹, X , and X^d are as defined above.

[0061] In some embodiments q is 0, X is CR¹ and X³ is N. This provides compounds of formula (lac).

Formula (lac)

[0062] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0063] wherein R¹, R², R³, A, B, D, X¹ and X² are as defined above.

[0064] In some embodiments q is 0, X is CR¹, X¹ and X² are CR⁷ and X³ is N. This provides compounds of formula (lad).

Formula (lad)

[0065] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0066] wherein R¹, R², R³, R⁷, A, B, and D are as defined above. [0067] In some embodiments q is 0, X is CR¹ and X¹ is N. This provides compounds of formula (lae).

Formula (lae)

[0068] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0069] wherein R¹, R², R³, A, B, D, X² and X³ are as defined above.

[0070] In some embodiments q is 0, X is CR¹, X¹ is N and X² and X³ are CR⁷. This provides compounds of formula (laf).

Formula (laf)

[0071] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0072] wherein R¹, R% R^ό, R\ A, B, and D are as defined above. [0073] In some embodiments of the compounds of the invention containing R⁷, each R⁷ is H.

[0074] In some embodiments of the compounds of the invention containing R⁷, two R⁷ groups, when taken together with the carbon atoms to which they are attached form an optionally substituted ring which may be an unsaturated, partially unsaturated, or saturated ring, the ring being fused to the five membered ring. The ring thus formed may be any suitable cycloalkyl or heterocycloalkyl ring and may in principle be of any suitable ring size. The ring is typically a 5 to 8 membered ring. In one embodiment the ring is a five membered ring. In another embodiment the ring is a six-membered ring. The ring may also be optionally substituted with one or more suitable substituents. The ring may be a cycloalkyl ring in that all ring atoms are carbon atoms or the ring may contain one or more heteroatoms as ring atoms. The heteroatom(s) may be chosen from any known heteroatom although they are typically independently selected from the group consisting of N, O, and S. In one specific embodiment each heteroatom is N.

[0075] In some embodiments two R⁷ groups when taken together with the carbon atoms to which they are attached form a phenyl moiety fused to the five membered ring, the phenyl moiety being substituted with 0, 1 , 2, 3 or 4 R¹⁵ groups wherein each R¹⁵ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NO2, CN, NH₂, 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-Ci₂heterocycloalkyl, optionally substituted C₂- Ci₂heterocycloalkenyl, optionally substituted Cβ-Cisaryl, optionally substituted Cr Cisheteroaryl, optionally substituted Ci-Ci₂alkyloxy, optionally substituted C₂-Ci₂ alkenyloxy, optionally substituted C₂-Ci₂alkynyloxy, optionally substituted C₂- Ci₂heteroalkyloxy, optionally substituted C₃-d₂cycloalkyloxy, optionally substituted C₃-Ci₂ cycloalkenyloxy, optionally substituted C₂-Ci₂heterocycloalkyloxy, optionally substituted C₂-Ci₂heterocycloalkenyloxy, optionally substituted Cβ-Cisaryloxy, optionally substituted CrCi₈heteroaryloxy, optionally substituted Ci-Ci₂alkylamino, SR¹⁶, SO₃H, SO₂NR¹⁶R¹⁷, SO₂R¹⁶, SONR¹⁶R¹⁷, SOR¹⁶, COR¹⁶, COOH, COOR¹⁶, CONR¹⁶R¹⁷, NR¹⁶COR¹⁷, NR¹⁶COOR¹⁷, NR¹⁶SO₂R¹⁷, NR¹⁶CONR¹⁷R¹⁸, NR¹⁶R¹⁷, and acyl,

[0076] each R¹⁶, R¹⁷ and R¹⁸ 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-Ci₂heterocycloalkyl, optionally substituted C₂-Ci₂heterocycloalkenyl, optionally substituted C₆-Ci8aryl, and optionally substituted Ci-Ci₈heteroaryl.

[0077] In some embodiments q is O, X is CR¹, X³ is N, X¹ and X² are CR⁷ wherein the two R⁷ groups when taken together with the carbon atoms to which they are attached form a phenyl moiety fused to the five membered ring, the phenyl moiety being substituted with 0, 1 , 2, 3 or 4 R¹⁵ groups and the compound has the formula (II):

Formula (II)

[0078] wherein R\ R , R , R^1&, A, B, and D are as defined above;

[0079] m is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;

[0080] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof. [0081] In some embodiments A is CR⁴, B is CR⁵ and D is CR⁶. In some embodiments A is CR⁴, B is CR⁵ and D is N. In some embodiments A is CR⁴, B is N and D is CR⁶. In some embodiments A is N, B is CR⁵ and D is N.

[0082] In some embodiments R⁴ when taken together with one of R² and R⁵, and the carbon atoms to which they are attached, forms an optionally substituted ring which may be an unsaturated, partially unsaturated, or saturated ring, the ring being fused to the six membered ring. The ring may be of any suitable size although it is typically a 5 to 8 membered ring. In one embodiment the ring is a five membered ring. In another embodiment the ring is a six-membered ring. The ring may be a cycloalkyl ring or a heterocycloalkyl ring containing from 1 to 4 heteroatoms independently selected from N, O and S.

[0083] In some embodiments R⁴ and R⁵ when taken together with the carbon atoms to which they are attached form an optionally substituted ring fused to the six membered ring, the ring being an unsaturated, partially unsaturated, or saturated ring.

The ring thus formed may be any suitable cycloalkyl or heterocycloalkyl ring and may in principle be of any suitable ring size. The ring is typically a 5 to 8 membered ring.

In one embodiment the ring is a five membered ring. In another embodiment the ring is a six-membered ring. The ring may also be optionally substituted with one or more suitable substituents. The ring may be a cycloalkyl ring in that all ring atoms are carbon atoms or the ring may contain one or more heteroatoms as ring atoms. The heteroatom(s) may be chosen from any known heteroatom although they are typically independently selected from the group consisting of N, O, and S. In one specific embodiment each heteroatom is N.

[0084] In some embodiments and R⁴ and R⁵ are joined and the compound is a compound of the formula (III):

Formula (III)

[0085] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0086] wherein X, X¹, X², X³, R², R³, and R⁶ are as defined above; and R¹⁹ is selected from the group consisting of H, OH, CH₂OH, NH₂, CrC₆alkyl, and CV C₆alkoxy.

[0087] In some embodiments and R⁴ and R⁵ are joined and X is CR¹ and the compound is a compound of the formula (Ilia):

Formula (Ilia)

[0088] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0089] wherein X¹, X², X³, R¹, R², R³, R⁶ and R¹⁹ are as defined above. [0090] In some embodiments of the compounds of formula (Ilia) X¹ and X² are CR⁷ and X³ is N and the compound is a compound of the formula (lllb):

Formula (IMb)

[0091] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0092] wherein R¹, R% R^ό, R^b, R' and R^ia are as defined above.

[0093] In some embodiments of the compounds of formula (Ilia) X¹ is N and X² and X³ are CR⁷ and the compound is a compound of the formula (IMc):

Formula (lllc) [0094] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0095] wherein R¹, R², R³, R⁶, R⁷ and R¹⁹ are as defined above.

[0096] In some embodiments R⁴ and R⁵ are joined and the compound is a compound of the formula (IV):

[0097] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0098] wherein X, X¹, X², X³, R², R³, and R⁶ are as defined above; and R¹⁹ is selected from the group consisting of H, OH, CH₂OH, NH₂, C-i-Cβalkyl, and C_r Cβalkoxy.

[0099] In some embodiments R⁴ and R⁵ are joined and X is CR¹ and the compound is a compound of the formula (IVa):

Formula (IVa)

[0100] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0101] wherein X¹, X², X³, R¹, R², R³, R⁶ and R¹⁹ are as defined above.

[0102] In some embodiments of the compounds of formula (IVa) X¹ and X² are CR⁷ and X³ is N and the compound is a compound of the formula (IVb):

[0103] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0104] wherein R¹, R², R³, R⁶, R⁷ and R¹⁹ are as defined above.

[0105] In some embodiments of the compounds of formula (IVa) X¹ is N and X² and X³ are CR⁷ and the compound is a compound of the formula (IVc):

Formula (IVc)

[0106] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0107] wherein R\ Fc, Fc, Fc, R' and R¹⁹ are as defined above.

[0108] In some embodiments R⁴ and R⁵ are joined and the compound is a compound of the formula (V):

Formula (V)

[0109] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0110] wherein X, X¹, X², X³, R², R³, and R⁶ are as defined above; and R¹⁹ is selected from the group consisting of H, OH, CH₂OH, NH₂, Ci-C₆alkyl, and Cr Cβalkoxy. [0111] In some embodiments R⁴ and R⁵ are joined and X is CR¹ and the compound is a compound of the formula (Va):

Formula (Va)

[0112] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof,

[0113] wherein X¹, X², X³, R¹, R², R³, R⁶ and R¹⁹ are as defined above.

[0114] In some embodiments of the compounds of formula (Va) X¹ and X² are CR⁷ and X³ is N and the compound is a compound of the formula (Vb):

Formula (Vb)

[0115] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof; [0116] wherein R¹, R², R³, R⁶, R⁷ and R¹⁹ are as defined above.

[0117] In some embodiments of the compounds of formula (Va) X¹ is N and X² and X³ are CR⁷ and the compound is a compound of the formula (Vc):

Formula (Vc)

[0118] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0119] wherein R¹, R², R³, R⁶, R⁷ and R¹⁹ are as defined above.

[0120] In some embodiments R⁴ and R² when taken together with the carbon atoms to which they are attached form an optionally substituted ring fused to the six membered ring, the ring being an unsaturated, partially unsaturated, or saturated ring. The ring thus formed may be any suitable cycloalkyl or heterocycloalkyl ring and may in principle be of any suitable ring size. The ring is typically a 5 to 8 membered ring. In one embodiment the ring is a five membered ring. In another embodiment the ring is a six-membered ring. The ring may also be optionally substituted with one or more suitable substituents. The ring may be a cycloalkyl ring in that all ring atoms are carbon atoms or the ring may contain one or more heteroatoms as ring atoms. The heteroatom(s) may be chosen from any known heteroatom although they are typically independently selected from the group consisting of N, O, and S. In one specific embodiment each heteroatom is N. [0121] In some embodiments R² and R⁴ are joined and the compound is a compound of the formula (Vl):

Formula (Vl)

[0122] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof.

[0123] wherein X, X¹, X², X³, R³, R⁵, and R⁶ are as defined above; and R²⁰ is selected from the group consisting of H, OH, CH₂OH, NH₂, Ci-C₆alkyl, and Ci- C₆alkoxy;

[0124] In some embodiments R² and R⁴ are joined and X is CR¹ and the compound is a compound of the formula (Via):

Formula (Via)

[0125] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof; [0126] wherein X¹, X^z, X^ό, R\ R^ά, R^b, R^b and R^ are as defined above.

[0127] In some embodiments of the compounds of formula (Via) X¹ and X² are CR⁷ and X³ is N and the compound is a compound of the formula (VIb):

Formula (VIb)

[0128] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0129] wherein R¹, R³, R⁵, R⁶, R⁷ and R²⁰ are as defined above.

[0130] In some embodiments of the compounds of formula (Via) X¹ is N and X² and X³ are CR⁷ and the compound is a compound of the formula (VIc):

Formula (VIc)

[0131] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof; [0132] wherein R¹, R³, R⁵, R⁶, R⁷ and R²⁰ are as defined above.

[0133] In some embodiments R² and R⁴ are joined and the compound is a compound of the formula (VII):

Formula (VII)

[0134] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0135] wherein X, X¹, X², X³, R³, R⁵, and R⁶ are as defined above; and each R²⁰ is selected from the group consisting of H, OH, CH₂OH, NH₂, Ci-C₆alkyl, and Cr Cβalkoxy.

[0136] In some embodiments R² i and R' * are joined and X is CR , and the compound is a compound of the formulc ) (Vila):

Formula (Vila) [0137] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0138] wherein X¹, X², X³, R¹, R³, R⁵, R⁶ and R²⁰ are as defined above.

[0139] In some embodiments of the compounds of formula (Vila) X¹ and X² are CR⁷ and X³ is N and the compound is a compound of the formula (VIIb):

Formula (VIIb)

[0140] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0141] wherein R¹, R³, R⁵, R⁶, R⁷ and R²⁰ are as defined above.

[0142] In some embodiments of the compounds of formula (Vila) X¹ is N and X² and X³ are CR⁷ and the compound is a compound of the formula (VIIc):

Formula (VIIc)

[0143] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0144] wherein R¹, R³, R⁵, R⁶, R⁷ and R²⁰ are as defined above.

[0145] In some embodiments R² and R⁴ are joined and the compound is a compound of the formula (VIII):

Formula (VIII)

[0146] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0147] wherein X, X¹, X², X³, R³, R⁵, and R⁶ are as defined above and R²⁰ is selected from the group consisting of H, OH, CH₂OH, NH₂, CrCβalkyl, and C_r Cβalkoxy. [0148] In some embodiments R² and R⁴ are joined and X is CR¹ and the compound is a compound of the formula (Villa):

Formula (Villa)

[0149] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0150] wherein X¹, X², X³, R¹, R³, R⁵, R⁶ and R²⁰ are as defined above.

