Pyrido-, Pyrazo- and Pyrimido-Pyrimidine Derivatives as mTOR Inhibitors

Abstract

There is provided a compound of formula I:

Description

BACKGROUND

Growth factor/mitogenic activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway ultimately leads to the key cell cycle and growth control regulator mTOR, the mammalian target of rapamycin (alternatively referred to as FRAP (FKBP12 and rapamycin associated protein), RAFT1 (rapamycin and FKBP12 target 1), RAPT1 (rapamycin target 1)—all derived from the interaction with the FK-506-binding protein FKBP12, and SEP (sirolimus effector protein)). mTOR is a mammalian serine/threonine kinase of approximately 289 kDa in size and a member of the evolutionary conserved eukaryotic TOR kinases (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 the other family members, e.g. DNA-PKcs (DNA dependent protein kinase), ATM (Ataxia-telangiectasia mutated). In addition to a catalytic domain in the C-terminus, mTOR contains a FKBP12/rapamycin complex binding domain (FRB). At the N-terminus up to 20 HEAT (Huntingtin, EF3, alpha regulatory subunit of PP2A and TOR) motifs are found whilst more C-terminal is a FAT (FRAP-ATM-TRRAP) domain, and at the extreme C-terminus of the protein an additional FAT domain is found (FAT-C) (refs. 5,6).

TOR has been identified as a central regulator of both cell growth (size) and proliferation, which is in part governed by translation initiation. TOR dependant phosphorylation of S6-kinase (S6K1) allows translation of ribosomal proteins involved in cell cycle progression (refs. 7-9). Cap-dependant translation is regulated by the phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1 (PHAS-1)). This modification prevents PHAS-1 binding eIF4E, thereby permitting formation of an active eIF4F translation complex (reviewed in refs. 10,11,12). Activation of these signalling elements is dependant on insulin, other growth factors and nutrients suggesting a gatekeeper role for mTOR in the control of cell cycle progression only under favourable environmental conditions. The PI3K/AKT signalling cascade lies upstream of mTOR and this has been shown to be deregulated in certain cancers and results in growth factor independent activation in, for example, PTEN deficient cells. mTOR lies at the axis of control for this pathway and inhibitors of this kinase (e.g. 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 receiving particular interest as novel agents for cancer treatment.

Tumour cell growth arises from the deregulation of normal growth control mechanisms such as the loss of tumour suppressor function(s). One such tumour suppressor is the phosphatase and tensin homologue deleted from chromosome ten (PTEN). This gene, also known as mutated in multiple advanced cancers (MMAC), has been shown to play a significant role in cell cycle arrest and is the most highly mutated tumour suppressor after p53. Up to 30% of glioblastoma, endometrial and prostate cancers have somatic mutations or deletions of this locus (refs. 15,16).

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

In addition to the evidence linking mTOR with 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 cell growth inhibition (Reviewed in refs. 7,18,19). The known inhibitor of mTOR, rapamycin, potently inhibits proliferation or growth of cells derived from a range of tissue types such as smooth muscle, T-cells as well as cells derived from a diverse range of tumour types including rhabdomyosarcoma, neuroblastoma, glioblastoma and medulloblastoma, small cell lung cancer, osteosarcoma, pancreatic carcinoma and breast and prostate carcinoma (reviewed in ref. 20). Rapamycin has been approved and is in clinical use as an immunosuppressant, its prevention of organ rejection being successful and with fewer side effects than previous therapies (refs. 20, 21). Inhibition of mTOR by rapamycin and its analogues (RAD001, CCI-779) is brought about by the prior interaction of the drug with the FK506 binding protein, FKBP12. Subsequently, the complex of FKBP12/rapamycin then binds to the FRB domain of mTOR and inhibits the downstream signalling from mTOR.

The potent but non-specific inhibitors of PI3K, LY294002 and wortmannin, also have been shown to inhibit the kinase function of mTOR but act through targeting the catalytic domain of the protein (ref. 21). Further to the inhibition of mTOR function by small molecules targeted to the kinase domain, it has been demonstrated that kinase dead mTOR cannot transmit the upstream activating signals to the downstream effectors of mTOR, PHAS-1 or p70S6 kinase (ref. 22). It is also shown that not all functions of mTOR are rapamycin sensitive 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 has revealed that in addition to the mTOR-Raptor complex, there is also an mTOR-Rictor complex representing a rapamycin insensitive activity of mTOR (B) (Sarbassov et al. Current Biology, 2004, 14, 1296-1302). This activity likely accounts for the discrepancy between kinase dead mTOR and the alteration of mTOR signalling by rapamycin and its derivatives. The discrepancy also identifies the possibility of a therapeutic advantage in inhibiting directly the 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 failure to completely disrupt pathway signalling (Choo and Blenis, Cancer Cell, 2006, 9, 77-79; Hay, Cancer Cell, 2005, 8, 179-183). Therefore, it is proposed that a kinase domain directed inhibitor of mTOR may be a more effective inhibitor of mTOR.

In addition to rapamycin's ability to induce growth inhibition (cytostasis) in its own right, 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). Potentiation of ionising radiation induced cell killing has also been observed following inhibition of mTOR (ref. 24). Experimental and clinical evidence has shown that rapamycin analogues are showing evidence of efficacy in treating cancer, either 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 treatment of the various forms of cancer comprising solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies. In particular, inhibitors of mTOR kinase should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.

Renal cell carcinoma in particular, has been identified as sensitive to the rapamycin derivative CCI-779, resulting from a loss of VHL expression (Thomas et al. Nature Medicine, 2006, 12, 122-127). Tumours that have lost the promyelocytic leukaemia (PML) tumour suppressor, have also been shown to be sensitive to inhibition of mTOR by rapamycin as a consequence of disruption of the regulation of the mTOR signalling pathway (Bernadi, Nature, 2006, 442, 779-785) and the use of an mTOR kinase inhibitor in these diseases should be of therapeutic value. These latter examples in addition to those of PTEN deficiency or PI3K mutation indicate where a targeted approach to the use of mTOR inhibitors may prove particularly effective due to an underlying genetic profile, but are not considered to be 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 demonstrated to be a potent immunosuppressant by inhibiting antigen-induced proliferation of T cells, B cells and antibody production (Sehgal, Transplantation Proceedings, 2003, 35, 7S-14S) and thus mTOR kinase inhibitors may also be useful immunosuppressives. Inhibition of the kinase activity of mTOR may also be useful in the prevention of restenosis, that is the control of undesired proliferation of normal cells in the vasculature in response to the introduction of stents in the treatment of vasculature disease (Morice et al., New England Journal of Medicine, 2002, 346, 1773-1780). Furthermore, the Rapamycin analogue, everolimus, can reduce the severity and incidence of cardiac allograft vasculopathy (Eisen et al., New England Journal of Medicine, 2003, 349, 847-858). Elevated mTOR kinase activity has been associated with cardiac hypertrophy, which is of clinical importance as a major risk factor for heart failure and is a consequence of increased cellular size of cardiomyocytes (Tee & Blenis. Seminars in Cell and Developmental Biology, 2005, 16, 29-37). Thus mTOR kinase inhibitors are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer.

The vast majority of mTOR pharmacology to date has focused on inhibition of mTOR via rapamycin or its analogues. However, as noted above, the only non-rapamycin agents that have been reported to inhibit mTOR's activity via a kinase domain targeted mechanism are the small molecule LY294002 and the natural product wortmannin (ref. 21).

SUMMARY OF THE INVENTION

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

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

wherein:one or two of X⁵, X⁶ and X⁸ is N, and the others are CH;R⁷ is selected from halo, OR^O1, SR^S1, NR^N1R^N2, NR^N7aC(═O)R^C1, NR^N7bSO₂R^S2a, n optionally substituted C_5-20 heteroaryl group, or an optionally substituted C_5-20 aryl group,where R^O1 and R^S1 are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, or an optionally substituted C_1-7 alkyl group; R^N1 and R^N2 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_5-20 aryl group or R^N1 and R^N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;R^C1 is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_1-7 alkyl group or NR^N8R^N9, where R^N8 and R^N9 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_5-20 aryl group or R^N8 and R^N9 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;R^S2a is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, or an optionally substituted C_1-7 alkyl group;R^N7a and R^N7b are selected from H and a C_1-4 alkyl group;R^N3 and R^N4, together with the nitrogen to which they are bound, form a heterocyclic ring containing between 3 and 8 ring atoms;R² is selected from H, halo, OR^O2, SR^S2b, NR^N5R^N6, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group,wherein R^O2 and R^S2b are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, or an optionally substituted C_1-7 alkyl group;R^N5 and R^N6 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group, or R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms,or a pharmaceutically acceptable salt thereof,with the proviso that when R² is unsubstituted morpholino, R^N3 and R^N4 together with the nitrogen atom to which they are attached form an unsubstituted morpholino and R⁷ is unsubstituted phenyl, and X⁵ is CH, then X⁶ is not N and X⁸ is not CH, or X⁶ is not CH and X⁸ is not N, andwhen R² is unsubstituted piperidinyl, R^N3 and R^N4 together with the nitrogen atom to which they are attached form an unsubstituted piperidinyl and R⁷ is unsubstituted phenyl, and X⁵ is CH, then X⁶ is not CH and X⁸ is not N.

In one embodiment of the first aspect, when R² is unsubstituted morpholino, R^N3 and R^N4 together with the nitrogen atom to which they are attached form an unsubstituted morpholino, R⁷ is unsubstituted morpholino or di-methylamino, and X⁶ is CH, then X⁵ is not N and X⁸ is not CH, or X⁵ is not CH and X⁸ is not N.

In another embodiment of the first aspect, when R² is unsubstituted piperazino or N-formyl piperazino, R^N3 and R^N4 together with the nitrogen atom to which they are attached form an unsubstituted morpholino, unsubstituted piperidinyl or unsubstituted oxidothiomorpholino, R⁷ is unsubstituted morpholino or benzylamino, and X⁶ is CH, then X⁵ is not N and X⁸ is not CH, or X⁵ is not CH and X⁸ is not N.

In another embodiment of the first aspect, when R² is unsubstituted morpholino, unsubstituted piperidino, unsubstituted pyrrolidino, R^N3 and R^N4 together with the nitrogen atom to which they are attached form a morpholino, piperazinyl, unsubstituted piperidinyl or unsubstituted pyrrolidinyl, R⁷ is unsubstituted morpholino, unsubstituted piperidinyl, unsubstituted pyrrolidinyl, and X⁵ is CH, then X⁶ is not N and X⁸ is not CH, or X⁶ is not CH and X⁸ is not N.

