ME01487B - PYRIDO-, PYRAZO- AND PYRIMIDOPYRIMIDINE DERIVATIVES AS mTOR INHIBITORS - Google Patents

Description

Description

This invention relates to compounds, pyrido-, pyrazo- and pyrimido-pyrimidine derivatives, which act as mTOR inhibitors.

Background of the invention

Growth factor/mitogen activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway ultimately leads to the key cell cycle and growth control regulator mTOR, the mammalian target of rapamycin molecule (alternatively referred to as FRAP (FKBP12 and Rapamycin Associated Protein), RAFT1 (Rapamycin and FKBP12 target 1), RAPT1 (rapamycin target 1) - all are derived from interaction with the FK-506-binding protein FKBP12, and SEP (sirolimus effector protein)). mTOR is a mammalian serine/threonine kinase with a size of approximately 289 kDa and is a member of the evolutionarily conserved eukaryotic TOR kinase (refs. 1-4). The mTOR protein is a member of the PI3-kinase-like kinase (PIKK) family of proteins due to its C-terminal homology (catalytic domain) with PI3-kinase and other family members, e.g. DNA-PKcs (DNA-dependent protein kinase), ATM (ataxia telangiectasia mutated gene). In addition to the catalytic domain at the C-terminus, mTOR contains the FKBP12/rapamycin binding domain (FRB) complex. At the N-terminus, up to 20 HEAT motifs (Huntingtin, EF3, alpha regulatory subunit for PP2A and TOR) were found, while more C-terminal FAT (FRAP-ATM-TRRAP) domains were found, and the extreme C-terminal ends of the protein on the additional FAT domain (FAT-C) (ref. 5,6).

TOR has been identified as a central regulator of cell growth (size) and proliferation, which is driven in part by translation initiation. TOR-dependent phosphorylation of S6-kinase (S6K1) enables the translation of ribosomal proteins involved in cell cycle progression (ref. 79). "Cap"-dependent translation is regulated by phosphorylation of eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP (PHAS-1)). This modification prevents PHAS-1 from binding to eIF4E, thereby allowing the formation of an active eIF4F translation complex (reviewed in refs. 10,11,12). Activation of these signaling elements is dependent on insulin, other growth factors, and nutrients, suggesting a gatekeeper role for mTOR in controlling cell cycle progression only under favorable environmental conditions. The PI3K/AKT signaling cascade lies upstream of mTOR and this has been shown to be deregulated in certain cancers resulting in growth factor-independent activation, for example, in cells lacking PTEN. mTOR lies in the control axis for this pathway and inhibitors of this kinase (eg, sirolimus (rapamycin or Rapamune™) and everolimus (RAD001 or Certican™)) are already approved for immunosuppression and drug-eluting stents (reviewed in refs. 13, 14). , and are now of special interest as new agents for cancer treatment.

Tumor cell growth results from deregulation of normal growth control mechanisms such as loss of tumor suppressor functions. One such tumor suppressor is phosphatase and tensin homolog deleted from chromosome ten (PTEN). This gene, also known as mutated in multiple advanced carcinomas (MMAC), has been shown to play a significant role in cell cycle arrest, and is the most mutated tumor suppressor after p53. Up to 30% of glioblastomas, endometrial cancers and prostate cancers have somatic mutations or deletions of this locus (ref. 15,16).

PI3K converts phosphatidylinositol 4,5, bisphosphate (PIP2) to phosphatidylinositol 3,4,5, triphosphate (PIP3) while PTEN is responsible for removing the 3' phosphate from PIP3 producing PIP2. PI3-K and PTEN act to maintain an appropriate level of PIP3 that recruits and therefore activates AKT (also known as PKB) and the downstream signaling cascade that is then initiated. In the absence of PTEN, regulation of this cascade is inappropriate, AKT becomes efficiently constitutively activated and cell growth is deregulated. An alternative mechanism for the deregulation of this cellular signaling process is the recent identification of a mutated form of the PI3K isoform, p110alpha (ref. 17). Apparently, the increased activity of this mutant is the result of an increase in PIP3 production, probably in its excess, which the function of PTEN can oppose. Increased signaling from PI3K therefore results in increased signaling of mTOR and thus, its downstream activators.

In addition to evidence linking mTOR to cell cycle regulation (from G1 to S-phase) and that inhibition of mTOR results in inhibition of these regulatory events, it has been shown that down-regulation of mTOR activity results in inhibition of cell growth (reviewed in refs. 7,18,19 ). A known mTOR inhibitor, rapamycin, potently inhibits the proliferation or growth of cells derived from a variety 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 cancer, and breast and prostate cancer (reviewed in ref. 20). Rapamycin is approved and in clinical use as an immunosuppressant, is successful in preventing organ rejection and has fewer side effects than previous therapies (ref. 20, 21). Inhibition of mTOR by rapamycin and its analogs (RAD001, CCI-779) is derived from the drug's prior interaction with the FK506 binding protein, FKBP12. Subsequently, the FKBP12/rapamycin complex then binds to the FRB domain of mTOR and inhibits downstream mTOR signaling.

Potent but non-specific inhibitors of PI3K, LY294002 and wortmannin, have also been shown to inhibit the kinase function of mTOR but act through targeting the catalytic domain of the protein (ref. 21). Furthermore, inhibition of mTOR function by small molecules targeting the kinase domain showed that kinase-dead mTOR cannot send upstream activation signals to the downstream effectors 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 substrate profile of mTOR rather than inhibiting its activity per se (ref. 23). Analysis of the interactions of mTOR with other cellular factors revealed that in addition to the mTOR-Raptor complex, there is also an mTOR-Rictor complex that represents mTOR (B) activity insensitive to rapamycin (Sarbassov et al. Current Biology, 2004, 14, 1296-1302). This activity probably accounts for the mismatch between mTOR dead kinase and the alteration of mTOR signaling by rapamycin and its derivatives. The discrepancy also identifies the possibility of a therapeutic advantage in inhibiting the direct catalytic activity of mTOR. It has been suggested that a catalytic inhibitor of mTOR may be a more effective antagonist of cancer cell proliferation and survival, and that rapamycin may be more useful in combination with agents that can compensate for its inability to fully disrupt pathway signaling (Choo and Blenis, Cancer Cell, 2006, 9 , 77-79; Hay, Cancer Cell, 2005, 8, 179-183). Therefore, it has been proposed that an mTOR inhibitor targeting the kinase domain may be a more effective mTOR inhibitor.

In addition to rapamycin's ability to induce growth inhibition (cytostasis) by its own action, rapamycin and its derivatives have been shown to potentiate the cytotoxicity of a number of chemotherapies including cisplatin, camptothecin, and doxorubicin (reviewed in ref. 20). Cell killing induced by potent ionizing radiation has also been observed after inhibition of mTOR (ref. 24). Experimental and clinical evidence has shown that rapamycin analogs provide evidence of efficacy in the treatment of cancer, alone or in combination with other therapies (see refs. 10, 18, 20). These findings suggest that pharmacological inhibitors of mTOR kinase should be of therapeutic value for the treatment of various forms of cancer including solid tumors such as carcinomas and sarcomas and leukemias and malignancies of the lymphatic system. In particular, mTOR kinase inhibitors should be of therapeutic value for the treatment of, for example, breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and bronchioalveolar cancer) and prostate cancer, and gallbladder cancer. tract, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testis, thyroid gland, uterus, cervix and vulva, and leukemia (including ALL and CML), multiple myeloma and lymphoma.

Renal cell carcinoma, in particular, has been identified as sensitive to the rapamycin derivative CCI-779, resulting in loss of VHL expression (Thomas et al. Nature Medicine, 2006, 12, 122127). Tumors that have lost the tumor suppressor promyelocytic leukemia (PML) have also been shown to be sensitive to mTOR inhibition by rapamycin as a consequence of dysregulation of the mTOR signaling pathway (Bemadi, Nature, 2006, 442, 779-785) and the use of mTOR kinase inhibitors in these diseases should be of therapeutic value. These later examples in addition to those for PTEN deficiency or PI3K mutation show where targeted approaches for using mTOR inhibitors can be used, and can be particularly effective due to the underlying genetic profile, but are not considered exclusive targets.

Recent studies have revealed a role for mTOR kinase in other diseases (Easton & Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551-564). Rapamycin has been shown to be a potent immunosuppressant to inhibit antigen-induced T cell proliferation, B cells and antibody production (Sehgal, Transplantation Proceedings, 2003, 35, 7S-14S) and thus mTOR kinase inhibitors may also be useful immunosuppressants. Inhibition of mTOR kinase activity may also be useful in the prevention of restenosis, that is, the control of unwanted proliferation of normal cells in the vasculature in response to the introduction of stents in the treatment of vascular disease (Morice et al., New England Journal of Medicine, 2002, 346, 1773-1780 ). Moreover, the Rapamycin analog, everolimus, can reduce the severity and incidence of cardiac allograft vasculopathy (Eisen et al., New England Journal of Medicine, 2003, 349, 847858). Increased mTOR kinase activity is associated with cardiac hypertrophy, which is of clinical importance as a major risk factor for heart failure, and is a consequence of increased cardiomyocyte cell size (Tee & Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37) . Therefore, in addition to cancer, mTOR kinase inhibitors are expected to be useful in the prevention and treatment of a wide range of diseases.

To date, the vast majority of mTOR pharmacology has focused on inhibiting mTOR via rapamycin or its analogs. However, as noted above, the only non-rapamycin agents reported to inhibit mTOR activity via a kinase domain targeting mechanism are the small molecules LY294002 and the natural product wortmannin (ref. 21).

EP0185259 (Dr Karl Thomae GMBH) discloses certain pteridines with valuable pharmacological properties, especially antithrombotics, and with the effects of inhibiting metastasis and inhibiting anti-tumor activity.

Summary of the invention

The inventors have identified compounds that are ATP-competitive inhibitors of mTOR, and are therefore non-rapamycin-like in their mechanism of action.

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

whereby:

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

wherein RN5 and RN6 are independently selected from the group consisting 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 where each C1-7alkyl, C5-20heteroaryl, C5-20aryl or heterocyclic ring is optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3 -7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido,

amino, acilamido, ureido, aciloksi, tioetar, sulfoksid, sulfonil, tioamido i sulfonamino),

or their pharmaceutically acceptable salt, and wherein

"C5-20 aryl" as used herein refers to a monovalent group obtained by removing a hydrogen atom from an aromatic ring atom of a C5-20 aromatic compound, said compound having one ring, or two or more rings (eg, fused), and has from 5 to 20 ring atoms, and wherein at least one of said rings is an aromatic ring and wherein the ring atoms may contain one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur;

"alkyl" as used herein refers to a monovalent group obtained by the removal of a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may to be saturated or unsaturated (eg partially unsaturated, fully unsaturated);

"alkenyl", as used herein, refers to an alkyl group having one or more carbon-carbon double bonds;

"alkynyl", as used herein, refers to an alkyl group having one or more carbon-carbon triple bonds;

"cycloalkyl", as used herein, refers to an alkyl group that is also a cyclic group; which is a monovalent group obtained by removing a hydrogen atom from an alicyclic ring atom from a carbocyclic ring of a carbocyclic compound, and said carbocyclic ring can be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated), said group has from 3 to 20 carbon atoms (except unless otherwise stated), including from 3 to 20 ring atoms;

"ether", as used herein, refers to an -OR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group;

"acyl", as used herein, refers to a -C(=O)R group, wherein R is H, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group;

"ester", as used herein, refers to a -C(=O)OR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group;

"amido", as used herein, refers to a -C(=O)NR1R2 group, 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 from 4 to 8 ring atoms;

"amino", as used herein, refers to a -NR^R2 group, 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 from 4 to 8 atoms in the ring;

"acylamido", as used herein, refers to a -NR1C(=O)R2 group, 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, C3-20 heterocyclyl group, or C5-20 aryl group, or R1 and R2 together with the atoms to which they are attached can form a succinimidyl, maleimidyl, and phthalimidyl group;

"ureido", as used herein, refers to a -N(R1)CONR2R3 group, wherein 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 R 3 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms, and R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group;

"acyloxy", as used herein, refers to the -OC(=O)R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclic group, or a C5-20 aryl group;

"thioether" as used herein refers to the -SR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclic group, or a C5-20 aryl group;

"sulfoxide" as used herein refers to the -S(=O)R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclic group, or a C5-20 aryl group;

"sulfonyl", as used herein, refers to the -S(=O)2R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclic group, or a C5-20 aryl group;

"thioamido", as used herein, refers to a -C(=S)NR1R2 group, 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 from 4 to 8 ring atoms;

"sulfonamino" as used herein refers to the -NR1S(=O)2R group, wherein R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclic group, or a C5-20 aryl group, and R is C1 -7 alkyl group, C3-20 heterocyclic group, or C5-20 aryl group; i

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 not unsubstituted phenyl, and when R2 is unsubstituted piperidinyl, RN3 and RN4 together with the nitrogen atom to which they are attached form unsubstituted piperidinyl , R 7 is not unsubstituted phenyl.