[0151] In some embodiments of the compounds of formula (Villa) X¹ and X² are CR⁷ and X³ is N and the compound is a compound of the formula (VIIIb):

Formula (VIIIb)

[0152] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0153] wherein R¹, R³, R⁵, R⁶, R⁷ and R²⁰ are as defined above. [0154] In some embodiments of the compounds of formula (Villa) X¹ is N and X² and X³ are CR⁷ and the compound is a compound of the formula (VIIIc):

Formula (VIIIc)

[0155] or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof;

[0156] wherein R¹, R³, R⁵, R⁶, R⁷ and R²⁰ are as defined above.

[0157] In some embodiments of the compounds of the invention containing R¹, R¹ is selected from the group consisting of: H, halogen, optionally substituted C_rC₆alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted Ci-C₆fluoroalkyl, OH, OR⁸, SR⁸, CO₂R⁹, CONR⁸R⁹' optionally substituted C₃-Ci ₂cycloalkyl optionally substituted Ce-C-iearyl, optionally substituted Ci-C-isheteroaryl, optionally substituted Ce- Ci₈arylCi-Cβalkyl and NR⁸R⁹.

[0158] In some embodiments R¹ is H.

[0159] In some embodiments R¹ is C-i-Cβalkyl. In some embodiments R¹ is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-methyl-propyl,

1-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, and hexyl. In some embodiments R¹ is methyl. In some embodiments R¹ is isopropyl. In some embodiments R¹ is ethyl. In some embodiments R¹ is propyl. In some embodiments R¹ is butyl. In some embodiments R¹ is 2-methyl-propyl. In some embodiments R¹ is 1-ethyl-propyl. [0160] In some embodiments R¹ is optionally substituted CrC₆alkyI. There are a wide range of optional substituents that may be present on the substituted alkyl group. In some embodiments R¹ is selected from the group consisting of 2-cyano- ethyl, phenyl-methyl, 2-phenyl-ethyl, and (2-carboxy-methyl)-ethyl.

[0161] In some embodiments R¹ is optionally substituted C₂-C₆alkenyl. There are a wide range of optional substituents that may be present on the substituted alkenyl group. In some embodiments R¹ is 2-cyano-ethenyl.

[0162] In some embodiments R¹ is Ci-Cβfluoroalkyl. In some embodiments R¹ is difluoro-methyl. In some embodiments R¹ is trifluoro-methyl.

[0163] In some embodiments R¹ is optionally substituted C₃-Ci ₂cycloalkyl. In some embodiments R¹ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments R² is cyclopropyl. In some embodiments R¹ is cyclopentyl.

[0164] In some embodiments R¹ is an optionally substituted Cβ-CisarylCi-Cealkyl. In some embodiments R¹ is optionally substituted phenyl-methyl. Suitable examples of optionally substituted phenyl-methyl groups include phenylmethyl, (2-chloro- phenyl)methyl, (3-chlorophenyl)methyl, and (4-chloro-phenyl)methyl. In some embodiments R¹ is optionally substituted phenyl-ethyl.

[0165] In some embodiments R¹ is CO₂R⁹. In some embodiments R¹ is CO₂CH₂CH₃. In some embodiments R¹ is CO₂H.

[0166] In some embodiments R¹ is CONR⁸R⁹. In some embodiments R¹ is CONH(CH₂)₂OCH₃. In some embodiments R¹ is CONH(cyclopropyl).

[0167] In some embodiments of the compounds that contain an R² moiety, R² is H.

[0168] In some embodiments of the compounds that contain an R³ moiety, R³ is H. [0169] In some embodiments of the compounds that contain an R⁴ moiety, R⁴ is selected from the group consisting of OH, CN, NHCOCH₃, F, Cl, OCH₃, and CH₂OH.

[0170] In some embodiments of the compounds that contain an R⁵ moiety, R⁵ is selected from the group consisting of H and NH₂.

[0171] In some embodiments of the compounds that contain an R⁶ moiety, R⁶ is H.

[0172] In some embodiments of the compounds that contain an R⁷ moiety, R⁷ is selected from the group consisting of H, optionally substituted C-rC^alkyl, optionally substituted d-Cβfluoroalkyl, optionally substituted C₂-Ci₂alkenyl, optionally substituted C₂-Ci2alkynyl, optionally substituted C₂-Ci₂heteroalkyl, optionally substituted C₆-C₁₈aryl, optionally substituted CrCisheteroaryl, and SR¹².

[0173] In some embodiments R⁷ is H.

[0174] In some embodiments R⁷ is CrC₆alkyl. In some embodiments R⁷ is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-methyl-propyl, 1-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, and hexyl. In some embodiments R⁷ is methyl. In some embodiments R⁷ is isopropyl. In some embodiments R⁷ is ethyl. In some embodiments R⁷ is propyl. In some embodiments R⁷ is butyl. In some embodiments R⁷ is 2-methyl-propyl. In some embodiments R⁷ is 1-ethyl-propyl.

[0175] In some embodiments R⁷ is optionally substituted CrC₆alkyl. There are a wide range of optional substituents that may be present on the substituted alkyl group. In some embodiments R⁷ is selected from the group consisting of 2-cyano- ethyl and hydroxy-methyl.

[0176] In some embodiments R⁷ is optionally substituted C₂-C₆alkenyl. There are a wide range of optional substituents that may be present on the substituted alkenyl group. In some embodiments R⁷ is selected from the group consisting of 2-cyano- ethenyl and 2(carboxy-methyl)ethenyl. [0177] In some embodiments R⁷ is Ci-C₆fluoroalkyl. In some embodiments R¹ is difluoro-methyl. In some embodiments R⁷ is trifluoro-methyl.

[0178] In some embodiments R⁷ is an optionally substituted C₂-Ci₂heteroalkyl group. In some embodiments the C₂-C₁₂ heteroalkyl group is selected from the group consisting of hydroxyCi-C_δalkyl, Ci-C_δalkyloxyCrCealkyl, aminoCrCβalkyl, Cr CβalkylaminoCrCealkyl, and di(Ci-C₆alkyl)aminoCi-C₆alkyl. Examples of possible values of R⁷ 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.

[0179] In some embodiments the C₂-Ci₂heteroalkyl is selected from the group consisting of -CH2-N(CH3)-(CH₂)₂-N(CH₂CH₃)2, -CH₂-NH-(CH₂)₃CH₃, and -CH₂-NH- (CH₂)₂OCH₃.

[0180] In some embodiments of the compounds containing R⁷, each R⁷ is H. In some embodiments of the compounds containing R⁷, the two R⁷ groups, when taken together with the carbon atoms to which they are attached form an optionally substituted ring which may be an unsaturated, partially unsaturated, or saturated ring, the ring being fused to the five membered ring. The ring thus formed may be any suitable cycloalkyl or heterocycloalkyl ring and may in principle be of any suitable ring size. The ring is typically a 5 to 8 membered ring. In one embodiment the ring is a five membered ring. In another embodiment the ring is a six-membered ring. The ring may also be optionally substituted with one or more suitable substituents. The ring may be a cycloalkyl ring in that all ring atoms are carbon atoms or the ring may contain one or more heteroatoms as ring atoms. The heteroatom(s) may be chosen from any known heteroatom although they are typically independently selected from the group consisting of N, O, and S. In one specific embodiment each heteroatom is N. In one specific embodiment the two R⁷ groups are joined to form a six membered aromatic ring.

[0181] In some embodiments two R⁷ groups when taken together with the carbon atoms to which they are attached form a phenyl moiety fused to the five membered ring, the phenyl moiety being substituted with 0, 1 , 2, 3 or 4 R¹⁵ groups wherein each R¹⁵ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NO₂, CN, NH₂, 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-Ci₂heterocycloalkyl, optionally substituted C₂- Ci₂heterocycloalkenyl, optionally substituted C₆-Ci₈aryl, optionally substituted C_r C-iβheteroaryl, optionally substituted C_rCi₂alkyloxy, optionally substituted C₂- Ci₂alkenyloxy, optionally substituted C₂-Ci ₂alkynyloxy, optionally substituted C₂- Ci₂heteroalkyloxy, optionally substituted C₃-C-|₂cycloalkyloxy, optionally substituted C₃-Ci₂cycloalkenyloxy, optionally substituted

optionally substituted C₂-Ci₂heterocycloalkenyloxy, optionally substituted C₆-Ci₈aryloxy, optionally substituted Ci-C-iβheteroaryloxy, optionally substituted Ci-Ci₂alkylamino, SR¹⁶, SO₃H, SO₂NR¹⁶R¹⁷, SO₂R¹⁶, SONR¹⁶R¹⁷, SOR¹⁶, COR¹⁶, COOH, COOR¹⁶, CONR¹⁶R¹⁷, NR¹⁶COR¹⁷, NR¹⁶COOR¹⁷, NR¹⁶SO₂R¹⁷, NR¹⁶CONR¹⁷R¹⁸, NR¹⁶R¹⁷, and acyl,

[0182] each R¹⁶, R¹⁷ and R¹⁸ is independently selected from the group consisting of H, optionally substituted Ci-C,₂alkyl, optionally substituted C₂-C-ι₂alkenyl, optionally substituted C₂-Ci₂alkynyl, optionally substituted Ci-Ci₂heteroalkyl, optionally substituted C₃-Ci₂cycloalkyl, optionally substituted C₃-Ci₂cycloalkenyl, optionally substituted C₂-Ci₂ heterocycloalkyl, optionally substituted C₂-Ci₂ heterocycloalkenyl, optionally substituted Cβ-Ciβaryl, and optionally substituted Ci-Ciaheteroaryl.

[0183] In some embodiments of the compounds containing the group R⁸, R⁸ is selected from H and Ci-Cβalkyl. In some embodiments R⁸ is methyl. In some embodiments R⁸ is H. [0184] In some embodiments of the compounds containing the group R⁹, R⁹ is selected from H and Ci-Cεalkyl. In some embodiments R⁹ is methyl. In some embodiments R⁹ is H.

[0185] In some embodiments of the compounds containing the group R¹⁰, R¹⁰ is selected from H and C-ι-C₆alkyl. In some embodiments R¹⁰ is methyl. In some embodiments R¹⁰ is H.

[0186] In some embodiments of the compounds containing the group R¹¹, R¹¹ is selected from H and Ci-C₆alkyl. In some embodiments R¹¹ is methyl. In some embodiments R¹¹ is H.

[0187] In some embodiments of the compounds containing the group R¹², R¹² is selected from H and C_rC₆alkyl. In some embodiments R¹² is methyl. In some embodiments R¹² is H.

[0188] In some embodiments of the compounds containing the group R¹³, R¹³ is selected from H and C_rC₆alkyl. In some embodiments R¹³ is methyl. In some embodiments R¹³ is H.

[0189] In some embodiments of the compounds containing the group R¹⁴, R¹⁴ is selected from H and C-i-Cβ alkyl. In some embodiments R¹⁴ is methyl. In some embodiments R¹⁴ is H.

[0190] In some embodiments of the compounds containing the group R¹⁵, R¹⁵ is selected from H, Cl, NH₂, and CrC₆ alkyl. In some embodiments R¹⁵ is methyl. In some embodiments R¹⁵ is H. In some embodiments R¹⁵ is Cl. In some embodiments R¹⁵ is NH₂.

[0191] In some embodiments of the compounds containing the group R¹⁶, R¹⁶ is selected from H and C_rC₆alkyl. In some embodiments R¹⁶ is methyl. In some embodiments R¹⁶ is H. [0192] In some embodiments of the compounds containing the group R¹⁷, R¹⁷ is selected from H and d-Cβalkyl. In some embodiments R¹⁷ is methyl. In some embodiments R¹⁷ is H.

[0193] In some embodiments of the compounds containing the group R¹⁸, R¹⁸ is selected from H and Ci-C₆alkyl. In some embodiments R¹⁸ is methyl. In some embodiments R¹⁸ is H.

[0194] In some embodiments of the compounds containing the group R¹⁹, R¹⁹ is selected from H and C-i-Cβalkyl. ^m some embodiments R¹⁹ is methyl. In some embodiments R¹⁹ is H.

[0195] In some embodiments of the compounds of the invention containing the group R²⁰, R²⁰ is selected from H and C_rC₆ alkyl. In some embodiments R²⁰ is methyl. In some embodiments R²⁰ is H.

[0196] Many if not all of the variables discussed above may be optionally substituted. If the variable is optionally substituted then in certain embodiments the optional substituent is selected from the group consisting of: halogen, =O, =S, -CN, - NO₂, -CF₃, -OCF₃, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, -COOH, -COR^a, -C(O)OR³, -SH, - SR^a, -OR^a, and acyl.

[0197] R^a is H, optionally substituted Ci-Ci₂alkyl, optionally substituted C₂- C-|₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C₂- C^heteroalkyl, optionally substituted C₃-Ci₂cycloalkyl, optionally substituted C₃- Ci₂cycloalkenyl, optionally substituted C₂-Ci₂heterocycloalkyl, optionally substituted C2-Ci₂heterocycloalkenyl, optionally substituted Cβ-Ciβaryl, optionally substituted Cr Cisheteroaryl, and acyl. [0198] Alternatively, two adjacent optional substituents may, when taken together with the atoms to which they are attached, form a cyclic moiety such as an optionally substituted C₃-Ci₂cycloalkyl moiety or an optionally substituted C2-C12 heterocycloalkyl moiety.