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

wherein:one or two of X⁵, X⁶ and X⁸ is N, and the others are CH;R^N3 and R^N4, together with the nitrogen to which they are bound, form a heterocyclic ring containing between 3 and 8 ring atoms;R² is selected from H, halo, OR^O2, SR^S2b, NR^N5R^N6, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group,wherein R^O2 and R^S2b are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, or an optionally substituted C_1-7 alkyl group; R^N5 and R^N6 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group, or R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;R^O3 is selected from hydrogen or an optionally substituted C_1-6 alkyl group; andR^N10 is selected from C(═O)R^C2, C(═S)R^C3, SO₂R^S3, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_5-20 aryl group, or an optionally substituted C_1-10 alkyl group where R^C2 and R^C3 are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_1-7 alkyl group or NR^N11R^N12, where R^N11 and R^N12 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_5-20 aryl group or R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms; and R^S3 is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, or an optionally substituted C_1-7 alkyl group,or a pharmaceutically acceptable salt thereof.

Accordingly, the third aspect of the present invention provides a compound of formula I(B):

or a pharmaceutically acceptable salt thereof, wherein:one or two of X⁵, X⁶ and X⁸ is N, and the others are CH;R⁷ is selected from halo, OR^O1, SR^S1, NR^N1R^N2, NR^N7aC(O)R^C1, NR^N7bSO₂R^S2a, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C_5-20 aryl group,where R^O1 and R^S1 are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C_1-7 alkyl group; R^N1 and R^N2 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C_5-20 aryl group or R^N1 and R^N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;R^C1 is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C_1-7 alkyl group or NR^N8R^N9, where R^N8 and R^N9 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C_5-20 aryl group or R^N8 and R^N9 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;R^S2a is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C_1-7 alkyl group;R^N7a and R^N7b are selected from H and a C_1-4 alkyl group;R² is selected from H, halo, OR^O2, SR^S2b, NR^N5R^N6, an optionally substituted 5- to 20-membered heteroaryl group, and an optionally substituted C_5-20 aryl group,wherein R^O2 and R^S2b are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C_1-7 alkyl group; R^N5 and R^N6 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, and an optionally substituted C_5-20 aryl group, or R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms.

According to a fourth aspect of the present invention there is provided a compound of formula I(B)i or I(B)ii:

or a pharmaceutically acceptable salt thereof, wherein:one or two of X⁵, X⁶ and X⁸ is N, and the others are CH;R⁷ is selected from halo, OR^O1, SR^S1, NR^N1R^N2, NR^N7aC(O)R^C1, NR^N7bSO₂R^S2a, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C_5-20 aryl group,where R^O1 and R^S1 are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C_1-7 alkyl group; R^N1 and R^N2 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C_5-20 aryl group or R^N1 and R^N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;R^C1 is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C_1-7 alkyl group or NR^N8R^N9, where R^N8 and R^N9 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C_5-20 aryl group or R^N8 and R^N9 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;R^S2a is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C_1-7 alkyl group;R^N7a and R^N7b are selected from H and a C_1-4 alkyl group;R² is selected from H, halo, OR^O2, SR^S2b, NR^N5R^N6, an optionally substituted 5- to 20-membered heteroaryl group, and an optionally substituted C_5-20 aryl group,wherein R^O2 and R^S2b are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C_1-7 alkyl group; R^N5 and R^N6 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, and an optionally substituted C_5-20 aryl group, or R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms.

According to a fifth aspect of the present invention there is provided a compound of formula I(B)i:

or a pharmaceutically acceptable salt thereof, wherein:one or two of X⁵, X⁶ and X⁸ is N, and the others are CH;R⁷ is selected from halo, OR^O1, SR^S1, NR^N1R^N2, NR^N7aC(O)R^C1, NR^N7bSO₂R^S2a, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C_5-20 aryl group,where R^O1 and R^S1 are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C_1-7 alkyl group; R^N1 and R^N2 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C_5-20 aryl group or R^N1 and R^N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;R^C1 is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C_1-7 alkyl group or NR^N8R^N9, where R^N8 and R^N9 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, an optionally substituted C_5-20 aryl group or R^N8 and R^N9 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;R^S2a is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C_1-7 alkyl group;R^N7a and R^N7b are selected from H and a C_1-4 alkyl group;R² is selected from H, halo, OR^O2, SR^S2b, NR^N5R^N6, an optionally substituted 5- to 20-membered heteroaryl group, and an optionally substituted C_5-20 aryl group,wherein R^O2 and R^S2b are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteroaryl group, or an optionally substituted C_1-7 alkyl group; R^N5 and R^N6 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted 5- to 20-membered heteroaryl group, and an optionally substituted C_5-20 aryl group, or R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms.

According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

According to a further aspect of the present invention there is provided of Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body.

According to a further aspect of the present invention there is provided the use of a compound of Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease ameliorated by the inhibition of mTOR.

The compounds of Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, have activity as pharmaceuticals, in particular as modulators or inhibitors of mTOR activity, and may be used in the treatment of proliferative and hyperproliferative diseases/conditions, examples of which include the following cancers:

(1) carcinoma, including that of the bladder, brain, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, colon, endometrium, thyroid and skin;

(2) hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukaemia, B-cell lymphoma and Burketts lymphoma;

(3) hematopoietic tumours of myeloid lineage, including acute and chronic myelogenous leukaemias and promyelocytic leukaemia;

(4) tumours of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and

(5) other tumours, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma.

Further aspects of the invention provide the use of a compound of Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of: cancer, immuno-suppression, immune tolerance, autoimmune disease, inflammation, bone loss, bowel disorders, hepatic fibrosis, hepatic necrosis, rheumatoid arthritis, restenosis, cardiac allograft vasculopathy, psoriasis, beta-thalassaemia, and ocular conditions such as dry eye. mTOR inhibitors may also be effective as antifungal agents.

We have found that the compounds defined in the present invention, or a pharmaceutically acceptable salt thereof, are effective anti-cancer agents which property is 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 mediated alone or in part by mTOR, i.e. the compounds may be used to produce a mTOR inhibitory effect in a warm-blooded animal in need of such treatment.

Thus the compounds of the present invention provide a method for treating cancer characterised by inhibition of mTOR, i.e. the compounds may be used to produce an anti-cancer effect mediated alone or in part by the inhibition of mTOR.

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 many human cancers, including but not limited to, melanoma, papillary thyroid tumours, cholangiocarcinomas, colon, ovarian and lung cancers. Thus it is expected that a compound of the invention will possess anti-cancer activity against these cancers. It is in addition expected that a compound of the present invention will possess activity against a range of leukaemias, lymphoid malignancies and solid tumours such as carcinomas and sarcomas in tissues such as the liver, kidney, bladder, prostate, endometrium, breast and pancreas. In particular such compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the skin, colon, thyroid, lungs, endometrium and ovaries. More particularly such compounds of the invention, or a pharmaceutically acceptable salt thereof, are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with mTOR, especially those tumours which are significantly dependent on mTOR for their growth and spread, including for example, certain tumours of the skin, colon, thyroid, endometrium, lungs and ovaries. Particularly the compounds of the present invention are useful in the treatment of melanomas and gliomas.

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

According to a further aspect of the invention there is provided the use of a compound of the Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the production of a mTOR inhibitory effect in a warm-blooded animal such as man.

According to this aspect of the invention there is provided the use of a compound of the Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as man.

According to a further feature of the invention, there is provided the use of a compound of the Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries.

According to a further feature of the invention, there is provided the use of a compound of the Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of melanoma, glioma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, endometrium, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries.

According to a further aspect of the invention there is provided the use of a compound of the Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein in the production of a mTOR inhibitory effect in a warm-blooded animal such as man.

According to this aspect of the invention there is provided the use of a compound of the Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein in the production of an anti-cancer effect in a warm-blooded animal such as man.

According to a further feature of the invention, there is provided the use of a compound of the Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein in the treatment of melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries.

According to a further feature of the invention, there is provided the use of a compound of the Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein in the treatment of melanoma, glioma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, endometrium, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries.

According to a further feature of this aspect of the invention there is provided a method for producing a mTOR inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein.

According to a further feature of this aspect of the invention there is provided a method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein.

According to an additional feature of this aspect of the invention there is provided a method of treating melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula I, I(A), I(B), I(B)i or I(B)ii or a pharmaceutically acceptable salt thereof as defined herein.

According to an additional feature of this aspect of the invention there is provided a method of treating melanoma, glioma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, endometrium, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula I, I(A), I(B), I(B)i or I(B)ii or a pharmaceutically acceptable salt thereof as defined herein.

In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a mTOR inhibitory effect in a warm-blooded animal such as man.

In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an anti-cancer effect in a warm-blooded animal such as man.

In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as man.

In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of melanoma, glioma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, endometrium, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as man.

Another further aspect of the invention provides for the use of a compound of Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use as an adjunct in cancer therapy or for potentiating tumour cells for treatment with ionizing radiation or chemotherapeutic agents.

Other further aspects of the invention provide for the treatment of disease ameliorated by the inhibition of mTOR, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of Formula I, I(A), I(B), I(B)i or I(B)ii, or a pharmaceutically acceptable salt thereof, preferably in the form of a pharmaceutical composition and the treatment of cancer, comprising 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 composition, simultaneously or sequentially with ionizing radiation or chemotherapeutic agents.

DEFINITIONS

The term “aromatic ring” is used herein in the conventional sense to refer to a cyclic aromatic structure, that is, a structure having delocalised π-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 heterocylic ring containing at least one nitrogen ring atom. The term “together with the nitrogen to which they are bound, form a heterocyclic ring containing between 3 and 8 ring atoms” as used herein refers to a 3 to 8 membered heterocylic ring containing at least one nitrogen ring atom. Examples of these groups include, but are not limited to:

• • N₁: aziridine (C₃ ie 3 membered), azetidine (C₄ ie 4 membered), pyrrolidine (tetrahydropyrrole) (C₅ ie 5 membered), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C₅ ie 5 membered), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C₅ ie 5 membered), piperidine (C₆ ie 6 membered), dihydropyridine (C₆ ie 6 membered), tetrahydropyridine (C₆ ie 6 membered), azepine (C₇ ie 7 membered);
  • N₂: imidazolidine (C₅ ie 5 membered), pyrazolidine (diazolidine) (C₅ ie 5 membered), imidazoline (C₅ ie 5 membered), pyrazoline (dihydropyrazole) (C₅ ie 5 membered), piperazine (C₆ ie 6 membered);
  • N₁O₁: tetrahydrooxazole (C₅ ie 5 membered), dihydrooxazole (C₅ ie 5 membered), tetrahydroisoxazole (C₅ ie 5 membered), dihydroisoxazole (C₅ ie 5 membered), morpholine (C₆ ie 6 membered), tetrahydrooxazine (C₆ ie 6 membered), dihydrooxazine (C₆ ie 6 membered), oxazine (C₆ ie 6 membered);
  • N₁S₁: thiazoline (C₅ ie 5 membered), thiazolidine (C₅ ie 5 membered), thiomorpholine (C₆ ie 6 membered);
  • N₂O₁: oxadiazine (C₆ ie 6 membered);
  • N₁O₁S₁: oxathiazine (C₆ ie 6 membered).