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

whereby:

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

wherein RN5 and RN6 are independently selected from the group consisting 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 where each C1-7alkyl, C5-20heteroaryl, C5-20aryl or heterocyclic ring is optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroethyl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3 -7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, 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 the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5 -20heteroaryl, 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, C5-20 heteroaryl optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol , or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl , C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), C5-20 aryl group per optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl , nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, 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 the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether , sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino) where RC2 and RC3 are selected from H , a C5-20 aryl group, a C5-20 heteroaryl group, a C1-7 alkyl group or NRNURN12, wherein RN11 and RN12 are independently selected from the group consisting of H, a C1-7 alkyl group, a C5-20 heteroaryl group, a C5-20 aryl group group or RN11 and RN12 together with the nitrogen to which they are attached form a heterocyclic ring containing between 3 and 8 ring atoms, where each C1-7alkyl, C5-20heteroaryl, C5-20aryl or heterocyclic ring is optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl , ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cydoalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, 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 C1-7alkyl, C5-20heteroaryl or C5-20aryl is optionally substituted with one or more groups selected from containing halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido,

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

and wherein "C5-20 aryl" as used herein refers to a monovalent group obtained by removing a hydrogen atom from an aromatic ring atom of a C5-20 aromatic compound, and said compound has one ring, or two or more rings (eg, condensed), and has from 5 to 20 ring atoms, and where at least one of said rings is an aromatic ring and where the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur;

"alkyl" as used herein refers to a monovalent group obtained by the removal of a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may to be saturated or unsaturated (eg partially unsaturated, fully unsaturated);

"alkenyl", as used herein, refers to an alkyl group having one or more carbon-carbon double bonds;

"alkynyl", as used herein, refers to an alkyl group having one or more carbon-carbon triple bonds;

"cycloalkyl", as used herein, refers to an alkyl group which is also a cyclyl group; that is, a monovalent group obtained by removing a hydrogen atom from an alicyclic ring atom from a carbocyclic ring of a carbocyclic compound, said carbocyclic ring may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated), said group having from 3 to 20 carbon atoms (unless not otherwise specified), including from 3 to 20 ring atoms;

"ether", as used herein, refers to an -OR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group;

"acyl", as used herein, refers to a -C(=O)R group, wherein R is H, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group;

"ester", as used herein, refers to a -C(=O)OR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group;

"amido", as used herein, refers to a -C(=O)NR1R2 group, 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 from 4 to 8 ring atoms;

"amino", as used herein, refers to a -NR^R2 group, 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 from 4 to 8 atoms in the ring;

"acylamido", as used herein, refers to a -NR1C(=O)R2 group, 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, C3-20 heterocyclyl group, or C5-20 aryl group, or R1 and R2 together with the atoms to which they are attached can form a succinimidyl, maleimidyl, and phthalimidyl group;

"ureido", as used herein, refers to a -N(R1)CONR2R3 group, wherein 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 R 3 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms, and R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group;

"acyloxy", as used herein, refers to the -OC(=O)R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclic group, or a C5-20 aryl group;

"thioether" as used herein refers to the -SR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclic group, or a C5-20 aryl group;

"sulfoxide", as used herein, refers to the -S(=O)R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclic group, or a C5-20 aryl group;

"sulfonyl", as used herein, refers to the -S(=O)2R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclic group, or a C5-20 aryl group;

"thioamido", as used herein, refers to a -C(=S)NR1R2 group, 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 from 4 to 8 ring atoms;

"sulfonamino" as used herein refers to the -NR1S(=O)2R group, wherein R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclic group, or a C5-20 aryl group, and R is C1 -7 alkyl group, C3-20 heterocyclic group, or C5-20 aryl group.

According to an additional aspect of this invention, a pharmaceutical mixture containing a compound of formula 1 or 1(A), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or solvent is provided.

According to an additional aspect of the present invention there is provided a compound of formula 1 or 1(A), or a pharmaceutically acceptable salt thereof, for use in a method for treating the human or animal body.

According to an additional aspect of the present invention, the use of a compound of formula 1 or 1(A), or a pharmaceutically acceptable salt thereof, is provided for the preparation of a medicament for the treatment of a disease that is alleviated by inhibition of mTOR.

Additional aspects according to the invention provide for the use of a compound of formula 1 or 1(A), or a pharmaceutically acceptable salt thereof, for the preparation of a drug for the treatment of: cancer, immunosuppression, immuno-tolerance, autoimmune diseases, inflammation, bone loss, intestinal disorders, hepatic fibrosis , hepatic necrosis, rheumatic arthritis, restenosis, cardiac allograft vasculopathy, psoriasis, beta-thalassemia, and eye conditions such as dry eye. Inhibitors of mTOR may also be effective as antifungal agents.

We have found that the compounds defined in this invention, or a pharmaceutically acceptable salt thereof, are effective anti-cancer agents which are believed to arise from their mTOR inhibitory properties. Accordingly, the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions that are mediated alone or in part by mTOR, ie. the compounds can be used to obtain an mTOR inhibitory effect in warm-blooded animals in need of such treatment.

Accordingly, the compounds of this invention provide a method for the treatment of cancer characterized by inhibition of mTOR, i.e. the compounds can be used to obtain an anticancer effect that is mediated alone or in part with mTOR inhibition.

Such a compound of the invention is expected to possess a wide range of anti-cancer properties as activating mutations in mTOR have been observed in a large number of human cancers, including but not limited to, melanoma, papillary thyroid tumors, cholangiocarcinomas, colon, ovarian and lung cancers. . Accordingly, the compound of the invention is expected to possess anti-cancer activity against these cancers. In addition, the compound of the present invention is expected to possess activity against a wide range of leukemias, lymphatic malignancies and solid tumors such as carcinomas and sarcomas in tissues such as the liver, kidney, bladder, prostate, breast and pancreas. In particular, such compounds of the invention are expected to favorably slow the growth of primary and recurrent solid tumors, for example, skin, colon, thyroid, lung and ovary. In particular, such compounds of the invention, or a pharmaceutically acceptable salt thereof, are expected to inhibit the growth of those primary and recurrent solid tumors that are associated with mTOR, particularly those tumors that are significantly dependent on mTOR for their growth and spread, including for example, certain skin, colon, thyroid, lung and ovarian tumors. In particular, the compounds of the present invention are useful in the treatment of melanoma.

Accordingly, this aspect of the invention provides a compound of formula I or I(A), or a pharmaceutically acceptable salt thereof, as defined herein for use as a medicament.

According to an additional aspect according to the invention, the use of a compound of formula I or I(A), or a pharmaceutically acceptable salt thereof, as defined herein, is provided in the manufacture of a drug for use in obtaining an mTOR inhibitory effect in warm-blooded animals such as humans.

According to this aspect, the invention provides for the use of a compound of formula I or I(A), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a drug for use in obtaining an anti-cancer effect in warm-blooded animals such as humans.

According to an additional feature of the invention, the use of a compound of formula I or I(A), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a drug for use in the treatment of melanoma, papillary thyroid tumors, cholangiocarcinoma, colon cancer, cancer ovarian, lung cancer, leukemia, lymphatic malignancies, carcinomas and sarcomas of the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid gland, lungs and ovaries.

In an additional aspect of the invention there is provided a pharmaceutical composition consisting of a compound of formula I or I(A), or a pharmaceutically acceptable salt thereof, as defined herein in combination with a pharmaceutically acceptable solvent or carrier for use in obtaining an mTOR inhibitory effect in warm-blooded animals. animals such as man.

In an additional aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula I or I(A), or a pharmaceutically acceptable salt thereof, as defined herein in combination with a pharmaceutically acceptable diluent or carrier for use in the preparation of an anti- carcinogenic effect in warm-blooded animals such as humans.

In an additional aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula I or I(A), or a pharmaceutically acceptable salt thereof, as defined herein in combination with a pharmaceutically acceptable diluent or carrier for use in the treatment of melanoma, papillary thyroid tumors, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, leukemia, lymphatic malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, intestine, thyroid gland , lungs and ovaries in warm-blooded animals such as humans.

In an additional aspect of the invention, the use of a compound of formula 1 or 1 (A), or a pharmaceutically acceptable salt thereof, is provided for the preparation of a drug for use as an adjunct in the treatment of cancer or for the potentiation of tumor cells for treatment with ionizing radiation or chemotherapy agents.

The compounds of the invention can be used to treat a disease that is alleviated by inhibiting mTOR, 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 thereof, preferably in the form of a pharmaceutical mixture, and for the treatment of cancer, which consists of 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 pharmaceutical mixture, for simultaneous or sequential administration with ionizing radiation or chemotherapy agents.

Definitions

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

Nitrogen-containing heterocyclic ring having from 3 to 8 ring atoms: the term "nitrogen-containing heterocyclic ring having from 3 to 8 ring atoms" as used herein refers to a 3- to 8-membered heterocyclic ring containing at least one ring atom ring nitrogen. The term "together with the nitrogen to which they are attached, 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 ring nitrogen atom. Examples of such groups include, but are not limited to:

N1: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazol ) (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), azepine (C7);

N2: imidazolidin (C5), pyrazolidine (diazolidine) (C5), imidazolin (C5), pyrazolin (dihydropyrazol) (C5), piperazine (C6);

N1O1: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), morpholine (C6), tetrahydrooxazin (C6), dihydrooxazin (C6), oxazine (C6);

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

N2O1: oxadiazine (C6);

N1O1S1: oxathiazine (C6).

Alkyl: The term "alkyl" as used herein refers to a monovalent group obtained by the removal of a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which can be saturated or unsaturated (eg partially unsaturated, fully unsaturated). Accordingly, the term "alkyl" includes the sub-classes of alkenyl, alkynyl, cycloalkyl, cycloalkyenyl, cycloalkynyl, etc., discussed below.

In the context of alkyl groups, prefixes (eg, C1-4, C1-7, C1-20, C2-7, C3-7, etc.) indicate the number of carbon atoms, or a range of carbon atom numbers. For example, the term "C1-4 alkyl" as used herein refers to an alkyl group having from 1 to 4 carbon atoms. Examples of groups with alkyl groups include C1-4 alkyl ("lower alkyl"), C1-7 alkyl, and C1-20 alkyl. It should be noted that the first prefix may vary according to other restrictions; for example, for unsaturated alkyl groups, the first prefix must be at least 2; for cyclic alkyl groups, the first prefix must be at least 3; etc.

Examples of (unsubstituted) saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), hexyl (C6), heptyl (C7), octyl (Cs), nonyl (C9),

decyl (C10), undecyl (C11), dodecyl (C12), tridecyl (C13), tetradecyl (C14), pentadecyl (C15), and eikodecyl (C20).

Examples of (unsubstituted) saturated straight chain 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), i n-heptyl (C7).

Examples of (unsubstituted) saturated 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, refers to an alkyl group having one or more carbon-carbon double bonds. Examples of groups with alkenyl groups include C2-4 alkenyl, C2-7 alkenyl, C2-20 alkenyl.

Primers of (unsubstituted) unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH2), 1-propenyl (-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, refers to an alkyl group having one or more carbon-carbon triple bonds. Examples of groups with alkynyl groups include C2-4 alkynyl, C2-7 alkynyl, C2-20 alkynyl.

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

Cycloalkyl: The term "cycloalkyl", as used herein, refers to an alkyl group which is also a cyclyl group; that is, to a monovalent group obtained by removing a hydrogen atom from an alicyclic ring atom from a carbocyclic ring of a carbocyclic compound, and said carbocyclic ring can be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated), said group has from 3 to 20 carbon atoms ( unless otherwise stated), including from 3 to 20 ring atoms. Accordingly, the term "cycloalkyl" includes the sub-classes cycloalkenyl and cycloalkynyl. Preferably, each ring has from 3 to 7 ring atoms. Examples of some cycloalkyl groups include C3-20 cycloalkyl, C3-15 cycloalkyl, C3-10 cycloalkyl, C3-7 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, those derived from:

saturated monocyclic hydrocarbon compounds: cyclopropane (C3), cyclobutane (C4), cyclopentane (C5), cyclohexane (C6), cycloheptane (C7), methylcyclopropane (C4), dimethylcyclopropane (C5), methylcyclobutane (C5), dimethylcyclobutane (C6),

methylcyclopentane (C6), dimethylcyclopentane (C7), methylcyclohexane (C7),

dimethylciclohexane (Cs), mentan (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 (Cs); of saturated polycyclic hydrocarbon compounds: thujane (C10), carane (C10), pinane (C10), bornane (C10), norcarane (C7), norpinane (C7), norbornane (C7), adamantane (C10), decalin (decahydronaphthalene) ( C10);

unsaturated polycyclic hydrocarbon compounds: camphene (C10), limonene (C10), pinene (C10);

polycyclic hydrocarbon compounds having an aromatic ring: indene (C9), indane (eg, 2,3-dihydro-1H-indene) (C9), tetralin (1,2,3,4-tetrahydronaphthalene) (C10), acenaphthene ( C12), fluorene (C13), phenalene (C13), acephenanthrene (C15), aceanthrene (C16), cholanthrene (C20). Heterocyclyl: The term "heterocyclyl" as used herein refers to a monovalent group obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, said group having from 3 to 20 ring atoms (unless otherwise specified), of which 1 to 10 are ring heteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of which 1 to 4 are ring heteroatoms.

In this context, prefixes (eg, C3-20, C3-7, C5-6, etc.) indicate the number of ring atoms, or a range of ring atom numbers, either carbon atoms or heteroatoms. For example, the term "C5-6heterocyclyl" as used herein refers to heterocyclyl groups having 5 or 6 ring atoms. Examples of some 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, C3-7 heterocyclyl , C5-7 heterocyclyl, and C5-6 heterocyclyl.

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

Ni: aziridin (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazol ) (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), azepine (C7);

Oi: oxirane (C3), oxetane (C4), oxolan (tetrahydrofuran) (C5), oxol (dihydrofuran) (C5), oxane (tetrahydropyran) (C6), dihydropyran (C6), pyran (C6), oxepin (C7) ;

S1: thiiran (C3); tietane (C4), thiolan (tetrahydrothiophene) (C5), tian (tetrahydrothiopyran) (C6), tiepane (C7);

O2: dioxolane (C5), dioxane (C6), and dioxepane (C7);

O3: trioxane (C6);

N2: imidazolidin (C5), pyrazolidine (diazolidine) (C5), imidazolin (C5), pyrazolin (dihydropyrazol) (C5), piperazine (C6);

N1O1: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), morpholine (C6), tetrahydrooxazin (C6), dihydrooxazin (C6), oxazine (C6);

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

N2O1: oxadiazine (C6);

O1S1: oxatiol (C5) and oxathian (thioxane) (C6); te N1O1S1: oxathiazine (C6).