[0199] In certain embodiments the substituents are selected from the group consisting of: F, Cl, Br, =0, =S, -CN, -NO₂, Ci-C₁₂alkyl, C₂-C₁₂alkenyl, C₂- C-ioheteroalkyl, C₂-Ci₂ alkynyl, Ci-Ci₂haloalkyl, Cβ-Cisaryl, C₃-Ci₂cycloalkyl, C₂- Ci₂heterocycloalkyl, C₁-Ci₈ heteroaryl, hydroxy, hydroxyCrCi₂alkyl, d-C^alkyloxy, Ci-Ci₂ alkylamino, phenoxy, Ci-Ci₂alkoxyCi-Ci₂alkyl, benzyloxy, Ci-Ci₂alkylsulfonyl, C₆-Ci₈arylsulfonyl, aminosulfonyl, COOH, SH and CrCi₂acyl,

[0200] In some embodiments each optional substituent is independently selected from the group consisting of: F, Br, Cl, =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, -NO₂, phenoxy, hydroxy, methoxy, trifluoro-methoxy, ethoxy, and methylenedioxy.

[0201] 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.

[0202] The invention also relates to pharmaceutical compositions including a compound of the invention with a pharmaceutically acceptable carrier, diluent or excipient.

[0203] In a further aspect the invention provides a method of inhibiting a protein kinase selected from the group consisting of a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof and a PI3 kinase or 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 of the invention.

[0204] 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.

[0205] 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.

[0206] In some embodiments the protein kinase is a PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof. In some embodiments the PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof, is a class I PI3K or a fragment thereof or a complex thereof or a functional equivalent thereof.

[0207] 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).

[0208] In an even further aspect the invention provides the use of a compound of the invention to inhibit one or more protein kinase(s) selected from the group consisting of a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof and a PI3 kinase or a fragment or a complex thereof or a functional equivalent thereof. [0209] 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.

[0210] In some embodiments the protein kinase is a PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof. In some embodiments the PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof, is a class I PI3K or a fragment thereof or a complex thereof or a functional equivalent thereof.

[0211] 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) selected from the group consisting of a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof and a PI3 kinase 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 the invention.

[0212] 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.

[0213] In some embodiments the protein kinase is a PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof. In some embodiments the PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof, is a class I PI3K or a fragment thereof or a complex thereof or a functional equivalent thereof. [0214] 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 and hyperproliferative conditions such as psoriasis and restenosis; 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. In other embodiments, compounds of this invention can be used to treat pre-cancer conditions or hyperplasia including familial adenomatous polyposis, colonic adenomatous polyps, myeloid dysplasia, endometrial dysplasia, endometrial hyperplasia with atypia, cervical dysplasia, vaginal intraepithelial neoplasia, benign prostatic hyperplasia, papillomas of the larynx, actinic and solar keratosis, seborrheic keratosis and keratoacanthoma.

[0215] In some embodiments the condition is an autoimmune or inflammatory disease or a disease supported by excessive neovascularisation. Diseases that have been attributed with some degree of autoimmune etiology, or that involve pathological inflammatory and neovascularization responses, include the following: acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophilia, cutaneous T-cell lymphoma, dermatitis erythrema multiforme, dermatomyositis, diabetic retinopathy, Dressler's syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, macular degeneration, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage- Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter's syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome and Wegener's granulomatosis.

[0216] In an even further aspect the invention provides use of a compound of the invention in the preparation of a medicament for treating a condition in an animal in which inhibition of one or more protein kinase(s) selected from the group consisting of a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof and a PI3 kinase or a fragment or a complex thereof or a functional equivalent thereof, prevents, inhibits or ameliorates a pathology or a symptomology of the condition.

[0217] In another aspect the present invention provides the use of a compound of the invention 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) selected from the group consisting of a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof and a PI3 kinase or a fragment or a complex thereof or a functional equivalent thereof, prevents, inhibits or ameliorates a pathology or a symptomology of the condition.

[0218] 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.

[0219] In some embodiments the protein kinase is a PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof. In some embodiments the PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof, is a class I PI3K or a fragment thereof or a complex thereof or a functional equivalent thereof.

[0220] 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 the invention.

[0221] In another aspect the present invention provides the use of a compound of the invention in the preparation of a medicament for treating a proliferative condition in a subject.

[0222] 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 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.

[0223] These and other features of the present teachings are set forth herein.

DETAILED DESCRIPTION

[0224] 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.

[0225] As used herein, the term "unsubstituted" means that there is no substituent or that the only substituents are hydrogen.

[0226] 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, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -C(=O)OH, -C(=O)R^a, -C(=O)OR^a, C(=O)NR^aR^b, C(=NOH)R^a, C(=NR^a)NR^bR°, NR^aR^b, NR^aC(=O)R^b, NR^aC(=O)OR^b, NR^aC(=O)NR^bR°, NR^aC(=NR^b)NR^cR^d, NR^aSO₂R^b,-SR^a, SO₂NR^aR^b, -OR^a, OC(=O)NR^aR^b, OC(=O)R^a and acyl,

[0227] wherein R^a, R^b, R° and R^d are each independently selected from the group consisting of H, Ci-Ci₂alkyl, CrCi₂haloalkyl, C₂-Ci₂alkenyl, C₂-Ci₂alkynyl, C2-C10 heteroalkyl, C₃-Ci₂cycloalkyl, C₃-Ci₂cycloalkenyl, C₂-Ci₂heterocycloalkyl, C₂-Ci₂ heterocycloalkenyl, Cβ-Cisaryl, d-Cisheteroaryl, 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.

[0228] Alternatively, two adjacent optional substituents may, when taken together with the atoms to which they are attached, form a cyclic moiety such as an optionally substituted C₃-C-|₂cycloalkyl moiety or an optionally substituted C₂-Ci₂ heterocycloalkyl moiety.

[0229] In some embodiments each optional substituent is 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, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, -COOH, -SH, and acyl.

[0230] Examples of particularly suitable optional substituents include F, Cl, Br, I, CH₃, CH₂CH₃, OH, OCH₃, CF₃, OCF₃, NO₂, NH₂, and CN.

[0231] 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.

[0232] "Acyl" means an R-C(=O)- 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.

[0233] "Acylamino" means an R-C(=O)-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.

[0234] "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.

[0235] "Alkenyloxy" refers to an alkenyl-O- group in which alkenyl is as defined herein. Preferred alkenyloxy groups are C_rC₆ 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.

[0236] "Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a C₁-C-₁₂ alkyl, more preferably a C1-C10 alkyl, most preferably d-Cβ unless otherwise noted. Examples of suitable straight and branched CrC_θ 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.

[0237] "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 Ci-Cβ 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.

[0238] "Alkylaminocarbonyl" refers to a group of the formula (Alkyl)_x(H)_yNC(=O)- 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.

[0239] "Alkyloxy" refers to an alkyl-O- group in which alkyl is as defined herein. Preferably the alkyloxy is a Ci-C₆alkyloxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group.

[0240] "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 alky] group.

[0241] "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.

[0242] "Alkyloxycarbonyl" refers to an alkyl-O-C(=O)- group in which alkyl is as defined herein. The alkyl group is preferably a CrCβ 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.

[0243] "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.

[0244] "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.

[0245] "Alkyloxyheterocycloalkyl" refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyl 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 heterocycloalkyl group.

[0246] "Alkylsulfinyl" means an alkyl-S-(=O)- group in which alkyl is as defined herein. The alkyl group is preferably a Ci-Cβ 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. [0247] "Alkylsulfonyl" refers to an alkyl-S(=O)₂- group in which alkyl is as defined above. The alkyl group is preferably a Ci-C₆alkyl 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.

[0248] "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.

[0249] "Alkynyloxy" refers to an alkynyl-O- group in which alkynyl is as defined herein. Preferred alkynyloxy groups are Ci-C₆alkynyloxy 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.

[0250] "Aminoalkyl" means an NH₂-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.

[0251] "Aminosulfonyl" means an NH₂-S(=O)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.

[0252] "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-Ci_S aryl group.

[0253] "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.

[0254] "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain a C_1-5alkyl 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.

[0255] "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.

[0256] "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.

[0257] "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.

[0258] "Aryloxy" refers to an aryl-O- group in which the aryl is as defined herein. Preferably the aryloxy is a Cβ-Cisaryloxy, more preferably a Cβ-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.

[0259] "Arylsulfonyl" means an aryI-S(=O)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.

[0260] 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.

[0261] "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- Ci₂ alkenyl group. .The group may be a terminal group or a bridging group.

[0262] "Cycloalkyl" 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 cycloalkyl group typically is a C3-C12 alkyl group. The group may be a terminal group or a bridging group.

[0263] "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl 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.

[0264] "Cycloalkylalkenyl" means a cycloalkyl-alkenyl- group in which the cycloalkyl 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.

[0265] "Cycloalkylheteroalkyl" means a cycloalkyl-heteroalkyl- group in which the cycloalkyl 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.

[0266] "Cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined herein. Preferably the cycloalkyloxy is a d-Cβcycloalkyloxy. 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.

[0267] "Cycloalkenyloxy" refers to a cycloalkenyl-O- group in which the cycloalkenyl is as defined herein. Preferably the cycloalkenyloxy is a Cr 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.

[0268] "Haloalkyl" 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 haloalkyl group typically has the formula C_nH₍₂π₊i-m)Xm wherein each X is independently selected from the group consisting of F, Cl, 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 haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.

[0269] "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, Cl, Br and I. [0270] "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, Cl, Br and I.

[0271] "Halogen" represents chlorine, fluorine, bromine or iodine.

[0272] "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 Ci-Ci2alkyl, optionally substituted C₃-Ci₂cycloalkyl, optionally substituted C₆-Ci₈aryl, and optionally substituted C_rCi₈heteroaryl. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. Examples of heteroalkyl also include hydroxyCi-C₆alkyl, Ci-CealkyloxyCrCβalkyl, aminoCi-C₆alkyl, CrC₆alkylaminoCi-C₆alkyl, and di(Ci-C₆alkyl)aminoCi-C₆alkyl. The group may be a terminal group or a bridging group.

[0273] "Heteroalkyloxy" refers to a 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.

[0274] "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, tetrazole, indole, isoindole, 1 H- indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-, 3- or 4- pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1-, 3-, A-, or 5- isoquinolinyl 1-, 2-, or 3- indolyl, and 2-, or 3-thienyl. A heteroaryl group is typically a C_rCi8 heteroaryl group. The group may be a terminal group or a bridging group.

[0275] "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.

[0276] "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.

[0277] "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.

[0278] "Heteroaryloxy" refers to a heteroaryl-O- group in which the heteroaryl is as defined herein. Preferably the heteroaryloxy is a C_rCi₈heteroaryloxy. 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.

[0279] "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 heterocycloalkyl, heterocycloalkenyl and heteroaryl.

[0280] "Heterocycloalkenyl" refers to a heterocycloalkyl group as defined herein but containing at least one double bond. A heterocycloalkenyl group typically is a C2- C₁₂ heterocycloalkenyl group. The group may be a terminal group or a bridging group. [0281] "Heterocycloalkyl" 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 heterocycloalkyl 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.

[0282] "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.

[0283] "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.

[0284] "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.

[0285] "Heterocycloalkyloxy" refers to a heterocycloalkyl-O- group in which the heterocycloalkyl is as defined herein. Preferably the heterocycloalkyloxy is a Ci- Cβheterocycloalkyloxy. 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. [0286] "Heterocycloalkenyloxy" refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is as defined herein. Preferably the Heterocycloalkenyloxy is a Cr 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.

[0287] "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 C_nH(2n+i-χ)(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.

[0288] "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.

[0289] "Sulfinyl" means an R-S(=O)- group in which the R group may be OH, 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 sulfur atom.

[0290] "Sulfinylamino" means an R-S(=O)-NH- group in which the R group may be OH, 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.

[0291] "Sulfonyl" means an R-S(O)₂- group in which the R group may be OH, 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 sulfur atom. [0292] "Sulfonylamino" means an R-S(=O)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.

[0293] It is understood that included in the family of compounds of Formula (1) 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.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] "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, maleates, methylene-bis-β-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).

[0298] 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.

[0299] 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. Many kinases have isoforms that arise from transcript variation. Other functional equivalents include kinases having altered post-translational modification such as glycosylation.

[0300] Specific compounds of the invention include the following:

[0301 ] or a pharmaceutically acceptable salt, N-oxide or prodrug thereof.

[0302] The compounds of the invention have the ability to inhibit the activity of certain protein kinases. The ability to inhibit kinase activity may be a result of the compounds of the invention 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.

[0303] The compounds may have activity against PI3 protein kinases or a fragment or a complex or a functional equivalent thereof.

[0304] The compounds may have activity against certain serine/threonine kinases such as mTOR or a fragment or complex or functional equivalent thereof.

[0305] 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 of the invention 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. [0306] Accordingly the compounds of the invention 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.

[0307] The compounds disclosed have the ability to be used in the treatment of proliferative disorders. An example of such a disorder is cancer. It is anticipated that the compounds will have the ability to treat both solid and liquid tumors. In some embodiments the cancers that may be treated by compounds of the present invention include solid tumors and hematological cancers.

[0308] As used herein, the term "cancer" is a general term intended to encompass the vast number of conditions that are characterized by uncontrolled abnormal growth of cells. 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.

[0309] 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 and hyperproliferative conditions such as psoriasis and restenosis; 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. Compounds of this invention may also be used to treat pre-cancer conditions or hyperplasia including familial adenomatous polyposis, colonic adenomatous polyps, myeloid dysplasia, endometrial dysplasia, endometrial hyperplasia with atypia, cervical dysplasia, vaginal intraepithelial neoplasia, benign prostatic hyperplasia, papillomas of the larynx, actinic and solar keratosis, seborrheic keratosis and keratoacanthoma.