Alkyl: The term “alkyl” as used herein, pertains to a monovalent moiety 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 be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated). Thus, the term “alkyl” includes the sub-classes saturated alkyl, alkenyl, alkynyl, saturated cycloalkyl, cycloalkyenyl, cylcoalkynyl, etc., discussed below. Unless otherwise specified, preferable “alkyl” groups are saturated alkyl or saturated cycloalkyl groups, more preferably saturated alkyl groups.

In the context of alkyl groups, the prefixes (e.g. C_1-4, C_1-7, C_1-20, C_2-7, C_3-7, etc.) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term “C_1-4 alkyl”, as used herein, pertains to an alkyl group having from 1 to 4 carbon atoms. Examples of groups of alkyl groups include C_1-4 alkyl (“lower alkyl”), C_1-7 alkyl, and C_1-20 alkyl. Note that the first prefix may vary according to other limitations; 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.

The term saturated alkyl group includes saturated linear alkyl and saturated branched alkyl.

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 (C₈), nonyl (C₉), decyl (C₁₀), undecyl (C₁₁), dodecyl (C₁₂), tridecyl (C₁₃), tetradecyl (C₁₄), pentadecyl (C₁₅), and eicodecyl (C₂₀).

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

Examples of (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, pertains to an alkyl group having one or more carbon-carbon double bonds. Examples of groups of alkenyl groups include C_2-4 alkenyl, C_2-7 alkenyl, C_2-20 alkenyl.

Examples 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, pertains to an alkyl group having one or more carbon-carbon triple bonds. Examples of groups of alkynyl groups include C_2-4 alkynyl, C_2-7 alkynyl, C_2-20 alkynyl.

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

Cycloalkyl: The term “cycloalkyl”, as used herein, pertains to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated), which moiety has from 3 to 20 carbon atoms (unless otherwise specified), including from 3 to 20 ring atoms. Thus, the term “cycloalkyl” includes the sub-classes cycloalkenyl and cycloalkynyl. Preferably, each ring has from 3 to 7 ring atoms. Examples of groups of cycloalkyl groups include C_3-20 cycloalkyl, C_3-15 cycloalkyl, C_3-10 cycloalkyl, C_3-7 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), dimethylcyclohexane (C₈), menthane (C₁₀);
  • unsaturated monocyclic hydrocarbon compounds: cyclopropene (C₃), cyclobutene (C₄), cyclopentene (C₅), cyclohexene (C₆), methylcyclopropene (C₄), dimethylcyclopropene (C₅), methylcyclobutene (C₅), dimethylcyclobutene (C₆), methylcyclopentene (C₆), dimethylcyclopentene (C₇), methylcyclohexene (C₇), dimethylcyclohexene (C₈);
  • saturated polycyclic hydrocarbon compounds: 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 (e.g., 2,3-dihydro-1H-indene) (C₉), tetraline (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, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified), of which from 1 to 10 are ring heteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms. Preferably the ring heteroatoms are selected from O, N and S. The heterocyclic ring may, unless otherwise specified, be carbon or nitrogen linked, and wherein a —CH₂— group can optionally be replaced by a —C(O)—, and a ring sulphur atom may be optionally oxidised to form the S-oxides.

In this context, the prefixes (e.g. C_3-20, C_3-7, C_5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term “C_5-6heterocyclyl” or “5 to 6 membered heterocyclyl”, as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms. Examples of groups of heterocyclyl groups include C_3-20 heterocyclyl (ie 3 to 20 membered heterocyclyl), C_5-20 heterocyclyl (ie 5 to 20 membered heterocyclyl), C_3-15 heterocyclyl (ie 3 to 15 membered heterocyclyl), C_5-15 heterocyclyl (ie 5 to 15 membered heterocyclyl), C_3-12 heterocyclyl (ie 3 to 12 membered heterocyclyl), C_5-12 heterocyclyl (ie 5 to 12 membered heterocyclyl), C_3-10 heterocyclyl (ie 3 to 10 membered heterocyclyl), C_5-10 heterocyclyl (ie 5 to 10 membered heterocyclyl), C_3-7 heterocyclyl (ie 3 to 7 membered heterocyclyl), C_5-7 heterocyclyl (ie 5 to 7 membered heterocyclyl), and C_5-6 heterocyclyl (ie 5 to 6 membered heterocyclyl).

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

• • N₁: aziridine (C₃ ie 3 membered), azetidine (C₄ ie 4 membered), pyrrolidine (tetrahydropyrrole) (C₅ ie 5 membered), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C₅ ie 5 membered), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C₅ ie 5 membered), piperidine (C₆ ie 6 membered), dihydropyridine (C₆ ie 6 membered), tetrahydropyridine (C₆ ie 6 membered), azepine (C₇ ie 7 membered);
  • O₁: oxirane (C₃ ie 3 membered), oxetane (C₄ ie 4 membered), oxolane (tetrahydrofuran) (C₅ ie 5 membered), oxole (dihydrofuran) (C₅ ie 5 membered), oxane (tetrahydropyran) (C₆ ie 6 membered), dihydropyran (C₆ ie 6 membered), pyran (C₆ ie 6 membered), oxepin (C₇ ie 7 membered);
  • S₁: thiirane (C₃ ie 3 membered), thietane (C₄ ie 4 membered), thiolane (tetrahydrothiophene) (C₅ ie 5 membered), thiane (tetrahydrothiopyran) (C₆ ie 6 membered), thiepane (C₇ ie 7 membered);
  • O₂: dioxolane (C₅ ie 5 membered), dioxane (C₆ ie 6 membered), and dioxepane (C₇ ie 7 membered);
  • O₃: trioxane (C₆ ie 6 membered);
  • N₂: imidazolidine (C₅ ie 5 membered), pyrazolidine (diazolidine) (C₅ ie 5 membered), imidazoline (C₅ ie 5 membered), pyrazoline (dihydropyrazole) (C₅ ie 5 membered), piperazine (C₆ ie 6 membered);
  • N₁O₁: tetrahydrooxazole (C₅ ie 5 membered), dihydrooxazole (C₅ ie 5 membered), tetrahydroisoxazole (C₅ ie 5 membered), dihydroisoxazole (C₅ ie 5 membered), morpholine (C₆ ie 6 membered), tetrahydrooxazine (C₆ ie 6 membered), dihydrooxazine (C₆ ie 6 membered), oxazine (C₆ ie 6 membered);
  • N₁S₁: thiazoline (C₅ ie 5 membered), thiazolidine (C₅ ie 5 membered), thiomorpholine (C₆ ie 6 membered);
  • N₂O₁: oxadiazine (C₆ ie 6 membered);
  • O₁S₁: oxathiole (C₅ ie 5 membered) and oxathiane (thioxane) (C₆ ie 6 membered); and,
  • N₁O₁S₁: oxathiazine (C₆ ie 6 membered).

Examples of substituted (non-aromatic) monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, furanoses (C₅ ie 5 membered), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C₆ ie 6 membered), such as allopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose.

Spiro-C_3-7 cycloalkyl or heterocyclyl: The term “spiro C_3-7 cycloalkyl or heterocyclyl” as used herein, refers to a C_3-7 cycloalkyl or C_3-7 heterocyclyl ring (3 to 7 membered) joined to another ring by a single atom common to both rings.

C_5-20 aryl: The term “C_5-20 aryl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a C_5-20 aromatic compound, said compound having one ring, or two or more rings (e.g., fused), and having from 5 to 20 ring atoms, and wherein at least one of said ring(s) 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 “C_5-20 carboaryl” group.

Examples of C_5-20 aryl groups which do not have ring heteroatoms (i.e. C_5-20 carboaryl groups) include, but are not limited to, those derived from benzene (i.e. phenyl) (C₆), naphthalene (C₁₀), anthracene (C₁₄), phenanthrene (C₁₄), and pyrene (C₁₆).

Alternatively, the ring atoms may include 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 “C_5-20 heteroaryl” group, wherein “C_5-20” denotes ring atoms, whether carbon atoms or heteroatoms. Preferably, each ring has from 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms. Commonly, heteroatoms are selected from oxygen, nitrogen or sulphur.

Examples of C_5-20 heteroaryl groups include, but are not limited to, C₅ heteroaryl groups (5 membered heteroaryl groups) derived from furan (oxole), thiophene (thiole), pyrrole (azole), imidazole (1,3-diazole), pyrazole (1,2-diazole), triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole and oxatriazole; and C₆ heteroaryl groups (6 membered heteroaryl groups) derived from isoxazine, pyridine (azine), pyridazine (1,2-diazine), pyrimidine (1,3-diazine; e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) and triazine.

The heteroaryl group may be bonded via a carbon or hetero ring atom.

Examples of C_5-20 heteroaryl groups which comprise fused rings, include, but are not limited to, C₉ heteroaryl groups (9 membered heteroaryl groups) derived from benzofuran, isobenzofuran, benzothiophene, indole, isoindole; C₁₀ heteroaryl groups (10 membered heteroaryl groups) derived from quinoline, isoquinoline, benzodiazine, pyridopyridine; C₁₄ heteroaryl groups (14 membered heteroaryl groups) derived from acridine and xanthene.

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

Halo: —F, —Cl, —Br, and —I.

Hydroxy: —OH.

Ether: —OR, wherein R is an ether substituent, for example, a C_1-7 alkyl group (also referred to as a C_1-7 alkoxy group), a C_3-20 heterocyclyl group (also referred to as a C_3-20 heterocyclyloxy group), or a C_5-20 aryl group (also referred to as a C_5-20 aryloxy group), preferably a C_1-7 alkyl group.

Nitro: —NO₂.

Cyano (nitrile, carbonitrile): —CN.

