ES2394470T3 - Derivatives of pyrido-, pyrazo- and pyrimido-pyrimidines as mTOR inhibitors - Google Patents

Abstract

A compound of formula I: wherein: X8 is N, and X5 and X6 are CH; R7 is a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamide, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl , C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); RN3 and RN4, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl , C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, sulfoxide, sulfonyl , thioamido and sulfonamino); R2 is selected from NRN5RN6, a C5-20 heteroaryl group optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, cycloalkyl C3-7, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino ( each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), and an optionally C5-20 aryl group substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl , C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), wherein RN5 and RN6 are selected independently of H, a C1-7 alkyl group, a C5-20 heteroaryl group and a C5-20 aryl group, or RN5 and RN6, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, in which each of C1-7 alkyl, C5-20 heteroaryl, C5-20 aryl or heterocyclic ring is optionally substituted with a or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5 aryl -20, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl , nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether , acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),

Description

Derivatives of pyrido-, pyrazo- and pyrimido-pyrimidines as mTOR inhibitors

The present invention relates to compounds, derivatives of pyrido-, pyrazo- and pyrimido-pyrimidines, which act as mTOR inhibitors.

Background

Activation of the growth / mitogenic factor of the phosphatidylinositol 3-kinase (PI3K) / AKT signaling pathway ultimately leads to the key regulator of cell cycle and mTOR growth control, the mammalian target of rapamycin (to which alternatively referred to as FRAP (FKBP12 and rapamycin-associated protein), RAFT1 (rapamycin and target 1 of FKBP12), RAPT1 (target 1 of rapamycin) - all derived from the interaction with the FK-506 binding protein, FKBP12, and SEP (sirolimus effector protein)). mTOR is a mammalian serine / threonine kinase of a size of approximately 289 kDa and a member of evolutionarily conserved eukaryotic TOR kinases (refs. 1-4). The mTOR protein is a member of the family of kinase proteins similar to PI3-kinase (PIKK) due to its C-terminal homology (catalytic domain) with kinase PI3 and the other family members, e.g. ex. DNA-PKcs (DNA-dependent protein kinase), ATM (mutated ataxia-telangiectasia). In addition to a catalytic domain at the C-terminus, mTOR contains a binding domain to the FKBP12 / rapamycin (FRB) complex. Up to 20 HEAT motifs (huntingtin, EF3, alpha-regulatory subunit of PP2A and TOR) are found in the N-terminus, while in a more C-terminal position there is a FAT domain (FRAP-ATM-TRRAP) and in the C term The end of the protein is an additional FAT domain (FAT-C) (refs. 5.6).

TOR has been identified as a major regulator of both growth (size) and cell proliferation, which is partly governed by the initiation of translation. TOR-dependent phosphorylation of S6kinase TOR (S6K1) allows the translation of ribosome proteins involved in the progress of the cell cycle (refs. 79). Cap-dependent translation is regulated by phosphorylation of protein 1 binding to the eukaryotic translation initiation factor 4E (eIF4E) (4E-BP PHAS-1)). This modification prevents PHAS-1 from joining eIF4E, thereby allowing the formation of an active translation complex of eIF4F (reviewed in refs. 10, 11, 12). The activation of these signaling elements depends on insulin, other growth factors and nutrients, suggesting a role of goalkeeper for mTOR in controlling cell cycle progress only under favorable environmental conditions. The PI3K / AKT signaling cascade is located upstream of mTOR, and it has been shown that it is deregulated in certain cancers and results in independent activation of the growth factor, for example in PTEN-deficient cells. mTOR is at the axis of control for this route, and inhibitors of this kinase (eg sirolimus (rapamycin or Rapamune ™) and everolimus (RAD001 or Certican ™)) have already been approved for immunosuppression and eluting drug stents (reviewed in refs. 13, 14) and are now receiving a particular interest as new agents for the treatment of cancer.

The growth of tumor cells arises from the deregulation of mechanisms for the control of normal growth such as the loss of tumor suppressor function or functions. A tumor suppressor of this type is phosphatase and tensin homolog suppressed on chromosome ten (PTEN). This gene, also known as mutated in multiple advanced cancers (MMAC) has been shown to play an important role in cell cycle arrest, and is the most highly mutated tumor suppressor after p53. Up to 30% of glioblastoma, endometrial and prostate cancers have somatic deletions or mutations of this locus (refs. 15, 16).

PI3K converts phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-triphosphate (PIP3), while PTEN is responsible for separating 3’-phosphate from PIP3, producing PIP2. PI3-K and PTEN act to maintain an appropriate level of PIP3 that recruits and thus activates AKT (also known as PKB) and the downstream signaling cascade that then starts. In the absence of PTEN there is an inappropriate regulation of this cascade, AKT becomes effectively activated constitutively and cell growth is deregulated. An alternative mechanism for deregulation of this cell signaling process is the recent identification of a mutant form of the PI3K isoform, p110alpha (ref. 17). It is thought that the apparent increased activity of this mutant results in an increased production of PIP3, presumably in an excess of which PTEN function can counteract. Increased signaling from PI3K thus results in increased signaling to mTOR and, consequently, of its downstream activators.

In addition to the evidence linking mTOR with the regulation of the cell cycle (from phase G1 to S) and that the inhibition of mTOR results in the inhibition of these regulatory phenomena, it has been shown that the sub-regulation of mTOR activity results in cell growth inhibition (reviewed in refs. 7, 18, 19). The known mTOR inhibitor, rapamycin, potentially inhibits the proliferation or growth of cells derived from a range of tissue types such as smooth muscle, T cells as well as cells derived from a diverse range of tumor types, including rhabdomyosarcoma, neuroblastoma, glioblastoma and medulloblastoma, small cell lung cancer, osteosarcoma, pancreatic carcinoma, and breast and prostate carcinoma (reviewed in ref. 20). Rapamycin has been approved and is in clinical use as an immunosuppressant, its prevention of organ rejection being successful and with fewer side effects than previous therapies (refs. 20, 21). The inhibition of mTOR by rapamycin and its analogs (RAD001, CCI-779) is encouraged by the previous interaction of the drug with the FK506 binding protein, FKBP12. Subsequently, the FKBP12 / rapamycin complex then binds to the FRB domain of mTOR and inhibits downstream signaling from mTOR.

The potent, but non-specific inhibitors of PI3K, LY294002 and wortmanin, have also been shown to inhibit mTOR kinase function, but act through targeting the catalytic domain of the protein (ref. 21). In addition to the inhibition of mTOR function by small molecules targeted to the kinase domain, it has been shown that mTOR dead kinase cannot transmit upstream activation signals to effectors downstream of mTOR, PHAS- 1 or p70S6 kinase (ref. 22). It has also been shown that not all mTOR functions are sensitive to rapamycin, and this may be related to the observation that rapamycin alters the mTOR substrate profile rather than inhibits its activity per se (ref. 23). The analysis of mTOR interactions with other cellular factors has revealed that, in addition to the mTOR-Raptor complex, there is also an mTOR-Rictor complex that represents a rapamycin insensitive activity of mTOR (B) (Sarbassov et al. Current Biology, 2004 , 14, 1296-1302). Possibly, this activity explains the discrepancy between the dead mTOR kinase and the alteration of mTOR signaling by rapamycin and its derivatives. The discrepancy also identifies the possibility of a therapeutic advantage by directly inhibiting the catalytic activity of mTOR. It has been suggested that an mTOR catalytic inhibitor may be a more effective antagonist of the proliferation and survival of cancer cells and that rapamycin may be more useful in combination with agents that can compensate for its failure to completely interrupt the signaling of the pathway ( Choo and Blenis, Cancer Cell, 2006, 9, 77-79; Hay, Cancer Cell, 2005, 8, 179-183). Therefore, it is proposed that an mTOR inhibitor directed to the kinase domain may be a more effective mTOR inhibitor.

In addition to the ability of rapamycin to induce growth inhibition (cytostasis) by itself, rapamycin and its derivatives have been shown to potentiate the cytotoxicity of a certain number of chemotherapies, including cisplatin, camptothecin and doxorubicin (reviewed in ref. 20). It has also been observed that an enhancement of ionizing radiation induced the death of cells after mTOR inhibition (ref. 24). Experimental and clinical evidence has shown that rapamycin analogues show evidence of efficacy in the treatment of cancer, either alone or in combination with other therapies (see refs. 10, 18, 20). These findings suggest that mTOR kinase pharmacological inhibitors should have therapeutic value for the treatment of various forms of cancer comprising solid tumors such as carcinomas and sarcomas and lymphoid leukemias and cancers. In particular, mTOR kinase inhibitors should be of therapeutic value for the treatment, for example, of breast, colorectal, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and of prostate, and cancer of the bile duct, bones, bladder, head and neck, kidneys, liver, gastrointestinal tissue, esophagus, ovaries, pancreas, skin, testicles, thyroid, uterus, cervix and vulva and leukemia (including ALL and CML), multiple myeloma and lymphomas.

Renal cell carcinoma, in particular, has been identified as sensitive to rapamycin derivative CCI779, which results from a loss of VHL expression (Thomas et al. Nature Medicine, 2006, 12, 122-127). Tumors that have lost the suppressor of promyelocytic leukemia (PML) tumors have also been shown to be sensitive to inhibition of mTOR by rapamycin as a result of interruption of the regulation of the mTOR signaling pathway (Bernadi, Nature, 2006, 442, 779-785) and the use of an mTOR kinase inhibitor in these diseases should be of therapeutic value. These latter examples, in addition to those of PTEN deficiency or PI3K mutation, indicate cases in which a strategy aimed at the use of mTOR inhibitors may prove to be particularly effective due to an underlying genetic profile, but not They consider them to be exclusive targets.

Recent studies have revealed a role of mTOR kinase in other diseases (Easton & Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551-564). Rapamycin has proven to be a potent immunosuppressant by inhibiting proliferation induced by T-cell, B-cell and antibody production (Sehgal, Transplantation Proceedings, 2003, 35, 7S-14S) and, thus, mTOR kinase inhibitors can also be useful immunosuppressants Inhibition of mTOR kinase activity may also be useful in the prevention of restenosis, which is the control of an unwanted proliferation of normal cells in the vasculature, in response to the introduction of stents in the treatment of disease of the vasculature (Morice et al., New England Journal of Medicine, 2002, 346, 1773-1780). In addition, the rapamycin analogue, everolimus, can reduce the severity and incidence of cardiac allograft vasculopathy (Eisen et al., New England Journal of Medicine, 2003, 349, 847-858). An elevated mTOR kinase activity has been associated with cardiac hypertrophy, which is of

5 clinical importance as a major 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). Thus, mTOR kinase inhibitors are expected to be of value in the prevention and treatment of a wide variety of diseases, in addition to cancer.

10 The vast majority of mTOR pharmacology to date has focused on the inhibition of mTOR through rapamycin or its analogues. However, as noted above, the only non-rapamycin agents that have been reported as inhibitors of mTOR activity through a mechanism that targets the kinase domain are the small molecule LY294002 and the natural product wortmanin (ref . twenty-one).

15 EP 0185259 (Dr. Karl Thomae GMBH) describes certain pteridines with valuable pharmacological properties, more particularly antithrombotic effects and metastasis inhibitors, and tumor activity inhibitors.

Summary of the invention

The authors of the present invention have identified compounds that are mP ATP-competitive inhibitors and, therefore, are not similar to rapamycin in their mechanism of action.

Accordingly, the first aspect of the present invention provides a compound of formula I:

where: X8 is N, and X5 and X6 are CH;

R7 is a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl , C3-7 cycloalkenyl, C320 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamide, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl,

C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); RN3 and RN4, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl,

C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro , cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl , ester, amido, amino, acylamido, ureido, acyloxy, sulfoxide, sulfonyl, thioamido and sulfonamino);

R2 is selected from NRN5RN6, a C5-20 heteroaryl group optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2 alkynyl

50 7, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), and a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, cycloalkyl C3-7, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino ( each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfone min), wherein RN5 and RN6 are independently selected from H, a C1-7 alkyl group, a C5-20 heteroaryl group and a C5-20 aryl group, or RN5 and RN6, together with the nitrogen to which they are attached , form a heterocyclic ring containing between 3 and 8 ring atoms, in which each of C1-7 alkyl, C5-20 heteroaryl, C5-20 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxyl , nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol , C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, heteroa C5-20 ryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),

or a pharmaceutically salt thereof, and wherein "C5-20 aryl," as used herein, belongs to a monovalent moiety obtained by separating a hydrogen atom from an aromatic ring atom from a C5-20 aromatic compound. , said compound having a ring, or two or more rings (e.g., condensed), and having 5 to 20 ring atoms, and wherein at least one of said ring or rings is an aromatic ring, and in which ring atoms may include one or more heteroatoms, which include but are not limited to oxygen, nitrogen and sulfur; "alkyl", as used herein, belongs to a monovalent moiety, obtained by separating a hydrogen atom from a carbon atom of a hydrocarbon compound having 1 to 20 carbon atoms (unless specified in another mode), which can be aliphatic or alicyclic, and which can be saturated or unsaturated (eg partially unsaturated, totally unsaturated); "alkenyl", as used herein, belongs to an alkyl group having one or more carbon-carbon double bonds;

"alkynyl", as used herein, belongs to an alkyl group having one or more triple bonds.

carbon-carbon; "cycloalkyl," as used herein, belongs to an alkyl group that is also a cyclyl group; is that is, a monovalent moiety obtained by separating a hydrogen atom from an atom of the alicyclic ring of a ring carbocyclic of a carbocyclic compound, carbocyclic ring that may be saturated or unsaturated (e.g. partially unsaturated, totally unsaturated), remainder that has 3 to 20 carbon atoms (unless specify otherwise), including 3 to 20 ring atoms; "ether", as used herein, belongs to a group -OR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "acyl", as used herein, belongs to a group -C (= O) R, where R is H, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "ester", as used herein, belongs to a group -C (= O) OR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "amido", as used herein, belongs to a group -C (= O) NR1R2, where R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 ring atoms; "amino", as used herein, belongs to a group -NR1R2, where R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 ring atoms; "acylamido", as used herein, belongs to a group -NR1C (= O) R2, where R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, R2 is a C1-7 alkyl group, a group C3-20 heterocyclyl, or a C5-20 aryl group, or R1 and R2 can form, together with the atoms to which they are attached, a succinimidyl, maleimidyl and phthalimidyl group; "ureido", as used herein, belongs to a group -N (R1) CONR2R3, where R2 and R3 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R2 and R3, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 ring atoms, and R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "acyloxy", as used herein, belongs to a group -OC (= O) R, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group;

"thioether", as used herein, belongs to a group -SR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "sulfoxide", as used herein, belongs to a group -S (= O) R, wherein R is a C17 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group;

"Sulfonyl", as used herein, belongs to a group -S (= O) 2R, wherein R is a C17 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "thioamido", as used herein, belongs to a group -C (= S) NR1R2, wherein R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or an aryl group C5-20, or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having 4 to 8

10 ring atoms; "sulfonamino", as used herein, belongs to a group -NR1S (= O) 2R, wherein R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group , and R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; and with the proviso that when R2 is unsubstituted morpholino, RN3 and RN4, together with the nitrogen atom to which

15 are attached, form an unsubstituted morpholino, R7 is unsubstituted phenyl, and when R2 is unsubstituted piperidinyl, RN3 and RN4, together with the nitrogen atom to which they are attached, form an unsubstituted piperidinyl, R7 is unsubstituted phenyl .