Examples of substituted (non-aromatic) monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, furanoses (C5) such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranose, and pyranoses (C6) such as allopyranose , altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose.

Spiro-C3-7 cycloalkyl or heterocyclyl: The term "spiro C3-7 cycloalkyl or heterocyclyl" as used herein refers to a C3-7 cycloalkyl or C3-7 heterocyclyl ring connected to another ring by a single atom common to both rings.

C5-20 aryl: the term "C5-20 aryl" as used herein refers to a monovalent group obtained by removing a hydrogen atom from an aromatic ring atom from a C5-20 aromatic compound, said compound having one ring, or two or more rings (e.g. ., condensed), and has from 5 to 20 atoms in the ring, and where at least one of the mentioned rings is an aromatic ring. Preferably, each ring has from 5 to 7 ring atoms.

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

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

Alternatively, the ring atoms may comprise one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur, as in "heteroaryl groups". In this case, the group may conveniently be referred to as a "C5-20 heteroaryl" group, wherein "C5-20" denotes the ring atoms, either carbon atoms or heteroatoms. Preferably, each ring has from 5 to 7 ring atoms, of which 0 to 4 are ring heteroatoms.

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

A heteroaryl group can be attached through a carbon or hetero atom in the ring.

Examples of C5-20 heteroaryl groups containing 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, e.g. alkyl, heterocyclyl, aryl, etc., whether alone or part of another substituent, may be alone optionally substituted with one or more selected from themselves and additional substituents mentioned below.

Halo: -F, -Cl, -Br, i -I.

Hydroxy: -OH.

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

Nitro: -NO2.

Cyano (nitrile, carbonitrile): -CN.

Acyl (keto): -C(=O)R, where R is an acyl substituent, for example, H, a C1-7 alkyl group (also called a C1-7 alkylacyl or C1-7 alkanoyl), a C3-20 heterocyclyl group (also called C3-20 heterocyclylacyl), or a C5-20 aryl group (also called C5-20 arylacyl), 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> (butyryl), and -C( =O)Ph (benzoyl, phenone).

Karboksi (karboxilna kiselina): -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 C1 -7 alkyl group. 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 where 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, C1-7 alkyl group (also called C1-7 alkylamino or di-C1-7 alkylamino), C3-20 heterocyclyl group, or C5 -20 aryl group, preferably H or C1-7 alkyl group, or, in the case of "cyclic" amino groups, R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms . Examples of amino groups include, but are not limited to, -

NH2, -NHCH3, -NHCH(CH3)2, -N(CHs)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 with any of the substituents defined herein, for example carboxy, carboxylate and amido.

Acylamido (acylamino): -NRjC(=O)R2, where 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 C1-7 an alkyl group, most preferably H, and R 2 is an acyl substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group. 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 succinimidyl, maleimidyl, and 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, C1-7alkyl, C3-20heterocyclyl, or C5-20aryl group, preferably hydrogen or a C1-7alkyl group. Examples of ureido groups include, but are not limited to, -NHCONH2, -NHCONHMe, -NHCONHEt, -NHCONMe2, -NHCONEt2, -NMeCONH2, -NMeCONHMe, -NMeCONHEt, -NMeCONMe2, -NMeCONEt2 and -NHC(=O)NHPh.

Acyloxy (reverse ester): -OC(=O)R, where 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 C1-7 alkyl group. 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.

Tiol : -SH.

Thioether (sulfide): -SR, where R is a thioether substituent, for example, a C1-7 alkyl group (also called a C1-7 alkylthio group), 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 C1-7 alkyl group. Examples of sulfoxide groups include, but are not limited to, -S(=O)CH3 and -S(=O)CH2CH3.

Sulfonyl (sulfon): -S(=O)2R, where R is a sulfonic substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclic group, or a C5-20 aryl group, preferably a C1-7 alkyl group. Sulfon group primers include, but are not limited to, -S(=O)2CH3 (methanesulfonyl, mesyl), -S(=O)2CF3, -S(=O)2CH2CH3, and 4-methylphenylsulfonyl (tozil).

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

As mentioned above, the groups forming the aforementioned substitution groups, e.g. C1-7 alkyl, C3-20 heterocyclyl, and C5-20 aryl may themselves be substituted. Therefore, the above definitions cover substituent groups that are substituted.

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

whereby:

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

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

RN5 i 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 where each C1-7alkyl , C5-20heteroaryl, C5-20aryl or heterocyclic ring is optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl , C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optional substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino), or their pharmaceutically acceptable salt,

and wherein "C5-20 aryl" as used herein refers to a monovalent group obtained by removing a hydrogen atom from an aromatic ring atom from a C5-20 aromatic compound, said compound having one ring, or two or more rings (eg, fused ), and has from 5 to 20 ring atoms, and where at least one said ring is an aromatic ring and where the ring atoms may include one or more heteroatoms, including but 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 unsubstituted morpholino, R7 is not unsubstituted phenyl, and when R2 is unsubstituted piperidinyl, RN3 and RN4 together with the nitrogen atom to which they are attached form unsubstituted piperidinyl , and R7 is not unsubstituted phenyl.

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

whereby:

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

C5-2oaryl, C5-2oheteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl , nitro, cijano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ethar, acyl, estar, 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 the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3- 7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl , ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino); and

RN10 is a C(=O)RC2, C(=S)RC3, SO2RS3, C5-20 heteroaryl group optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1 -7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide , sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3- 7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), C5-20 aryl group optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl , 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 from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, 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 the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1- 7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-2heterocyclyl, C5-2oaryl, C5-2heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl , C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),

where RC2 and RC3 are H, C5-20 aryl group, C5-20 heteroaryl group, C1-7 alkyl group or NRN11RN12, where RN11 and RN12 are independently H, C1-7 alkyl group, C5-20 heteroaryl group, C5-20 the aryl group or RN11 and RN12 together with the nitrogen to which they are attached form a heterocyclic ring containing between 3 and 8 ring atoms, where each C1-7alkyl, C5-20heteroaryl, C5-20aryl or heterocyclic ring is optionally substituted with one or more a group selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5- 20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy , thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-

20heterocyclyt, C5-20aryl, C5-20heteroaryl, ethar, acyl, estar, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido i sulfonamino), and RS3 is H, C5-20 arylna grupa, C5- 20 heteroaryl group, or C1-7 alkyl group where each C1-7alkyl, C5-20heteroaryl or C5-20aryl is optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, ili C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, estar, amido, amino, acylamido, ureido, acyloxy, thioether , sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, estar, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino), or their pharmaceutically acceptable salts,

and wherein "C5-20 aryl" as used herein refers to a monovalent group obtained by removing a hydrogen atom from an aromatic ring atom of a C5-20 aromatic compound, and said compound has one ring, or two or more rings (eg, condensed), and has from 5 to 20 ring atoms, wherein at least one said ring is an aromatic ring and where the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur.

Additional preferences

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

X5, X, i 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 optionally substituted with a 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 optional substituents are selected from cyano, halo, hydroxyl, and C1-7 alkyl and C1-7 alkoxy (wherein the alkyl groups can be optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, C1-7 alkoxy, amino and C5-6 aryl). In a further embodiment of the invention, 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 can be optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, C1-7 alkoxy, amino and C5-6 aryl). In an additional embodiment of the invention, 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. In an additional embodiment of the invention R7 is 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or 3-hydroxymethylphenyl group . In yet another additional embodiment of the invention, R7 is an aryl group as defined in any example 1a, 1b, 1d, 1e, 1f, 1g, 1i, 1k, 1l, 1m, 1n, 1o, 1p, 1q, 1bb, 1bc, 1bd , 1be, 1bf, 1bg, 1bh, 1bi, 1bj or 1br.

rN10

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

If RN10 is C(=S)RC3, then preferably RC3 is NRN11RN12, where 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 a C5-10 heteroaryl group and more preferably a C5-6 heteroaryl group. The most preferred 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 C5-20 aryl group, preferably a C5-10 aryl group and more preferably a C5-6 aryl group. An optionally substituted phenyl group is most preferred, wherein the optional substituents are preferably selected from halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy.

If RN 10 is a C 1-10 alkyl group, preferably a C 1-10 alkyl group and more preferably a C 1-10 alkyl group. Most preferably, an optionally substituted C1-6 alkyl group, wherein optional substituents are preferably 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, C5-20 heteroaryl, cyano, ester, for example -C(=O)OR where R is C1-7alkyl, and amino, for example C1-7alkylamino, di-C1-7alkylamino 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, 81, 8m, 8n, 8o, 8t, 8u, 8aa, 8ab , 8ac, 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, 8bc, 8bd, 8be and 8bg.

R03

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.

A more preferably formed group is morpholino or thiomorpholino, which are preferably unsubstituted. The most preferred group is morpholino.

R2

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

In a further embodiment of the invention, R2 is selected from NRN5RN6, optionally substituted C5-6 heteroaryl group, and optionally substituted C6 aryl group.

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

In yet another additional embodiment of the invention, R2 is an aryl group as shown in any of Examples 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 91, 9m, 9n and 9ae.

Preferably R2 is NRN5RN6, where 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 from 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 piperazinyl and homopiperazinyl groups include esters, in particular, esters bearing a C1-7 alkyl group as an ester substituent, e.g. -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 bear one or more substituents, for example one or two substituents.

More preferred groups are morpholino and piperidinyl. They are preferably substituted with one or two methyl substituents. If the new two methyl substituents, they are preferably on separate carbon atoms. Particularly desirable groups include:

In one embodiment of the invention, a subgroup of compounds with formula (I) and its pharmaceutically acceptable salts is provided, where:

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 can be optionally substituted; and R2 is selected from NRN5RN6, optionally substituted C5-20 heteroaryl group, and optionally substituted C5-20 aryl group.

In the next embodiment of the invention, a subgroup of compounds with formula (I) and its pharmaceutically acceptable salts is provided, where:

X8 is N, and X5 and X6 are CH;

R7 is an optionally substituted C5-6 aryl group, wherein 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 the group consisting of halo, hydroxyl, C1-7 alkoxy, amino and C5-6 aryl);

RN3 and RN4 together with the nitrogen to which they are attached preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and R2 is selected from NRN5RN6, optionally substituted C5-6 heteroaryl group, and optionally substituted C6 aryl group.

In the next embodiment of the invention, a subgroup of compounds with formula (I) and its pharmaceutically acceptable salts is provided, where:

X8 is N, and X5 and X6 are CH;

R7 is an optionally substituted C5-6 aryl group, wherein 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 the group consisting of halo, hydroxyl, C1-7 alkoxy, amino and C5-6 aryl);

rN3 and rN4 together with the nitrogen to which they are attached preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and R2 is NRN5RN6 where 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 optionally be substituted.

In an additional embodiment of the invention, a subgroup of compounds with formula (I) and its pharmaceutically acceptable salts is provided, where:

X8 is N, and X5 and X6 are CH;

R7 is an optionally substituted C5-6 aryl group, wherein 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 the group consisting of halo, hydroxyl, C1-7 alkoxy, amino and C5-6 aryl);

RN3 and RN4 together with the nitrogen to which they are attached preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and R2 is NRN5RN6 where RN5 and RN6 together with the nitrogen to which they are attached form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group.

In an additional embodiment of the invention, a subgroup of compounds with formula (I) and its pharmaceutically acceptable salts is provided, where:

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

In an additional embodiment of the invention, a subgroup of compounds with formula (I) and its pharmaceutically acceptable salts is provided, where:

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

homopiperazinyl (preferably N-substituted) or pyrrolidinyl group optionally substituted on carbon with one or more C1-4 alkyl groups.

In an additional embodiment of the invention, a subgroup of compounds with formula (I) and its pharmaceutically acceptable salts is provided, where:

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 morpholino or thiomorpholino; and

R2 is NRN5RN6 where 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 group optionally substituted on carbon with one or more C1- 4 alkyl groups.

In an additional embodiment of the invention, a subgroup of compounds with formula (I) and its pharmaceutically acceptable salts is provided, where:

X8 is N, and X5 and X6 are CH;

R7 is 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or 3-hydroxymethylphenyl group;

rN3 and rN4 together with the nitrogen to which they are attached preferably form morpholino or thiomorpholino; and

R2 is NRN5RN6 where RN5 and RN6 together with the nitrogen to which they are attached form

group.

In an additional embodiment of the invention, a subgroup of compounds with formula (I) and its pharmaceutically acceptable salts is provided, where:

X8 is N, and X5 and X6 are CH;

R7 is 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or 3-hydroxymethylphenyl group;

RN3 and RN4 together with the nitrogen to which they are attached preferably form an unsubstituted morpholino; and

R2 is NRN5RN6 where RN5 and RN6 together with the nitrogen to which they are attached form

group.

In one embodiment of the invention, a subgroup of compounds with formula I(A) and its pharmaceutically acceptable salts is provided, where:

X8 is N, and X5 and X6 are CH;

RN 10 is selected from C(=S)RC 3 , an optionally substituted C 5-20 heteroaryl group, an optionally substituted C 5-20 aryl group, and an optionally substituted C 1-10 alkyl group wherein RC 3 is as defined above;

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, optionally substituted C5-20 heteroaryl group, and optionally substituted C5-20 aryl group.

In the following embodiment of the invention, a subgroup of compounds with formula I(A) and its pharmaceutically acceptable salts is provided, where:

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 or an optionally substituted C1-10 alkyl group where RC3 is NRN11RN12 and where RN11 and RN12 together with the nitrogen to which they are attached connected to 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 preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and R2 is selected from NRN5RN6, optionally substituted C5-6 heteroaryl group, and optionally substituted C6 aryl group.