[0310] It is also anticipated that the compounds of the invention will be useful in treating autoimmune or inflammatory diseases or diseases supported by excessive neovascularisation. Diseases that have been attributed with some degree of autoimmune etiology, or that involve pathological inflammatory and neovascularization responses, include, but are not limited to, the following: acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophilia, cutaneous T-cell lymphoma, dermatitis erythrema multiforme, dermatomyositis, diabetic retinopathy, Dressler's syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, macular degeneration, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage- Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter's syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome and Wegener's granulomatosis.

[0311] The compounds of the invention 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 symptomology of the condition. The compounds of the invention may also be used in the preparation of a medicament for the treatment or prevention of a kinase-related disorder.

[0312] Administration of compounds within 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.

[0313] In using the compounds of the invention 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, 19^th edition, Mack Publishing Co. (1995) for further information.

[0314] The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. The compounds of the invention, 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.

[0315] 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 the present invention provides 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.

[0316] The invention in other embodiments provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. 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.

[0317] The compounds of the invention 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 of the invention may be administered sequentially or simultaneously with the other drug(s).

[0318] In addition to being able to be administered in combination with one or more additional drugs, the compounds of the invention 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 of the invention 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.

[0319] Pharmaceutical compositions of this invention 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. [0320] 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.

[0321] 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.

[0322] 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.

[0323] 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 poly(ethylene glycol)s, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [0324] 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.

[0325] 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.

[0326] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0327] 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, poly(ethylene glycol)s and fatty acid esters of sorbitan, and mixtures thereof.

[0328] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0329] 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. [0330] 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.

[0331] 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.

[0332] 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.

[0333] 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

[0334] 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, 3^rd 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.

[0335] Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.

GENERAL SYNTHETIC SCHEME [0336] A wide range of trisubstituted triazines can be prepared in a straightforward three-step procedure starting from cyanuric chloride i which is commercially available from a number of sources. The scheme 1 below outlines the general synthetic procedure used although it should be noted that the sequence of addition of the three substituents can be altered if required. Careful control of reaction conditions during steps 1 and 2 is necessary so as to ensure the preferential addition of only one substituent in each case thereby yielding the desired intermediates.

[0337] A typical procedure involves initial reaction of morpholine with a slight excess of cyanuric chloride in a non-nucleophilic solvent such as dichloromethane in the presence of a suitable base. The base may be a non-reactive tertiary amine or an appropriate inorganic salt such as sodium carbonate. Although the mono addition product predominates small quantities of 2-chloro-4,6-di-morpholin-4-yl-[1 ,3,5]triazine, resulting from the addition of two molecules of morpholine, are generally formed but can be efficiently removed during purification in the final steps. Intermediate ii is then treated with a nucleophilic nitrogen containing heterocycle in the presence of a base such as a tertiary amine or sodium hydride. Purification by chromatography at this stage will yield a very pure intermediate iii for the final palladium catalysed Suzuki coupling reaction. The boronic acids and esters employed were generally commercially available or could be prepared in a straightforward manner using procedures known to one versed in the art. In certain circumstances the substituents on the rings of the compound(s) of formula (I) produced by this procedure were further elaborated using standard techniques to arrive at other members of the series.

Scheme 1

Step 3.

1 ArB(OR)₂

General procedure for the preparation of triazines of formula (I)

[0338] Step i: Synthesis of 2,4-Dichloro-6-morpholin-4-yl-[1,3,5]triazine (ii)

[0339] A solution of diisopropylethylamine (0.43ml_, 2.44mmol, 0.9eq) and morpholine (0.21 mL, 2.44mmol, 0.9eq) in dichloromethane (5ml_) was added drop wise to a solution of cyanuric chloride (0.5Og, 2.71 mmol) in dichloromethane (1OmL) at O¹C. The mixture was allowed to slowly warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane, washed with a small quantity of aqueous 1 M HCI followed by water and dried over sodium sulfate. Removal of solvents under reduced pressure yielded 2,4-dichloro-6-morpholin-4-yl- [1 ,3,5]triazine as a white solid (0.52g) with a yield of 82%.

[0340] Step 2: Addition of heterocyclic nucleophile to 2,4-dichloro-6- morpholin-4-yl-[1 ,3,5]triazine

[0341] 2,4-Dichloro-6-morpholin-4-yl-[1 ,3,5]-triazine, K₂CO₃ (1-3eq) and the heterocyclic nucleophile were taken up in dioxane (ca.0.2M). The reaction was heated at between 85⁰C and 95⁰C overnight. The reaction mixture was cooled to room temperature, filtered, and concentrated under vacuum. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate as eluent. Product isolated in a yield of 45-80%.

[0342] Step 3: Suzuki coupling

[0343] Chlorotriazine iii, the boronic acid or ester (1-1.3eq) and potassium carbonate (1.8-3eq) were taken up in a degassed mixture of dioxane (1OmL) and water (4:1 , 0.01-0.06M) under an atmosphere of nitrogen. 1 ,1 '- Bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (10mol%) was added and the resulting mixture heated at 50-80¹C for between 3 and 8 hours. 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 3x50 ml portions of ethyl acetate. The combined ethyl acetate layers were washed once with brine solution (25ml). The organics were dried over sodium sulfate and the solvents removed under vacuum to give the crude product. The product was purified by chromatography on a preparative HPLC column to give the desired product in a yield of 20-80%.

Representative procedures for the preparation of compounds of formula (I)

[0344] The detailed procedures below serve as examples of how the compounds of formula (I) may be prepared using the general procedure detailed above or minor variations thereof.

[0345] In most cases the heterocyclic nucleophile used in step 2 and the boronic acid or ester used in step 3 were commercially available. However, in some cases these were prepared and representative examples are also detailed below.

[0346] Example 1 (Compound 4)

[0347] Synthesis of 2-Chloro-4-(2-methyl-imidazol-1 -yl)-6-morpholin-4-yl- [1 ,3,5]triazine

[0348] 2,4-Dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.85g, 7.87mmol) and 2- methylimidazole (0.35g, 4.26mmol) were dissolved in acetonitrile (5OmL). The solution was cooled to O¹C and triethylamine (1.65m L, 11.81 mmol) added slowly. After 15 minutes an additional portion of 2-methylimidazole (0.3Og, 3.65mmol) was added and the reaction mixture slowly allowed to warm to room temperature. After 2 hours the solvents were removed under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate, 1 :1 to 1 :3) to yield the desired product as a white solid (1.28g) with a yield of 58%.

[0349] Synthesis of 3-[4-(2-Methyl-imidazol-1-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2- yl]-phenol (4)

[0350] 2-Chloro-4-(2-methyl-imidazol-1 -yl)-6-morpholin-4-yl-[1 ,3,5]triazine (135.9mg, 0.4841 mmol), 3-hydroxyphenylboronic acid (66.8mg, 0.4841 mmol, 1eq) and potassium carbonate (200.7mg, 1.4523mmol, 3eq) were taken up in a degassed mixture of dioxane (1 OmL) and water (2.5ml_) under an atmosphere of nitrogen. 1 ,1'- Bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (40mg, 10mol%) was added and the resulting mixture heated at 5OO for 3h. 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 3x50 ml portions of ethylacetate. The combined ethyl acetate layers were washed once with brine solution (25ml). The organics were dried over sodium sulfate and the solvents removed under vacuum to give the crude product. The product was purified by chromatography on a preparative HPLC column to give the desired product 4 (42mg) with a yield of 27%. 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (s,1 H), 8.39 (s,1 H), 7.94 (d,1 H), 7.91 (s,1 H), 7.46 (bs,1 H), 7.38 (t,1 H), 7.06 (d,1 H), 4.04 (m,2H), 3.91 (m,2H), 3.7 (m,4H), 2.98 (s,3H); MS (m/z): 518 [MH]⁺ 339.

[0351] Example 2 (Compound 11)

[0352] Synthesis of 4-[4-(2- Methyl-benzimidazol-1-yl-[1 , 3, 5] triazin-2-yl]-pyridin-

2-ol (11)

[0353] 1-[4-(2-Fluoro-pyridin-4-yl)-6-morpholin-4-yl-[1 ₎3,5]triazin-2-yl]-2-methyl-1A7- benzimidazole was prepared using the standard three step procedure (starting from commercially available reagents) described above for other triazines such as 3-[4-(2- methyl-imidazol-1-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-phenol. To 1 -[4-(2-fluoro- pyridin-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-2-methyl-1 H-benzimidazole (5mg, 0.0127mmol) was added 2ml of 6N hydrochloric acid. The reaction mixture was heated at 8O⁰C for 1Oh. The reaction was followed by LCMS for the formation of the product. The crude reaction upon HPLC purification yielded 4-[4-(2-methyl- benzimidazol-1-yl-[1 , 3, 5] triazin-2-yl]-pyridin-2-ol 11 (3.2mg), 1 H NMR (DMSO-d6) δ 8.34 (d, 1 H), 7.7 (d, 1 H), 7.61 (d, 1 H), 7.48 (m, 3H), 7.06 (d, 1 H), 4.04 (m, 2H), 3.93 (m, 2H), 3.78 (m, 4H), 3.0 (s, 3H); MS (m/z): 390.43[MH⁺].

[0354] Example 3 (Compound 39)

[0355] Synthesis of 2-Chloro-4-(3-methyl-pyrazol-1-yl)-6-morpholin-4-yl- [1 ,3,5]triazine

[0356] 2,4-Dichloro-6-morpholin-4-yl-[1 ,3,5]triazine (1.0g, 4.254mmol) and 3- methyl-1 H-pyrazole (0.384g, 4.679mmol) were dissolved in acetone (1OmL). To the solution was added potassium carbonate (1.469g, 10.635mmol) slowly and the reaction was left stirring. After 72h the solvent was filtered and the solvents were removed under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate) to yield the desired product as a white solid (0.50Og).

[0357] Synthesis of 4-[4-(3-Methyl-pyrazol-1-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2- yl]-1 H-indole (39)

39

[0358] 2-Chloro-4-(3-methyl-pyrazol-1-yl)-6-morpholin-4-yl-[1 ,3,5]triazine (50.0mg, 0.178 mmol), 4-indoleboronic acid (35mg, 0.213mmol) and potassium carbonate (61 mg, 0.445mmol, 3eq) were taken up in a degassed mixture of dioxane (1OmL) and water (2.5ml_) under an atmosphere of nitrogen. 1 ,1 '- Bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (14mg, 10mol%) was added and the resulting mixture heated at 50¹C for 3h. 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 3x50 ml portions of ethyl acetate. The combined ethyl acetate layers were washed once with brine solution (25ml). The organics were dried over sodium sulfate and the solvents removed under vacuum to give the crude product. The product was purified by chromatography on a preparative HPLC column to give the desired product 4-[4-(3- methyl-pyrazol-1-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H-indole 39 (25mg). 1H NMR (400 MHz, DMSO-d6) δ 11.42 (bs, 1 H), 8.71 (d, 1 H), 8.33 (d, 1 H), 7.69 (d, 1H), 7.54 (t, 1H), 7.44 (m, 1H), 7.26 (t, 1 H), 6.47 (d, 1H), 3.76-4.09 (m, 8H), 2.33 (s, 3H).; [MH]⁺ 362.22. [0359] Examples 4 and 5 (Compounds 44 and 46)

[0360] ' Synthesis of 4-[4-Morpholin-4-yl-6-(4-pyrrolidin-1-ylmethyl-imidazol-1-yl)- [1 ,3,5]triazin-2-yl]-1 H-indole (46) and {1 -[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5] tιϊazin-2-yl]-1 H-imidazol-4-yl}-methanoI (44)

[0361] 1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H-imidazole-4- carbaldehyde was prepared using the standard three step procedure (starting from commercially available reagents) described above for other triazines such as 3-[4-(2- methyl-imidazol-1 -yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-phenol. 1 -[4-(1 H-lndol-4-yl)- 6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H-imidazole-4-carbaldehyde (42mg, 0.112mmol) and pyrrolidine (50μL, 0.60mmol) were stirred in dichloromethane (4mL) for 40 minutes. Sodium triacetoxyborohydride (14mg, 0.224mmol) and methanol (1 mL) were added and the reaction mixture was allowed to stir at room temperature. After 4 hours, the solvents were removed under reduced pressure. The crude products were purified by chromatography on a preparative HPLC column to give the desired products 44 and 46 (10mg and 4mg).

[0362] 4-[4-Morpholin-4-yl-6-(4-pyrrolidin-1-ylmethyl-imidazol-1-yl)-[1 ,3,5]triazin-2- yl]-1 H-indole (46): 1 H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1 H), 10.08 (brs, 1 H), 8.90 (s, 1 H), 8.37 (d,1 H), 8.31 (s, 1 H), 7.72 (d, 1 H), 7.58 (t, 1 H), 7.36 (t, 1 H), 7.27 (t, 1 H), 4.38 (s, 2H), 4.07 (brs, 2H), 3.99 (brs, 2H), 3.80 - 3.76 (m, 4H), 3.22 - 3.19 (m, 2H), 2.03 - 2.00 (m, 2H), 1.91 - 1.86 (m, 2H); MS (m/z): 431.23 [MH]⁺.