According to a second aspect of the present invention there is provided a compound of formula I (A):

where: X8 is N, and X5 and X6 are CH; RN3 and RN4, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 atoms

25 of the ring optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl , C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, heterocyclyl

C3-20, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); R2 is selected from NRN5RN6, a C5-20 heteroaryl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido,

Ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C27 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), and a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, alkenyl

C2-7, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy , thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl , C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),

Wherein RN5 and RN6 are independently selected from H, a C1-7 alkyl group, a C5-20 heteroaryl group and a C5-20 aryl group, or RN5 and RN6, together with the nitrogen to which they are attached, form a ring heterocyclic containing between 3 and 8 ring atoms, in which each of C1-7 alkyl, C5-20 heteroaryl, C5-20 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano , carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl , ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1 alkyl -7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, heteroaryl C5-20, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);

RO3

 is selected from hydrogen or a C1-6 alkyl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C27 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, heterocyclyl C3-20, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); and RN10 is selected from C (= O) RC2, C (= S) RC3, SO2RS3, a C5-20 heteroaryl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino , acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C27 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), a C5-20 aryl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, alkenyl or C2-7, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy , thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl , C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C1-10 alkyl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3 cycloalkyl -7, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl , thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C27 alkynyl, C3-7 cycloalkyl, C3 cycloalkenyl -7, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), in which RC2 and RC3 are selected from H, a C5-20 aryl group, a C5-20 heteroaryl group, a C1-7 alkyl group or NRNN11RNN12, in which RN11 and RN12 are independently selected from H, a C1-7 alkyl group, a C5 heteroaryl group -20, a C5-20 or RN11 and RN12 aryl group, together with the nitrogen to which they are attached form a heterocyclic ring containing between 3 and 8 ring atoms, in which each of C1-7 alkyl, C5-20 heteroaryl , C5-20 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carb oxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1- alkyl 7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido , acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); and RS3 is selected from H, a C5-20 aryl group, a C5-20 heteroaryl group or a C1-7 alkyl group, wherein each of C1-7 alkyl, C5-20 heteroaryl or C5-20 aryl is optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl , C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5- heteroaryl 20, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),

or a pharmaceutically acceptable salt thereof, and wherein "C5-20 aryl," as used herein, belongs to a monovalent moiety, obtained by separating a hydrogen atom from an aromatic ring atom from a C5 aromatic compound. -20, said compound having a ring, or two or more rings (eg condensed), and having 5 to 20 ring atoms, and wherein at least one of said rings is an aromatic ring, and in which the ring atoms may include one or more heteroatoms, which include, but are not limited to oxygen, nitrogen and sulfur; "alkyl", as used herein, belongs to a monovalent moiety, obtained by separating a hydrogen atom from a carbon atom of a hydrocarbon compound having 1 to 20 carbon atoms (a

unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (eg partially unsaturated, totally unsaturated); "alkenyl", as used herein, belongs to an alkyl group with one or more double bonds. carbon-carbon; "alkynyl," as used herein, belongs to an alkyl group with one or more triple bonds. carbon-carbon; "cycloalkyl," as used herein, belongs to an alkyl group that is also a cyclyl group; is that is, a monovalent moiety, obtained by separating a hydrogen atom from an atom of the alicyclic ring of a ring carbocyclic of a carbocyclic compound, carbocyclic ring that may be saturated or unsaturated (e.g. partially unsaturated, totally unsaturated), remainder that has 3 to 20 carbon atoms (unless specify otherwise), including 3 to 20 ring atoms; "ether", as used herein, belongs to a group -OR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "acyl", as used herein, belongs to a group -C (= O) R, where R is H, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "ester", as used herein, belongs to a group -C (= O) OR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "amido", as used herein, belongs to a group -C (= O) NR1R2, where R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 ring atoms; "amino", as used herein, belongs to a group -NR1R2, where R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 ring atoms; "acylamido", as used herein, belongs to a group -NR1C (= O) R2, where R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, R2 is a C1-7 alkyl group, a group C3-20 heterocyclyl or a C5-20 aryl group, or R1 and R2, together with the atoms to which they are attached, form a group succinimidyl, maleimidyl and phthalimidyl; "ureido", as used herein, belongs to a group -N (R1) CONR2R3, where R2 and R3 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R2 and R3, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 ring atoms, and R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "acyloxy", as used herein, belongs to a group -OC (= O) R, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "thioether", as used herein, belongs to a group -SR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "sulfoxide", as used herein, belongs to a group -S (= O) R, wherein R is a C17 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "sulfonyl", as used herein, belongs to a group -S (= O) 2R, wherein R is a C17 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "thioamido", as used herein, belongs to a group -C (= S) NR1R2, where R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring of 4 to 8 atoms of the ring; "sulfonamino", as used herein, belongs to a group -NR1S (= O) 2R, where R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, and R is a C1-7 alkyl group, a group C3-20 heterocyclyl or a C5-20 aryl group.

In accordance with a further aspect of the present invention, a pharmaceutical composition is provided which comprises a compound of formula 1 or 1 (A) or a pharmaceutically acceptable salt thereof and a support or pharmaceutically acceptable diluent.

In accordance with a further aspect of the present invention, a compound of formula 1 or 1 (A) or a pharmaceutically acceptable salt thereof for use in a method of treating the human body or animal.

In accordance with a further aspect of the present invention, the use of a compound of formula 1 is provided

or 1 (A) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease enhanced by mTOR inhibition.

Additional aspects of the invention provide the use of a compound of formula 1 or 1 (A) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of cancer, immunosuppression, immuno-tolerance, autoimmune disease, inflammation. , bone loss, bowel disorders, liver fibrosis, liver necrosis, rheumatoid arthritis, restenosis, cardiac allograft vasculopathy, psoriasis, beta-thalassemia and eye conditions such as dry eye. MTOR inhibitors can also be effective as antifungal agents.

The inventors have found that the compounds defined in the present invention or a pharmaceutically acceptable salt thereof are effective anti-cancer agents, the property of which is thought to be crossing their mTOR inhibitory properties. Accordingly, the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated only or in part by mTOR, that is, the compounds can be used to produce an mTOR inhibitory effect on a homeothermal animal that Need such a treatment.

Thus, the compounds of the present invention provide a method for treating cancer characterized by mTOR inhibition, that is, the compounds can be used to produce an anticancer effect mediated only or in part by mTOR inhibition.

A compound of this type of the invention is expected to possess a wide range of anti-cancer properties, since activating mutations in mTOR have been observed in many human cancers, including, but not limited to melanoma, thyroid papillary tumors, cholangiocarcinomas, cancers of colon, ovaries and lung. Thus, a compound of the invention is expected to possess anticancer activity against these cancers. In addition, a compound of the present invention is expected to possess activity against a range of leukemia, lymphoid cancers and solid tumors such as carcinomas and sarcomas in tissues such as the liver, kidney, bladder, prostate, breast and pancreas. in particular, compounds of this type of the invention are expected to advantageously slow the development of primary and recurrent solid tumors, for example, of the skin, colon, thyroid, lungs and ovaries. More particularly, compounds of this type of the invention or a pharmaceutically acceptable salt thereof are expected to inhibit the development of those primary and recurrent solid tumors that are associated with mTOR, especially those tumors that are significantly dependent on mTOR in terms of their development and spread including, for example, certain tumors of the skin, colon, thyroid, lungs and ovaries. Particularly, the compounds of the present invention are useful in the treatment of melanomas.

Thus, in accordance with this aspect of the invention, there is provided a compound of the formula 1 or 1 (A) or a pharmaceutically acceptable salt thereof, as defined herein, for use as a medicament.

In accordance with a further aspect of the invention, the use of a compound of the formula I or I (A) is provided

or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for use in the production of an mTOR inhibitory effect in a homeothermal animal such as man.

In accordance with this aspect of the invention, the use of a compound of the formula I or I (A) or a pharmaceutically acceptable salt thereof, as defined herein, is provided in the manufacture of a medicament for use in the production of an anticancer effect in a homeothermal animal such as man.

In accordance with a further feature of the invention, the use of a compound of the formula I is provided

or I (A) or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for use in the treatment of melanoma, papillary thyroid tumors, cholangiocarcinomas, colon cancer, ovarian cancer, cancer. of lung, leukemia, lymphoid cancers, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas and solid and recurrent tumors of the skin, colon, thyroid, lungs and ovaries.

In a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the formula I or I (A) or a pharmaceutically acceptable salt thereof, as defined herein, in association with a pharmaceutically acceptable diluent or carrier. for use in the production of an mTOR inhibitory effect of a homeothermal animal such as man.

In a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the formula I or I (A) or a pharmaceutically acceptable salt thereof, as defined herein. In a further aspect of the invention, a Pharmaceutical composition comprising a compound of the formula I or I (A) or a pharmaceutically acceptable salt thereof, as defined herein, in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of melanoma, papillary tumors of Thyroid, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemia, lymphoid cancers, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas and solid and recurring tumors of the skin, colon, thyroid, lungs and ovaries in a homeothermal animal such as man.

A further aspect of the invention provides the use of a compound of formula 1 or 1 (A) or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use as an adjuvant in cancer therapy or to enhance tumor cells for treatment with ionizing radiation or chemotherapeutic agents.

The compounds of the invention can be used for the treatment of diseases enhanced by mTOR inhibition, which comprises administering to a subject in need of treatment a therapeutically effective amount of a compound of formula 1 or 1 (A) or a pharmaceutically acceptable salt of the same, preferably in the form of a pharmaceutical composition and cancer treatment, which comprises administering to a subject in need of treatment a therapeutically effective amount of a compound as defined in the first or second aspect in combination, preferably in the form of a composition. Pharmaceutical, simultaneously or sequentially, with ionizing radiation or chemotherapeutic agents.

Definitions

The term "aromatic ring" is used herein in the conventional sense to refer to a cyclic aromatic structure, that is, a structure with delocalized π electron orbitals.

Nitrogen-containing heterocyclic ring having 3 to 8 ring atoms: the term "nitrogen-containing heterocyclic ring having 3 to 8 ring atoms", as used herein, refers to a heterocyclic ring 3 to 8 members containing at least one ring nitrogen atom. The expression

"Together with the nitrogen to which they are attached, they form a heterocyclic ring containing between 3 and 8 ring atoms", as used herein, refers to a 3 to 8-membered heterocyclic ring containing at least one atom of ring nitrogen. Examples of these groups include, but are not limited to:

N1: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (eg 3-pyrroline, 2.5

dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), piperidine (C6), dihydropyridine (C6),

tetrahydropyridine (C6), azepine (C7);

N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5),

piperazine (C6);

N1O1: tetrahydrooxazol (C5), dihydrooxazol (C5), tetrahydroisoxazol (C5) dihydroisoxazole (C5), morpholine (C6),

tetrahydrooxazine (C6), dihydrooxazine (C6), oxazine (C6);

N1S1: thiazoline (C5), thiazolidine (C5), thiomorpholine (C6);

N2O1: oxadiazine (C6);

N1O1S1: oxathiazine (C6).

Alkyl: the term "alkyl", as used herein, belongs to a monovalent moiety

obtained by separating a hydrogen atom from a carbon atom of a hydrocarbon compound having 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic and may be saturated or unsaturated ( eg partially unsaturated, totally unsaturated).

Thus, the term "alkyl" includes the alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl subclasses,

etc., which are discussed below.

In the context of alkyl groups, the suffixes (eg C1-4, C1-7, C1-20, C2-7, C3-7, etc.) indicate the number of carbon atoms or the range of the number of carbon atoms For example, the term "C1-4 alkyl" as used herein belongs to an alkyl group having 1 to 4 carbon atoms. Examples of alkyl groups include C1-4 alkyl ("lower alkyl"), C1-7 alkyl and C1-20 alkyl. Note that the first suffix may vary according to other limitations; for example, for unsaturated alkyl groups, the first suffix must be at least 2; for cyclic alkyl groups, the first suffix must be at least 3; etc.

Examples of saturated (unsubstituted) alkyl groups include, but are not limited to methyl (C1), ethyl (C2), propyl. Examples of saturated (unsubstituted) linear alkyl groups include, but are not limited to methyl (C1), ethyl. (C2), n-propyl (C3), n-butyl (C4), n-pentyl (amyl) (C5), n-hexyl (C6) and n-heptyl (C7).

Examples of saturated (unsubstituted) branched alkyl groups include iso-propyl (C3), iso-butyl (C4), sec-butyl (C4), tert-butyl (C4), iso-pentyl (C5) and neo-pentyl ( C5).

Alkenyl: The term "alkenyl", as used herein, belongs to an alkyl group having one or more carbon-carbon double bonds. Examples of groups of alkenyl groups include C2-4 alkenyl, C27 alkenyl, C2-20 alkenyl.

Examples of unsaturated (unsubstituted) alkenyl groups include, but are not limited to ethenyl (vinyl, -CH = CH2), 1propenyl (-CH = CH-CH3), 2-propenyl (allyl, -CH-CH = CH2), isopropenyl (1-methylvinyl, -C (CH3) = CH2), butenyl (C4), pentenyl (C5) and hexenyl (C6).

Alkynyl: The term "alkynyl," as used herein, belongs to an alkyl group having one or more triple carbon-carbon bonds. Examples of alkynyl group groups include C2-4 alkynyl, C2-7 alkynyl, C2-20 alkynyl.

Examples of unsaturated (unsubstituted) alkynyl groups include, but are not limited to ethynyl (ethynyl, -C = CH) and 2-propynyl (propargyl, -CH2-C = CH).

Cycloalkyl: the term "cycloalkyl", as used herein, belongs to an alkyl group that is also a cyclyl group; that is, a monovalent moiety, obtained by separating a hydrogen atom from an atom of the alicyclic ring of a carbocyclic ring of a carbocyclic compound, a carbocyclic ring that can be saturated or unsaturated (eg partially unsaturated, totally unsaturated), moiety having 3 to 20 carbon atoms (unless otherwise specified), which include 3 to 20 ring atoms. Thus, the term "cycloalkyl" includes the cycloalkenyl and cycloalkynyl subclasses. Preferably, each of the rings has 3 to 7 ring atoms. Examples of cycloalkyl groups include C3-20 cycloalkyl, C3-15 cycloalkyl, C310 cycloalkyl, C3-7 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to derivatives of:

saturated monocyclic hydrocarbon compounds: cyclopropane (C3), cyclobutane (C4), cyclopentane (C5), cyclohexane (C6), cycloheptane (C7), methylcyclopropane (C4), dimethylcyclopropane (C5), methylcyclobutane (C5), dimethylcyclobutane methylcyclopentane (C6), dimethylcyclopentane (C7), methylcyclohexane (C7), dimethylcyclohexane (C8), mint (C10); unsaturated monocyclic hydrocarbon compounds: cyclopropene (C3), cyclobutene (C4), cyclopentene

(C5),

cyclohexene (C6), methylcyclopropene (C4), dimethylcyclopropene  (C5), methylcyclobutene

(C5),

dimethylcyclobutene

(C6), methylcyclopentene (C6), dimethylcyclopentene (C7), methylcyclohexene (C7),

dimethylcyclohexene (C8);

saturated polycyclic hydrocarbon compounds: tujano (C10), carano (C10), pinano (C10), bornano (C10), norcarano (C7), norpinano (C7), norbornano (C7), adamantano (C10), decalina (decahidronaftaleno) ( C10); unsaturated polycyclic hydrocarbon compounds: canphene (C10), limonene (C10), pinene (C10); polycyclic hydrocarbon compounds having an aromatic ring: indene (C9), indane (e.g., 2,3-dihydro-1H-indene) (C9), tetralin (1,2,3,4-tetrahydronaphthalene) (C10), acenaphthene (C12), fluorene (C13), phenalene (C13), acefenanthrene (C15), aceantrene (C16), collantrene (C20). Heterocyclyl: The term "heterocyclyl", as used herein, belongs to a monovalent moiety, obtained by separating a hydrogen atom from a ring atom of a heterocyclic compound, which has 3 to 20 carbon atoms ( unless otherwise specified), of which 1 to 10 are ring heteroatoms. Preferably, each of the rings has 3 to 7 ring atoms, of which 1 to 4 are ring heteroatoms.

In this context, suffixes (eg C3-20, C3-7, C5-6, etc.) designate the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. . For example, the term "C56 heterocyclyl," as used herein, belongs to a heterocyclyl group having 5 or 6 ring atoms. Examples of groups of heterocyclyl groups include C3-20 heterocyclyl, C5-20 heterocyclyl, C3-15 heterocyclyl, C5-15 heterocyclyl, C3-12 heterocyclyl, C5-12 heterocyclyl, C3-10 heterocyclyl, C5-10 heterocyclyl, C3- heterocyclyl 7, C5-7 heterocyclyl and C5-6 heterocyclyl.

Examples of monocyclic heterocyclyl groups include, but are not limited to those derived from:

N1: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole ) (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), azepine (C7); O1: oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxol (dihydrofuran) (C5), oxano (tetrahydropyran) (C6), dihydropyran (C6), pyran (C6), oxepine (C7); S1: tiirano (C3); thietane (C4), thiolane (tetrahydrothiophene) (C5), thiano (tetrahydrothiopyran) (C6), tiepane (C7); O2: dioxolane (C5), dioxane (C6) and dioxepane (C7); O3: trioxane (C6); N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine (C6); N1O1: tetrahydrooxazole (C5), dihydrooxazol (C5), tetrahydroisoxazol (C5), dihydroisoxazole (C5), morpholine (C6), tetrahydrooxazine (C6), dihydrooxazine (C6), oxazine (C6); N1S1: thiazoline (C5), thiazolidine (C5), thiomorpholine (C6); N2O1: oxadiazine (C6); O1S1: oxatiol (C5) and oxatiano (thioxane) (C6); Y N1O1S1: oxathiazine (C6).

Examples of substituted (non-aromatic) monocyclic herocyclyl groups include those derived from saccharides, in cyclic form, for example furanoses (C5) such as arabinofuranose, lixofuranose, ribofuranose, and xylofuranose, and pyranous (C6) such as allopuriranose, allotropyranose, glucopyrranose, manopiranosa, gulopiranosa, idopiranosa, galactopiranosa and talopiranosa.

C3-7 spirocycloalkyl or heterocyclyl: the term "C3-7 spirocycloalkyl or heterocyclyl", as used herein, refers to a C3-7 cycloalkyl or C3-7 heterocyclyl ring attached to another ring by a single atom common to both rings.

C5-20 aryl: the term "C5-20 aryl", as used herein, belongs to a monovalent moiety, obtained by separating a hydrogen atom from an aromatic ring atom from a C5-20 aromatic compound, having said compound a ring, or two or more rings (eg condensed) and having 5 to 20 ring atoms, and wherein at least one of said or said rings is an aromatic ring. Preferably, each of the rings has 5 to 7 ring atoms.

The ring atoms can all be carbon atoms as in the case of "carboaryl groups", in which case the group can be conveniently referred to as a "C5-20 carboaryl" group.

Examples of C5-20 aryl groups that do not have ring heteroatoms (i.e., C5-20 carboaryl groups) include, but are not limited to benzene derivatives (i.e., phenyl) (C6), naphthalene (C10), anthracene (C14), phenanthrene (C14) and pyrene (C16).

Alternatively, the ring atoms may include one or more heteroatoms, which include, but are not limited to

oxygen, nitrogen and sulfur, as in "heteroaryl groups". In this case, the group can be conveniently referred to as a "C5-20 heteroaryl" group, wherein "C5-20" designates ring atoms, whether atoms of

carbon or heteroatoms. Preferably, each of the rings has 5 to 7 ring atoms, of which 0 to 4 are ring heteroatoms.

Examples of C5-20 heteroaryl groups include, but are not limited to C5 heteroaryl groups derived from furan (oxol), thiophene (thiol), pyrrole (azol), imidazole (1,3-diazole), pyrazole (1,2-diazole ), triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole and oxatriazole; and C6 heteroaryl groups derived from isoxazine, pyridine (azine), pyridazine (1,2diazine), pyrimidine (1,3-diazine); p. ex. cytosine, thymine, uracil), pyrazine (1,4-diazine) and triazine.