In the following embodiment of the invention, a subgroup of compounds with formula I(A) and its pharmaceutically acceptable salts is provided, where:

X8 is N, and X5 and X6 are CH;

RN10 is a C(=S)NRN11RN12 group where 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 selected from the group consisting of halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a phenyl group optionally substituted with one or more selected from the group consisting of halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a C1-6 alkyl group optionally substituted with one or more selected from the group consisting of halo, hydroxyl, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-20 aryl, C3-20 heterocyclyl, C5-20 heteroaryl , cyano, ester, for example -

C(=O)OR where R is C 1-7 alkyl, i amino, na primer C 1-7 alkylamino, di-C 1-7 alkylamino i C 1-7 alkoxycarbonylamino;

RO3 is a methyl group;

rN3 and rN4 together with the nitrogen to which they are attached preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and R2 is NRN5RN6 where 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 optionally be substituted.

In an additional embodiment of the invention, a subgroup of compounds with formula I(A), i

of its pharmaceutically acceptable salts, where:

X8 is N, and X5 and X6 are CH;

RN10 is a C(=S)NRN11RN12 group where 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 selected from the group consisting of halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a phenyl group optionally substituted with one or more selected from the group consisting of halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a C1-6 alkyl group optionally substituted with one or more selected from the group consisting of halo, hydroxyl, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-20 aryl, C3-20 heterocyclyl, C5-20 heteroaryl , cyano, ester, for example -C(=O)OR where R is C1-7alkyl, and amino, for example C1-7alkylamino, di-C1-7alkylamino and C1-7 alkoxycarbonylamino;

RO3 is a methyl group;

RN3 and RN4 together with the nitrogen to which they are attached preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and R2 is NRN5RN6 where RN5 and RN6 together with the nitrogen to which they are attached form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group.

In an additional embodiment of the invention, a subgroup of compounds with formula I(A), i

of its pharmaceutically acceptable salts, where:

X8 is N, and X5 and X6 are CH;

RN10 is a C(=S)NRn11Rn12 group where 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 selected from the group consisting of halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a phenyl group optionally substituted with one or more selected from the group consisting of halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a C1-6 alkyl group optionally substituted with one or more selected from the group consisting of halo, hydroxyl, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-20 aryl, C3-20 heterocyclyl, C5-20 heteroaryl , cyano, ester, for example -C(=O)OR where R is C1-7alkyl, and amino, for example C1-7alkylamino, di-C1-7alkylamino and C1-7 alkoxycarbonylamino;

RO3 is a methyl group;

RN3 and RN4 together with the nitrogen to which they are attached preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and R2 is NRN5RN6 where RN5 and RN6 together with the nitrogen to which they are attached form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group.

In an additional embodiment of the invention, a subgroup of compounds with formula I(A) and its pharmaceutically acceptable salts is provided, where:

X8 is N, and X5 and X6 are CH;

RN10 is a C(=S)NRN11RN12 group where 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 selected from the group consisting of halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a phenyl group optionally substituted with one or more selected from the group consisting of halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a C1-6 alkyl group optionally substituted with one or more selected from the group consisting of halo, hydroxyl, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-20 aryl, C3-20 heterocyclyl, C5-20 heteroaryl , cyano, ester, for example -C(=O)OR where R is C1-7alkyl, and amino, for example C1-7alkylamino, di-C1-7alkylamino and C1-7 alkoxycarbonylamino;

RO3 is a methyl group;

RN3 and RN4 together with the nitrogen to which they are attached preferably form a morpholino or thiomorpholino group; and

R2 is NRN5RN6 where 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 group optionally substituted on carbon with one or more C1- 4 alkyl groups.

In an additional embodiment of the invention, a subgroup of compounds with formula I(A) and its pharmaceutically acceptable salts is provided, where:

X8 is N, and X5 and X6 are CH;

RN10 is a C(=S)NRN11RN12 group where 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 selected from the group consisting of halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a phenyl group optionally substituted with one or more selected from the group consisting of halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a C1-6 alkyl group optionally substituted with one or more selected from the group consisting of halo, hydroxyl, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-20 aryl, Z3-20 heterocyclyl, C5-20 heteroaryl , cyano, ester, for example -C(=O)OR where R is C1-7alkyl, and amino, for example C1-7alkylamino, di-C1-7alkylamino and C1-7alkylamino;

RO3 is a methyl group;

RN3 and RN4 together with the nitrogen to which they are attached preferably form a morpholino or thiomorpholino group; and

R2 is NRN5RN6 where RN5 and RN6

together with the nitrogen to which they are attached form

group.

In an additional embodiment of the invention, a subgroup of compounds with formula I(A) and its pharmaceutically acceptable salts is provided, where:

X8 is N, and X5 and X6 are CH;

RN10 is a C(=S)NRN11RN12 group where 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 selected from the group consisting of halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a phenyl group optionally substituted with one or more selected from the group consisting of halo, hydroxyl, C1-7 alkyl and C1-7 alkoxy, or a C1-6 alkyl group optionally substituted with one or more selected from the group consisting of halo, hydroxyl, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-20 aryl, C3-20 heterocyclyl, C5-20 heteroaryl , cyano, ester, for example -C(=O)OR where R is C1-7alkyl, and amino, for example C1-7alkylamino, di-C1-7alkylamino 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

R2 is NR5RN6 where RN5 and RN6 together with the nitrogen to which they are attached form

or

group.

In yet another aspect of the invention, particular compounds of the invention are any of the aforementioned examples or pharmaceutically acceptable salts thereof.

In yet another aspect of the invention, particular compounds of the invention are any 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, 8as, 8at, 8au, 8av, 8aw, 8ax, 8ay, 8az, 8ba, 8bb, 8bc, 8bd, 8be, 8bg, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n and 9ae, or their pharmaceutically acceptable salts.

Isomers, salts, solvates, protected forms, and drug precursors

Certain compounds may exist in one or more distinct geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including, but not limited to, cis- and trans-forms; E- and Z-forms; c-, ti r-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and Z-forms; d- and /-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal and anticlinal forms; a- and P-forms; axial and equatorial forms; boat forms, chairs, envelopes, and half-chairs; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

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

It should be noted that, except when discussing tautomeric forms below, specifically excluded from the term "isomers" as used herein are structural (or constitutional) isomers (ie, isomers that differ in the bonds between atoms but only by the position of the atom in space). For example, reference to the methoxy group, -OCH3, should not be interpreted as a reference to its structural isomer, the hydroxymethyl group, -CH2OH. Similarly, reference to ortho-chlorophenyl should not be construed as a reference to its structural isomer, meta-chlorophenyl. However, mention of a structural class may include structural isomeric forms that fall within that class (eg C1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above limitation does not apply to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, A-nitroso/hyroxyazo, and nitro/acy-nitro.

Unless otherwise noted, reference to a specific compound includes all such isomeric forms, including (in whole or in part) racemic and other mixtures thereof. Methods for the preparation (eg, asymmetric synthesis) and separation (eg, fractional crystallization and chromatographic means) of such isomeric forms are already known in the art or are readily obtained by adapting the methods herein, or known methods, in a known manner.

Unless otherwise stated, reference to a specific compound also includes ionic forms; salts, solvates, and protected forms thereof, for example, such as those discussed below, as well as various polymorphic forms thereof.

It may be convenient or desirable to prepare, purify, and/or handle an appropriate 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 to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and to other cations such as Al3+ Examples of suitable organic cations include, but are not limited to, ammonium ion (ie, NH4+) and substituted ammonium cations (eg, 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 the salt can be built with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfuric, nitrite, nitric, phosphoric, and phosphoric acids. 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, pamoate, tartaric, citric, gluconic, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, aspartic, benzoic, cinnamic, pyruvic, salicylic, sulfanil, 2-acetioxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethanedisulfonic, oxalic, isethionic, valerian, and gluconic acids. 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 the appropriate solvate of the active compound. The term "solvate" is used herein in the conventional sense to refer to a complex of a solute (eg, an active compound, a salt of an active compound) and a solvent. If the solvent is water, the solvate may conveniently be referred to as a hydrate, eg, mono-hydrate, di-hydrate, tri-hydrate, etc.

It may be convenient or desirable to prepare, purify and/or handle the active compound in a chemically protected form. The term "chemically protected form", as used herein, refers to a compound where one or more reactive functional groups are protected from undesirable chemical reactions, that is, they are in the form of a protective or protected group (also known as a masked or masking group or blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed without affecting the unprotected group; the protecting group can be removed, usually in a subsequent step, without significantly affecting the rest of the molecule. See, for example, ref. 26.

Na primer, hydroxy group može da bude protected kao ether (-OR) ili estar (-OC(=O)R), na primer, kao: ^-butyl ether; benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; trimethylsilyl 3-butyldimethylsilyl ether; ili acetyl estar (-OC(=O)CH3, -OAc).

For example, an aldehyde or ketone group can be protected as an acetal or a ketal, respectively, where the carbonyl group (>C=O) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is easily regenerated with hydrolysis using a large excess of water in the presence of acid.

For example, the amine group can be protected, for example as an amide or urethane, for example, as: methyl amide (-NHCO-CH3); benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz); as t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); 2-Biphenyl-2-propoxy amide (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as 9-Fluorenylmethoxy amide (-NH-Fmoc), as 6-Nitroveratryloxy amide (-NH-Nvoc), as 2 -trimethylsilylethyloxy amide (-NH-Teoc), as 2,2,2-trichloroethyloxy amide (-NH-Troc), as allyloxy amide (-NH-Alloc), as 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec) ; or, in suitable cases, as A-oxide (>NO ).

For example, the carboxylic acid group can be protected for example as an ester, such as: C1-7 alkyl ester (eg methyl ester; t-butyl ester); C1-7 haloalkyl ester (eg C1-7 trihaloalkyl ester); triC1-7 alkylsilyl-C1-7 alkyl ester; or C5-20 aryl-C1-7 alkyl ester (eg benzyl ester; nitrobenzyl ester); or as an amide, for example, as methyl amide.

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

It may be convenient or desirable to prepare, purify and/or handle the active compound in the form of a drug precursor. The term "drug precursor", as used herein, refers to a compound that, when metabolized (eg, in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide favorable handling, administration, or metabolic characteristics.

For example, some drug precursors are esters of the active compound (eg, a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterifying, for example, any carboxylic acid group (-C(=O)OH) in the parent compound, where appropriate, prior to protection of any other reactive groups present in the parent compound, then if necessary with deprotection. Examples of such metabolically labile esters include those where R is C1-20 alkyl (eg -Me, -Et); C1-7 aminoalkyl (eg aminoethyl; 2-(N,N diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C1-7 alkyl (eg, acyloxymethyl; acyloxyethyl; eg, pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexylcarbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; 1-(4-

tetrahydropyranyloxy)carbonyloxyethyl; (4-tetrahydropyranyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonyloxyethyl).

Other suitable prodrug forms include phosphonate and glycolate salts. In particular, hydroxy groups (-OH) can be converted into phosphonate drug precursors by reaction with chlorodibenzylphosphite, followed by hydrogenation, to form the phosphonate group -OP(=O)(OH)2. Such a group can be cleaved by the enzyme phosphotase during metabolism to obtain an active drug with a hydroxy group.

Also, some drug precursors are enzymatically activated to obtain an active compound, or a compound that, after an additional chemical reaction, produces an active compound. For example, the drug precursor may be a sugar derivative or other glycosidic conjugate, or it may be an amino acid ester derivative.

Acronyms

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

For convenience, many chemical compounds are represented using well-known abbreviations, including but 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 dimethyl sulfoxide (DMSO).

General synthesis

Compounds of formula I can be represented by formula 1:

where R4 represents NRN3RN4

Compounds of formula 1 can be synthesized from compounds of formula 2:

When R7 is NRN1RN2, this reacts with k7H. When R7 is an optionally substituted C3-20 heterocyclyl group or a C5-20 aryl group, this reacts with R7B(OAlk)2, where each Alk is independently C1-7 alkyl or together with the oxygen to which they are attached form a C5-7 heterocyclyl group . When R 7 is an amide, urea or sulfonamide group, this is reacted with ammonium, and then by reacting the resulting primary amide with an appropriate acid chloride, isocyanate, or sulfonyl chloride. When R7 is ORO1 or SRS1, this is reacted with potassium carbonate in an appropriate alcohol or thiol solvent.

Therefore, according to an additional aspect of the present invention there is provided a process for preparing a compound of formula 1 from a compound of formula 2:

whereby:

R4 is NRN3RN4 where RN3 and RN4, together with the nitrogen to which they are attached, build

a heterocyclic ring containing between 3 and 8 ring atoms;

R2 is selected from H, halo, ORO2, SRS2b, NRN5RN6, optionally substituted C5-20 heteroaryl group, and optionally substituted C5-20 aryl group, wherein RO2 and RS2b are selected from H, optionally substituted C5-20 aryl group, optionally substituted C5-20 heteroaryl group, or optionally substituted C1-7 alkyl group, and RN5 and RN6 are independently selected from the group consisting of H, optionally substituted C1-7 alkyl group, optionally substituted C5-20 heteroaryl group, and optionally a 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 atoms in the ring, and the mentioned process contains

(a) when R7 is NRN1RN2, reacting a compound of formula 2 with R7H; or

(b) when R7 is an optionally substituted C3-20 heterocyclyl group or a C5-20 aryl group, reacting a compound of formula 2 with R7B(OAlk)2, wherein each Alk is independently C1-7 alkyl or together with the oxygen to which they are attached build a C5-7 heterocyclyl group, or

(c) when R 7 is an amide, urea or sulfonamide group, reacting a compound of formula 2 with ammonium followed by reacting the resulting primary amine with a suitable acid chloride, isocyanate or sulfonyl chloride, or

(d) when R 7 is ORO 1 or SRS 1 , reacting a compound of formula 1 in the presence of a base in a suitable alcohol or thiol solvent.

[0143] Compounds of formula I(A) can be synthesized by reacting compounds of formula 1a:

wherein R4 represents NRN3RN4, and

R7 I

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

Compounds of formula 1a can be synthesized by reacting compounds of formula 1b

wherein R4 is 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 compounds of formula 2:

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

Compounds of formula 2 can be synthesized from compounds of formula 3:

by responding to HR4 (HNRN3RN4) then by responding to HR2.

