MX2008008945A - Morpholino pyrimidine derivatives and their use in therapy - Google Patents

Abstract

A compound of formula (I) or a salt, ester or prodrug thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in disease mediated by an mTOR kinase and/or one or more PI3K enzyme.

Description

DERIVATIVES OF MORFOLI NO-PI RIMIDI N A AND ITS USE IN THERAPY Description of the Invention The present invention relates to morpholino-pyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative diseases such as cancer and particularly in diseases mediated by a mTOR kinase and / or one or more PI3K enzymes. It is now well known that the deregulation of oncogenes and tumor suppressor genes contributes to the formation of malignant tumors, for example by way of increased cell proliferation or increased cell survival. It is also known that the signaling pathways mediated by the PI3K-mTOR families have a fundamental role in numerous cellular processes that include proliferation and survival, and the deregulation of these trajectories is a causal factor in a broad spectrum of human cancers and other diseases. The target in mammals of the macrolide antibiotic Rapamycin (sirolimus) is the mTOR enzyme. This enzyme belongs to the family of protein kinases related to phosphatidylinositol (Pl) kinase (PIKK), which also includes ATM, ATR, DNA-PK and hSMG-1. mTOR, like other members of the PIKK family, has no detectable lipid kinase activity, but instead functions as a serine / threonine kinase. Much of the knowledge of mTOR signaling is based on the use of Rapamycin. Rapamycin binds first to the FK506 immunofilin binding protein of 12 kDa (FKBP12) and this complex inhibits mTOR signaling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). The mTOR protein is constituted by a kinase catalytic domain, a rapamycin binding domain FKBP12 (FRB), a repressor domain assumed near the C-terminus and up to 20 HEAT repeats in tandem in the N-terminus, as well as a FRAP- domain. ATM-TRRAP (FAT) and the term C FAT (Huang and Houghton, Current Opinion in Pharmacology, 2003, 3. 371-377). The mTOR kinase is a fundamental regulator of cell growth and has been shown to regulate a wide range of cellular functions including translation, transcription, mRNA replacement, protein stability, reorganization of the actin cytoskeleton and autophagy (Jacinto and Hall, Nature Reviews Molecular and Cell Biology, 2005, 4, 117-126).

The mTOR kinase integrates signals from growth factors (such as insulin or insulin-like growth factor) and nutrients (such as amino acids and glucose) that regulate cell growth. The mTOR kinase is activated by growth factors along the PI3K-Akt path. The best characterized function of mTOR kinase in mammalian cells is the regulation of the translation by two trajectories, namely activation of ribosomal S6K1 to intensify the translation of mRNAs carrying a stretch of 5'-terminal oligopyrimidine (TOP) and deletion of 4E-BP1 to leave the mRNA translation dependent on CAP. Generally, researchers have explored the physiological and pathological roles of mTOR using inhibition with Rapamycin and Rapamycin-like analogues based on their specificity for mTOR as an intracellular target. However, recent data suggest that Rapamycin exhibits variable inhibitory actions on the signaling functions of mTOR and suggest that direct inhibition of the mTOR kinase domain may exhibit substantially broader anti-cancer activities than that achieved by Rapamycin (Edinger et al., Cancer Research, 2003, 63, 8451-8460). For this reason, potent and selective inhibitors of mTOR kinase activity could be useful to leave a more complete understanding of the function of mTOR kinase and provide useful therapeutic agents. There is now considerable evidence that the trajectories upstream of mTOR such as the PI3K pathway are frequently activated in cancer (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501; Bjornsti and Houghton, Nature Reviews Cancer, 2004, 4, 335-348; Inoki et al., Nature Genetics, 2005, 37, 19-24). For example, components of the PI3K pathway that are mutated in different human tumors include activating mutations of growth factor receptors and the amplification and / or overexpression of PI3K and Akt. Additionally, there is evidence that the proliferation of endothelial cells may also depend on mTOR signaling. The proliferation of endothelial cells is stimulated by the activation of vascular endothelial cell growth factor (VEGF) of the PI3K-Akt-mTOR signaling pathway (Dancey, Expert Opinion on Investigational Drugs, 2005, 14, 313-328). In addition, it is believed that mTOR kinase signaling partially controls VEGF synthesis by effects on hypoxia-inducible factor-1a expression (HIF-1a) (Hudson et al., Molecular and Cellular Biology, 2002, 22, 7004-7014). Therefore, tumor angiogenesis may depend on signaling by mTOR kinase in two ways, by synthesis of VEGF induced by hypoxia by tumor and stromal cells and by VEGF stimulation of endothelial proliferation and survival by signaling PI3K-Akt-mTOR. These findings suggest that pharmacological inhibitors of mTOR kinase should possess therapeutic value for the treatment of the various forms of cancer comprising solid tumors such as carcinomas and sarcomas and leukemias and lymphoid malignancies. In particular, mTOR kinase inhibitors should possess therapeutic value for the treatment of, for example, breast, colorectal, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and prostate, cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, of uterus, cervix and vulva, as well as leukemias, including ALL and CML), multiple myeloma and lymphomas. In addition to tumorigenesis, there is evidence that mTOR kinase plays a role in a set of hamartoma syndromes. Recent studies have shown that tumor suppressor proteins such as TSC1, TSC2, PTEN and LKB1 rigidly control mTOR kinase signaling. The loss of these tumor suppressor proteins leads to a series of hamartoma conditions as a result of elevated signaling by mTOR kinase (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). Syndromes with a molecular link established for deregulation of mTOR kinase include Peutz-Jeghers syndrome (PJS), Cowden disease, Bannayan-Riney-Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-duclos disease and Tuberose sclerosis (TSC) (Inoki et al., Nature Genetics, 2005, 37, 19-24). Patients with these syndromes characteristically develop benign hamartomatous tumors in multiple organs. Recent studies have revealed a role for mTOR kinase in other diseases (Easton &Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551-564). It has been shown that rapamycin is a potent immunosuppressant by inhibiting the proliferation of T cells induced by antigen, B cells and production of antibodies (Sehgal, Transplantation Proceedings, 2003, 35, 7S-14S) and therefore inhibitors of the mTOR kinase can be useful immunosuppressants. Inhibition of mTOR kinase activity may also be useful in the prevention of restenosis, i.e., control of undesirable proliferation of normal cells in the vasculature in response to the introduction of dilators in the treatment of vasculature diseases. (Morice et al., New England Journal of Medicine, 2002, 346, 1773-1780). Additionally, the Rapamycin analog, everolimus, can reduce the severity and incidence of cardiac allograft vasculopathy (Eisen et al., New England Journal of Medicine, 2003, 349, 847-858). A high activity of mTOR kinase has been associated with cardiac hypertrophy, which is of clinical importance as a fundamental risk factor for heart failure, and is a consequence of the increased cell size of cardiomyocytes (Tee &Blenis, Seminars in Cell and Developmental Biology , 2005, 16, 29-37). Therefore, it is expected that mTOR kinase inhibitors have value in the prevention and treatment of a wide variety of diseases in addition to cancer. It is also believed that a number of these morpholino-pyrimidine derivatives may have inhibitory activity against the phosphatidyl-inositol (PI) -3-kinase family of kinases. Phosphatidyl-inositol (PI) -3-kinases (PI3Ks) are ubiquitous lipid kinases that function both as signal transducers downstream of cell surface receptors and in trafficking pathways constituting the intracellular membrane and proteins. All PI3Ks are double specific enzymes with a lipid kinase activity that phosphorylates phosphoinositoids in the 3-hydroxy position, and a less well characterized protein kinase activity. The lipid products of the PI3K catalyzed reactions comprising phosphatidyl inositol-3,4,5-trisphosphate [PI (3.4.5) P3], fofatidilinositol-3,4-bisphosphate [PI (3.4) P2] and phosphatidylinositol-3-monophosphate [ PI (3) P] constitute second messengers in a variety of signal transduction pathways, including those essential for cell proliferation, adhesion and survival, cytoskeletal rearrangement and vesicle trafficking. PI (3) P is constitutively present in all cells and its levels do not change dramatically after stimulation by agonists. Conversely, PI (3.4) P2 and PI (3.4.5) P3 are virtually absent in most cells but accumulate rapidly by stimulation with agonists. The downstream effects of the 3-phosphoinositide second messengers produced by PI3K are mediated by target molecules that contain 3-phosphoinositide binding domains such as the Pleckstrin homology domain (PH) and the newly identified FYVE and phox domains. Well-characterized protein targets for PI3K include PDK1 and protein kinase B (PKB). Additionally, tyrosine kinases such as Btk and Itk are dependent on the activity of PI3K. The PI3K family of lipid kinases can be classified into three groups according to their physiological substrate specificity (Vanhaesebroeck et al., Trends in Biol. Sci., 1997, 22, 267). PI3K enzymes of Class III exclusively phosphorylate Pl. In contrast, PI3K enzymes of Class II phosphorylate both Pl and PI4-phosphate [PI (4) P]. The PI3K enzymes of Class I phosphorylate Pl, PI (4) P and PI-4,5-bisphosphate [PI (4.5) P2], although it is believed that only PI (4.5) P2 is the cellular physiological substrate. Phosphorylation of PI (4.5) P2 produces the second lipid messenger PI (3.4.5) P3. Closely related members of the lipid kinase superfamily are Class IV kinases such as mTOR (described above) and the DNA-dependent kinase that phosphorylate serine / threonine residues within protein substrates. The best studied and understood of the PI3K lipid kinases are the PI3K Class I enzymes. The Class I PI3Ks are heterodimers consisting of a p 110 catalytic subunit and a regulatory subunit. The family is further divided into the class and class enzymes Ib on the basis of regulatory partners and the regulatory mechanism. The enzymes of the Class are constituted by three different catalytic subunits (p110a, p 110β and p110d) that are dimerized with five different regulatory subunits (p85a, p55a, p50a, p85ß and p55?), All catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers. Class PI3Ks are generally activated in response to stimulation of growth factors of receptor tyrosine kinases via the interaction of their SH2 regulatory subunit domains with specific phospho-tyrosine residues of receptor proteins or activated adapters such as IRS. -1. Both p110a and p110β are constitutively expressed in all cell types, whereas the expression of p110d is more restricted to populations of leukocytes and some epithelial cells. In contrast, the only enzyme of Class Ib is constituted by a catalytic subunit p110? which interacts with a regulatory subunit p101. Additionally, the Class Ib enzyme is activated in response to receptor systems coupled to G protein (GPCRs) and its expression seems to be limited to leukocytes and cardiomyocytes. There is currently considerable evidence that the PI3K enzymes of the Class contribute to tumorigenesis in a wide variety of human cancers, either directly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, the p110a subunit is amplified in some tumors such as those of the ovary (Shayesteh et al., Nature Genetics, 1999, 21, 99-102) and cervix (Ma et al., Oncogene, 2000, 19, 2739-2744) . More recently, activating mutations within the catalytic site of the p110a catalytic subunit have been associated with various other tumors such as those in the colorectal and breast and lung regions (Samuels et al., Science, 2004, 304, 554). Mutations related to tumors in the p85a regulatory subunit have also been identified in cancers such as those of the ovary and colon (Philp et al., Cancer Research, 2001, 61, 7426-7429). In addition to direct effects, it is believed that the activation of the Class PI3Ks contributes to tumorigenic events that occur upstream in signaling pathways, for example through the activation, dependent or independent of ligands, of receptor tyrosine kinases, GPCR systems or integrins (Vara et al., Cancer Treatment Reviews, 2004, 30, 193-204). Examples of such upstream signaling pathways include over-expression of the erbB2 receptor tyrosine kinase in a variety of tumors leading to the activation of PI3K-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102-6114) and overexpression of ras oncogene (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548). Additionally, Class PI3Ks may indirectly contribute to the tumorigenesis caused by various downstream signaling events. For example, the loss of the effect of PTEN tumor suppressor phosphatase that catalyses the conversion of PI (3.4.5) P3 back to PI (4.5) P2 is associated with a very wide range of tumors by the deregulation pathway. the production of PI (3.4.5) P3 mediated by PI3K (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41). Additionally, it is believed that the increase in the effects of other signaling events mediated by PI3K contributes to a variety of cancers, for example by activation of Akt (Nicholson and Anderson, Cellular Signaling, 2002, 14, 381-395). In addition to a role in the mediation of proliferative signaling and survival in tumor cells, there is evidence that Class PI3K enzymes contribute to tumorigenesis in tumor-associated stromal cells. For example, it is known that PI3K signaling plays an important role in the mediation of angiogenic events in endothelial cells in response to pro-angiogenic factors such as VEGF (Abid et al., Arterioscler. Thromb. Vasc. Biol., 2004, 24, 294-300). Since Class I PI3K enzymes are also involved in motility and migration (Sawyer, Expert Opinion Investig. Drugs, 2004, 13, 1-19), inhibitors of PI3K enzymes should provide therapeutic benefits by inhibiting the invasion and metastasis of tumor cells.

Additionally, Class I PI3K enzymes play an important role in the regulation of immune cells that contribute to pro-tumorigenic effects of inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867). These findings suggest that pharmacological inhibitors of Class I PI3K enzymes will be therapeutically valuable for the treatment of various diseases including different forms of cancer disease comprising solid tumors such as carcinomas and sarcomas and leukemias and lymphoid malignancies. In particular, inhibitors of Class I PI3K enzymes should be therapeutically valuable for the treatment of, for example, breast, colorectal, lung cancer (including small cell lung cancer, non-small cell lung cancer). and bronchoalveolar cancer) and prostate, as well as cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix, and vulva, as well as leukemias (including ALL and CML), multiple myeloma, and lymphomas. PI3K ?, Class Ib PI3K, is activated by GPCRs, as was finally demonstrated in mice lacking the enzyme. So, neutrophages and macrophages derived from animals deficient in PI3K? failed to produce PI (3.4.5) P3 in response to stimulation with various chemotactic substances (such as IL-8, C5a, fMLP and MIP-1a), whereas signaling by protein-coupled receptor tyrosine kinases for PI3Ks Class la remained intact (Hirsch et al., Science, 2000, 287 (5455), 1049-1053, Li et al., Science, 2002, 287 (5455), 1046-1049, Sasaki et al., Science 2002, 287 (5455 ), 1040-1046). Additionally, phosphorylation of PKB mediated by PI (3.4.5) P3 was not initiated by these GPCR ligands in cells lacking PI3K ?. Taken as a whole, the results showed that, at least in resting hematopoietic cells, PI3K? it is the only PI3K isoform that is activated by GPCRs in vivo. When neutrophils derived from murine bone marrow and peritoneal macrophages from wild-type and PI3Kα "'" mice were tested in vitro, reduced, but not completely null, efficiency was observed in the chemotaxis and adhesion assays. However, this resulted in a dramatic deterioration of neutrophil infiltration driven by IL-8 in tissues (Hirsch et al., Science, 2000, 287 (5455), 1049-1053.). Recent data suggest that PI3K? is involved in the exploration process rather than in the generation of mechanical force for motility, given that random migration did not deteriorate in cells lacking PI3K? (Hannigan et al., Proc. Nat. Acad. Of Sciences of U.S.A., 2002, 99 (6), 3603-8). Data that linked PI3K? with the pathology of respiratory diseases were acquired with the demonstration that PI3K? it has a fundamental role in the regulation of endotoxin-induced pulmonary infiltration and activation of neutrophils leading to acute lung injury (Yum et al., J. Immunology, 2001, 167 (11), 6601-8). The fact that, although PI3K? is expressed strongly in leukocytes, its loss seems not to interfere with hematopoiesis, and the fact that mice lacking PI3K? they are viable and fertile, this isoform PI3K further implicates as a potential target drug. The work with mice with a silenced gene ("knock out") also established that PI3K? it is an essential amplifier of the activation of mast cells (Laffargue et al., Immunity, 2002, 16 (3), 441-451). Thus, in addition to tumorigenesis, there is evidence that Class I PI3K enzymes play a role in other diseases (Whymann et al., Trends in Pharmacological Science, 2003, 24, 366-376). Both the PI3K enzymes of Class la and the only enzyme of Class Ib have important roles in the cells of the immune system (Koyasu, Nature Immunolgy, 2003, 4, 313-319) and therefore are therapeutic targets for inflammatory and allergic indications. Recent reports show that mice deficient in PI3K? and PI3Kd are viable, but have attenuated inflammatory and allergic responses (Ali et al., Nature, 2004, 431 (7011), 1007-11). Inhibition of PI3K is also useful for treating cardiovascular diseases via anti-inflammatory effects or directly by affecting cardiac myocytes (Prasad et al., Trends in Cardiovascular Medicine, 2003, 13, 206-212). Thus, inhibitors of Class I PI3K enzymes are expected to be valuable in the prevention and treatment of a wide variety of diseases in addition to cancer. Several compounds have been identified that inhibit the PI3Ks and the kinase related to phosphatidylinositol (Pl) kinase (PI3KKs), which include wortmannin and the quercetin derivative LY294002.

These compounds are reasonably specific inhibitors of PI3Ks and PI3KKs compared to other kinases, but lack potency and exhibit poor selectivity within PI3K families. Accordingly, it would be desirable to provide additional effective inhibitors of mTOR and / or PI3K for use in the treatment of cancer, inflammatory or obstructive airway diseases, and immune or cardiovascular diseases. Morpholino-pyrimidine derivatives and PI3K inhibitors are known in the art. International Patent Application WO 2004/048365 discloses compounds that possess inhibitory activity of PI3K enzymes and are useful in the treatment of cancer. These compounds are pyrimidines substituted with arylamino and heteroarylamino, which differ from the compounds of the present invention with respect to their arylamino and heteroarylamino substituents. These substituents are not equivalent to the substituents -XR1 of the present invention. PI3K activity inhibitors useful in the treatment of cancer are also described in European Patent Application 1 277 738, which mentions bicyclic heteroaryl compounds substituted with 4-morpholino such as derivatives of quina'zoline and pyrido [3,2-djpyrimidine and compounds tricyclic heteroaryl substituted with 4-morpholino, but not monocyclic pyrimidine derivatives. Various compounds such as 4-morpholin-4-yl-6- (phenylsulfonylmethyl) -2-pyridin-4-yl-pyrimidine and 4-. { 6- [(phenylsulfonyl) methyl] -2-pyridin-2-ylpyrimidin-4-yl} morpholine have been registered in the Chemical Abstracts database, but no utility has been indicated and therefore there is no suggestion that these compounds have inhibitory activity on mTOR and / or PI3K or useful therapeutic properties. Surprisingly, it has been found that certain morpholino-pyrimidine derivatives, which include some previously known compounds, possess useful therapeutic properties.

Without wishing to be bound by theoretical limitations, it is believed that the therapeutic utility of the derivatives is derived from their inhibitory activity against the mTOR kinase and / or one or more PI3K enzymes (such as the enzyme of the Class la and / or the enzyme of Class Ib). Given that the signaling pathways mediated by the PI3K / mTOR families have a fundamental role in numerous cellular processes that include proliferation and survival, and since the deregulation of these trajectories is a causative factor in a broad spectrum of human cancers and other diseases, the derivatives are expected to be therapeutically useful. In particular, the derivatives are expected to have anti-proliferative and / or apoptotic properties, which means that they will be useful in the treatment of proliferative diseases such as cancer. The compounds of the present invention can also be useful in the inhibition of uncontrolled cell proliferation which is a consequence of various non-malignant diseases such as inflammatory diseases, obstructive diseases of the airways, immune diseases or cardiovascular diseases. As a rule, the compounds of the present invention possess potent inhibitory activity against the mTOR kinase, but the compound may also possess potent inhibitory activity against one or more PI3K enzymes (such as the enzyme of the Class la and / or the enzyme of the Class Ib).