The heteroaryl group may be linked through a carbon atom or a ring heteroatom.

Examples of C5-20 heteroaryl groups comprising fused rings include, but are not limited to C9 heteroaryl groups derived from benzofuran, isobenzofuran, benzothiophene, indole, isoindole; C10 heteroaryl groups derived from quinoline, isoquinoline, benzodiazine, pyridopyridine; C14 heteroaryl groups derived from acridine and xanthene.

The groups defined above, p. ex. alkyl, heterocyclyl, aryl, etc., whether alone or part of another substituent, may themselves be optionally substituted with one or more groups selected from themselves and from the additional substituents listed below.

Hydroxy: -OH.

5 Ether: -OR, where R is an ether substituent, for example a C1-7 alkyl group (also referred to as a C1-7 alkoxy group), a C3-20 heterocyclyl group (also referred to as a C3-20 heterocyclyloxy group) or a C5-20 aryl group (also referred to as a C5-20 aryloxy group), preferably a C1-7 alkyl group.

Nitro: -NO2.

Cyano (nitrile, carbonitrile): -CN.

Acyl (keto): -C (= O) R, wherein R is an acyl substituent, for example H, a C1-7 alkyl group (also referred to as a C1-7-acyl alkyl or C1-7 alkonyl ), a C3-20 heterocyclyl group (also referred to as

C3-20 heterocyclyl-acyl) or a C5-20 aryl group (also referred to as C5-20-acyl aryl), preferably a C1-7 alkyl group. Examples of acyl groups include, but are not limited to -C (= O) CH3 (acetyl), -C (= O) CH2CH3 (propionyl), -C (= O) C (CH3) 3 (butyryl) and -C (= O) Ph (benzoyl, phenyl).

Carboxy (carboxylic acid): -COOH.

Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C (= O) OR, where R is an ester substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group , preferably a C1 alkyl group

7. Examples of ester groups include but are not limited to -C (= O) OCH3, -C (= O) OCH2CH3, -C (= O) OC (CH3) 3 and C (= O) OPh.

Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C (= O) NR1R2, wherein R1 and R2 are independently amino substituents as defined for amino groups. Examples of amido groups include, but are not limited to -C (= O) NH2, -C (= O) NHCH3, -C (= O) N (CH3) 2, -C (= O) NHCH2CH3 and -C ( = O) N (CH2CH3) 2 as well as amido groups, in which R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclic structure such as, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl and piperazinylcarbonyl.

Amino: -NR1R2, wherein R1 and R1 are independently amino substituents, for example hydrogen, a C1-7 alkyl group (also referred to as C1-7-amino alkyl or C1-7-amino dialkyl), a heterocyclyl group C3-20 or a

C5-20 aryl group preferably H a C1-7 alkyl group or, in the case of a "cyclic" amino group, R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having 4 to 8 ring atoms. Examples of amino groups include, but are not limited to -NH2, -NHCH3, -NHCH (CH3) 2, -N (CH3) 2, -N (CH2CH3) 2 and -NHPh. Examples of cyclic amino groups include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, perhydrodiazepinyl, morpholino and thiomorpholino. Cyclic amino groups may be substituted on their ring by any of the substituents defined herein, for example carboxy, carboxylate and amido.

Acylamido (acylamino): -NR1C (= O) R2, wherein R1 is an amide substituent, for example hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, preferably H or a C1-7 alkyl group, the most

Preferably H, and R2 is an acyl substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of acylamide groups include, but are not limited to -NHC (= O) CH3, -NHC (= O) CH2CH3 and -NHC (= O) Ph. R1 and R2 can together form a cyclic structure such as, by

succinimidyl maleimidyl phthalimidyl

Ureido: -N (R1) CONR2R3, wherein R2 and R3 are independently amino substituents as defined for amino groups, and R1 is a ureido substituent, for example hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, preferably hydrogen or a C1-7 alkyl group. Examples of ureido groups include,

55 but not limited to -NHCONH2, -NHCONHMe, -NHCONHEt, -NHCONHMe2. -NHCONEt2, -NMeCONH2, -NMeCONHMe, -NMeCONHEt, -NMeCONMe2, -NMeCONEt2 and -NHC (= O) NHPh.

Acyloxy (reverse ester): -OC (= O) R, wherein R is an acyloxy substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, preferably a C1 alkyl group -7. Examples of acyloxy groups include, but are not limited to -OC (= O) CH3 (acetoxy), -OC (= O) CH2CH3, -OC (= O) C (CH3) 3, -OC (= O) Ph, -OC (= O) C6H4F and -OC (= O) CH2Ph.

5 Thiol: -SH.

Thioether (sulfide): -SR, where R is a thioether substituent, for example a C1-7 alkyl group (also referred to as C1-7 alkylthio), a C3-20 heterocyclyl group or a C5-20 aryl group , preferably a C1-7 alkyl group.

Examples of C1-7 alkylthio groups include, but are not limited to -SCH3 and -SCH2CH3.

Sulfoxide (sulfinyl): -S (= O) R, wherein R is a sulfoxide substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, preferably a C1- alkyl group 7. Examples of sulfoxide groups include, but are not limited to -S (= O) CH3 and -S (= O) CH2CH3.

Sulfonyl (sulfone): -S (= O) 2R, wherein R is a sulfone substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, preferably a C1 alkyl group -7. Examples of sulfone groups include, but are not limited to -S (= O) 2CH3 (methanesulfonyl, mesyl), -S (= O) 2CF3 ,, -S (= O) 2CH2CH3 and 4-methylphenylsulfonyl (tosyl).

Thioamido (thiocarbamyl): -C (= S) NR1R2, wherein R1 and R2 are independently amino substituents as defined for amino groups. Examples of amido groups include, but are not limited to -C (= S) NH2, -C (= S) NHCH3, C (= S) N (CH3) 2 and -C (= S) NHCH2CH3.

Sulfonamino: -NR1S (= O) 2R, wherein R1 is an amino substituent as defined for amino subgroups, and R is a sulfonamino substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group or a group C5-20 aryl, preferably a C1-7 alkyl group. Examples of sulfonamino groups include, but are not limited to -NHS (= O) 2CH3, -NHS (= O) 2Ph and -N (CH3) S (= O) 2C6H5.

30 As mentioned above, the groups that form the substituent groups listed above, p. ex. C1-7 alkyl, C3-20 heterocyclyl and C5-20 aryl may themselves be substituted. Thus, the above definitions cover substituent groups that are substituted.

Accordingly, a further aspect of the present invention provides a compound of formula I.

where: X8 is N, and X5 and X6 are CH; R7 is a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxyl, nitro,

Cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C320 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1- alkyl 7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido acyloxy thioether

45 sulfoxide, sulfonyl, thioamido and sulfonamino),

RN3

 and RN4, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1 alkyl -7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and 50 sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, heterocyclyl

C3-20, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, sulfoxide, sulfonyl, thioamido and sulfonamino); R2 is NRN5RN6, a C5-20 heteroaryl group optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl,

C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5- aryl 20, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C5-20 aryl group optionally substituted with one

10 or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, aryl C5-20, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C27 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl ester

15 amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), where

RN5

 and RN6 are, independently, H, a C1-7 alkyl group, a C5-20 heteroaryl group, a C5-20 aryl group, or RN5 and RN6, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, in which each of C1-7 alkyl, C5-20 heteroaryl, C5-20 aryl or heterocyclic ring optionally is

20 substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3- heterocyclyl 20, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more selected groups halo, hydroxy, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5 heteroaryl -twenty,

25 ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),

or a pharmaceutically salt thereof, and wherein "C5-20 aryl," as used herein, belongs to a monovalent moiety obtained by separating a hydrogen atom from an aromatic ring atom from a C5-20 aromatic compound. , said compound having a ring, or two or more rings (eg, condensed), and having 5 to 20 ring atoms, and wherein

At least one of said or said rings is an aromatic ring, and in which the ring atoms may include one or more heteroatoms, which include but are not limited to oxygen, nitrogen and sulfur; and with the proviso that when R2 is unsubstituted morpholino, RN3 and RN4, together with the nitrogen atom to which they are attached, form an unsubstituted morpholino, R7 is unsubstituted phenyl, and when R2 is unsubstituted piperidinyl, RN3 and RN4, together with the nitrogen atom to which they are attached, form a

35 unsubstituted piperidinyl, R7 is unsubstituted phenyl.

In accordance with a further aspect of the present invention a compound of formula I (A) is provided:

40 where: one or two of X5, X6 and X8 is N and the others are CH;

RN3

 and RN4, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1- alkyl 7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl,

C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro , cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl , ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); R2 is selected from NRN5RN6, a C5-20 heteroaryl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C27 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, heterocyclyl C3-20, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), and an optionally substituted C5-20 aryl group with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl , C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), wherein RN5 and RN6 are independently H, a C1-7 alkyl group, a C5-20 heteroaryl group and a C520 aryl group, or RN5 and RN6, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, in that each of C1-7 alkyl, C5-20 heteroaryl, C5-20 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); RO3 is hydrogen or a C1-6 alkyl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3 cycloalkyl -7, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamide, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each one of them optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, heterocyclyl C3-20, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); and RN10 is C (= O) RC2, C (= S) RC3, SO2RS3, a C5-20 heteroaryl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1 alkyl -7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulphonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, alkynyl C27, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), a C5-20 aryl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, alkyne C2-7, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl , C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C1-10 alkyl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3 cycloalkenyl -7, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and its lfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3- cycloalkenyl 7, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), in which RC2 and RC3 are H, a C5-20 aryl group, a C5-20 heteroaryl group, a C1-7 alkyl or NRN11RN12 group, in which

RN11

 and RN12 are independently selected from H, a C1-7 alkyl group, a C5-20 heteroaryl group, a C5-20 or RN11 and RN12 aryl group, together with the nitrogen to which they are attached form a heterocyclic ring containing between 3 and 8 ring atoms, in which each of C1-7 alkyl, C5-20 heteroaryl, C5-20 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl , C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, aci lo, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); and RS3 is H, a C5-20 aryl group, a C5-20 heteroaryl group, or a C1-7 alkyl group, wherein each of C1-7 alkyl, C5-20 heteroaryl or C5-20 aryl is optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, aryl C5-20, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);

or a pharmaceutically acceptable salt thereof, and wherein "C5-20 aryl," as used herein, belongs to a monovalent moiety, obtained by separating a hydrogen atom from an aromatic ring atom from a C5 aromatic compound. -20, said compound having a ring, or two or more rings (eg condensed), and having 5 to 20 ring atoms, and wherein at least one of said rings is an aromatic ring, and in which the Ring atoms may include one or more heteroatoms, which include, but are not limited to oxygen, nitrogen and sulfur.

Additional Preferences

The following preferences may apply to each of the aspects of the present invention, where applicable. Preferences for each of the groups may be combined with those for any or all of the other groups, as appropriate.

X5, X6 and X8

X8 is N and X5 and X6 are CH.

R7

R7 is preferably selected from an optionally substituted C5-20 aryl group.

If R7 is a C5-20 aryl group, it is preferably a C5-10 aryl group and more preferably a C5-6 aryl group. Most preferably, R7 is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy.

In one embodiment, R7 is an optionally substituted C5-10 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxyl and C1-7 alkyl and C1-7 alkoxy (where alkyl groups can be optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkoxy, amino and C5-6 aryl). In another embodiment, R7 is an optionally substituted C5-6 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxyl and C1-7 alkyl and C1-7 alkoxy (where alkyl groups can be optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkoxy, amino and C5-6 aryl). In a further embodiment, R 7 is a thiophenyl group or a phenyl group optionally substituted with one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl. In a further embodiment, R 7 is 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or a group 3 -hydroxymethylphenyl. In a still further embodiment, R7 is an aryl group as defined in any of examples 1a, 1b, 1d, 1e, 1f, 1g, 1i, 1k, 1l, 1m, 1n, 1o, 1p, 1q, 1bb, 1bc , 1be, 1bf, 1bg, 1bh, 1bi, 1bj or 1br.

RN10

RN10 is preferably selected from C (= S) RC3, an optionally substituted C5-20 heteroaryl group, an optionally substituted C5-20 aryl group and an optionally substituted C1-10 alkyl group, in which RC3 is as previously defined.

If RN10 is C (= S) RC3, then preferably RC3 is NRN11RN12, in which RN11 and RN12, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms.

If RN10 is a C5-20 heteroaryl group, preferably it is a C5-10 heteroaryl group and, more preferably, a C5-6 heteroaryl group. Most preferably, it is an optionally substituted pyrazole group, wherein the optional substituents are preferably selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy.

If RN10 is a C1-10 alkyl group, preferably it is a C1-10 alkyl group and, more preferably, a C1-10 alkyl group. Most preferably it is an optionally substituted C1-6 alkyl group, wherein the optional substituents are preferably selected from halo, hydroxyl, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, aryl C5-20, C3-20 herocyclyl, C5-20 heteroaryl, cyano, ester, for example -C (= O) OR, where R is C1-7 alkyl and amino, for example C1-7 alkyl-amino, C1-alkyl -7-amino and C1-7 alkoxycarbonylamino.

In one embodiment RN10 is a group as shown in any of examples 8a, 8b, 8c, 8d, 8e, 8f, 8g, 8h, 8i, 8j, 8k, 8l, 8m, 8n, 8o, 8t, 8u, 8aa, 8ab, 8ac, 8ad, 8ae, 8af, 8ag, 8ah, 8ai, 8aj, 8ak, 8al, 8am, 8an, 8ao, 8ap, 8aq, 8ar, 8a, 8at, 8au, 8av, 8aw, 8ax, 8ay, 8az, 8ba, 8bb, 8bc, 8bd, 8be and 8bg.

RO3

RO3 is preferably an optionally substituted C1-6 alkyl group. More preferably, RO3 is an unsubstituted C1-3 alkyl group, preferably a methyl group.

RN3 and RN4

RN3 and RN4, together with the nitrogen to which they are attached, preferably form a heterocyclic ring containing between 5 and 7 ring atoms, which may be optionally substituted. Preferred optionally substituted groups include, but are not limited to morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) and pyrrolidinyl.

More preferably, the group formed is morpholino or thiomorpholino which are preferably unsubstituted. The most preferred group is morpholino.

R2

In one embodiment, R2 is selected from NRN5RN6, an optionally substituted C5-20 heteroaryl group and an optionally substituted C5-20 aryl group.

In another embodiment, R2 is selected from NRN5RN6, an optionally substituted C5-6 heteroaryl group and an optionally substituted C6 aryl group.

In a further embodiment, R2 is a phenyl group optionally substituted with one or more groups selected from hydroxyl, amino, nitro, carboxyl, formyl, cyano, methyl, amido, methyl, methoxymethyl and hydroxymethyl.

In still a further embodiment, R2 is an aryl group as shown in any of examples 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n and 9ae.

Preferably, R2 is NRN5RN6, in which RN5 and RN6 are as previously defined and, more preferably, RN5 and RN6, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, which may be optionally substituted. The ring preferably has 5 to 7 ring atoms. Preferred optionally substituted groups include, but are not limited to morpholino, thiomorpholino, piperidinyl, piperazinyl, (preferably N-substituted), homopiperazinyl (preferably N-substituted) and pyrrolidinyl.

Preferred N substituents for the piperazinyl and homopiperazinyl groups include esters, in particular esters bearing a C1-7 alkyl group as an ester substituent, e.g. ex. -C (= O) OCH3, -C (= O) OCH2CH3 and C (= O) OC (CH3) 3.

Preferred C substituents for the groups include C1-4 alkyl, preferably methyl. The groups may carry one or more substituents, for example one or two substituents.

More preferred groups are morpholino and piperidinyl. These are preferably substituted with one or two methyl substituents. If these groups carry two methyl substituents, they are preferably found in separate carbon atoms. Particularly preferred groups include:

In one embodiment of the invention a subset of compounds of formula (I) and salts is provided.

pharmaceutically acceptable thereof, in which: X8 is N, and X5 and X6 are CH; R7 is an optionally substituted C5-20 aryl group; RN3 and RN4, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 5 and 7 ring atoms, which may be optionally substituted; and R2 is selected from NRN5RN6, an optionally substituted C5-20 heteroaryl group, and an optionally substituted C5-20 aryl group.

In another embodiment, a subset of compounds of formula (I) and pharmaceutically acceptable salts is provided.

acceptable thereof, in which: X8 is N, and X5 and X6 are CH; R7 is an optionally substituted C5-6 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C1-7 alkyl and C1-7 alkoxy (wherein the alkyl groups may be optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkoxy, amino and C5-6 aryl);

RN3

 and RN4, together with the nitrogen to which they are attached, preferably form a morpholino group

optionally substituted, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted),

homopiperazinyl (preferably N-substituted) or pyrrolidinyl; Y

R2 is selected from NRN5RN6, an optionally substituted C5-6 heteroaryl group and a C6 aryl group

optionally substituted.

In another embodiment, a subset of compounds of formula (I) and pharmaceutically acceptable salts is provided.

acceptable thereof, in which: X8 is N, and X5 and X6 are CH; R7 is an optionally substituted C5-6 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C1-7 alkyl and C1-7 alkoxy (wherein the alkyl groups may be optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkoxy, amino and C5-6 aryl);

RN3

 and RN4, together with the nitrogen to which they are attached, preferably form a morpholino group

optionally substituted, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted),

homopiperazinyl (preferably N-substituted) or pyrrolidinyl; Y

R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form a heterocyclic ring

containing between 5 and 7 ring atoms, which may be optionally substituted.