Compounds of formula 3 can be synthesized from compounds of formula 4:

for example with treatment with POCb and N,N-diisopropylamine.

Compounds of formula 4 can be synthesized from compounds of formula 5:

for example by treatment with oxalyl chloride.

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:

[0151] When R2 is NRN5RN6, this reacts with R2H. When R2 is an optionally substituted C3-20 heterocyclyl group or a C5-20 aryl group, this reacts with R2B(OAlk)2, where each Alk is independently C1-7 alkyl or together with the oxygen to which they are attached form a C5-7 heterocyclyl group . When R2 is ORO2 or SRS2b, this is reacted with potassium carbonate in the appropriate alcohol or thiol as solvent.

Therefore, according to an additional aspect of the present invention there is provided a process for preparing a compound of formula 1 from a compound of formula 2A:

at what

R4 is NRN3RN4 where 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, an optionally substituted C5-20 heteroaryl group, or an optionally substituted C5-20 aryl group,

wherein RO1 and RS1 are selected from H, optionally substituted C5-20 aryl group, optionally substituted C5-20 heteroaryl group, or optionally substituted C1-7 alkyl group; RN1 and R12 are independently selected from the group consisting of 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 to which they are attached a heterocyclic ring containing between 3 and 8 ring atoms;

RC1 is selected from H, optionally substituted C5-20 aryl group, optionally substituted C5-20 heteroaryl group, optionally substituted C1-7 alkyl group or NRN8RN9, wherein RN8 and RN9 are independently selected from the group containing H, optionally a substituted C1-7 alkyl group, an optionally substituted C5-20 heteroaryl group, an optionally substituted C5-20 aryl group or RN8 and RN9 together with the nitrogen to which they are attached form a heterocyclic ring containing between 3 and 8 ring atoms;

RS2a is selected from H, optionally substituted C5-20 aryl group, optionally substituted C5-20 heteroaryl group, or optionally substituted C1-7 alkyl group; and RN7a and RN7b are selected from H and C1-4 alkyl; and the mentioned process contains

(a) when R2 is NRN5RN6, reacting a compound of formula 2A with R2H, or

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

(c) when R2 is ORO2 or SRS2b, reacting a compound of formula 2A in the presence of a base in a suitable alcohol or thiol solvent.

Compounds of formula 2A can be synthesized from compounds of formula 3:

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

Using

The present invention describes active compounds, in particular, active to inhibit mTOR activity.

The term "active" as used herein refers to compounds capable of inhibiting mTOR activity, and specifically includes compounds with intrinsic activity (drugs) as well as drug precursors of such compounds, and said drug precursors may themselves exhibit little or no intrinsic activity .

One assay that can be conveniently used to assess mTOR inhibition by a particular compound is described in the examples below.

The present invention further contemplates a method for inhibiting mTOR activity in a cell, comprising contacting said cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable mixture. The mentioned method can be practiced in vitro or in vivo.

For example, a sample of cells can be grown in vitro and an active compound is brought into contact with said cells, and the effect of the compound on those cells is observed. As examples of "effects", inhibition of cell growth over a period of time or accumulation of cells in the G1 phase of the cell cycle over a period of time can be determined. Where an active compound is found to exert an effect on cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in a procedure 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 refers to treatment and therapy, whether human or animal (eg, in veterinary applications), where some desired therapeutic effect is achieved, for example, inhibition of the progression of the condition, and includes reducing the rate of progress, stopping the rate of progress, improving the condition, and treating said condition. Treatment as a prophylactic measure (ie prophylaxis) is also covered.

[0160] The term "adjuvant" as used herein refers to the use of active compounds in conjunction with known therapeutic agents. Such agents include cytotoxic drug regimens and/or ionizing radiation as used in the treatment of various types of cancer. Examples of adjunctive anticancer agents that can be combined with the compounds of the invention include, but are not limited to, the following: alkylating agents: nitrogen mustards, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil; Nitrosoureas: carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), ethyleneimine/methylmelamine, triethylenemelamine (TEM), triethylene thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine): Alkyl sulfonates; busulfan; triazine, dacarbazine (DTIC): antimetabolites; folic acid analogs, methotrexate, trimetrexate, pyrimidine analogs, 5-fluorouracil, fluorodeoxyuridine, gemcitabine, cytosine arabinoside (AraC, cytarabine), 5-azacytidine, 2,2'-difluorodeoxycytidine: purine analogs; 6-mercaptopurine, 6-thioguanine, azathioprine, 2'-deoxycoformycin (pentostatin, erythrohydroxynoniladenine (EHNA), fludarabine phosphate, 2-chlorodeoxyadenosine (cladribine, 2-CdA): topoisomerase I inhibitors; camptothecin, topotecan, irinotecan, rubitecan: natural products ; antimitotic drugs, paclitaxel, vinca alkaloids, vinblastine (VLB), vincristine, vinorelbine, Taxotere™ (docetaxel), estramustine, estramustine phosphate; epipodophyllotoxins, etoposide, teniposide: antibiotics; actimomycin D, daunomycin (rubidomycin), doxorubicin (adriamycin), mitoxantrone, idarubicin, bleomycin, plicamycin (mithramycin), mitomycin C, dactinomycin: enzymes; L-asparaginase, RNAse A: biological response modifiers; interferon-alpha, IL-2, G-CSF, GM-CSF: differentiation agents; retinoic acid derivatives acids: radiosensitizers, metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, RSU 1069, EO9, RB 6145, SR4233, nicotinamide, 5-bromodeosiuridine, 5-iododeoxyuridine, bromodeoxycytidine: platinum coordination complexes; cisplatin, carboplatin: anthracenedione; mitoxantrone, AQ4N substituted urea, hydroxyurea; methylhydrazine derivatives, N-methylhydrazine (MIH), procarbazine; adrenocortical suppressors, mitotane (o.p'-DDD), aminoglutethimide: cytokines; interferon (a, P, y), 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; anti-androgens, flutamide, gonadotropin-releasing hormone analogues, leuprolide; non-steroidal anti-androgens, flutamide; EGFR inhibitors, VEGF inhibitors; proteasome inhibitors.

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

Active compounds may also be used as part of an in vitro assay, for example, to determine the likelihood that a candidate host will benefit from treatment with said compound.

Rak

The present invention provides active compounds that are anti-cancer agents or adjuvant agents for the treatment of cancer. One skilled in the art will readily determine whether a compound is or is not a candidate to treat a cancerous condition for any particular cell type, 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 cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer , brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma and leukemia.

Any cell type can be treated, including but not limited to, lung, gastrointestinal (including, e.g., intestine, colon), breast, ovary, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.

The anti-cancer treatment defined herein may be administered as a single therapy or may include, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents:

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

(ii) cytostatic agents such as antiestrogens (eg tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxifene), antiandrogens (eg bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (eg goserelin, leuprorelin and buserelin), progestogens (eg megestrol acetate), aromatase inhibitors (eg anastrozole, letrozole, vorazole and exemestane) and 5*-reductase inhibitors such as finasteride; (iii) anti-invasion agents (for example c-Src kinase family inhibitors such as 4-(6-chloro-2,3-;methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl] ethoxy)- 5-tetrahydropyran-4-;yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl ]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), and metalloproteinase inhibitors such as marimastat, inhibitors of the activation function of the urokinase plasminogen receptor or Heparanase antibodies); (iv) inhibitors of growth factor functions: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (eg anti erbB2 antibody trastuzumab [Herceptin™], anti-EGFR antibody panitumumab, anti erbB1 antibody cetuximab [ Erbitux, C225] and any growth factor or growth factor receptor antibody disclosed by Stern et al. Critical Reviews in Oncology/Hematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the family epidermal growth factor (eg EGFR inhibitors of the tyrosine kinase family such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI 774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy )-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, hepatocyte growth factor family inhibitors, platelet-derived growth factor family inhibitors such as imatinib, serine/threonine kinase inhibitors (eg Ras/Raf signaling inhibitors as farnesyl, transferase inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signaling through MEK and/or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, IGF receptor kinase inhibitors (insulin-like growth factor); aurora kinase inhibitors (eg 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, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoroanilino) -6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; example 2 of WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7 -(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 of WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), compounds such as those disclosed in international patent applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds acting by other mechanisms (eg linomid, inhibitors of integrin avb3 function and angiostatin)]; ;(vi) vascular damage agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) "antisense" therapies, for example those directed against the aforementioned targets, such as ISIS 2503, an anti-ras "antisense"; ;(viii) gene therapy approaches, including for example approaches to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches such as those using cytosine deaminase, thymidine kinases or bacterial nitroreductase enzymes and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multidrug resistance gene therapy; and ;(ix) immunotherapeutic approaches, including for example ex vivo and in vivo approaches to increase the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte colony-stimulating factor macrophages, approaches to reduce T cell anergy, approaches using transfected immune cells as cytokine transfected dendritic cells, approaches using cytokine transfected tumor cell lines and approaches using anti-idiotype antibodies. ;Administration ;The active compound or pharmaceutical composition containing the active compound may be administered to a subject by any convenient route of administration, either systemic/peripheral or at the site of desired action, including but not limited to, orally (eg, by ingestion); topical (including eg transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. aerosols, e.g. through the mouth or nose); rectal; vaginal; parenterally, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrahecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implanting a depot preparation, for example, subcutaneously or intramuscularly. ;The subject can be a eukaryote, animal, vertebrate, mammalian rodent (eg, guinea pig, hamster, rat, mouse), mouse, dog, cat, horse, primate, simian (eg, monkey), ape (eg, marmoset, baboon) , a great ape (eg gorilla, chimpanzee, orangutan, gibbon), or human. ;Formulations ;While it is possible for the active compound to be administered separately, it is preferably administered as a pharmaceutical composition (eg, a formulation) containing at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, solvents, fillers, buffers, stabilizers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents. Accordingly, the present invention further describes pharmaceutical compositions, as defined above, and a method for obtaining a pharmaceutical composition consisting of a mixture of at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers , adjuvants, stabilizers, or other materials, as described herein. ;The term "pharmaceutically acceptable" as used herein refers to compounds, materials, mixtures, and/or dosage forms which, within the scope of reasonable medical judgment, are suitable for use in contact with the tissues of a subject (eg, a human) without undue toxicity , irritation, allergic reaction, or other problem or complication, in proportion to the reasonable benefit/risk. Any carrier, excipient, etc. it must also be "acceptable" in the sense that it is compatible with the other ingredients of the formulation. Suitable carriers, solvents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, ref. 27 to 29. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing the active compound into contact with a carrier that represents one or more auxiliary ingredients. In general, formulations are prepared by uniformly and intimately contacting the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. ;Formulations can be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, pills, ampoules, suppositories, vagitories, ointments, gels, pastes, creams, sprays, mists, foams , lotion, oil, bolus, electuary or aerosol. Formulations suitable for oral administration (eg, ingestion) may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of active compound; as powder or granules; as a solution or suspension in diluted or non-diluted liquids; or as liquid oil-in-water emulsions or liquid water-in-oil emulsions; as a bolus; as an electuary; or as a paste. ;The tablet can be made using conventional methods, e.g. compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets may be obtained by compressing the active compound in a free liquid form such as powder or granules in a suitable machine, and may optionally be mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or solvents (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 dispersing agents or wetting agents (eg, sodium lauryl sulfate); and preservatives (eg, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Molded tablets may be made from a mixture of powdered compounds moistened with an inert liquid solvent by molding in a suitable machine. Tablets may optionally be coated or coated and may be formulated to provide a slow or controlled release of the active compound using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets can optionally be prepared with an enteric coating, to ensure release in parts of the intestine, and not in the stomach. Formulations suitable for topical administration (eg, transdermal, intranasal, ocular, buccal, and sublingual) may be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol, or oil. Alternatively, the formulation may comprise a patch or bandage such as a bandage or adhesive patch impregnated with the active compound and optionally one or more excipients or a solvent. Formulations suitable for topical administration to the bone include lozenges containing the active compound in a flavored base, usually sucrose and acacia or tragacanth; lozenges containing the active compound in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active compound in a suitable liquid carrier. Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable vehicle, particularly an aqueous solvent for the active compound. ;Formulations suitable for nasal administration, wherein the carrier is in solid form, and contains a coarse powder having particle sizes, for example, in the range of about 20 to about 500 microns which is administered by snorting, i.e. by rapidly inhaling through the nasal passage from a powder container held close to the nose. Suitable formulations wherein the carrier is a liquid for administration as, for example, a nasal spray, nasal drops, or by aerosol administration with 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 pack using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide, or other suitable gases. Formulations suitable for topical administration to the skin include ointments, creams and emulsions. When formulated as an ointment, the active compound can optionally be used with either a paraffin base or a water miscible base. Alternatively, the active compounds may be formulated as a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and their mixtures. Topical formulations may preferably comprise a compound that enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancing agents include dimethylsulfoxide and related analogs. When formulated as topical emulsions, the oil phase may optionally contain only an emulsifier (otherwise known as an emulsifier), or they may contain a mixture of at least one emulsifier with fat or oil or with both fat and oil. Preferably, the hydrophilic emulsifier is combined together with a lipophilic emulsifier that acts as a stabilizer. It is also desirable to contain oils and fats. Together, the emulsifier(s) with or without stabilizers form the so-called emulsifying wax, and the wax together with the oil and/or fat form the so-called emulsion fat base which forms the oil-dispersed phase of the cream formulation. Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for formulation is based on achieving the desired cosmetic characteristics, because the solubility of the active compound in most oils used in pharmaceutical emulsion formulation can be very low. Therefore, the cream should preferably be non-greasy, non-staining and a washable product with the appropriate consistency to avoid leakage from the tube or other packaging. Mono- or dibasic straight or branched chain alkyl esters can be used, such as diisoadipate, isoacetyl stearate, propylene glycol diester, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a mixture of branched chain esters known as Crodamol CAP, and the last three are the desired esters. They can be used alone or in combination depending on the required characteristics. 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 containing, for example, cocoa butter or salicylate. ;Formulations suitable for vaginal administration can be presented as vagitories, tampons, creams, gels, pastes, foams or spray formulations which, in addition to the active compound, contain carriers which are known in the state of the art to be suitable. Formulations suitable for parenteral administration (eg, by injection, including cutaneous, subcutaneous, intramuscular, intravenous, and intradermal) include diluted and undiluted isotonic, pyrogen-free, sterile injectable solutions that may contain antioxidants, buffers, preservatives, stabilizers, bacteriostats, and solutions that deliver the isotonic formulation to the target recipient's blood; and diluted and non-diluted sterile suspensions that may contain suspending and thickening agents, and liposomes or other microparticulate systems that are designed to target the active compound to blood components or to one or more organs. Examples of suitable isotonic vehicles for use in such formulations include sodium chloride injection, Ringer's solution, or lactated 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. Formulations may be presented as unit dose or sealed multiple-dose containers, e.g., ampoules and vials, and may be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier, e.g., water for injection, immediately prior to use. . Injection solutions for immediate use and suspensions can be prepared from sterile powders, granules, and tablets. The formulations may be in the form of liposomes or other microparticulate systems designed to target the active compound to blood components or one or more organs. ;Dosage ;It should be known that the appropriate doses of active compounds, and mixtures containing active compounds, may vary from patient to patient. Determining the optimal dose will generally involve balancing the level of therapeutic benefit against the risk or adverse side effects for the treatments of the present invention. The dosage level selected will depend on a number of factors including, but not limited to, the activity of the individual compound, route of administration, time of administration, rate of excretion of the compound, duration of treatment, other drugs, compounds and/or materials used in combination, and age , gender, weight, condition, general health, and previous medical history of the patient. The amount of compound and the direction of administration will ultimately be determined at the discretion of the physician, although the dosage will generally be such as to achieve a local concentration at the site of action that achieves the desired effect, without causing significant harm or adverse side effects. Administration in vivo can be carried out in a single dose, continuously or intermittently (eg, in divided doses at convenient intervals) throughout the treatment. Methods for determining the most effective agent and dosage amount for administration are well known to those skilled in the art and will vary depending on the formulations used for treatment, the goal of treatment, the target cell being treated, and the subject being treated. Single or multiple administrations can be performed with a dosage level and model chosen by the physician. Generally, a suitable dosage of the active compound is in the range of about 100 µg to about 250 mg per kilogram of body weight of the subject per day. Where the active compound is a salt, ester, drug precursor, or the like, the amount given is calculated on the basis of the parent compound, and the actual weight used is thus proportionally increased. ;Examples ;General experimental methods ;Thin layer chromatography was performed using Merck Kieselgel 60 F254 glass plate substrate. Plates were illuminated using a UV lamp (254 nm). For "flash" chromatography, Silica gel 60 (particle size 40-63 pm) supplied by E.M. Merck was used. ! H NMR spectra were recorded at 300 MHz on a Bruker DPX-300 instrument. Chemical shifts are referenced relative to tetramethylsilane. ;Sample Purification and Identification ;Samples were purified on Gilson LC units. Mobile phase A - 0.1% liquid TFA, mobile phase B - Acetonitrile; flow rate 6 ml/min; gradient - typically starts at 90% A/10% B for 1 minute, rises to 97% after 15 minutes, holds for 2 minutes, then back to initial conditions. Column: Jones Chromatography Genesis 4pm, C18 column, 10 mm x 250 mm. Maximum acquisition based on UV detection at 254 nm. Mass spectrometry was recorded on a Finnegan LCQ instrument in positive ion mode. Mobile phase A - 0.1% liquid formic acid. Mobile phase B - Acetonitrile; flow rate 2 ml/min; gradient - starts at 95% A/5% B for 1 minute, rises to 98% B after 5 minutes and holds for 3 minutes before returning to initial conditions. Column: Varies, but always C18 50 mm x 4.6 mm (currently Genesis C18 4 pm. Jones Chromatography). PDA detection Waters 996, scanning range 210-400 nm. ;Microwave synthesis ;Reactions were carried out using a Personal Chemistry™ Emrys Optimiser microwave synthesis unit with a robotic arm. The power range was between 0-300 W at 2.45 GHz. The pressure range is between 0-20 bar; temperature rise between 2-5°C/sec; temperature range 60-250°C. ;Synthesis of 2,4,7-substituted pyridopyrimidine derivatives ;Intermediates: ;a) 2-Amino-6-chloronicotinic acid (Inter. 2) ;In 2,6-dichloronicotinic acid (Inter. 1) (1 equiv.) was added liquid ammonia (enough to obtain a 0.6M solution of substrate in ammonia). The suspension was sealed in a pressure vessel which was then slowly heated to 130°C. It was established that at this temperature a pressure of 18 bar was reached. This temperature and pressure were maintained for a further 16 hours, after which the mixture was cooled to room temperature. The pressure vessel was opened and the reaction was poured into cold water (1 reaction volume). The resulting solution was acidified to pH 1-2 using concentrated HCl which caused a precipitate to form. The sour mixture was allowed to warm to room temperature and stirred as such for an additional 30 minutes. The suspension was then extracted with diethyl ether (3 x 400 ml). The combined organic extracts were then filtered and the filtrate was concentrated in vacuo to give a white solid which was dried over P2O5 to give the title compound (90% yield and 96% purity) in the corresponding pure form which was used without further purification. m/z (LC-MS, ESP): 173 [M+H]+ R/T = 3.63 minutes;b) 2-Amino-6-chloronicotinamide (Inter. 3) ;In a 0.3M solution of 2-amino-6- of chloronicotinic acid (Inter. 2) (1 equiv.) in anhydrous THF, under an inert atmosphere, thionyl chloride (3.3 equiv.) was added dropwise. 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. The crude solid was dissolved in THF (equal to the initial reaction volume) and concentrated in vacuo to recover the crude yellow solid. The precipitate was dissolved once more in THF and concentrated as before to give a solid precipitate which was then dissolved in THF (to give a 0.3M solution) and ammonia gas was bubbled through the solution for 1 hour. The resulting precipitate was removed by filtration and the filtrate was concentrated in vacuo to give a yellow precipitate which was triturated with water at 50°C and then dried to give the title compound (92% yield, 93% purity), in the corresponding pure form to is used without further purification. m/z (LC-MS, ESP): 172 [M+H]+ R/T = 3.19 minutes. ;c) 7-Chloro-1H-pyrido[2,3-d]pyrimidine-2,4-dione * (Inter.4)