Acyl (keto): —C(═O)R, wherein R is an acyl substituent, for example, H, a C_1-7 alkyl group (also referred to as C_1-7 alkylacyl or C_1-7 alkanoyl), a C_3-20 heterocyclyl group (also referred to as C_3-20 heterocyclylacyl), or a C_5-20 aryl group (also referred to as C_5-20 arylacyl), preferably a C_1-7 alkyl group. Examples of acyl groups include, but are not limited to, —C(═O)CH₃ (acetyl), —C(═O)CH₂CH₃ (propionyl), —C(═O)C(CH₃)₃ (butyryl), and —C(═O)Ph (benzoyl, phenone).

Carboxy (carboxylic acid): —COOH.

Ester (carboxylate, carboxylic acid ester, oxycarbonyl): —C(═O)OR, wherein R is an ester 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 ester groups include, but are not limited to, —C(═O)OCH₃, —C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃, and —C(═O)OPh.

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

Amino: —NR¹R², wherein R¹ and R² are independently amino substituents, for example, hydrogen, a C_1-7 alkyl group (also referred to as C_1-7 alkylamino or di-C_1-7 alkylamino), a C_3-20 heterocyclyl group, or a C_5-20 aryl group, preferably H or a C_1-7 alkyl group, or, in the case of a “cyclic” amino group, R¹ and R², taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms. Examples of amino groups include, but are not limited to, —NH₂, —NHCH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₂CH₃)₂, and —NHPh. Examples of cyclic amino groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, perhydrodiazepinyl, morpholino, and thiomorpholino. The cyclic amino groups may be substituted on their ring by any of the substituents defined here, for example carboxy, carboxylate and amido.

Aminosulfonyl —S(═O)₂NR¹R², wherein R¹ and R² each independently is an amino substituent, as defined for amino groups. Examples of aminosulfony groups include, but are not limited to, —S(═O)₂NH₂—S(═O)₂NHCH₃, —S(═O)₂NHCH₂CH₃ and —S(═O)₂N(CH₃)₂.

Acylamido (acylamino): —NR¹C(═O)R², wherein R¹ is an amide substituent, for example, hydrogen, a C_1-7 alkyl group, a C_3-20 heterocyclyl group, or a C_5-20 aryl group, preferably H or a C_1-7 alkyl group, most preferably H, and R² 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 may together form a cyclic structure, as in, for example, 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, a C_1-7alkyl group, a C_3-20heterocyclyl group, or a C_5-20aryl group, preferably hydrogen or a C_1-7alkyl 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, wherein R is an acyloxy 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 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.

Thiol: —SH.

Thioether (sulfide): —SR, wherein R is a thioether substituent, for example, a C_1-7 alkyl group (also referred to as a C_1-7 alkylthio group), a C_3-20 heterocyclyl group, or a C_5-20 aryl group, preferably a C_1-7 alkyl group. Examples of C_1-7 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 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 sulfoxide groups include, but are not limited to, —S(═O)CH₃ and —S(═O)CH₂CH₃.

Sulfonyl (sulfone): —S(═O)₂R, wherein R is a sulfone substituent, for example, a 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 sulfone groups include, but are not limited to, —S(═O)₂CH₃ (methanesulfonyl, mesyl), —S(═O)₂CF₃, —S(═O)₂CH₂CH₃, and 4-methylphenylsulfonyl (tosyl).

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

Sulfonamino: —NR¹S(═O)₂R², wherein R¹ is an amino substituent, as defined for amino groups, and R is a sulfonamino substituent, for example, a C_1-7alkyl group, a C_3-20heterocyclyl group, or a C_5-20aryl group, preferably a C_1-7alkyl group. Examples of sulfonamino groups include, but are not limited to, —NHS(═O)₂CH₃, —NHS(═O)₂Ph and —N(CH₃)S(═O)₂C₆H₅.

In addition, two or more adjacent substituents may be linked such that together with the atoms to which they are attached from a C_3-7 cycloalkyl, C_3-20 heterocyclyl or C_5-20 aryl ring.

As mentioned above, the groups that form the above listed substituent groups, e.g. C_1-7 alkyl, C_3-20 heterocyclyl, and C_5-20 aryl, may themselves be substituted. Thus, the above definitions cover substituent groups which are substituted.

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

wherein:one or two of X⁵, X⁶ and X⁸ is N, and the others are CH;R⁷ is halo, OR^O1, SR^S1, NR^N1R^N2, NR^N7aC(═O)R^C1, NR^N7bSO₂R^S2a, a C_5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C_5-20 aryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),where R^O1 and R^S1 are H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl, or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^N1 and R^N2 are independently H, a C_1-7alkyl group, a C_5-20heteroaryl group, a C_5-20 aryl group or R^N1 and R^N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^C1 is H, a C_5-20 aryl group, a C_5-20 heteroaryl group, a C_1-7 alkyl group or NR^N8R^N9 where R^N8 and R^N9 are independently selected from H, a C_1-7 alkyl group, a C_5-20 heteroaryl group, a C_5-20 aryl group or R^N8 and R^N9 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic ring is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^S2a is H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^N7a and R^N7b are H or a C_1-4 alkyl group;R^N3 and R^N4, together with the nitrogen to which they are bound, form a heterocyclic ring containing between 3 and 8 ring atoms optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R² is H, halo, OR^O2, SR^S2b, NR^N5R^N6, a C_5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C_5-20 aryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),wherein R^O2 and R^S2b are H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^N5 and R^N6 are independently H, a C_1-7 alkyl group, a C_5-20 heteroaryl group, a C_5-20 aryl group, or R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic ring is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),or a pharmaceutically acceptable salt thereof,with the proviso that when R² is unsubstituted morpholino, R^N3 and R^N4 together with the nitrogen atom to which they are attached form an unsubstituted morpholino and R⁷ is unsubstituted phenyl, and X⁵ is CH, then X⁶ is not N and X⁸ is not CH, or X⁶ is not CH and X⁸ is not N, andwhen R² is unsubstituted piperidinyl, R^N3 and R^N4 together with the nitrogen atom to which they are attached form an unsubstituted piperidinyl and R⁷ is unsubstituted phenyl, and X⁵ is CH, then X⁶ is not CH and X⁸ is not N.

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

wherein:one or two of X⁵, X⁶ and X⁸ is N, and the others are CH;R^N3 and R^N4, together with the nitrogen to which they are bound, form a heterocyclic ring containing between 3 and 8 ring atoms optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R² is H, halo, OR^O2, SR^S2b, NR^N5R^N6, a C_5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or C_5-20 aryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),wherein R^O2 and R^S2b are H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^N5 and R^N6 are independently H, a C_1-7 alkyl group, a C_5-20 heteroaryl group, a C_5-20 aryl group, or R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic ring is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^O3 is hydrogen or a C_1-6 alkyl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); andR^N10 is C(═O)R^C2, C(═S)R^C3, SO₂R^S3, a C_5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), a C_5-20 aryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C_1-10 alkyl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),where R^C2 and R^C3 are H, a C_5-20 aryl group, a C_5-20 heteroaryl group, a C_1-7 alkyl group or NR^N11R^N12, where R^N11 and R^N12 are independently H, a C_1-7 alkyl group, a C_5-20 heteroaryl group, a C_5-20 aryl group or R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic ring is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), and R^S3 is H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof, wherein:one or two of X⁵, X⁶ and X⁸ is N, and the others are CH;R⁷ is halo, OR^O1, SR^S1, NR^N1R^N2, NR^N7aC(═O)R^C1, NR^N7bSO₂R^S2a, a C_5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C_5-20 aryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),where R^O1 and R^S1 are H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl, or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^N1 and R^N2 are independently H, a C_1-7alkyl group, a C_5-20heteroaryl group, a C_5-20 aryl group or R^N1 and R^N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^C1 is H, a C_5-20 aryl group, a C_5-20 heteroaryl group, a C_1-7 alkyl group or NR^N8R^N9 where R^N8 and R^N9 are independently selected from H, a C_1-7 alkyl group, a C_5-20 heteroaryl group, a C_5-20 aryl group or R^N8 and R^N9 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic ring is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^S2a is H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);

• • R^N7a and R^N7b are H or a C_1-4 alkyl group;
  • R² is H, halo, OR^O2, SR^S2b, NR^N5R^N6, a C_5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C_5-20 aryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),wherein R^O2 and R^S2b are H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^N5 and R^N6 are independently H, a C_1-7 alkyl group, a C_5-20 heteroaryl group, a C_5-20 aryl group, or R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic ring is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-2 heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino).

According to a further aspect of the present invention there is provided a compound of formula I(B)i or I(B)ii:

or a pharmaceutically acceptable salt thereof, wherein:one or two of X⁵, X⁶ and X⁸ is N, and the others are CH;R⁷ is halo, OR^O1, SR^S1, NR^N1R^N2, NR^N7aC(═O)R^C1, NR^N7bSO₂R^S2a, a C_5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C_5-20 aryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),where R^O1 and R^S1 are H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl, or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-2 heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^N1 and R^N2 are independently H, a C_1-7alkyl group, a C_5-20heteroaryl group, a C_5-20 aryl group or R^N1 and R^N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^C1 is H, a C_5-20 aryl group, a C_5-20 heteroaryl group, a C_1-7 alkyl group or NR^N8R^N9 where R^N8 and R^N9 are independently selected from H, a C_1-7 alkyl group, a C_5-20 heteroaryl group, a C_5-20 aryl group or R^N8 and R^N9 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic ring is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20 aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^S2a is H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^N7a and R^N7b are H or a C_1-4 alkyl group;R² is H, halo, OR^O2, SR^S2b, NR^N5R^N6, a C_5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C_5-20 aryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-2 aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),wherein R^O2 and R^S2b are H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^N5 and R^N6 are independently H, a C_1-7 alkyl group, a C_5-20 heteroaryl group, a C_5-20 aryl group, or R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic ring is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino).