In a further embodiment a subset of compounds of formula (I) and salts is provided.

pharmaceutically acceptable thereof, in which: X8 is N, and X5 and X6 are CH; R7 is an optionally substituted C5-6 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C1-7 alkyl and C1-7 alkoxy (wherein the alkyl groups may be optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkoxy, amino and C5-6 aryl);

RN3

 and RN4, together with the nitrogen to which they are attached, preferably form a morpholino group

optionally substituted, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted),

homopiperazinyl (preferably N-substituted) or pyrrolidinyl; Y

R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form a morpholino group

optionally substituted, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted),

homopiperazinyl (preferably N-substituted) or pyrrolidinyl.

In a further embodiment a subset of compounds of formula (I) and salts is provided.

pharmaceutically acceptable thereof, in which: X8 is N, and X5 and X6 are CH; R7 is a thiophenyl group or a phenyl group optionally substituted with one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl;

RN3

 and RN4, together with the nitrogen to which they are attached, preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted) group,

5 homopiperazinyl (preferably N-substituted) or pyrrolidinyl; and R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form an optionally substituted morpholino group, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl.

In a further embodiment, a subset of compounds of formula (I) and pharmaceutically acceptable salts thereof are provided, wherein: X8 is N, and X5 and X6 are CH; R7 is a thiophenyl group or a phenyl group optionally substituted with one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl;

RN3

15 and RN4, together with the nitrogen to which they are attached, preferably form an optionally substituted morpholino group, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl; and R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N

Substituted) or pyrrolidinyl, optionally substituted on carbon with one or more C1-4 alkyl groups.

In a further embodiment, a subset of compounds of formula (I) and pharmaceutically acceptable salts thereof are provided, wherein: X8 is N, and X5 and X6 are CH; R7 is a thiophenyl group or a phenyl group optionally substituted with one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl;

RN3

 and RN4, together with the nitrogen to which they are attached, preferably form a morpholino or thiomorpholino group; and R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form a morpholino group,

Thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl, optionally substituted on the carbon with one or more C1-4 alkyl groups.

In a further embodiment, a subset of compounds of formula (I) and pharmaceutically acceptable salts thereof are provided, in which:

X8 is N, and X5 and X6 are CH; R7 is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxyphenyl, 3,5-dimethoxy-4hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or a 3-hydroxymethylphenyl group;

RN3

 and RN4, together with the nitrogen to which they are attached, preferably form a morpholino or thiomorpholino group; and 40 R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form a group

In a further embodiment, a subset of compounds of formula (I) and pharmaceutically acceptable salts thereof are provided, in which:

X8 is N, and X5 and X6 are CH; R7 is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxyphenyl, 3,5-dimethoxy-4hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or a 3-hydroxymethylphenyl group; RN3 and RN4, together with the nitrogen to which they are attached, preferably form an unsubstituted morpholino; and R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form a group. In a further embodiment a subset of compounds of formula I (A) and salts is provided.

pharmaceutically acceptable thereof, in which: X8 is N, and X5 and X6 are CH; RN10 is selected from C (= S) RC3, an optionally substituted C5-20 heteroaryl group, an optionally substituted C5-20 aryl group and an optionally substituted C1-10 alkyl group, in which RC3 is as previously defined; RO3 is an optionally substituted C1-6 alkyl group; RN3 and RN4, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 5 and 7 ring atoms, which may be optionally substituted; and R2 is selected from NRN5RN6, an optionally substituted C5-20 heteroaryl group, and an optionally substituted C5-20 aryl group.

In a further embodiment a subset of compounds of formula I (A) and salts is provided.

pharmaceutically acceptable thereof, in which: X8 is N, and X5 and X6 are CH; RN10 is C (= S) RC3, an optionally substituted C5-6 heteroaryl group, an optionally substituted C5-6 aryl group and an optionally substituted C1-10 alkyl group, in which RC3 is NRN11RN12 and in which RN11 and RN12, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms; RO3 is an unsubstituted C1-3 alkyl group; RN3 and RN4, together with the nitrogen to which they are attached, form an optionally substituted morpholino group, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl; and R2 is selected from NRN5RN6, an optionally substituted C5-6 heteroaryl group, and an optionally substituted C6 aryl group.

In another embodiment, a subset of compounds of formula I (A) and pharmaceutically acceptable salts is provided.

acceptable thereof, in which: X8 is N, and X5 and X6 are CH; RN10 is a C (= S) NRN11RN12 group, in which RN11 and RN12, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, or a pyrazole group, optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a phenyl group, optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or an alkyl group C1-6 optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-20 aryl, C3-20 heterocyclyl, heteroaryl C5-20, cyano, ester, for example -C (= O) OR, where R is C1-7 alkyl, and amino, for example C1-7-alkyl, C1-7 dialkyl and C1-7 alkoxy -carbonylamino; RO3 is a methyl group; RN3 and RN4, together with the nitrogen to which they are attached, form an optionally substituted morpholino group, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl; and R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 5 and 7 ring atoms that may be optionally substituted.

In a further embodiment a subset of compounds of formula I (A) and salts is provided.

pharmaceutically acceptable thereof, in which: X8 is N, and X5 and X6 are CH; RN10 is a C (= S) NRN11RN12 group, in which RN11 and RN12, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, or a pyrazole group, optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a phenyl group, optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or an alkyl group C1-6 optionally substituted with one or more groups selected from halo,

hydroxyl, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-20 aryl, heterocyclyl C3-20, C5-20 heteroaryl, cyano, ester, for example -C (= O) OR, in which R is C 1-7 alkyl, and amino, for example C 1-7 alkyl, C 1-7 dialkyl, and C 1-7 alkoxycarbonylamino; RO3 is a methyl group;

RN3

 and RN4, together with the nitrogen to which they are attached, preferably form a morpholino group

optionally substituted, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted),

homopiperazinyl (preferably N-substituted) or pyrrolidinyl; Y

R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form a morpholino group

optionally substituted, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted),

homopiperazinyl (preferably N-substituted) or pyrrolidinyl.

In a further embodiment a subset of compounds of formula I (A) and salts is provided.

pharmaceutically acceptable thereof, in which: X8 is N, and X5 and X6 are CH; RN10 is a C (= S) NRN11RN12 group, in which RN11 and RN12, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, or a pyrazole group, optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a phenyl group, optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or an alkyl group C1-6 optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-20 aryl, C3-20 heterocyclyl, heteroaryl C5-20, cyano, ester, for example -C (= O) OR, where R is C1-7 alkyl, and amino, for example C1-7-alkyl, C1-7 dialkyl and C1-7 alkoxy -carbonylamino; RO3 is a methyl group;

RN3

 and RN4, together with the nitrogen to which they are attached, preferably form a morpholino group

optionally substituted, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted),

homopiperazinyl (preferably N-substituted) or pyrrolidinyl; Y

R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form a morpholino group

optionally substituted, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted),

homopiperazinyl (preferably N-substituted) or pyrrolidinyl.

In a further embodiment a subset of compounds of formula I (A) and salts is provided.

pharmaceutically acceptable thereof, in which: X8 is N, and X5 and X6 are CH; RN10 is a C (= S) NRN11RN12 group, in which RN11 and RN12, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, or a pyrazole group, optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a phenyl group, optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or an alkyl group C1-6 optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-20 aryl, C3-20 heterocyclyl, heteroaryl C5-20, cyano, ester, for example -C (= O) OR, where R is C1-7 alkyl, and amino, for example C1-7-alkyl, C1-7 dialkyl and C1-7 alkoxy -carbonylamino; RO3 is a methyl group;

RN3

 and RN4, together with the nitrogen to which they are attached, preferably form a morpholino group or

thiomorpholino; Y

R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form a morpholino group,

thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N

substituted) or pyrrolidinyl, optionally substituted on the carbon with one or more C1-4 alkyl groups.

In a further embodiment a subset of compounds of formula I (A) and salts is provided.

pharmaceutically acceptable thereof, in which: X8 is N, and X5 and X6 are CH; RN10 is a C (= S) NRN11RN12 group, in which RN11 and RN12, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, or a pyrazole group, optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a phenyl group, optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or an alkyl group C1-6 optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-20 aryl, C3-20 heterocyclyl, heteroaryl C5-20, cyano, ester, for example -C (= O) OR, where R is C1-7 alkyl, and amino, for example C1-7-alkyl, C1-7 dialkyl and C1-7 alkoxy -carbonylamino; RO3 is a methyl group;

RN3

 and RN4, together with the nitrogen to which they are attached, preferably form a morpholino group or

thiomorpholino; Y

R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form a group

In a further embodiment, a subset of compounds of formula I (A) and pharmaceutically acceptable salts thereof are provided, in which:

X8 is N, and X5 and X6 are CH; RN10 is a group C (= S) NRN11RN12, in which RN11 and RN12, together with the nitrogen to which they are attached, form

10 a heterocyclic ring containing between 3 and 8 ring atoms, or a pyrazole group, optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a phenyl group, optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a C1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxyl, C1-7 alkyl, ether, for example alkoxy C1-7, thioether, for example C1-7 alkylthio, C5-20 aryl, heterocyclyl

C3-20, C5-20 heteroaryl, cyano, ester, for example -C (= O) OR, where R is C1-7 alkyl, and amino, for example C1-7 alkyl, amino C1-7 dialkyl amino and C1-7 alkoxycarbonylamino; RO3 is a methyl group;

RN3

 and RN4, together with the nitrogen to which they are attached, preferably form an unsubstituted morpholino group; and 20 R2 is NRN5RN6, in which RN5 and RN6, together with the nitrogen to which they are attached, form a group

In another aspect of the invention, particular compounds of the invention are any one of the Examples or their pharmaceutically acceptable salts.

In a further aspect of the invention, particular compounds of the invention are any one of Examples 1a, 1b, 1d, 1e, 1f, 1g, 1i, 1k, 1l, 1m, 1n, 1o, 1p, 1q, 1bb, 1bc, 1bd, 1be, 1bf, 1bg, 1bh, 1bi, 1br, 8a, 8b, 8c, 8d, 8e, 8f, 8g, 8h, 8i, 8j, 8k, 8l, 8m, 8n, 8o, 8t, 8u, 8aa, 8ab, 8ac, 8ad, 8ae, 8af, 8ag, 8ah, 8ai, 8aj, 8ak, 8al, 8am, 8an, 8ao, 8ap, 8aq, 8ar, 8a, 8at, 8au, 8av, 8aw, 8ax, 8ay, 8az, 8ba, 8bb, 8bc, 8bd, 8be, 8bg, 9a, 9b, 9c, 9d, 9e, 9f,

30 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n and 9ae, or their pharmaceutically acceptable salts.

Isomers, salts, solvates, protected forms and prodrugs

Certain compounds may exist in one or more geometric, optical, enantiomeric forms,

35 diastereomeric, epimeric, stereoisomeric, tautomeric, conformational or particular anomeric which include, but are not limited to cis, and trans, forms E and Z; forms c, t and r; endo and exo forms, R, S and meso forms; forms D and L; d and l forms; forms (+) and (-); keto, enol and enolate forms; sin and anti forms; syncline and anticline forms; α and β forms; axial and equatorial forms; boat, chair, cone, envelope and half chair shapes; and combinations thereof, referred to here collectively as "isomers" (or "forms

40 isomeric ”).

If the compound is in crystalline form, it may exist in a number of different polymorphic forms.

Note that, except as discussed below for tautomeric forms, they are specifically

Excluded from the term "isomers", as used herein, structural (or constitutional) isomers (ie, isomers that differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl has not been interpreted as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class The foregoing exclusion does not pertain to tautomeric forms, for example keto, enol and enolate forms, such as, for example, in the following tautomeric pairs: keto / enol, imino / enamine, amide / imino alcohol , amidine / amidine, nitroso / oxime, thioketone / ethanolol, N-nitroso / hydroxyazo and nitro / aci-nitro.

Unless otherwise specified, a reference to a particular compound includes all such isomeric forms that include (in whole or in part) racemic mixtures and other mixtures thereof. Methods for the preparation (eg asymmetric synthesis) and separation (eg fractional crystallization and chromatographic media) of isomeric forms of this type are known in the art or are easily obtained by adapting the methods taught herein, or methods known, in a known way.

Unless otherwise specified, a reference to a particular compound also includes ionic forms, salt, solvate and protected forms thereof, for example as discussed below, as well as their different polymorphic forms.

It may be convenient or desirable to prepare, purify and / or manipulate a corresponding salt of the active compound, for example a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are discussed in ref. 25.

For example, if the compound is anionic or has a functional group that can be anionic (eg -COOH can be -COO-), then a salt can be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to alkali metal ions such as Na + and K +, alkaline earth cations such as Ca2 + and Mg2 +, and other cations such as Al3 +. Examples of suitable organic cations include, but are not limited to ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R +, NH2R2 +, NHR3 +, NR4 +). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N (CH3) 4+.

If the compound is cationic or has a functional group that can be cationic (eg -NH2 can be -NH3 +), then a salt with a suitable anion can be formed. Examples of suitable inorganic anions include, but are not limited to those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric and phosphorous. Examples of suitable organic anions include, but are not limited to those derived from the following organic acids: acetic, propionic, succinic, glycolic, stearic, palmitic, lactic, malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic, hydroxyloleic, phenylacetic, glutamic, aspartic, benzoic, cinnamic, pyruvic, salicylic, sulphanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethanedisulfonic, oxalic, isethionic, valeric and gluconic. Examples of suitable polymeric anions include, but are not limited to those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

It may be convenient or desirable to prepare, purify and / or handle a corresponding solvate of the compound

active. The term "solvate" is used herein in the conventional sense to refer to a complex of

solute (eg active compound, salt of active compound) and solvent. If the solvent is water, the solvate can conveniently be referred to as a hydrate, for example a monohydrate, a dihydrate, a trihydrate, etc.

It may be convenient or desirable to prepare, purify and / or manipulate the active compound in a form.

chemically protected. The expression "chemically protected form", as used herein,

it belongs to a compound in which one or more reactive functional groups are protected against undesirable chemical reactions, that is, they are in the form of a protected or protective group (also known as a masked or masked group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; The protected group can be separated, usually at a subsequent stage, without substantially affecting the rest of the molecule. See, for example, ref. 26.

For example, a hydroxy group can be protected as an ether (-OR) or an ester (-OC (= O) R), for example, as: a t-butyl ether, a benzyl-, benzhydryl (diphenylmethyl) - or trityl (triphenylmethyl) ether; a trimethylsilyl- or t-butyldimethylsilyl ether; or an acetyl ester (OC (= O) CH3, -OAc).

For example, an amine group can be protected, for example, as an amide or a urethane, for example as: a methyl amide (-NHCO-CH3); a benzyloxy-amide (-NHCO-OCH2C6H5), -NH-Cbz); as a t-butoxyamide (-NHCOOC (CH3) 3, -NH-Boc); a 2-biphenyl-2-propoxy-amide (-NHCO-OC (CH3) 2C6H4C6H5, -NH-Bpoc), such as a 9-fluorenylmethoxy-amide (-NH-Fmoc), such as a 6-nitroveratryloxy-amide (-NH-Nvoc ), as a 2-trimethylsilylethyloxyamide (-NH-Teoc), as a 2,2,2-trichlorethyloxy-amide (-NH-Troc), such as an allyloxy-amide (-NH-Alloc), such as a 2 (-phenylsulfonyl) ) ethyloxy-amide (-NH-Psec); or, in suitable cases, as an N-oxide (> NO ·).

For example, a carboxylic acid group can be protected as an ester, for example as: a C1-7 alkyl ester

(eg a methyl ester; a t-butyl ester); a C1-7 haloalkyl ester (eg, a C1-7 trihaloalkyl ester); a C1-7 trialkyl-C1-7 alkyl-alkyl ester; or a C5-20-C 1-7 alkyl ester (eg a benzyl ester, a nitrobenzyl ester); or as an amide, for example as a methyl amide.

For example, a thiol group can be protected as a thioether (-SR), for example as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC (= O) CH3).

It may be convenient or desirable to prepare, purify and / or manipulate the active compound in the form of a prodrug.

The term "prodrug", as used herein, belongs to a compound that, when metabolized

(p.

 ex. in vivo), provides the desired active compound. Typically, the prodrug is inactive or less active than the active compound, but may provide advantageous handling, administration or metabolic properties.

For example, some prodrugs are esters of the active compound (eg a metabolically labile, physiologically acceptable ester). During metabolism, the ester group (-C (= O) OR) is cleaved to provide the active drug. Esters of this type may be formed by esterification, for example of any of the carboxylic acid groups (-C (= O) OH) in the parent compound, where appropriate, with prior protection of any other reactive groups present in the parent compound, followed by deprotection, if required. Examples of metabolically labile esters of this type include those wherein R is C1-20 alkyl (eg -Me, -Et); C 1-7 aminoalkyl (eg aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) ethyl); and acyloxy-C1-7 alkyl

(p.

ex. acyloxymethyl; acyloxyethyl; p. ex. pivalyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1- (1-Methoxy-1-methyl) ethylcarbonyloxyethyl; 1- (benzoyloxy) ethyl; isopropoxycarbonyloxymethyl; 1-isopropoxycarbonyloxyethyl; cyclohexylcarbonyloxymethyl; 1-cyclohexylcarbonyloxyethyl; cyclohexyloxycarbonyloxymethyl; 1-cyclohexyloxycarbonyloxyethyl; (4 tetrahydropyranyloxy) carbonyloxymethyl; 1- (4-tetrahydropyranyloxy) carbonyloxyethyl; 4- (tetrahydropyranyl) carbonyloxymethyl; and 1- (4-tetrahydropyranyl) carbonyloxyethyl.