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

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

Diisopropylethylamine (3 equiv.) was slowly added to a stirred 0.5 M suspension of dione (Inter. 4) (1 equiv.) in anhydrous toluene under an inert atmosphere. The reaction mixture was then heated to 70°C over 30 minutes and then cooled to room temperature before addition of POCl3 (3 equivalents). The reaction was then heated to 100°C for 2.5 hours before cooling and concentrated in vacuo to give a crude slurry 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 which was dissolved in CH2Cl2 and stirred through silica gel for 30 minutes. After this time the silica was removed by filtration, the filtrate was concentrated and the crude precipitate was purified by flash chromatography (SiO2) to give the title compound in analytically pure form (48% yield, 96% purity). m/z (LC-MS, ESP): 234 [M+H]+ R/T = 4.21 minutes

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

Diisopropylethylamine (1 equiv.) was added dropwise to a cooled (0-5°C) mixed solution (0.1 M) of trichloro substrate (Inter. 5) (1 equiv.) in CH2Cl2. A suitable amine (1 equiv.) was then added to the reaction mixture in portions over a period of 1 hour. The solution was maintained at room temperature with stirring for an additional 1 hour before the mixture was washed with water (2 x 1 reaction volume). The aqueous extracts were mixed and extracted with CH2O2 (2 x 1 reaction volume). The organic extracts were then combined, dried (sodium sulfate), filtered and concentrated in vacuo to give an oily residue which solidified after prolonged drying. The solid was triturated with diethyl ether and then filtered and the cake washed with cold diethyl ether to leave the title compound in a pure form suitable for use without further purification.

Inter. 6a: 2,7-Dichloro-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine; R4= morpholino; (92% prines, 90% Istoća) m/z (LC-MS, ESP): 285 [M+H]+ R/T = 3.90 minutes 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% prines, 90% Istoća) m/z (LC-MS, ESP): 313 [M+H]+ R/T = 4.39 minutes

f) 2,4-Diamino-7-hloropiridopirimidini (Inter. 7)

To a solution (0.2 M) of the corresponding dichloro-substrate (Inter. 6a or 6b) (1 equiv.) in anhydrous dimethyl acetamide 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 cooling to ambient temperature. The reaction was diluted with CH2O2 (1 reaction volume) and then washed with water (3x1 reaction volumes). The organic extract was concentrated in vacuo to give a syrup which was dissolved in EtOAC (1 reaction volume) and washed with saturated brine before drying (sodium sulfate) and concentrated in vacuo to give an oil. The crude residue was purified by flash chromatography (SiO2, eluting with EtOAc:Hexane (7:3) down to (1:1)) to give the title compound as a yellow solid in a suitable pure form to be used without further 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 = cis-dimethylmorpholine; (45% yield, 85% purity) m/z (LC-MS, ESP): 348 [M+H]+ R/T = 4.16 minutes

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 minutes

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 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 minutes

Inter. 7d: 7-Chloro-2-((S)-3-methyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine (intermediate for compound 11a): R4 = morpholine, R2= (S)-3-Methylmorpholine; (70% yield, 97% purity) m/z (LC-MS, ESP): 350 [M+H]+ R/T = 3.44 minutes Inter. 7e: 7-Chloro-2-(2-ethyl-piperidin-1-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine (intermediate for compound 11ay): R4 = morpholine, R2= 2-Ethyl-piperidine; (56% yield, 95% purity) m/z (LC-MS, ESP): 362 [M+H]+ R/T = 3.78 minutes

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

To a solution (0.09 M) of the corresponding boronic acid or ester (1 equiv.) in water (1 volume) was added the corresponding 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 with nitrogen in bubbles flowing through the solution with sonication for 15 min before the addition of tetrakis(triphenylphosphine)palladium (0.03 equiv.). The mixture was degassed for an additional 5 minutes before heating in an inert atmosphere at 95 °C for 2 hours. Upon completion, the reaction mixture was cooled to room temperature and filtered under vacuum. The filtrate was concentrated in vacuo to give a solid residue which was dissolved in CHaCl (1 vol) and washed with water (1 vol). The organic extract was then dried (MgSO4), filtered and concentrated in vacuo to give an amorphous solid which was triturated with Et2O to leave the desired product as a fine powder.

Inter. 8a (R4=Morfoline, R7= 4-chlorophenyl)

2-Hloro-7-(4-chloro-fenil)-4-morfolin-4-il-pirido[2,3-d]pyrimidin; 1H NMR (300 MHz, Rastvarač CDCb 5 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).

First 1

R7=aril (Primeri 1a-bx)

The corresponding chloro-substrate (Inter. 7a-e) (1 equiv.) was dissolved in a toluene/ethanol (1:1) solution (0.02 M). Sodium carbonate (2 equiv.) and the corresponding boronic acid (1 equiv.) were then added prior to the addition of tetrakis(triphenylphosphine)palladium (0.1 equiv.). The reaction vessel was closed and the mixture was exposed to microwave radiation (140°C, medium absorption setting) for 30 minutes. Upon completion, the samples were filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to afford the compounds mentioned below.

Primer 1bj:- 1H NMR (300 MHz, Rastvarač CDCI3) 5 ppm 8.72 (s, 1H), 8.46 (d, J = 8.70), 8.37 d, 2.34 Hz, 1H), 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

R7= substituted amino (Reference compounds 2a-2bg)

To a solution of the appropriate chloro-substrate (Inter. 7a-e) (1 equiv) in 1,4-dioxane (0.04M) was added the appropriate amine (1.2 equiv), cesium carbonate (2 equiv), Xantphos™ and tris (dibenzylideneacetone)dipalladium(0). The reaction vessel is closed and exposed to heating under the influence of microwave radiation (normal absorption setting, 150°C, 20 minutes). The crude reaction mixture was then purified by preparative HPLC to afford the below-mentioned compounds.

Reference compound 2bf:- 1H NMR (300 MHz, Solvent CDCl3) 5 ppm 8.50 (s, 1H), 8.05 (d, J=9.32 Hz, 1H), 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

R7 = NH2 (Reference compound 3a-b)

To a solution of the appropriate chloro-substrate (Inter. 7a-e) (1 equiv.) in isopropanol (0.6 M) was added a concentrated solution of liquid ammonia (5 volumes). The reaction vessel was sealed and heated under microwave radiation (high absorption setting, 150°C, 30 minutes). The reaction mixture was then cooled, diluted with water (3 volumes) and extracted with EtOAc (2x3 volumes). The combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to give a crude residue which was further purified by flash chromatography (SiO2) (eluent-EtOAc/MeOH (95:5) down to (9:1) ) to obtain the compounds mentioned below in analytically pure form.

Reference compound 4

R7=Urea (Reference Compound 4a-i)

To a solution (0.02M) of a suitable amino-substrate (eg, Reference compound 3a or 3b) (1 equiv.) in anhydrous THF was added the appropriate isocyanate (2 equiv.). The reaction vessel was stoppered and heated to 60°C for 1 hour. The crude reaction mixture was then purified by preparative HPLC to afford the below-mentioned compounds.

Reference compound 5

R7=Amido (Reference compounds 5a-g)

To a solution (0.02M) of the appropriate amine substrate (Reference Compound 3a or 3b) (1 equiv.) in anhydrous CH2Ch was added triethylamine (2 equiv.) and the appropriate acid chloride (2 equiv.). The mixture was stirred at room temperature for 1 hour when the solvent was allowed to evaporate at atmospheric pressure, and the crude residue was purified by preparative HPLC to give the compounds mentioned below.