According to one aspect of the present invention, a compound of formula (I) is provided formula (I) or a salt, ester or prodrug thereof; where m is 0. 1. 2, 3 or 4; X is a linker group selected from -CR4 = CR5-CR4 = CR5CR6R7-, -CR6R7CR5 = CR4-, -C = C-, -C = CCR6R7- -CR6R7C = C-, -NR4CR6R7-, -OCR6R7-, - SCR6R7-, -S (O) CR6R7-S (O) 2CR6R7-, -C (O) NR CR6R7-, -NR C (O) CR6R7- -NR4C (O) NR5CR6R7-, -NR4S (O) 2CR6R7- , -S (O) 2NR4CR6R7- -C (O) NR4-, -NR C (O) -, -NR4C (O) NR5-, -S (O) 2NR4- and -NR4S (O) 2-; 1Y and Y2 are independently N or CR8, with the proviso that one of 1Y and Y2 is N and the other is CR8; R1 is a group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl- alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10 , -NR .9arR_ > 1l Ou, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; R2 is a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR1R12, -NR11COR12 and -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14; R4 and R5 are independently hydrogen or alkyl of 1 to 6 carbon atoms; or R1 and R4, together with the atom or atoms to which they are attached, form a 5- or 10-membered carbocyclic or heterocyclic ring wherein 1. 2 or 3 ring carbon atoms are (are) optionally substituted with N, O or S, and whose ring is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alko I of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (C 1 -C 6 alkoxy) amino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkylsulfonyl, alkylsulfonylamino from 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkyl of 1 to 6 carbon atoms-carbamoyl, and bis (alkyl of 1) to 6 carbon atoms) carbamoyl; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and alkyl of 1 to 6 carbon atoms; R8 is selected from hydrogen, halo, cyano and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbons) ono) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkyl of 1 to 6 carbon atoms-carbamoyl and bis (a Iq ui I of 1 to 6 carbon atoms) carbamoyl; R11 and R12 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) bond) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (C 1-6 alkyl) amino, carbamoyl, C 1-6 alkylcarbamoyl and bis (C 1-6 alkyl) carbamoyl; R13, R14, R15 and R16 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms , alkoxy of 1 to 6 carbon atoms - alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (to Iqu i I of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6) carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 atoms carbon (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkyl of 1 to 6 carbon atoms-carbamoyl and bis (alkyl of 1 to 6 carbon atoms) carbamoyl; with the proviso that when X is -C (O) NH-, R1 is not the group for use as a medicine in the treatment of a proliferative disease. According to one aspect of the present invention, a compound of formula (I) is provided formula (I) or a salt, ester or prodrug thereof; where m is 0. 1.2, 304; X is a linker group selected from -CR4 = CR5-CR = CR5CR6R7-, -CR6R7CR5 = CR4-, -C = C-, -C = CCR6R7- -CR6R7C-C-, -NR CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7 -S (O) 2CR6R7-, -C (O) NR4CR6R7-, -NR4C (O) NR5CR6R7- -S (O) 2NR CR6R7-, -C (O) NR4- , -NR C (O) -, -NR4C (O) NR5- -S (O) 2NR4- and -NR4S (O) 2-; 1Y and Y2 are independently N or CR8, with the proviso that one of 1Y and Y2 is N and the other is CR8; R1 is a group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl- alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10 , -NRaCONR ?? R -NR9COCONR10R15 and -NR9SO2R10; R2 is a group selected from C,,, carbocyclyl and heterocyclyl alkyl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R1, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, and -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14; R4 and R5 are independently hydrogen or alkyl of 1 to 6 carbon atoms; or R1 and R4, together with the atom or atoms to which they are attached, form a 5- or 10-membered carbocyclic or heterocyclic ring wherein 1. 2 or 3 ring carbon atoms are (are) optionally substituted with N, O or S, and whose ring is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) carbon) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amine, carbamoyl, alkyl of 1 to 6 carbon atoms-carbamoyl, and bis (alkoyl of 1 to 6 carbon atoms) carbamoyl; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and alkyl of 1 to 6 carbon atoms; R8 is selected from hydrogen, halo, cyano and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms- alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkoxy of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl from 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis ( alkyl of 1 to 6 carbon atoms) sulfamoyl, aoylamino of 1 to 6 carbon atoms, aoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, al 1 to 6 carbon atoms - carbamoyl and bis (alkoxy I to 6 carbon atoms) carbamoyl; R11 and R12 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alko Ii of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms carbon, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl) of 1 to 6 carbon atoms carbon) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (C 1 -C 6 alkyl) amino, carbamoyl, C 1 -C 6 alkylcarbamoyl and bis (C 1 -C 6 alkoxy I) carbamoyl; R13, R14, R1S and R16 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 ato carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 atoms carbon (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (to Iq il of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, C 1 -C 6 -alkanoyl (C 1-6 -alkyl) amino, carbamoyl, C 1-6 -carbamoyl-alkyl and bis (C 1-6 -alkyl) alkyanoyl carbamoyl; with the proviso that when X is -C (O) NH-, R1 is not the group for use as a medicine in the treatment of a proliferative disease. According to one aspect of the present invention, a compound of formula (I) is provided formula (I) or a salt, ester or prodrug thereof; where m is 0. 1. 2, 3 or 4; X is a linker group selected from -CR4 = CR5 -CR = CR5CR6R7-, -CR6R7CR5 = CR4-, -C = C-, -C = CCR6R7 -CR6R7C = C-, -NR CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7 -S (O) 2CR6R7-, -C (O) NR4CR6R7-, -NR4C (O) NR5CR6R7 -S (O) 2NR4CR6R7-, -C (O) NR4-, -NR4C (O) -, -NR C (O) NR5 -S (O) 2NR4- and -NR4S (O) 2-; 1Y and Y2 are independently N or CR8, with the proviso that one of 1Y and Y2 is N and the other is CR8; R1 is a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; R2 is a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -COR13, -CONR13R14, -NR13R14 and -NR13COR14; R4 and R5 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and alkyl of 1 to 6 carbon atoms; R8 is selected from hydrogen, halo, cyano and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (to Iq ui I of 1 to 6 carbon atoms) amine; R11 and R12 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (alkyl of 1 to 6 carbon atoms) amino; R13 and R4 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms - alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms - alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (alkoyl of 1 to 6 carbon atoms) amino; with the proviso that when X is -C (O) NH-, R1 is not the group for use as a medicine in the treatment of a proliferative disease. According to another aspect of the present invention, there is provided the use of a compound of formula (I) formula (I) or a salt, ester or prodrug thereof; where m is 0. 1. 2, 3 or 4; X is a linker group selected from -CR4 = CR5-, -CR4 = CR5CR6R7-, -CR6R7CR5 = CR4-, -C = C-, -C = CCR6R7-, • CR6R7C = C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7-, -S (O) 2CR6R7-, -C (O) NR4CR6R7-, -NR4C (O) CR6R7-, -NR4C (O) NR5CR6R7-, -NR4S (O) 2CR6R7-, -S (O) 2NR CR6R7-, -C (O) NR4-, -NR4C (O) -, -NR4C (O) NR5-, -S (O) 2NR4- and -NR4S (O) 2-; 1Y and Y2 are independently N or CR8, with the proviso that one of 1Y and Y2 is N and the other is CR8; R1 is a group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl- alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; R2 is a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11 , -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, and -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14; R4 and R5 are independently hydrogen or alkyl of 1 to 6 carbon atoms; or R1 and R4, together with the atom or atoms to which they are attached, form a 5- or 10-membered carbocyclic or heterocyclic ring wherein 1. 2 or 3 ring carbon atoms are (are) optionally substituted with N, O or S, and whose ring is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxyalkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms - alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkoyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkyl of 1 to 6 carbon atoms-carbamoyl, and bis (a lq ui I of 1 to 6 carbon atoms) carbamoyl; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and alkyl of 1 to 6 carbon atoms; R8 is selected from hydrogen, halo, cyano and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alk ii of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkyl of 1 to 6 carbon atoms carbamoyl and bis (alkyl of 1 to 6 carbon atoms) carbon) carbamoyl; R11 and R12 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (to Iqu il of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms carbon, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) rbono) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (C 1-6 alkyl) amino, carbamoyl, alkyl of 1 to 6 carbon atoms-carbamoyl and bis (alky) of 1 to 6 carbon atoms) carbamoyl; R13, R14, R15 and R16 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms , alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (at 1 to 6 at t alkyl) carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 atoms carbon (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkyl of 1 to 6 carbon atoms-carbamoyl and bis (alkyl of 1 to 6 carbon atoms) carbamoyl; with the proviso that when X is -C (O) NH-, R1 is not the group in the manufacture of a medicament for use in the treatment of a proliferative disease. According to another aspect of the present invention, there is provided the use of a compound of formula (I) formula (I) or a salt, ester or prodrug thereof; where m is 0. 1. 2, 3 or 4; X is a linker group selected from -CR4 = CR5-, -CR4 = CR5CR6R7-, -CR6R7CR5 = CR4-, -C = C-, -C = CCR6R7-, -CR6R7C = C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7-, S (O) 2CRbR'- C (O) NR4CRbR'- -NR * C (O) NR0CR ° RX -S (O) 2NR CR6R7-, -C (O) NR4-, -NR4C (O) -, -NR4C (O) NR5-, -S (O) 2NR4- and -NR4S (O) 2-; 1Y and Y2 are independently N or CR8, with the proviso that one of 1Y and Y2 is N and the other is CR8; R1 is a group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl- alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10 , -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; R 2 is a group selected from C 1-6 alkyl, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R 11, -OR 11, -SR 11, -SOR 11, - SO2R11, -COR11, -CO2R 11 -CONR ^ R1 -NR 1? 1? DR12 -NR "COR 12 -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR 3R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR 3SO2R14; R4 and R5 are independently hydrogen or alkyl of 1 to 6 carbon atoms; or R1 and R4, together with the atom or atoms to which they are attached, form a 5- or 10-membered carbocyclic or heterocyclic ring wherein 1. 2 or 3 ring carbon atoms are (are) optionally substituted with N, O or S, and whose ring is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alko I of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) carbon) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkyl of 1 to 6 carbon atoms-carbamoyl, and bis (alkyl of 1 to 6 carbon atoms) carbamoyl; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and alkyl of 1 to 6 carbon atoms; R8 is selected from hydrogen, halo, cyano and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (C1-C6 alkyl) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) carbon) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkyl of 1 to 6 carbon atoms-carbamoyl and bis (a Iq ui I of 1 to 6 carbon atoms) carbamoyl; R 1 and R 12 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, halo-alkoxy from 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms , (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) bond) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (C 1-6 -alkyl) amino, carbamoyl, C 1-6 -carbamoyl-alkyl and bis (a Iq Ii I of C 1-6) carbamoyl; R13, R14, R15 and R16 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, Halo-alkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms , alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alko Ii of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl from 1 to 6) carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 atoms carbon (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (to Iq ui I of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, C 1 -C 6 -alkanoyl (C 1-6 -alkyl) amino, carbamoyl, C 1-6 -carbamoyl-alkyl and bis (C 1-6 -alkyl) alkyanoyl carbamoyl; with the proviso that when X is -C (O) NH-, R1 is not the group in the manufacture of a medicament for use in the treatment of a proliferative disease. According to another aspect of the present invention, there is provided the use of a compound of formula (I) formula (I) or a salt, ester or prodrug thereof; where m is 0. 1. 2, 304; X is a linker group selected from -CR4 = CR5-, CR4 = CR5CR6R7-, -CR6R7CR5 = CR4-, -C = C-, -C = CCR6R7-, • CR6R7C = C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7-, -S (O) 2CRbR'- -C (O) NR4CRbRX NR4C (O) NR5CR6R7- -S (O ) 2NR4CR6R7-, -C (O) NR4-, -NR4C (O) -, -NR C (O) NR5-, -S (O) 2NR4- and -NR4S (O) 2-; 1Y and Y2 are independently N or CR8, with the proviso that one of 1Y and Y2 is N and the other is CR8; R1 is a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; R2 is a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -COR13, -CONR13R14, -NR13R14 and -NR 3COR14; R4 and R5 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and alkyl of 1 to 6 carbon atoms; R8 is selected from hydrogen, halo, cyano and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (alkyl of 1 to 6 carbon atoms) amino; R11 and R12 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (alkyl of 1 to 6 carbon atoms) amino; R13 and R14 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (alkyl of 1 to 6 carbon atoms) amino; with the proviso that when X is -C (O) NH-, R1 is not the group Me NHCOR10 in the manufacture of a medicament for use in the treatment of a proliferative disease. According to a further aspect of the present invention, there is also provided a compound of formula (I) formula (I) or a salt, ester, or prodrug thereof; where m is 0. 1. 2, 3 or 4; X is a linker group selected from -CR4 = CR5 -CR4 = CR5CR6R7-, -CR6R7CR5 = CR4-, -C = C-, -C = CCR6R7 -CR6R7C = C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7- , -S (O) CR6R7 -S (O) 2CR6R7-, -C (O) NR4CR6R7-, -NR4C (O) CR6R7 -NR4C (O) NR5CR6R7-, -NR S (O) 2CR6R7-, -S (O) 2NR4CR6R7 -C (O) NR4-, -NR C (O) -, -NR4C (O) NR5-, - (O) 2NR4- and -NR4S (O) 2-; 1Y and Y2 are independently N or CR8, with the proviso that one of 1Y and Y2 is N and the other is CR8; R1 is a group selected from C6-6alkyl, C2-6alkenyl, C2.6alkynyl, carbocyclyl, carbocyclyl-C6-6alkyl, heterocyclyl, and heterocyclyl-C4-6alkyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -SR9, -SOR9, -O2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and - NR9SO2R10; R2 is a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11 , -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, and -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -R13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR 3R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14; R4 and Rs are independently hydrogen or alkyl of 1 to 6 carbon atoms; or R1 and R4, together with the atom or atoms to which they are attached, form a 5- or 10-membered carbocyclic or heterocyclic ring wherein 1. 2 or 3 ring carbon atoms are (are) optionally substituted with N, O or S, and whose ring is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl , alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkyl of 1 to 6 carbon atoms-carbamoyl, and bis (to Iq ui I from 1 to 6 carbon atoms) carbamoyl; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and alkyl of 1 to 6 carbon atoms; R8 is selected from hydrogen, halo, cyano and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, halo-alkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms carbon, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano- alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl from 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6) carbon atoms) amino, carbamoyl, alkyl of 1 to 6 carbon atoms-carbamoyl and bis (alkyl of 1 to 6 carbon atoms) carbamoyl; R11 and R12 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (to Iq ui I of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 atoms carbon, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) carbon) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms carbon (C 1 -C 6 alkyl) amino, carbamoyl, C 1 -C 6 alkylcarbamoyl and bis (C 1 -C 6 alkyl) carbamoyl; R13, R14, R15 and R16 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 atoms, carbon) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 ato carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 atoms carbon (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (to Iq il of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, C 1 -C 6 -alkanoyl (C 1 -C 6 -alkyl) amino, carbamoyl, C 1-6 -carbamoyl-alkyl and bis (C 1-6 -alcoxy) carbamoyl; with the proviso that the compound of formula (I) is not a compound included in the List of Excluded Compounds 1 and with the proviso that when X is -C (O) NH-, R1 is not the group According to a further aspect of the present invention, there is also provided a compound of formula (I) formula (I) or a salt, ester or prodrug thereof; where m is 0. 1. 2, 304; X is a linker group selected from -CR4 = CR5 - CR = CR5CR6R7-, -CR6R7CR5 = CR4-, -C = C-, -C = CCR6R7 - CR6R7C = C-, -NR CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7- -S (O) 2CR6R7-, -C (O) NR CR6R7-, -NR C (O) NR5CR6R7- -S (O) 2NR4CR6R7-, -C (O) NR4 -, -NR4C (O) -, -NR4C (O) NR5- -S (O) 2NR4- and -NR4S (O) 2-; 1 Y and Y2 are independently N or CR8, with the proviso that one of Y and Y2 is N and the other is CR8; R1 is a group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl- alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9, -O2R9, -COR9, -CO2R9, - CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; R2 is a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, and -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -R13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14; R4 and R5 are independently hydrogen or alkyl of 1 to 6 carbon atoms; or R1 and R4, together with the atom or atoms to which they are attached, form a 5- or 10-membered carbocyclic or heterocyclic ring wherein 1. 2 or 3 ring carbon atoms are (are) optionally substituted with N, O or S, and whose ring is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) arbono) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkyl of 1 to 6 carbon atoms-carbamoyl, and bis (alkyl of 1 to 6 carbon atoms) carbamoyl; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and alkyl of 1 to 6 carbon atoms; R8 is selected from hydrogen, halo, cyano and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms- alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6) carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl) of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amine, carbamoyl, a l-C 1 -C 6 -carbamoyl and bis (C 1 -C 6 alkyl) carbamoyl; R11 and R12 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) bond) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (C 1-6 alkyl) amino, carbamoyl, C 1-6 alkylcarbamoyl and bis (C 1-6 alkyl) carbamoyl; R13, R14, R5 and R16 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms , which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms , halo-alkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms carbon, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 atoms) carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 atoms carbon (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (to Iq il of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, C 1 -C 6 -alkanoyl (C 1 -C 6 -alkyl) amino, carbamoyl, C 1-6 -carbamoyl-alkyl and bis (C 1 -C 6 to C 1) carbamoyl; with the proviso that the compound of formula (I) is not a compound included in the List of Excluded Compounds 1 and with the proviso that when X is -C (O) NH-, R1 is not the group According to a further aspect of the present invention, there is also provided a compound of formula (I) formula (I) or a salt, ester or prodrug thereof; where m is 0. 1. 2, 364; X is a linker group selected from -CR4 = CR5-CR4 = CR5CR6R7-, -CR6R7CR5 = CR4-, -C = C-, -C = CCR6R7- CR6R7CsC-, -NR4CR6R7-, -OCR6R7-, -SCR6R7- , -S (O) CR6R7- -S (O) 2CR6R7-, -C (O) NR4CR6R7-, -NR4C (O) NR5CR6R7- -S (O) 2NR4CR6R7-, -C (O) NR4-, -NR4C ( O) -, -NR4C (O) NR5- -S (O) 2NR4- and -NR4S (O) 2-; 1Y and Y2 are independently N or CR8, with the proviso that one of 1Y and Y2 is N and the other is CR8; R1 is a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; R2 is a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR1 R12, -NR11R12 and -NR11COR12; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -COR13, -CONR13R14, -NR13R14 and -NR13COR14; R4 and R5 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and alkyl of 1 to 6 carbon atoms; R8 is selected from hydrogen, halo, cyano and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (alkyl of 1 to 6 carbon atoms) amino; R11 and R12 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (alkyl of 1 to 6 carbon atoms) amino; R13 and R14 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (alkyl of 1 to 6 carbon atoms) amino; with the proviso that the compound of formula (I) is not a compound included in the List of Excluded Compounds 1 and with the proviso that when X is -C (O) NH-, R1 is not the group List of Excluded Compounds 1: 4-. { 6- [methylthio) methyl] -2-methylpyrimidin-4-yl} morpholine; 4- (6-. {((4-chlorophenyl) thio] methyl} -2-methyl-pyrimidin-4-yl) morpholine; 4- (6-. {((4-chlorophenyl) thio] methyl} -2-methylpyridimidin-4-yl) -2,6-dimethylmorpholine; 4-. { 6- [Phenylsulfinyl) methyl] -2-methylpyrimidin-4-yl} morpholine; 4- (6-. {(4-chlorophenyl) sulfinyl] methyl} -2-methylpyrimidin-4-yl) morpholine 4-. { 6- [phenylsulfonyl) methyl] -2-methylpyrimidin-4-yl} morpholine; 4- (6-. {(4-chlorophenyl) sulfonyl] methyl} -2-methylpyrimidin-4-yl) morpholine 4-. { 6- [methylthio) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4-. { 6- [phenylthio) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4- (6-. {(4-chlorophenyl) thio] methyl} -2-phenylpyrimidin-4-yl) morpholine; 4- (6-. {(4-chlorobenzyl) thio] methyl} -2-phenylpyrimidin-4-yl) morpholine; 4- (6-. {((4-chlorobenzyl) thio] methyl} -2-phenylpyrimidin-4-yl) -2,6-dimethylmorpholine; 4-. { 6- [Methylsulfinyl) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4-. { 6- [phenylsulfinyl) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4- (6-. {(4-chlorophenyl) sulfinyl] methyl} -2-phenylpyrimidin-4-yl) morpholine 4-. { 6- [methylsulfonyl) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4-. { 6- [phenylsulfonyl) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4-. { 6- [methylthio) methyl] -2-pyridin-2-ylpyrimidin-4-yl} morpholine; 4-. { 6- [phenylthio) methyl] -2-pyridin-4-ylpyrimidin-4-yl} morpholine; 4- (6- { [(4-chlorophenyl) thio] methyl.} -2-pyridin-2-ylpyrimidin-4-yl) morpholine; 4-. { 6 - [(methylsulfonyl) methyl] -2-pyridin-3-ylpyrimidin-4-yl} morpholine; 4-. { 6 - [(methylsulfonyl) methyl] -2-pyridin-4-ylpyrimidin-4-yl} morpholine; 4-. { 6 - [(phenylsulfonyl) methyl] -2-pyridin-2-ylpyrimidin-4-yl} morpholine; 4-. { 6 - [(phenylsulfonyl) methyl] -2-pyridin-3-ylpyrimidin-4-yl} morpholine; 4-. { 6 - [(phenylsulfonyl) methyl] -2-pyridin-4-ylpyrimidin-4-yl} morpholine; 4-. { 6 - [(methoxy) methyl] -2-methylpyrimidin-4-yl} morpholine; 4-. { 6 - [(methoxy) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4-. { 6 - [(methoxy) methyl] -2-phenylpyrimidin-4-yl} -2,6-dimethylmorpholine; 4-. { 6 - [(phenoxy) methyl] -2- (6-methylpyrid-2-yl) pyrimidin-4-yl} -2,6-dimethylmorpholine; N- [5 - [[3- (1-cyano-1-methylethyl) benzoyl] amino] -2-methylphenyl] -2,6-di-4-morph or linyl-4-pyrimidine carboxamide; N- [5 - [[3- (1-cyano-1-methylethyl) benzoyl] amino] -2-methylphenyl] -6- (4-morph or Mnil) -2- (trifluoro-meth] I) -4-pyrimidinecarboxamide; N- [4-fluoro-3 - [(pyrazinyloxy) methyl] phenyl] -2,6-di-4-morpholinyl-4-pyrimidinecarboxamide; 4- [2-methyl-6 - [(1 E) -2- [3- (trifluoromethyl) phenyl] ethenyl] -4-pyrimidinylj-morpholine; 4- [6-methyl-2 - [(1 E) -2- [3- (trifluoromethyl) phenyl] ethenyl] -4-pyrimidinylj-morpholine; 3,4,5-trimethoxy-N- [4-methyl-6- (4-morpholinyl) -2-pyrimidinyl] -benzamide; N- (2,3-dimethyl-1H-indol-5-yl) -2,6-di-4-morpholinyl-4-pyrimidine carboxamide; N- (2,3-dimethyl-1H-indol-5-yl) -4,6-di-4-morpholinyl-2-pyridinecarboxamide; N- (3,4-dimethylphenyl) -2,6-di-4-morpholinyl-4-p i ri m id i n carboxamide; N- [3- (aminocarbonyl) phenyl] -2,6-di-4-morpholinyl-4-pyrimidinecarboxamide; N- (4,6-di-4-morpholinyl-2-pyridinyl) -N '- (3-methylphenyl) -urea; N- (2,3-dimethyl-1H-indol-5-yl) -4,6-di-4-morpholinyl-2-pyridinecarboxamide; 4,6-di-4-morpholinyl-N- (1,2,3-trimethyl-1H-indol-5-yl) -2-pyridinecarboxamide; N- (2,3-Dimethyl-1H-indol-5-yl) -2 - [(2R, 6S) -2,6-dimethyl-4-morpholinyl] -6- (4-morpholinyl) -4-pyrimidinecarboxamide; 2,6-di-4-morpholinyl-N- (1,2,3-trimethyl-1H-indol-5-yl) -4-pyrimidine carboxamide; N- [3- (dimethylamino) phenyl] -2,6-di-4-morpholinyl-4-pyrimidine carboxamide; N- [3,4,5-trimethoxyphenyl] -2,6-di-4-morpholinyl-4-p i ri ide carboxamide; 2,6-di-4-morpholinyl-N- (6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) -4-pyrimidinecarboxamide; and 4- [2-methyl-6- [2- (5-nitro-2-furyl) vinyl] -4-pyrimidinyl] -morpholine. Additionally, the invention provides a compound of formula (I) as defined herein, or a salt, ester or prodrug thereof, with the proviso that (a) when 1 Y is CH, Y 2 is N, X is -SCH 2 ) -S (O) CH2- or -S (O) 2CH2-, and R2 is methyl, phenyl or pyridyl, then R1 is not methyl, phenyl, 4-chlorophenyl or 4-chlorobenzyl; and (b) when 1 Y is CH, Y 2 is N, X is -O CH 2 - and R 2 is methyl, phenyl or 2-methylpyrid-2-yl, then R 1 is not methyl or phenyl. The following compounds from the List of CompoundsExcluded 1 can also be identified by its Chemical Abstracts Number, N- [5 - [[3- (1-cyano-1-methylethyl) benzoyl] amino] -2-methylphenyl] -2,6-di-4-morpholinyl- 4-pyrimidinecarboxamide (873449-41-3); N- [5 - [[3- (1-cyano-1-methylethyl) benzoyl] amino] -2-methylphenyl] -6- (4-mo rf or linyl) -2- (trifluoromethyl) -4-pyrimidine carboxamide ( 873449-50-4); N- [4-fluoro-3 - [(pyrazinyloxy) methyl] phenyl] -2,6-di-4-morpholinyl-4-p yrimodicarboxamide (642085-32-3); 4- [2-methyl-6 - [(1 E) -2- [3- (trifluoromethyl) phenyl] ethenyl] -4-pyrimidinylj-morpholine (425423-56-9); 4- [6-methyl-2 - [(1 E) -2- [3- (trifluoromethyl) phenyl] ethenyl] -4-pyrimidinylj-morpholine (425423-57-0); 3,4,5-trimethoxy-N- [4-methyl-6- (4-morpholinyl) -2-pyrimidinyl] -benzamide (168197-68-0); N- (2,3-dimethyl-1H-indol-5-yl) -2,6-di-4-morpholinyl-4-pyrimidine carboxamide (887133-39-3); N- (2,3-dimethyl-1H-indol-5-yl) -4,6-di-4-morpholinyl-2-pyridinecaboxamide (887133-47-3); N- (3,4-dimethylphenyl) -2,6-di-4-morpholinyl-4-pyrimidine carboxamide (887133-68-8); N- [3- (aminocarbonyl) phenyl] -2,6-di-4-morpholinyl-4-pyrimidine carboxamide (87133-69-9); N- (4,6-di-4-morpholinyl-2-pyridinyl) -N '- (3-methylphenyl) -urea (87133-93-9); N- (2,3-dimethyl-1H-indol-5-yl) -4,6-di-4-morpholinyl-2-pyridine carboxamide (887134-72-7); 4,6-di-4-morpholinyl-N- (1,2,3-trimethyl-1H-indol-5-yl) -2-pyridine carboxamide (887134-74-9); N- (2,3-dimethyl-1H-indol-5-yl) -2 - [(2R, 6S) -2,6-dimethyl-4-morpholinyl] -6- (4-morpholine, n-1) -4- Inca pirimid rboxam ida (887136-28-9); 2,6-di-4-morpholinyl-N- (1,2,3-trimethyl-1H-indol-5-yl) -4-pyrimidine carboxamide (887136-30-3); N- [3- (dimethylamino) phenyl] -2,6-di-4-morpholinyl-4-pyrimidinecarboxamide (887136-53-0); 2,6-di-4-morpholinyl-N- (6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) -4-pyrimidinecarboxamide (450367-63-2); and 4- [2-methyl-6- [2- (5-nitro-2-furyl) vinyl] -4-pyrimidinyl] -morpholine (4592-48-7). The following compound from the List of Excluded Compounds 1. N- [3,4,5-trimethoxyphenyl] -2,6-di-4-morpholinyl-4-pyrimidinecarboxamide can also be referred to as 2,6-dimohmorin-4-yl- N- (3,4,5-trimethoxyphenyl) pyrimidine-4-carboxamide. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention. Solvates and mixtures thereof also form an aspect of the present invention. For example, a suitable solvate of a compound of formula (I) is, for example, a hydrate such as a half-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate, or an alternative amount thereof. . The present invention relates to the compounds of formula (I) as defined hereinabove as well as to salts thereof. Salts for use in the pharmaceutical compositions will be pharmaceutically acceptable salts, although other salts may be useful in the production of the compounds of formula (I) and their pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the invention may include, for example, acid addition salts of the compounds of formula (I) as defined herein, which are sufficiently basic to form said salts. Such acid addition salts include, but are not limited to, the fumarate, methanesulfonate, hydrochloride, hydrobromide, citrate and maleate salts, and salts formed with the phosphoric and sulfuric acids. Additionally, in cases where the compounds of formula (I) are sufficiently acidic, the salts are salts of bases, and examples include, but are not limited to, an alkali metal salt, for example sodium or potassium, a metal salt alkaline earth metal, for example calcium or magnesium, or a salt of an organic amine, for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylpiperidine,? / -ethylpiperidine, dibenzylamine or amino acids such as lysine. The compounds of formula (I) can also be provided as hydrolysable esters in vivo. An in vivo hydrolysable ester of a compound of formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester that is cleaved in the human or animal body to produce the originating acid or alcohol. Such esters can be identified, for example, by administering intravenously the compound under test to an animal to be tested, and subsequently examining the body fluid of the tested animal. Suitable pharmaceutically acceptable esters for carboxy include alkoxy esters of 1 to 6 carbon atoms-methyl, for example of methoxymethyl, esters of alkanoyl of 1 to 6 carbon atoms-oxymethyl, for example of pivaloyloxymethyl, phthalidyl esters, esters of cycloalkoxy from 3 to 8 carbon atoms-carbonyloxy-alkyl of 1 to 6 carbon atoms of 1 to 6 carbon atoms, for example of 1-cyclohexylcarbonyloxyethyl, esters of 1,3-dioxolen-2-onylmethyl, for example of 5-methyl- 1,3-dioxolen-2-onylmethyl, and alkoxy esters of 1 to 6 carbon atoms-carbonyloxyethyl, for example of 1-methoxycarbonyloxyethyl; and they can be formed in any carboxy group in the compounds of this invention. Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters such as phosphate esters (including cyclic phosphoramide esters) and α-acyloxyalkyl ethers and related compounds which, as a result of the in vivo hydrolysis of the ester, decompose to give the hydroxy group (s) originating Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl of 1 to 10 carbon atoms, for example substituted formyl, acetyl, benzoyl, phenylacetyl, benzoyl and phenylacetyl; C 1 -C 10 alkoxycarbonyl (to give alkylcarbonate esters), for example ethoxycarbonyl; di-alkyl of 1 to 4 carbon atoms-carbamoyl and / - (di-alkyl of 1 to 4 carbon atoms-aminoethyl) -? / - alkyl of 1 to 4 carbon atoms-carbamoyl (to give carbamates); di-alkyl of 1 to 4 carbon atoms-aminoacetyl and carboxyacetyl. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, alkyl of 1 to 4 carbon atoms, aminomethyl and d i- (alkoxy I to 4 carbon atoms) aminomethyl, and morpholino or piperazino linked from an atom of nitrogen from the ring via a methylene linkage group to the 3 or 4 position of the benzoyl ring. Other interesting hydrolysable esters in vivo include, for example, RAC (O) O-alkyl of 1 to 6 carbon atoms -CO-, where RA is, for example, benzyloxy-alkyl of 1 to 4 carbon atoms, or phenyl. Suitable substituents in a phenyl group in such esters include, for example, 4-piperazino having 1 to 4 carbon atoms-alkyl having 1 to 4 carbon atoms, piperazino-alkyl having 1 to 4 carbon atoms, and morpholino-alkyl 1 to 4 carbon atoms. The compounds of the formula (I) can also be administered in the form of a prodrug which decomposes in the human or animal body to give a compound of the formula (I).

Various forms of prodrug are known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, compiled by H. Bundgaard (Elsevier, 1985) and Methods in Enzymology, vol. 42, p. 309-396, compiled by K. Widder, and collaborators (Academic Press, 1985); b) A Textbook of Drug Design and Development, compiled by Krogsgaard-Larsen and H. Bundgaard, Chapter 5"Design and Application of Prodrugs", by H. Bundgaard, p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al., Chem Pharm Bull, 32, -692 (1984). In this specification, the generic term "Cp.q alkyl" includes both straight chain and branched chain alkyl groups. However, references to individual alkyl groups such as "propyl" are specific for the straight chain version only (ie, p-propyl and isopropyl) and references to individual branched chain alkyl groups such as "urea-butyl" they are specific exclusively for the branched chain version. The prefix Cp.q in alkyl Cp.q and other terms (where p and q are integers) indicates the range of carbon atoms that are present in the group, for example alkyl of 1 to 4 carbon atoms includes alkyl of 1 carbon atom (methyl), alkyl of 2 carbon atoms (ethyl), alkyl of 3 carbon atoms (propyl as p-propyl and isopropyl) and alkyl of 4 carbon atoms (n-butyl, sec-butyl, isobutyl, and butyl). The term Cp.q. alkoxy comprises -O-Cp.q. alkyl groups. The term Cp.q alkanoyl comprises -C (O) -alkyl groups. The term "halo" includes fluoro, chloro, bromo and iodo. "Carbocyclyl" is a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 14 ring atoms, wherein a CH2 group of the ring may be replaced with a C = O group. "Carbocyclyl" includes "aryl", "cycloalkyl Cp.q" and "cycloalkenyl Cp.q". "Aryl" is an aromatic, monocyclic, bicyclic or tricyclic carbocyclic ring system. "Cycloalkenyl Cp-q" is an unsaturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing at least one C = C bond and wherein a CH2 group on the ring may be replaced with a C = O group. " Cycloalkyl Cp.q "is a saturated, monocyclic, bicyclic or tricyclic carbocyclic ring system, and wherein a CH2 group on the ring may be replaced with a C = O group." Heterocyclyl "is a saturated, unsaturated ring system, or partially saturated monocyclic, bicyclic or tricyclic containing from 3 to 14 ring atoms of which 1. 2, 3 or 4 ring atoms are selected from nitrogen, sulfur or oxygen, ring which may be bonded by carbon or nitrogen and where a nitrogen or sulfur atom of the ring may be oxidized and wherein a CH2 group on the ring may be replaced with a C = O group. "Heterocyclyl" includes "heteroaryl", "cycloheteroalkyl" and "cycloheteroalkenyl". "Heteroaryl" is a monocyclic, bicyclic or tricyclic aromatic heterocyclyl, having in particular 5 to 10 ring atoms, of which 1. 2, 3 or 4 ring atoms are selected from nitrogen, sulfur or oxygen, wherein one nitrogen or Sulfur in the ring may be oxidized. "Cycloheteroalkenyl" is an unsaturated or partially saturated monocyclic heterocyclyl ring system, bicyclic or tricyclic, having in particular 5 to 10 ring atoms, of which 1. 2, 3 or 4 ring atoms are selected from nitrogen, sulfur or oxygen, ring which may be linked by carbon or nitrogen and wherein a The nitrogen or sulfur atom of the ring can be oxidized and wherein a CH2 group of the ring can be replaced with a C = O group. "Cycloheteroalkyl" is a monocyclic, bicyclic or tricyclic saturated heterocyclic ring system, having in particular 5 to 10 ring atoms, of which 1. 2, 3 or 4 ring atoms are selected from nitrogen, sulfur or oxygen, which ring may be bonded by carbon or nitrogen and wherein a nitrogen or sulfur atom of the ring may be oxidized and wherein a CH2 group on the ring can be replaced with a C = O group. This specification can make use of compound terms to describe groups comprising more than one functionality. Unless otherwise described herein, such terms should be interpreted as understood in the art. For example, carbocyclyl-Cp.q. alkyl comprises Cp.q. alkyl substituted with carbocyclyl, heterocyclyl-Cp.q. alkyl includes Cp-q alkyl substituted with heterocyclyl, and bis (Cp.q.alkyl) amino comprises amino substituted with two Cp alkyl groups .q, which may be the same or different. Haloalkyl Cp-q is a Cp.q. alkyl group which is substituted with one or more halo substituents and particularly 1. 2 or 3 halo substituents. Analogously, other generic terms containing halo such as haloalkoxy Cp.q may contain one or more halo substituents and particularly 1. 2 or 3 halo substituents. Hydroxy-alkyl Cp.q is a Cp-q alkyl group which is substituted with one or more hydroxy substituents and particularly with 1. 2 or 3 hydroxy substituents. Similarly, other generic terms containing hydroxy such as hydroxyalkoxy Cp.q may contain one or more, and particularly 1. 2 or 3 hydroxy substituents. Cp.q.alkyl-Cp.q.alkyl is a Cp.q group that is substituted with one or more Cp.q. alkoxy substituents and particularly 1. 2 or 3 Cp.q. alkoxy substituents. Similarly, other generic terms containing Cp-q alkoxy such as Cp-q-alkoxy Cp-q alkoxy may contain one or more Cp.q. alkoxy substituents and particularly 1.2 or 3 Cp-q alkoxy substituents. Where the optional substituents are selected from "1 or 2", from "1, 2 or 3" or from "1, 2, 3 or 4" groups or substituents, it should be understood that this definition includes cases in which all substituents are selected of one of the specified groups, ie cases in which all the substituents are the same, or cases in which the substituents are selected from two or more of the specified groups, ie cases in which the substituents are not the same. The compounds of the present invention have been named with the aid of computer software (ACD / Version of Name 8.0). "Proliferative disease (s)" includes malignant disease (s) such as cancer and non-malignant disease (s) such as inflammatory diseases, obstructive airway diseases, immunological diseases or cardiovascular diseases. Suitable values for any R group or any part or substituent for such groups include: for alkyl of 1 to 4 carbon atoms: methyl, ethyl, propyl, butyl, 2-methylpropyl and fer-butyl; for alkyl of 1 to 6 carbon atoms: alkyl of 1 to 4 carbon atoms, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and hexyl; for cycloalkyl of 3 to 6 carbon atoms: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; for cycloalkyl of 3 to 6 carbon atoms - alkyl of 1 to 4 carbon atoms: cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; for aryl: phenyl and naphthyl; for aryl-alkyl of 1 to 4 carbon atoms: benzyl, phenethyl, naphthylmethyl and naphthylethyl; for carbocyclyl: aryl, cyclohexenyl and cycloalkyl of 3 to 6 carbon atoms; for halo: fluoro, chloro, bromo and iodo; for alkoxy of 1 to 4 carbon atoms: methoxy, ethoxy, propoxy and isopropoxy; for alkoxy of 1 to 6 carbon atoms: alkoxy of 1 to 4 carbon atoms, pentyloxy, 1-ethylpropoxy and hexyloxy; for C 1 -C 6 alkanoyl: acetyl, propanoyl and 2-methylpropanoyl; for heteroaryl: pyridyl, imidazolyl, quinolinyl, cinnolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, dibenzofuranyl and benzothienyl; for heteroaryl-C 1 -C 4 -alkyl: pyrrolylmethyl, pyrrolethyl, imidazolylmethyl, imidazolyl ethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridylmethyl, pyridylethyl, pyrazinylmethyl, piperyl, pyrimidinylmethyl, pyrimidinylethyl. , pyrimidinylpropyl, pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl, quinolinylpropyl, 1,3,4-triazolylpropyl and oxazolylmethyl; for heterocyclyl: heteroaryl, pyrrolidinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, tetrahydroquinquinolinyl, tetrahydroquinolinyl, indolinyl, dihydro-2/7-pyranyl and tetrahydrofuranyl. It should be noted that the examples given for the terms used in the description are not limiting. Particular values of m, X, Y and Y2, R1, R2 and R3 are as follows. Such values may be used as appropriate, in connection with any aspect of the invention, or part thereof, and with any of the definitions, claims or modalities defined herein.

In one aspect of the invention, m is 0. 1. 2 or 3. In another aspect, m is 0. 1 or 2. In an additional aspect m is 0 or 1. In another additional aspect, m is 0 so that R3 is absent. X In one aspect of the invention, X is a linker group selected from -NR4CRbR'-, -OCR 6DR7-, -SCR > 6brR > 7'-, -S (O) CR > 6bDR7X S (O) 2CR R'- -C (O) NR4CRbR'- NR4C (O) NR5CR6R7-, -S (O) 2NR4CR6R7-, -NR4C (O) -, -C (O) NR4-, -S (O) 2NR4- and -NR4S (O) 2-. In another aspect X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -CR6R7-, -S (O) CR6R7-, -S (O) 2CR6R7-, -C (O) NR4CR6R7-, -NR C (O) NR5CR6R7-, - (O) 2NR4CR6R7 , -C (O) NR4- and -NR4C (O) -. In a further aspect X is a linker group selected from -NR CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7-, -S (O) 2CR6R7-, -C (O) NR4-, and -NR C (O) -. In a further aspect X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7- and -S (O) 2CR6R7-. In another aspect more X is a linker group selected from -SCR6R7-, -S (O) CR6R7- and -S (O) 2CR6R7-. In another aspect X is a linker group selected from -NR4CH2-, -O CH2-, -SCH2-, -S (O) CH2-, -S (O) 2CH2-, -C (O) NR4-, and -NR4C (OR)-. In another aspect X is a linker group selected from -NR4CH2-, -O CH2-, -SCH2-, -S (O) CH2- and -S (O) 2CH2-. In a further aspect X is a linker group selected from -NHCH2-, -N (CH3) CH2-, -OCH2-, -SCH2-, -S (O) CH2-, -S (O) 2CH2-, -C ( O) NH-, -C (O) N (CH3) -, -NHC (O) - and -N (CH3) C (O) -.

In still another aspect, X is a linker group selected from -NHCH2-, -N (CH3) CH2-, -OCH2-, -SCH2- and -S (O) 2CH2-. In another aspect X is -SCH2- or -S (O) 2CH2-. In another aspect, X is -S (O) 2CH2-. 1Y and Y2 In one aspect of the invention, Y is N and Y2 is CR8. In another aspect, 1Y is N and Y2 is CH. In a further aspect, 1Y is CR8 and Y2 is N. In a further aspect, 1Y is CH or CF and Y2 is N. In a further aspect, 1Y is CH and Y2 is N.

In one aspect of the invention, R1 is a group selected from alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms , aryl-alkyl of 1 to 4 carbon atoms, cycloheteroalkyl, heteroaryl, cycloheteroalkyl-alkyl of 1 to 4 carbon atoms, heteroaryl-alkyl of 1 to 4 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9 , -COR9, -CONR9R10, -NR9R10 and -NR9COR10. In another aspect, R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pi rrolid in ylmethyl, pi RRol idi n ylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pi ridi or Imetilo, pyridinylethyl, pyrimidinylmethyl, pi iniletilo rimid, pyrazinylmethyl and pyrazinylethyl, whose group is optionally substituted with 1. 2 or 3 substituent groups selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10. In a further aspect, R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, and pyrazinylethyl, which group is optionally substituted with 1 or 2 substituent groups selected from halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -CONH2 and -CONHCH3. In a further aspect, R1 is a group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclohexyl, -CH2CN, -CH2C (O) NH2, -CH2CH2NC (O) CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 4-trifluoromethylphenyl, -trifluoromethoxyphenyl, 4-cyanophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4- (N-methylaminocarbonyl) phenyl, benzyl, 4-fluorobenzyl, 2-chlorobenzyl, 2-chloro-6-fluorobenzyl, 4-methoxybenzyl, phenethyl, 3-trifluorophenethyl, furan-2-ylmethyl, thien-2-ylmethyl, 2-pyrazin-2-ylethyl, pyridin-3-yl, 2-methylpyridin-3-yl and 2-aminocarbonylpyridin-3-yl.