According to a further aspect of the present invention there is provided a compound of formula I(B)i:

or a pharmaceutically acceptable salt thereof, wherein:one or two of X⁵, X⁶ and X⁸ is N, and the others are CH;R⁷ is halo, OR^O1, SR^S1, NR^N1R^N2, NR^N7aC(═O)R^C1, NR^N7bSO₂R^S2a, a C_5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C_5-20 aryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-2 aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),where R^O1 and R^S1 are H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl, or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^N1 and R^N2 are independently H, a C_1-7alkyl group, a C_5-20heteroaryl group, a C_5-20 aryl group or R^N1 and R^N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^C1 is H, a C_5-20 aryl group, a C_5-20 heteroaryl group, a C_1-7 alkyl group or NR^N8R^N9 where R^N8 and R^N9 are independently selected from H, a C_1-7 alkyl group, a C_5-20 heteroaryl group, a C_5-20 aryl group or R^N8 and R^N9 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic ring is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^S2a is H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^N7a and R^N7b are H or a C_1-4 alkyl group;R² is H, halo, OR^O2, SR^S2b, NR^N5R^N6, a C_5-20 heteroaryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C_5-20 aryl group optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino),wherein R^O2 and R^S2b are H, a C_5-20 aryl group, a C_5-20 heteroaryl group, or a C_1-7 alkyl group where each C_1-7alkyl, C_5-20heteroaryl or C_5-20aryl is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);R^N5 and R^N6 are independently H, a C_1-7 alkyl group, a C_5-20 heteroaryl group, a C_5-20 aryl group, or R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms where each C_1-7alkyl, C_5-20heteroaryl, C_5-20aryl or heterocyclic ring is optionally substituted by one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, and thiol, or C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxy, thiol, C_1-7alkyl, C_2-7alkenyl, C_2-7alkynyl, C_3-7cycloalkyl, C_3-7cycloalkenyl, C_3-20heterocyclyl, C_5-20aryl, C_5-20heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino).

Further Preferences

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

X⁵, X⁶, and X⁸

When two of X⁵, X⁶ and X⁸ are N, preferably X⁵ and X⁸ are N.

It is preferred that only one of X⁵, X⁶ and X⁸ is N. More preferably one of X⁵ and X⁸ is N, and most preferably X⁸ is N.

R⁷

R⁷ is preferably selected from an optionally substituted C_5-20 aryl group, OR^O1, SR^S1, NR^N1R^N2, NR^N7aC(═O)R^C1 and NR^N7bSO₂R^S2a, where R^O1, R^S1, R^N1, R^N2, R^N7a, R^N7b, R^C1 and R^S2a are as previously defined. It is further preferred that R⁷ is preferably selected from an optionally substituted C_5-20 aryl group, OR^O1, NR^N1R^N2, NR^N7aC(O)R^C1 and NR^N7bSO₂R^S2a.

If R⁷ is OR^O1, then preferably R^O1 is a C_1-7 alkyl group, which may be substituted.

If R⁷ is NR^N1R^N2, then preferably R^N2 is selected from H and C_1-4 alkyl (e.g. methyl) and more preferably is H. If R^N1 is C_1-7 alkyl, it is preferably selected from C_3-7 cycloalkyl. If R^N1 is C_5-20 aryl, it is preferably selected from C_5-10 aryl and more preferably C_5-6 aryl (e.g. phenyl, pyrrolyl, pyridyl, furanyl, thiophenyl, pyrazinyl, pyrimidinyl, thiazolyl, imidazolyl, triazolyl, oxadiazolyl). Particularly preferred groups include phenyl, pyridyl, pyrrolyl, and thiophenyl. The aforementioned groups are optionally substituted, and in some embodiments are preferably substituted. Substituent groups may include, but are not limited to, C_1-7 alkyl, C_3-20 heterocyclyl, C_5-20 aryl, carboxy, ester, hydroxy, aryloxy, cyano, halo, nitro, and amino.

If R⁷ is NR^N1R^N2, then preferably R^N2 is selected from H and C_1-4 alkyl (e.g. methyl) and more preferably is H. If R^N1 is C_1-7 alkyl, it is preferably selected from C_3-7 cycloalkyl. If R^N1 is C_5-20 aryl, it is preferably selected from C_5-10 aryl (e.g. phenyl, pyrrolyl, pyridyl, pyrazolyl, furanyl, thiophenyl, pyrazinyl, pyrimidinyl, tetrazolyl, thiazolyl, indazolyl, imidazolyl, triazolyl, oxadiazolyl) and more preferably C_5-6 aryl (e.g. phenyl, pyrrolyl, pyridyl, pyrazolyl, furanyl, thiophenyl, pyrazinyl, pyrimidinyl, tetrazolyl, thiazolyl, imidazolyl, triazolyl, oxadiazolyl). Particularly preferred groups include furyl, phenyl, pyridyl, pyrrolyl, pyrazolyl and thiophenyl. The aforementioned groups are optionally substituted, and in some embodiments are preferably substituted. Substituent groups may include, but are not limited to, C_1-7 alkyl, C_3-20 heterocyclyl, C_5-20 aryl, carboxy, ester, ether (eg C_1-7alkoxy), hydroxy, aryloxy, cyano, halo, nitro, amido, sulfonyl, sulfonylamino, amino sulfonyl and amino.

If R⁷ is NR^N7aC(═O)R^C1, then R^N7a is preferably H. R^C1 may be an optionally substituted C_5-20 aryl group (e.g. phenyl, imidazolyl, quinoxalinyl), C_3-20 heterocyclyl, C_1-7 alkyl (e.g. propenyl, methyl (substituted with thiophenyl)) or NR^N8R^N9. R^N8 is preferably hydrogen, and R^N9 is preferably C_1-7 alkyl (e.g. ethyl).

If R⁷ is NR^N7bSO₂R^S2a, then R^N7b is preferably H. R^S2a is preferably C_1-7 alkyl (e.g. methyl).

If R⁷ is a C_5-20 aryl group, it is preferably a C_5-10 aryl and more preferably C_5-6 aryl group. Most preferably R⁷ is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy.

If R⁷ is a C_5-20 aryl group, it is preferably an optionally substituted C_5-10 aryl and more preferably an optionally substituted C_5-6 aryl group. Most preferably it is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6arylamino and C_1-7alkylamino and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6aryl, C_5-6arylamino and C_1-7alkylamino.

In one embodiment, R⁷ is an optionally substituted C_5-10 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C_1-7 alkyl and C_1-7 alkoxy (wherein the alkyl groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl). In another embodiment, R⁷ is an optionally substituted C_5-6 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C_1-7 alkyl and C_1-7 alkoxy (wherein the alkyl groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl). In a further embodiment R⁷ is a thiophenyl group or a phenyl group optionally substituted by one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl. In a further embodiment R⁷ is 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or a 3-hydroxymethylphenyl group. In a still further embodiment R⁷ is an aryl group as defined in any of examples 1a, 1b, 1d, 1e, 1f, 1g, 1i, 1k, 1l, 1m, 1n, 1o, 1p, 1q, 1bb, 1bc, 1bd, 1be, 1bf, 1bg, 1bh, 1bi, 1bj or 1br.

If R⁷ is a 5 to 20 membered heteroaryl group, it is preferably an optionally substituted 5 to 10 membered heteroaryl and more preferably an optionally substituted 5 or 6 membered heteroaryl group.

In one embodiment, R⁷ is an optionally substituted C_5-20 aryl group or an optionally substituted 5 to 20 membered heteroaryl group, wherein the optional substituents are preferably selected from halo, hydroxyl, cyano, C_1-7 alkyl, C_1-7alkoxy, sulfonamino (for example —NHS(═O)₂C_1-7alkyl)amino (for example —NH₂, C_5-6arylamino, C_1-7alkylamino, and di-(C_1-7alkyl)amino), and amido (for example —CONH₂, —CONHC_1-7alkyl, —CON(C_1-7alkyl)₂ and —CONHheterocycyl) and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6aryl, —NHS(═O)₂C_1-7alkyl, C_5-6arylamino, di-(C_1-7alkyl)amino and C_1-7alkylamino.

In one embodiment, R⁷ is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from halo, hydroxyl, cyano, C_1-7 alkyl, C_1-7alkoxy, sulfonamino (for example —NHS(═O)₂C_1-7alkyl)amino (for example —NH₂, C_5-6arylamino, C_1-7alkylamino, and di-(C_1-7alkyl)amino), and amido (for example —CONH₂, —CONHC_1-7alkyl, —CON(C_1-7alkyl)₂ and —CONHheterocycyl) and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6aryl, —NHS(═O)₂C_1-7alkyl, C_5-6arylamino, di-(C_1-7alkyl)amino and C_1-7alkylamino.

In one embodiment, R⁷ is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from halo, hydroxyl, cyano, C_1-7 alkyl, C_1-7alkoxy, amino (for example —NH₂, C_5-6arylamino, C_1-7alkylamino, and di-(C_1-7alkyl)amino), and amido (for example —CONH₂, —CONHC_1-7alkyl, —CON(C_1-7alkyl)₂ and —CONHheterocycyl) and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6aryl, C_5-6arylamino, di-(C_1-7alkyl)amino and C_1-7alkylamino.

In one embodiment, R⁷ is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from fluoro, hydroxyl, cyano, nitro, methyl, methoxy, —OCH₂CH₃, —NH₂, —NHSO₂CH₃, —CH₂NHSO₂CH₃, —OCHF₂, —CH₂OH, —CO₂H, —CONH₂, —CONHMe, —CONHEt, —CONHCH(CH₃)₂, —CONHCH₂CH₂F, —CONHCH₂CHF₂, —CONHCH₂CH₂OH, —CONMeEt, —CONMe₂, N-methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl.

In one embodiment, R⁷ is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from fluoro, hydroxyl, cyano, nitro, methyl, methoxy, —CH₂OH, —CO₂H, —CONH₂, —CONHMe, —CONHEt, —CONHCH₂CH₂F, —CONHCH₂CHF₂, —CONHCH₂CH₂OH, —CONMeEt, —CONMe₂, N-methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl.

In one embodiment, R⁷ is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from methoxy, —OCH₂CH₃, —NH₂, —NHSO₂CH₃, —CH₂NHSO₂CH₃, —OCHF₂, —CH₂OH, —CONH₂, —CONHMe and —CONHCH(CH₃)₂.

In one embodiment R⁷ is an optionally substituted 5 or 6 membered nitrogen containing heteroaryl group such as a pyridine group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C_1-7 alkyl, C_1-7alkoxy, amino (for example —NH₂, C_5-6arylamino, C_1-7alkylamino, and di-(C_1-7alkyl)amino), and amido (for example —CO₂NH₂, —CO₂NHC_1-7alkyl, —CO₂N(C_1-7alkyl)₂ and —CONHheterocycyl) and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6aryl, C_5-6arylamino, di-(C_1-7alkyl)amino and C_1-7alkylamino.

In one embodiment, R⁷ is a pyridinyl group optionally substituted halo, hydroxyl, cyano, C_1-7 alkyl, C_1-7alkoxy, amino (for example —NH₂, C_5-6arylamino, C_1-7alkylamino, and di-(C_1-7alkyl)amino), and amido (for example —CO₂NH₂, —CO₂NHC_1-7alkyl, —CO₂N(C_1-7alkyl)₂ and —CONHheterocycyl) and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6aryl, C_5-6arylamino, di-(C_1-7alkyl)amino and C_1-7alkylamino.