Reference compound 6 R7=Sulfonamido

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

Reference Compound 7 R7= Alkoxy

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

First 8

Et3N (1 equiv.) was added to a 0.1 M solution from Example 1a (1 equiv.) in CH2Cl2, and then methanesulfonyl chloride (1.1 equiv.) was added dropwise. The reaction was stirred under an inert atmosphere for 90 minutes when it was quenched with water (2x1 volume), the organic extracts were separated and dried (MgSO4), and filtered and concentrated in vacuo. The crude yellow gum was then diluted in diethyl ether and vigorously mixed. The resulting yellow precipitate was then collected by filtration to give the title compound (98%) in pure form suitable for use without further purification.

7-(3-Chloromethyl-methoxy-phenyl)-2-((2S,6R)-2,6-dimethyl-morphoHn-4-yl)-4-morphoHn-4-yl-pyrido[2,3-d] pyrimidine; (98.9% yield, 94% purity) m/z (LC-MS, ESP): No ionization [M+H]+ R/T = 3.98 minutes

[0214] In a 0.03 M solution of 7-(3-Chloromethyl-4-methoxy-phenyl)-2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-4-morpholin-4-yl of pyrido[2,3-d]pyrimidine (1 equiv.) in dimethylformamide, potassium carbonate (2.6 equiv.) was added, followed by triethylamine (1 equiv.) and finally the appropriate amine (1.1 equiv.). The reaction mixture was then heated to 40°C for 16 hours when it was purified by preparative HPLC to give the desired product.

First 9

R2=aril; R7=aril (Prime 9a - 9ae)

To the corresponding 2-chloro-pyridopyrimidine (Inter. 8a) (1 equiv.) in acetonitrile/water (1:1 ratio -0.025 M) was added the appropriate boronic acid or ester (1 equiv.), potassium carbonate (3.5 equiv.) and tetrakis(triphenylphosphine) palladium (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 mixture was then filtered through a thin pad of silica, washed with 1:1 MeOH/CH2Cl2 (1 volume), concentrated in vacuo and then purified by preparative HPLC to give the desired product (9a-9ae).

First 10

Enzyme test

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

U ovom testu su bila testirana sledeća edinjenja:- 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1j, 1k, 1l, 1l, 1m, 1n, 1o, 1p, 1q, 1r, 1s, 1t, 1u, 1v, 1w, 1x, 1y, 1z, 1aa, 1ab, 1ac, 1ad, 1ae, 1af, 1ag, 1ah, 1ai, 1aj, 1ak, 1al, 1am, 1an, 1ao, 1ap, 1aq, 1ar, 1as, 1at, 1au, 1av, 1aw, 1ax, 1ay, 1az, 1ba, 1bb, 1bc, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 21, 2m, 2n, 2o, 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, 81, 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 i 8bg.

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

1aa, 1ab, 1ac, 1ad, 1ae, 1af, 1ag, 1ah, 1ai, 1aj, 1al, 1am, 1an, 1ao, 1ap, 1aq, 1ar, 1as, 1at, 1au, 1av, 1aw, 1ax, 1c, 1k, 1r, 1s, 1t, 1u, 1v, 1w, 1x, 1y, 1z, 2a, 2aa, 2ac, 2ad, 2af, 2ah, 2ap, 2aq, 2ar, 2as, 2av, 2aw, 2ax, 2az, 2b, 2bb, 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, 8 v, 8 w, 8 , 1e, 1f, 1g, 1i, 1k, 1l, 1m, 1n, 1o, 1p, 1q, 1bb, 1bc, 2ba, 8a, 8b, 8c, 8d, 8e, 8f, 8g, 8h, 8i, 8j, 8k , 81, 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. Na primer, new 1k je is polljilo IC50 of 0.043^M

First 11

An alternative enzyme assay

The assay used AlfaScreen technology (Gray et al., AnalyticalBiochemistry, 2003, 313: 234245) to determine the ability of test compounds to inhibit phosphorylation by recombinant mTOR.

A C-terminal truncation of amino acid residues 1362 to 2549 encompassing mTOR from mTOR (EMBL accession no. L34075) was stably expressed as a FLAG-tagged fusion in HEK293 cells as described in Vilella-Bach et al., Journal of Biochemistry, 1999, 274, 4266-4272. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely maintained at 37°C with 5% CO2 until 70-90% confluency in Dulbecco's modified Eagle's growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalog no. 41966-029) containing 10% heat-inactivated fetal calf serum (FCS; Sigma, Poole, Dorset, UK, Catalog No. F0392), 1% L-glutamine (Gibco, Catalog No. 25030-024), and 2 mg/ml Geneticin (G418 sulfate; Invitrogen Limited, UK Catalog No. 10131-027). After expression in the HEK293 mammalian cell line, the expressed protein was purified using a FLAG epitope tag using standard purification techniques.

Test compounds were prepared as 10 mM stock solutions in DMSO and diluted in water as required to obtain a range of final test concentrations. Diluted aliquots (2 µl) of each compound were placed in the wells of a Greiner 384-well low volume (LV) plate on a white polystyrene plate (Greiner Bio-one). A mixture of 30 µl 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 buffer solution [containing Tris-HCl pH 7.4 buffer (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 that produced maximal signal correspond to maximal enzyme activity and were created using 5% DMSO instead of test compound. Control wells that produced minimal signal correspond to fully inhibited enzyme and 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 pH 7.4 buffer (50 mM) containing p70 S6 Kinase (T389) 1A5 Monoclonal Antibody (Cell Signaling Technology, Catalog No. 9206B) AlfaScreen Streptavidin Donor and Protein A Acceptor Beads (200 ng; Perkin Elmer, Catalog No. 6760002B and 6760137R, respectively) were added and the assay plates were left for about 20 hours at room temperature in the dark. The obtained signals resulting from excitation with laser light at 680 nm were read on a Packard Envision instrument.

The phosphorylated biotinylated peptide is formed in situ as a result of mTOR-mediated phosphorylation. Phosphorylated biotinylated peptide bound to AlfaScreen Streptavidin donor beads forms a complex with p70 S6 Kinase (T3 89) 1A5 Monoclonal antibody bound to Alfascreen Protein A acceptor beads. After excitation with 680 nm laser light, the donor grain: acceptor grain complex gives a signal that can be measured. Therefore, the presence of mTOR kinase activity results in a test signal. In the presence of mTOR kinase inhibitors, the signal strength is reduced. For a given test compound, mTOR enzyme inhibition is expressed as an IC50 value. The following compounds were examined in this test:- 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, 9aa, 9ab, 9ac, 9ad and 9ae.

All compounds tested exhibited IC50 values against mTOR of less than 10 µm. The following compounds exhibited IC50 values against mTOR of less than 1 µm: 1bk, 1bm, 1bn, 1bo, 1bp, 1bq, 1br, 1bs, 1bt, 1bu, 9m, 9n, 9p, 9r, 9aa, and 9ad, with the following compounds which exhibited IC50 values against mTOR of less than 300nM: 1bd, 1be, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9ae, 91, 9j, 9k, 9i, 9h, 1bj, 1bi, 1bh, 1bg and 1 bf. For example, Compound 1b exhibited an IC50 of 0.057 µM

First 12

Cell Proliferation Assay (GIso)

Cell growth was assessed using the sulforhodamine B (SRB) assay (A). T47D (ECACC, 85102201) cells were routinely passaged in RPMI (Invitrogen, 42401018) plus 10% fetal calf serum (FCS), 1% L-glutamine (Gibco BRL, 25030) to no greater than 80% confluence. To initiate the assay, T47D cells were seeded at 2.5x103 cells/well in 90 µl RPMI plus 10% fetal calf serum, 1% L-glutamine in 96-well plates (Costar, 3904) and incubated at 37°C (+5 % CO2) in an incubator with a humidifier. Once the cells were fully attached (typically after 4-5 hours) the plate was removed from the incubator and 10^L of solvent was added to the control wells (A1-12 and B1-12). The compound was prepared in a semi-log dilution with 6 points to 10x the required final concentration, e.g. for a 6-point scale from 30^M to 100nM in semi-log steps, dilutions were started in the prepared plate at 300^M. Dosing was completed by adding 10^L of the compound at the highest concentration in C1-12 to the lowest concentration in H1-12. The plates were then incubated for 120 hours before SRB analysis.

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

(A) Skehan, P., Storung, R., Scudiero, R., Monks, A., McMahon, J., Vistica, D., Warren, J. T., Bokesch, H., Kenny, S. i Boyd, M. R. (1990) New colorimetric citotoksicity test for anticancer-drugscreening. J. Natl. Cancer Inst. 82, 1107-1112.

All tested compounds exhibited GI50 values of less than 10 .mu.M.

The following compounds exhibited GI50 values of less than 1^M 8c, 8e, 8h, 8m, 8n, 8o, 8p, 8q, 8s, 8v, 8w, 8x, 8y, 8z, 8aa, and 8ac, with the following compounds being exhibited GI50 values of less than 300nM: 1g, 8a, 8b, 8d, 8f, 8g, 8i, 8k, 81, 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, 8bc, 8bd, 8be, 8bf, and 8bg. For example, Compound 1r exhibited a GI50 of

0.232^M.

First 13

In Vitro fosfo-Ser473 Akt test

This assay determines the ability of test compounds to inhibit phosphorylation of Serine 473 in Akt as assessed using Acumen Explorer technology (Acumen Bioscience Limited), a plate reader that can be used to rapidly quantify features of images generated with laser scanning.

The MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Teddington, Middlesex, UK, catalog number HTB-132) was routinely maintained at 37°C with 5% CO2 until 70–90% confluency in DMEM containing 10 % heat-inactivated FCS (fetal calf serum) and 1% L-glutamine.

For analysis, cells were detached from the culture flask using 'Accutase' (Innovative Cell Technologies Inc., San Diego, CA, USA; catalog number AT104) and using standard tissue culture methods and resuspended in medium to obtain 1.7x105 cells per Jr. Aliquots (90 µl) were seeded into each of the inner 60 wells of a Packard 96-well black plate (PerkinElmer, Boston, MA, USA; catalog number 6005182) to obtain a density of ∼15,000 cells per well. Aliquots (90 µl) of culture medium were placed in outer wells to prevent edge effects. Cells were incubated overnight at 37°C with 5% CO2 to allow adherence.

On day 2, cells were treated with test compounds and incubated for 2 hours at 37°C with 5% CO2. Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required with nutrient medium to give a range of concentrations that were 10-fold the required final test concentrations. Diluted aliquots (10 µl) of each compound were placed in a well (triplicate) to obtain the final desired concentrations. As a minimal response control, each plate contained wells containing a final concentration of 100 µM LY294002 (Calbiochem, Beeston, UK, catalog number 440202). As a peak response control, wells contained 1% DMSO instead of test compound. After incubation, the plate contents were fixed by treatment with 1.6% aqueous formaldehyde solution (Sigma, Poole, Dorset, UK, catalog number F1635) at room temperature for 1 hour.

All subsequent aspiration and washing steps were performed using a Tecan 96-well plate washer (aspiration speed 10 mm/sec). The fixative solution was removed and the plate contents 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 cell permeabilization buffer consisting of a mixture of PBS and 0.5% Tween-20. The 'permeabilization' buffer was removed and non-specific binding sites were blocked by treatment for 1 hour at room temperature with an aliquot (50 µl) of blocking buffer containing 5% skimmed milk powder ['Marvel' (registered trademark); Premier Beverages, Stafford, GB] in a mixture of PBS and 0.05% Tween-20. The 'blocking' buffer was removed and the cells were incubated for 1 hour at room temperature with an anti-phospho-Akt (Ser473) rabbit antibody solution (50 µl per well; Cell Signaling, Hitchin, Herts, U.K., Catalog No. 9277) that was diluted 1:500 in 'blocking' buffer. Cells were washed three times in a mixture of PBS and 0.05% Tween-20. Cells were subsequently incubated for 1 hour at room temperature with Alexafluor488-labeled goat anti-rabbit IgG (50 µl per well; Molecular Probes, Invitrogen Limited, Paisley, UK, catalog number A11008) diluted 1:500 in to a 'blocking' buffer. 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 were covered with black sealing plates, and the fluorescence signal was detected and analyzed.

Fluorescence pattern response data obtained with each compound were analyzed and the degree of inhibition of Serine 473 in Akt was expressed as an IC50 value. The following compounds were tested and exhibit cellular IC50s, as measured by pAkt, of less than 25 µM: 1bj, 1bd, 1bh, 1bi, 9j, 9a, 9aa, 9r, 9d, 9f, 9e with the following compounds exhibiting cellular IC50s, as measured with pAkt, of less than 2.5^M: 1br, 1bg, 1be, 91, 9n, 9k, 9h, 9g, 9m and 9i. For example, compound 91 has a pAkt IC50 of 2.2 µM.