In one aspect of the invention, R2 is selected from aryl and heteroaryl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R1, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12. In another aspect, R 2 is selected from phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl, quinolinyl, benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR 1R12, -NR11R12 and -NR11COR12. In another aspect, R 2 is selected from phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl, quinolinyl, benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl whose group is optionally substituted with one or more substituent groups independently selected from halo, methyl, methoxy, hydroxymethyl, cyanomethyl, phenoxy, pyrrolidinyl, -CONH2, -CONHCH3 and -CON (CH3) 2. In still another aspect, R2 is 3- (hydroxymethyl) phenyl, 4- (hydroxymethyl) phenyl, 4- (cyanomethyl) phenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-phenoxyphenyl, 3-pyrrolidin-1- ilphenyl, 3- (aminocarbonyl) phenyl, 4- (d-methylaminocarbonyl) phenyl, furan-3-yl, thien-3-yl, 5- (hydroxymethyl) thien-2-yl, pyridin-2-yl, pyridin-4-yl, 2-methoxypyridin-5-yl, 2-methoxypyrimidin-5-yl, 2-methoxynaphth-6-yl, 5,7-diazabicyclo [4.3.0] nona-2,4,8,10-tetraenyl, azaindolyl, indol-5-yl, 1-methylindol-5-yl, quinolin-6-yl, benzimidazolyl, benzofuran-2-yl, dibenzofuran-1-yl and benzothien-3-yl. In another aspect, R2 is phenyl optionally substituted with -NR11COR12. In still another aspect, R2 is pyridin-2-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl or indole-5-yl. In still another aspect, R2 is azaindolyl, indol-5-yl, benzimidazolyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl or 4-hydroxymethylphenyl. In another aspect, R2 is pyridin-2-yl. In a further aspect, R2 is 3-hydroxyphenyl or 4-hydroxyphenyl. In a further one, R2 is 3-hydroxymethylphenyl or 4-hydroxymethylphenyl. In still another aspect, R2 is indole-5-yl. In one aspect, R2 is morpholinyl. In another aspect, R2 is morpholino. In one aspect of the invention, R 4 is hydrogen or methyl. In another aspect R4 is hydrogen.

In one aspect of the invention, R5 is hydrogen or methyl. In another aspect R5 is hydrogen.

In one aspect of the invention, R6 is hydrogen or methyl. In another aspect, R6 is hydrogen. In one aspect of the invention, R7 is hydrogen or methyl. In another aspect, R7 is hydrogen. In one aspect of the invention, R8 is hydrogen or halo. In another aspect, R8 is hydrogen or fluoro. In a further aspect, R8 is hydrogen. In one aspect of the invention, R9 is hydrogen or alkyl of 1 to 4 carbon atoms optionally substituted with 1, 2, 6, 3 substituent groups selected from halo, cyano, nitro, hydroxy, alkoxy of 1 to 4 carbon atoms, amino, alkylamino of 1 to 4 carbon atoms and bis (alkyl) 1 to 4 carbon atoms) amino. In another aspect, R9 is hydrogen or alkyl of 1 to 4 carbon atoms optionally substituted with 1. 2 or 3 halo substituents. In a further aspect, R9 is hydrogen, methyl or trifluoromethyl. .10 In an aspect of the invention, R10 is hydrogen. AND__. In one aspect of the invention, R11 is hydrogen or a group selected from alkyl of 1 to 4 carbon atoms, aryl and cycloheteroaryl, which group is optionally substituted with 1. 2 or 3 groups selected from halo, hydroxy and cyano. In another aspect, R 1 is hydrogen, methyl optionally substituted with hydroxy or cyano, phenyl or pyrrolidinyl. In another aspect, R11 is hydrogen or methyl. R12 In one aspect of the invention, R12 is hydrogen or methyl. In a particular class of compound of formula (I), or a salt, ester or prodrug thereof; m is 0. 1. 2, 3 or 4; X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7-, -S (O) 2CR6R7-, -C (O) NR4CR6R7-, -NR4C (O) NR5CR6R7- , -S (O) 2NR4CR6R7-, -NR C (O) -, -S (O) 2NR4- and -NR4S (O) 2-; 1Y and Y2 are independently N or CR8 with the proviso that one of 1Y and Y2 is N and the other is CR8; R1 is a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; R2 is selected from aryl and heteroaryl, which group is optionally substituted by one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -COR13, -CONR3R14, -NR13R14 and -NR3COR14; R4 and R5 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and alkyl of 1 to 6 carbon atoms; R8 is selected from hydrogen, halo, cyano and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyalkoxy of 1 to 6 carbon atoms , alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (C 1 -C 6 alkyl) amino; R11 and R12 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyalkoxy of 1 to 6 atoms carbon, C 1-6 alkoxy-C 1-6 -alkyl, C 1-6 -alkoxy-C 1-6 -alkoxy, amino, C 1-6 -alkyl- amino and bis (alkyl of 1 to 6 carbon atoms) amino; R13 and R14 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxyalkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms carbon and bis (alkyl of 1 to 6 carbon atoms) amino; with the proviso that (a) when 1Y is CH, Y2 is N, X is -SCH2-, -S (O) CH2- or -S (O) 2CH2- and R2 is methyl, phenyl or pyridyl, then R1 does not is methyl, phenyl, 4-chlorophenyl or 4-chlorobenzyl; and (b) when 1 Y is CH, Y 2 is N, X is -O CH 2 - and R 2 is methyl, phenyl or 2-methylpyrid-2-yl then R 1 is not methyl or phenyl.

In another particular class of compound of formula (I), or a salt, ester or prodrug thereof: m is 0. 1. 2, 3 or 4; X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7-, -S (O) 2CR6R7-, -C (O) NR4CR6R7-, -NR4C (O) NR5CR6R7-, -S (O) 2NR4CR6R7- and -NR4C (O) -; 1Y is CR8 and Y2 is N; R1 is a group selected from alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, a ril-a Iq u ilo of 1 to 4 carbon atoms, cycloheteroalkyl, heteroaryl, cycloheteroalkyl-alkyl of 1 to 4 carbon atoms, heteroaryl-alkyl of 1 to 4 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; R2 is selected from aryl and heteroaryl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR1R12, -NR11R12 and -NR11COR12; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -COR13, -CONR13R14, -NR13R14 and -NR13COR14; R4 and R5 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R6 and R7 are independently selected from hydrogen, halo, halo, cyano, nitro and alkyl of 1 to 6 carbon atoms; R8 is selected from hydrogen, halo, cyano and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (alkyl of 1 to 6 carbon atoms) amino; R11 and R12 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (alkyl of 1 to 6 carbon atoms) amino; R13 and R14 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms and bis (alkyl of 1 to 6 carbon atoms) amino; with the proviso that (a) when 1Y is CH, Y2 is N, X is -SCH2-, -S (O) CH2- or -S (O) 2CH2- and R2 is methyl, phenyl or pyridyl, then R1 does not is methyl, phenyl, 4-chlorophenyl or 4-chlorobenzyl; and (b) when 1 Y is CH, Y 2 is N, X is -O CH 2 - and R 2 is methyl, phenyl or 2-methylpyrid-2-yl then R 1 is not methyl or phenyl. In an additional particular class of formula compound (I), or a salt, ester or prodrug thereof; m is 0. whereby R3 is absent X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7- and -S (O) 2CR6R7-; 1 Y is CH or CF and Y2 is N. R is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, and pyrazinylethyl, The group is optionally substituted with 1 or 2 substituent groups selected from halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -CONH2 and -CONHCH3. R2 is selected from phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl, quinolinyl, benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl whose group is optionally substituted with one or more substituent groups independently selected of halo, methyl, methoxy, hydroxymethyl, cyanomethyl, phenoxy, pyrrolidinyl, -CONH2, -CONHCH3 and -CON (CH3) 2. R 4 is hydrogen or methyl; R is hydrogen or methyl; R7 is hydrogen or methyl; with the proviso that (a) when 1Y is CH, Y2 is N, X is -SCH2-, -S (O) CH2- or -S (O) 2CH2- and R2 is methyl, phenyl or pyridyl, then R1 does not is methyl, phenyl, 4-chlorophenyl or 4-chlorobenzyl; and (b) when 1 Y is CH, Y 2 is N, X is -O CH 2 - and R 2 is methyl, phenyl or 2-methylpyrid-2-yl then R 1 is not methyl or phenyl. Another aspect of the invention provides a compound, or a combination of compounds, selected from: 4- (methylsulfonylmethyl) -6-morpholin-4-yl-2-thiophen-3-yl-pyrimidine; 2-benzofuran-2-yl-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine; 2-dibenzofuran-1-yl-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine; 5- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 2- (6-methoxy-pyridin-3-yl) -4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine; 2- (6-methoxynaphthalen-2-yl) -4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine; [3- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] methanol; [4- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] methanol; N, N-dimethyl-4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -benzamide; 2- (2-methoxypyrimidin-5-yl) -4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine; 6- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-ylquinoline; 3- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl-benzamide; 4- (Benzenesulfonylmethyl) -6-morpholin-4-yl-2-thiophen-3-yl-pyrimidine; 4- (Benzenesulfonylmethyl) -2- (3,4-dimethoxyphenyl) -6-morpholin-4-yl-pyrimidine; 4- (Benzenesulfonylmethyl) -2- (3-furyl) -6-morpholin-4-yl-pyrimidine; 4- (Benzenesulfonylmethyl) -2-benzothiophen-3-yl-6-morpholin-4-yl-pyrimidine; 4- (Benzenesulf onyl methyl I) -6-morpholin-4-yl-2 - (4-phenoxyphenyl) pyrimidine; 2- [4- [4- (Benzenesulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] acetonitrile; 4- (benzenesulfonylmethyl) -2- (3-fluoro-4-methoxy-phenyl) -6-morpholin-4-yl-pyrimidine; [5- [4- (Benzenesulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] thiophen-2-yl] methanol; 4- (Benzenesulfonylmethyl) -6-morpholin-4-yl-2- (3-pyrrolidin-1-ylphenyl) pyrimidine; 5- [4- (Benzenesulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1-methyl-indole; 5- [4- (Benzenesulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole; 4- (Benzenesulfonylmethyl) -2- (6-methoxypyridin-3-yl) -6-morpholin-4-yl-pyrimidine; 4-morpholin-4-yl-6- (phenylsulfanylmethyl) -2-pyridin-2-yl-pyrimidine; 4- (2-furylmethylsulfanylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(4-methoxyphenyl) sulfanylmethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4- (butan-2-ylsulfanylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4- (butylsulfanylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-2-pyridin-2-yl-6- (tert-butylsulfanylmethyl) pyrimidine; 4-morpholin-4-yl-6- (propane-2-ylsulfanylmethyl) -2-pyridin-2-yl-pyrimidine; 4 - [(2-chloro-6-fluoro-phenyl) methylsulfanylmethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4- (cyclohexylsulfanylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(4-fluorophenyl) sulfanylmethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4- (ethylsulfanylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(4-fluorophenyl) methylsulfanylmethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(4-methoxyphenyl) methylsulfanylmethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-6- (phenethylsulfanylmethyl) -2-pyridin-2-yl-pyrimidine; 4 - [(6-morpholin-4-yl-2-pyridin-2-yl-pyrimidin-4-yl) methylsulfanyl] benzonitrile; 4- (2-methylpropylsulfanylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-6- (2-pyrazin-2-ylethylsulfanylmethyl) -2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-2-pyridin-2-yl-6- (thiophen-2-ylmethylsulfanylmethyl) pyrimidine; 4- (2-furylmethylsulfonylmethyl) -6-morpholin-4-yl-2-pyrridin-2-yl-pyrimidine; 4 - [(4-methoxyphenyl) sulfonylmethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4- (butan-2-ylsulfonylmethyl) -6-morpholin-4-yl-2-pyrridin-2-yl-pyrimidine; 4- (2-methylpropylsulfonylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-6- (propylsulfonylmethyl) -2-pyridin-2-yl-pyrimidine; 4- (butylsulfonylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-6- (propan-2-ylsulfonylmethyl) -2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-2-pyridin-2-yl-6 - [[3- (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidine; 4-morpholin-4-yl-6- (2-pyrazin-2-ylethylsulfonylmethyl) -2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-2-pyridin-2-yl-6- (thiophen-2-yl methylsulfonylmethyl) pyrimidine; 4- (cyclohexylsulfonylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(4-fluorophenyl) sulfonylmethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4- (ethylsulfonylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(4-fluorophenyl) methylsulfonylmethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-2-pyridin-2-yl-6 - [[4- (trifluoromethoxy) phenyl] sulfonylmethyl] pyrimidine; 4 - [(4-methoxyphenyl) methylsulfonylmethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(3,4-dimethoxyphenyl) sulfonylmethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(4-brom-2-f-luoro-f-enyl) -is-fonylmethyl] -6-m or rfo-l-4-yl-2-pyridin-2-yl-pyrimidine; N-methyl-2 - [(6-morpholin-4-yl-2-pyridin-2-yl-pyrimidin-4-yl) methylsulfonyl-benzamide; 4-morpholin-4-yl-6- (phenethylsulfonylmethyl) -2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-2-pyridin-2-yl-6- [2- [3- (trifluoromethyl) phenyl] -ethylsulfonylmethyljpyrimidine; 4 - [(6-morpholin-4-yl-2-pyridin-2-yl-pyrimidin-4-yl) methylsulfonyl] benzonitrile; 4 - [(2-chloro-4-fluoro-phenyl) sulfonylmethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(3-methoxyphenoxy) methyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-6- (phenoxymethyl) -2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-6- (phenylmethoxymethyl) -2-pyridin-2-yl-pyrimidine; 4- (ethoxymethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(2-chlorophenoxy) methyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(3-chlorophenoxy) methyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(3-methoxyphenoxy) methyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(4-methoxyphenoxy) methyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4 - [(2-chlorophenyl) methoxymethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 3 - [(6-morpholin-4-yl-2-pyridin-2-yl-pyrimidin-4-yl) methoxy] pyridine-2-carboxamide; 4 - [(2-methylpyridin-3-yl) oxymethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 4-morpholin-4-yl-2-pyridin-2-yl-6- (pyridin-3-yloxymethyl) pyrimidine; N-benzyl-N-methyl-1- (6-morpholin-4-yl-2-pyridin-2-yl-pyrimidin-4-yl) methanamine; N - [(6-morpholin-4-yl-2-pyridin-2-yl-pyrimidin-4-yl) methyl] propan-2-amine; 1- (2-chlorophenyl) -N - [(6-morpholin-4-yl-2-pyridin-2-yl-pyrimidin-4-yl) methyl] methanamine; 4- (Benzenesulfonylmethyl) -5-fluoro-6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 5-fluoro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 6-morpholin-4-yl-N-phenyl-2-pyridin-2-yl-pyrimidine-4-carboxamide; N, N-dimethyl-6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine-4-carboxamide; 5- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1,3-dihydroindol-2-one; Methyl 2-amino-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl-benzoate; [2-methoxy-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] methanol; 2-methyl-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H -benzoimidazole; - [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1,3-dihydro-benzoimidazol-2-one; [5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-ind azo I -3- i I] methanol; 6- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] chroman-4-ol; 1-Acetyl-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -2H-indol-3-one; 1-methyl -4- [4- (methylsulfonylmethyl) -6-morf or lin-4-yl-pyridin-2-yl] piperazin-2-one; 1- (4-chlorophenyl) -4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] piperazin-2-one; 2- [3- (4,4-dimethyl-5H-1,3-oxazol-2-yl) -4-methoxy-phenyl] -4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine; N- (1H-benzoimidazol-5-yl) -2,6-dimorpholin-4-yl-pyrimidine-4-carboxamide; N- (5-methyl-2H-pyrazol-3-yl) -2,6-dimorpholin-4-yl-pyrimidine-4-carboxamide; N- (1H-indol-5-yl) -2,6-dimorpholin-4-yl-pyrimidine-4-carboxamide; N- [5- (methoxymethyl) -1,3,4-thiadiazol-2-yl] -2,6-dimorpholin-4-yl-pyrimidine-4-carboxamide; 5- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indazole; 3-methyl-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indazole; 5- [2- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-4-yl] -1H-indole; 5- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-benzoimidazole; 4- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 3- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -5,7-diazabicyclo [4.3.0] nona-1, 3,5,8-tetraene; 4- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] aniline; 2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidine-4-carboxylic acid; [2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methanol; 5- [4-morpholin-4-yl-6- (morpholin-4-ylmethyl) pyrimidin-2-yl] -1 H-indole; N - [[2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methyl] -1- (4-methoxyphenyl) methanamine; 1- (4-chlorophenyl) -N - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methyl] methanamine; 5- [4 - [(2-methylpyridin-3-yl) oxymethyl] -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 5- [4- (methoxymethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 5- [4- (2-furylmethylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole; 5- [4- (Ethylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole; - [4 - [(4-methoxyphenyl) sulfonylmethyl] -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 5- [4-morpholin-4-yl-6- (propane-2-ylsulfonylmethyl) pyrimidin-2-yl] -1H-indole; 5- [4- (butan-2-ylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole; 5- [4 - [(2-chloro-4-fluoro-phenyl) sulfonylmethyl] -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 2 - [[2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] -N, N-dimethyl-acetamide; 5- [4 - [(5-chloro-1,2,4-thiadiazol-3-yl) methylsulfonylmethyl] -6-mo rf or lin -4-yl-pyrimidin-2-yl] -1 H-indole; 5- [4-morpholin-4-yl-6- (1,3-thiazol-4-ylmethylsulfonylmethyl) pyrimidin-2-yl] -1 H-indole; 3 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] propanenitrile; 2 - [[2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] -1-morphine-4-yl-ethanone; 5- [4 - [(3,5-dimethyl-1,2-oxazol-4-yl) methylsulfonylmethyl] -6-mo rf or lin -4-yl-pyrimidin-2-yl] -1 H-indole; (2S) -1- [2 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] acetyl] pyrrolidine-2-carbonitrile; 5- [4-morpholin-4-yl-6- (pyridin-3-ylmethylsulfonylmethyl) pyrimidin-2-yl] -1 H-indole; 5- [4- (2-imidazol-1-ylethylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 5- [4 - [(5-ethyl-1H-imidazol-4-yl) methylsulfonylmethyl] -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 5- [4- (2-fluoroethylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole; 4 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonylmethyl] -2H-phthalazin-1-one; 4 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] butanonitrile; 2 - [[2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] -1-pyrrolidin-1-yl-ethanone; 2 - [[2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] -N-propan-2-yl-acetamide; 5- [4- [2- (2-methoxyethoxy) ethylsulfonylmethyl] -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 5- [4 - [(2-methyl-1,3-thiazol-4-yl) methylsulfonylmethyl] -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 2 - [[2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] -N-propyl-acetamide; 5- [4- (2,2-difluoroethylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 5- [4-morpholin-4-yl-6 - [(5-tert-butyl-1,3,4-thiadiazol-2-yl) methylsulfonylmethyl] pyrimidin-2-yl] -1 H-indole; 5- [4- (3-methoxypropylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; - [4-morpholin-4-yl-6- (prop-2-ynylsulfonylmethyl) pyrimidin-2-yl] -1H-indole; 5- [4-morpholin-4-yl-6- (2-morpholin-4-ylethylsulfonylmethyl) pyrimidin-2-yl] -1 H-indole; N- [4 - [[2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonylmethyl] phenyl] acetamide; 2 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] -N-tert-butyl-acetamide; 5- [4-morpholin-4-yl-6- (3-morpholin-4-ylp-ropylsulfonylmethyl) pyrimidin-2-yl] -1 H-indole; 2 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] -1- (1-piperidyl) et anona; 5- [4- (2-ethoxy-ethylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole; 5- [4-morpholin-4-yl-6- (oxolan-2-ylmethylsulfonylmethyl) pyrimidin-2-yl] -1 H-indole; 3 - [[2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] -N, N-dimethyl-propan-1-amine; N, N-diethyl-2 - [[2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] acetamide; 5- [4-morpholin-4-yl-6- (propylsulfonylmethyl) pyrimidin-2-yl] -1H-indole; 2 - [[2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonylmethyl] -1H-benzoimidazole; 3 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonylmethyl] benzonitrile; 8 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonylmethyl] -5-methyl-1.7-diazabicyclo [4.3.0] nona-2.4 , 6,8-tetraene; N-benzyl-2 - [[2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] acetamide; 2 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] -N-methyl-N-phenyl-acetamide; 5- [4- (Butylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole; 5- [4 - [(5-methyl-1,3,4-oxadiazol-2-yl) methylsulfonylmethyl] -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 2 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] to keta mide; 3 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] propanamide; 2 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] acetonitrile; 5-amino-1- [2 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] ethyl] pyrazole-4-carbonitrile; 2 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] -N- (2-methoxyethyl) acetamide; 5- [4- (2-cyclohexylethylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 5- [4- [3- (4-chlorophenyl) propylsulfonylmethyl] -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; N- [2 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] ethyl] acetamide; 2 - [[2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonylmethyl] -3H-quinazolin-4-one; 5- [4- (Cyclohexylmethylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole; 5- [4- [3- (4-fluorophenoxy) propylsulfonylmethyl] -6-morpholin-4-yl-pi rimidi n-2-yl] -1 H-indole; * 5- [4- (5-methylhexylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole; 4-morpholin-4-yl-2-pyridin-2-yl-6- (tert-butylsulfonylmethyl) pyrimidine; 2-methyl-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole; 4 - [(5-methyl-2H-pyrazol-3-yl) oxymethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine; 2- (3-furyl) -4- (methylsulfonylmethyl) -6-morpholin-4-yl-pi rimidine; 4- (methylsulfonylmethyl) -6-morpholin-4-yl-2-naphthalen-1-yl-pyrimidine; or a salt, ester or prodrugs thereof and particularly a pharmaceutically acceptable salt thereof. Additional compounds of the invention include: N- (1H-benzoimidazol-5-yl) -2,6-dimorpholin-4-yl-pyrimidine-4-carboxamide; N- (5-methyl-2H-pyrazol-3-yl) -2,6-dimorpholin-4-yl-pyrimidine-4-carboxamide; or a salt, ester or prodrugs thereof and particularly a pharmaceutical salt thereof. In certain aspects of the invention such as a compound of formula (I) for use as a medicament for the treatment of a proliferative disease; or the use of a compound of formula (I) in the manufacture of a medicament for use in the treatment of a proliferative disease; a compound of formula (I) can be 4-morpholin-4-yl-6- (phenylsulfonylmethyl) -2-pyridin-4-ylpyrimidine or 4-. { 6- [(phenylsulfonyl) methyl] -2-pyridin-2-ylpyrimidin-4-yl} morpholine. The invention also provides processes for the preparation of a compound of formula (I) or a salt, ester or prodrug thereof. A compound of formula (I), wherein X is -S (O) 2CR6R7-, can be prepared by oxidation of a compound of formula (I), wherein X is -SCR6R7-, for example by using Oxona® at the room temperature in a mixed solvent system of water and ethanol. (I) According to a further aspect of the present invention, there is provided a process for preparing a compound of formula (I) as defined in claim 1. wherein X is -S (O) 2CR6R7-, by reaction of a compound of formula (I), wherein X is -SCR6R7-, with an oxidizing agent (for example using Oxona® at room temperature in a mixed solvent system of water and ethanol). A compound of formula (I), wherein X is -X1CR6R7- and X1 is -NR4-, -O-, -S-, -S (O) -, or -S (O) 2- can be prepared from a compound of formula (II), wherein L1 is a leaving group such as halo (for example chloro), tosyl, mesyl, etc. by reaction with a compound of formula (III) in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N,? / - a7 methylformamide: According to a further aspect of the present invention, there is provided a process for preparing a compound of formula (I) according to claim 1. wherein X is X1CR6R7- and X1 is -NR4-, -O-, -S -, -S (O) -, or -S (O2) -. (0 which comprises reacting a compound of formula (II), wherein L is a leaving group (such as halo (for example chloro), tosyl, mesyl, etc.) with a compound of formula (III) R1-X1H (lll) (optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N, N- / methylformamide). A compound of formula (II) can be prepared from a compound of formula (IV), wherein L2 is a leaving group such as halo (for example chloro), tosyl, mesyl, etc .: (IV) by reaction with a compound of formula (V) (V) This reaction can be carried out in a solvent such as tetrahydrofuran in the presence of a suitable base such as triethylamine. The compounds of formula (V) are commercially available or can be prepared using convenient methods described in the literature, known to those skilled in the art or described in the examples herein. A compound of formula (IV) can be prepared from a compound of formula (VI): (VI) When L2 is halo such as chlorine, a compound of formula (IV) can be prepared using a chlorinating agent such as phosphorus oxychloride at an elevated temperature such as from 50 ° C to 150 ° C, particularly from 75 ° C to 125 ° C and more particularly to about 100 ° C. ° C. A compound of formula (VI) can be prepared by reacting a compound of formula (VII): (VII) with a compound of formula (VIII) (VIII) The compounds of formula (VII) and the compounds of formula (VIII) are commercially available or can be prepared using convenient methods described in the literature, known to those skilled in the art or described in the examples herein. A compound of formula (I), wherein X is -S (O) 2CR6R7-, can also be prepared by reacting a compound of formula (IX) with a suitable organometallic reagent (such as the activated ester of boronic acid R2B ( OR) 3 wherein R is alkyl of 1 to 4 carbon atoms such as methyl), in the presence of a suitable metal catalyst (such as palladium or copper) using a solvent (such as an organic solvent, eg 1,4-dioxane).

A compound of formula (IX) can be prepared by reaction of a compound of formula (X): (X) with a compound of formula (XI) in a solvent such as tetrahydrofuran or? /./ v-d / 'methylformamide. OR II RIS- NaO (XI) A compound of formula (X) can be prepared by reaction of a compound of formula (XII) L2 with a compound of formula (V) (V) This reaction can be carried out in a solvent such as tetrahydrofuran in the presence of a suitable base such as triethylamine. A compound of formula (XII) can be prepared from a compound of formula (Xlll): (XIII) When L2 is halo such as chloro, a compound of formula (XII) can be prepared using a chlorinating agent such as phosphorus oxychloride at an elevated temperature such as from 50 ° C to 150 ° C, particularly from 75 ° C. C at 125 ° C and more particularly at approximately 100 ° C. A compound of formula (XII) can be prepared by reaction of a compound of formula (VII) (VII) with a compound of formula (XIV) (XIV) The compounds of formula (VII) and the compounds of formula (XIV) are commercially available or can be prepared using convenient methods described in the literature, known to those skilled in the art or described in the examples herein. A compound of formula (I) wherein X is -C (O) NR4CR6R7-, -NR4C (O) NR5CR6R7- or -S (O) 2NR4CR6R7- can be prepared by reaction of a compound of formula (I) wherein X is -NH2CR6R7- with the appropriate compound of formula (XVI) in the presence of a suitable base such as triethylamine.

(XVI) Analogously, a compound of formula (I), wherein X is -C (O) NR4-, -NR C (O) NR5- or -S (O) 2NR4-, can be prepared by reaction of a compound of formula (XV) with the appropriate compound of formula (XVI) in the presence of a suitable base such as triethylamine.

(XVI) A compound of formula (XV) can be prepared by reacting a compound of formula (XVII) with diphen-ylphosphoryl azide and triethylamine in a solvent such as N, N-a7methyl keta.

Where R4 is alkyl of 1 to 6 carbon atoms, this step can be followed by alkylation of the resulting amine using reductive amination conditions, such as an aldehyde in the presence of sodium cyanoborohydride in a solvent such as dichloromethane. A compound of formula (XVII) can be prepared by reacting a compound of formula (XVIII) with a base such as sodium hydroxide.

A compound of formula (XVII I) can be prepared by reacting a compound of formula (XIX) wherein L3 is a leaving group such as halo (for example chloro) or trifluoromethane sulfonate). with a suitable organometallic reagent such as the tributyltin derivative or the zinkate of formula (XX) wherein Y can be halo such as chloro. Where R 2 is unsaturated such as aryl or optionally substituted heteroaryl, the tributyltin derivative should be used, while zincate should be used for cases where R 2 is saturated. R2-Sn R3 or R2-Zn-Y (XX) This reaction is carried out in the presence of a suitable metal catalyst such as palladium or copper in a solvent such as tetrahydrofuran, at an elevated temperature such as 100 ° C. A compound of formula (XIX) can be prepared by reacting a compound of formula (XXI) wherein L 2 is a leaving group such as halo (for example chloro), tosyl, mesyl, etc. with a compound of formula (V) (V) This reaction can be carried out in a solvent such as tetrahydrofuran in the presence of a suitable base such as triethylamine. A compound of formula (XXI) can be prepared from a compound of formula (XXII) When L2 and L3 are chlorine, chlorination can be carried out using phosphorus oxychloride at an elevated temperature such as 100 ° C. The compounds of formula (VII) and the compounds of formula (VIII) are commercially available or can be prepared using convenient methods described in the literature, known to those skilled in the art or described in the examples herein. A compound of formula (I) can also be prepared by reaction of a compound of formula (XXIII) L2 (XXIII) with a compound of formula (V) (V) This reaction can be carried out in a solvent such as tetrahydrofuran in the presence of a suitable base such as triethylamine. A compound of formula (XXIII), wherein X is -CR4 = CR5-, -CR4 = CRsCR R'-, -CR6R7CR5 = CR4-, -C = C-, -C = CCR 6bDR7 -CR6R7C = C-, can be prepared by reaction of a compound of formula (XXIV) (XXIV) with the appropriate compound of formula (XXV) where M is a metal. For the alkynyl compounds M can be hydrogen or a metal.

R'CR4 = CR5-M Ri- -CR6R7-M Ri-CR4 = CR5CR6R7-M R1 '-MR'-CR6R7CR5 = CR4-M R'-CR6R7- -M (XXV) Typically, a tributyltin derivative is used in the presence of a suitable metallic catalyst such as palladium or copper in an organic solvent such as tetrahydrofuran at an elevated temperature such as 100 ° C. A compound of formula (XXIV) can be prepared from a compound of formula (XXVI) (XXVI) Where L1 and L2 are chlorine, a chlorinating agent such as phosphorus oxychloride can be used.

A compound of formula (XXVI) can be prepared by reaction of a compound of formula (XXVII) wherein PG1 and PG2 are alkyl CL groups. such as methyl or ethyl: (XXVII) with a compound of formula (VIII): (VIII) The compounds of formula (XXVII) and the compounds of formula (VIII) are commercially available or can be prepared using convenient methods described in the literature, known to those skilled in the art or described in the examples herein. A compound of formula (I) wherein X is -NR C (O) - can be prepared by reaction of a compound of formula (XVII) with an amine R4NH2 and a suitable activating reagent such as O- (7-azabenzotriazol-1-yl) -? /,? /,? / ', /' - tetramethyluronium hexafluorophosphate using a base such as diisopropylethyl amine and a solvent such as tetrahydrofuran. A compound of formula (XVII) can be prepared as described herein. A compound of formula (I), wherein X is -S (O) 2CR6R7-, can be prepared by oxidation of a compound of formula (I), wherein X is -SCR6R7-, for example using Oxona® at temperature environment in a mixed solvent system of water and ethanol.

A compound of formula (I), wherein X is -X1CR6R7 and X1 is -NR4-, -O-, -S-, -S (O) -, can be prepared by reaction of a compound of formula (XXVIII) L2 (XXVIII) with a compound of formula (V) (V) This reaction can be carried out in a solvent such as tetrahydrofuran in the presence of a suitable base such as triethylamine. A compound of formula (XXVIII) can be prepared by reaction of a compound of formula (XXIX) wherein L3 is a leaving group such as halo (for example chloro). L2 (XXIX) with a suitable organometallic reagent such as the tributyltin derivative or the zinkate of formula (XX) wherein Y can be halo such as chloro. Where R 2 is unsaturated, such as aryl or optionally substituted heteroaryl, the tributyltin derivative should be used, whereas zincate should be used for cases where R 2 is saturated. R2-SnR3 or R2-Zn-Y (XX) A compound of formula (XXIX) can be prepared from a compound of formula (XXX) (XXX) When L2 and L3 are chloro, a chlorinating agent such as phosphorus oxychloride. A compound of formula (XXX) can be prepared by reaction of a compound of formula (XXVII) wherein PG1 and PG2 are alkyl of 1 to 6 carbon atoms such as methyl or ethyl: (XXVII) with a compound of formula (XXXI) (XXXI) The compounds of formula (XXVII) and the compounds of formula (XXXI) are commercially available or can be prepared using convenient methods described in the literature, known to those skilled in the art or described in the examples herein. A compound of formula (I) wherein X is -C (O) NR4 CR6R7-, -NR4C (O) NR5CR6R7- or -S (O) 2NR CR6R7- can be prepared by reacting a compound of formula (I) wherein X is -NH2CR6R7- with the appropriate compound of formula (XVI) in the presence of a suitable base such as triethylamine.