[0363] {1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H-imidazol-4-yl}- methanol (44): 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1 H), 8.94 (brs, 1 H), 8.15 (d,1 H), 7.69 (d, 1 H), 7.43 - 7.41 (m, 1 H), 7.34 - 7.29 (m, 2H), 7.21 - 7.17 (m, 1 H), 4.94 (S, 2H), 4.18 (brs, 2H), 3.98 (brs, 2H), 3.88 - 3.86 (m, 4H); MS (m/z): 378.25 [MH]⁺.

[0364] Example 6 (Compound 64)

[0365] Synthesis of 3-{1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H- imidazol-4-yl}-acrylic acid methyl ester (64)

[0366] 1-(4-Chloro-6-morpholino-1 ,3,5-triazin-2-yl)-1H-imidazole-4-carbaldehyde was prepared using the standard procedure described above. 1-(4-Chloro-6- morpholino-1,3,5-triazin-2-yl)-1/7-imidazole-4-carbaldehyde (58mg, 0.2mmol) and methyl(triphenyl phosphoranylidene)-acetate (70.3mg, 0.3mmol) were then dissolved in dioxane (5mL). The reaction was heated to 9O⁰C and stirred overnight. The reaction mixture was cooled to room temperature, and concentrated under vacuum. The residue was purified by flash chromatography to give the trans-product (49 mg) with a yield of 70%. This was converted to 3-{1-[4-(1H-lndol-4-yl)-6-morpholin-4-yl- [1 ,3,5]triazin-2-yl]-1 H-imidazol-4-yl}-acrylic acid methyl ester (64) using the standard coupling procedure as described for methyl-pyrazol-1-yl)-6-morpholin-4-yl- [1 ,3,5]triazin-2-yl]-1 H-indole (39) above. 1 H NMR (DMSO-d6) δ 11.49 (s, 1 H), 8.86 (s, 1 H), 8.56 (s, 1 H), 8.39 (dd, 1 H), 7.70 (m, 2H), 7.57 (t, 1 H), 7.36 (d, 1 H), 7.27 (t, 1 H), 6.54 (d, 1 H), 4.06 (m, 4H), 3.77 (m, 4H), 3.32 (s, 3H); MS(m/z): 432.16 [MH⁺].

[0367] Examples 7 and 8 (Compounds 65 and 67) [0368] Synthesis of 3-{1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H- imidazo!-4-yl}-acrylonitrile (67) and 3-{1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl- [1 ,3,5]triazin-2-yl]-1 H-imidazol-4-yl}-acrylonitrile (65)

[0369] 1 -(4-Chloro-6-morpholino-1 ,3,5-triazin-2-yl)-1 H-imidazole-4-carbaldehyde (70mg, 0.24mmol) and (triphenylphosphoranylidene)-acetonitrile (93mg, 0.31 mmol) were dissolved in dioxane (7mL). The reaction was heated to 9O⁰C and stirred overnight. The reaction mixture was cooled to room temperature, and concentrated under vacuum. The residue was purified by flash chromatography to give the (E)- product (18 mg) with a yield of 24% and (Z)-product (33mg) with a yield of 44%. The geometric isomers were then taken forward separately using the standard coupling procedure as described for methyl-pyrazol-1-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]- 1H-indole (39) above to furnish 3-{1-[4-(1H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin- 2-yl]-1 H-imidazol-4-yl}-acrylonitrile (67) and 3-{1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl- [1 ,3,5]triazin-2-yl]-1 H-imidazol-4-yl}-acrylonitrile (65).

[0370] 3-{1 -[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H-imidazol-4-yl}- acrylonitrile (67): 1 H NMR (DMSO-d6) δ 11.52 (s, 1 H), 8.90 (s, 1 H), 8.49 (s, 1 H), 8.40 (d, 1 H), 7.73 (d, 1 H), 7.61 (m, 2H), 7.38 (s, 1 H), 7.30 (t, 1 H), 6.32 (d, 1 H), 4.08 (m, 4H), 3.80 (m, 4H) ; MS(m/z): 399.11 [MH⁺].

[0371] 3-{1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H-imidazol-4-yl}- acrylonitrile (65): 1 H NMR (DMSO-d6) δ 11.49 (s, 1 H), 8.92 (s, 1 H), 8.59 (s, 1 H), 8.36 (d, 1H), 7.70 (d, 1 H), 7.56 (t, 1H), 7.30 (m, 3H), 5.71 (d, 1H), 4.08 (m, 4H), 3.78 (m, 4H) ; MS(m/z): 399.15 [MH⁺].

[0372] Example 9 (Compound 68) [0373] Synthesis of 4-[4-(4-ethyl-imidazol-1-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl] -1H-indole (68)

[0374] 4-[4-(4-Vinyl-imidazol-1-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1H-indole (40mg, 0.11 mmol) and 10% palladium on carbon (6mg) were taken up in ethyl acetate( 6mL) under an atmosphere of hydrogen. The reaction mixture was stirred at room temperature overnight, filtered, and concentrated under vacuum. The residue was purified by flash chromatography to give the product 68 (40 mg) with a yield of 100%.1 H NMR (DMSO-d6) δ 11.46 (s, 1H), 8.67 (s, 1H), 8.34 (d, 1H), 7.76 (s, 1H), 7.68 (d, 1H), 7.56 (t, 2H), 7.34 (s, 1H), 7.27 (t, 1 H), 4.03 (m, 4H), 3.76 (m, 4H), 2.57 (q, 2H), 1.23 (t, 3H); MS(m/z): 376.14 [MH⁺].

[0375] Example 10 (Compound 76)

[0376] Synthesis of 3-{1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H- imidazol-2-yl}-acrylonitrile (76)

76 [0377] 1 -(4-Chloro-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl)-1 H-imidazole-2- carbaldehyde was prepared using the standard procedure described above. 1-(4- Chloro-6-morpholino-1 ,3,5-triazin-2-yl)-1 /-/-imidazole-2-carbaldehyde (200mg,

0.68mmol) and triphenylphosphoranylidene)-acetonitrile (301 mg, LOmmol) were then dissolved in dioxane (1 OmL). The reaction was heated to 95⁰C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography to give the trans-product (65.0 mg) with a yield of 30%. This was converted to 3-{1-[4-(1 H-lndol- 4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H-imidazol-2-yl}-acrylonitrile (76) using the standard coupling procedure as described for methyl-pyrazol-1-yl)-6-morpholin-4-yl- [1 ,3,5]triazin-2-yl]-1 H-indole (39) above. 1 H NMR (DMSO-d6) δ 11.49 (s, 1 H), 8.52 (d, 1 H), 8.26 (m, 2H), 7.72 (d, 1 H), 7.57 (t, 1 H), 7.30 (m, 3H), 6.53 (d, 1 H), 4.08 (m, 2H), 3.92 (m, 2H), 3.78 (m, 4H) ; MS(m/z): 399.16 [MH⁺].

[0378] Example 11 (Compound 81)

[0379] Synthesis of 1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-2- trifluoro methyl-1 H-benzoimidazol-5-ylamine (81)

81

[0380] {1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-2-trifluoromethyl- 1 H-benzoimidazol-5-yl}-carbamic acid førf-butyl ester was prepared using the standard three step procedure (starting from commercially available reagents) described above for other triazines such as 3-[4-(2-methyl-imidazol-1-yl)-6-morpholin- 4-yl-[1 ,3,5]triazin-2-yl]-phenol. To a stirred solution of {1-[4-(1 H-indol-4-yl)-6- morpholin^-yl-CI .S.SJtriazin^-yll^-trifluoromethyl-I H-benzoimidazol-δ-ylJ-carbamic acid terf-butyl ester (0.047 mmol) in 1 mL of DCM was added 200μl_ of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 2 hrs. The reaction can be monitored using LC/MS. The solvents were removed under vacuum and the residue purified by reverse phase preparative HPLC to give the desired product 81 (5.58mg) with 25% yield. 1 H NMR (400 MHz, CDCI₃) δ 8.98 (bs, 1 H), 8.55 (d, 1 H), 8.41 (m, 1 H), 7.80 (d, 1 H), 7.65 (d, 1 H), 7.51 (m, 1 H), 7.38 (m, 2H), 7.10 (dd, 1 H), 6.69 (bs, 1 H), 4.17 (m, 4H), 3.91 (t, 4H), 1.53 (bs, 9H).

[0381] Example 12 (Compound 91)

[0382] Synthesis of 4-[4-(2-ethyl-imidazol-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]- 1 H-pyrrolo[2,3-b]pyridine (91)

91

[0383] 2-Chloro-4-(2-ethyl-1 H-imidazol-1-yl)-6-morpholino-1 ,3,5-triazine (40.0mg, 0.14mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridine (44mg, 0.18 mmol), 1 ,1 '-Bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (8.6mg, 8mol%) and potassium phosphate (85mg, 0.42mmol) were taken up in a degassed mixture of dioxane (5ml_) and water (0.7ml_) under an atmosphere of nitrogen. The resulting mixture was heated at 90¹C for 3h. 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 3x50 ml portions of ethyl acetate. The combined ethyl acetate layers were washed with water, brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on a preparative HPLC column to give the desired product 4-(4-(2-ethyl-1 H-imidazol-1-yl)-6-morpholino-1 ,3,5-triazin-2-yl)-1 H- pyrrolo[2,3-b]pyridine 91 (40mg). 1H NMR (DMSO-d6) δ 12.09 (s, 1H), 8.45 (m, 2H), 8.11 (d, 1 H), 7.72 (d, 2H), 7.21 (s, 1 H), 4.09 (m, 2H), 3.93 (m, 2H), 3.78 (m, 4H), 3.50 (q, 2H), 1.40 (t, 3H); MS(m/z): 377.20 [MH⁺]. [0384] Example 13 (Compound 102)

[0385] Synthesis of 1-(4-Chloro-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl)-1 H-indoIe-2- carboxylic acid ethyl ester

[0386] Ethyl 2-indolecarboxylate (0.75g, 3.96mmol) was dissolved in degassed tetrahydrofuran (25mL) and sodium hydride (60% in mineral oil, 0.3Og, 7.5mmol) was added portion-wise. The solution was allowed to stir at room temperature for 30 minutes. 2,4-Dichloro-6-morpholin-4-yl-[1 ,3,5]triazine (1.0g, 4.25mmol) dissolved in minimum THF (3mL) was added and the resulting mixture heated at 80¹C for 5 hours. 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 3x30 ml portions of ethyl acetate. The combined ethyl acetate layers were washed once with brine solution (25ml). The organics were dried over sodium sulfate and the solvents removed under vacuum to give the crude product. The product was purified by column chromatography (hexane: ethyl acetate, 25:1 to 15:1 ) to give the desired product (0.52g) with a yield of 32%. MS (m/z): 388.08 [MH]⁺.

[0387] Synthesis of 1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H- indole-2-carboxylic acid ethyl ester (102)

[0388] 1-(4-Chloro-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl)-1 H-indole-2-carboxylic acid ethyl ester (115mg, 0.297mmol), 4-indoleboronic acid (57mg, 0.354mmol) and potassium carbonate (74mg, 0.534mmol) were taken up in a degassed mixture of 1 ,4- dioxane (5mL) under an atmosphere of nitrogen. 1 ,1 '- Bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (12mg, 10mol%) was added and the resulting mixture heated at 80O for 8 hours. 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 3x20 ml portions of ethyl acetate. The combined ethyl acetate layers were washed once with brine solution (15ml). The organics were dried over sodium sulfate and the solvents removed under vacuum to give the crude product. The product was purified by column chromatography (hexane: ethyl acetate, 20:1 to 4:1) to give the desired product 102 (102mg) with a yield of 73%. 1 H NMR (400 MHz, CDCI₃) δ 8.51 (d, 1 H), 8.43 (S, 1 H), 8.41 (d, 1H), 7.67 (d, 1H)₁ 7.60 (d, 1 H), 7.54 (t, 1 H), 7.43 - 7.39 (m, 1 H), 7.36 - 7.35 (m, 1 H), 7.33 - 7.29 (m, 1 H), 7.27 (s, 1 H), 7.26 (s, 1 H), 4.28 (q, 2H), 4.15 (brs, 2H), 3.97 (brs, 2H), 3.85 (brs, 4H), 1.23 (t, 3H); MS (m/z): 469.17 [MH]⁺.

[0389] Example 14 (Compound 113) [0390] Synthesis of 1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H- indole-2-carboxylic acid (113)

113

[0391] 1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H-indole-2- carboxylic acid ethyl ester (300mg, 0.640mmol) was dissolved in tetrahydrofuran (5mL), and Lithium hydroxide (100mg, 4.175mmol) dissolved in minimum water (1 mL) was added. The resulting mixture was heated at 70"C for 3 hours. The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure. The crude product was purified by chromatography on a preparative HPLC column to give the desired product 113 (220mg) with a yield of 78%. 1 H NMR (400 MHz, CDCI₃) 8 9.54 (s, 1 H), 8.56 (d, 1 H), 8.33 (d, 1 H), 7.68 (d, 1 H), 7.65 (d, 1 H), 7.45 - 7.39 (m, 4H), 7.27 - 7.22 (m, 1 H), 4.17 (brs, 2H), 4.02 (brs, 2H), 3.87 (brs, 4H); MS (m/z): 441.20 [MH]⁺.