In one embodiment, R⁷ is a pyridinyl group optionally substituted with NH₂.

In one embodiment, R⁷ is an optionally substituted phenyl group selected from

wherein

Z is H, F or OR^O3;

R^O3 is selected from hydrogen or an optionally substituted C_1-6 alkyl group; R^N10 is selected from hydrogen, C(O)R^C2, C(S)R^C3, SO₂R^S3, an optionally substituted C_5-20 heterocyclyl group, an optionally substituted C_5-20 aryl group, or an optionally substituted C_1-10 alkyl group where R^C2 and R^C3 are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heterocyclyl group, an optionally substituted C_1-7 alkyl group or NR^N11R^N12, where R^N11 and R^N12 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heterocyclyl group, an optionally substituted C_5-20 aryl group or R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms; and R^S3 is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, or an optionally substituted C_1-7 alkyl group;R^N10a is selected from hydrogen or an optionally substituted C_1-10 alkyl group; orR^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms.

In one embodiment, R⁷ is an optionally substituted phenyl group selected from

whereinR^O3 is selected from hydrogen or an optionally substituted C_1-6 alkyl group; andR^N10 is selected from C(O)R^C2, C(S)R^C3, SO₂R^S3, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_5-20 aryl group, or an optionally substituted C_1-10 alkyl group where R^C2 and R^C3 are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_1-7 alkyl group or NR^N11R^N12, where R^N11 and R^N12 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_5-20 aryl group or R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms; and R^S3 is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, or an optionally substituted C_1-7 alkyl group.

In one embodiment, R⁷ is

wherein

Z is H, F or OR^O3;

R^N10 is selected from hydrogen, C(O)R^C2, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_5-20 aryl group, or an optionally substituted C_1-10 alkyl group where R^C2 are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heterocyclyl group, an optionally substituted C_1-7 alkyl group or NR^N11R^N12, where R^N11 and R^N12 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heterocycly group, an optionally substituted C_5-20 aryl group or R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;R^N10a is selected from hydrogen or an optionally substituted C_1-10 alkyl group; orR^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms.

In one embodiment, R⁷ is

wherein

Z is H, F or OR^O3;

R^N10 is selected from hydrogen, C(O)R^C2, an optionally substituted C_5-6 heteroaryl group, an optionally substituted C₆ aryl group, or an optionally substituted C_1-10 alkyl group where R^C2 are selected from CH₃ or CH₂OH;R^N10a is selected from hydrogen or an optionally substituted C_1-10 alkyl group; orR^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms;and where the optional substituents are selected from cyano, halo, hydroxyl, C_1-7alkyloxy, C_1-7alkylamino and di-C_1-7alkylamino.

In one embodiment, R⁷ is

wherein

Z is H, For OR^O3;

R^N10 is selected from hydrogen, —C(O)CH₃, —C(O)CH₂OH, —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH(CH₃)₂, —CH₂CH₂OMe, —CH₂C(CH₃)₂, —CH₂CH₂C(CH₃)₂, —CH(CH₃)CH₂C(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, —CH₂cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, —CH₂imidazole;R^N10a is hydrogen; orR^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms;and where the optional substituents are selected from halo, hydroxyl, C_1-7alkyloxy.

In a further embodiment of the invention R⁷ is selected from

R^N10

R^N10 is preferably selected from C(═S)R^C3, 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 where R^C3 is as previously defined.

If R^N10 is C(═S)R^C3, then preferably R^C3 is NR^N11R^N12, where R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms.

If R^N10 is a C_5-20 heteroaryl group, it is preferably a C_5-10 heteroaryl group and more preferably C_5-6 heteroaryl group. Most preferably it is an optionally substituted pyrazole group, wherein the optional substituents are preferably selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy.

If R^N10 is a C_5-20 aryl group, it is preferably a C_5-10 aryl and more preferably C_5-6 aryl group. Most preferably it is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy.

If R^N10 is a C_1-10 alkyl group, it is preferably a C_1-10 alkyl group and more preferably C_1-10 alkyl group. Most preferably it is an optionally substituted C_1-6 alkyl group, wherein the optional substituents are preferably selected from halo, hydroxyl, C_1-7 alkyl, ether, for example C_1-7 alkoxy, thioether, for example C_1-7 alkylthio, C_5-20 aryl, C_3-20 heterocyclyl, C_5-20 heteroaryl, cyano, ester, for example —C(═O)OR where R is C_1-7alkyl, and amino, for example C_1-7alkylamino, di-C_1-7alkylamino and C_1-7alkoxycarbonylamino.

In one embodiment R^N10 is a group as shown in any of examples 8a, 8b, 8c, 8d, 8e, 8f, 8g, 8h, 8i, 8j, 8k, 8l, 8m, 8n, 8o, 8t, 8u, 8aa, 8ab, 8ac, 8ad, 8ae, 8af, 8ag, 8ah, 8ai, 8aj, 8ak, 8al, 8am, 8an, 8ao, 8ap, 8aq, 8ar, 8as, 8at, 8au, 8av, 8aw, 8ax, 8ay, 8az, 8ba, 8bb, 8bc, 8bd, 8be and 8bg.

R^O3

R^O3 is preferably an optionally substituted C_1-6 alkyl group. More preferably R^O3 is an unsubstituted C_1-3 alkyl group, preferably a methyl group.

R^N3 and R^N4

R^N3 and R^N4 together with the nitrogen to which they are bound preferably form a heterocyclic ring containing between 5 and 7 ring atoms, which may optionally be substituted. Preferred optionally substituted groups include, but are not limited, to morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) and pyrrolidinyl.

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

R²

In one embodiment R² is OR^O2 where R^O2 is an optionally substituted C_1-7alkyl group.

In one embodiment R² is OR^O2 where R^O2 is —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, or —CH(CH₃)CH₂N(CH₃)₂.

In one embodiment R² is selected from NR^N5R^N6, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group.

In another embodiment R² is selected from NR^N5R^N6, an optionally substituted C_5-6 heteroaryl group, and an optionally substituted C₆ aryl group.

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

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

Preferably R² is NR^N5R^N6, where R^N5 and R^N6 are as previously defined, and more preferably R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, which may optionally be substituted. The ring preferably has from 5 to 7 ring atoms. Preferred optionally substituted groups include, but are not limited, to morpholino, thiomorpholino, piperadinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) and pyrrolidinyl.

Preferably R² is NR^N5R^N6, where R^N5 and R^N6 are as previously defined, and more preferably R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, which may optionally be substituted. The ring preferably has from 5 to 7 ring atoms. Preferred optionally substituted groups include, but are not limited, to imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) and pyrrolidinyl.

Preferred N-substituents for the piperazinyl and homopiperazinyl groups include esters, in particular, esters bearing a C_1-7 alkyl group as an ester substituent, e.g. —C(═O)OCH₃, —C(═O)OCH₂CH₃ and —C(═O)OC(CH₃)₃.

Preferred N-substituents for the piperazinyl and homopiperazinyl groups include C_1-7alkyl groups or esters, in particular, esters bearing a C_1-7 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 C_1-4 alkyl, preferably methyl. The groups may bear one or more substituents, for example one or two substituents.

Preferred C-substituents for the groups include phenyl, ester, amide and C_1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl. The groups may bear one or more substituents, for example one or two substituents.

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

In one embodiment R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing 5 to 7 ring atoms which may be optionally be substituted, wherein the optional substituents are selected from amino, cyano, halo, hydroxyl, ester, a C_3-7 cycloalkyl ring, a C₆carboaryl ring, a heterocyclic ring containing 5 to 7 ring atoms and C_1-7 saturated alkyl and C_1-7 saturated alkoxy (wherein the heterocyclic ring, the cycloalkyl ring, the carboaryl ring, the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl)

In one embodiment R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 5 to 7 ring atoms which may be optionally be substituted, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C_1-7 saturated alkyl and C_1-7 saturated alkoxy (wherein the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl)

In one embodiment R² is NR^N5R^N6, where R^N5 is an optionally substituted C_1-7alkyl group or an optionally substituted phenyl group, and R^N6 is hydrogen.

In one embodiment R² is NR^N5R^N6, where R^N5 is —CH(CH₃)CH₂OCH₃, cyclopentyl or a phenyl group, and R^N6 is hydrogen.

More preferred groups are morpholino and piperadinyl. These are preferably substituted with one or more alkyl substituents, for example methyl or ethyl substituents. More preferably these are substituted with one or two methyl substituents. If these groups bear two methyl substituents, these are preferably on separate carbon atoms. Particularly preferred groups include methylmorpholino groups, dimethylmorpholino groups and methyl piperidinyl groups, for example:

Preferred R² groups are pyrrolidinyl, morpholino, piperadinyl and homopiperadinyl groups. More preferred groups are morpholino and piperadinyl. These are preferably substituted with one or more alkyl substituents, for example methyl or ethyl substituents. More preferably these are substituted with one or two methyl substituents. If these groups bear two methyl substituents, these are preferably on separate carbon atoms. The alkyl substituents may also be optionally substituted. Examples of optional substituents of the alkyl substitutents include halo, hydroxy, ether or amino. Particularly preferred groups include methylmorpholino groups, dimethylmorpholino groups and methyl piperidinyl groups, for example:

Preferred R² groups are pyrrolidinyl, morpholino, piperadinyl and homopiperadinyl groups. More preferred groups are morpholino and piperadinyl. These are preferably substituted with one or more alkyl substituents, for example methyl or ethyl substituents. More preferably these are substituted with one or two methyl substituents. If these groups bear two methyl substituents, these are preferably on separate carbon atoms. The alkyl substituents may also be optionally substituted. Examples of optional substituents of the alkyl substitutents include halo, hydroxy, ether or amino. Particularly preferred groups include methylmorpholino groups, dimethylmorpholino groups and methyl piperidinyl groups, for example:

Further preferred R² groups are optionally substituted pyrrolidinyl, morpholino, piperadinyl and homopiperadinyl wherein the optional substituents are selected from hydroxyl, C_1-7 alkyl, C_1-7alkoxy, amino (for example —NH₂, C_5-6arylamino, C_1-7alkylamino, and di-(C_1-7alkyl)amino), amido (for example —CONH₂, —CONHC_1-7alkyl, —CON(C_1-7alkyl)₂), ester (for example —CO₂C_1-7alkyl), C₆aryl and 3 to 7 membered heterocyclyl group and wherein the substitutent alkyl, alkoxy, aryl or heterocyclyl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, —NH₂, di-(C_1-7alkyl)amino and C_1-7alkylamino. More preferred groups are morpholino, piperadinyl and homopiperadinyl which may be optionally substituted by one or more groups selected from hydroxyl, methyl, ethyl, —CO₂Me, —CO₂Et, —CH₂OH, —CH₂Ome, —CH₂NMe₂, —CONH₂, —CONHMe, —CONMe₂, phenyl, pyrrolidinyl, morpholino and piperadinyl.