Analogously, a compound of formula (I) wherein X is -C (O) NR 4 -, - NR C (O) NR 5 - or -S (O) 2 NR 4 - can be prepared by reaction of a compound of formula (XXXII) with an appropriate compound of formula (XVI): (XVI) A compound of formula (XXXII) can be prepared by reaction of a compound of formula (XXXIII) (XXXIII) with a compound of formula (V) (V) This reaction can be carried out in a solvent such as tetrahydrofuran in the presence of a suitable base such as triethylamine. A compound of formula (XXXI I I) can be prepared by reaction of a compound of formula (XXXVI) wherein L3 is a labile group such as halo (for example chlorine).

(XXXIV) with a suitable organometallic reagent such as the tributyltin derivative or the zinkate of formula (XX) wherein Y can be halo such as chloro. Wherein R2 is unsaturated such as optionally substituted aryl or heteroaryl, the tributyltin derivative should be used, while the zincate should be used for the cases in which R2 is saturated. R2-Sn R3 or R2-Zn-Y (XX) A compound of formula (XXXIV) can be prepared from a compound of formula (XXXV) (XXXV) When L2 and L3 are chlorine, a chlorinating agent can be used such as phosphorus oxychloride. A compound of formula (XXXV) can be prepared by reacting a compound of formula (XXVII) wherein PG1 and PG2 are alkyl of 1 to 4 carbon atoms such as methyl or ethyl.

(XXVII) with a compound of formula (XXXVI) (XXXI) Analogously, compounds can be prepared wherein X is -NR S (O) 2- starting from a compound of formula (XXVII) and a compound of formula (XXXVI) wherein PG3 is a thiol protecting group .

(XXXVI) A compound of formula (I), wherein X is -X1CR6R7- and X1 is -NR4-, -O-, -S-, -S (O) -, or -S (O) 2- can be prepare from a compound of formula (XXXVII), wherein L1 is a leaving group such as halo (for example, chloro), tosyl, mesyl, etc., by reaction with a compound of formula (XXXVIII) in the presence of a Suitable base such as triethylamine or sodium hydride and a solvent such as tetrahydrofuran or A /./ Vd / methylformamide: (X A compound of formula (I) wherein X is -X1CR6R7- and X1 is -S- can be prepared from a compound of formula (XXXIX), by reaction with a compound of formula (XXXVIII) in the presence of a Suitable base such as sodium hydroxide and a solvent such as /,? / - / p7-ethylformamide: (A compound of formula (XXXIX), can be prepared from a compound of formula (II), by reaction with thiourea in a suitable solvent such as ethanol: A compound of formula (I), wherein X is -X1CR6R7- and X1 is -NR4-, -O-, -S-, -S (O) -, or -S (O) 2- can be prepared by the reaction of a compound of formula (XXXX), with a suitable organometallic reagent (such as the activated ester of boronic acid) R2B (OR) 3 wherein R is alkyl of 1 to 4 carbon atoms such as methyl), in the presence of a suitable metal catalyst (such as palladium or copper) using such a solvent as 1,4-dioxane.

A compound of formula (XXXX) can be prepared by reacting a compound of formula (XXXXI) with a compound of formula (V).

(XXXXI) (XXXX) A compound of formula (XXXXII), wherein X 1 is -S-, -S (O) -, -S (O) 2-, -NR 4 SO 2 - or -NR 4 C (O) - can be prepared from a compound of formula (I) by reaction with compounds of formula (XXXXIII) and formula (XXXXIV), wherein L1 and L2 are leaving groups such as halo (for example chloro), tosyl, mesyl, etc., in presence of a suitable base such as sodium hydride and a solvent such as tetrahydrofuran.

A compound of formula (XXXXII) can be prepared from a compound of formula (XXXXV) by reaction with a compound of formula (III) or by the reaction of a compound of formula (XXXXVI) with a compound of formula (XXXVIII).

A compound of formula (XXXXV) can be prepared by standard interconversions of functional groups well known in the literature, from a compound of formula (XXXXVII).

( A compound of formula (XXXXVII) can be prepared from a compound of formula (XVIII), or a suitable derivative thereof, such as a? / - methoxy -? / - methyl amide, with suitable organometallic reagents, such as R6MgBr and R7MgBr, in a one-stage or two-stage process.

A compound of formula (I), wherein X is -NR4C (O) -, -NR4C (O) CR6R7-, -NRS (O) 2-, or -NR4S (O) 2CR6R7-, can be prepared from of a compound of formula (XXXXVIII) wherein X1 is -C (O) -, -C (O) CR6R7-, -S (O) 2-, or -S (O) 2CR6R7- and L1 is a suitable leaving group such as chlorine or an activated ester, with an amine of formula (XXXXIX), in the presence of a suitable base such as triethylamine.

( A compound of formula (I), wherein X is -NR4CHR6-, can be prepared by the reaction of a compound of formula (XXXXX) with an amine of formula (XXXXIX) in the presence of a suitable reducing agent such as NaCNBH3.

( It will be appreciated that some of the various substituents on the ring in the compounds of the present invention can be introduced by standard aromatic substitution reactions or generated by conventional modifications of functional groups either before or immediately after the above-mentioned processes, and as such they include in the process aspect of the invention. For example, the compounds of formula (I) can be converted to other compounds of formula (I) by standard aromatic substitution reactions or by conventional modifications of functional groups. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and the reaction conditions for such processes are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example an acyl halide and Lewis acid (such as aluminum trichloride) under Friedel reaction conditions. -Crafts; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminum trichloride) under Friedel-Crafts reaction conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group to an amino group for example, by catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl. It will also be appreciated that in some of the reactions mentioned herein it may be necessary / desirable to protect any sensitive groups in the compounds. The cases in which protection and adequate methods for protection are necessary or desirable are known to those skilled in the art. Conventional protecting groups can be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if the reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl group, ethoxycarbonyl or ferc-butoxycarbonyl, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protective groups necessarily vary with the choice of the protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed, for example by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be removed, for example , by hydrogenation on a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example boron tris (trifluoroacetate). An alternative protecting group suitable for a primary amino group is, for example, a phthaloyl group, which can be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of the protecting group. Thus, for example, an acyl group such as an alkanoyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an arylmethyl group such as a benzyl group can be removed, for example by hydrogenation on a catalyst such as palladium on carbon.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or ethyl group which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which can be removed, for example by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which can be removed, for example by hydrogenation on a catalyst such as palladium on carbon. The protecting groups can be removed at any convenient stage of the synthesis using conventional methods well known in the chemical art. Many of the intermediates defined herein are new, and these are provided as a further feature of the invention. Biological Assays The following assays can be used to measure the effects of the compounds of the present invention as inhibitors of mTOR kinase, as inhibitors of PI3 kinases, as in vitro inhibitors of the activation of signaling pathways of PI3 kinases and as inhibitors in Vitro proliferation of human breast adenocarcinoma cells MDA-MB-468. (a) mTOR In Vitro Kinase Assay The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant mTOR. -terminal of mTOR that covers the residues of amino acids 1362 to 2549 of mTOR (Access No. to EMBL L34075) was stably expressed as a FLAG-labeled fusion in HEK293 cells as described by Vilella-Bach et al., Journal of Biochemistry, 1999, 274, 4266-4272. The stable HEK293 mTOR cell line labeled with FLAG (1362-2549) was routinely maintained at 37 ° C with 5% CO2 to a confluence of 70-90% in Dulbecco's modified Eagle growth medium (DMEM).; Invitrogen Limited, Paisley, UK, Catalog No. 41966-029) containing 10% inactivated fetal calf serum by heating (FCS; Sigma, Poole, Dorset, UK, Catalog No. F0392), 1% L-glutamine (Gibco, Catalog No. 25030-024) and 2 mg / ml Geneticin (G418 sulfate; Invitrogen Limited, UK, Catalog No. 10131-027). Following expression in the mammalian HEK293 cell line, the expressed protein was purified using the FLAG epitope tag using standard purification techniques. Test compounds were prepared as 10 mM stock solutions in DMSO and diluted in water as required to give a range of final test concentrations. Aliquots (2 μl) of each dilution of the compounds were placed in a well of a 384-well small volume (LV) Greiner polystyrene white plate (Greiner Bio-ona). A mixture of 30 μl of the purified recombinant mTOR enzyme, 1 μM biotinylated peptide substrate (Biotin-Ahx-Lys-Lys-Ala-Asn-GIn-Val-Phe-Leu-Gly-Phe-Thr-Tyr-Val-Ala- Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH2; Bachem UK Ltd.), ATP (20 μM) and a buffer solution [comprising Tris-HCl buffer pH 7.4 (50 mM), EGTA (0.1 mM), bovine serum albumin (0.5 mg / ml), DTT (1.25 mM) and manganese chloride (10 mM)] was stirred at room temperature for 90 minutes. Control wells were created that produced a maximum signal corresponding to the maximum activity of the enzyme using 5% DMSO instead of the test compound. Control wells were created that produced a minimal signal corresponding to the enzyme totally inhibited by the addition of EDTA (83 mM) in place of the test compound. These test solutions were incubated for 2 hours at room temperature. Each reaction was stopped by the addition of 10 μl of a mixture of EDTA (50 mM), bovine serum albumin (BSA, 0.5 mg / ml) and Tris-HCl buffer pH 7.4 (50 mM) containing Monoclonal Antibody 1A5 of the p70 S6 kinase (T389) (Cell Signaling Technology, Catalog No. 9206B) and Streptavidin donor and protein A Alpha-Screen acceptor beads (200 ng; Perkin Elmer, Catalog No.-6760002B and -6760137R, respectively) were added and the test plates were left for approximately 20 hours at room temperature in the dark. The resulting signals from excitation with laser light at -680 nm were read using a Packard Envision instrument. The phosphorylated biotinylated peptide is formed in situ as a result of mTOR-mediated phosphorylation. The phosphorylated biotinylated peptide that is associated with the Streptavidin AlphaScreen donor beads forms a complex with the Monoclonal Antibody 1A5 of the p70 S6 kinase (T389) which is associated with the acceptor accounts of Protein A Alpha-Screen. After excitation with laser light at -680 nm, the complex donor accounts: acceptor accounts produce a signal that can be measured. Accordingly, the presence of the mTOR kinase activity results in a test signal. In the presence of a mTOR kinase inhibitor, the intensity of the signal is reduced. Inhibition of the mTOR enzyme for a given test compound was expressed as Cl50 value. (b) In Vitamin PI3K Enzyme Assay The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant PI3K enzymes Type I of the lipid PI (4.5) P2. DNA fragments encoding the human PI3K catalytic and regulatory subunits were isolated from cDNA libraries using standard molecular biology techniques and PCR cloning. The selected DNA fragments were used to generate baculovirus expression vectors. In particular, total length DNA of each of the p110 isoforms of human PI3K Type p110a, p110β and p110d (EMBL Accession Nos. HSU79143, S67334, Y10055 for p110a, p110β and p110d respectively) were subcloned into a vector pDESTIO (Invitrogen Limited, Fountain Drive, Paisley, United Kingdom). The vector is a version adapted by Gataway from FastBad that contains an epitope-6-His marker. A truncated form of the p110 isoform? of Human PI3K Type Ib corresponding to amino acid residues 144-1102 (Access No. to EMBL X8336A) and the total length human p85a regulatory subunit (EMBL Accession No. HSP13KIN) were also subcloned into the pFastBad vector containing an epitope-6-His marker. The p110 constructs of Type la were co-expressed with the p85a regulatory subunit. Following expression in the baculovirus system using standard baculovirus expression techniques, the expressed proteins were purified using the His epitope tag using standard purification techniques. The DNA corresponding to amino acids 263 to 380 of the human general receptor for the PH domain of phosphoinositides (Grp1) was isolated from a cDNA library using standard molecular biology techniques and PCR cloning. The resulting DNA fragment was subcloned into an E. coli expression vector pGEX 4T1, which contained a marker of the GST epitope (Amersham Pharmacia Biotech, Rainham, Essex, United Kingdom) as described by Gray et al., Analytical Biochemistry. 2003, 313: 234-245). The PH domain of Grp1 labeled with GST was expressed and purified using standard techniques. Test compounds were prepared as stock solutions mM in DMSO and diluted in water as required to give a range of final assay concentrations. Aliquots (2 μl) of each dilution of the compounds were placed in a well of a 384-well small volume (LV) polystyrene Greiner white plate (Greiner Bio-ona, Brunel Way, Stonehouse, Gloucestershire, United Kingdom, Catalog No. 784075). A mixture of each selected purified recombinant PI3K enzyme (15 ng), substrate Dic8-PI (4.5) P2 (40 μM, Cell Signis Inc., Kinnear Road, Columbus, USA, Catalog No. 901), adenosine triphosphate (ATP; 4 μM) and a buffer solution [comprising tris-HCl buffer pH 7.6 (40 mM, 10 μl), 3 - [(3-colamidopropyl) dimethylammonium 1-propanesulfonate] (CHAPS, 0.04%), dithiothreitol (DTT, 2 mM) and chloride of magnesium (10 mM) was stirred at room temperature for 20 minutes. Control wells were created that produced a minimum signal corresponding to the maximum activity of the enzyme using 5% DMSO instead of the test compound. Control wells were created that produced a maximum signal corresponding to the enzyme totally inhibited by the addition of wortmannin (6 μM, Calbiochem / Merck Bioscience, Padge Road, Beeston, Nottingham, United Kingdom, Catalog No. -681675) in place of the test compound. These test solutions were also stirred for 20 minutes at room temperature. Each reaction was stopped by the addition of 10 μl of a mixture of EDTA (100 mM), bovine serum albumin (BSA, 0.045%) and buffer Tris-HCl pH 7.6 (40 mM). Biotinylated Dic8-PI (3.4.5) (50 nM; Cell Signis Inc., Catalog No. 107), purified recombinant protein GST-Grp1 PH (2.5 nM) and AlphaScreen Anti-GST donor and acceptor beads (100 ng) were added.; Packard Bioscience Limited, Station Road, Pangbourne, Berkshire, United Kingdom, Catalog No.-6760603M) and the assay plates were left for approximately 5 to 20 hours at room temperature in the dark. The resulting signals from excitation with laser light at -680 nm were read using an instrument Packard AlphaQuest. As a result of the phosphorylation of PI (4.5) P2 mediated by PI3K, PI (3.4.5) P3 is formed in situ. The GST-Grp1 PH domain protein that is associated with the AlphaScreen Anti-GST donor beads forms a complex with the biotinylated PI (3.4.5) P3, which is associated with the Streptavidin AlphaScreen acceptor accounts. PI (3.4.5) P3 produced enzymatically competes with biotinylated PI (3.4.5) P3 for binding to the PH domain protein. After excitation with laser light at -680 nm, the donor / acceptor account complex produces a signal that can be measured. Accordingly, the enzymatic activity of PI3K to form PI (3.4.5) P3 and competition with biotinylated PI (3.4.5) P3 results in a reduced signal. In the presence of an inhibitor of the PI3K enzymes, the intensity of the signal is recovered. Inhibition of the PI3K enzymes for a given test compound was expressed as a Cl50 value. (c) Assay of phospho-Ser473 Akt in Vitro This assay determines the ability of test compounds to inhibit phosphorylation of Serine 473 in Akt as assessed using Acumen Explorer technology (Acumen Bioscience Limited), a plate reader which can be used to quickly quantify the characteristics of the images generated by laser scanning. A line of human breast adenocarcinoma cells MDA-MB-468 (LGC Promochem, Teddington, Middlesex, UK, Catalog No. HTB-132) was routinely maintained at 37 ° C with 5% CO2 to a confluence of 70-90% in DMEM containing 10% FCS deactivated by heating and 1% L-glutamine.

For the assay, cells were removed from the culture flask using 'Accutase' (Innovative Cell Technologies Inc., San Diego, CA, USA, Catalog No. AT104) using standard tissue culture methods, and resuspended in medium to give 1.7 x 10 5 cells per ml. Aliquots (90 μl) were seeded in each of the 60 internal wells of a 96-well Packard black plate (Perkin Elmer, Boston, MA, USA, Catalog No. -6005182) to give a density of ~ 15,000 cells per well. Aliquots (90 μl) of culture medium were placed in the outer wells to prevent edge effects. The cells were incubated overnight at 37 ° C with 5% CO2 to allow them to adhere. On day 2, the cells were treated with the test compounds and incubated for 2 hours at 37 ° C with 5% CO2. The test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required with growth medium to give a range of concentrations that were 10 times higher than the final test concentrations required. Aliquots (10 μl) of each dilution of the compound were placed in a well (in triplicate) to give the required final concentrations. As a control of the minimum response, each plate contained wells having a final concentration of 100 μM LI294002 (Calbiochem, Beeston, United Kingdom, Catalog No. 440202). As a control of the maximum response, the wells contained 1% DMSO in place of the test compound. After incubation, the contents of the plates were fixed by treatment with a 1.6% formaldehyde aqueous solution (Sigma, Poole, Dorset, UK, Catalog No. F1635) at room temperature for 1 hour. All subsequent aspiration and washing steps were carried out using a 96-well Tecan plate washer (aspiration speed 10 mm / sec). The fixation solution was removed and the contents of the plates were washed with phosphate buffered saline (PBS); 50 μl; Gibco, Catalog No. 10010015). The contents of the plates were treated for 10 minutes at room temperature with an aliquot (50 μl) of a cell permeabilization plug constituted by a mixture of PBS and 0.5% Tween-20. The permeabilization buffer1 was removed and the non-specific binding sites were blocked by treatment for 1 hour at room temperature of an aliquot (50 μl) of a blocking buffer consisting of 5% non-fat dry milk ['Marvel' ( Registered trademark); Premier Beverages, Stafford, GB] in a mixture of PBS and 0.05% Tween-20. The 'blocking' buffer was removed and the cells were incubated for 1 hour at room temperature with anti-phospho-Akt rabbit antibody solution (Ser473) (50 μl per well; Cell Signaling, Hitchin, Herts, UK, Catalog No. 9277) that had been diluted in a 1: 500 ratio in blocking buffer. The cells were washed 3 times in a mixture of PBS and 0.05% Tween-20.

Subsequently, the cells were incubated for 1 hour at room temperature with goat anti-rabbit IgG labeled with Alexafluor488 (50 μl per well, Molecular Probes, Invitrogen Limited, Paisley, UK, Catalog No. A11008) which had been diluted 1: 500 ratio in 'blocking buffer' The cells were washed 3 times with a mixture of PBS and 0.05% Tween-20, An aliquot of PBS (50 μl) was added to each well, the plates were sealed with Black plate sealers, and the fluorescence signal was detected and analyzed The fluorescence response data at the dose obtained with each compound were analyzed and the degree of inhibition of Serine 473 in Akt was expressed as a Cl50 value. In Vitro Trial of Proliferation of Human Breast Adenocarcinoma MDA-MB-468 This assay determines the ability of test compounds to inhibit cell proliferation as assessed using Cellomics Arrayscan technology. Human breast adenocarcinoma cells (MDA-MB-468) (LGC Promochem, Catalog No. HTB-132) was routinely maintained as described in Biological Assay (b) herein. For the proliferation assay, the cells were detached from the culture flask using Accutase and seeded in the interior 60 wells of a 96-well black Packard plate at a density of 8000 cells per well in 100 μl of complete growth medium. The outer wells contained 100 μl of sterile PBS. The cells were incubated overnight at 37 ° C with 5% CO2 to allow the same to adhere. On day 2, the cells were treated with the test compounds and incubated for 48 hours at 37 ° C with 5% CO2. The test compounds were prepared as stock solutions 10 mM in DMSO and serially diluted if required with growth medium to give a range of test concentrations. Aliquots (50 μl) of each dilution of the compound were placed in a well and the cells were incubated for 2 days at 37 ° C with 5% CO2. Each plate contained control wells without test compound. On day 4, the BrdU labeling reagent (Sigma, Catalog No. B9285) was added at a final dilution of 1: 1000, and the cells were incubated for 2 hours at 37 ° C. The medium was removed and the cells from each well were fixed by treatment with 100 μl of a mixture of ethanol and glacial acetic acid (90% ethanol, 5% glacial acetic acid and 5% water) for 30 minutes at room temperature. Cells from each well were washed twice with PBS (100 μl). Aqueous hydrochloric acid (2M, 100 μl) was added to each well. After 20 minutes at room temperature, the cells were washed twice with PBS. Hydrogen peroxide (3%, 50 μl, Sigma, Catalog No. H1009) was added to each well. After 10 minutes at room temperature, the wells were again washed with PBS.

Incorporation of BrdU was detected by incubation for 1 hour at room temperature with anti-BrdU mouse antibody (50 μl, Caltag, Burlingame, CA, USA, Catalog No. MD5200) that was diluted 1:40 in PBS containing 1% BSA and 0.05% Tween-20. The unbound antibody was removed with two PBS washes. For visualization of the incorporated BrdU, the cells were treated for 1 hour at room temperature with PBS (50 μl) and 0.05% Tween-20 buffer containing a 1: 1000 dilution of goat anti-mouse IgG labeled with Alexafluor 488. For visualization of the cell nucleus, a 1: 1000 dilution of Hoechst dye (Molecular Probes, Catalog No. H3570) was added. Each plate was washed in turn with PBS. Subsequently, PBS (100 μl) was added to each well and the plates analyzed using a Cellomics network scan to evaluate the total number of cells and the number of BrdU-positive cells. The fluorescence response data were analyzed at the dose obtained with each compound and the degree of growth inhibition of the MDA-MB-468 cells was expressed as a Cl50 value. Although the pharmacological properties of the compounds of formula (I) vary with the change in structure as would be expected, it is generally believed that the activity possessed by the compounds of formula (I) can be demonstrated at the following concentrations or doses in one or more than tests (a) to (d) above: - Test (a): - Cl50 versus mTOR kinase at less than 10 μM, in particular 0.001-0.5 μM for many compounds; for Example-65, the Cl50 value was measured three times, with the values 3.9, 4.1 and 8.2 μM, resulting in an average value of 5.4 μM. Test (b): - CI5o versus human PI3K p110? Type Ib less than 10 μM, in particular 0.001-0.5 μM for many compounds; and CI5o versus human PI3K p110a Type a at less than 10 μM, in particular 0.001- 0.5 μM for many compounds; for Example-65, the Cl50 value was measured three times, with the values 1.9, 13.0 and 5.7 μM, resulting in an average value of -6.8 μM. Test (c): - Cl50 versus Serine 473 in Akt at less than 10 μM, in particular 0.1-20 μM for many compounds); for Example 44 the Cl50 value was measured five times, with the values 12.5, 5.6, 9.7, 10.3 and-6.1 μM, resulting in an average value of 8.84 μM. Test (d): - Cl50 at less than 20 μM. The compounds of the present invention are advantageous in the sense that they possess pharmacological activity. In particular, the compounds of the present invention modulate (in particular, inhibit) the mTOR kinase and / or the phosphatidyl-inositol-3-kinase (PI3K) enzymes, such as the PI3K enzyme enzymes of Class la (eg PI3Kalfa, PI3Kbeta and PI3Kdelta). ) and the PI3K enzyme of Class Ib (PI3Kgamma). More particularly, the compounds of the present invention modulate (in particular, inhibit) the mTOR kinase. More particularly, the compounds of the present invention modulate (in particular, inhibit) one or more PI3K enzymes. The inhibitory properties of the compounds of formula (I) can be demonstrated using the test procedures set forth herein and in the experimental section. Accordingly, the compounds of formula (I) can be used in the treatment (therapeutic or prophylactic) of conditions / -diseases in human and non-human animals that are mediated by mTOR kinase and / or one or more PI3K enzymes, and in particular for the mTOR kinase. The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically acceptable diluent or carrier. The compositions of the invention can be in a form suitable for oral use (for example as tablets, pills, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for administration parenteral (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intraperitoneal or intramuscular dosing, or as a suppository for rectal dosing). The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavorings and / or preservatives. The amount of active ingredient that is combined with one or more excipients to produce a simple dosage form will necessarily vary depending on the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 1 mg to 1 g of active agent (more conveniently from 1 to 250 mg, for example from 1 to 100 mg) mixed with an appropriate and convenient amount. of excipients which may vary from about 5 to about 98 weight percent of the total composition. The size of the dose for therapeutic or prophylactic purposes of a compound of formula (I) will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, in accordance with well-known medicine principles. In the use of a compound of formula (I) for therapeutic or prophylactic purposes, it will generally be administered in such a way that a daily dose in the range, for example, from 1 mg / kg to 100 mg / kg is received. body weight, administered if necessary in divided doses. In general, lower doses will be administered when a parenteral route is used. Thus, for example, for intravenous administration, a dose in the range of, for example, 1 mg / kg to 25 mg / kg of body weight will generally be used. Similarly, for administration by inhalation, a dose in the range of, for example, 1 mg / kg to 25 mg / kg of body weight will be used. As a rule, the unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention. As indicated herein, it is known that mTOR kinase and PI3K enzymes play roles in tumorigenesis as well as in numerous other diseases. It has been found that the compounds of formula (I) possess potent antitumor activity, which is believed to be obtained by the inhibition of mTOR kinase and / or one or more of the PI3K enzymes. Accordingly, the compounds of the present invention are valuable as antitumor agents.

Particularly, the compounds of the present invention are valuable as anti-proliferative, apoptotic and / or anti-invasive agents in the containment and / or treatment of solid and / or liquid tumor diseases. In particular, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumors that are sensitive to the inhibition of mTOR and / or one or more of the PI3K enzymes such as the Class PI3K enzymes and the PI3K enzyme of Class Ib. Additionally, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumors that are mediated exclusively or in part by mTOR and / or one or more of the PI3K enzymes such as PI3K enzymes of Class la and the PI3K enzyme of Class Ib. The compounds can therefore be used to produce an inhibitory effect of the mTOR enzyme in a warm-blooded animal in need of treatment. Certain compounds can be used to produce an inhibitory effect of the PI3K enzymes in a warm-blooded animal in need of treatment. As indicated herein, mTOR kinase inhibitors and / or one or more of the PI3K enzymes, should be therapeutically valuable for the treatment of proliferative diseases such as cancers and in particular solid tumors such as carcinomas and sarcomas and leukemias. and malignant lymphoid diseases, and in particular for the treatment of, for example, breast, colorectal, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchoalveolar lung cancer) and prostate, cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovaries, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and leukemias [including acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML)], multiple myeloma and lymphomas. According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use as a medicament in a warm-blooded animal such as man. According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the production of an anti-proliferative effect in a blood animal. hot like man. According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the production of an apoptotic effect in a warm-blooded animal such like man. According to a further feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in a warm-blooded animal such as man, as an anti-inflammatory agent. -invasive in the containment and / or treatment of a proliferative disease such as cancer. According to a further aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for the production of an anti-proliferative effect in an animal of hot blood such as man. According to a further feature of this aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

According to a further aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for the production of an apoptotic effect in a warm-blooded animal such as man. According to a further feature of this aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the production of an apoptotic effect in a warm-blooded animal such as man. According to a further feature of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for use in an animal of warm blood such as man as an anti-invasive agent in the containment and / or treatment of a proliferative disease such as cancer. According to a further feature of this aspect of the invention, there is provided a method for the production of an anti-proliferative effect in a warm-blooded animal such as the man in need of treatment, which comprises administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. According to the additional feature of this aspect of the invention, there is provided a method for producing an anti-invasive effect by the containment and / or treatment of a solid tumor disease in a warm-blooded animal, such as man, in need of treatment, which comprises administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. According to a further aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for use in the prevention or the treatment of a proliferative disease such as cancer, in a warm-blooded animal such as man. According to a further feature of this aspect of the invention, there is provided a method for the prevention or treatment of a proliferative disease such as cancer in a warm-blooded animal, such as man, in need of treatment, which comprises administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for use in the prevention or treatment of those tumors that are sensitive to the inhibition of mTOR kinase and / or one or more PI3K enzymes (such as the Class a enzymes and / or the PI3K enzyme of Class Ib) that are involved in the signal transduction steps that lead to proliferation, survival, invasiveness and migratory fitness of tumor cells. According to a further feature of this aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the use in the prevention or treatment of those tumors that are sensitive to the inhibition of mTOR kinase and / or one or more PI3K enzymes (such as PI3K enzymes of Class la and / or PI3K enzyme of Class Ib) that are involved in the transduction steps of signals that lead to the proliferation, survival, invasiveness and migratory ability of tumor cells. According to a further feature of this aspect of the invention, there is provided a method for the prevention or treatment of those tumors that are sensitive to the inhibition of mTOR kinase and / or one or more PI3K enzymes (such as PI3K enzymes). of the Class la and / or the PI3K enzyme of Class Ib) that are involved in the steps of signal transduction leading to proliferation, survival, invasiveness and migratory ability of tumor cells, comprising administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in making available an inhibitory effect of mTOR kinase and / or an inhibitory effect of a PI3K enzyme (such as an inhibitory effect of a PI3K enzyme of Class la or of the PI3K enzyme of Class Ib). According to a further feature of this aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined herein, in the manufacture of a medicament for use in the providing an inhibitory effect of the mTOR kinase and / or an inhibiting effect of a PI3K enzyme (such as an inhibitory effect of a PI3K enzyme of Class or PI3K enzyme of Class Ib). According to a further aspect of the invention, there is also provided a method for providing an inhibitory effect of the mTOR kinase and / or an inhibiting effect of a PI3K enzyme (such as an inhibitory effect of a PI3K enzyme of Class a or PI3K enzyme of Class Ib) comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined herein. According to a further feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer, inflammatory diseases, obstructive pathway diseases. air, immunological diseases or cardiovascular diseases.