[0392] Example 15 (Compound 117)

[0393] Synthesis of 1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H- indole-2-carboxylic acid cyclopropylamide (117)

117

[0394] 1-[4-(1 H-lndol-4-yl)-6-morpholin-4-yl-[1 ,3,5]triazin-2-yl]-1 H-indole-2- carboxylic acid (20mg, 0.045mmol) and cyclopropylamine (5 μL, 0.068mmol) were dissolved in tetrahydrofuran (5mL). 1-Hydroxybenzotriazole (11 mg, 0.082mmol) and

N-(3-dimethylaminopropyl)-Λ/'-ethylcarbodimide hydrochloride (16mg, 0.082mmol) were added subsequently, and the resulting mixture was allowed to stir at room temperature. After 2 hours, the solvents were removed under reduced pressure. The crude product was purified by chromatography on a preparative HPLC column to give the desired product 117 (5mg) with a yield of 23%. 1H NMR (400 MHz, CD₃OD) δ

8.62 (d, 1 H), 8.36 (d, 1 H), 7.65 - 7.63 (m, 1H), 7.45 - 7.44 (m, 1 H), 7.41 - 7.36 (m,

2H), 7.29 - 7.23 (m, 2H), 6.97 (s, 1 H), 4.13 (brs, 2H), 4.00 (brs, 2H), 3.85 - 3.83 (m,

4H), 2.95 - 2.90 (m, 1H), 0.80 - 0.77 (m, 2H), 0.66 - 0.64 (m, 2H); MS (m/z): 480.26 [MH]⁺.

[0395] Procedures for the preparation of heterocyclic nucleophiles

[0396] Synthesis of (2-Trifluoromethyl-1 H-benzoimidazol-5-yl)-carbamic acid tert- butyl ester

[0397] To a stirred solution of 2-trifluoromethyl-1 H-benzoimidazol-5-ylamine (2.49mmol) in 8.3mL of DCM was added di-ferf-butyl dicarbonate (2.49mmol) and triethylamine (2.49mmol). The reaction mixture was stirred at room temperature for 2Oh. The reaction can be monitored using either TLC or LC/MS. The reaction mixture was evaporated to dryness and was purified on the silica gel column (10-50% ethyl acetate in hexane, step-gradient), to give the desired compound in a yield of 79%.

[0398] Synthesis of 4-Methylsulfanyl-1 H-imidazole

[0399] 4-lodo-1tf-imidazole (2.8g, 14.6mmol) and trityl chloride (5.Og, 20.5mmol) were dissolved in Λ/,Λ/-dimethylacetamide (45mL). The solution was cooled to 0"C and triethylamine (4mL, 29.2mmol) added slowly. The reaction mixture was slowly warmed to room temperature. After 48 hours the solution was poured to water

(15OmL). The solid was filtered, washed with water, hexane and dried to give a white solid (5.7g) with a yield of 90%. The product was pure enough for the next step reaction without further purification.

[0400] To a solution of 4-iodo-1-trityl-1 H-imidazole (424mg, I .Ommol) in dichloromethane (5mL) was added 3.0 M ethylmagnesium bromide solution in diethyl ether (0.35mL, 1.1mmol) under argon. The mixture was stirred at room temperature for 30mins followed by the addition of 1 , 2-dimethyldisulfane (0.11 mL, 1.3mmol). The reaction was stirred at room temperature overnight, quenched with saturated aqueous NH₄CI solution and extracted with ethyl acetate (3 x 3OmL). The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography to give 4-(methylthio)-1 -trityl -1H-imidazole (150 mg) with a yield of 44%.

[0401] To a solution of 4-(methylthio)-1 -trityl -1H-imidazole (150 mg, 0.44mmol) in methanol (1OmL) was added acetic acid (1mL), and the reaction mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the product (44 mg) with a yield of 90%.

[0402] Synthesis of 4-Phenyl-1H-imidazole

[0403] 4-lodo-1H-imidazole (194mg, LOmmol), phenylboronic acid (158.5 mg, 1.3mmol), potassium carbonate (345mg, 2.5mmol) and Pd (PPh₃)₂Cl₂ (42 mg, 6%) were taken up in a degassed mixture of 1 ,4-dioxane (5mL) and water (0.8mL) under an atmosphere of nitrogen. The resulting mixture was heated at 90¹C for 3 hours. The reaction mixture was cooled to room temperature, and taken up in ethyl acetate and water. The organic phase was separated and the aqueous layer further extracted with 3x20 ml portions of ethyl acetate. The combined ethyl acetate layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography to give the product (112 mg) with a yield of 78%.

[0404] Synthesis of 4-Vinyl-1 H-imidazole

[0405] To a solution of methyltriphenylphosphonium bromide (557mg, 1.56mmol) in THF (8mL) was added 1.0 M NaHMDS solution in THF (1.56mL, 1.56mmol) under argon at O⁰C. The mixture was stirred at this temperature for 30mins followed by the addition of 1-trityl-1H-imidazole-4-carbaldehyde (440mg, 1.3mmol). The reaction was stirred at O⁰C to room temperature for 3 hours, quenched with saturated aqueous NH₄CI solution, extracted with ethyl acetate (3 x 3OmL). The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography to give 1-trityl-4-vinyl-1H-imidazole (374 mg) with a yield of 86%.

[0406] To a solution of 1-trityl-4-vinyl-1H-imidazole (374 mg, 1.1mmol) in methanol (1OmL) was added acetic acid (1mL), and the reaction mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature, and concentrated under vacuum. The residue was purified by flash chromatography to give 4-vinyl-1/-/- imidazole (55 mg) in a yield of 53%.

[0407] Synthesis of 2-Vinyl-1 H-imidazole

[0408] To a solution of methyltriphenylphosphonium bromide (920mg, 2.6mmol) in THF (13mL) was added 1.0 M NaHMDS solution in THF (2.8mL, 2.8mmol) under argon at O⁰C. The mixture was stirred at this temperature for 30mins followed by the addition of 1-trityl-1H-imidazole-2-carbaldehyde (660mg, 2.0mmol). The reaction was stirred at O⁰C to room temperature for 4 hours, quenched with saturated aqueous NH₄CI solution, extracted with ethyl acetate (3 x 5OmL). The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography to give 1-trityl-2-vinyl-1 H-imidazole (515 mg) in a yield of 77%.

[0409] To a solution of 1-trityl-2-vinyl-1 /-/-imidazole (515 mg, 1.5mmol) in methanol (1OmL) was added acetic acid (1mL), and the reaction mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography to give 2-vinyl- 1H-imidazole (145mg) in a quantitative yield. [0410] Synthesis of 3-(1 H-imidazol-2-yl)-propionitrile

[0411] i-Trityl-IW-imidazole-2-carbaldehyde (507mg, 1.5mmol) and triphenyl phosphoranylidene)-acetonitrile (542.3mg, 1.8mmol) were dissolved in dioxane (15mL). The reaction was heated to 85⁰C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography to give a mixture of (E) - and (Z) - 3-(1- trityl-1H-imidazole-2-yl)acrylonitrile (504mg) with a yield of 92.3%.

[0412] (E)-3-(1-trityl-1H-imidazole-2-yl)acrylonitrile, (Z)-3-(1-trityl-1 H-imidazole-2- yl)acrylo-nitrile (500mg, 1.38mmol) and 10% palladium on carbon (100mg) were taken up in THF (15ml_) under an atmosphere of hydrogen. The reaction mixture was stirred at room temperature for 48 hours, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give -(1-trityl-1H- imidazol-2-yl)propanenitrile (400 mg) with a yield of 80%.

[0413] To a solution of 3-(1-trityl-1H-imidazol-2-yl)propanenitrile (400 mg, 1.1 mmol) in methanol (1OmL) was added acetic acid (1 mL), and the reaction mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography to give 3-(1 H-imidazol-2-yl)-propionitrile (84mg) with a yield of 63%.

[0414] Synthesis of 2-(2-Chloro-benzyl)-1H-imidazole

[0415] To a solution of (methoxymethyl)triphenylphophonium chloride (4.29g, 12.5mmol) in THF (3OmL) was added 1.0 M NaHMDS solution in THF (12.5mL, 12.5mmol) under argon at O⁰C. The mixture was stirred at this temperature for 20mins followed by the addition of 2-chlorobenzaldehyde (1.4g, lOmmol). The reaction was stirred at O⁰C to room temperature for 2 hours, quenched with saturated aqueous NH₄CI solution, extracted with ethyl acetate (3 x 6OmL). The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography to give 1-chloro-2-(2-methoxyvinyl)benzene (1.51g) with a yield of 90%.

[0416] To a solution of 1-chloro-2-(2-methoxyvinyl)benzene (1.51g, 9mmol) in acetone (45mL) and water (5mL) was added concentrated hydrochloric acid (0.1 mL), and heated at 65⁰C for 1 hour. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO₃ solution, and concentrated under reduced pressure. The residue was taken up in ethyl acetate (15OmL), washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography to give 2-(2- chlorophenyl)acetaldehyde (1.Og) with a yield of 71 %.

[0417] To a solution of 2-(2-chlorophenyl)acetaldehyde (1.0g, 6.5mmol), glyoxal (1.1 mL, 9.8mmol) in methanol (3OmL) was added 30% aqueous ammonia solution (3.7mL) at O⁰C. The reaction was stirred for 30mins at O⁰C, then warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was taken up in ethyl acetate (15OmL), washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography to give 2-(2-chloro- benzyl)-1 W-imidazole (690mg) with a yield of 54%.

[0418] Synthesis of 2-Ethyl-4-ethynyl-1 H-imidazole

[0419] 2-Ethyl-4-iodo-1H-imidazole (666mg, 3.0mmol), Pd (PPh₃)₄ (200mg, 6%), copper (I) iodide (57mg, 10mol%) were taken up in a degassed DMF (13ml_) under an atmosphere of nitrogen. Triethylamine (1.3ml_, 9mmol) and ethynyltrimethylsilane (1.OmL, 7.5mmol) were added and the resulting mixture heated at 80O for 4 hours.

The reaction mixture was cooled to room temperature and filtered through a thin pad of Celite (eluting with ethyl acetate). The eluent was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography to give 2-ethyl-4-(2-(trimethylsiyl)ethynyl)-1H- imidazole (410mg) with a yield of 71%.

[0420] To a solution of 2-ethyl-4-(2-(trimethylsiyl)ethynyl)-1H-imidazole (410 mg, 2.14mmol) in methanol (3OmL) was added K₂CO₃ (1.38g, lOmmol). The reaction mixture was stirred at room temperature for 5 hours, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 2-ethyl- 4-ethynyl-1H-imidazole (234mg) with a yield of 91 %.

[0421] Synthesis of 2,4,-Diethyl-1H-imidazole

[0422] 2-Ethyl-4-ethynyl-1 H-imidazole (100mg, 0.83mmol) and 10% palladium on carbon (20mg) were taken up in THF (15mL) under an atmosphere of hydrogen. The reaction mixture was stirred at room temperature for 48 hours, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give the product (54 mg) with a yield of 54%.

[0423] Synthesis of 2- (2-methyl-1 H-imidazol-4-ylethynyl)-pyridine

[0424] 2-Ethyl-4-iodo-1 H-imidazole (376mg, Urnmol), Pd (PPh₃)₄ (117mg, 6%), copper (I) iodide (32mg, 10mol%) and 2-ethynylpyridine (258mg, 2.5mmol) were taken up in a degassed DMF (8mL) under an atmosphere of argon. Triethylamine (0.65mL, 5mmol) was added and the resulting mixture heated at 80¹C for 4 hours. The reaction mixture was cooled to room temperature, filtered through a thin pad of Celite (eluting with ethyl acetate). The eluent was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography to give the product (195mg) with a yield of 60%.

[0425] Synthesis of 2-Ethyl-4-prop-1 -ynyl-1 H-imidazole

[0426] Stepi : 2-Ethyl-4-iodo-1-trityl-imidazole (2.32g, 5.0mmol), Pd(PPh₃)₄ (345mg, 6%), copper (I) iodide (96mg, 10mol%) were taken up in a degassed DMF (13ml_) under an atmosphere of nitrogen. Triethylamine (2.2mL, 15mmol) and ethynyltrimethylsilane (1.7mL, 12.5mmol) were added and the resulting mixture heated at 80O for 5 hours. The reaction mixture wa s cooled to room temperature, filtered through a thin pad of Celite (eluting with ethyl acetate). The eluent was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography to give 2-ethyl-4-(2- (trimethylsiyl)ethynyl)-1-trityl-imidazole (1.48g) with a yield of 68%.

[0427] To a solution of 2-ethyl-4-(2-(trimethylsiyl)ethynyl)-1-trityl-imidazole (1.48g, 3.4 mmol) in methanol (3OmL) and THF (2OmL) was added K₂CO₃ (3.Og, 20mmol). The reaction mixture was stirred at room temperature for 8 hours, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 2-ethyl-4-ethynyl-1-trityl-imidazole (1.1g) with a yield of 89%. To a solution of 2-ethyl-4-ethynyl-1-trityl-imidazole (1.1g, 3.0mmol) in THF (2OmL) was added 2.0 IvI solution of n-BuLi in hexane (1.75mL, 3.5mmol) at -40O slowly. The reaction mixture was stirred at -40¹C for 30min s followed by the addition of TMEDA (0.9mL, 6.0mmol) and stirred for another 15mins at -20¹C. Then methyl iodide (0.6mL, 12mmol) was added. The resulting mixture was warmed to room temperature and stirred for 2 hours, quenched with saturated aqueous NH₄CI solution, extracted with ethyl acetate (3 x 6OmL). The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography to give 2-ethyl-4- (prop-1 -ynyl)-1 -trityl-1 H-imidazole (0.95g) with a yield of 83%.