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Claims (13)

1. 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 the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, 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 the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether , sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, 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 the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5 -20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino), and C5-20 aryl groups optionally substituted with one or more groups selected from the group containing halo , hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester , amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), wherein RN5 and RN6 are independently selected from the group consisting 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 a heterocyclic ring containing between 3 and 8 ring atoms wherein each C1-7alkyl, C5-20heteroaryl, C5-20aryl or heterocyclic ring is optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy , and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido , acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino), or pharmaceuticals thereof acceptable salt, and wherein "C5-20 aryl" as used herein refers to a monovalent group obtained by removing a hydrogen atom from an aromatic ring atom of a C5-20 aromatic compound, said compound having one ring, or two or more rings (e.g. ., condensed), and has from 5 to 20 atoms in the ring, and wherein at least one mentioned ring is an aromatic ring and where the atoms in the ring can include one or more heteroatoms, including but not limited to oxygen, nitrogen and sulfur; "alkyl" as used herein refers to a monovalent group obtained by the removal of 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 which may be saturated or unsaturated (eg partially unsaturated, fully unsaturated); "alkenyl", as used herein, refers to an alkyl group having one or more carbon-carbon double bonds; "alkynyl", as used herein, refers to an alkyl group having one or more carbon-carbon triple bonds; "cycloalkyl", as used herein, refers to an alkyl group that is also a cyclic group; that is, a monovalent group obtained by removing a hydrogen atom from an alicyclic ring atom from a carbocyclic ring of a carbocyclic compound, said carbocyclic ring may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated), said group having from 3 to 20 carbon atoms (unless not otherwise specified), including from 3 to 20 ring atoms; "ether", as used herein, refers to an -OR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "acyl", as used herein, refers to a -C(=O)R group, wherein R is H, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "ester", as used herein, refers to a -C(=O)OR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "amido", as used herein, refers to a -C(=O)NR1R2 group, 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 from 4 to 8 ring atoms; "amino", as used herein, refers to a -NR 1 R 2 group, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, or R 1 and R 2 , taken together with the nitrogen atom to which they are attached, they build a heterocyclic ring that has from 4 to 8 atoms in the ring; "acylamido", as used herein, refers to a -NR1C(=O)R2 group, 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, C3-20 heterocyclyl group, or C5-20 aryl group, or R1 and R2 together with the atoms to which they are connected can form a succinimidyl, maleimidyl and phthalimidyl group; "ureido", as used herein, refers to a -N(R1)CONR2R3 group, wherein 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 R 3 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms, and R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group; "acyloxy", as used herein, refers to an -OC(=O)R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "thioether", as used herein, refers to a -SR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "sulfoxide", as used herein, refers to a -S(=O)R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "sulfonyl", as used herein, refers to a -S(=O) 2 R group, wherein R is a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group; "thioamido", as used herein, refers to a -C(=S)NR1R2 group, 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 from 4 to 8 ring atoms; "sulfonamino", as used herein, refers to a -NR1S(=O)2R group, wherein R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, and R is C1 -7alkyl group, C3-20heterocyclyl group, or C5-20aryl 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 not unsubstituted phenyl, and when R2 is unsubstituted piperidinyl, RN3 and RN4 together with the nitrogen atom to which they are attached form unsubstituted piperidinyl, R7 is not unsubstituted phenyl. 2. The compound according to claim 1, characterized in that R7 is a phenyl group optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2 -7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5- 20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino), and wherein heteroatoms from the ring of any C5-20 heteroaryl group or C3-20heterocyclyl are selected from nitrogen, oxygen, and sulfur, wherein "C5-20 aryl" as used herein refers to a monovalent group obtained by removing a hydrogen atom from an aromatic ring atom of a C5-20 aromatic compound, and said compound has one ring, or two or more rings (eg, fused), and has from 5 to 20 ring atoms, and wherein at least one said ring is an aromatic ring and wherein the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen and sulphur; "alkyl" as used herein refers to a monovalent group obtained by the removal of a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may to be saturated or unsaturated (eg partially unsaturated, fully unsaturated); "alkenyl", as used herein, refers to an alkyl group having one or more carbon-carbon double bonds; "alkynyl", as used herein, refers to an alkyl group having one or more carbon-carbon triple bonds; "cycloalkyl", as used herein, refers to an alkyl group that is also a cyclic group; that is, to a monovalent group obtained by removing a hydrogen atom from an alicyclic ring atom from a carbocyclic ring of a carbocyclic compound, and said carbocyclic ring can be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated), said group has from 3 to 20 carbon atoms ( unless otherwise stated), including from 3 to 20 ring atoms; "ether", as used herein, refers to an -OR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "acyl", as used herein, refers to a -C(=O)R group, wherein R is H, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "ester", as used herein, refers to a -C(=O)OR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "amido", as used herein, refers to a -C(=O)NR1R2 group, 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 from 4 to 8 ring atoms; "amino", as used herein, refers to a -NR 1 R 2 group, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, or R 1 and R 2 , taken together with the nitrogen atom to which they are attached, they build a heterocyclic ring that has from 4 to 8 atoms in the ring; "acylamido", as used herein, refers to a -NR1C(=O)R2 group, 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, C3-20 heterocyclyl group, or C5-20 aryl group, or R1 and R2 together with the atoms to which they are connected can form a succinimidyl, maleimidyl and phthalimidyl group; "ureido", as used herein, refers to a -N(R1)CONR2R3 group, wherein 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 R 3 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms, and R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group; "acyloxy", as used herein, refers to an -OC(=O)R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "thioether", as used herein, refers to a -SR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "sulfoxide", as used herein, refers to a -S(=O)R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "sulfonyl", as used herein, refers to a -S(=O) 2 R group, wherein R is a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group; "thioamido", as used herein, refers to a -C(=S)NR1R2 group, 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 from 4 to 8 ring atoms; and "sulfonamino," as used herein, refers to a -NR1S(=O)2R group, wherein R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, and R is C1-7alkyl group, C3-20heterocyclyl group, or C5-20aryl group. 3. The compound according to claim 2, characterized in that R7 is a phenyl group optionally substituted with one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl. 4. Compound according to claim 2, characterized in that R7 is 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3- hydroxyphenyl or 3-hydroxymethylphenyl group. 5. The compound according to claim 1 characterized in that the compound is a compound with formula I(A): wherein: 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 ring atoms optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether , sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, 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 the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5 -20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino), and C5-20 aryl groups optionally substituted with one or more groups selected from the group containing halo , hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester , amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), wherein RN5 and RN6 are independently selected from the group consisting 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 a heterocyclic ring containing between 3 and 8 ring atoms wherein each C1-7alkyl, C5-20heteroaryl, C5-20aryl or heterocyclic ring is optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy , and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido , acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, 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 the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5 -20heteroaryl, 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, C5-20 heteroaryl optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy , thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3- 7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino), C5-20 aryl groups optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl , C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, 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 the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol , or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl , C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino) where RC2 and RC3 are selected from H, C5-20 aryl group, C5-20 heteroaryl group, C1-7 alkyl group or NRN11RN12, where RN11 and RN12 are independently selected from the group consisting of H, C1-7 alkyl group, C5-20 heteroaryl group, C5-20 aryl group or RN11 and RN12 together with the nitrogen to which they are attached form a heterocyclic ring containing between 3 and 8 ring atoms, where each C1-7alkyl, C5-20 heteroaryl, C5-20aryl or heterocyclic ring is optionally substituted with one or a plurality of groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5 -20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, 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 C1-7alkyl, C5-20heteroaryl or C5-20aryl is optionally substituted with one or more groups selected from containing halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, thiol, C1 -7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, 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 refers to a monovalent group obtained by removing a hydrogen atom from an aromatic ring atom of a C5-20 aromatic compound, said compound has one ring, or two or more rings (eg, fused), and has from 5 to 20 ring atoms, and wherein at least one said ring is an aromatic ring and where the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen and sulphur; "alkyl" as used herein refers to a monovalent group obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may to be saturated or unsaturated (eg partially unsaturated, completely unsaturated); "alkenyl", as used herein, refers to an alkyl group having one or more carbon-carbon double bonds; "alkynyl", as used herein, refers to an alkyl group having one or more carbon-carbon triple bonds; "cycloalkyl", as used herein, refers to an alkyl group which is also a cyclic group; that is, to a monovalent group obtained by removing a hydrogen atom from an alicyclic ring atom from the carbocyclic ring of a carbocyclic compound, and said carbocyclic ring can be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated), said group has from 3 to 20 carbon atoms ( unless otherwise stated), including from 3 to 20 ring atoms; "ether", as used herein, refers to an -OR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "acyl", as used herein, refers to a -C(=O)R group, wherein R is H, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "ester", as used herein, refers to a -C(=O)OR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "amido", as used herein, refers to a -C(=O)NR1R2 group, 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 from 4 to 8 atoms in the ring; "amino", as used herein, refers to a -NR1R2 group, 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, they form a heterocyclic ring that has from 4 to 8 atoms in the ring; "acylamido", as used herein, refers to a -NR1C(=O)R2 group, 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, C3-20 heterocyclyl group, or C5-20 aryl group, or R1 and R2 can, together with the atoms to which they are connected, form a succinimidyl, maleimidyl and phthalimidyl group; "ureido", as used herein, refers to a -N(R1)CONR2R3 group, wherein 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 R 3 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms, and R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group; "acyloxy", as used herein, refers to an -OC(=O)R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "thioether", as used herein, refers to a -SR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "sulfoxide", as used herein, refers to a -S(=O)R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "sulfonyl", as used herein, refers to a -S(=O) 2 R group, wherein R is a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group; "thioamido", as used herein, refers to a -C(=S)NR1R2 group, 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 from 4 to 8 atoms in the ring; and "sulfonamino", as used herein, refers to a -NR1S(=O)2R group, wherein R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, and R is C1-7 alkyl group, C3-20 heterocyclyl group, or C5-20 aryl group. 6. The compound according to any one of claims 1 to 5, characterized in that RN3 and RN4 together with the nitrogen to which they are attached form a morpholino group. 7. The compound according to any one of claims 1 to 6, characterized in that R2 is NRN5RN6, where RN5 and RN6 together with the nitrogen to which they are attached form a heterocyclic ring containing between 3 and 8 atoms in the ring, which can be optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5- 20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino (each optionally substituted with one or more selected from the group consisting of halo, hydroxyl, nitro , cyano, carboxy, thiol, C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-20heterocyclyl, C5-20aryl, C5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido , ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino), wherein the ring heteroatoms of any C5-20 heteroaryl group, C3-20heterocyclyl, or heterocyclic ring containing between 3 and 8 ring atoms are selected from nitrogen, oxygen and sulfur, and wherein "C5-20 aryl" as used herein refers to a monovalent group obtained by removing a hydrogen atom from an aromatic ring atom of a C5-20 aromatic compound, said compound having one ring, or two or more rings ( e.g., condensed), and has from 5 to 20 ring atoms, and wherein at least one said ring is an aromatic ring and wherein the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur; "alkyl" as used herein refers to a monovalent group obtained by removing 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 which may be saturated or unsaturated (eg partially unsaturated, fully unsaturated); "alkenyl", as used herein, refers to an alkyl group having one or more carbon-carbon double bonds; "alkynyl", as used herein, refers to an alkyl group having one or more carbon-carbon triple bonds; "cycloalkyl", as used herein, refers to an alkyl group that is also a cyclic group; that is, to a monovalent group obtained by removing a hydrogen atom from an alicyclic ring atom from a carbocyclic ring of a carbocyclic compound, said carbocyclic ring may be saturated or unsaturated (e.g., partially unsaturated, fully unsaturated), said group having from 3 to 20 carbon atoms (except unless otherwise stated), including from 3 to 20 ring atoms; "ether", as used herein, refers to an -OR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "acyl", as used herein, refers to a -C(=O)R group, wherein R is H, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "ester", as used herein, refers to a -C(=O)OR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "amido", as used herein, refers to a -C(=O)NR1R2 group, 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 from 4 to 8 ring atoms; "amino", as used herein, refers to a -NR 1 R 2 group, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, or R 1 and R 2 , taken together with the nitrogen atom to which they are attached, they build a heterocyclic ring that has from 4 to 8 atoms in the ring; "acylamido", as used herein, refers to a -NR1C(=O)R2 group, 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, C3-20 heterocyclyl group, or C5-20 aryl group, or R1 and R2 together with the atoms to which they are connected can form a succinimidyl, maleimidyl and phthalimidyl group; "ureido", as used herein, refers to a -N(R1)CONR2R3 group, wherein 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 R 3 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms, and R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group; "acyloxy", as used herein, refers to an -OC(=O)R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "thioether", as used herein, refers to a -SR group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "sulfoxide", as used herein, refers to a -S(=O)R group, wherein R is a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group; "sulfonyl", as used herein, refers to a -S(=O) 2 R group, wherein R is a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group; "thioamido", as used herein, refers to a -C(=S)NR1R2 group, 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 from 4 to 8 ring atoms; and "sulfonamino," as used herein, refers to a -NR1S(=O)2R group, wherein R1 is hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, and R is C1-7alkyl group, C3-20heterocyclyl group, or C5-20aryl group. 8. Compound according to claim 7, characterized in that R2 is selected from the group consisting of: morpholino, thiomorpholino, piperidinyl, piperazinyl, homopiperazinyl and pyrrolidinyl, wherein each morpholino, thiomorpholino, piperidinyl, piperazinyl, homopiperazinyl and pyrrolidinyl can optionally be substituted on carbon with one or more methyl groups. 9. The compound according to claim 8, characterized in that R2 is . 10. Next month, 1 day, when I started using the primer: R7 NR3R4 R2 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m 1n 1o 1p 1q 1r 1s 1t 1u 1v 1w 1x 1y 1z 1aa 1ab 1ac 1ad 1ae 1af 1ag 1ah 1ai 1aj 1ak 1al 1am 1an 1ao 1ap 1aq 1ar 1as 1at 1au 1av 1aw 1ax 1ay 1az 1ba 1bb 1bc 1bd 1be 1bf 1bg 1bh 1bi 1bk 1bl 1bm 1bn 1bo 1 bp 1bq 1br 1bs 1bt 1bu 1bv 1bw 1bx 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 8 ar 8as 8at 8au 8av 8aw 8ax 8ay 8az 8ba 8bb 8bc 8bd 8be 8bf 8bg 9a 9b 9c 9d 9e 9f 9g 9h 9i 9j 9k 9l 9m 9n 9o 9p 9q 9r 9s 9t 9u 9v 9w 9x 9y 9z 9aa 9ab 9ac 9ad 9ae ili njegove farmace utski prihvatljive soli. 11. Pharmaceutical mixture characterized in that it consists of 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. The compound according to any one of claims 1 to 10, or its pharmaceutically acceptable salt, indicated that it is for use as a medicine. 13. The use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, without any conditions indicated that it is for the preparation of a drug for the treatment of a disease that is alleviated by inhibiting mTOR.