According to a further feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of solid tumors such as carcinomas and sarcomas and leukemias. and malignant lymphoid diseases. According to a further feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of breast, colorectal, pulmonary (including of small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and prostate cancer. According to a further feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovaries, pancreas, skin, testes, thyroid, uterus of cervix and vulva, and leukaemias (including of ALL and CML), multiple myeloma and lymphomas. According to a further feature of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of cancer. , inflammatory diseases, obstructive diseases of the airways, immunological diseases or cardiovascular diseases. According to a further feature of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of tumors. solids such as carcinomas and sarcomas and from leukemias and malignant lymphoid diseases. According to a further feature of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of cancer. breast, colorectal, pumonar (including small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and prostate cancer. According to a further feature of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of cancer. of the bile ducts, bones, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovaries, pancreas, skin, testes, thyroid, uterus, cervix and vulva, as well as leukemias (including ALL and CML), multiple myeloma and lymphomas. According to a further feature of the invention, a method is provided for the treatment of cancer, inflammatory diseasesObstructive diseases of the airways, immunological diseases or cardiovascular diseases in a warm-blooded animal such as man, which needs treatment, which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. same, as defined in this report. According to a further feature of the invention, there is provided a method for treatment of solid tumors such as carcinomas and sarcomas and of leukemias and lymphoid malignancies in a warm-blooded animal such as man, which needs treatment, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. According to a further feature of the invention, there is provided a method for treatment of breast, colorectal, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and prostate cancer in a a warm-blooded animal such as man, which needs treatment, which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. According to a further feature of the invention, there is provided a method for treatment of cancer of bile ducts, bones, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovaries, of pancreas, skin, testicles, thyroid, uterus, cervix and vulva, and leukemias (including ALL and CML), multiple myeloma and lymphomas in a warm-blooded animal such as the man who needs the treatment, which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. As indicated herein, the in vivo effects of a compound of formula (I) may be exerted in part by one or more metabolites that are formed in the human or animal body after administration of a compound of formula (I). The invention further relates to combination therapies in which a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of formula (I) is administered simultaneously or sequentially or as a preparation combined with another treatment of use in the control of an oncological disease. In particular, the treatment defined herein may be applied as a single therapy or may involve, in addition to the compounds of the invention, conventional surgery, radiotherapy or chemotherapy. Accordingly, the compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of cancer. Suitable agents for use in combination include: - (i) antiproliferative / antineoplastic agents and combinations thereof, as used in medical oncology, such as alkylating agents (eg cis-platinum, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil , busulfan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine-arabinoside, hydroxyurea and gemcitabine); antitumor antibiotics (for example anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids such as vincristine, vinblastine, vindesine and vinorrelbine, and taxoids such as paclitaxel and taxotere); and inhibitors of topoisomerases (for example epipodophylotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecins); (ii) cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and yodoxifen), decreasing regulators of estrogen receptors (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorrelide and buselerin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and reductase 5a inhibitors such as Finasteride); (iii) anti-invasive agents (for example inhibitors of the c-Src family of kinases, such as 4- (6-chloro-2,3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl) ethoxy] - 5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and? / - (2-chloro-6-methylphenyl) -2- { 6- [4- (2-hydroxyethyl) piperazine- 1-yl] -2-methylpyrimidin-4-ylamino, thiazole-5-carboxamide (dasatinib, BMS-354825, J. Med. Chem., 2004, 47, -6658-6661), and inhibitors of metalloproteases as marimastat and inhibitors of plasminogen activator receptor function urokinase); (iv) inhibitors of growth factor function: for example, such inhibitors include antibodies to growth factors and antibodies to growth factor receptors (for example the anti-erbB2 trastuzumab [Herceptin ™] antibody and the anti-cancer antibody). erbB1 cetuximab [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors (eg, inhibitors of the epidermal growth factor family (eg, EGFR family of tyrosine kinase inhibitors such as / - (3-chloro-4-fluorophenyl) ) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, ZD1839), / - (3-etinylphenyl) -6.7-bis (2-methoxyethoxy) -quinazolin-4-amino (erlotinib, OSI-774) and -6-acrylamido- / - (3-chloro-4-fluorophenyl) -7 - (3-morpholinopropoxy) quinazolin-4-amine (Cl 1033) and erbB2 tyrosine kinase inhibitors such as lapatinib), inhibitors of the family of growth factors of hepatocytes, inhibitors of the family of the growth factor derived from platelets such as imatinib, serine / threonine kinase inhibitors (for example inhibitors of Ras / Raf signaling such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)) and inhibitors of cell signaling by MEK and / or Akt kinases; (v) anti-angiogenic agents such as those that inhibit the effects of vascular endothelial growth factor, [e.g., the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin ™) and the inhibitors of the VEGF receptor tyrosine kinase such as 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy) quinazoline (ZD6474; Example 2 in WO 01/32651), 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD 2171; Example 240 in WO 00 / 47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and compounds that act by other mechanisms (for example, linomide, inhibitors of the integrin function avß3 and angiostatin)]; (vi) vascular deterioration agents such as combretastatin A4 and compounds described in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense therapeutics (eg those targeting the targets listed above, such as ISIS 2503, an anti-ras antisense agent; (viii) gene therapy methods, which include methods for replacing aberrant genes such as aberrant p53 or Aberrant BRCA1 or BRCA2, GDEPT (gene-directed prodrug enzyme therapy) methods such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme, and methods to increase patient tolerance to chemotherapy or radiotherapy such as Multi-drug resistance gene therapy; and (ix) immunotherapeutic approaches, including ex vivo and in vivo methods for enhancing the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, methods to decrease the anergy of T cells, methods using transfected immune cells such as dendritic cells transfected by cytokines, methods using tumor cell lines transfected by cytokines and methods using anti-idiotypic antibodies. The invention will be explained in more detail below with reference to the following illustrative examples. Unless otherwise indicated, the starting materials were commercially available. All commercial solvents and reagents were laboratory grade and were used as received. In the examples, 1 H NMR spectra were recorded on a Bruker DPX 300 (300 MHz), Bruker DRX 400 (400 MHz) or a Bruker DRX 500 (500 MHz) instrument. The central peaks of chloroform-d (dH 7.27 ppm), dimethylsulfoxide-d6 (dH 2.50 ppm), or acetone-d6 (dH 2.05 ppm) were used as internal references. The following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, expand. Column chromatography was carried out using silica gel (0.04-0.063 mm, Merck). In general, a reverse phase Kromasil KR-100-5-C18 column (250 x 20 mm, Akzo Nobel) was used for preparative HPLC, with mixtures of acetonitrile and water [containing 0.1% trifluoroacetic acid (TFA)] used as the eluent at a flow rate of 10 ml / min. The following methods were used for analysis by liquid chromatography (LC) / mass spectrometry (MS): - HPLC: Agilent 1100 or Waters Alliance HT (2790 &2795) Mass spectrometer: Waters ZQ ESCi Column of CLAR The column CLAR standard used is the Phemonenex Gemini C18 of 5 μm, 50 x 2 mm. HPLC Methods Acids The mobile phases used are: Mobile phase A: water Mobile phase B: acetonitrile Mobile phase C: 1% formic acid in water: 50:50 MeCN (v / v) Each method is followed by rapid equilibration using a flow rate of 5 ml for 0.45 min. Four generic CLAR methods are available: Acid Method with 5 Minute Monitor Early acid method for early elution compounds Medium acid method for intermediate elution compounds Late acid method for late elution compounds Basic HPLC methods In some cases, acid standard methods may be unsuitable for the ionization of the compounds or the required chromatographic separation. In such cases, four comparable basic CLAR methods are available. The mobile phases used are: Mobile phase A: water Mobile phase B: acetonitrile Mobile phase D: ammonia 880 0.1% in acetonitrile Each method is followed by a rapid equilibration using a 5 ml candal for 0.45 min.

Basic Method with Minute Monitor Early basic method for early elution compounds Average basic method for intermediate elution compounds Late basic method for late elution compounds The following method was used for analysis by liquid chromatography (LC) / mass spectrometry (MS): - Instrument: Agilent 1100; Column: Waters 'Symmetry' 2.1 x 30 mm; Mass spectral analysis using chemical ionization (APCI); flow rate: 0.7 ml / min; Absorption Wavelength: 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA; Gradient of Solvent: 15-95% Solvent B for 2.7 minutes, followed by 95% Solvent B for 0.3 minutes. The following methods were used for LC analysis: - Method A: - Instrument: Agilent 1100; Column: Kromasil C18 reverse phase silica, 100 x 3 mm, particle size 5 μm; Solvent A: 0.1% TFA / water, Solvent B: 0.08% TFA / acetonitrile; Flow rate: 1 ml / min; Solvent Gradient: 10-100% Solvent B for 20 minutes followed by 100% Solvent B for 1 minute; Absorption Wavelengths: 220, 254 and 280 nm. In general, the retention time of the product was noted. Method B Instrument: Agilent 1100; Column: Waters, reverse phase silica 'Xterra' C8, 100 x 3 mm, particle size 5 μm; Solvent A: 0.015 M ammonia in water, Solvent B: acetonitrile; Flow rate: 1 ml / min, Gradient Solvent: 10-100% Solvent B for 20 minutes followed by 100% Solvent B for 1 minute; Wavelength of Absorption: 220, 254 and 280 nm. In general, the retention time of the product was noted. The following abbreviations are used herein or in the following illustrative examples: - CLAR High Resolution Liquid Chromatography HBTU O- (Benzotriazol-1 -yl) -? /,? /, / ',? /' - tetramethyluronium hexafluorophosphate; HATU hexafluorophosphate O- (7-azabenzotriazol-1-yl) -? /,? /,? / ',? /' - tetramethyluronium; HOBT 1-hydroxybenzotriazole; HOAT 1-hydroxy-7-azabenzotriazole; DIEA? /,? / - diisopropylethylamine; NMP? / - methylpyrrolidin-2-one; DMSO dimethyl sulfoxide; DMF? /,? / - d / methylformamide; DMA? /,? / - d / methylacetamide; THF tetrahydrofuran; DME 1.2-dimethoxyethane; DCCI dicyclohexylcarbodiimide; MeOH methanol; MeCN acetonitrile; DCM dichloromethane; DIPEA? /,? / - diisopropylethylamine. The chemical names were generated by software that used the tool Lexichem Toolkit (v.1.40) of OpenEye Scientific Software (www.eyesopen.com) to generate the names according to the IUPAC. Example 1: 4- (Methylsulfonylmethyl) -6-morpholin-4-yl-2-thiophen-3-yl-pyrimidine 2-Methylsulfanyl-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (151 mg, 0.5 mmol), thiophene-3-boronic acid (141 mg, 1.1 mmol), copper thiophene-2-carboxylate were added. (l) (248 mg, 1.3 mmol), palladium-refractory / s-trifluoropholine (47 mg, 0.04 mmol) with addition of 1,4-dioxane (5 ml) to a microwave container. The system was degassed with nitrogen, sealed and heated in a microwave reactor at 130 ° C for 45 minutes. The resulting products were solubilized with NMP and purified by SCX chromatography, eluting the desired compounds with 7N ammoniacal methanol. The product was further purified using preparative reverse phase HPLC. (see purification details after the table) to provide the title compound (4.3 mg). Spectrum LCEM: MH + 340.5, Retention Time 1.86, Method: see the details after the following table. NMR spectrum: 1 H NMR (300.132 MHz, DMSO) d 3.20 (s, 3H), 3. 71 (s, 8H), 4.47 (s, 2H), 6.83 (s, 1H), 7.60 (dd, 1H), 7.76 (dd, 1H), 8.29 (dd, 1H) The starting material 2-methylsulfanyl-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine was prepared as follows: 2-methylsulfanyl-4- (methylsulfonylmethyl) -6-morpholine -4-pyrimidine 2-Methylsulfanyl-6- (methylsulfonylmethyl) pyrimidin-4-ol (15 g, -63.97 mmol) was heated at reflux in phosphorus oxychloride (100 ml) for about one hour. The phosphorus oxychloride was evaporated and the residue was neutralized with sodium hydroxide solution and extracted into ethyl acetate. The resulting mixture was then dried over magnesium sulfate, filtered and evaporated to dryness to give crude 4-chloro-2-methylsulfanyl-6- (methylsulfonylmethyl) pyrimidine. This was then dissolved in DCM, morpholine (319 mmol, 28 ml) was added and the reaction mixture was stirred at room temperature. After the reaction was complete, the resulting precipitate was collected as a white solid. The concentration of the filtrate gave more solid 2-methylsulfanyl-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (in total 13.7 g). Spectrum LCEM: MH + 304.50, Retention Time 1.49, Method: Basic monitor NMR spectrum: 1H NMR (300.132 MHz, DMSO) d 2.45 (s, 3H), 3. 49-3.74 (m, 8H), 4.37 (s, 2H), 6.66 (s, 1H) ppm. 2-methylsulfanyl-6- (methylsulfonylmethyl) pyrimidin-4-ol It was suspended-6- (chloromethyl) -2-methylsulfanyl-pyrimidin-4-ol (19.07 g, 100 mmol) in acetonitrile (400 ml). To this stirring suspension was added sodium salt of methanesulfinic acid (12.255 g, 120 mmol) and DMF (100 ml). The reaction mixture was then heated to 100 ° C to give a dark suspension and monitored by LCEM. After completion of the reaction, the solvents were removed and the resulting product was added to MeOH: DCM 1: 1 (200 ml) and acidified with acetic acid (10 ml). The resulting precipitate was collected, washed with water (200 ml) and MeOH (100 ml) and dried under vacuum overnight to give the title compound as a white solid (16.45 g). LCEM Spectrum: MH + 235.2, Retention Time 0.5, Method: basic early NMR spectrum: 1 H NMR (300.132 MHz, DMSO) d2.50 (s, 3 H), 3.12 (s, 3 H), 4.39 (s, 2 H), 6.25 (s, 1H), 13.09 (s, 1H) ppm. 6- (Chloromethyl) -2-methylsulfanyl-pyrimidin-4-ol S-methyl-2-thiopseudourea sulfate (20 g, 71.85 mmol), ethyl 4-chloroacetoacetate (10755 ml, 79.04 mmol) and sodium carbonate (13.925 g, 107.78 mmol) were dissolved in water (100 ml). and were stirred at room temperature overnight. The reaction mixture was monitored by TLC, and once completed, the reaction precipitate was collected and the supernatant was neutralized with 6 N hydrochloric acid to provide more reaction precipitate, which was also collected. The accumulated precipitate was then washed with water (x3) and an off white solid was obtained. This was dried under vacuum at -60 ° C for 48 hours to provide the desired compound as a pale yellow / white solid (43.2 g). Mass spectrum: M + 190 NMR spectrum: 1 H NMR (300.132 MHz, CDCl 3) d2.59 (s, 3 H), 4.35 (s, 2H), 6.41 (s, 1H), 12.70 (s, 1H) ppm The compounds shown in Table 1 were prepared in a manner analogous to 4- (methylsulfonylmethyl) -6-morpholin-4-yl- 2-thiophen-3-yl-pyrimidine (Example 1), except where indicated.

Table 1 Example 2: H NMR (300.132 MHz, DMSO) d 3.24 (s, 3H), 3.74 (s, 8H), 4.54 (s, 2H), 6.93 (s, 1H), 7.32 (t, 1H), 7.42 (t , 1H), 7.49 -7.82 (m, 3H) Example 4: H NMR (300.132 MHz, DMSO) d 3.25 (s, 3H), 3.74 (s, 8H), 4.50 (s, 2H), 6.55 (d, 1H), 6.81 (s, 1H), 7.39 (dd, 1H), 7.45 (d, 1H), 7.96 (s, 1H), 8.17 (dd, 1H) ), 8.61 (s, 1H), 11.24 (s, 1H) Example 5: H NMR (300.132 MHz, DMSO) d 3.20 (s, 3H), 3.72 (s, 8H), 3.93 (s, 3H), 4.50 (s, 2H), 6.88 (s, 1H), 6.92 (d , 1H), 8.53 (dd, 1H), 9.11 (d, 1H) Example-6: H NMR (300.132 MHz, DMSO) d 3.25 (s, 3H), 3.76 (s, 8H), 3.91 (s, 3H), 4.54 (s, 2H), 6.90 (s, 1H), 7.21 ( dd, 1H), 7.38 (d, 1H), 7.90 (d, 1H), 7.99 (d, 1H), 8.42 (dd, 1H), 8.83 (s, 1H) Example 7: 1 H NMR (300.132 MHz, DMSO) d 3.22 (s, 3H), 3.73 (s, 8H), 4.52 (s, 2H), 4.58 (d, 2H), 5.25 (t, 1H), 6.90 ( s, 1H), 7.43 (s, 1H), 7.45 (s, 1H), 8.22 (td, 1H), 8.31 (s, 1H) Example 9: H NMR (300.132 MHz, DMSO) d 2.93 (s, 3H), 2.99 (s, 3H), 3.21 (s, 3H), 3.74 (s, 8H), 4.53 (s, 2H), 6.93 (s) , 1H), 7.51 (d, 2H), 8.38 (d, 2H) Example 10: H NMR (300.132 MHz, DMSO) d 3.19 (s, 3H), 3.72 (s, 8H), 4.01 (s, 3H), 4.50 (s, 2H), 6.94 (s, 1H), 9.38 (s, 2H) 1 Example 11: H NMR (300.132 MHz, DMSO) d 3.26 (s, 3H), 3.78 (s, 8H), 4.57 (s) , 2H), 6.97 (s, 1H), 7.59 (dd, 1H), 8.12 (d, 1H), 8.55 (d, 1H), 8.71 (dd, 1H), 8.96 (m, 2H) Details of Purification / Analysis for examples 1 to 12: Example 13: 4- (Benzenesulfonylmethyl) -6-morpholin-4-yl-2-thiophen-3-yl-pyrimidine A suspension of 4- (benzenesulfonylmethyl) -2-methylsulfanyl-6-morpholin-4-yl-pyrimidine (183 mg), 3-thiopheneboronic acid (129.5 mg), copper thiophene-2-carboxylate (l) (248 mg) and tetrakis (triphenylphosphine) palladium (0) (47 mg) in 1,4-dioxane (5 ml) was degassed with a stream of dry nitrogen. This suspension was heated in a microwave reactor (Emrys Optimizer, Personal Chemistry, Sweden) at 130 ° C for 45 minutes. The reaction mixture was then diluted with 1: 9 methanolLDCM and this mixture was purified by chromatography on an 'Isolute SCX-2' column (10 g); International Sorbent Technology Limited, Mid Glamorgan, United Kingdom) by first washing the column with a gradient of 10 to 100% methanol in DCM, followed by elution of the crude product with a mixture of methanolic ammonia (7M): DCM, 1: 3. The methanolic ammonia solution was evaporated and the residues were further purified by HPLC using a Phenomenex 'Gemini' reverse phase preparative column (5 micron silica, 21.2 mm diameter, 100 mm length) using decreasingly polar mixtures of water and acetonitrile. (containing 2% formic acid) as eluent, to give the title compound (87.3 mg). LCEM Spectrum: MH + 402.73, Retention Time 1.96, Method: Acid Monitor NMR Spectrum: 1H NMR (300.132 MHz, DMSO) d 3.56 - 3.74 (m, 8H), 4.68 (s, 2H), 6.66 (s, 1H), 7.37 (dd, 1H), 7.50 (dd, 1H), 7.54-7.69 (m, 2H), 7.75 (tt, 1H), 7.78-7.84 (m, 2H), 7.90 (dd, 1H) The starting material 4- (benzenesulfonylmethyl) -2-methylsulfanyl-6-morpholine-4-yl-pyrimidine was prepared as follows: 4- (benzenesulf onyl methyl) -2-methylsulfanyl-6-morpholine- 4-pyrimidine They were heated to reflux-6- (benzenesulfonyl) -2-methylsulfanyl-pyrimidin-4-ol (15.99 g) and phosphorus oxychloride (87.4 ml) for 4 hours. The phosphorus oxychloride was removed by evaporation and the residue was adjusted to pH 7 with aqueous sodium hydroxide solution. The crude product was extracted into ethyl acetate, the ethyl acetate layer was separated and dried over magnesium sulfate. The solvent was removed by evaporation to provide crude 4- (benzenesulfonylmethyl) -6-chloro-2-methylsulfanyl-pyrimidine. This was dissolved in DCM (100 ml) and morpholine (23.6 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation, the residue was dissolved in DCM and purified on silica eluting with a gradient from 0% to 20% methanol in DCM to give the title compound as a white solid (11.26 g). Spectrum LCEM: MH + 366, Retention Time 1.97, Method: Basic Monitor NMR Spectrum: (DMSOd6 2.14 (3H, s), 3.51 - 3.53 (4H, m), 3.64 -3.66 (4H, m), 3.67 (1H, s ), 4.57 (2H, s), 6.47 (1H, s), 7.61-7.65 (2H, m), 7.72-7.76 (1H, m), 7.77-7.80 (2H, m); 6- (Benzenesulfonylmethyl) -2-methylsulfanyl-pyrimidin-4-ol It was suspended in acetonitrile (400 ml) -6- (chloromethyl) -2-methylsulfanyl-pyrimidin-4-ol (19.07 g, from Example 1). Benzene sulfinic acid, sodium salt (19.7 g) and DMF (100 ml) were added to this suspension. The mixture was heated to 100 ° C to give a dark suspension. The solvent was removed in vacuo until it was practically dry and a 1: 1 mixture of methane DCM (200 ml) was added. Acetic acid (10 ml) was then added and the resulting precipitate was collected and washed with water (200 ml) and methanol (100 ml). This material was dried overnight under vacuum to give the title compound as a white solid (19.55 g). Spectrum LCEM: MH + 297, Retention Time 0.72, Method: Basic Monitor NMR Spectrum: (DMSOd6) 2.01 (s, 3H), 4.59 (s, 2H), 6.15 (s, 1H), 7.62 (t, 2H), 7.74 (tt, 1H), 7.81 (dd, 2H), 12.31 - 13.08 (m, 1H); The compounds of Table 2 were prepared in a manner analogous to 4- (benzenesulfonylmethyl) -6-morpholin-4-yl-2-thiophen-3-yl-pyrimidine (Example 13) using the appropriate boronic acid.

Table 2: Example 15: H NMR (300.132 MHz, DMSO) d 3.43-3.74 (m, 8H), 4.65 (s, 2H), 6.60 (d, 1H), 6.63 (s, 1H), 7.50-7.87 (m, -6H), 7.93. (s, 1H) Example 16: H NMR (300.132 MHz, DMSO) d 3.61-3.78 (m, 8H), 4. 77 (s, 2H), 6.75 (s, 1H), 7.30-7.43 (m, 2H), 7.56-7.75 (m, 3H), 7.81-7.88 (m, 2H), 8.00 (d, 1H), 8.33 ( s, 1H), 8.56 (dd, 1H) Example 20: H NMR (300.132 MHz, DMSO) d 2.13 (s, 2H), 3.45 -3.71 (m, 8H), 4.57 (s, 2H), 6.47 (s, 1H), 7.62 (t, 2H), 7.70 - 7.83 (m, 5H), 1xOH not observed Example 21: H NMR (300.132 MHz, DMSO) d 3.12 - 3.43 (m, 8H), 3.56 - 3.78 (m, 8H), 4.71 (s, 2H), 6.59 - 6.61 (m, 1H), 6.72 (s, 1H), 7.14 (t, 1H), 7.24 (d, 2H), 7.46-7.89 (m, 5H) Example 22: H NMR (300.132 MHz, DMSO) d 3.58-3.77 (m, 8H), 3.80 (s, 3H), 4.72 (s, 2H), 6.48 (t, 1H), 6.67 (s, 1H), 7.34 (s, 1H), 7.36 (d, 1H), 7.57-7.69 (m, 3H), 7.69-7.89 (m, 4H) Example 26: 4-Morpholin-4-yl-6- (phenylsulfanylmethyl) -2-pyridine -2-pyrimidine Sodium ethoxide (49 mg, 0.72 mmol) was fractionally added to a stirred solution of thiophenol (79.4 mg, 0.72 mmol) in acetonitrile (2.5 mL) at room temperature in an inert atmosphere. This mixture was stirred for 30 minutes before adding dropwise 4- (chloromethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine (174 mg, 0.60 mmol) as a solution in acetonitrile (2.5 ml). Stirring was continued overnight at room temperature and under a nitrogen atmosphere, after which the reaction mixture was evaporated to dryness and the residue partitioned between ethyl acetate and water. The combined organic phases were then dried over magnesium sulfate, filtered and evaporated to dryness to give a crude product.

The product was purified by basic preparative HPLC chromatography (gradient elution 35-55% MeCN in water) and the desired product was obtained as a clear gum (94 mg, 43%). LCEM Spectrum: MH + 365.5, Retention Time 2.15, Method: Basic Monitor NMR Spectrum: 1H NMR (300.132 MHz, DMSO) 3.67 (d, 8H), 4.22 (s, 2H), 6.83 (s, 1H), 7.20 (t, 1H), 7.32 (t, 2H), 7.42 - 7.50 (m, 3H), 7.91 (td, 1H), 8.25 (d, 1H), 8.70 (d, 1H) The starting material 4- (chloromethyl) ) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine was prepared as follows: 4- (chloromethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine 6-Chloromethyl-2-pyridin-2-yl-pyrimidin-4-ol (14.07 g, -63.46 mmol) was dissolved in phosphorus oxychloride (50 mL) and heated to reflux for 1 hour. The phosphorus oxychloride was then evaporated, and azeotropically distilled with toluene (100 ml). Water (100 ml) was added and the mixture adjusted to pH 10 with sodium hydroxide. The reaction mixture was then extracted with ethyl acetate (2 x 200 ml), washed with brine (100 ml) and dried over magnesium sulfate. Evaporation afforded a beige solid, 4-chloro-6- (chloromethyl) -2-pyridin-2-yl-pyrimidine (3.563 g). 4-Chloro-6- (chloromethyl) -2-pyridin-2-yl-pyrimidine (3.563 g, 14.84 mmol), morpholine (1.295 g, 14.84 mmol) and DIPEA (5.745 g, 44.52 mmol) were dissolved. in THF (20 ml) and the reaction mixture was stirred at room temperature for 2 hours. PS-isocyanate resin (5 g) was then added and stirring was continued for 3 hours, after which the reaction mixture was filtered and washed with THF followed by methanol. The combined organic phases were evaporated on silica and the product was purified by flash chromatography. The pure fractions were evaporated to provide the desired product as a crystalline solid (2.7 g). Spectrum LCEM: MH + 291.51, Retention Time 1.69, Method: Acid Monitor NMR Spectrum: 1HRMN (300.132 MHz, DMSO) d 3.75 (s, 8H), 4.68 (s, 2H), 7.02 (s, 1H), 7.49 (m, 1H), 7.92 (dt, 1H), 8.31 (d, 1H), 8. 71 (d, 1H) ppm. 6- (Chloromethyl) -2-pyridin-2-yl-pyrimidin-4-ol Sodium ethoxide (3.6 mmol, 245 mg) and methyl 4-chloroacetoacetate (3.3 mmol, 498 mg) were added to a solution of 2-pyridylamidine (3 mmol, 364 mg) in ethanol (10 ml) and the mixture of reaction was heated to reflux. After three hoursThe reaction mixture was concentrated in vacuo and acidified with hydrochloric acid to provide the desired compound as a pale beige solid (445 mg). LCEM Spectrum: MH + 222.48, Retention Time 0.76, Method: Basic Monitor NMR Spectrum: H NMR (300.132 MHz, DMSO) d 4.36 (d, 2H), 6.32 (s, 1H), 7.65 (ddd, 1H), 8.04 ( td, 1H), 8.28 (d, 1H), 8.74 (d, 1H), 11.17-12.28 (m, 1H) ppm. The compounds of Table 3 were prepared in a manner analogous to 4-morpholin-4-yl-6- (phenylsulfanylmethyl) -2-pyridin-2-yl-pyrimidine (Example 26) by reaction of the appropriate starting material with 4- (chloromethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine. Table 3: Example 31: H NMR (400.132 MHz, DMSO) d 1.32 (s, 9H), 3.65 (s, 8H), 3.72 (s, 2H), 6.83 (s, 1H), 7.41 (ddd, 1H), 7.85 (td, 1H), 8.23 (dt, 1H), 8.64 (ddd, 1H) Example 39: H NMR (400.132 MHz, DMSO) d 2.75-2.84 (m, 4H), 3.65 (s, 8H), 3.69 (s, 2H), 6.80 (s, 1H), 7.10 - 7.20 (m, 5H), 7.42 (ddd, 1H), 7.85 (td, 1H), 8.24 (dt, 1H), 8.65 (ddd, 1H) Example 44: 4- (Benzenesulfonylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine A solution of Oxona® (110 mg, 0.18 mmol) in water (2.5 mL) was added to a stirred solution of 4-morpholin-4-yl-6- (phenylsulfanylmethyl) -2-pyridin-2-yl-pyrimidine (Example 26) (46.5 mg, 0.13 mmol) in ethanol (2.5 ml) at room temperature and stirring was continued for 3 hours at that temperature. Water (5 ml) was then added and the organic phases were extracted with DCM (3 x 10 ml). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product which was purified by basic preparative HPLC chromatography (gradient elution 25-45% MeCN in water) to give the desired product, which was obtained as an off-white solid (28.4 mg, 55%). LCEM Spectrum: MH + 397.53, Retention Time 1.70, Method: Basic Monitor NMR Spectrum: 1H NMR (300.132 MHz, DMSO) d 3.65 - 3.70 (m, 8H), 4.74 (s, 2H), 6.77 (s, 1H), 7.42-7.47 (m, 1H), 7.60-7.65 (m, 2H), 7.72-7.77 (m, 1H), 7.80-7.86 (m, 4H), 8.66 (ddd, 1H) The compounds shown in Table 4 were prepared in a manner analogous to 4- (benzenesulfonylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine (Example 44) using the appropriate starting material from Table 3. Where a starting material is not shown in Table 3, it was prepared in a manner analogous to Example 26 by replacement of thiophenol with the appropriate reactant. Table 4: Example 45: 1 H NMR (500.133 MHz, DMSO) d 3.74 (s, 8H), 4.53 (s, 2H), 4.97 (s, 2H), 6.53 (d, 1H), 6.75 (d, 1H), 6.99 (s) , 1H), 7.50 (m, 1H), 7.74 (s, 1H), 7.95 (td.1H), 8.35 (d, 1H), 8.73 (d, 1 H) Example 46: 1H NMR (500.133 MHz, DMSO) d 3.62 (m, 8H), 3.76 (s, 3H), 4.58 (s, 2H), 6.68 (s, 1H), 7.04 (d, 2H), 7.38 (m, 1H), 7. 66 (d, 2H), 7.74 (t, 1H), 7.80 (d, 1H), 8.60 (d, 1H) Example 47: 1 H NMR (500.133 MHz, DMSO) d 1.01 (t, 3H), 1.34 (d, 3H), 1.50 (m.1H), 2.10 (m, 1H), 3.45 (m, 1H), 3.73 (s, 8H), 4.52 (s, 2H), 6.98 (s, 1H), 7.50 (m.1H ), 7.93 (td, 1H), 8.29 (d, 1H), 8.72 (d, 1H) Example 48: 1 H NMR (500.133 MHz, DMSO) d 1.00 (d, -6H), 2.20-2.27 (m, 1H) , 3.32 (d, 2H), 3.66 (s, 8H), 4.43 (s, 2H), 6.91 (s, 1H), 7.42 (ddd, 1H), 7.87 (td, 1H), 8.23 (dt, 1H), 8.64 (ddd, 1H) Example 53: H NMR (500.133 MHz, DMSO) d 3.39 - 3.42 (m, 2H), 3.74 (s, 8H), 3.90 - 3.93 (m, 2H), 4.64 (s, 2H), 7.02 (s, 1H) , 7.49 (ddd, 1H), 7.90 (td, 1H), 8.53 (d, 1H), 8.59 (dd, 1H), 8.32 (dt, 1H), 8.66 (ddd, 1H), 8.76 (d, 1H) Example 54: H NMR (500.133 MHz, DMSO) d 3.67 (s, 8H), 4.41 (s, 2H), 5.05 (s, 2H), 6.91 (s, 1H), 7.03 (dd, 1H), 7.35 (d, 1H), 7.42-7.45 (m, 1H), 7.53 (dd, 1H), 7.89 (td, 1H), 8.29 (d, 1H), 8.66 - 8.67 (m, 1H) Example 55: H NMR (500.133 MHz, DMSO) d 1.08-1.40 (m, -6H), 1.78 (d, 2H), 2.16 (d, 2H), 3.42-3.47 (m, 1H), 3.66 (s, 8H ), 4.41 (s, 2H), 6.90 (s, 1H), 7.43 (ddd, 1H), 7.88 (td, 1H), 8.23 (dt, 1H), 8.65 (ddd, 1H) Example 57: H NMR (500.133 MHz, DMSO) d 1.32 (t, 3H), 3.35 (q, 2H), 3.73 (s, 8H), 4.51 (s, 2H), 6.98 (s, 1H), 7.49 (ddd, 1H), 7. 94 (td, 1H), 8.29 (d, 1H), 8.72 (d, 1H) Example-68: 4 - [(3-methoxyphenoxy) methyl] -6-morpholin-4-yl-2-pyridin-2-yl -pyrimidine Sodium hydride (18 mg, 0.45 mmol) was added to a stirred solution of 3-methoxy-phenol (56 mg, 0.45 mmol) in DMF (2 mL) at room temperature and stirring was continued for 30 minutes. A solution of 4- (chloromethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine (87 mg, 0.30 mmol, from Example 26) in DMF (1 ml) was then added dropwise rapidly. , followed by a catalytic amount of sodium iodide. This reaction mixture was then stirred at room temperature for 5 minutes and then heated at 70 ° C for 1.5 hours. After evaporation to dryness, the residue was partitioned between ethyl acetate and water, and the combined organic phases were dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the crude product, which was purified by chromatography Basic preparative HPLC to obtain the desired product as a light yellow gum (69 mg, -61%). Spectrum LCEM: MH + 379.6, Retention Time 2.20, Method: Basic monitor NMR spectrum: 1 H NMR (300.132 MHz, DMSO) d 3.72 (s, 8H), 3. 75 (s, 3H), 5.08 (s, 2H), 6.57 (m, 1H), 6.67 (m, 2H), 6.94 (s, 1H), 7.22 (t, 1H), 7.49 (ddd, 1H), 7.93 (td, 1H), 8.32 (d, 1H), 8.71 (d, 1H) The compounds shown in Table 5 were prepared in a manner analogous to 4 - [(3-methoxyphenoxy) methyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine ( Example-68) by reaction of the appropriate starting material with 4- (chloromethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine (from Example 26).