In a further embodiment of the invention R² is selected from

In a further embodiment of the invention R² is selected from

In a further embodiment of the invention R² is selected from

In an embodiment of the invention, there is provided a subset of compounds of formula (I), and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N;
  • R⁷ is selected from an optionally substituted C_5-20 aryl group, OR^O1, NR^N1R^N2, NR^N7aC(═O)R^C1 and NR^N7bSO₂R^S2a;
  • R^N3 and R^N4 together with the nitrogen to which they are bound form a heterocyclic ring containing between 5 and 7 ring atoms, which may optionally be substituted; and
  • R² is selected from NR^N5R^N6, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group.

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

• • only one of X⁵, X⁶ and X⁸ is N;
  • R⁷ is an optionally substituted C_5-6 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C_1-7 alkyl and C_1-7 alkoxy (wherein the alkyl groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl);
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and
  • R² is selected from NR^N5R^N6, an optionally substituted C_5-6 heteroaryl group, and an optionally substituted C₆ aryl group.

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

• • only one of X⁵, X⁶ and X⁸ is N;
  • R⁷ is an optionally substituted C_5-6 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C_1-7 alkyl and C_1-7 alkoxy (wherein the alkyl groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl);
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 5 to 7 ring atoms which may be optionally be substituted.

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

• • only one of X⁵, X⁶ and X⁸ is N;
  • R⁷ is an optionally substituted C_5-6 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C_1-7 alkyl and C_1-7 alkoxy (wherein the alkyl groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl);
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group.

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

• • X⁸ is N;
  • R⁷ is a thiophenyl group or a phenyl group optionally substituted by one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl;
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group.

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

• • X⁸ is N;
  • R⁷ is a thiophenyl group or a phenyl group optionally substituted by one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl;
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group optionally substituted on carbon with one or more C_1-4alkyl groups.

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

• • X⁸ is N;
  • R⁷ is a thiophenyl group or a phenyl group optionally substituted by one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl;
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form a morpholino or thiomorpholino; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group optionally substituted on carbon with one or more C_1-4alkyl groups.

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

• • X⁸ is N:
  • R⁷ is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or a 3-hydroxymethylphenyl group;
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form a morpholino or thiomorpholino; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a

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

• • X⁸ is N;
  • R⁷ is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or a 3-hydroxymethylphenyl group;
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form an unsubstituted morpholino; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a

In an embodiment of the invention, there is provided a subset of compounds of formula I(A), and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N;
  • R^N10 is selected from C(═S)R^C3, 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 where R^C3 is as previously defined;
  • R^O3 is an optionally substituted C_1-6 alkyl group;
  • R^N3 and R^N4 together with the nitrogen to which they are bound form a heterocyclic ring containing between 5 and 7 ring atoms, which may optionally be substituted; and
  • R² is selected from NR^N5R^N6, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group.

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

• • only one of X⁵, X⁶ and X⁸ is N;
  • R^N10 is C(═S)R^C3, an optionally substituted C_5-6 heteroaryl group, an optionally substituted C_5-6 aryl group or an optionally substituted C_1-10 alkyl group where R^C3 is NR^N11R^N12 and where R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;
  • R^O3 is an unsubstituted C_1-3 alkyl group;
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and
  • R² is selected from NR^N5R^N6, an optionally substituted C_5-6 heteroaryl group, and an optionally substituted C₆ aryl group.

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

• • only one of X⁵, X⁶ and X⁸ is N;
  • R^N10 is a C(═S)NR^N11R^N12 group where R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, or a pyrazole group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy, or a phenyl group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy, or a C_1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl, ether, for example C_1-7 alkoxy, thioether, for example C_1-7 alkylthio, C_5-20 aryl, C_3-20 heterocyclyl, C_5-20 heteroaryl, cyano, ester, for example —C(═O)OR where R is C_1-7alkyl, and amino, for example C_1-7alkylamino, di-C_1-7alkylamino and C_1-7alkoxycarbonylamino;
  • R^O3 is a methyl group;
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 5 to 7 ring atoms which may be optionally be substituted.

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

• • only one of X⁵, X⁶ and X⁸ is N;
  • R^N10 is a C(═S)NR^N11R^N12 group where R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, or a pyrazole group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy, or a phenyl group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy, or a C_1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl, ether, for example C_1-7 alkoxy, thioether, for example C_1-7 alkylthio, C_5-20 aryl, C_3-20 heterocyclyl, C_5-20 heteroaryl, cyano, ester, for example —C(═O)OR where R is C_1-7alkyl, and amino, for example C_1-7alkylamino, di-C_1-7alkylamino and C_1-7alkoxycarbonylamino;
  • R^O3 is a methyl group;
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group.

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

• • X⁸ is N;
  • R^N10 is a C(═S)NR^N11R^N12 group where R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, or a pyrazole group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy, or a phenyl group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy, or a C_1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl, ether, for example C_1-7 alkoxy, thioether, for example C_1-7 alkylthio, C_5-20 aryl, C_3-20 heterocyclyl, C_5-20 heteroaryl, cyano, ester, for example —C(═O)OR where R is C_1-7alkyl, and amino, for example C_1-7alkylamino, di-C_1-7alkylamino and C_1-7alkoxycarbonylamino;
  • R^O3 is a methyl group;
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group.

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

• • X⁸ is N;
  • R^N10 is a C(═S)NR^N11R^N12 group where R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, or a pyrazole group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy, or a phenyl group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy, or a C_1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl, ether, for example C_1-7 alkoxy, thioether, for example C_1-7 alkylthio, C_5-20 aryl, C_3-20 heterocyclyl, C_5-20 heteroaryl, cyano, ester, for example —C(═O)OR where R is C_1-7alkyl, and amino, for example C_1-7alkylamino, di-C_1-7alkylamino and C_1-7alkoxycarbonylamino;
  • R^O3 is a methyl group;
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form a morpholino or thiomorpholino group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group optionally substituted on carbon by one or more C_1-4alkyl groups.

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

• • X⁸ is N;
  • R^N10 is a C(═S)NR^N11R^N12 group where R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, or a pyrazole group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy, or a phenyl group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy, or a C_1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl, ether, for example C_1-7 alkoxy, thioether, for example C_1-7 alkylthio, C_5-20 aryl, C_3-20 heterocyclyl, C_5-20 heteroaryl, cyano, ester, for example —C(═O)OR where R is C_1-7alkyl, and amino, for example C_1-7alkylamino, di-C_1-7alkylamino and C_1-7alkoxycarbonylamino;
  • R^O3 is a methyl group;
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form a morpholino or thiomorpholino group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a

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

• • X⁸ is N;
  • R^N10 is a C(═S)NR^N11R^N12 group where R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, or a pyrazole group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy, or a phenyl group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl and C_1-7 alkoxy, or a C_1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxyl, C_1-7 alkyl, ether, for example C_1-7 alkoxy, thioether, for example C_1-7 alkylthio, C_5-20 aryl, C_3-20 heterocyclyl, C_5-20 heteroaryl, cyano, ester, for example —C(═O)OR where R is C_1-7alkyl, and amino, for example C_1-7alkylamino, di-C_1-7alkylamino and C_1-7alkoxycarbonylamino;
  • R^O3 is a methyl group;
  • R^N3 and R^N4 together with the nitrogen to which they are bound preferably form an unsubstituted morpholino group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a

In an embodiment of the invention, there is provided a subset of compounds of Formula I(B) or I(B)i, and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N;
  • R⁷ is selected from an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteraryl group, OR^O1, NR^N1R^N2, NR^N7aC(═O)R^C1 and NR^N7bSO₂R^S2a; and
  • R² is selected from OR^O2, NR^N5R^N6, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group.

In another embodiment, there is provided a subset of compounds of Formula I(B), or I(B)i, and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N;
  • R⁷ is an optionally substituted C_5-6 aryl group or an optionally substituted 5 or 6 membered heteraryl group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C_1-7 alkyl, C_1-7alkoxy, amino (for example —NH₂, C_5-6arylamino, C_1-7alkylamino, and di-(C_1-7alkyl)amino), and amido (for example —CONH₂, —CONHC_1-7alkyl, —CON(C_1-7alkyl)₂ and —CONHheterocycyl) and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6aryl, C_5-6arylamino, di-(C_1-7alkyl)amino and C_1-7alkylamino; and
  • R² is selected from OR^O2, NR^N5R^N6, an optionally substituted C_5-6 heteroaryl group, and an optionally substituted C₆ aryl group.

In another embodiment, there is provided a subset of compounds of Formula I(B), or I(B)i, and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N;
  • R⁷ is an optionally substituted C_5-6 aryl group or an optionally substituted 5 or 6 membered heteraryl group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C_1-7 alkyl, C_1-7alkoxy, amino (for example —NH₂, C_5-6arylamino, C_1-7alkylamino, and di-(C_1-7alkyl)amino), and amido (for example —CONH₂, —CONHC_1-7alkyl, —CON(C_1-7alkyl)₂ and —CONHheterocycyl) and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6aryl, C_5-6arylamino, di-(C_1-7alkyl)amino and C_1-7alkylamino; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 5 to 7 ring atoms which may be optionally be substituted, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C_1-7 saturated alkyl and C_1-7 saturated alkoxy (wherein the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl).

In a further embodiment, there is provided a subset of compounds of Formula I(B), or I(B)i, and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N;
  • R⁷ is an optionally substituted C_5-6 aryl group or an optionally substituted 5 or 6 membered heteraryl group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C_1-7 alkyl, C_1-7alkoxy, amino (for example —NH₂, C_5-6arylamino, C_1-7alkylamino, and di-(C_1-7alkyl)amino), and amido (for example —CONH₂, —CONHC_1-7alkyl, —CON(C_1-7alkyl)₂ and —CONHheterocycyl) and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6aryl, C_5-6arylamino, di-(C_1-7alkyl)amino and C_1-7alkylamino; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl, wherein optional N-substituents on the piperazinyl and homopiperazinyl groups include C_1-7alkyl groups or esters, in particular, esters bearing a C_1-7 alkyl group as an ester substituent, e.g. —C(═O)OCH₃, —C(═O)OCH₂CH₃ and —C(═O)OC(CH₃)₃, and optional C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C_1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.