Additional suitable prodrug forms include phosphonate salts and glycolate. In particular, hydroxy groups (-OH) can be introduced into phosphonate prodrugs by reaction with chlorodibenzyl phosphite, followed by hydrogenation, to form a phosphonate group -O-P (= O) (OH) 2. Such a group can be clarified by phosphatase enzymes during metabolism to provide the active drug with the hydroxy group.

Also, some prodrugs are enzymatically activated to provide the active compound or a compound that, after the subsequent chemical reaction, provides the active compound. For example, the prodrug can be a sugar derivative or another glycoside conjugate or it can be a derivative of an amino acid ester.

Acronyms

For convenience, many chemical moieties are represented using well known abbreviations that include, but are not limited to methyl (Me), ethyl (Et), n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu) , tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naf), methoxy (MeO), ethoxy (EtO), benzoyl (Bz) and acetyl (Ac).

For convenience, many chemical compounds are represented using well known abbreviations that include, but are not limited to methanol (MeOH), ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), ether or diethyl ether (Et2O), acetic acid (AcOH), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF) and dimethylsulfoxide (DMSO).

Compounds of formula I may be represented by Formula 1:

5 where R4 represents NRN3RN4. Compounds of formula 1 can be synthesized from compounds of Formula 2:

Formula 2

When R7 is NRN1RN2, this is done by reaction with K7H. When R7 is a C3-20 heterocyclyl group or a

optionally substituted C5-20 aryl group, this is done by reaction with R7B (OAlk) 2, in which each of 15 Alk is independently C1-7 alkyl or, together with the oxygen to which they are attached, form a C5 heterocyclyl group

7. When R7 is an amide, urea, or sulfonamide group, it is synthesized by reaction with ammonia, followed by reaction of the resulting primary amide with the appropriate acid, isocyanate or sulfonyl chloride chloride. When R7 is ORO1 or SRS1, this is by reaction with potassium carbonate in the appropriate alcohol or thiol solvent.

Therefore, in accordance with a further aspect of the present invention, there is provided a process for the preparation of a compound of Formula 1 from a compound of Formula 2:

 Formula 2 where:

R4 is NRN3RN4, in which RN3 and RN4, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms; R2 is selected H, halo ORO2, SRS2b, NRN5RN6, an optionally substituted C5-20 heteroaryl group and an optionally substituted C5-20 aryl group,

and RS2b

Wherein RO2 is selected from H, an optionally substituted C5-20 aryl group, an optionally substituted C5-20 heteroaryl group or an optionally substituted C1-7 alkyl group and RN5 and RN6 are independently selected from H, a C1- alkyl group 7 optionally substituted, an optionally substituted C5-20 heteroaryl group and an optionally substituted C5-20 aryl group, or RN5 and RN6, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms,

35 comprising

(to)

when R7 is NRN1NRN2, reaction of the compound of formula 2 with R7H; or

(b)

when R7 is a C3-20 heterocyclyl group or an optionally substituted C5-20 aryl group, reaction of the compound of formula 2 with R7B (OAlk) 2 in which each of Alk is independently C1-7 alkyl or, together with the oxygen at which are attached, form a C5-7 heterocyclyl group, or

(C) when R7 is an amide, urea or sulfonamide group, reaction of a compound of formula 2 with ammonia, followed by reaction of the resulting primary amine with the appropriate acid, isocyanate or sulfonyl chloride chloride, or

(d) when R7 is ORO1 or SRS1, by reaction of the compound of formula 1 in the presence of a base in the appropriate alcohol or thiol solvent.

where R4 represents NRN3RN4, and R7 is

Wherein Lv is a labile group such as a halogen, for example chlorine, or an OSO2R group, wherein R is alkyl or aryl such as methyl, by reaction with RN10NH2.

Compounds of Formula 1a can be synthesized by reaction of a compound of Formula 1b 15

where R4 represents NRN3RN4, and R7 is

with an alkyl- or aryl-sulfonyl chloride in the presence of a base. Compounds of Formula 1b can be synthesized by reacting a compound of Formula 2:

Formula 2 with R7B (OAlk) 2 in which each of Alk is independently C1-7 alkyl or, together with the oxygen to which they are attached, form a C5-7 heterocyclyl group.

Compounds of Formula 2 can be synthesized from compounds of Formula 3: 30

by reaction with HR4 (HNRN3RN4) followed by reaction with HR2. Compounds of Formula 3 can be synthesized from compounds of Formula 4:

by treatment with POCl3 and N, N-diisopropylamine, for example. Compounds of Formula 4 can be synthesized from compounds of Formula 5:

by treatment with oxalyl chloride, for example.

Compounds of Formula 5 can be synthesized from compounds of Formula 6, for example by reaction with liquid ammonia followed by reaction with thionyl chloride and ammonia gas:

Alternatively, compounds of formula 1 can be synthesized from compounds of Formula 2A:

When R2 is NRN5RN6, this is done by reaction with R2H. When R2 is a C3-20 heterocyclyl group or an optionally substituted C5-20 aryl group, this is accomplished by reaction with R2B (OAlk) 2, in which each of Alk is independently C1-7 alkyl or, together with the oxygen at which are attached, form a C5 heterocyclyl group

7. When R2 is ORO2 or SRS2b, this is done by reaction with potassium carbonate in the appropriate thiol alcohol solvent.

wherein R4 is NRN3RN4, in which RN3 and RN4, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms; and R7 is selected from halo, ORO1, SRS1, NRN1RN2, NRN7aC (= O) RC1, NRN7bSO2RS2a, a C5-20 heteroaryl group

Optionally substituted or an optionally substituted C5-20 aryl group, wherein RO1 and RS1 are selected from H, an optionally substituted C5-20 aryl group, an optionally substituted C5-20 heteroaryl group or an optionally substituted C1-7 alkyl group; RN1 and R12 are independently selected from H, an optionally substituted C1-7 alkyl group, an optionally substituted C5-20 heteroaryl group, an optionally substituted C5-20 aryl group, or RN1 and RN2, together with the nitrogen

15 to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms;

RC1

is selected from H, an optionally substituted C5-20 aryl group, an optionally substituted C5-20 heteroaryl group, an optionally substituted C1-7 alkyl group or NRN8RN9 in which RN8 and RN9 are independently selected from H, a C1-7 alkyl group optionally substituted, an optionally substituted C5-20 heteroaryl group, an optionally substituted C5-20 aryl group, or RN8 and RN9, together with the

20 nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms;

RS2a

selected from H, an optionally substituted C5-20 aryl group, an optionally substituted C5-20 heteroaryl group or an optionally substituted C1-7 alkyl group; Y

RN7a

and RN7b are selected from H and a C1-4 alkyl group; which comprises 25 (a) when R2 is NRN5RN6, reacting a compound of formula 2A with R2H, or

(b) when R2 is a C3-20 heterocyclyl group or an optionally substituted C5-20 aryl group, reacting a compound of formula 2A with R2B (OAlk) 2, wherein each of Alk is independently C1-7 alkyl or, together with the oxygen to which they are attached, they form a C5-7 heterocyclyl group, or

(C) when R2 is ORO2 or SRS2b, react a compound of formula 2A in the presence of a base in the appropriate alcohol or thiol solvent.

Formula 3

35 by reaction with HR4 (HNRN3RN4), followed by reaction with HR7 or an equivalent of HR7. For example, when R7 is a C3-20 heterocyclyl group or an optionally substituted C5-20 aryl group, this is done by reaction with R7B (OAlk) 2, where each of Alk is independently C1-7 alkyl or, together with the oxygen to which they are attached, form a C5-7 heterocyclyl group.

Use

The present invention provides active compounds, specifically active to inhibit mTOR activity.

The term "active", as used herein, pertains to compounds that are capable of inhibiting mTOR activity and, specifically, includes both compounds with intrinsic activity (drugs) and prodrugs of compounds of this type, prodrugs that they can themselves exhibit a small activity or no intrinsic activity.

The present invention further considers a method of inhibiting mTOR activity in a cell, which comprises contacting said cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable composition. Such a method can be implemented in vitro or in vivo.

For example, a sample of cells can be grown in vitro and an active compound can be contacted with said cells, and the effect of the compound on those cells is observed. As examples of "effect", the inhibition of cell growth in a given time or the accumulation of cells in the G1 phase of the cell cycle over a certain time can be determined. In cases where it is found that the active compound exerts an influence on the cells, it can be used as a prognostic or diagnostic marker of the efficacy of the compound in methods to treat a patient carrying cells of the same cell type.

The term "treatment", as used herein in the context of treating a condition, generally belongs to the treatment and therapy, either of a human being or an animal (eg in veterinary applications) in which it achieves a desired therapeutic effect, for example the inhibition of the progress of the condition, and includes a reduction in the speed of progress, a stop in the speed of progress, an improvement in the condition and a cure of the condition. Treatment is also included as a prophylactic measure (ie, prophylaxis).

The term "attached", as used herein, refers to the use of active compounds in conjunction with known therapeutic means. Means of this type include cytotoxic drug regimens and / or ionizing radiation as used in the treatment of different types of cancer. Examples of anticancer agents that may be combined with compounds of the invention include, but are not limited to the following: alkylating agents: mustard nitrogen, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil: nitrosoureas: carmustine (BCNU), lomustine (CCNU) , semustine (methyl-CCNU), ethyleneimine / methylmelamine, triethylenemelamine (TEM), triethylene thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine): alkyl sufonates; busulfan; triazines, dacarbazine (DTIC): antimetaboliteo; folic acid analogs, methotrexate, trimetrexate, pyrimidine analogues, 5-fluorouracil, fluorodeoxyuridine, gemcitabine, arabinoside cytosine (AraC, cytarabine), 5-azacytidine, 2,2’-difluorodeoxycytidine: purine analogues; 6-mercaptopurine, 6-thioguanine, azathioprine, 2'-deoxycoformycin (pentostatin, erythrohydroxynonyladenine (EHNA), fludarabine phosphate, 2-chlorodeoxyadenosine (cladribine, 2-CdA): topoisomerase I inhibitors, camptotecinate, natural products: camptotecinate, natural products; antimitotic drugs, paclitaxel, vinca alkaloids, vinblastine (VLB), vincristine, vinorelbine, Taxotere ™ (docetaxel), estramustine, estramustine phosphate; epipodophyllotoxins, etoposide, teniposide: antibiotics; actimomycin D, daunomycin (rubidomycin) adipomycin) , idarubicin, bleomycins, plicamycin (mitramycin), mitomycin C, dactinomycin: enzymes; L-asparaginase, RNAse A: biological response modifiers; interferon-alpha, IL-2, GCSF, GM-CSF: differentiation agents; derivatives of retinoic acid: radiosensitizers; metronidazole, misonidazole, demethylmisonidazole, pimonidazole, ethanidazole, nimorazole, RSU 1069, EO9, RB 6145, SR4233, nicotinamide, 5 -bromodeoxyuridine, 5-iododeoxyuridine, bromodeoxycytidine: platinum coordination complexes; cisplatin, carboplatin: anthracenedione; mitoxantrone, substituted AQ4N urea, hydroxyurea; methylhydrazine derivatives, N-methylhydrazine (MIH), procarbazine; adrenocortical suppressor, mitotane (o.p’-DDD), aminoglutethimide: cytokines; interferon (α, β, γ), interleukin; hormones and antagonists; adrenocorticosteroids / antagonists, prednisone and equivalents, dexamethasone, aminoglutethimide; progestins, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate; estrogens, diethylstilbestrol, ethinyl estradiol / equivalents; antiestrogen, tamoxifen; androgens, testosterone propionate, fluoxymesterone / equivalents; antiandrogens, flutamide, gonadotropin-releasing hormone analogues, leuprolide; non-steroidal anti-androgens, flutamide; EGFR inhibitors, VEGF inhibitors; proteasome inhibitors

Active compounds can also be used as additives to cell cultures to inhibit mTOR, for example in order to sensitize cells to known chemotherapeutic agents or in vitro ionizing radiation treatments.

Active compounds can also be used as part of an in vitro assay, for example in order to determine if a candidate host is likely to benefit from treatment with the compound in question.

The present invention provides active compounds that are anticancer agents or adjuvants for treating cancer. A person of ordinary skill in the art is easily able to determine whether or not a candidate compound treats a cancerous condition for any particular cell type, either alone or in combination.

Examples of cancers include, but are not limited to lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carcinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer. , kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma and leukemia.

Any type of cell that includes, but is not limited to, lung, gastrointestinal (including, e.g., intestine, colon), breast (mammary), ovaries, prostate, liver (liver), kidney (renal) can be treated , bladder, pancreas, brain and skin.

The anti-cancer treatment defined hereinbefore may be applied as a therapy alone or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Chemotherapy of this type may include one or more of the following categories of antitumor agents:

(i)

 other anti-proliferative / anti-neoplastic drugs and combinations thereof such as are used in medical oncology, such as alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mustard nitrogen, melphalan, chlorambucil, busulfan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines such as 5fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (for example anthracyclines, such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, dactinomycin and mitramycin); antimitotic agents (for example vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine, and taxoids such as taxol and taxotere and polykinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii)

 cytostatic agents such as anti-estrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxifene), anti-androgens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example LHRH agonists) goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example such as anastrozole, letrozole, vorazol and exemestane) and 5 * -reductase inhibitors such as finasteride;

(iii) anti-invasion agents (for example inhibitors of the c-Src kinase family such as 4- (6-chloro2,3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl) ethoxy] -5-tetrahydropyran-4-yloxyquinazoline (AZD0530; international patent application WO 01/94341) and N- (2-chloro-6-methylphenyl) -2- [6- [4- [4- (2-hydroxyethyl) piperazin-1il] -2-methylpyrimidin-4-ylamino} thiazol-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 66586661) and metalloproteinase inhibitors such as marimastat, activator receptor function inhibitors of plasminogen urokinase or antibodies against heparanase);

(iv)

inhibitors of growth factor function: for example, inhibitors of this type include antibodies against growth factor and antibodies against growth factor receptors (for example, anti-erbB2 trastuzumab antibody [Herceptin ™], the anti-antibody EGFR panitumumab, the anti-erbB1 cetuximab [Erbitux, C225] antibody and any antibodies against the growth factor

or growth factor receptors described by Stern et al. Critical reviews in oncology / haematology, 2005, Vol. 54, p. 11-29); Inhibitors of this type also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy -6- (3-morpholinopropoxy) quinazolin4-amine (gefitinib, ZD1839), N- (3-ethylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI 774) and 6-acrylamido-N - (3-Chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) -quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, hepatocyte growth factor family inhibitors, inhibitors from the family of platelet-derived growth factors such as imatinib, serine / threonine kinase inhibitors (for example Ras / Raf signaling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signaling through MEK and / or AKT kinases, f inhibitors hepatocyte growth factor amyla, c-kit inhibitors, abl kinase inhibitors, IGF receptor kinase inhibitors (insulin-like growth factor); aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors;

(v)

anti-angiogenic agents such as those that inhibit the effects of vascular endothelial growth factor [eg, anti-vascular endothelial cell growth factor antibody bevacizumab

(Avastin ™) and VEGF receptor tyrosine kinase inhibitors such as 4- (4-bromo-2-fluoroanilino) -6methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline (ZD6474; Example 2 in WO 01 / 32651), 4- (4fluoro-2-methylindole-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD2171; Example 240 in WO 00/47212), vatalanib ( PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), compounds such as those described in international patent applications WO97 / 22596, WO 97/30035, WO 97/32856 and WO 98/13354, and compounds that act by other mechanisms (for example linomide, inhibitors of integrin avb3 function and angiostatin)];

(saw)

 vascular injury agents such as Combrestastine 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 therapies, for example those that target the targets listed above such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy strategies that include, for example, strategies to replace aberrant genes such as aberrant p53 or BRCA1 or aberrant BRCA2, GDEPT (gene directed enzyme prodrug therapy) strategies such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme, and strategies to increase the patient's tolerance to chemotherapy or radiotherapy such as multiple drug resistance gene therapy; Y

(ix) immunotherapy strategies that include, for example, ex vivo and in vivo strategies to increase the immunogenicity of tumor cells from patients such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor , strategies to reduce the anergy of T cells, strategies that use immune cells such as dendritic cells transfected with cytokine, strategies that use tumor cell lines transfected with cytokine and strategies that use anti-idiotypic antibodies.

Administration

The active compound or pharmaceutical composition comprising the active compound can be administered to a subject by any convenient route of administration, either systemically / peripherally or at the desired site of action, which includes, but is not limited to oral, (eg by ingestion), topical (including, eg, transdermal, intranasal, ocular, buccal and sublingual routes); pulmonary (eg, by inhalation or insufflation therapy using, eg, an aerosol, eg through the mouth or nose); rectal; vaginal; parenteral (for example by injection including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid and intrasternal; by implanting a reservoir, for example subcutaneously or intramuscularly.

The subject can be a eukaryotic, an animal, a vertebrate animal, a mammal, a rodent (eg a guinea pig, a hamster, a rat, a mouse), murine (eg a mouse), canine (p eg a dog), feline (eg a cat), equine (eg a horse), a primate, ape (eg a monkey or ape), a monkey (eg titi , baboon), an ape (eg gorilla, chimpanzee, orangutan, gibbon) or a human being.

Formulations

Although it is possible for the active compound to be administered alone, it is preferable that it is present as a pharmaceutical composition (eg formulation) comprising at least one active compound as defined above, together with one or more vehicles, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, pharmaceutically acceptable lubricants or other materials well known to those skilled in the art and, optionally, other therapeutic or prophylactic agents.

Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods for preparing a pharmaceutical composition comprising mixing at least one active compound, as defined above, together with one or more carriers, excipients, buffers, adjuvants. , stabilizers or other pharmaceutically acceptable materials as described herein.