Table 5: Example-69: 1 H NMR (300.132 MHz, DMSO) d 3.75 (s, 8H), 5.12 (s, 2H), 6.94 (s, 1H), 6.98 (t, 1H), 7.09 (d, 2H), 7.33 (t, 2H), 7.49 (m, 1H), 7.93 (dt, 1H), 8.32 (d, 1H), 8.71 (d, 1H). Example 70: 1 H NMR (300.132 MHz, DMSO) d 3.75 (s, 8H), 4.56 (s, 2H), 4.69 (s, 2H), 6.84 (s, 1H), 7.29 - 7.50 (m, -6H), 7.91 (dt, 1H), 8.29 (d, 1H), 8.69 (d, 1H). Example 71: 1 H NMR (300.132 MHz, DMSO) d 1.22 (t, 3H), 3.62 (q, 2H), 3.75 (s, 8H), 4.50 (s, 2H), 6.80 (s, 1H), 7.47 (m, 1H), 7. 91 (dt, 1H), 8.29 (d, 1H), 8.69 (d, 1H). Example 72: 1 H NMR (300.132 MHz, DMSO) d 3.76 (s, 8H), 5.23 (s, 2H), 6.97 (s, 1H), 7.01 (dt, 1H), 7.32 (m, 2H), 7.49 (m, 2H), 7. 93 (dt, 1H), 8.32 (d, 1H), 8.71 (d, 1H). Example 73: H NMR (300.132 MHz, DMSO) d 3.77 (s, 8H), 5.16 (s, 2H), 6.97 (s, 1H), 7.07 (dt, 2H), 7.23 (t, 1H), 7.35 (t, 1H), 7.49 (m, 1H), 7.93 (dt, 1H), 8.32 (d, 1H), 8.71 (d, 1H). Example 74: 1 H NMR (300.132 MHz, DMSO) d 3.72 (s, 8H), 3.75 (s, 3H), 5.08 (s, 2H), 6.57 (m, 1H), 6.67 (m, 2H), 6.94 (s, 1H), 7. 22 (t, 1H), 7.49 (ddd, 1H), 7.93 (td, 1H), 8.32 (d, 1H), 8.71 (d, 1H) Example 75: 1 H NMR (300.132 MHz, DMSO) d 3.72 (s, 11H), 5.04 (s, 2H), 6.96 (d, 5H), 7.49 (m, 1H), 7.93 (td, 1H), 8.32 (d, 1H), 8. 71 (d, 1H) Example 80: β-Benzyl-N-methyl-1- (6-morpholin-4-yl-2-pyridin-2-yl-pyrimidin-4-yl) methanamine N-methyl-benzylamine was added (25 mg, 0.2 mmol) and DIPEA (52 mg, 0.4 mmol) to 4- (chloromethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine (60 mg, 0.2 mmol, from Example 26 ) in DMF (4 ml) and the reaction mixture was heated to 150 ° C in the microwave for 20 minutes. After cooling, the product was purified directly by preparative HPLC (5-40% MeCN / H2O) and evaporation afforded the desired compound as a gum (25.3 mg). LCEM Spectrum: MH + 376.70, Retention Time 2.14, Method: Basic Monitor NMR Spectrum: 1H NMR (300.132 MHz, DMSO) d 2.22 (s, 3H), 3.58 (s, 2H), 3.62 (s, 2H), 3.65 - 3.77 (m, 8H), 6.89 (s, 1H), 7.23 -7.28 (m, 1H), 7.33 (d, 2H), 7.39 (t, 2H), 7.46 (dd, 1H), 7.91 (td, 1H) 8.30 (d, 1H), 8.70 (d, 1H) Example 81? / - [(6-morpholin-4-yl-2-pyridin-2-yl-pyrimidin-4-yl) methyl] propan -2-amine Isopropylamine (25 mg, 0.4 mmol) and DIPEA (52 mg, 0.4 mmol) were added to 4- (chloromethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine (60 mg, 0.2 mmol, of Example 26) in DMF (4 ml) and the reaction mixture was heated at 150 ° C in the microwave for 20 minutes. After cooling, the product was purified directly by preparative HPLC (5-40% MeCN / H2O) and evaporation gave the desired compound as a gum (32.6 mg).

Spectrum LCEM: MH + 314.64, Retention Time 1.71, Method: Basic monitor NMR spectrum: 1 H NMR (300, 132 MHz, DMSO) d 1.03 (s, 3 H), 1.05 (s, 3 H), 2.77 (septete, 1 H), 3.31 (s, 2 H), 3.71 (s, 8 H), 6.88 (s, 1H), 7.46 (ddd, 1H), 7.90 (td, 1H), 8.31 (d, 1H), 8.69 (dd, 1H), 1x NH not observed.

The compounds shown in Table-6 were prepared in a manner analogous to α / - [(6-morpholin-4-yl-2-pyridin-2-yl-pyrimidin-4-yl) methyl] propan-2- amine (Example 81) using 4- (chloromethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine (from Example 26) and the appropriate amine.

Table 6: Ex. Structure NAME LCEM Time of MH + Retention (min) 1- (2-chlorophenyl) -N- [(6-morpholin-4-yl-2- 82 pyridin-2-yl-396.62 2.03 pyrimidin-4-yl) methyl ] metanamine Example 83: 4- (Benzenesulf onyl meth I) -5-f I uoro-6-morph oli-4-yl-2-pyrid n-2-i I-pyrimidine Sodium salt of benzene sulfinic acid (32 mg, 0.19 mmol) was added to a stirred solution of 4- (chloromethyl) -5-fluoro-6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine ( 50 mg, 0.16 mmol) in dry DMF. The mixture was heated at 80 ° C for 1 hour and then concentrated. The residue was purified by flash chromatography-eluting with 0-10% MeOH / DCM to give 4- (benzenesulfonylmethyl) -5-fluoro-6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine as a white solid. (47.6 mg, 72%). Spectrum LCEM: MH + 415.41, Retention Time 1.44, Method: Acid Monitor NMR Spectrum: 1 H NMR (300.132 MHz, DMSO) d 3.72 - 3.84 (m, 8H), 4.88 (d, 2H), 7.48-7.54 (m, 1H), 7.63-7.73 (m, 2H), 7.77-7.93 (m, 5H), 8.72 (d, 1H) Example 84: 5-FI uoro -4- (Methylsulfonylmethyl) -6-morphino n-4-yl-2-pyrid i n-2-ylpyrimidine This compound was prepared using a method analogous to that used in Example 83 for 4- (benzenesulfonylmethyl) -5-fluoro-6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine using sodium salt of methanesulfinic acid ( 20 mg, 0.19 mmol) to give 5-fluoro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-2-pyridin-2-ylpyrimidine as a white solid (20.5 mg, 36%). LCEM Spectrum: MH + 353.52, Retention Time 0.90, Method: Acid Monitor NMR Spectrum: 1H NMR (300.132 MHz, DMSO) d 3.25 (s, 3H), 3.72 - 3.79 (m, 4H), 3.81 - 3.87 (m, 4H ), 4.68 (s, 2H), 7.47 - 7.53 (m, 1H), 7.90 - 7.98 (m, 1H), 8.27 (d, 1H), 8.71 (d, 1H) The starting material 4- (chloromethyl) - 5-fluoro-6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine was prepared as follows: 4- (chloromethyl) -5-fluoro-6-morpholin-4-yl-2-pyridin-2- il-pyrimidine Selectfluor ™ (1.35 g, 3.78 mmol) was added to a solution of 4- (chloromethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine (1 g, 3.44 mmol, from Example 26) in methanol (25 ml) and heated at 50 ° C for 16 hours. Saturated sodium hydrogencarbonate (5 ml) was added to the reaction mixture, and the methanol was removed in vacuo. Water (50 ml) was added to the aqueous residues and the resulting precipitate was filtered, washed with water and dried. The whole was purified by chromatography eluting with ethyl acetate to give 4- (chloromethyl) -5-fluoro-6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine as a white solid (210 mg, 20% ). Spectrum LCEM: MH + 309.35, Retention Time 1.34, Method: Acid Monitor NMR spectrum: 1 H NMR (300.132 MHz, DMSO) d 3.71 - 3.79 (m, 4H), 3.80-3.87 (m, 4H), 4.75 (d, 2H), 7.46-7.52 (m 1H), 7.89-7.97 (m, 1H), 8.27 (d, H), 8.71 (d, 1H) Example 85: 6-morpholin-4-yl-N-phenyl-2-pyridin-2-yl-pyrimidine-4-carboxamide DIPEA (114 mg, 0.88 mmol), HATU (168 mg, 0.44 mmol) and aniline ( 41 mg, 0.44 mmol) to acid-6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine-4-carboxylic acid (115 mg, 0.4 mmol) in THF (4 mL) and the reaction mixture was stirred at room temperature for 2 hours, after which water was added. The resulting precipitate was collected by filtration and dried in vacuo to give the title compound as a white solid (87 mg). LCEM Spectrum: MH + 362.51, Retention Time 2.39, Method: Basic Monitor NMR Spectrum: 1H NMR (300.132 MHz, DMSO) d 3.70 - 3.91 (m, 8H), 7.18 (t, 1H), 7.39 - 7.44 (m, 3H ), 7.55 (ddd, 1H), 7.87 (d, 2H), 7.99 (td, 1H), 8.66 (d, 1H), 8.77 (d, 1H), 10.48 (s, 1H) ppm. Example 86: N, N-dimethyl-6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine-4-carboxamide This compound was prepared in a manner analogous to that used in Example 85 para-6-morpholin-4-yl-N-phenyl-2-pyridin-2-yl-pyrimidine-4-carboxamide using 6-morpholin-4-acid -yl-2-pyridin-2-yl-pyrimidine-4-carboxylic acid. LCEM Spectrum: MH + 314.45, Retention Time 1.26, Method: Basic Monitor NMR Spectrum: 1H NMR (300.132 MHz, DMSO) d 2.97 (s, 3H), 3.01 (s, 3H), 3.72 (s, 8H), 6.93 ( s, 1H), 7.50 (ddd, 1H), 7.93 (td, 1H), 8.31 (d, 1H), 8.71 (d, 1H). The starting material 6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine-4-carboxylic acid was prepared as follows: Acid-6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine-4-carboxylic acid Methyl orotate (5 g, 29.41 mmol) was suspended in phosphorus oxychloride (50 ml) and the mixture was heated to reflux for 4 hours. After this time, the excess phosphorus oxychloride was removed under reduced pressure. The resulting dark residue was poured into ice with vigorous stirring and the solution was allowed to stir until the ice had completely melted. The crude product was then collected by filtration and the filtrate was extracted with ether (x2). The filtrate was added to the ether washings and dried over magnesium sulfate. The solution was then concentrated to give methyl 2,6-dichloropyrimidine-4-carboxylate (5.25 g, 25.37 mmol) as a yellow oil which solidified upon standing. Morpholine (2005 g, 25.37 mmol) and THF (40 ml) were added to the above, and the mixture was left for 2 hours at room temperature. The reaction mixture was then evaporated to dryness to give methyl 2-chloro-6-morpholin-4-yl-pyrimidine-4-carboxylate (5.41 g, 21 mmol). LCEM Spectrum: MH + 258.39, Retention Time 1.56, Method: Basic Monitor Methyl 2-chloro-6-morpholin-4-yl-pyrimidine-4-carboxylate (2.58 g, 10 mmol), 2-tributylstannil-pyridine ( 4.055 g, 11 mmol) and tetrakis (triphenylphosphine) palladium (0) (10 mol%, 1 mmol, 1116 g) in THF (20 ml) and heated at 100 ° C for 30 minutes in the microwave. Sodium hydroxide (20 ml, 4 M in H2O) was added to this mixture, and the reaction mixture was carried out for 1 hour. The resulting precipitate was collected by filtration, found to be the monosodium salt of 6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine-4-carboxylic acid (1.53 g). LCEM Spectrum: (M + Na) + 308.47, Retention Time 1.42, Method: Basic Monitor NMR Spectrum: H NMR (300.132 MHz, D2O) d 3.70 - 3.86 (m, 8H), 7.11 (s, 1H), 7.51 ( ddd, 1H), 7.94 (td, 1H), 8.28 (d, 1H), 8.60 (d, 1 H) ppm.

Example 87: 5- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1,3-dihydroindol-2-one 2-Chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (120 mg) was dissolved in a solvent mixture (18% DMF in 7: 3: 2 DME: water: ethanol) (7 ml ). Then 5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1,3-dihydroindol-2-one (303 mg), a 2M solution of sodium carbonate (2 ml) and dichlorobis (triphenylphosphine) -palladium (40 mg), and the mixture was heated at 100 ° C for 30 minutes in a microwave reactor. The reaction mixture was loaded onto an SCX-2 column (10 g), washed with methanol and separated with 7 N ammonia in methanol. The material was concentrated in vacuo and purified by preparative (basic) HPLC to give the desired material as a white solid (18 mg). Mass Spectrum: MH + 389. NMR spectrum: 1 H NMR (DMSO-d 6) d 3.20 (3 H, s), 3.57 (2 H, s), 3.71 - 3.73 (8 H, m), 4.48 (2 H, s), 6.82 ( 1H, s), 6.91 (1H, d), 8.20 (1H, s), 8.23 - 8.25 (1H, m), 10.55 (1H, s) The preparation of 5- (4,4,5,5-tetramethyl- 1, 3,2-dioxaborolan-2-yl) -1,3-dihydroindol-2-one is described below: 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- il) -1,3-dihydroindol 2-one A mixture of 5-bromo-2,3-dihydroindol-2-one (500 mg), bis (pinacolato) diboro (899 mg) and potassium acetate (695 mg) in DMF (20 ml) was degassed for 5 minutes. To the mixture was added 1,1'-bis (diphenylphosphino) ferro-phenyl-chloro-palladium (II) -dichloromethane (78 mg) adduct and the reaction mixture was heated to 80 ° C and allowed to stir for 3 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. The residue was suspended in water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic bases were dried (MgSO4), filtered and concentrated in vacuo to give the desired material as a brown solid (611 mg). Mass spectrum: M + H + MeCN + 301. NMR spectrum: 1 H NMR (DMSO-d 6) d 1.28 (12 H, s), 3.47 (2 H, s), 6.82 - 6.84 (1 H, d), 7.51 (2 H, m ), 10.52 (1H, s) The preparation of 2-chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine is described below: 2-chloro-4- (methylsulfonylmethyl) -6-morpholin-4 -yl-pyrimidine A suspension of 2,4-dichloro-6- (methylsulfonylmethyl) pyrimidine (10.56 g) in DCM (230 ml) was stirred magnetically and cooled to -5 ° C. Triethylamine (6.78 ml) was added followed by the dropwise addition of a morpholine solution (3.85 ml) in DCM (30 ml) keeping the reaction temperature below -5 ° C. The reaction mixture was stirred at room temperature for 1 hour and thereafter the organic mixture was washed with water (300 ml). The organic phase was dried (MgSO), filtered and evaporated to give a brown solid which was chromatographed on silica, eluting with 50% ethyl acetate in DCM, to give the desired material (6.81 g) as a white solid. Mass spectrum: MH + 292. NMR spectrum: 1 H NMR (DMSO-d 6) d 3.12 (3 H, s), 3.63 (4 H, s), 3.68 - 3.70 (4 H, m), 4.45 (2 H, s), 6.96 ( 1H, s) 2,4-dichloro-6- (methylsulfoni I meti I) pyrimidine It was suspended-6- (methylsulfonylmethyl) -1 - / - pyrimidine-2,4-dione (12.72 g) in phosphorus oxychloride (125 ml) and heated to reflux under nitrogen for 14 hours. The solution was cooled and concentrated in vacuo. Ice water (250 ml) was slowly added to the residue and the product was then extracted with DCM (3 x 200 ml). The organic phases were concentrated in vacuo to give the desired material as a brown solid (10.56 g). Mass spectrum: (MH) "239. NMR spectrum: H NMR (DMSO-d6) d 3.14 (3H, s), 4.79 (2H, s), 7.88 (1H, s) 6- (methylsulfonylmethyl) -1H-pyrimidine -2,4-dione 6- (Chloromethyl) uracil (10.00 g) was dissolved in DMF (300 ml) and sodium salt of methanesulfinic acid (7.64 g) was added. The reaction mixture was heated at 125 ° C for 1 hour. The reaction mixture was allowed to cool, filtered and the filtrate was concentrated in vacuo to give the desired material as a yellow solid (12.72 g). NMR spectrum: 1 H NMR (DMSO-d 6) d 3.10 (3 H, s), 4.27 (2 H, s), 5.63 (1 H, s), 10.94 (1 H, s), 11.16 (1 H, s), Example 88 : Methyl 2-amino-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] benzoate A mixture of methyl 2-amino-5-bromobenzoate (250 mg), potassium acetate (320 mg), and bis (pinacolato) diboron (332 mg) in 1,4-dioxane (10 ml) was degassed for 5 minutes . Add 1, 1'-bis (diphenylphosphino) ferro-phenyl-chloro-palladium (II) -dichloromethane adduct (54 mg) was added and the reaction mixture was heated at 80 ° C for 2.5 hours. 2-Chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (381 mg), ethanol (0.75 ml), a 2M solution of sodium carbonate (2.7 ml) and an additional amount of adduct 1 were added. , 1'-bis (diphenylphosphino) ferro-phenyl-chloropalladium (II) -dichloromethane (54 mg) and the heating was continued for a further 3.5 hours. The cooled reaction mixture was loaded on SCX-2 (10 g), separated with 7 N ammonia in methanol and the solution was concentrated in vacuo. The residue was chromatographed on silica, eluting with 50% ethyl acetate in DCM, to give the desired material as a yellow solid (82 mg). Mass spectrum: MH + 407. NMR spectrum: 1 H NMR (DMSO-d 6) d 3.22 (3 H, s), 3.69 (4 H, s), 3.73 (4 H, s), 3.84 (3 H, s), 4.49 (2 H, s), 6.77 (1H, s), 6.87 (1H, d), 7.05 (2H, s), 8.24 (1H, d), 8.79 (1H, s) Example 89: [2-m ethoxy -5- [4 - (methylsulfonylmethyl I) -6-morphine-4-yl-pi rimidi n-2-yl] phenyl] methanol A mixture of 5-bromo-2-methoxybenzyl alcohol (250 mg), potassium acetate (339 mg) and bis (pinacolato) diboro (352 mg) in 1,4-dioxane (10 ml) was degassed for 5 minutes. Adduct 1,1'-bis (diphenylphosphino) ferro-arnickloropalladium (II) -dichloromethane (57 mg) was added and the reaction mixture was heated at 80 ° C for 3 hours. 2-Chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (337 mg), ethanol (0.75 ml), a 2M solution of sodium carbonate (2.7 ml) and an additional amount of adduct were added. 1,1'-bis (diphenylphosphino) ferro-phenyl-chloropalladium (II) -dichloromethane (57 mg) and the heating was continued for -66 hours more. The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml) and filtered. The organic phase was dried (MgSO4), concentrated in vacuo and chromatographed on silica, eluting with 5% methanol in DCM. The chromatography was repeated and the residue was triturated with diethylether to give the desired compound as a white solid (158 mg). Mass spectrum: MH + 394. NMR spectrum: 1 H NMR (DMSO-d 6) d 3.23 (3 H, s), 3.73 - 3.74 (8 H, m), 3.84 (3 H, d), 4.51 (2 H, s), 4.54 ( 2H, d), 5.08 (1H, t), 6.83 (1H, s), 7.00 - 7.06 (1H, m), 8.23 - 8.26 (1H, m), 8.41 (1H, d) Example 90: 2-methyl-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] - 1H-benzoimidazole A mixture of 5-bromo-2-methyl-1H-benzoimidazole (250 mg), potassium acetate (349 mg) and bis (pinacolato) diboro (362 mg) in 1,4-dioxane (10 ml) was degassed for 5 minutes. Adduct 1,1'-bis (diphenylphosphino) ferro-arnickloropalladium (II) -dichloromethane (59 mg) was added and the reaction mixture was heated at 80 ° C for 18 hours. 2-chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (346 mg), ethanol (0.75 ml), 2M sodium carbonate (2.7 mL) and an additional amount of adduct is added 1, 1'-bis (diphenylphosphino) ferro-phenyl-chloropalladium (II) -dichloromethane (59 mg) and heating was continued for 3 more hours. The cooled reaction mixture was concentrated in vacuo, dissolved in methanol and loaded onto an SCX-2 column (10 g). The column was washed with methanol and the compound was separated with 7 N ammonia in methanol. The solution was concentrated in vacuo and the residue was chromatographed by preparative (basic) HPLC to give the desired compound as a gray solid (5 mg).

Mass spectrum: MH + 388. Preparation of 5-bromo-2-methyl-1 H-benzoimidazol described below: 5-bromo-2-methyl-1 H-benzimidazole was dissolved 4-bromobenzene-1, 2-diamine (1 g) in phosphorus oxychloride (10 ml). Acetic acid (0.297 ml) was added to the mixture at room temperature. The reaction mixture was then heated to 95CC for 2 hours. The reaction mixture was allowed to cool and the excess phosphorus oxychloride was removed in vacuo. The reaction mixture was quenched with water and evaporated to dryness. The residue was dissolved in methanol and loaded onto an SCX-2 column (20 mg) and the compound was separated with 7 N ammonia in methanol. The solution was concentrated in vacuo and chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (731 mg) as a white solid. Mass spectrum: MH + 213. NMR spectrum: 1 H NMR (DMSO-d 6) d 2.62 (3 H, s), 7.31 - 7.34 (1 H, m), 7.39 (1 H, d), 7.67 (1 H, s) Example 91 : 5- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1,3-dihydrobenzoimidazole-2 -one A mixture of 5-bromo-1, 3-dihydro-2-one (250 mg), potassium acetate (346 mg) and bis (pinacolato) diboron (358 mg) in 1,4-dioxane (10 ml) was degassed for 5 minutes. Addic acid 1,1 '-bis (diphenylphosphino) ferro-arnickloropalladium (II) -dichloromethane (58 mg) was added and the reaction mixture was heated at 80 ° C for 3 hours. 2-chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (343 mg), ethanol (0.75 ml), 2M sodium carbonate (2.7 mL) and an additional amount of adduct is added 1, 1'-bis (diphenylphosphino) ferro-phenyl-chloropalladium (II) -dichloromethane (58 mg) and heating was continued for a further 18 hours. The cooled reaction mixture was concentrated in vacuo, dissolved in methanol and loaded onto an SCX-2 column (10 g). The column was washed with methanol and the compound was separated with 7 N ammonia in methanol. The solution was concentrated in vacuo and the residue was chromatographed by preparative (basic) HPLC to give the desired compound as a white solid (26 mg). Mass spectrum: MH + 390. NMR spectrum: 1 H NMR (DMSO-d 6) d 3.21 (3 H, s), 3.72 (8 H, t), 4.50 (2 H, s), 6.83 (1 H, s), 7.01 (1 H, d), 7.93 (1H, d), 8.04 - 8.07 (1H, m), 10.68 (1H, s), 10.81 (1H, s) The preparation of 5-bromo-1,3-dihydrobenzoimidazole-2 -one is described below: 5-bromo-1,3-dihydrobenzoimidazol-2-one 4-Bromobenzene-1,2-diamine (1 g) was dissolved in DCM (15 ml) and triethylamine (1.50 ml). Phosgene solution (5.3 ml) was slowly added to the solution at 0 ° C. The reaction mixture was allowed to warm to room temperature and was allowed to stir at room temperature for 2 hours. The reaction mixture was quenched with water (2 ml) and then evaporated to dryness. The residue was chromatographed on silica, eluting with 5% methanol in DCM to give the desired material (657 mg) as a white solid. Mass spectrum: MH + 213. NMR spectrum: 1 H NMR (DMSO-d 6) d 6.88 (1 H, d), 7.06 - 7.10 (2 H, m), 10.74 (2 H, s) Example 92: [5- [4- (methi Isulfonilmeti I) -6-morph oli-4-yl-pi rimidi n-2-yl] -1 Akin dazol-3-i I] methanol A mixture of (5-bromo-1 / - indazol-3-yl) methanol (90 mg), potassium acetate (117 mg) and bis (pinacolato) diboro (121 mg) in 1,4-dioxane (5 ml) ) was degassed for 5 minutes. Adduct 1,1'-bis (diphenylphosphino) ferro-arylchloro-palladium (II) -dichloromethane (20 mg) was added and the reaction mixture was heated at 80 ° C for 2.5 hours. 2-Chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (116 mg), ethanol (0.4 ml), a 2 M solution of sodium carbonate (1.3 ml) and an additional amount of adduct were added. 1, 1'-bis (diphenylphosphino) ferro-phenyl-chloropalladium (II) -dichloromethane (20 mg), and heating was continued for 3 more hours. The cooled reaction mixture was concentrated in vacuo, dissolved in methanol and loaded onto an SCX-2 column (20 g). The column was washed with methanol and the compound was separated with 7 N ammonia in methanol. The solution was concentrated in vacuo and the residue was chromatographed on silica, eluting with 0-5% methanol in DCM, to give the desired material (37 mg) as a white solid. Mass spectrum: MH + 404. NMR spectrum: 1 H NMR (DMSO-d 6) d 3.24 (3 H, s), 3.76 (8 H, s), 4.51 - 4.54 (2 H, m), 4.84 (2 H, d), 5.29 ( 1H, t), 6.87 (1H, s), 7.50 -7.59 (1H, m), 8.39 - 8.42 (1H, m), 8.88 (1H, s), 12.93 (1H, s) The preparation of (5-bromine -1 H-indazol-3-yl) methanol is described below: (5-bromo-1 H-indazol-3-i I) methanol To a stirred solution of 5-bromo-1 H-indazole-3-carbaldehyde (500 mg) in methanol (10 ml) and water (1 ml) at 0 ° C was added sodium borohydride (337 mg) fractionally. The reaction mixture was allowed to warm to room temperature and was then kept under stirring for 1 hour. The reaction mixture was quenched with water and loaded onto an SCX-2 column (10 g). The column was washed with methanol and the product was separated with 7 N ammonia in methanol. The solution was concentrated in vacuo and the residue was chromatographed on silica, eluting with 0-5% methanol in DCM, to give the desired material (90 mg) as a white solid. Mass spectrum: (M-H) "224. NMR spectrum: 1 H NMR (DMSO-d 6) d 4.78 (2 H, d), 5.26 (1 H, t), 7. 43 - 7.46 (1H, m), 7.47 - 7.50 (1H, m), 8.07 (1H, d), 12.97 (1H, s) Example 93: 6- [4- (methylsulphonyl methyl) -6-morph oli-4-i-pi rimidi n-2-i I] chroman-4-ol A mixture of-6-bromochroman-4-ol (250 mg), potassium acetate (321 mg) and bis (pinacolato) diboro (333 mg) in 1,4-dioxane (10 ml) was degassed for 5 minutes. Adduct 1,1'-bis (diphenylphosphino) ferro-arnickloropalladium (II) -dichloromethane (54 mg) was added and the reaction mixture was heated at 80 ° C for 2.5 hours. 2-Chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (319 mg), ethanol (0.75 ml), a 2 M solution of sodium carbonate (2.7 ml) and an additional amount of adduct were added. 1,1'-bis (diphenylphosphino) ferro-phenyl-chloropalladium (II) -dichloromethane (54 mg), and the heating was continued for a further 3 hours. The cooled reaction mixture was concentrated in vacuo, dissolved in methanol and loaded onto an SCX-2 column (20 g). The column was washed with methanol and the compound was separated with 7 N ammonia in methanol. The solution was concentrated in vacuo and the residue was chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (113 mg) as a white solid. Mass spectrum: MH + 406. NMR spectrum: 1 H NMR (DMSO-d 6) d 1.90 - 1.94 (1 H, m), 2.03 - 2.05 (1 H, m), 3.21 (3 H, s), 3.68 - 3.74 (8 H, d ), 4.25 (2H, d), 4.50 (2H, s), 4.70 (1H, q), 5.46 (1H, d), 6.83 (1H, d), 6.86 (1H, s), 8.14 - 8.16 (1H, m), 8.34 (1H, d) Example 94: 1 -Aceti I -5- [4- (methylsulfonylmethyl I) -6 -morph oli-4-yl-pi rimidi n-2- il] - 2H-indol-3-one A mixture of 1-acetyl-5-bromo-1H-indole-3-ol (250 mg), potassium acetate (290 mg) and bis (pinacolato) diboro (300 mg) in 1,4-dioxane (10 ml) it was degassed for 5 minutes. Adduct 1, 1'-bis (di phenylphosphino) fer ruby n-dichloro palladium (II) -dichloromethane (49 mg) was added and the reaction mixture was heated at 80 ° C for 3 hours. 2-Chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (288 mg), ethanol (0.75 ml), a 2-fold solution were added.

M sodium carbonate (2.7 ml) and an additional amount of adduct 1,1'-bis (diphenylphosphino) ferro-phenyl-chloropalladium (II) -dichloromethane (54 mg), and heating was continued for a further 2.5 hours. The cooled reaction mixture was concentrated in vacuo and the residue was chromatographed on silica, eluting with methanol % in DCM, to give the desired material (87 mg) as a white solid. Mass spectrum: MH + 431. NMR spectrum: 1 H NMR (DMSO-d 6) d 2.30 (3 H, s), 3.21 (3 H, s), 3. 75 (8H, s), 4.54 (2H, s), 4.66 (2H, s), 6.92 (1H, s), 8.58 - 8.58 (2H, m), 8.71 - 8.74 (1H, m) Example 95: 1-methyl-4- [4- (methylsulfonylmethyl) -6-morphino-4-yl-pi rimidi-2-yl ] piperazin-2-one A mixture of 2-chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (200 mg), 1-methylpiperazin-2-one (157 mg) and sodium carbonate (146 mg) in DMA (4 mg). ml) was heated in a microwave reactor at 160 ° C for 10 minutes. The reaction mixture was loaded on a SCX-2 column and the product was separated with 7 N ammonia in methanol. The solution was evaporated to dryness and chromatographed on silica, eluting with 0-2.5% methanol in DCM, to give the desired material (179 mg) as a white solid.

Mass spectrum: MH + 370. NMR spectrum: 1 H NMR (DMSO-d 6) d 2.89 (3 H, s), 3.13 (3 H, s), 3.38 (2 H, t), 3.55 - 3.56 (4 H, m), 3.67 - 3.68 (4H, m), 3.93 (2H, t), 4.19 (2H, s), 4.28 (2H, s), 6.28 (1H, s) The following compound was prepared in an analogous manner from 2-chloro- 4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine and the appropriate piperazin-2-one.