[0428] To a solution of 2-ethyl-4-(prop-1-ynyl)-1 -trityl-1 H-imidazole (470 mg, 1.25mmol) in methanol (15mL) was added acetic acid (1.3mL), and the reaction was refluxed for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography to give 2-ethyl-4-prop-1-ynyl-1 H-imidazole (163mg) in a yield of 97%.

[0429] Synthesis of 2-Ethyl-4-propyl-1 H-imidazole

[0430] 2-Ethyl-4-(prop-1 -ynyl)-1 -trityl-1 /-/-imidazole (475 mg, 1.26mmol) and 10% palladium on carbon (50mg) were taken up in ethyl acetate (15ml_) under an atmosphere of hydrogen. The reaction mixture was stirred at room temperature for 48 hours, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 2-ethyl-4-propyl-1 -trityl-1 H-imidazole (440 mg) with a yield of 92.6 %.

[0431] To a solution of 2-ethyl-4-propyl-1 -trityl-1 H-imidazole (440 mg, 1.16mmol) in methanol (15mL) was added acetic acid (1.2mL), and the reaction was refluxed for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography to give 2- ethyl-4-propyl-1 H-imidazole (160mg) with a yield of 96%.

[0432] Procedures for the preparation of boronic acids and esters [0433] General procedure for the preparation of 4-substituted 5-bromopyrimidines and 4-substituted pyrimidine 5-boronic acid pinacol esters

R₁= H, CH₃, OCH₃ R₁= H, CH₃, OCH₃ RI= H, CH₃, OCH_{3 RI= H CH3 OCH3}

R₂= CI R₂= H R₂= H and R₃= Br R₂= H and R₃= Boronic acid ester

[0434] Stage A: 4-Chloro-6-methoxy-pyrimidin-2-ylamine (2.00, 12.58mmol) was dissolved in ethanol: ethyl acetate mixture (1 :1.3 ratios) to which was added di/sopropylethylamine (4.35ml, 25.2 mmol) and 10mol% of 10%Pd-C. The reaction mixture was stirred under a positive hydrogen pressure using a hydrogen balloon for 14h. TLC was used, to follow the completion of the reaction (solvent 1 :1 ; hexane: ethyl acetate). The reaction mixture was flushed with nitrogen and then filtered off the palladium carbon over a celite bed. The bed was washed thoroughly with ethyl acetate. The filtrate was dried over anhydrous Na₂SO₄. The solvents were evaporated under reduced pressure to get 4-Methoxy-pyrimidin-2-ylamine as a pure material (94%). This material was directly taken to the next stage without further purification. [0435] Stage B: 4-Methoxy-pyrimidin-2-ylamine (1.17g, 9.35mmol) was taken in chloroform (600ml) to which was added N-bromosuccinimide (1.67g, 9.35mmol). After stirring in the dark for 5h, the solution was added to dichloromethane (125ml) and 1N NaOH (65 ml). Upon mixing thoroughly, the layers were separated. The organic layer was separated, washed with saturated sodium chloride solution (75ml), dried over anhydrous sodium sulphate and filtered. The organic solvents were removed under reduced pressure to yield 1.72 (90%) of 5-bromo-4-methoxy- pyrimidin-2-yl-amine. This material was pure (HPLC and 1 H NMR) and did not need any further purification.

[0436] Stage C: To 5-Bromo-4-methoxy-pyrimidin-2-yl-amine (1.72g, 8.43mmol), potassium acetate (2.5g, 25.29mmol), bis(pinacolato)diborane (2.23g, 8.8mmol), Pd(dppf)CI₂ (0.365g, 0.42mmol) in anhydrous dioxane was heated at 115⁰C for 24h, under nitrogen atmosphere. The reaction mixture was cooled and the solvents were removed under reduced pressure. The residue was taken up in ethyl acetate and filtered through a bed of celite. The combined organics were dried, evaporated and purified over silica gel to get 4-methoxy-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2- ylamine (0.89g, 42%).

[0437] Synthesis of Methyl-[5-(4,4,5,5,-tetramethyl-[1 ,3,2]dioxaborolan-2-yl]amine:

[0438] Stage D: To 5-bromo-2-chloropyrimidine (2g, 10.34mmol) was added 1 M methylamine solution in THF (20ml). The contents were stirred at 6O⁰C for 6h after which TLC confirmed the absence of the reactant. The contents were allowed to cool down. The volatiles were evaporated under reduced pressure and the residue was subjected to flash chromatography (hexane/ethyl acetate) to get (5-bromo-pyrimidin- 2-yl)-methyl-amine (1.75g, 90%). This material was taken through Stage C (as described above) to get methyl-[5-(4,4,5,5,-tetramethyl-[1 ,3,2]dioxaborolan-2- yl]amine. [0439] Synthesis of 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrroli[2,3- n]-pyridine

[0440] 4-chloro-1 H-pyrrolo[2,3-b]pyridine (457mg, 3mmol), palladium acetate (13.2mg, 2%), 2-(dicyclohexylphosphino)biphenyl (42mg, 4%), bis(pinacolato) diborane (1.5g, 6mmol) and potassium acetate (590mg, 6mmol) were taken up in a degassed dioxane (1OmL) under an atmosphere of nitrogen. The resulting mixture was stirred at 100¹C for 5 hours, cooled to room te mperature and filtered through a thin pad of Celite (eluting with ethyl acetate). The eluent was washed with water, brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography to give the product (690mg) with a yield of 94%.

[0441] Synthesis of 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-indazole

[0442] 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-indazole was prepared via a 4 step procedure starting from 2-methyl-3-nitroaniline previously described in the literature (WO2007/129161 ).

[0443] The compounds outlined in Table 1 were synthesized following the procedures outlined above or variations thereof. [0444] Table 1 Synthesised compounds

[0445] BIOLOGICAL TESTING [0446] mTOR Assay

[0447] Truncated mTOR kinase and His-tagged 4eBP1 were produced in-house. [T³³P]-ATP was purchased from Amersham (GE Healthcare). All chemicals, unless otherwise stated, were from Sigma-AIdrich.

[0448] Phosphorylation assays were initially performed in a final volume of 20μL in 384-well polypropylene plate (Greiner). Compounds were typically tested over the range from 100 μM to 0.006 μM, in 8 step dilutions, in duplicate. 10 μL/well of 2X Enzyme-Substrate solution (1.5 μg/mL mTOR, 40μg/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 μL/well of test compound in neat DMSO. The reaction was initiated by adding 10 μL/well of 20 μM ATP solution (final assay concentration 10 μM ATP and 0.4 μCi/well of [7³³P]-ATP). After 1 hour incubation at room temperature, the reaction was terminated with 40 μL/well of 20 mM EDT A/1 mM ATP solution. [0449] 50 μL/well of the stopped reaction mix was then transferred to 384-well Multiscreen HTS-PH filter plate (Millipore) pre-added with 50 μL/well of 1 % phosphoric acid. The plate was washed 4 times with 120 μL/well of 0.5 % phosphoric acid via vacuum filtration. Finally, 10 μL/well 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. IC₅O is defined as the concentration of compound required for 50% inhibition of kinase enzyme activity. IC₅₀ data are shown in Table 2 below.

[0450] PI3K Assay

[0451] Recombinant PI3K p110α/p85 was prepared in-house. Phosphatidylinositol (Ptdlns), phosphotidylserine (PtdSer) and all other unspecified chemicals were purchased from Sigma-Aldrich. [7³³P]ATP and Optiphase scintillant were obtained from Perkin Elmer.

[0452] Assays were performed in a final assay volume of 25 μL in 384-well Maxisorp plates (Nunc). Compounds were tested at 8 concentrations in 3-fold serial dilution, generally starting from 10 μM. Maxisorp plates were coated with 20 μL/well of a 1 :1 mixture of Ptdlns and PtdSer [0.1 mg/mL each dissolved in chloroform :ethanol (3:7)] and left overnight in a fume hood at room temperature (RT) to dry.

[0453] The enzyme reaction was created by pipetting 5 μL/well of compound (in 2.5% DMSO), 10 μL/well of enzyme (0.5 μg/mL p110α + 1 μg/mL p85), and 10 μL/well of 5 μM ATP with 5 μCi/mL [7³³P]ATP in assay buffer (final concentrations: 0.2 μg/mL p110α, 2 μM ATP, 0.05 μCi/well [7³³P]ATP in 1X assay buffer: 100 mM Tris- HCI pH 7.0, 200 mM NaCI, 8 mM MgCI₂). The reaction was incubated for 1 hour at RT and terminated with 30 μL/well of 50 mM EDTA solution. The plate was then washed twice with TBS, dried, and added with 30 μL/well of scintillant before it was counted in a MicroBeta Trilux. IC₅₀ is defined as the concentration of compound required for 50% inhibition of kinase enzyme activity. IC₅₀ data are shown in Table 2 below. Table 2- In vitro mTOR inhibition activity assay IC50 data

+++ <1μM

++ 1 μM-5μM

+ >5μM

[0455] 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):

Formula (I) wherein:

A is selected from the group consisting of N and CR ,4.

B is selected from the group consisting of N and CR 5⁰.

D is selected from the group consisting of N and CR ;

X is selected from the group consisting of N and CR¹

R¹ is selected from the group consisting of: H, F, Cl, Br, I, OH, NO2, CN, NH2, optionally substituted CrCi₂alkyl, optionally substituted C₂-Ci₂alkenyl, optionally substituted CrC₆fluoroalkyl, optionally substituted C₂-Ci₂alkynyl, optionally substituted C₂-Ci₂heteroalkyl, optionally substituted C₃-Ci₂cycloalkyl, optionally substituted Ca-Ci_∑cycloalkenyl, optionally substituted C₂-Ci2heterocycloalkyl, optionally substituted C₂-Ci₂heterocycloalkenyl, optionally substituted C₆-Ci₈aryl, optionally substituted CrCiβheteroaryl, optionally substituted C6-Ci₈arylCi-C₆alkyl, OR⁸, SR⁸, CO₂R⁹, (CH₂)_VCO₂R⁹, (CH₂)_VCONR⁸R⁹, CONR⁸R⁹, NR⁸R⁹; optionally substituted CrCi₂alkyloxy, 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- Ci₂heterocycloalkenyloxy, optionally substituted C₆-Ci ₈aryloxy, optionally substituted Ci-C-iβheteroaryloxy, optionally substituted Ci-Ci2alkylamino, SR¹², SO3H, SO₂NR¹²R¹³, SO₂R¹², SONR¹²R¹³, SOR¹², COR¹², COOH, NR¹²COR¹³, NR¹²COOR¹³, NR¹²SO₂R¹³, NR¹²CONR¹³R¹⁴, NR¹²R¹³, (CH₂)_vNR¹²R¹³and acyl,

R², R³, R⁴, R⁵, and R⁶, are each independently selected from the group consisting of H, F, Cl, Br, CN, optionally substituted d-C^alkyl, OR¹⁰, OCOR¹⁰, CH₂OR¹⁰, CH₂NR¹⁰R¹¹, CH₂SO₂R¹⁰, NR¹⁰R¹¹, NR¹⁰COR¹¹, and NR¹⁰SO₂R¹¹, or

R⁴, when taken together with one of R² and R⁵, and the carbon atoms to which they are attached, forms an optionally substituted ring which may be an unsaturated, partially unsaturated, or saturated ring, the ring being fused to the six membered ring;

X¹, X² and X³ are each independently selected from the group consisting of N and CR⁷;

each R⁷ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NO₂, CN, NH₂, optionally substituted C-i-Ci₂alkyl, optionally substituted d-

Cβfluoroalkyl, optionally substituted C₂-Ci₂alkenyl, optionally substituted C₂-

Ci₂alkynyl, optionally substituted C₂-Ci₂heteroalkyl, optionally substituted C₃-

Ci₂cycloalkyl, optionally substituted C₃-C-|₂cycloalkenyl, optionally substituted C₂-

Ci₂heterocycloalkyl, optionally substituted C₂-Ci₂heterocycloalkenyl, optionally substituted C₆-Ci₈aryl, optionally substituted Ci-Ci₈heteroaryl, optionally substituted

C_rCi₂alkyloxy, optionally substituted C₂-C-i₂alkenyloxy, optionally substituted C₂-

Ci₂alkynyloxy, optionally substituted C₂-Ci₀heteroalkyloxy, optionally substituted C₃-

Ci₂cycloalkyloxy, optionally substituted C₃-C-ι₂cycloalkenyloxy, optionally substituted

C₂-Ci₂heterocycloalkyloxy, optionally substituted C₂-Ci ₂heterocycloalkenyloxy, optionally substituted C₆-Ci₈aryloxy, optionally substituted C_rCi₈heteroaryloxy, optionally substituted C_rCi₂alkylamino, SR¹², SO₃H, SO₂NR¹²R¹³, SO₂R¹²,

SONR¹²R¹³, SOR¹², COR¹², COOH, COOR¹², CONR¹²R¹³, NR¹²COR¹³,

NR¹²COOR¹³, NR¹²SO₂R¹³, NR¹²CONR¹³R¹⁴, NR¹²R¹³, (CH₂)_vNR¹²R¹³and acyl, or any two R⁷ on adjacent carbon atoms when taken together with the carbon atoms to which they are attached form an optionally substituted ring which may be an unsaturated, partially unsaturated, or saturated ring, the ring being fused to the five membered ring;

each R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is independently selected from the group consisting of H, optionally substituted CrCi₂alkyl, optionally substituted C₂- Ci₂alkenyl, optionally substituted C₂-Ci₂alkynyl, optionally substituted C₂- C-|₂heteroalkyl, optionally substituted C₃-Ci₂cycloalkyl, optionally substituted C₃- Ci₂cycloalkenyl, optionally substituted C₂-Ci₂heterocycloalkyl, optionally substituted C₂-Ci₂heterocycloalkenyl, optionally substituted C₆-Ci₈aryl, and optionally substituted CrCiβheteroaryl, or

any two R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ when taken together with the atoms to which they are attached may form a cyclic moiety;

v is an integer selected from the group consisting of 1 , 2, 3, and 4;

each R^z is independently selected from the group consisting of C-i-Cealkyl, halo-d-Cβalkyl, hydroxyCi-C₆alkyl, Ci-C₆alkyloxyCi-C₆alkyl, cyanoCi-C₆alkyl, aminoCi-C₆alkyl, Ci-C₆alky!aminoCi-C₆alkyl, and di(Ci-C₆alkyl)aminoCi-C₆alkyl;

q 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 X is CR¹.