The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions and / or dosage forms that are, within the scope of good medical judgment, suitable for use in contact with the tissues of a subject (p eg human being) without toxicity, irritation, allergic response or other problem or excessive complication, in accordance with a reasonable benefit / risk ratio.

Each of the vehicles, excipients, etc. it must also be "acceptable", in the sense of being compatible with the

Other ingredients of the formulation.

The formulations can be conveniently present in unit dosage form and can be prepared by any methods well known in the art of pharmacy. Methods of this type include the step of associating the active compound with the vehicle constituting one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately associating the active compound with liquid vehicles or finely divided solid vehicles or both and then, if necessary, forming the product.

The formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, pills, granules, powders, capsules, seals, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, vapors , foams, lotions, oils, bowling, electuaries or aerosols.

Formulations suitable for oral administration (eg by ingestion) may be presented in the form of discrete units such as capsules, seals or tablets, each containing a predetermined amount of the active compound; in the form of a powder or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of a liquid oil-in-water emulsion or a liquid water-in-oil emulsion; in the form of a bolus; in the form of an electuary; or in the form of a paste.

A tablet can be prepared by conventional means, e.g. ex. compression or molding, optionally with one

or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the freely flowing active compound such as a powder or granules, optionally mixed with one or more binders (eg povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropyl methylcellulose); fillers or diluents (eg lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (eg magnesium stearate, talc, silica); disintegrants (eg sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surfactants or dispersants or humectants (eg sodium lauryl sulfate); and preservatives (eg methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be coated or provided with incisions and may be formulated in order to provide a slow or controlled release of the active compound containing it, using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. The tablets may optionally be provided with an enteric coating to provide release in parts of the intestine other than the stomach.

Formulations suitable for topical administration (eg transdermal, intranasal, ocular, buccal and sublingual) can be formulated in the form of an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, spray or oil. Alternatively, a formulation may comprise a patch or dressing such as a bandage or adhesive adhesive impregnated with active compounds and, optionally, one or more excipients or diluents.

Formulations suitable for topical administration in the mouth include tablets comprising the active compound in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert base such as gelatin and glycerol, or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid vehicle.

Formulations suitable for topical administration to the eyes also include eye drops, wherein the active compound is dissolved or suspended in a suitable vehicle, especially an aqueous solvent for the active compound.

Formulations suitable for nasal administration, wherein the vehicle is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns that is administered in the manner in which it is sniffed, that is by rapid inhalation through the nasal passage from a container to the powder kept close to the nose. Suitable formulations in which the vehicle is a liquid for administration such as, for example, nasal spray, nasal drops or by aerosol administration by means of a nebulizer, include aqueous or oily solutions of the active compound.

Formulations suitable for administration by inhalation include those presented as an aerosol spray from a pressurized container, with the use of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable gases.

Formulations suitable for topical administration through the skin include ointments, creams and emulsions. When formulated in an ointment, the active compound may optionally be used as a paraffinic base or a water-miscible ointment base. Alternatively, the active compounds can be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w / w of a polyhydric alcohol, that is, an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1. , 3-diol, mannitol, sorbitol, glycerol and polyethylene glycol, and mixtures thereof. Topical formulations may desirably include a compound that enhances the absorption or penetration of the active compound through the skin or other affected areas. Examples of dermal penetration enhancers of this type include dimethylsulfoxide and related analogs.

When formulated as a topical emulsion, the oil phase may optionally comprise merely an emulsifier (otherwise known as an emulsifier) or it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and a oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without stabilizer or stabilizers constitute the so-called emulsifying wax, and the wax together with the oil and / or grease constitutes the so-called emulsifying ointment base that forms the oil dispersed phase of the cream formulations.

Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, ketostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils, which may be used in pharmaceutical emulsion formulations, can be very low. Thus, the cream should preferably be a non-greasy product, which does not stain and washable, with adequate consistency to avoid loss of tubes or other containers. Mono- or di-basic straight or branched chain alkyl esters can be used, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, stearate butyl, 2-ethylhexyl palmitate or a mixture of branched chain esters known as Crodamol CAP, the last three being preferred esters. These can be used alone or in combination depending on the required properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for vaginal administration may be presented in the form of pessaries, buffers, creams, gels, pastes, foams or spray formulations containing, in addition to the active compound, vehicles such as those known in the art as appropriate.

Formulations suitable for parenteral administration (eg, by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal) include aqueous and non-aqueous, isotonic, aprogenic and sterile injection solutions that may contain antioxidants, buffers, preservatives , stabilizers, bacteriostatic agents and solutes that make the isotonic formulation with the intended recipient's blood; and sterile aqueous and non-aqueous suspensions that may include suspending agents and thickening agents, and liposomes or other microparticle systems that are designed to target the compound to blood components or one or more organs. Examples of isotonic vehicles suitable for use in formulations of this type include sodium chloride injection, Ringer's solution or lacteal Ringer's injection. Typically, the concentration of the active compound in the solution is from about 1 ng / ml to about 10 µg / ml, for example from about 10 ng / ml to about 1 µg / ml. The formulations can be presented in unit dose or in sealed multi-dose containers, for example ampoules and vials, and can be stored in a freeze-dried (lyophilized) state that requires only the addition of the sterile liquid vehicle, for example water for injections, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets. The formulations may be in the form of liposomes or other microparticle systems that are designed to target the active compound to blood components or one or more organs.

Dosage

It will be appreciated that appropriate dosages of the active compounds and compositions comprising the active compounds may vary from one patient to another. The determination of the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or harmful side effect of the treatments of the present invention. The dosage level selected will depend on a variety of factors that include, but are not limited to the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds and / or materials used in combination and the patient's age, sex, weight, condition, general health and previous medical history. The amount of compound and route of administration will ultimately be at the discretion of the physician, although, in general, the dosage will be to achieve local concentrations at the site of action that achieve the desired effect without causing harmful side effects. or substantial harmful.

Administration in vivo can be carried out in one dose, continuously or intermittently (eg in divided doses at appropriate intervals) throughout the course of treatment. Methods for determining the most effective means and dosage of administration are well known to those skilled in the art and will vary with the formulation used for the therapy, the purpose of the therapy, the target cell being treated and the subject being treated. treaty. Single or multiple administrations can be carried out, selecting the level and dose model by the attending physician.

In general, a suitable dose of the active compound is in the range of about 100 µg to about 250 mg per kilogram of the subject's body weight per day. In cases where the active compound is a salt, an ester, prodrug or the like, the amount administered is calculated on the basis of the parent compound and, thus, the actual weight to be used is proportionally increased.

Examples

General Experimental Methods

Thin layer chromatography was carried out using Merck Kieselgel 60 F254 backed glass plates. The plates were visualized by using a UV lamp (254 nm). For flash chromatography, silica gel 60 (particle sizes 40-63 µm) supplied by E. M. Merck was used. The 1 H-NMR spectra were recorded at 300 MHz on a Bruker DPX-300 instrument. Chemical shifts were referenced in relation to tetramethylsilane.

Purification and identification of bank samples

The samples were purified in Gilson LC units. Mobile phase A-0.1% aqueous TFA, mobile phase B-acetonitrile; flow rate 6 ml / min; gradient - typically starting at 90% A / 10% B for 1 minute, increasing up to 97% after 15 minutes, holding for 2 minutes, then back to the starting conditions. Column: Jones Chromatography Genesis 4 µm, column C18, 10 mm x 250 mm. Acquisition of the peak based on UV detection at 254 nm.

Mass spectra were recorded on a Finnegan LCQ instrument in positive ion mode. Mobile phase A - 0.1% aqueous formic acid, mobile phase B - acetonitrile; flow rate 2 ml / min; gradient - starting at 95% A / 5% B for 1 minute, increasing to 98% B after 5 minutes and maintaining for 3 minutes before returning to the starting conditions. Column; varies, but always C18 50 mm x 4.6 mm (currently Genesis C18 4 µm. Jones Chromatography). Waters 996 PDA detection, 210-400 nm scan interval.

Microwave synthesis

The reactions were carried out using a Personal Chemistry ™ Emrys Optimiser microwave synthesis unit with robotic arm. Power range between 0-300 W at 2.45 GHz. Pressure range between 0-20 bar; temperature increase between 2-5ºC / s; temperature range 60-250 ° C.

Intermediate Compounds:

a) 2-Chloronicotinic Acid (Inter. 2)

To liquid 2,6-dichloronicotinic acid (Inter. 1) (1 equiv) was added ammonia (sufficient to prepare a 0.6M substrate solution in ammonia. The suspension was sealed in a pressure vessel that was then slowly heated to 130 ° C. It was noted that at this temperature a pressure of 18 bar was observed.This temperature and pressure were maintained for an additional 16 hours, after which the mixture was cooled to room temperature.The pressure vessel was opened and the reaction was poured in ice-cold water (1 reaction volume) The resulting solution was acidified to pH 1-2 using concentrated HCl that caused a precipitate to form.The acid mixture was allowed to warm to room temperature and stirred from it form for an additional 30 minutes, then the suspension was extracted with diethyl ether (3 x 400 ml), the combined organic extracts were then filtered and the filtrate was concentrated under vacuum to give a white solid that was further dried over P2O5 to give the title compound (90% yield and 96% purity) in a suitably pure form to be used without any further purification. m / z (LC-MS, ESP): 173 [M + H] + R / T = 3.63 min.

b) 2-amino-6-chloronicotinamide (Inter. 3)

To a 0.3 M solution of 2-amino-6-chloronicotinic acid (Inter. 2) (1 equiv) in anhydrous THF, under an inert atmosphere, thionyl chloride (3.3 equiv) was added in a dropwise manner. gout. The reaction mixture was stirred at room temperature for 2 hours. After this time, the reaction was concentrated in vacuo to give a crude yellow solid residue. The crude solid was dissolved in THF (equal to the initial reaction volume) and concentrated in vacuo to give a yellow solid residue. The residue was dissolved once more in THF and concentrated as before to give a solid residue which was then dissolved in THF (to give a 0.3 M solution) and ammonia gas was bubbled through the solution for 1 hour. The resulting precipitate was filtered off and the filtrate was concentrated in vacuo to give a yellow precipitate that was triturated with water at 50 ° C and then dried to give the title compound (92% yield, 93% purity), suitably clean. to be used without

c) 7-Chloro-1H-pyrido [2,3-d] pyrimidine-2,4-dione (Inter. 4)

To a stirred solution (0.06 M) of 2-amino-6-chloronicotinamide (Inter. 3) (1 equiv) in anhydrous toluene under an inert atmosphere was added oxalyl chloride (1.2 equiv) in a dropwise manner. gout. The resulting mixture was then heated at reflux (115 ° C) for 4 hours, after which it was cooled and stirred for an additional 16 hours. The crude reaction mixture was then concentrated to half its volume in vacuo and filtered to give the desired product in a suitably pure form (95% yield, 96% purity) to be used without any further purification. m / z (LC-MS, ESP): 196 [M + H] - R / T = 3.22 min.

d) 2,4,7-trichloro-pyrido [2,3-d] pyrimidine (Inter. 5)

To a stirred 0.5 M suspension of the dione (Inter. 4) (1 equiv) in anhydrous toluene under an inert atmosphere, diisopropylethylamine (3 equiv) was slowly added. The reaction mixture was then heated to 70 ° C for 30 minutes and then cooled to room temperature before the addition of POCl3 (3 equivalents). Then, the reaction was heated to 100 ° C for 2.5 hours before being cooled and concentrated in vacuo to give a crude suspension which was then suspended in EtOAc and filtered through a thin pad of Celite ™. The filtrate was concentrated in vacuo to give a brown oil that was dissolved in CH2Cl2 and stirred on silica gel for 30 minutes. After this time, the silica was filtered off, the filtrate was concentrated and the crude residue was purified by flash chromatography (SiO2) to give the title compound in an analytically pure form (yield 48%, purity 96 %). m / z (LC-MS, ESP): 234 [M + H] + R / T = 4.21 min.

e) 4-amino-2,7-dichloropyridopyrimidines (Inter. 6)

To a stirred and cooled solution (0-5 ° C) (0.1 M) of the trichloro substrate (Inter. 5) (1 equiv) in CH2Cl2 was added diisopropylethylamine (1 equiv) in a dropwise manner. The appropriate amine (1 equiv) was then added to the reaction mixture in portions over the period of 1 hour. The solution was kept at room temperature with stirring for an additional 1 hour before washing the mixture with water (2 x 1 reaction volume). The aqueous extracts were combined and extracted with CH2Cl2 (2 x 1 reaction volume). The organic extracts were then combined, dried (sodium sulfate), filtered and concentrated in vacuo to give an oily residue that solidified after prolonged drying. The solid was triturated with diethyl ether and then filtered and the cake was washed with cold diethyl ether to leave the title compound in a clean form suitable for use without further purification. Inter. 6a: 2,7-dichloro-4-morpholin-4-yl-pyrido [2,3-d] pyrimidine; R4 = morpholino; (92% yield, 90% purity) m / z (LC-MS, ESP): 285 [M + H] + R / T = 3.90 min. Inter. 6b: 2,7-dichloro-4 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) -pyrido [2,3-d] pyrimidine; R4 = (2R, 6S) -2,6-dimethyl-morpholino; (99% yield, 90% purity) m / z (LC-MS, ESP): 313 [M + H] + R / T = 4.39 min.

f) 2,4-diamino-7-chloropyridopyrimidines (Inter. 7)

To a solution (0.2 M) of the appropriate dichloro substrate (Inter. 6a or 6b) (1 equiv) in anhydrous dimethylacetamide under an inert atmosphere was added diisopropylethylamine (1 equiv) followed by the appropriate amine (1 equiv). The resulting mixture was heated for 48 hours at 70 ° C before being cooled to room temperature. The reaction was diluted with CH2Cl2 (1 reaction volume) and then washed with water (3 x 1 reaction volume). The organic extract was concentrated in vacuo to give a syrup that was dissolved in EtOAc (1 reaction volume) and washed with saturated brine solution before drying (sodium sulfate) and concentrated in vacuo to give an oil. The crude residue was purified by flash chromatography (SiO2, eluted with EtOAc: Hex (7: 3) to (1: 1)) to give the title compound as a yellow solid that was suitably clean for use without additional purification. Inter. 7a: 7-chloro-2 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) -4-morpholin-4-yl-pyrido [2,3-d] pyrimidine; R4 = morpholine; R2 = cisdimethylmorpholine; (45% yield, 85% purity) m / z (LC-MS, ESP): 348 [M + H] + R / T = 4.16 min. Inter. 7b: 7-chloro-4- (2-methyl-piperidin-1-yl) -2-morpholin-4-yl-pyrido [2,3-d] pyrimidine; R4 = morpholine; R2 = 2 methylpiperidine; (57% yield, 95% purity) m / z (LC-MS, ESP): 348.1 [M + H] + R / T = 3.42 min. Inter. 7c: 7-chloro-4 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) -2 - ((S) -3-methyl-morpholin-4-yl) pyrido [2,3 -d] pyrimidine (intermediate compound for compound 11k); R4 = cis-dimethylmorpholine; R2 = (S) -3-methyl-morpholine; (48% yield, 90% purity) m / z (LC-MS, ESP): 378 [M + H] + R / T = 3.74 min. Inter. 7d: 7-chloro-2 ((S) -3-methyl-morpholin-4-yl) -4-morpholin-4-yl-pyrido [2,3-d] pyrimidine (intermediate 11a); R4 = morpholine; R2 = (S) -3-methyl-morpholine; (70% yield, 97% purity) m / z (LC-MS, ESP): 350 [M + H] + R / T =

g) 4-amino-7-aryl-2-chloropyridopyrimidines (Inter. 8)

To a solution (0.09 M) of the appropriate boronic acid or ester (1 equiv) in water (1 volume) was added the appropriate 2,7-dichloro-4-amino-pyridopyrimidine (1 equiv) (Inter. 6a or 6b), potassium carbonate (2.5 equiv) and acetonitrile (1 volume). The mixture was degassed by bubbling nitrogen through the solution, while treating by ultrasound for 15 minutes before the addition of tetrakis (triphenylphosphine) palladium (0.03 equiv). The mixture was degassed for an additional 5 minutes before heating under an inert atmosphere at 95 ° C for 2 hours. After completion, the reaction was cooled to room temperature and filtered in vacuo. The filtrate was concentrated in vacuo to give a solid residue that was dissolved in CH2Cl2 (1 volume) and washed with water (1 volume). The organic extract was then dried (MgSO4), filtered and concentrated in vacuo to give an amorphous solid that was triturated with Et2O (to give the desired product as a fine powder. Inter. 8a (R4 = morpholine, R7 = 4 -chlorophenyl) 2-chloro-7- (4-chloro-phenyl) -4-morpholin-4-yl-pyrido [2,3-d] pyrimidine; 1 H-NMR (300 MHz, CDCl 3 solvent δ ppm 8.29- 7.96 (m, 2H), 7.75 (d, J = 8.70 1Hz, 1H), 7.54-7.21 (m, 2H), 5.29 (s, 1H), 3.91 (m, 8H).

Example 1

R7 = aryl (Examples 1a - bx)

The appropriate chlorine substrate (Inter. 7a-e) (1 equiv) was dissolved in a toluene / ethanol solution (1: 1) (0.02 M). Then sodium carbonate (2 equiv) and the appropriate boronic acid (1 equiv) were added, followed by tetrakis (triphenylphosphine) palladium (0.1 equiv). The reaction vessel was sealed and the mixture was exposed to microwave radiation (140 ° C, stipulation of media absorption) for 30 minutes. After completion, the samples were filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the compounds listed below.