EXAMPLE 96: NMR spectrum: H NMR (DMSO-d6) d 3.15 (3H, s), 3. 59 (4H, d), 3.68 - 3.69 (4H, m), 3.79 - 3.81 (2H, d), 4.04 - 4.07 (2H, m), 4.30 (2H, s), 4.40 (2H, s), 6.31 ( 1H, s), 7.41-7.46 (2H, m), 7.47-7.49 (2H, m). Example 97: 2- [3- (4,4-dimethyl-5A / -1,3-oxazol-2-yl) -4-methoxy-pheny] -4- (methylsulfonylmethyl) -6-morpholin-4-yl -pyrimidine A mixture of 2- (5-bromo-2-methoxyphenyl) -4,4-dimethyl-4,5-dihydro-1,3-oxazole (250 mg), potassium acetate (259 mg) and bis (pinacolato) diboro (269 mg) in 1,4-dioxane (10 ml) was degassed for 5 minutes and then adduct 1,1'-bis (diphenylphosphino) ferro-arylchloro-palladium (II) -dichloromethane (44 mg) was added. The reaction mixture was heated at 80 ° C for 2.5 hours. 2-Chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (257 mg), ethanol (0.75 ml), 2 N sodium carbonate solution (2.7 ml) and 1,1'-adduct were added. bis (diphenylphosphino) ferro-phenyl-chloropalladium (II) -dichloromethane (44 mg), and heating was continued for 3 hours. The reaction mixture was concentrated in vacuo and then dissolved in methanol.

The solution was passed through a SCX-2 column, the column was washed with methanol and then the desired material was eluted with 7 N ammonia in methanol. The fractions were concentrated in vacuo, and then chromatographed on silica, eluting with 5% methanol in DCM, to give the desired compound (43 mg) as a white solid. Mass spectrum: MH + 461. NMR spectrum: 1 H NMR (DMSO-d 6) d 1.35 (6 H, s), 3.23 (3 H, s), 3. 45 (2H, d), 3.74 (8H, d), 3.98 (3H, s), 4.53 (2H, s), 5.06 (1H, t), 6. 87 (1H, s), 7.26 (1H, d), 8.15 (1H, s), 8.42 - 8.45 (1H, m), 8.85 (1H, d) Example 98:? - (1 H-Benzoyl id azo I -5-yl) -2,6-di morph oli n-4-yl-pi rimidi na-4-carboxamide A mixture of 2,6-dimorpholin-4-yl-pyrimidine-4-carboxylic acid (45 mg, 0.15 mmol), HATU (65 mg, 0.17 mmol) and 1 H-benzoimidazol-5-amine (23 mg, 0.17 mmol) ) in DMF (1 ml) and triethylamine (0.054 ml, 0.31 mmol) was stirred at room temperature overnight. Water (4 ml) was added and the mixture was extracted with ethyl acetate (3 x 4 ml). The combined organic phases were dried (MgSO) and concentrated in vacuo. The residue was chromatographed on silica, eluting with 10-45% ethyl acetate in isohexane, to give the desired material as a pale yellow solid (43.6 mg). LCEM Spectrum: MH + 410, Retention Time 2.05, Method: Acid Monitor NMR Spectrum: 1 H NMR (399.9 MHz, CDCl 3) d 3.75 (m, 12 H), 3.85 - 3.86 (m, 4 H), 5.90 (s, 1 H), 6.93 (m, 1H), 6.96 (m, 1H), 7.32 (m, 1H), 7.34 (s, 1H) The following compounds were prepared in an analogous manner from 2,6-dimorpholin-4-ylpyrimidine- Commercially available 4-carboxylic acid and the appropriate amine.

Example 99: 1 H NMR (399.9 MHz, CDCl 3) d 2.34 (s, 3 H), 3.67 (m, 4 H), 3.75 - 3.80 (m, 12 H), 6.58 (s, 1 H), 6.82 (s, 1 H), 9.99 (s, 1 H) Example 100: 1 H NMR (399.9 MHz, CDCl 3) d 3.67 (m, 4 H), 3.80 (m, 12H), 6.57 (m, 1H), 6.9 (s, 1H), 7.22 (m, 1H), 7.39 (d, 1H), 7. 45 (m, 1H), 8.09 (d, 1H), 8.15 (s, 1H), 9.78 (s, 1H) Example 101: 1 H NMR (399.9 MHz, DMSO-d6) d 3.48 (s, 3H), 3.69 (m, 4H), 3.78 (m, 12H), 4.81 (s, 2H), 6.30 (s, 1H), 10.92 (s, 1H) Example 102: 5- [4- (Methylsulfonylmethyl) -6-morph oli-4-i I -pi rimidi n-2-yl] -1H-indazole 1- (4-Methylphenyl) sulfonyl-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] indazole (95 mg, 0.18 mmol) and 1.0 M fluoride solution were heated together. tetrabutylammonium in tetrahydrofuran (1.0 ml, 1.0 mmol) and tetrahydrofuran (5 ml) at 50 ° C for 2 hours. The solvent was evaporated and the residue was partitioned between water and dichloromethane. The organic solution was further washed with water, dried over magnesium sulfate, filtered and concentrated, after which the residue was purified using preparative reverse phase HPLC (basic conditions) to give the title compound, 36 mg. LCEM Spectrum: MH + 374, Retention Time 1.28, Method: Acid Monitor NMR Spectrum: 1H NMR (300.132 MHz, DMSO) d 3.17 (3H, s), 3.68 (8H, s), 4.45 (2H, s), 6.79 ( 1H, s), 7.53 (1H, d), 8.14 (1H, s), 8.32 (1H, dd), 8.73 (1H, s), 13.12 (1H, s), The starting material 1 - (4-methylphenyl) ) Sulfonyl-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] indazole was prepared as follows: 1- (4-methylphenyl) sulfonyl-5- [4- (methylsulfonylmethyl) - 6-morpholin-4-yl-pyrimidin-2-yl] indazole 1- (4-Methylphenyl) sulfonyl-5- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) indazole (209 mg, 0.53 mmol), 2-chloro-4 were heated - (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (44 mg, 0.15 mmol), 2 M aqueous solution of sodium carbonate (1 ml), dichlorobis (triphenylphosphine) -palladium (II) (15 mg), and 18% dimethylformamide in 7: 3: 2 and dimethoxyethane: water: ethanol (3.5 ml) in a microwave reactor at 100 ° C for 10 minutes. The reaction mixture was partitioned between dichloromethane and water. The organic solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica eluting with ethyl acetate to give the desired compound as a brown solid (112 mg).

Spectrum LCEM: MH + 528, Retention Time 2.55, Method: Acid Monitor NMR Spectrum: 1H NMR (500.133 MHz, DMSO) d 2.31 (3H, s), 3.20 (3H, s), 3.27 (4H, s), 3.30 ( 4H, s), 4.52 (2H, s), 6.91 (1H, s), 7.39 (2H, d), 7.82 (2H, d), 8.21 (1H, d), 8.63 (1H, d) , 8.64 (1H, s), 8.79 (1H, s) 1- (4-methylphenyl) sulfon i I -5- (4, 4, 5, 5 -tetra meth i 1-1,3, 2-dioxabo rolan-2-yl) indazole 80-C 5-bromo-1- (4-methylphenyl) sulfonyl-indazole was stirred at 80 ° C. (3.0 g, 8.54 mmol), potassium acetate (2.52 g, 25.62 mmol), bis (pinacolato) diboron (3.04 g, 11.96 mmol) and 1,1'-bis (diphenylphosphino) ferro-phenyl-chloropalladium (II) (375 mg, 0.51 g) mmol) in 1,4-dioxane (45 ml) under inert atmosphere for 48 hours. The solvent was removed by evaporation and the residue was taken up in methanol and filtered. The filtrate was concentrated to give the desired compound as a brown solid, (4.1 g). LCEM Spectrum: MH + 399, Retention Time 3.27, Method: Acid Monitor 5-bromo-1- (4-methylphenyl) sulfonyl-indazole A solution of 5-bromo-1 / - / - indazole (3.8 g, 19.29 mmol, CAS number 53857-57-1) in dimethyl formamide (25 ml) was added to a mixture of sodium hydride at 60% in Oil (771 mg, 19.29 mmol) in dimethylformamide (25 ml) at 0 ° C under inert atmosphere and stirred for 30 minutes. Tosyl chloride (5.15 g, 27.0 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was poured into ice / water with vigorous stirring and the product was extracted into ethyl acetate. The organic solution was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in dichloromethane and filtered through a plug of silica. The filtrate was concentrated and the residue was triturated with diethylether, after which the solid was collected by filtration to give the desired compound (6.37 g). LCEM Spectrum: MH + 353, Retention Time 2.92, Method: Acid Monitor NMR Spectrum: 1 H NMR (300,132 MHz, DMSO.) D 2.34 (s, 3 H), 7.40 (d, 2 H), 7.76 - 7.85 (m, 3 H) , 8.05 - 8.14 (m, 2H), 8.50 (s, 1H) Example 103: 3-methyl-5- [4- (methylsulfonylmethyl) -6-morph oli-4-yl-pi rimidi n-2 il] -1 / 7-indazole. Tetrabutylammonium fluoride (1M solution in THF, 2 mL) to a solution of 3-methyl-1- (4-methylphenyl) sulfonyl-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] indazole (AZ12581939) ( 26 mg, 0.05 mmol) in THF (2 ml). It was heated at 50 ° C for 3 hours, poured into water and thoroughly extracted with DCM. The organic phase was washed with water (3x) and dried over MgSO 4, filtered and evaporated under reduced pressure. Purification on silica (gradient elution 50% ethyl acetate / 50% / so-hexane to 100% ethyl acetate) gave the title compound as a light brown solid (10.4 mg, 54%). LCEM Spectrum: MH + 388.56, Retention Time 2.46, Method: Early acid monitor. NMR spectrum: 1 H NMR (300.132 MHz, DMSO) d 2.55 (3 H, s), 3.24 (3 H, s), 3.75 (8 H, s), 4.53 (2 H, s), 6.86 (1 H, s), 7.52 (1 H , d), 8.38 (1H, dd), 8.69 (1H, s), 12.80 (1H, s) The starting material, 3-methyl-1- (4-methylphenyl) sulfonyl-5- [4- ( Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] indazole was prepared as follows :. 3-methyl-1- (4-methylphenyl) sulfonyl-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] indazole 2-Chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (146 mg, 0.50 mmol), 3-methyl-1- (4-methylphenyl) sulfonyl-5- (4,4,5 , 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) indazole (413 mg, 1 mmol), 2 M solution of sodium carbonate (2 ml) and dichlorobis (triphenylphosphine) Pd (ll) (40 mg) in a solution of 18% DMF in DME / H2O / EtOH (7: 3: 2) (7 ml) in a microwave tube for 10 minutes at 100 ° C. The reaction mixture was then evaporated to dryness under reduced pressure and the residue was partitioned between DCM and water. The aqueous phase was extracted twice with DCM and the combined organic phases were washed with water, saturated NaHCO3 solution and brine. The solution was then dried over MgSO 4, filtered and evaporated under reduced pressure. The residue was then purified on a SCX-2 column, eluting with methanol followed by 4% NH 4 OH in methanol to elute the title compound, which was finally obtained (after evaporation) as an off-white solid (26 mg, 9%) . LCEM Spectrum: MH + 542.59, Retention Time 2.18, Method: Intermediate Acid Monitor NMR Spectrum: H NMR (300.132 MHz, DMSO) d 2.33 (3H, s), 2.56 (3H, s), 3.21 (3H, s), 3.75 (8H, s), 4.54 (2H, s), 6.92 (1H, s), 7.39 (2H, d), 7.81 (2H, d), 8.18 (1H, d), 8.63 - 8.66 (2H, m) 3 -methyl-1- (4-methylphenyl) sulfonyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indazole Anhydrous 1,4-dioxane (20 ml) was added to 5-bromo-3-methyl-1- (4-methylphenyl) sulfonyl-indazole (876.6 mg, 2.4 mmol), bis (pinacolato) diborane (701 mg, 2.76 mmol ), Dppf (40 mg, 0.072 mmol), PdCI2 (dppf) (58.8 mg, 0.072 mmol) and potassium acetate (707 mg, 7.2 mmol). The mixture was degassed 3 times before being heated to reflux under nitrogen for 2 hours. The reaction mixture was then cooled and evaporated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with water (2x), then with 1 M HCl (2x) and finally with brine. The solution was then dried over MgSO 4, filtered and evaporated to dryness to give a brown solid (1.07 g). This was then applied to a silica column (20 g). Gradient elution with 90% / so-hexane / 10% ethyl acetate - > • 50% / so-hexane / 50% ethyl acetate gave the title compound as an off-white solid (0.94 g, 95%). Spectrum LCEM: MH + 413.57, Retention Time 3.22, Method: Acid Monitor NMR Spectrum: 1 H NMR (300.132 MHz, DMSO) d 1.32 (12H, s), 2. 32 (3H, s), 7.37 (2H, d), 7.76 (2H, d), 7.91 (1H, d), 8.09 - 8.12 (2H, m) (1x CH3 darkened by the DMSO peak). 5-bromo-3-methyl-1- (4-methylphenyl) sulfonyl-indazole Sodium hydride, (dispersion in al-60% oil, 440 mg, 11 mmol) in anhydrous DMF (25 ml) was cooled under nitrogen at 0 ° C (ice / water bath). 5-Bromo-3-methyl-1 H-indazole (2115 g, 10 mmol, prepared according to WO 2003/051366, Example 102c) was added dropwise as a solution in DMF (10 ml). After 30 minutes, tosyl chloride (2.67 g) was added in one portion.14 mmol). The reaction mixture was allowed to warm to room temperature and then stirred overnight. The reaction mixture was quenched with ice / water. It was extracted with ethyl acetate (3x). It was washed with water and brine. It was dried over MgSO 4, filtered and evaporated under reduced pressure to give a solid of creamy consistency. It was ground with a small volume of ether (the ether removes color and minor impurities). Dry in vacuo to give the title compound as a white solid (2.9 g, 79%). LCEM Spectrum: MH + 365.35 / 367.38, Retention Time 2.82, Method: Acid Monitor NMR Spectrum: 1H NMR (300.132 MHz, DMSO) d 2.33 (3H, s), 2.47 (3H, s), 7.38 (2H, d), 7.76 - 7.80 (3H, m), 8.03 (1H, d), 8.10 (1H, d) Example 104: 5- [2- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-4-yl] -1H-indole - [6-Chloro-2- (methylsulfonylmethyl) -pyrimidin-4-yl] -1-indole (110 mg, 0.34 mmol) and morpholine (3 ml) were heated in a microwave reactor at 120 ° C for 10 minutes. minutes The reaction solution was purified using reverse phase preparative HPLC (basic conditions to provide the title compound (35 mg) LCEM Spectrum: MH + 373, Retention Time 1.38, Method: Acid Monitor NMR Spectrum: 1 H NMR (300.132 MHz, DMSO) d 3.17 (3H, s), 3.73 (8H, s), 4.52 (2H, s), 6.54 (1H, dd) .7.28 (1H, s), 7.41 (1H, m) .7.48 (1H, d) ) .7.95 (1H, dd), 8.44 (1H, s), 11.27 (1H, s) The starting material 5- [6-chloro-2- (methylsulfonylmethyl) pyrimidin-4-yl] -1H-indole prepared as follows: 5- [6-Chloro-2- (methylsulfonylmethyl) pyrimidin-4-yl] -1 H-indole. 4,6-Dichloro-2- (methylsulfonylmethyl) pyrimidine (82 mg, 0.34 mmol), acid was heated indole-5-boronic acid (55 mg, 0.34 mmol), 2 M aqueous solution of sodium carbonate (1 ml), dichloroxy (triphenylphosphine) palladium (ll) (15 mg) and 18% DMF in 7: 3: 2-dimethoxyethane: water: ethanol (3.5 ml) in a microwave reactor at 100 ° C for 10 minutes The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired compound as a pale green gum (149 mg). Spectrum LCEM: MH + 322, Time of Retention 2.08, Method: Monitor acid 4,6-dichloro-2- (methylsulfonylmethyl) pyrimidine 2- (Methylsulfonylmethyl) pyrimidine-4,6-diol (2.1 g, 5.0 mmol) and phosphorus oxychloride (20 ml) were heated to reflux for 4 hours. The resulting solution was concentrated in vacuo and azeotropically distilled with toluene. The residue was partitioned between dichloromethane and ice-cold water. The organic solution was dried by filtration through a PTFE frit and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with hexane: ethyl acetate to give the desired product as a white solid, 87 mg. LCEM Spectrum: MH + 241, Retention Time 1.75, Method: Early monitor NMR spectrum: 1H NMR (300.132 MHz, CDCI3) d 3.19 (3H, s), 4.56 (2H, s), 7.43 (1H, s) 2- (methylsulfonylmethyl) pyrimidine-4,6-diol 2-Methylsulfonyl etimidamide (172 mg, 1.00 mmol), potassium carbonate (143 mg, 1.05 mmol) and diethyl malonate (1 ml) were stirred and heated at 150 ° C for two hours. The reaction mixture was cooled and diluted with diethyl ether, and the solid was collected by filtration and dried to give the desired product as a white solid (294 mg). LCEM Spectrum: MH + 205, Retention Time 0.43, Method: Early monitor 2-methylsulphonylethaneimidamide 2-Methanesulfonyllacetonitrile (11.9 g, 100.0 mmol) in ethanol was stirred and the mixture was cooled in ice. Hydrogen chloride gas was bubbled through the mixture and the solid gradually dissolved. After saturation of the solvent with hydrogen chloride, the solution was stirred at room temperature overnight. The mixture was diluted with ether and the white precipitate was collected by filtration and dried. The solid imidoyl ether was stirred in ethanol (200 ml), 7 M ammonia in methanol (13 ml, 0.1 mmol) was added and the mixture was stirred at room temperature for 48 hours. The mixture was concentrated to half its volume and the solid was collected by filtration and dried to give the desired product as a white solid (15.35 g). NMR spectrum: 1 H NMR (300.132 MHz, D 2 O) d 3.30 (3 H, s), 4.69 (2 H, s) Example 105: 5- [4- (Methylsulfonylmethyl) -6-morphine-4-yl-pi rimidi n-2-i I] -1H-benzoimidazole Trimethyl- [2 - [[5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] benzoimidazol-1-yl] methoxy] ethyl] silane (53 mg, 0.11 mmol) was heated and 2 M aqueous hydrochloric acid (3 ml) in ethanol, in a microwave reactor at 100 ° C for 10 minutes. The reaction mixture was then evaporated to give a white solid which was purified by reverse phase preparative HPLC (basic conditions) to give the title compound as a white solid (17 mg). 'LCEM Spectrum: MH + 347, Retention Time 0.91, Method: Acid Monitor NMR Spectrum: 1H NMR (500.133 MHz, DMSO) d 3.23 (3H, s), 3. 73 (8H, s), 4.51 (2H, s), 6.85 (1H, s), 7.64 (1H, d), 8.26 (1H, d), 8. 30 (1H, s), 8.59 (1H, s), 12.60 (1H, s) The starting material trimethyl- [2 - [[5- [4- (methylsulfonylmethyl) -6-morph oli-4- il-pi rimidi n-2-yl] benzoim idazol-1-yl] methoxy] ethyl] silane was prepared as follows: Trimethyl- [2 - [[5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl] -pyrimidin-2-yl] benzoimidazol-1-yl] methoxy] ethyl] silane Trimethyl- [2 - [[5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzoimidazol-1-yl] methoxy] ethyl] silane (57 mg, 0.15 g) was heated. mmol), 2-chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (44 mg, 0.15 mmol), 2 M aqueous sodium carbonate solution (1 ml), dichlorobis (triphenylphosphine) palladium ( ) (15 mg) and 18% dimethylformamide in 7: 3: 2 dimethoxyethane: water: ethanol (3.5 ml) in a microwave oven at 160 ° C for 3.5 minutes. The reaction mixture was partitioned between dichloromethane and water. The organic solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica eluting with ethyl acetate to give the desired compound as a brown solid (54 mg). Spectrum LCEM: MH + 504, Retention Time 2.10, Method: Acid monitor Trimethyl- [2 - [[5- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) benzoimidazol-1-yl] methoxy] ethyl] silane 2 - [(5-Bromobenzoimidazol-1-yl) methoxy] ethyl-trimethyl-silane (1.42 g, 4.33 mmol), potassium acetate (849 mg, 8.66 mmol), bis (pinacolato) diboron were stirred at reflux. 1.32 g, 5.20 mmol) and 1,1 '-bis (diphenylphosphino) ferro-chernichloropalladium (II) (71 mg, 0.09 mmol) in 1,4-dioxane (25 ml) under reflux in an inert atmosphere for 24 hours. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and filtered. The filtrate was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica eluting with ethyl acetate to give the desired compound as a pale green solid (1.45 g). Spectrum LCEM: MH + 375, Retention Time 2.76, Method: Acid Monitor 2 - [(5-bromobenzoimidazol-1-yl) methoxy] ethyl-trimethyl-silane A solution of 5-bromo-benzimidazole (2.96 g, 15 mmol, CAS number 4887-88-1) in dimethyl formamide (15 ml) was added dropwise to a suspension of 60% sodium hydride in oil ( 660 mg, 16.5 mmol) in dimethyl formamide (20 ml) under inert atmosphere and stirred for 30 minutes. The reaction mixture was cooled to 0 ° C, a solution of 2- (trimethylsilyl) ethoxymethyl chloride (2.74 g, 16.5 mmol) in dimethyl formamide (15 ml) was added dropwise and the mixture was stirred at room temperature. the ambient temperature for 18 hours. The reaction mixture was poured with stirring into ice water, and the product was extracted into ethyl acetate. The organic solution was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica eluting with 70% ethyl acetate in hexane. The product fractions were concentrated to give a pale yellow oil which was a mixture of tautomers of the desired compound (2.83 g).

LCEM Spectrum: MH + 329, Retention Time 2.79, Method: Acid Monitor Example 106: 4- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole 4- [6 - [(Methylsulfonyl) methyl] -2- (methylthio) pyrimidin-4-yl] morpholine (151 mg, 0.5 mmol), indole-4-boronic acid (141 mg, 1.1 mmol), thiophene- Copper 2-carboxylate (I) (248 mg, 1.3 mmol), palladium-. efra? r - // 's-triphenylphosphine (47 mg, 0.04 mmol), zinc acetate (175 mg, 1.1 mmol) and additional 1,4-dioxane (5 ml) were added to a microwave container. The system was degassed with nitrogen, sealed and heated in a microwave reactor at 130 ° C for 45 minutes. The reaction mixture was poured into water and extracted with ethyl acetate, washed with water, brine and dried over magnesium sulfate. The product was further purified using preparative HPLC in reverse phase to provide the title compound (43 mg). Spectrum LCEM: MH + 373, Retention Time 2.60, Method: Acid Monitor NMR Spectrum: 1H NMR (300.132 MHz, DMSO) d 3.20 (d.3H), 3.75 (s, 8H), 4.56 (s, 2H), 6.87 (s, 1H ), 7.19 (t.1H), 7.38 (d.1H), 7.44 (t.2H), 7.54 (d.1H), 8.07 (dd, 1H), 11.36 (s, 1H). 3- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl) -5,7-diazabicyclo [4.3.0] nona-1, 3,5,8-tetraene which is sample is then prepared in an analogous manner using 5,7-diazabicyclo [4.3.0] nona-1, 3,5,8-tetraen-3-ylboronic acid and 4- [6 - [(methylsulfonyl) methyl] -2- (methylthio) pyrimidin-4-yl] morpholine.

Example 108: 4- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] aniline 2-Methylsulfanyl-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (1.00 g, 3.3 mmol), 4-aminophenylboronic acid (904 mg, -6.60 mmol), thiophene-2-carboxylate were added. copper (L) (1.64 g, 8.58 mmol), Pd (PPH3) 4 (153 mg, 0.04 equiv., 0.13 mmol) was added to a microwave vessel and 1,4-dioxane (20 ml) was added. The system was degassed with N2, sealed and heated in a microwave reactor at 130 ° C for 1 hour. After cooling, the reaction mixture was poured into water and the resulting precipitate was collected by filtration and dried under vacuum to give the title compound as an off-white solid (988 mg). LCEM spectrum: MH + 349.41, retention time 1.43, Method: Acid monitor NMR spectrum: 1H NMR (300.132 MHz, DMSO) d 3.20 (3H, s), 3.61 - 3.83 (8H, m), 4.43 (2H, s) , 5.57 (1H, s), 6.60 (2H, d), 6.70 (1H, s), 8.04 (2H, d) Example 109: 2- (1H-indol-5-yl) -6-morphine acid -4-il-pi rimidi na-4-carboxylic Methyl 2-chloro-6-morpholin-4-yl-pyrimidine-4-carboxylate (10.0 g, 38.91 mmol, CAS number 107973-01-3), 1 / - / - indol-5-ylboronic acid (9.7 g, -60.31 mmol), dichlorobis (triphenylphosphine) palladium (II) (2.1 g, 2.92 mmol) and sodium carbonate (2 M in water, 100 mL) in 18% DMF in dimethoxyethane: water: ethanol (7: 3) : 2) (320 ml) in a microwave oven in 8 batches at 120 ° C for 30 minutes. The combined batches were evaporated, brought to pH = 2 with 2N HCl, stirred for 30 minutes and a solid separated by filtration. This was dried overnight at 40 ° C to give the title compound (17 g). Spectrum LCEM: MH + 325, retention time 1.23, Method: Acid monitor. NMR spectrum: 1 H NMR (300.132 MHz, DMSO.) D 3.70 - 3.83 (8H, m), 6.56 -6.57 (1H, m), 7.18 (1H, s), 7.39 - 7.40 (1H, m), 7.45 (1H , d), 8.22-8.25 (1H, m), 8.70 (1H, s), 11.24 (1H, s), Example 110: [2- (1H-lndol-5-yl) -6-morpholin-4-yl) -pyrimidin-4-yl] methanol 2- (1-Indol-5-yl) -6-morpholin-4-yl-pyrimidine-4-carboxylic acid (14.0 g, 38.89 mmol) in THF (600 mL) was treated with lithium aluminum hydride (1.0 M in tetrahydrofuran) (117 mL, 116.67 mmol) at 0 ° C and stirred. After 5 h, the mixture was treated with water (4.43 ml), then with 15% NaOH (4.43 ml), and then with water (13.30 ml), the mixture was diluted with ethyl acetate (200 ml) and it was stirred for 35 minutes. The organic phases were evaporated and the residue was purified by SCX chromatography to give a crude product. The foam was purified by MPLC [35-90% ethyl acetate: / so-hexane] to give the title compound (5.58 g). LCEM spectrum: MH + 310, retention time 1.03, Method: Acid monitor NMR spectrum: 1 H NMR (300.132 MHz, DMSO) d 3.73 - 3.82 (8 H, m), 4.54 (2 H, d), 5.44 (1 H, t) , 6.57 - 6.61 (1H, m), 6.76 (1H, s), 7.41 - 7.44 (1H, m), 7.47 (1H, s), 8.20 - 8.24 (1H, m), 8.66 (1H, s), 11.24 (1H, s), Example 111: 5- [4-Morpholin-4-yl-6- (morpholin-4-ylmethyl) pyrimidin-2-yl] -1H-indole [2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methanol (100 mg, 0.32 mmol, from Example 110) was suspended in dichloromethane (2 ml) and treated with methanesulfonyl chloride (0.038 ml, 0.48 mmol) and triethylamine (0.068 ml, 0.48 mmol). The mixture was stirred overnight, then treated with morpholine (1 ml), and stirred again overnight. The solution was evaporated and purified by preparative HPLC [5-95% MeCN: water] to give the title compound (10 mg). LCEM spectrum: MH + 379, retention time 1.03, Method: Acid monitor NMR spectrum: H NMR (300.132 MHz, DMSOJ d 3.32 - 3.41 (4H, m), 3.69 - 3.79 (8H, m), 3.86 - 3.94 (4H , m), 4.35 (2H, s), 6.52 -6.57 (1H, m), 6.78 (1H, d), 7.38-7.42 (1H, m), 7.46 (1H, d), 8.20 (1H, d), 8.68 (1H, s), Example 112:? / - [[2- (1H-lndol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methyl] -1- (4-methoxyphenyl) ) methanamine To a solution of 5- [4- (methylsulfonyloxymethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole in DCM (4 ml, which was assumed to contain 50 mg of material) a solution was added of 4-methoxybenzylamine (28 mg) and DIPEA (0.040 ml) in DCM (2 ml) was added thereto. The reaction mixture was stirred at room temperature overnight, then NMP (1 ml) was added and the DCM was removed in vacuo. DIPEA (0.030 ml) and a pair of potassium iodide crystals were added, and the mixture was heated in a microwave reactor at 100 ° C for 10 minutes. The mixture was evaporated, loaded on an SCX-2 column, the column was washed with methanol and the product was then eluted with 7 N ammonia in methanol. The fractions were concentrated in vacuo and the residue was purified by preparative HPLC (acid) to give the desired compound as a solid (20 mg).

LCEM spectrum: MH + 430, retention time 1.40, Method: Acid monitor NMR spectrum: 1H NMR (400.132 MHz, DMSO) d 3.74 (8H, s), 3.79 (3H, s), 4.15 (2H, s), 4.27 (2H, s), 6.55 (1H, d), 6.75 (1H, s), 7.03 (2H, d), 7.41 (1H, s), 7.49 (1H, s), 7.47 (1H, s), 7.49 (1H, s), 7.47 (1H, s), 7.49 ( 2H, d), 8.27 (1H, dd), 8.74 (1H, d), 9.32 (1H, s) The following compound was prepared in an analogous manner using the appropriate amine.

Example 113: 1 H NMR spectrum NMR (400.132 MHz, DMSO) d 3. 74 (8H, s), 4.19 (2H, s), 4.34 (2H, s), 6.55 (1H, d), 6.75 (1H, s), 7.41 (1H, t), 7.46 (1H, d), 7.55 (2H, d), 7.59 (2H, d), 8.27 (1H, d), 8.74 (1H, dd), 9.45 (1H, bs) The preparation of 5- [4- (methylsulfonyloxymethyl) -6-morpholin-4 -yl-pyrimidin-2-yl] -1 H-indole is described below. - [4- (Methylsulfonyloxymethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole [2- (1-Indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methanol (200 mg) and triethylamine (0.135 ml) in DCM (5 ml) were stirred at the temperature environment and methanesulfonyl chloride (0.075 ml) was added dropwise. The reaction mixture was stirred for 1 hour, and new amounts of DCM (5 ml) and water (5 ml) were added. The organic phase was separated, a new amount of DCM (5 ml) was added and then the organics were washed with brine (5 ml), dried (Na2SO4) and filtered. It was assumed that the reaction had been quantitative and the mixture was diluted to 20 ml of total volume with additional DCM (assuming it contained a total of 250 mg of material). This material was used without further purification or characterization. Example 114: 5- [4 - [(2-methylpyridin-3-yl) oxymethyl] -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole To a stirred solution of [2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methanol (from Example 110, 40.6 mg, 0.13 mmol) and triethylamine (0.027 ml) , 0.195 mmol) in DCM (5 ml) at room temperature was added methanesulfonyl chloride (0.015 ml, 0.195 mmol) dropwise. The reaction mixture was then stirred for 1 hour, and then diluted with DCM (5 ml), washed with water (5 ml), brine (5 ml), dried (Na2SO4) and filtered, after which evaporated to give the crude mesylate. A solution of 3-hydroxy-2-methylpyridine (22 mg, 0.19 mmol) in DMF (2 ml) was added to sodium hydride (8 mg of 60% dispersion in oil, 0.19 mmol), and stirred in DMF (1 ml) at room temperature. After stirring for 5 minutes, the mesylate (50 mg, 0.13 mmol) in DCM (4 ml) was added, and stirring was then continued at room temperature overnight. The solvent was removed in vacuo, water (10 ml) was then added, and the aqueous phase was extracted into ethyl acetate (2 x 20 ml, 1 x 10 ml) and DCM (10 ml). The combined organic extract was washed with water (5 ml) and brine (5 ml), dried (MgSO4) and evaporated to give a gummy solid. The crude material was purified on an Isolute silica gel column of 10 g, and eluted with 2% methanol / DCM to give a white solid (22 mg). LCEM spectrum: MH + 402, retention time 1.01, Method: Acid monitor NMR spectrum: 1 H NMR (400.132 MHz, DMSO) d 3.28 or 3.31 (3 H, s), 3.73 (8 H, s), 5.15 (2 H, s) , 6.55 (1H, d), 6.75 (1H, s), 7.19 - 7.22 (1H, m), 7.38 (1H, t), 7.44 (1H, d), 7.45 (1H, d), 8.05 (1H, d ), 8.18 (1H, d), 8.63 (1H, d), 11.22 (1H, s) Example 115: 5- [4- (methoxymethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1 H-indole To a stirred solution of [2- (1 / - indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methanol (from Example 110, 47 mg, 0.15 mmol) and triethylamine (0.031 ml, 0.225 mmol) in DCM (5 ml) at room temperature was added methanesulfonyl chloride (0.017 ml, 0.225 mmol) dropwise. The reaction mixture was then stirred for 1 hour, and then diluted with DCM (5 ml), washed with water (5 ml), brine (5 ml), dried (Na2SO) and filtered, after which was evaporated to give the crude mesylate. This was then diluted in MeCN (1 ml) and added to a solution of sodium methoxide (26 mg, 0.46 mmol) in methanol (3 ml) at room temperature, after which it was stirred for 30 hours. The solvent was removed in vacuo and the crude material was purified on a column of silica gel, and eluted with 25% ethyl acetate in DCM to give the title compound as a solid (27 mg). LCEM Spectrum: MH + 325, retention time 2.01, Method: NMR Spectrum Based Monitor: 1H NMR (300.13 MHz, DMSO-d6) d 3.43 (3H, s), 3. 72 (8H, s), 4.42 (2H, s), 6.54 (1H, s), 6.62 (1H, s), 7.37 (1H, t), 7. 42 (1H, d), 8.14 - 8.18 (1H, m), 8.60 (1H, s), 11.20 (1H, s) Example 116: 5- [4- (2-f-urylmethylsulfonylmethyl) -6- morph oli n-4-yl-pi rimidi n-2-yl] - 1H-indole To a stirred solution of 5- [4- (2-furylmethylsulfanylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole (47 mg), in dioxane / methanol (3 ml / 0.5 ml) ) at room temperature, 3-chloroperbenzoic acid (43 mg, 0.17 mmol) was added, followed immediately by 1 N sodium hydroxide solution (0.180 ml, 0.17 mmol).