3. A compound according to claim 1 or 2 wherein q is 0.

4. A compound according to any one of claims 1 to 3 wherein X³ is N.

5. A compound according to any one of claims 1 to 4 wherein X¹ and X² are CR⁷.

6. A compound according to any one of claims 1 to 5 wherein A, B and D are such that

(i) A is CR⁴, B is CR⁵ and D is CR⁶, or (ii) A is CR⁴, B is CR⁵ and D is N, or (iii) A is CR⁴, B is N and D is CR⁶, or (iv) A is N, B is CR⁵ and D is N.

7. A compound according to any one of claims 1 to 6 wherein R⁴ and R⁵ when taken together with the carbon atoms to which they are attached form an optionally substituted ring fused to the six membered ring, the ring being an unsaturated, partially unsaturated, or saturated ring.

8. A compound according to claim 7 wherein the compound is a compound of the formula:

wherein R¹, R², R³, R⁶ and R⁷ are as defined in claim 1 ; and

R¹⁹ is selected from the group consisting of H, OH, CH₂OH, NH₂, C_rC₆ alkyl, and Ci-Cβalkoxy.

9. A compound according to claim 7 wherein the compound is a compound of the formula:

wherein R¹, R², R³, R⁶ and R⁷ are as defined in claim 1; and

each R¹⁹ is independently selected from the group consisting of H, OH, CH₂OH, NH₂, Ci-Cβalkyl, and C_rC₆alkoxy.

10. A compound according to claim 7 wherein the compound is a compound of the formula:

wherein R¹, R , R^d, R^b and R^/ are as defined in claim 1; and R¹⁹ is selected from the group consisting of H, OH, CH₂OH, NH₂, C₁-C₆ alkyl, and CrC₆ alkoxy.

11. A compound according to any one of claims 1 to 6 wherein R² and R⁴ when taken together with the carbon atoms to which they are attached form an optionally substituted ring fused to the six membered ring, the ring being an unsaturated, partially unsaturated, or saturated ring.

12. A compound according to claim 11 wherein the compound is a compound of the formula:

wherein R¹, R³, R⁵, R⁶ and R⁷ are as defined in claim 1 ; and

R²⁰ is selected from the group consisting of H, OH, CH₂OH, NH₂, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

13. A compound according to claim 11 wherein the compound is a compound of the formula:

wherein R¹, R³, R⁵, R⁶ and R⁷ are as defined in claim 1 ; and

each R²⁰ is independently selected from the group consisting of H, OH, CH₂OH, NH₂, C₁-C₆ alkyl, and C_rC₆ alkoxy.

14. A compound according to claim 11 wherein the compound is a compound of the formula:

wherein R¹, R³, R⁵, R⁶ and R⁷ are as defined in claim 1 ; and

15. A compound according to claim 11 wherein the compound is a compound of the formula:

wherein R¹, R³, R⁵, R⁶ and R⁷ are as defined in claim 1 ; and

R²⁰ is selected from the group consisting of H, OH, CH₂OH, NH₂, CrC₆ alkyl, and C-_I-C₆ alkoxy.

16. A compound according to any one of claims 1 to 15 wherein R¹ is selected from the group consisting of: H, halogen, optionally substituted CrC₆alkyl, optionally substituted C₂-C₆aikenyl, optionally substituted C_rC₆fluoroalkyI, OH, OR⁸, SR⁸, CO₂R⁹, CONR⁸R⁹' optionally substituted C₃-C₁₂cycloalkyl optionally substituted C₆- Ci₈aryl, optionally substituted Ci-Ci₈heteroaryl, optionally substituted optionally substituted C₆-Ci₈arylCrC₆alkyl and NR⁸R⁹;

17. A compound according to any one of claims 1 to 16 wherein R¹ is Ci-C₆alkyl.

18. A compound according to any one of claims 1 to 17 wherein R¹ is methyl.

19. A compound according to any one of claims 1 to 10 wherein R² is H.

20. A compound according to any one of claims 1 to 19 wherein R³ is H.

21. A compound according to any one of claims 1 to 5 wherein R⁴ is selected from the group consisting of OH, CN, NHCOCH₃, F, Cl, OCH₃, and CH₂OH.

22. A compound according to any one of claims 1 to 4, and 12 to 14 wherein R⁵ is selected from the group consisting of H and NH₂.

23. A compound according to any one of claims 1 to 22 wherein each R⁷ is H.

24. A compound according to any one of claims 1 to 22 wherein two R⁷ groups, when taken together with the carbon atoms to which they are attached form an optionally substituted ring which may be an unsaturated, partially unsaturated, or saturated ring, the ring being fused to the five membered ring.

25. A compound according to claim 24 wherein the two R⁷ groups when taken together with the carbon atoms to which they are attached form a phenyl moiety fused to the five membered ring, the phenyl moiety being substituted with 0, 1 , 2, 3, or 4, R¹⁵ groups; wherein each R¹⁵ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NO₂, CN, NH₂, optionally substituted CrC₁₂alkyl, optionally substituted C₂-Ci₂alkenyl, optionally substituted C₂-Ci₂alkynyl, optionally substituted C₂-C-|₂heteroalkyl, optionally substituted C₃-C-|₂cycloalkyl, optionally substituted C₃- Ci₂cycloalkenyl, optionally substituted C₂-Ci₂heterocycloalkyl, optionally substituted C₂-Ci₂heterocycloalkenyl, optionally substituted C₆-Ci₈aryl, optionally substituted Cr Ci₈heteroaryl, optionally substituted d-C^alkyloxy, optionally substituted C2-Ci₂ alkenyloxy, optionally substituted C₂-Ci₂alkynyloxy, optionally substituted C₂- C-i₂heteroalkyloxy, optionally substituted C₃-Ci₂cycloalkyloxy, optionally substituted C₃-Ci ₂cycloalkenyloxy, optionally substituted Ci-C-i₂heterocyclo alkyloxy, optionally substituted C₂-Ci₂heterocycloalkenyloxy, optionally substituted C₆-C-_I8 aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionally substituted CrCi₂ alkylamino, SR¹⁶, SO₃H, SO₂NR¹⁶R¹⁷, SO₂R¹⁶, SONR¹⁶R¹⁷, SOR¹⁶, COR¹⁶, COOH, COOR¹⁶, CONR¹⁶R¹⁷, NR¹⁶COR¹⁷, NR¹⁶COOR¹⁷, NR¹⁶SO₂R¹⁷, NR¹⁶CONR¹⁷R¹⁸, NR¹⁶R¹⁷, and acyl,

each R¹⁶, R¹⁷ and R¹⁸ is independently selected from the group consisting of H, optionally substituted C-ι-Ci₂alkyl, optionally substituted C₂-Ci₂alkenyl, optionally substituted C₂-Ci₂alkynyl, optionally substituted C₂-Ci₂heteroalkyl, optionally substituted C₃-Ci₂cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₂-Ci₂heterocycloalkyl, optionally substituted Ca-C^heterocycloalkenyl, optionally substituted C₆-Ci₈aryl, and optionally substituted Ci-Ci₈heteroaryl.

26. A compound according to claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt or prodrug thereof.

27. A pharmaceutical composition including a compound according to any one of claims 1 to 26 and a pharmaceutically acceptable diluent, excipient or carrier.

28. A method of inhibiting a protein kinase selected from the group consisting of a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof and a PI3 kinase or 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 any one of claims 1 to 26.

29. A method according to claim 28 wherein the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof.

30. A method according to claim 29 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.

31. A method according to claim 29 or 30 wherein the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof.

32. A method according to claim 30 wherein the protein kinase is a PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof.

33. A method according to claim 32 wherein the P13 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof, is a class I PI3K or a fragment thereof or a complex thereof or a functional equivalent thereof.

34. Use of a compound according to any one of claims 1 to 26 to inhibit one or more protein kinase(s) selected from the group consisting of a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof and a PI3 kinase or a fragment or a complex thereof or a functional equivalent thereof.

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 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.

38. A use according to claim 34 wherein the protein kinase is a PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof.

39. A use according to claim 38 wherein the PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof, is a class I PI3K or a fragment thereof or a complex thereof or a functional equivalent thereof.

40. A method of treating or preventing a condition in a mammal in which inhibition of one or more protein kinase(s) selected from the group consisting of a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof and a PI3 kinase 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 according to any one of claims 1 to 26.

41. A method according to claim 40 wherein the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof.

42. A method according to claim 41 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.

43. A method according to claim 41 or 42 wherein the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof.

44. A method according to claim 40 wherein the protein kinase is a PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof.

45. A method according to claim 44 wherein the PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof, is a class I PI3K or a fragment thereof or a complex thereof or a functional equivalent thereof.

46 A method according to any one of claims 40 to 45 wherein the condition is cancer.

47. A method according to claim 46 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.

48. A method according to any one of claims 40 to 45 wherein the condition is a pre-cancer condition or hyperplasia.

49. A method according to claim 48 wherein the condition is selected from the group consisting of familial adenomatous polyposis, colonic adenomatous polyps, myeloid dysplasia, endometrial dysplasia, endometrial hyperplasia with atypia, cervical dysplasia, vaginal intraepithelial neoplasia, benign prostatic hyperplasia, papillomas of the larynx, actinic and solar keratosis, seborrheic keratosis and keratoacanthoma.

50. A method according to any one of claims 40 to 45 wherein the condition is an autoimmune or inflammatory disease or a disease supported by excessive neovascularisation.

51. A method according to claim 50 wherein the condition is selected from the group consisting of the following: acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophil, cutaneous T-cell lymphoma, dermatitis erythrema multiforme, dermatomyositis, diabetic retinopathy, Dressler's syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, macular degeneration, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter's syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy- Koyanagi-Harada syndrome and Wegener's granulomatosis.

52. Use of a compound according to any one of claims 1 to 26 in the preparation of a medicament for treating a condition in an animal in which inhibition of one or more protein kinase(s) selected from the group consisting of a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof and a PI3 kinase or a fragment or a complex thereof or a functional equivalent thereof, prevents, inhibits or ameliorates a pathology or a symptomology of the condition.

53. A use according to claim 52 wherein the protein kinase is a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof.

54. A use according to claim 53 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.

55. A use according to claim 53 or 54 wherein the serine/threonine protein kinase is mTORCI or a fragment or complex thereof or a functional equivalent thereof.

56. A use according to claim 53 wherein the protein kinase is a PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof.

57. A use according to claim 56 wherein the PI3 kinase or a fragment thereof or a complex thereof or a functional equivalent thereof, is a class I PI3K or a fragment thereof or a complex thereof or a functional equivalent thereof.

58. A use according to any one of claims 53 to 57 wherein the condition is cancer.

59. A use according to claim 58 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 and hyperproliferative conditions such as psoriasis and restenosis; 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.

60. A use according to any one of claims 52 to 57 wherein the condition is a precancer condition or hyperplasia.

61. A use according to claim 60 wherein the condition is selected from the group consisting of familial adenomatous polyposis, colonic adenomatous polyps, myeloid dysplasia, endometrial dysplasia, endometrial hyperplasia with atypia, cervical dysplasia, vaginal intraepithelial neoplasia, benign prostatic hyperplasia, papillomas of the larynx, actinic and solar keratosis, seborrheic keratosis and keratoacanthoma.

62. A use according to any one of claims 52 to 57 wherein the condition is an autoimmune or inflammatory disease or a disease supported by excessive neovascularisation.

63. A use according to claim 62 wherein the condition is selected from the group consisting of the following: acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophilia, cutaneous T-cell lymphoma, dermatitis erythrema multiforme, dermatomyositis, diabetic retinopathy, Dressler's syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, macular degeneration, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter's syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy- Koyanagi-Harada syndrome and Wegener's granulomatosis.

64. Use of a compound according to any one of claims 1 to 26 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) selected from the group consisting of a serine/threonine protein kinase or a fragment or a complex thereof or a functional equivalent thereof and a PI3 kinase or a fragment or a complex thereof or a functional equivalent thereof, prevents, inhibits or ameliorates a pathology or a symptomology of the condition.

65. 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 26 to the subject

66. A method according to claim 65 wherein the condition is cancer.

67. A method according to claim 66 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.

68. Use of a compound according to any one of claims 1 to 26 in the preparation of a medicament for treating a proliferative condition in a subject

69. A use according to claim 68 wherein the condition is cancer.

70. A use according to claim 69 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.

71. Use of a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt, N-oxide or prodrug thereof in the treatment of a proliferative condition.