Example 1bj: -1H-NMR (300 MHz, CDCl3 solvent) δ ppm 8.72 (s, 1H), 8.46 (d, J = 8.70), 8.37 (d, 2.34 Hz, 1H ), 5 8.17 (dd, J = 8.60, 2.34 Hz, 1H), 8.02 (d, J = 8.77 Hz, 1H), 7.14 (d, J = 8.68 Hz, 1H), 4.59 (s, 1H), 3.95-3.71 (m, 8H), 2.50 (m, 3H).

Reference compound 2

10 R7 = Amino substituted (Reference compounds 2a-2bg)

To a solution of the appropriate chlorine substrate (Inter. 7a-e) (1 equiv.) In 1,4-dioxane (0,04M) was added amine (1,2 equiv.), Cesium carbonate (2 equiv) , Xantphos ™ and tris (dibenzylidenacetone) dipaladium (0). The reaction vessel was sealed and exposed to heating under the influence of microwave radiation (stipulation of

15 normal absorption, 150 ° C, 20 minutes). The crude reaction mixture was then purified by preparative HPLC to give the compounds listed below.

Reference compound 2bf: 1 H-NMR (300 MHz, CDCl 3 solvent δ ppm 8.50 (s, 1 H), 8.05 (d, J = 9.32 Hz, 1 H), 5. 7.10 (d, J = 9.37 Hz, 1H), 4.46 (d, J = 12.95 Hz, 1H), 3.82-3.50 (m, 11H), 3.31 (s, 1H), 2.70- 2.43 (m, 4H), 1.17 (d, J = 6.30 Hz, 1H)

Reference compound 3

10 R7 = NH2 (Reference compound 3a-b)

To a solution of the appropriate chlorine substrate (Inter. 7a-e) (1 equiv) in isopropanol (0.6 M) was added concentrated aqueous ammonia solution (5 volumes). The reaction vessel was sealed and heated under the influence of microwave radiation (high absorption setting, 150 ° C, 30 minutes). The reaction mixture was then cooled,

15 diluted with water (3 volumes) and extracted with EtOAc (2 x 3 volumes). The combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to give a crude residue that was further purified by flash chromatography (SiO2) (eluent - EtOAc / MeOH (95: 5) to (9: 1 )) to give the compounds listed below in an analytically pure form.

R7 = Urea (Reference compound 4a-i)

To a solution (0.02 M) of the appropriate amine substrate (eg Reference compounds 3a or 3b) (1 equiv) in anhydrous THF was added the appropriate isocyanate (2 equiv). The reaction vessel was sealed and heated to 60 ° C for 1 hour. The crude reaction mixture was then purified by preparative HPLC to give the compounds listed below.

Reference compound 5

5 R7 = Amido (Reference compounds 5a-g)

To a solution (0.02 M) of the appropriate amine substrate (eg Reference compounds 3a or 3b) (1 equiv) in anhydrous CH2Cl2 was added triethylamine (2 equivalents) and the appropriate acid chloride (2 equivalents) . The mixture was stirred at room temperature for 1 hour, after which the solvent was allowed to evaporate under pressure.

Atmospheric and the crude residue was then purified by preparative HPLC to give the compounds listed below.

Reference compound 6

R7 = Sulfonamido

To a solution (0.02 M) of the appropriate amine substrate (eg Reference compounds 3a or 3b) (1 equiv) in anhydrous CH2Cl2 was added triethylamine (2 equiv) and the propylene sulfonyl chloride (2 equiv ). The mixture was stirred at room temperature for 1 hour, after which the solvent was allowed to evaporate at atmospheric pressure and the crude mixture was purified by preparative HPLC to give the desired product.

R7 = Alkoxy

To a solution of the appropriate chlorine substrate (eg Inter. 7a-e) (1 equiv) in the appropriate alcohol solvent (0.16 M) was added potassium carbonate (5 equiv). The reaction vessel was sealed and heated under the influence of microwave radiation (160 ° C, high absorption setting, 30 minutes). Then, the reaction mixture was concentrated to dryness and purified by preparative HPLC to give the desired product.

Example 8: R7 = 4-alkoxy-3-aminomethyl-phenyl (Examples 8a - 8bh)

To a 0.1 M solution of Example 1a (1 equiv) in CH2Cl2 was added Et3N (1 equiv.), Followed by methanesulfonyl chloride (1.1 equiv.) Which was added dropwise. The reaction was stirred under an inert atmosphere for 90

20 minutes, after which it was quenched with water (2 x 1 volume), the organic extract was separated and dried (MgSO4), filtered and concentrated in vacuo. Then, the crude yellow gum was diluted in diethyl ether and stirred vigorously. The resulting yellow precipitate was then collected by filtration to give the title compound (98%) in a clean form suitable for use without further purification.

7- (3-Chloromethyl-4-methoxy-phenyl) -2 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) -4-morpholin-4-yl-pyrido [2,3 -d] pyrimidine; (98.9% yield, 94% purity) m / z (LC-MS, ESP): [M + H] + R / T = 3.98 min was not ionized.

Example 9

5 R2 = aryl; R7 = aryl (Examples 9a - 9ae)

To the appropriate 2-chloro-pyrido-pyridopyridine (Inter. 8a) (1 equiv) in acetonitrile / water (1: 1 - 0.025 M ratio) was added the appropriate boric acid or ester (1 equiv), potassium carbonate (3 , 5 equiv) and tetrakis (triphenylphosphine) palladium

10 (0.05 equiv). The mixture was heated to 95 ° C under an inert atmosphere for 2 hours, after which it was cooled to room temperature. The reaction was then filtered through a thin silica pad, which was washed with a 1: 1 mixture of MeOH / CH2Cl2 (1 volume), was run under vacuum and then purified by preparative HPLC to give the desired product ( 9a-9ae).

Example 10

Enzymatic assay

For assays of the mTOR enzymatic activity, the mTOR protein was isolated from the cytoplasmic extract of HeLa cells by immunoprecipitation, and the activity was essentially determined as previously described using recombinant PHAS-1 as a substrate (ref. 21).

The following compounds were tested in this test: - 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1j, 1k, 1l, 1l, 1m, 1n, 1o, 1p, 1q, 1r, 1s, It, 1u, 1v, 1w, 1x, 1y, 1z, 1aa, 1ab, 1ac, 1ad, 1ae, 1af, 1ag, 1ah, 1ai, 1aj, 1ak, 1al, 1am, 1an, 1ao, 1ap, 1aq, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2p, 2q, 2r, 2s, 2t, 2u, 2v, 2w, 2x, 2y, 2z, 2aa, 2ab, 2ac, 2ad, 2ae, 2af, 2ag, 2ah, 2ai, 2aj, 2ak, 2al, 2am, 2an, 2ao, 2ap, 2aq, 2ar, 2as, 2at, 2au, 2av, 2aw, 2ax, 2ay, 2az, 2ba, 2bb, 2bc, 2bd, 2be, 2bf, 2bg, 8bm, 8bn, 4a, 5a, 5b, 5c, 5d, 5e, 5f, 5g, 6, 7, 8a, 8b, 8c, 8d, 8e, 8f, 8g, 8h, 8i, 8j, 8k, 8l, 8m, 8n, 8o, 8p, 8q, 8r, 8s, 8t, 8u, 8v, 8w, 8x, 8y, 8z, 8aa, 8ab, 8ac, 8ad, 8ae, 8af, 8ag, 8ah, 8ai, 8aj, 8ak, 8al, 8am, 8an, 8ao, 8ap, 8aq, 8ar, 8as, 8at, 8au, 8av, 8aw, 8ax, 8az, 8ba, 8bb, 8bc, 8bd, 8be, 8bf and 8bg.

All compounds tested exhibited IC50 values against mTOR less than 10 µm. The following compounds exhibited IC50 values against mTOR less than 1 µm:

1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, 1st, It, 1st, 1st, 1st, 1st, 2nd, 1st, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2nd, 2bd, 2be, 2c, 2e, 2g, 2h, 2i, 2j, 2k, 2n, 2p, 2q, 2t, 2u, 2z, 2bi, 3a, 3b, 5c, 8p, 8q, 8r, 8s, 8t, 8u, 8v, 8w, 8x, 8y, 8ae, 8af, 8am, 8ao, 8at, 8au, 8ay, 8az, 8ba, 8bd and 8bf, exhibiting the following compound IC50 values against mTOR less than 100 nM: 1a, 1b, 1d , 1e, If, 1g, 1i, 1k, 1l, 1m, In, 1o, 1p, 1q, 1bb, 1bc, 2ba, 8a, 8b, 8c, 8d, 8e, 8f, 8g, 8h, 8i, 8j, 8k , 8l, 8m, 8n, 8o, 8aa, 8ab, 8ac, 8ad, 8ag, 8ah, 8ai, 8aj, 8ak, 8al, 8an, 8ap, 8aq, 8ar, 8as, 8av, 8aw, 8ax, 8bb, 8bc, 8be , 8bg. For example, compound 1k has an IC50 of 0.043 µM.

Example 11

Alternative Enzymatic Assay

The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) for a C-terminal mTOR truncation that encompasses amino acid residues 1362 to 2549 of mTOR (EMBL Accession No. L34075) was expressed stably in the form of a FLAG-labeled fusion in HEK293 cells as described by Vilella-Bach et al., Journal of Biochemistry, 1999, 274, 4266-4272. The FLAG tag cell line, HEK293, stable against mTOR (1362-2549) was routinely maintained at 37 ° C with 5% CO2 to a confluence of 70-90% in Dulbecco-modified Eagle's growth medium (DMEM; Invitrogen Limited, Paisley, United Kingdom, Catalog No. 41966-029) containing 10% heat-inactivated fetal calf serum (FCS; Sigma, Poole, Dorset, United Kingdom, Catalog No. F0392), 1% L-Glutamine (Gibco, Catalog No. 25030024) and 2 mg / ml of geneticin (G418 sulfate; Invitrogen Limited, United Kingdom, Catalog No. 10131-027). After expression in the mammalian HEK293 cell line, the expressed protein was purified using the FLAG epitope tag using conventional purification techniques.

Test compounds were prepared in the form of 10 mM standard solutions in DMSO and diluted in water as required to give a range of final test concentrations. Aliquots (2 µl) of each of the compound dilutions were placed in a well of a low volume white polystyrene (LV) plate of 384 Grainer wells (Greiner Bio-one). A mixture of 30 µl of recombinant purified mTOR enzyme, 1 µM biotinylated peptide substrate (biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-Tyr-Val-Ala- Pro-Ser-Val-Leu-Glu-Ser-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 enzymatic activity using 5% DMSO instead of test compound. Control wells that produced a minimum signal corresponding to a totally inhibited enzyme were created by adding EDTA (83 mM) instead of test compound. These test solutions were incubated for 2 hours at room temperature.

Each reaction was stopped by adding 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 p70 S6 kinase (T389), 1A5 monoclonal antibody (Cell Signaling Technology, Catalog No. 9206B) and AlphaScreen Streptavidin donor beads and A protein acceptors (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 that arose from the excitation with laser light at 680 nm were read using a Packard Envision instrument.

The biotinylated phosphorylated peptide is formed in situ as a result of mTOR-mediated phosphorylation. The biotinylated phosphorylated peptide that is associated with AlphaScreen Streptavidin donor beads forms a complex with monoclonal antibody 1A5 kinase p70 S6 (T389) which is associated with AlphaScreen protein A acceptor beads. After excitation with laser light at 680 nm, the donor pearl complex: acceptor pearl produces a signal that can be measured. Therefore, the presence of the mTOR kinase activity results in an assay signal. In the presence of an mTOR kinase inhibitor the signal intensity is reduced. Inhibition of the mTOR enzyme for a given test compound was expressed as an IC50 value. The following compounds were screened in this assay: 1bd, 1be, 1bk, 1bl, 1bm, 1bn, 1bo, 1bp, 1bq, 1br, 1bs, 1bt, 1bu, 1bv, 1bw, 1bx, 2bf, 9a, 9b, 9c, 9d , 9e, 9f, 9g, 9i, 9j, 9m, 9n, 9o, 9p, 9q, 9r, 9s, 9t, 9u, 9v, 9w, 9x, 9y, 9z, 9ab, 9ac, 9ad and 9ae.

All compounds tested were exhibited IC50 values against mTOR less than 10 µm. The following compounds exhibited IC50 values against mTOR less than 1 µm: 1bk, 1bm, 1bn, 1bo, 1bp, 1bq, 1br, 1bs, 1bt, 1bu, 9m, 9n, 9p, 9r, 9aa and 9ad, exhibiting the following compounds IC50 values versus mTOR less than 300 nM: 1bd, 1be, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9ae, 9l, 9j, 9k, 9i, 9h, 1bj, 1bi, 1bh, 1bg and 1bf. For example, compound 1b has an IC50 of 0.057 µM.

Example 12

Cell Proliferation Assay (GI50)

Cell growth was assessed using the sulforrodamine B (SRB) assay (A). T47D cells (ECACC, 85102201) were routinely passed in RPMI (Invitrogen, 42401018) plus 10% fetal calf serum (FCS), 1% L-glutamine (Gibco, BRL, 25030) to a confluence no greater than 80 %. To face the assay, T47D cells were seeded at a rate of 2.5 x103 cells / well in 90 µl of RPMI plus 10% fetal calf serum, 1% L-glutamine in 96-well plates (Costar, 3904) and they were incubated at 37 ° C (+ 5% CO2) in a humidified incubator. Once the cells had adhered completely (typically after 4-5 hours of incubation), the plate was removed from the incubator and 10 µL of the diluent was added to the control wells (A1-12 and B112). The compound was prepared in a six-point semi-logarithmic dilution at 10x the final concentration required,

p. ex. for a 6-point interval of 30 µM, up to 100 nM in semi-logarithmic stages, the dilution started at 300 µM on the starting plate. The dosage was completed by the addition of 10 µL of compound at the highest concentration to C1-12 through the lowest concentration H1-12. Then, the plates were incubated for 120 hours before the SRB analysis.

After completion of the incubation, the media were removed and the cells were fixed with 100 µl of 10% (w / v) ice cold trichloroacetic acid. The plates were incubated at 4 ° C for 20 minutes and then washed four times with water. Then, each of the cell wells was stained with 100 µl of 0.4% (w / v) SRB (Sulforrodamine B, Sigma, Poole, Dorset, UK, catalog number S-9012) in acetic acid at 1% for 20 minutes before washing four times with 1% acetic acid. Then, the plates were dried for 2 hours at room temperature. The dye from the stained cells was solubilized by the addition of 100 µl of 10 mM Tris base in each of the wells. The plates were gently shaken and left at room temperature for 30 minutes before measuring the optical density at 564 nm in a Microquant microtiter plate reader. The inhibitor concentration that induces a 50% reduction in growth (GI50) was determined by analysis of the staining intensity of the treated cells as a percentage of the control wells vehicles using the Excelfit software.

(A) Skehan, P., Storung, R., Scudiero, R., Monks, A., McMahon, J., Vistica, D., Warren, J T., Bokesch, H., Kenny, S. and Boyd , MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 82, 1107-1112.

All compounds tested tested exhibited GI50 values less than 10 µM.

The following compounds exhibited GI50 values less than 1 µM 8c, 8e, 8h, 8m, 8n, 8o, 8p, 8q, 8s, 8v, 8w, 8x, 8y, 8z, 8aa and 8ac, showing the following compounds GI50 values less than 300 nM: 1g, 8a, 8b, 8d, 8f, 8g, 8i, 8k, 8l, 8r, 8t, 8u, 8ab, 8ad, 8ae, 8af, 8ag, 8ah, 8ai, 8aj, 8ak, 8al, 8am, 8an , 8ao, 8ap, 8aq, 8ar, 8as, 8at, 8au, 8av, 8aw, 8ax, 8ay, 8az, 8ba, 8bb, 8bd, 8be, 8bf and 8bg: For example, compound 1r has a GI50 of 0.232 µM.

Example 13

In vitro phospho-Ser473 Akt assay

This assay determines the ability of test compounds to inhibit phosphorylation of serine 473 in Akt as evaluated using Acumen Explorer technology (Acumen Bioscience Limited), a plate reader that can be used to quickly quantify image characteristics generated by laser scanning .

A line of human breast adenocarcinoma cells MDA-MB-468 (LGC Promochem, Teddington, Middlesex, United Kingdom, Catalog No. HTB-132) was routinely maintained at 37 ° C with 5% CO2 up to 70-90% confuence in DMEM containing 10% heat inactivated FCS and 1% L-glutamine.

For the assay, cells were detached 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 1.7x105 cells per ml. Aliquots (90 µl) were seeded in each of the 60 inner wells of a black Packard 96-well plate (Perkin Elmer, Boston, MA, USA; Catalog No. 6005182) to give a density of ~ 15,000 cells per well. Aliquots (90 µl) of the 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 test compounds and incubated for 2 hours at 37 ° C with 5% CO2. The test compounds were prepared as 10 mM standard solutions in DMSO and serially diluted as required with growth media to give a range of concentrations that were 10 times the required final test concentrations. Aliquots (10 µl) of each of the dilutions of the compound were placed in a well (in triplicate) to give the final required concentrations. As a minimum response control, each plate contained wells with a final concentration of 100 µM of LY294002 (Calbiochem, Beeston, United Kingdom, Catalog No. 440202). As a maximum response control, the wells contained 1% DMSO instead of test compound. After incubation, the contents of the plates were fixed by treatment with a 1.6% aqueous formaldehyde solution (Sigma, Poole, Dorset, United Kingdom, No. All subsequent aspiration and washing steps were carried out using a Tecan 96-well plate washer (suction speed 10 mm / s) The fixing 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 buffer consisting of a mixture of 0.5% PBS and Tween-20. "Permeabilization" was removed and 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% dried skim milk ["Marvel" (registered trademark); Premier Beverages, Stafford, Great Britain] 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 rabbit anti-phospho-Akt antibody solution (Ser473) (50 µl) per well; Cell, Signaling, Hitchin,

Herts, United Kingdom, Catalog No. 9277) that had been diluted in the 1: 500 ratio in "block" buffer. The

cells were washed three times in a mixture of PBS and 0.05% Tween-20. Subsequently, the cells are incubated for 1 hour at room temperature with goat anti-rabbit IgG labeled with Alexafluor488 (50 µl per well; Molecular Probes, Invitrogen, Limited, Paisley, United Kingdom, Catalog No. A11008) that had been diluted in the 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 and the plates sealed with black plate sealants and the fluorescence signal was detected and analyzed.