After 2 hours and 40 minutes, a new amount of 3-chloroperbenzoic acid (17 mg, 0.07 mmol) was added, washed with a little methanol (<0.2 ml) followed immediately by 1 M sodium hydroxide solution ( 0.70 ml, 0.07 mmol). The reaction mixture was stirred for a further 40 minutes and then loaded onto an SCX-3 column (pretreated with 30 ml of methanol). The column was washed thoroughly with methanol (30 ml), after which the product was eluted with 10% 7 N ammonia in methanol / methanol (60 ml). Evaporation provided a brown gum which was purified by preparative HPLC to give the product as a colorless solid (15 mg, 55%). Spectrum LCEM: MH + 439, retention time 2.28, Method: Acid monitor The following compounds were prepared in an analogous manner from the appropriate sulfides.

The starting material 5- [4- (2-furylmethylsulfanylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1H-indole was prepared as follows: 5- [4- (2-f-uryl-methyl) Isulfanilmeti l) -6-morph oli n-4-yl-pi rimidi n-2-i I] -1H-indole Sodium ethoxide (18 mg, 0.26 mmol) was added to a stirred solution of furfuryl mercaptan (30 mg, 0.26 mmol) in acetonitrile (4 ml) at room temperature in an MPS tube under nitrogen. After stirring for 70 minutes, a solution of 5- [4- (methylsulfonyloxymethyl) -6-morpholin-4-yl-pyrimidin-2-yl] -1-indole was added (Example 112, 60 mg, 0.15 mmol ) in acetonitrile (1 ml), and the reaction mixture was then stirred at room temperature for -65 hours. The reaction mixture was then loaded onto an SCX-3 column (pretreated with 25 ml of methanol). The column was washed with methanol (25 ml) to elute the non-basic material, before eluting with 10% normal ammonia in methanol / methanol (60 ml). Evaporation gave the sulfur as a gum (47 mg). LCEM spectrum: MH + 407, retention time 2.60, Method: Base Monitor The following sulfides were prepared in an analogous manner from 5- [4- (methylsulfonyloxymethyl) -6-morpholin-4-yl-pyrimidin-2 -yl] -1 / - indole (from Example 112) and the appropriate thiol.

Example 122: 2 - [[2- (1 H-lndol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfonyl] N, N-dimet I acetamide The salt of 2.2.2-trifluoroacetic acid from [2- (1 / - / - indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfanylmethanimidamide (0.080 g, 0.11 mmol) in DMF (2 ml) was added to a solution of 2-bromo-N, α / - d / 'methyalkyl (0.11 mmol) in DMF (1 ml). This solution was treated with sodium hydroxide (35 mg, 0.87 mmol) in water (1 ml) and shaken for 1 hour. The solvent was evaporated. The residue was dissolved in ethyl acetate / water / brine (4 ml: 2 ml: 1 ml) with sonication and stirring. The organic phases were removed and the aqueous layer was subjected to another extraction with ethyl acetate (2 ml). The combined organic phases were evaporated and purified by preparative HPLC to give the sulfide which was dissolved in dioxane: water (3 ml: 0.5 ml) and treated with 3-chloroperbenzoic acid (0.056 g, 0.13 mmol) and immediately after with permanganate sodium (0.027 g, 0.17 mmol). The mixture was stirred at room temperature for about 1 hour. The mixture was purified by SCX chromatography to give the title compound (9 mg).

LCEM spectrum: MH + 444, retention time 1.27, Method: Acid monitor The following compounds were prepared in an analogous manner from the salt of 2.2.2-trifluoroacetic acid of [2- (1 / - / - indole-5 -yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfanylmethanimidamide and the appropriate alkyl halide.

The 2.2.2-trifluoroacetic acid salt starting material of [2- (1H-indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-ylmethyl-sulfanylmethanimidamide was prepared as follows: 2.2.2-trifluoroacetic acid salt of [2- (1 H -indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methylsulfanylmethanimidamide [2- (1H-Indol-5-yl) -6-morpholin-4-yl-pyrimidin-4-yl] methanol (from Example 110, 3.27 g, 10.55 mmol) was suspended in DCM and treated with methanesulfonyl chloride (1.23 ml, 15.82 mmol) and triethylamine (2.21 ml, 15.82 mmol). After 15 minutes, the suspension was evaporated to give a crude material and redissolved in ethanol (25 ml). Thiourea (0.882 g, 11.60 mmol) was added and the reaction mixture was heated at 70 ° C for 30 minutes. Most of the ethanol was removed by distillation. The residue was triturated with ether and the solvent was discarded. This trituration was repeated twice more to give the crude product as a solid. This was purified by preparative HPLC to give the desired compound (1.16 g). LCEM spectrum: MH + 369, retention time 1.14, Method: Acid Monitor NMR Spectrum: 1H NMR (DMSO-d6) d 3.68 - 3.80 (8H, m), 4.42 (2H, s), 6.56 (1H, s), 6.80 (1H, s), 7.40 - 7.44 ( 1H, m), 7.46 (1H, d), 8.03 - 8.08 (1H, m), 8.52 (1H, s), 9.33 (1H, s), 9.84 (1H, s), 11.29 (1H, s) , Example 173: 4-Morfol i n-4-i I -2-pyridin-2-yl-6- (f-butylsulfonylmethyl) pyrimidine It was prepared in a manner analogous to Example 44, 4- (benzenesulfonylmethyl) -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine, from the appropriate sulfide. LCEM Spectrum: MH + 377.6, retention time 3.16, Method: NMR Spectrum Based Monitor: 1H NMR (500.133 MHz, DMSO) d 1.40 (9H, s), 3.73 (8H, s), 4.51 (2H, s) , 6.95 (1H, s), 7.48-7.51 (1H, m), 7.94 (1H, dt), 8.31 (1H, d), 8.71-8.73 (1H, m) The starting sulfides were prepared in a manner analogous to Example 26, 4-morpholin-4-yl-6- (phenylsulfanylmethyl) -2-pyridin-2-yl-pyrimidine, by reaction of the appropriate diol with 4- (chloromethyl) -6-morpholin-4-yl-2-pyridine -2-pyrimidine (from Example 26).

Example 174: 2-methyl-5- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] 1H-indole 2-Chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (292 mg, 1 mmol), 2-methyl-1- (4-methylphenyl) sulfonyl-5- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) indole (617 mg, 1.5 mmol), 2 M aqueous sodium carbonate solution (1 ml), dichloro-D / 's- (triphenylphosphine) palladium Or (ll) (20 mg) and 18% DMF in DME: water: 7: 3: 2 ethanol (3.5 ml) in a microwave tube and heated at 125 ° C for 30 minutes. The solvent was then evaporated and the residue was partitioned between water and DCM. The layers were then separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (MgSO) and evaporated to give an oil. This was dissolved in a methanol / water mixture and treated with sodium hydroxide solution (2 M, -6 ml) for four hours. The reaction mixture was neutralized with hydrochloric acid (2 M) and evaporated. The crude solid was purified by preparative HPLC to give the title compound as a white solid (30 mg). LCEM Spectrum: MH + 387.60, retention time 1.97, Method: NMR Spectrum Based Monitor: 1 H NMR (300.132 MHz, CDCI3) d 3.09 (3 H, s), 3.48 (3 H, s), 3.68 - 3.91 (8 H, m), 4.27 (2H, s), 6.42 (1H, s), 6.52 (1H, s), 8.21 (1H, d), 8.29 (1H, dd), 8.40 (1H, d). The starting material 2-methyl-1- (4-methylphenyl) sulfonyl-5- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) indole was prepared as follows: 2- methyl-1- (4-methylphenyl) sulfonyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indole -Bromo-2-methyl-1- (4-methylphenyl) sulfonyl-indole was suspended (1095 g, 3 mmol), bis (pinacolato) diboro (915 mg, 3.6 mmol), palladium dichloride-di (dppf) dichloromethane complex (25 mg, 0.03 mmol) and potassium acetate (588 mg, -6 mmol) in dioxane (20 ml) and heated at 80 ° C for 10 hours. The reaction mixture was then applied to a column of silica gel, and purified by flash chromatography (0-10% EtOAc / isohexane) to give the title compound as a waxy solid (951 mg). NMR spectrum: 1 H NMR (300.132 MHz, CDCl 3) d 1.28 (12H, s), 2.26 (3H, s), 2.52 (3H, s), 6.26 (1H, s), 7.11 (2H, d), 7.57 (2H , d), 7.62 (1H, dd), 7.81 (1H, s), 8.07 (1H, d) 5-bromo-2-methyl-1- (4-methylphenyl) sulfonyl-indole 2-Methyl-5-bromoindole (5 g, 23.8 mmol) was dissolved in DMF (50 mL) and fractionally added to the sodium hydride solution (1.05 g, 26.18 mmol). After 30 minutes, toluenesulfonyl chloride (5 g, 26.18 mmol) was added and the reaction mixture was allowed to stir at room temperature for -6 hours. The reaction mixture was then poured into water and extracted into ethyl acetate. The combined organic extracts were dried over MgSO and evaporated to give a solid. This was purified by flash chromatography (0-5% ethyl acetate / isohexane) to give the title compound as a light brown solid (5.23 g). LCEM: M + H + 364.27, retention time 3.29, Method: Monitor Base NMR Spectrum: 1H NMR (300.132 MHz, DMSO-d6) d 2.32 (3H, s), 2. 59 (3H, s), 6.55 (1H, s), 7.37 (2H, d), 7.41 (1H, dd), 7.69 (1H, d), 7.74 (2H, d), 7.97 (1H, d) Example 175 : 4 - [(5-methyl-2H-pyrazol-3-yl) oxymethyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine Prepared in a manner analogous to Example-68, 4- [(3-methoxyphenoxy) methyl] -6-morpholin-4-yl-2-pyridin-2-yl-pyrimidine, from 4- (chloromethyl) -6-morpholin-4-yl-2-pyridin-2- il-pyrimidine (del Example 26) and the appropriate starting material. LCEM Spectrum: MH + 353.6, retention time 1.59, Method: NMR Spectrum Based Monitor: 1H NMR (300.132 MHz, DMSO-d6) d 2.16 (s, 3H), 3.70 (s, 8H), 5.09 (s, 2H), 5.56 (s, 1H), 6.82 (s, 1H), 7.48 (m, 1H), 7.92 (td, 1H), 8.31 (d, 1H), 8.70 (d, 1H), 11.57 (s, 1H) Example 176: 2- (3-furyl) -4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine Prepared analogously to Example 1. 4- (Methylsulfonylmethyl) -6-morpholin-4-yl-2-thiophen-3-yl-pyrimidine, from 2-methylsulfanyl-4- (methylsulfonylmethyl) -6-morpholine- 4-yl-pyrimidine and the appropriate boronic acid. LCEM spectrum: MH + 324.5, retention time 1.63, Method: Base Monitor Example 177: 4- (Methylsulfonylmethyl) -6-morpholin-4-yl-2-naphthalen-1-yl-pyrimidine Prepared in a manner analogous to Example 1. 4- (Methylsulfonylmethyl) -6-morpholin-4-yl-2-thiophen-3-yl-pyrimidine, from 2-methylsulfanyl-4- (methylsulfonylmethyl) -6-morpholine -4-yl-pyrimidine and the appropriate boronic acid. LCEM spectrum: MH + 384.6, retention time 2.16, Method: Base Monitor.

Claims (41)

1. A compound of formula (I) formula (I) or a salt, ester or prodrug thereof; wherein m is 0, 1, 2, 304; X is a linker group selected from -CR4 = CR5-CR4 = CR5CR6R7-, -CR6R7CR5 = CR4-, -C = C-, -C = CCR6R7- -CR6R7C = C-, -NR4CR6R7-, -OCR6R7-, - SCR6R7-, -S (O) CR6R7- S (O) 2CRbRX -C (O) NR CR ° RX • NR * C (O) CR 6 ° DR7 -NR C (O) NR5CR6R7-, -NR4S (O) 2CR6R7-, -S (O) 2NR CR6R7- -C (O) NR4-, -NR4C (O) -, -NR C (O) NR5-, - S (O) 2 NR4- and -NR4S (O) 2-; 1Y and Y2 are independently N or CR8, with the proviso that one of 1Y and Y2 is N and the other is CR8; R1 is a group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl- alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2Ra, -CONRs -DRilu-, NRaR1 NRaCOR -NRsCO2R 10 NRMCONR11u0RD15 -NR9COCONR10R15 and -NR9SO2R10; R2 is a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl and heterocyclyl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11 , -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12 and -NR11COCONR 2R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14; R4 and R5 are independently hydrogen or alkyl of 1 to 6 carbon atoms; or R1 and R4, together with the atom or atoms to which they are attached, form a 5- or 10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms are (are) optionally substituted with N, O or S, and the ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxyalkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino- alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) carbon) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, and bis (alkyl of 1 to 6 carbon atoms) carbamoyl; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and alkyl of 1 to 6 carbon atoms; R8 is selected from hydrogen, halo, cyano and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxyalkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms carbon, bis (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (to Iq u il of 1 to 6 carbon atoms) sulfamoyl , alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms carbamoyl and bis (C1-C6 alkyl); R11 and R12 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, whose group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) bond) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (C 1 -C 6 alkyl) amino, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms and bis (C 1 -C 6 alkoxy I) carbamoyl; R13, R14, R15 and R16 are independently hydrogen or a group selected from alkyl of 1 to 6 carbon atoms, carbocyclyl, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl and heterocyclyl-alkyl of 1 to 6 carbon atoms, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, hydroxy-alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms , alkoxy of 1 to 6 carbon atoms - alkoxy of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, bis (alko Ii of 1 to 6 carbon atoms) amino, amino-alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, bis (alk 1 to 6 carbon atoms) amino-alkyl of 1 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 atoms carbon (alkyl of 1 to 6 carbon atoms) amino, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms, bis (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanoylamino of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms (alkyl of 1 to 6 carbon atoms) amino, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms and bis (alkyl of 1 to 6 carbon atoms) carbamoyl; with the proviso that when X is -C (O) NH-, R1 is not the group for use as a medicine in the treatment of a proliferative disease.

2. A compound of formula (I) according to claim 1, wherein X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7-, -S (O) 2CR6R7-, -C (O) NR4CR6R7-, -NR4C (O) NR5CR6R7-, -S (O) 2NR CR6R7-, -NR4C (O) -, -C (O) NR4-, -S (O) 2NR4- and -NR4S (O) 2- for use as a medicament in the treatment of a proliferative disease.

3. A compound of formula (I) according to claim 1, wherein X is a linker group selected from -SCR6R7-, -S (O) CR6R7 and -S (O) 2CR6R7- for use as a medicament in the treatment of a proliferative disease.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein R4 is hydrogen or methyl for use as a medicament in the treatment of a proliferative disease.

5. A compound of formula (I) according to any one of claims 1 to 4, wherein R5 is hydrogen or methyl for use as a medicament in the treatment of a proliferative disease.

6. A compound of formula (I) according to any one of claims 1 to 5, wherein R6 is hydrogen or methyl for use as a medicament in the treatment of a proliferative disease.

7. A compound of formula (I) according to any one of claims 1 to 6, wherein R7 is hydrogen or methyl for use as a medicament in the treatment of a proliferative disease.

8. A compound of formula (I) according to any one of claims 1 to 7, wherein R1 is a group selected from alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, cycloalkyl from 3 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, aryl-alkyl of 1 to 4 carbon atoms, cycloheteroalkyl, heteroaryl, cycloheteroalkyl-alkyl of 1 to 4 carbon atoms, heteroarylalkyl of 1 to 4 carbon atoms carbon, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10 for use as a medicament in the treatment of a proliferative disease.

9. A compound of formula (I) according to claim 8, wherein R1 is a group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclohexyl, -CH2CN, -CH2C (O) NH2, -CH2CH2NC (O) CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-4-fluorophenyl, 4-bromo -2-fluorophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4- (N-methylaminocarbonyl) phenyl, benzyl, 4-fluorobenzyl, 2-chlorobenzyl, 2- chloro-6-fluorobenzyl, 4-methoxybenzyl, phenethyl, 3-trifluorophenethyl, furan-2-ylmethyl, thien-2-ylmethyl, 2-pyrazin-2-ylethyl, pyridin-3-yl, 2-methylpyridin-3-yl and 2-aminocarbonylpyridin-3-yl, for use as a medicament in the treatment of a proliferative disease.

10. A compound of formula (I) according to any one of claims 1 to 9, wherein R2 is selected from aryl and heteroaryl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro , -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12 for use as a medicament in the treatment of a proliferative disease.

11. A compound of formula (I) according to claim 10, wherein R2 is selected from phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl, quinolinyl, benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl, which group is optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12 for use as a medicament in the treatment of a proliferative disease.

12. A compound of formula (I) according to claim 11, wherein R2 is 3- (hydroxymethyl) phenyl, 4- (hydroxymethyl) phenyl, 4- (cyanomethyl) phenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-phenoxyphenyl, 3-pyrrolidin-1-phenyl, 3- (aminocarbonyl) phenyl, 4- (dimethylaminocarbonyl) phenyl, furan-3-yl, thien-3-yl, 5- (hydroxymethyl) thien-2-yl, pyridin-2-yl, pyridin-4-yl, 2-methoxypyridin-5-yl, 2-methoxypyrimidin-5-yl, 2-methoxynaphth-6-yl, 5,7-diazabicyclo [4.3.0] nona-2,4,8,10-tetraenyl, azaindolyl, indole-5- ilo, 1-methylindol-5-yl, quinolin-6-yl, benzimidazolyl, benzofuran-2-yl, dibenzofuran-1-yl and benzothien-3-yl for use as a medicament in the treatment of a proliferative disease.

13. A compound of formula (I) according to claim 12, wherein R2 is azaindolyl, indol-5-yl, benzimidazolyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl or 4-hydroxymethylphenyl, for use as a medicament in the treatment of a proliferative disease.

A compound of formula (I) according to any one of claims 1 to 13, wherein 1Y is CR8 and Y2 is N for use as a medicament in the treatment of a proliferative disease.

15. A compound of formula (I) according to claim 14, wherein Y is CH or CF and Y2 is N for use as a medicament in the treatment of a proliferative disease.

16. A compound of formula (I) according to claim 15, wherein 1Y is CH and Y2 is N for use as a medicament in the treatment of a proliferative disease.

17. A compound of formula (I) according to any one of claims 1 to 16, wherein m is 0 such that R3 is absent, for use as a medicament in the treatment of a proliferative disease.

18. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 17 in the manufacture of a medicament for use in the treatment of a proliferative disease.

19. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 17 for the production of an antiproliferative effect in a warm-blooded animal such as man. .

20. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 17 in the manufacture of a medicament for use in the production of an antiproliferative effect in a warm-blooded animal such as man.

21. A method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of treatment, which comprises administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. , as defined in any one of claims 1 to 17.

22. A method for the treatment of cancer, inflammatory diseases, obstructive diseases of the airways, immunological diseases or cardiovascular diseases in a warm-blooded animal such as man, in need of treatment, which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 17.

23. A compound of formula (I) according to any one of claims 1 to 17, with the proviso that the compound of formula (I) is not: 4-. { 6 - [(methylthio) methyl] -2-methylpyrimidin-4-yl} morpholine; 4- (6- { [(4-chlorophenyl) thio] methyl} -2-methylpyrimid i n-4-yl) morpholine; 4- (6-. {[[(4-chlorophenyl) thio] methyl} -2-methylpyrimidin-4-yl) -2,6-dimethylmorpholine; 4-. { 6 - [(phenylsulfinyl) methyl] -2-methylpyrimidin-4-yl} morpholine; 4- (6- { [(4-chlorophenyl) sulfinyl] methyl} -2-methylpyrimidin-4-yl) morpholine; 4-. { 6 - [(phenylsulfonyl) methyl] -2-methylpyrimidin-4-yl} morpholine; 4- (6- { [(4-chlorophenyl) sulfonyl] methyl} -2-methylpyrimidin-4-yl) morpholine; 4-. { 6 - [(methylthio) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4-. { 6 - [(phenylthio) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4- (6- { [(4-chlorophen-1-thio] methyl]} -2-phenylpyrimidin-4-yl) morpholine; 4- (6-. {[[(4-chlorobenzyl) thio] methyl} -2-phenylpyrimidin-4-yl) morpholine; 4- (6-. {[[(4-chlorobenzyl) thio] methyl} -2-phenylpyrimidin-4-yl) -2,6-dimethylmorpholine; 4-. { 6 - [(methylsulfinyl) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4-. { 6 - [(phenylsulfinyl) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4- (6- { [(4-chlorophenyl) sulfinyl] methyl.} -2-phenylpyrimidin-4-yl) morpholine; 4-. { 6 - [(Methylsulfonyl) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4-. { 6 - [(phenylsulfonyl) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4-. { 6 - [(methylthio) methyl] -2-pyridin-2-ylpyrimidin-4-yl} morpholine; 4-. { 6 - [(phenylthio) methyl] -2-pyridin-4-ylpyrimidin-4-yl} morpholine; 4- (6- { [(4-chlorophenyl) thio] methyl.} -2-pyridin-2-ylpyrimidin-4-yl) morpholine; 4-. { 6 - [(methylsulfonyl) methyl] -2-pyridin-3-ylpyrimidin-4-yl} morpholine; 4-. { 6 - [(methylsulfonyl) methyl] -2-pyridin-4-ylpyrimidin-4-yl} morpholine; 4-. { 6 - [(phenylsulfonyl) methyl] -2-pyridin-2-ylpyrimidin-4-yl} morpholine; 4-. { 6 - [(phenylsulfonyl) methyl] -2-pyridin-3-ylpyrimidin-4-yl} morpholine; 4-. { 6 - [(phenylsulfonyl) methyl] -2-pyridin-4-ylpyrimidin-4-yl} morpholine; 4-. { 6 - [(methoxy) methyl] -2-methylpyrimidin-4-yl} morpholine; 4-. { 6 - [(methoxy) methyl] -2-phenylpyrimidin-4-yl} morpholine; 4-. { 6 - [(methoxy) methyl] -2-phenylpyrimidin-4-yl} -2,6-dimethylmorpholine; 4-. { 6 - [(phenoxy) methyl] -2- (6-methylpyrid-2-yl) pyrimidin-4-yl} -2,6-dimethylmorpholine; N- [5 - [[3- (1-cyano-1-methylethyl) benzoyl] amino] -2-methylphenyl] -2,6-d i-4-m or rfolin i 1-4-pyrimidine carboxamide; N- [5 - [[3- (1-cyano-1-methylethyl) benzoyl] amino] -2-methylphenyl] -6- (4-morpholinyl) -2- (trifluoromethyl) -4-pyrimidinecarboxamide; N- [4-fluoro-3 - [(pyrazinyloxy) methyl] phenyl] -2,6-di-4-morpholinyl-4-pyrimidinecarboxamide; 4- [2-methyl-6 - [(1 E) -2- [3- (trifluoromethyl) phenyl] ethenyl] -4-pyrimidinyl] -morpholine; 4- [6-methyl-2 - [(1 E) -2- [3- (trifluoromethyl) phenyl] ethenyl] -4-pyrimidinyl] -morpholine; 3,4,5-trimethoxy-N- [4-methyl-6- (4-morpholinyl) -2-pi rimidi n i I] -benzamide; N- (2,3-dimethyl-1H-indol-5-yl) -2,6-di-4-morpholinyl-4-pyrimidine carboxamide; N- (2,3-dimethyl-1H-indol-5-yl) -4,6-di-4-morpholinyl-2-pyridinecarboxamide; N- (3,4-dimethylphenyl) -2,6-di-4-morpholinyl-4-p i rim id inca rboxam id a; N- [3- (aminocarbonyl) phenyl] -2,6-di-4-morpholinyl-4-pyrimidine carboxamide; N- (4,6-di-4-morpholinyl-2-pyridinyl) -N '- (3-methylphenyl) -urea; N- (2,3-d-methyl-1 H -indol-5-yl) -4,6-di-4-morpholinyl-2-pyridinecarboxamide; 4,6-di-4-morpholinyl-N- (1,2,3-trimethyl-1H-indol-5-yl) -2-pyridinecarboxamide; N- (2,3-dimethyl-1H-indol-5-yl) -2 - [(2R, 6S) -2,6-dimethyl-4-morpholinyl] -6- (4-morpholinyl) -4-pyrimidinecarboxamide; 2,6-di-4-morpholinyl-N- (1,2,3-trimethyl-1H-indol-5-yl) -4-p i rim id inca rboxam id a; N- [3- (dimethylamino) phenyl] -2,6-di-4-morpholinyl-4-pyrimidinecarboxamide; N- [3,4,5-tri-methoxyphenyl] -2,6-d i-4-morpholinyl-4-pyrimidine carboxamide; 2,6-di-4-morpholinyl-N- (6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) -4-pyrimidinecarboxamide; and 4- [2-methyl-6- [2- (5-nitro-2-furyl) vinyl] -4-pyrimidinyl] -morpholine.

24. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 23, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

25. A compound of formula (I) as defined in claim 23, or a pharmaceutically acceptable salt thereof, for use as a medicament.

26. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -S (O) 2CR6R7-, by reaction of a compound of formula (I), wherein X is -SC6R7 -, with an oxidizing agent (for example using Oxona® at room temperature in a mixed solvent system of water and ethanol).

27. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -X1CR6R7- and X1 is -NR4-, -O-, -S-, -S (O) -, or -S (O) 2-, which comprises reacting a compound of formula (II), wherein L1 is a leaving group (such as halo (for example chloro), tosyl, mesyl, etc.) (II) with a compound of formula (III) R1-X1H (III) (optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N, N-cf / methylformamide).

28. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -S (O) 2CR6R7-, which comprises reacting a compound of formula (IX) with a suitable organometallic reagent (such as the activated ester of boronic acid R2B (OR) 3 wherein R is alkyl of 1 to 4 carbon atoms such as methyl), in the presence of a suitable metal catalyst such as palladium or copper).

29. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -C (O) NR4CR6R7-, -NR C (O) NR5CR6R7- or -S (O) 2NR4CR6R7- which comprises reacting a compound of formula (I) wherein X is -NH2CR6R7- with a compound of formula (XVI) selected from optionally in the presence of a suitable base (such as triethylamine).

30. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -C (O) NR4-, -NR C (O) NR5- or -S (O) 2NR4-, which comprises reacting a compound of formula (XVI) (XV) with a compound of formula (XVI) selected from in the presence of a suitable base (such as triethylamine).

31. A process for preparing a compound of formula (I) as defined in claim 1, which comprises reacting a compound of formula (XXIII) L2 (XXIII) with a compound of formula (V) (V)

32. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -NR4C (O) - which comprises reacting a compound of formula (XVII) with an amine R4NH2 and a suitable activating reagent such as O- (7-azabenzotriazol-1-yl) - /,? /,? / ', /' - tetramethyluronium hexafluorophosphate, using a base such as diisopropylethylamine and a solvent such as tetrahydrofuran.

33. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -S (O) 2CR6R7-, which comprises reacting a compound of formula (I), wherein X is -SCR6R7- (Or with an oxidizing agent (for example using Oxona® at room temperature in a mixed solvent system of water and ethanol.)

34. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -X1CR6R7 and X1 is -NR4-, -O-, -S-, -S (O) -, which comprises reacting a compound of formula (XXVIII) L2 (XXVIII) with a compound of formula (V) (V)

35. A process for preparing a compound of formula (I) as defined in claim 1. wherein X is -C (O) NR4CR6R7-, -NR C (O) NR5CR6R7- or -S (O) 2NR4CR6R7- which comprises reacting a compound of formula (I) wherein X is -NH2CR6R7- with a compound of formula (XVI) selected from in the presence of a suitable base such as triethylamine.

36. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -C (O) NR4-, -NR C (O) NR5- or -S (O) 2NR4-, which comprises reacting a compound of formula (XXXII) (XXXII) with a compound of formula (XVI) selected from

37. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -X1CR6R7- and X1 is -NR4-, -O -, -S-, -S (O) -, or -S (O) 2-, which comprises reacting a compound of formula (XXXVII), wherein L1 is a leaving group (such as halo (for example chlorine) , tosyl, mesyl etc.) (XXXVII) with a compound of formula (XXVIII) R1-L1 (XXXVIII) in the presence of a suitable base (such as triethylamine or sodium hydride and a solvent such as tetrahydrofuran or N, N- / methylformamide).

38. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -X1CR6R7- and X1 is -S-, which comprises reacting a compound of formula (XXXIX). with a compound of formula (XXXVIII) R1-L1 (XXXVIII) in the presence of a suitable base (such as sodium hydroxide) and a solvent (such as? /,? / - a7methylformamide).

39. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -X1CR6R7- and X1 is -NR4-, -O-, -S-, -S (O) -, or -S (O) 2-, which comprises reacting a compound of formula (XXXX), (XXXX) with a suitable organometallic reagent (such as the boronic acid activated ester R2B (OR) 3, wherein R is alkyl of 1 to 4 carbon atoms such as methyl), in the presence of a suitable metal catalyst (such as palladium or copper) ) using a solvent (such as 1,4-dioxane).

40. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -NR4C (O) -, -NR4C (O) CR6R7-, -NR4S (O) 2-, or - NR S (O) 2CR6R7-, which comprises reacting a compound of formula (XXXXVIII). (XXXXVIII) wherein X1 is -C (O) -, -C (O) CR6R7-, -S (O) 2-, or -S (O) 2CR6R7- and L1 is a suitable leaving group (such as chloro or an activated ester). with an amine of formula (XXXXIX), R4 \ NH R (XXXXIX) in the presence of a suitable base (such as triethylamine).

41. A process for preparing a compound of formula (I) as defined in claim 1, wherein X is -NR4CHR6-, which comprises reacting a compound of formula (XXXXX) with an amine of formula (XXXXIX) R4 \ NH R (XXXXIX) in the presence of a suitable reducing agent (such as NaCN BH3).