The fluorescence dose response data obtained with each of the compounds was analyzed, and the degree of inhibition of serine 473 in Akt was expressed as an IC50 value. The following compounds were tested and exhibited a cellular IC50, measured by pAkt, less than 25 µM: 1bj, 1bd, 1bh, 1bi, 9j, 9a, 9aa, 9r, 9d, 9f, 9e, the following compounds displaying a cellular IC50, measured by pAkt, less than 2.5 µM: 1br, 1bg, 1be, 9l, 9n, 9k, 9h, 9g, 9m and 9i. For example, compound 9l has a IC50 pAkt 2.2 µM.

Reference List

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29) "Handbook of Pharmaceutical Excipients", 2nd edition, 1994.

Claims (11)

1.- A compound of formula I: where: X8 is N, and X5 and X6 are CH; R7 is a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxyl, nitro, Cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C320 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1- alkyl 7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido acyloxy thioether Sulfoxide, sulfonyl, thioamido and sulfonamino); RN3 and RN4, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and 20 sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3 cycloalkenyl -7, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, sulfoxide, sulfonyl, thioamido and sulfonamino); R2 is selected from NRN5RN6, a C5-20 heteroaryl group optionally substituted with one or more groups 25 selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl , C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro , cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C27 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester amido amino Acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), and a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1- alkyl 7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido , acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, alkyl C1-7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), wherein RN5 and RN6 are independently selected from H, a C1-7 alkyl group, a C5-20 heteroaryl group and a C5-20 aryl group , or RN5 and RN6, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, in which each of C1-7 alkyl, C5-20 heteroaryl, C5-20 aryl or ring heterocyclic is 40 optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3 heterocyclyl -20, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups Selected from halo, hydroxy, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a pharmaceutically salt thereof, and wherein "C5-20 aryl," as used herein, belongs to a monovalent moiety obtained by separating an atom from 50 hydrogen of an aromatic ring atom of a C5-20 aromatic compound, said compound having a ring, or two or more rings (eg, condensed), and having 5 to 20 ring atoms, and wherein at less one of said or said rings is an aromatic ring, and in which the ring atoms may include one or more heteroatoms, which include but are not limited to oxygen, nitrogen and sulfur; "alkyl", as used herein, belongs to a monovalent moiety, obtained by separating a hydrogen atom from a carbon atom of a hydrocarbon compound having 1 to 20 carbon atoms (unless specified in another mode), which can be aliphatic or alicyclic, and which can be saturated or unsaturated (eg partially unsaturated, totally unsaturated); "alkenyl", as used herein, belongs to an alkyl group having one or more carbon-carbon double bonds; "alkynyl", as used herein, belongs to an alkyl group having one or more triple carbon-carbon bonds; "cycloalkyl", as used herein, belongs to an alkyl group which is also a group cyclyl; that is, a monovalent moiety obtained by separating a hydrogen atom from an atom of the alicyclic ring of a carbocyclic ring of a carbocyclic compound, a carbocyclic ring that may be saturated or unsaturated (eg partially unsaturated, totally unsaturated), remainder having 3 to 20 carbon atoms (unless otherwise specified), including 3 to 20 ring atoms; "ether", as used herein, belongs to a group -OR, in where R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "acyl", as used herein, belongs to a group -C (= O) R, in where R is H, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "é ster ", as used herein, belongs to a group -C (= O) OR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "amido", as used herein, belongs to a group -C (= O) NR1R2, wherein R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or an aryl group C5-20, or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having 4 to 8 ring atoms; "amino", as used herein, belongs to a group -NR1R2, wherein R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having 4 to 8 ring atoms; "acylamido", as used herein, belongs to a group -NR1C (= O) R2, wherein R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5- aryl group 20, R2 is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, or R1 and R2 can form, together with the atoms to which they are attached, a succinimidyl, maleimidyl group and phthalimidyl; "ureido", as used herein, belongs to a group -N (R1) CONR2R3, wherein R2 and R3 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5 aryl group -20, or R2 and R3, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having 4 to 8 ring atoms, and R1 is hydrogen, a C1-7 alkyl group, a C3 heterocyclyl group -20 or a C5-20 aryl group; "acyloxy", as used herein, belongs to a group -OC (= O) R, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "thioether", as used herein, belongs to a group -SR, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "sulfoxide", as used herein, belongs to a group -S (= O) R, wherein R is a C17 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "sulfonyl", as used herein, belongs to a group -S (= O) 2R, wherein R is a C17 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "thioamido", as used herein, belongs to a group -C (= S) NR1R2, wherein R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or an aryl group C5-20, or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having 4 to 8 ring atoms; "sulfonamino", as used herein, belongs to a group -NR1S (= O) 2R, wherein R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group , and R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; and with the proviso that when R2 is unsubstituted morpholino, RN3 and RN4, together with the nitrogen atom to which they are attached, form an unsubstituted morpholino, R7 is unsubstituted phenyl, and when R2 is unsubstituted piperidinyl, RN3 and RN4, together with the nitrogen atom to which they are attached, form an unsubstituted piperidinyl, R7 is unsubstituted phenyl. 2. A compound according to claim 1, wherein R7 is a phenyl group optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl , C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide , sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- cycloalkyl 7, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamide, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), and wherein the ring heteroatoms of any of the C5-20 heteroaryl or C3-20 heterocyclyl group are selected from nitrogen, oxygen and sulfur, and wherein "C5-20 aryl," as used herein, belongs to a monovalent moiety obtained by separating a hydrogen atom from an aromatic ring atom from a C5-20 aromatic compound, said compound having a ring, or two or more rings (p. condensates), and having 5 to 20 ring atoms, and wherein at least one of said ring or rings is an aromatic ring, and in which the ring atoms may include one or more heteroatoms, which include but not they are limited to oxygen, nitrogen and sulfur; "alkyl", as used herein, belongs to a monovalent moiety, obtained by separating a hydrogen atom from a carbon atom of a hydrocarbon compound having 1 to 20 carbon atoms (unless specified in another mode), which can be aliphatic or alicyclic, and which can be saturated or unsaturated (eg partially unsaturated, totally unsaturated); "alkenyl", as used herein, belongs to an alkyl group having one or more carbon-carbon double bonds; "alkynyl", as used herein, belongs to an alkyl group having one or more triple carbon-carbon bonds; "cycloalkyl", as used herein, belongs to an alkyl group which is also a group cyclyl; that is, a monovalent moiety obtained by separating a hydrogen atom from an atom of the alicyclic ring of a carbocyclic ring of a carbocyclic compound, a carbocyclic ring that may be saturated or unsaturated (eg partially unsaturated, totally unsaturated), remainder having 3 to 20 carbon atoms (unless otherwise specified), including 3 to 20 ring atoms; "ether", as used herein, belongs to a group -OR, in where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "acyl", as used herein, belongs to a group -C (= O) R, where R is H, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "this er ", as used herein, belongs to a group -C (= O) OR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "amido", as used herein, belongs to a group -C (= O) NR1R2, wherein R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or an aryl group C5-20, or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having 4 to 8 ring atoms; "amino", as used herein, belongs to a group -NR1R2, wherein R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having 4 to 8 ring atoms; "acylamido", as used herein, belongs to a group -NR1C (= O) R2, wherein R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group , R2 is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, or R1 and R2 can form, together with the atoms to which they are attached, a succinimidyl, maleimidyl and phthalimidyl group; "ureido", as used herein, belongs to a group -N (R1) CONR2R3, wherein R2 and R3 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5 aryl group -20, or R2 and R3, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having 4 to 8 ring atoms, and R1 is hydrogen, a C1-7 alkyl group, a C3 heterocyclyl group -20 or a C5-20 aryl group; "acyloxy", as used herein, belongs to a group -OC (= O) R, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "thioether", as used herein, belongs to a group -SR, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "sulfoxide", as used herein, belongs to a group -S (= O) R, wherein R is a C17 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "sulfonyl", as used herein, belongs to a group -S (= O) 2R, wherein R is a C17 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "thioamido", as used herein, belongs to a group -C (= S) NR1R2, wherein R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or an aryl group C5-20, or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having 4 to 8 ring atoms; and "sulfonamino", as used herein, belongs to a group -NR1S (= O) 2R, wherein R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5- aryl group 20, and R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group. 4. A compound according to claim 2, wherein R7 is 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, hydroxymethyl-4-methoxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl , 3-hydroxyphenyl or a 3-hydroxymethylphenyl group. 5. A compound according to claim 1, wherein the compound is a compound of formula I (A): where: X8 is N, and X5 and X6 are CH; RN3 and RN4, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 atoms of the ring optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and Thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy thioether sulfoxide Sulfonyl, thioamido and sulfonamino); R2 is selected from NRN5RN6, a C5-20 heteroaryl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with One or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C27 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5- aryl 20, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), and a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5 heteroaryl -20, ether, acyl, 30 ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1 alkyl -7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), wherein RN5 and RN6 are independently selected from H, a C1-7 alkyl group, a C5-20 heteroaryl group and a C5-20 aryl group, or RN5 and RN6, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, in which each of C1-7 alkyl, C5-20 heteroaryl, C5-20 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl , C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and 40 sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3 cycloalkenyl -7, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); RO3  is selected from hydrogen or a C1-6 alkyl group, optionally substituted with one or more groups 45 selected from halo, hydroxy, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5- aryl 20, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C27 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); and RN10 is selected from C (= O) RC2, C (= S) RC3, SO2RS3, a C5-20 heteroaryl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino , acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C27 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), a C5-20 aryl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, alkenyl or C2-7, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy , thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl , C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C1-10 alkyl group, optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3 cycloalkyl -7, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl , thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C27 alkynyl, C3-7 cycloalkyl, C3 cycloalkenyl -7, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), in which RC2 and RC3 are selected from H, a C5-20 aryl group, a C5-20 heteroaryl group, a C1-7 or NRN11RN12 alkyl group, wherein RN11 and RN12 are independently selected from H, a C1-7 alkyl group, a C5 heteroaryl group -20, a C5-20 or RN11 and RN12 aryl group, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, in which each of C1-7 alkyl, C5- heteroaryl 20, C5-20 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carbo xi, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C1- alkyl 7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido , acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); and RS3 is selected from H, a C5-20 aryl group, a C5-20 heteroaryl group or a C1-7 alkyl group, wherein each of C1-7 alkyl, C5-20 heteroaryl or C5-20 aryl is optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl , C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5- heteroaryl 20, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a pharmaceutically acceptable salt thereof, and wherein "C5-20 aryl," as used herein, belongs to a monovalent moiety, obtained by separating a hydrogen atom from an aromatic ring atom from a C5 aromatic compound. -20, said compound having a ring, or two or more rings (eg condensed), and having 5 to 20 ring atoms, and wherein at least one of said rings is an aromatic ring, and in which the ring atoms may include one or more heteroatoms, which include, but are not limited to oxygen, nitrogen and sulfur; "alkyl", as used herein, belongs to a monovalent moiety, obtained by separating a hydrogen atom from a carbon atom of a hydrocarbon compound having 1 to 20 carbon atoms (unless specified in another mode), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (eg partially unsaturated, totally unsaturated); "alkenyl", as used herein, belongs to an alkyl group with one or more carbon-carbon double bonds; "alkynyl", as used herein, belongs to an alkyl group with one or more triple carbon-carbon bonds; "cycloalkyl," as used herein, belongs to an alkyl group that is also a cyclyl group; that is, a monovalent moiety, obtained by separating a hydrogen atom from an atom of the alicyclic ring of a carbocyclic ring of a carbocyclic compound, a carbocyclic ring that can be saturated or unsaturated (e.g. partially unsaturated, totally unsaturated), remainder that has 3 to 20 carbon atoms (unless specify otherwise), including 3 to 20 ring atoms; "ether", as used herein, belongs to a group -OR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "acyl", as used herein, belongs to a group -C (= O) R, where R is H, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "ester", as used herein, belongs to a group -C (= O) OR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "amido", as used herein, belongs to a group -C (= O) NR1R2, where R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 ring atoms; "amino", as used herein, belongs to a group -NR1R2, where R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 ring atoms; "acylamido", as used herein, belongs to a group -NR1C (= O) R2, where R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, R2 is a C1-7 alkyl group, a group C3-20 heterocyclyl or a C5-20 aryl group, or R1 and R2, together with the atoms to which they are attached, form a group succinimidyl, maleimidyl and phthalimidyl; "ureido", as used herein, belongs to a group -N (R1) CONR2R3, where R2 and R3 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R2 and R3, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 ring atoms, and R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "acyloxy", as used herein, belongs to a group -OC (= O) R, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "thioether", as used herein, belongs to a group -SR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "sulfoxide", as used herein, belongs to a group -S (= O) R, wherein R is a C17 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "sulfonyl", as used herein, belongs to a group -S (= O) 2R, wherein R is a C17 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "thioamido", as used herein, belongs to a group -C (= S) NR1R2, where R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring of 4 to 8 atoms of the ring; Y "sulfonamino", as used herein, belongs to a group -NR1S (= O) 2R, where R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, and R is a C1-7 alkyl group, a group C3-20 heterocyclyl or a C5-20 aryl group. 6. A compound according to any one of claims 1 to 5, wherein RN3 and RN4, together with the Nitrogen to which they are attached form a morpholino group. 7. A compound according to any one of claims 1 to 6, wherein R2 is NRN5RN6, wherein RN5 and RN6, together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 atoms of the ring which may be optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C320 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), and wherein the ring heteroatoms of any heteroaryl group C5-20, C3-20 heterocyclyl or heterocyclic ring containing between 3 and 8 ring atoms are selected from nitrogen, oxygen and sulfur, and where "C5-20 aryl", as used herein, belongs to a monovalent moiety, obtained by separating an atom of hydrogen of an aromatic ring atom of a C5-20 aromatic compound, said compound having a ring, or two or more rings (eg condensed), and having 5 to 20 ring atoms, and where at least one of said rings is an aromatic ring, and in which the ring atoms may include one or more heteroatoms, which they include, but are not limited to oxygen, nitrogen and sulfur; "alkyl", as used herein, belongs to a monovalent moiety, obtained by separating an atom from hydrogen of a carbon atom of a hydrocarbon compound having 1 to 20 carbon atoms (a unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (eg partially unsaturated, totally unsaturated); "alkenyl", as used herein, belongs to an alkyl group with one or more double bonds. carbon-carbon; "alkynyl," as used herein, belongs to an alkyl group with one or more triple bonds. carbon-carbon; "cycloalkyl," as used herein, belongs to an alkyl group that is also a cyclyl group; is that is, a monovalent moiety, obtained by separating a hydrogen atom from an atom of the alicyclic ring of a ring carbocyclic of a carbocyclic compound, carbocyclic ring that may be saturated or unsaturated (e.g. partially unsaturated, totally unsaturated), remainder that has 3 to 20 carbon atoms (unless specify otherwise), including 3 to 20 ring atoms; "ether", as used herein, belongs to a group -OR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "acyl", as used herein, belongs to a group -C (= O) R, where R is H, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "ester", as used herein, belongs to a group -C (= O) OR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "amido", as used herein, belongs to a group -C (= O) NR1R2, where R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 ring atoms; "amino", as used herein, belongs to a group -NR1R2, where R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 ring atoms; "acylamido", as used herein, belongs to a group -NR1C (= O) R2, where R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, R2 is a C1-7 alkyl group, a group C3-20 heterocyclyl or a C5-20 aryl group, or R1 and R2, together with the atoms to which they are attached, form a group succinimidyl, maleimidyl and phthalimidyl; "ureido", as used herein, belongs to a group -N (R1) CONR2R3, where R2 and R3 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R2 and R3, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 ring atoms, and R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "acyloxy", as used herein, belongs to a group -OC (= O) R, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "thioether", as used herein, belongs to a group -SR, where R is a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "sulfoxide", as used herein, belongs to a group -S (= O) R, wherein R is a C17 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "sulfonyl", as used herein, belongs to a group -S (= O) 2R, wherein R is a C17 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group; "thioamido", as used herein, belongs to a group -C (= S) NR1R2, where R1 and R2 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, they form a heterocyclic ring of 4 to 8 atoms of the ring; Y "sulfonamino", as used herein, belongs to a group -NR1S (= O) 2R, where R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, and R is a C1-7 alkyl group, a group C3-20 heterocyclyl or a C5-20 aryl group. 8. A compound according to claim 7, wherein R2 is selected from morpholino, thiomorpholino, piperidinyl, piperazinyl, homopiperazinyl and pyrrolidinyl, wherein each of morpholino, thiomorpholino, piperidinyl, piperazinyl, homopiperazinyl and pyrrolidinyl may be optionally substituted on the carbon with one or more methyl groups. 9. A compound according to claim 8, wherein R2 is  OR  OR . 10. A compound according to claim 1, selected from any of the following Examples (keep going) or pharmaceutically acceptable salts thereof. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 12. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use as a medicament. 13. The use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, without the conditions in the preparation of a medicament for treating a disease enhanced by mTOR inhibition.