In an embodiment of the invention, there is provided a subset of compounds of Formula I(B), I(B)i or I(B)ii, and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N;
  • R⁷ is selected from an optionally substituted C_5-20 aryl group, an optionally substituted 5- to 20-membered heteraryl group, OR^O1, NR^N1R^N2, NR^N7aC(═O)R^C1 and NR^N7bSO₂R^S2a; and
  • R² is selected from R^O2, NR^N5R^N6, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group.

In another embodiment, there is provided a subset of compounds of Formula I(B), I(B)i or I(B)ii, and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N;
  • R⁷ is an optionally substituted C_5-6 aryl group or an optionally substituted 5 or 6 membered heteraryl group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C_1-7 alkyl, C_1-7alkoxy, amino (for example —NH₂, C_5-6arylamino, C_1-7alkylamino, and di-(C_1-7alkyl)amino), and amido (for example —CONH₂, —CONHC_1-7alkyl, —CON(C_1-7alkyl)₂ and —CONHheterocycyl) and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6aryl, C_5-6arylamino, di-(C_1-7alkyl)amino and C_1-7alkylamino; and
  • R² is selected from R^O2, NR^N5R^N6, an optionally substituted C_5-6 heteroaryl group, and an optionally substituted C₆ aryl group.

In another embodiment, there is provided a subset of compounds of Formula I(B), I(B)i or I(B)ii, and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N;
  • R⁷ is an optionally substituted C_5-6 aryl group or an optionally substituted 5 or 6 membered heteraryl group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C_1-7 alkyl, C_1-7alkoxy, amino (for example —NH₂, C_5-6arylamino, C_1-7alkylamino, and di-(C_1-7alkyl)amino), and amido (for example —CONH—, —CONHC_1-7alkyl, —CON(C_1-7alkyl)₂ and —CONHheterocycyl) and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6aryl, C_5-6arylamino, di-(C_1-7alkyl)amino and C_1-7alkylamino; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 5 to 7 ring atoms which may be optionally be substituted, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C_1-7 saturated alkyl and C_1-7 saturated alkoxy (wherein the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl).

In a further embodiment, there is provided a subset of compounds of Formula I(B), I(B)i or I(B)ii, and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N;
  • R⁷ is an optionally substituted C_5-6 aryl group or an optionally substituted 5 or 6 membered heteraryl group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C_1-7 alkyl, C_1-7alkoxy, amino (for example —NH₂, C_5-6arylamino, C_1-7alkylamino, and di-(C_1-7alkyl)amino), and amido (for example —CONH₂, —CONHC_1-7alkyl, —CON(C_1-7alkyl)₂ and —CONHheterocycyl) and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkyl, C_1-7 alkoxy, C_5-6aryl, C_5-6arylamino, di-(C_1-7alkyl)amino and C_1-7alkylamino; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl, wherein optional N-substituents on the piperazinyl and homopiperazinyl groups include C_1-7alkyl groups or esters, in particular, esters bearing a C_1-7 alkyl group as an ester substituent, e.g. —C(═O)OCH₃, —C(═O)OCH₂CH₃ and —C(═O)OC(CH₃)₃, and optional C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C_1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.

In a further embodiment, there is provided a subset of compounds of Formula I(B), or I(B)ii, and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • R⁷ is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from fluoro, hydroxyl, cyano, nitro, methyl, methoxy, —OCH₂CH₃, —NH₂, —NHSO₂CH₃, —CH₂NHSO₂CH₃, —OCHF₂, —CH₂OH, —CO₂H, —CONH₂, —CONHMe, —CONHEt, —CONHCH(CH₃)₂, —CONHCH₂CH₂F, —CONHCH₂CHF₂, —CONHCH₂CH₂OH, —CONMeEt, —CONMe₂, N-methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing 5 to 7 ring atoms which may be optionally be substituted, wherein the optional substituents are selected from amino, cyano, halo, hydroxyl, ester, a C_3-7 cycloalkyl ring, a C₆carboaryl ring, a heterocyclic ring containing 5 to 7 ring atoms and C_1-7 saturated alkyl and C_1-7 saturated alkoxy (wherein the heterocyclic ring, the cycloalkyl ring, the carboaryl ring, the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl).

In a further embodiment, there is provided a subset of compounds of Formula I(B), I(B)i or I(B)ii, and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH; X⁸ is N;
  • R⁷ is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from fluoro, hydroxyl, cyano, nitro, methyl, methoxy, —OCH₂CH₃, —NH₂, —NHSO₂CH₃, —CH₂NHSO₂CH₃, —OCHF₂, —CH₂OH, —CO₂H, —CONH₂, —CONHMe, —CONHEt, —CONHCH(CH₃)₂, —CONHCH₂CH₂F, —CONHCH₂CHF₂, —CONHCH₂CH₂OH, —CONMeEt, —CONMe₂, N-methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl, wherein optional N-substituents on the piperazinyl and homopiperazinyl groups include C_1-7alkyl groups or esters, in particular, esters bearing a C_1-7 alkyl group as an ester substituent, e.g. —C(═O)OCH₃, —C(═O)OCH₂CH₃ and —C(═O)OC(CH₃)₃, and optional C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C_1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.

In a further embodiment, there is provided a subset of compounds of Formula I(B), or I(B)i, and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • R⁷ is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from —NH₂, fluoro, hydroxyl, cyano, nitro, methyl, methoxy, —CH₂OH, —CO₂H, —CONH₂, —CONHMe, —CONHEt, —CONHCH₂CH₂F, —CONHCH₂CHF₂, —CONHCH₂CH₂OH, —CONMeEt, —CONMe₂, N-methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl, wherein optional N-substituents on the piperazinyl and homopiperazinyl groups include C_1-7alkyl groups or esters, in particular, esters bearing a C_1-7 alkyl group as an ester substituent, e.g. —C(═O)OCH₃, —C(═O)OCH₂CH₃ and —C(═O)OC(CH₃)₃, and optional C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C_1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.

In a further embodiment, there is provided a subset of compounds of Formula I(B), I(B)i or I(B)ii, and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • R⁷ is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from —NH₂, fluoro, hydroxyl, cyano, nitro, methyl, methoxy, —CH₂OH, —CO₂H, —CONH₂, —CONHMe, —CONHEt, —CONHCH₂CH₂F, —CONHCH₂CHF₂, —CONHCH₂CH₂OH, —CONMeEt, —CONMe₂, N-methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl, wherein optional N-substituents on the piperazinyl and homopiperazinyl groups include C_1-7alkyl groups or esters, in particular, esters bearing a C_1-7 alkyl group as an ester substituent, e.g. —C(═O)OCH₃, —C(═O)OCH₂CH₃ and —C(═O)OC(CH₃)₃, and optional C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C_1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.

In a further embodiment, there is provided a subset of compounds of Formula I(B), I(B)i or I(B)ii, and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • R⁷ is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from fluoro, hydroxyl, cyano, nitro, methyl, methoxy, —OCH₂CH₃, —NH₂, —NHSO₂CH₃, —CH₂NHSO₂CH₃, —OCHF₂, —CH₂OH, —CO₂H, —CONH₂, —CONHMe, —CONHEt, —CONHCH(CH₃)₂, —CONHCH₂CH₂F, —CONHCH₂CHF₂, —CONHCH₂CH₂OH, —CONMeEt, —CONMe₂, N-methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl; and
  • R² is a group selected from

In a further embodiment, there is provided a subset of compounds of Formula I(B), or I(B)i, and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • R⁷ is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from —NH₂, fluoro, hydroxyl, cyano, nitro, methyl, methoxy, —CH₂OH, —CO₂, —CONH₂, —CONHMe, —CONHEt, —CONHCH₂CH₂F, —CONHCH₂CHF₂, —CONHCH₂CH₂OH, —CONMeEt, —CONMe₂, N-methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl; and
  • R² is a group selected from

In a further embodiment, there is provided a subset of compounds of Formula I(B), I(B)i or I(B)ii, and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • R⁷ is an optionally substituted phenyl or pyridinyl group, wherein the optional substituents are preferably selected from —NH₂, fluoro, hydroxyl, cyano, nitro, methyl, methoxy, —CH₂OH, —CO₂H, —CONH₂, —CONHMe, —CONHEt, —CONHCH₂CH₂F, —CONHCH₂CHF₂, —CONHCH₂CH₂OH, —CONMeEt, —CONMe₂, N-methylpiperazinylcarbonyl and 4-hydroxypiperidinylcarbonyl; and
  • R² is a group selected from

In a further embodiment, there is provided a subset of compounds of Formula I(B), I(B)i or I(B)ii, and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • R⁷ is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or a 3-hydroxymethylphenyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a

In a further embodiment, there is provided a subset of compounds of Formula I(B), or I(B)i, and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • R⁷ is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or a 3-hydroxymethylphenyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a

In a further embodiment, there is provided a subset of compounds of Formula I(B), I(B)i or I(B)ii, and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • R⁷ is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxy-phenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or a 3-hydroxymethylphenyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a

In a further embodiment, there is provided a subset of compounds of Formula I(B), I(B)i or I(B)ii, and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;

• • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a

In an embodiment of the invention, there is provided a subset of compounds of Formula I(B) or I(B)i wherein the compound is a compound of formula (II) or (IIa), and pharmaceutically acceptable salts thereof,

wherein:

• • only one of X⁵, X⁶ and X⁸ is N, and the others are CH;
  • Z is H, F or OR^O3;

R^N10 is selected from hydrogen, C(O)R^C2, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_5-20 aryl group, or an optionally substituted C_1-10 alkyl group where R^C2 are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heterocyclyl group, an optionally substituted C_1-7 alkyl group or NR^N11R^N12, where R^N11 and R^N12 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heterocycyl group, an optionally substituted C_5-20 aryl group or R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;

• • R^N10a is selected from hydrogen or an optionally substituted C_1-10 alkyl group; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms;
  • R^O3 is an optionally substituted C_1-6 alkyl group; and
  • R² is selected from NR^N5R^N6, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group.

In another embodiment, there is provided a subset of compounds of formula (II) or (IIa), and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N, and the others are CH;
  • Z is H, F or OR^O3
  • R^N10 is R^N10 is selected from hydrogen, C(O)R^C2, an optionally substituted C_5-6 heteroaryl group, an optionally substituted C₆ aryl group, or an optionally substituted C_1-10 alkyl group where R^C2 are selected from CH₃ or CH₂OH where the optional substituents are selected from cyano, halo, hydroxyl, C_1-7alkyloxy, C_1-7alkylamino and di-C_1-7alkylamino;
  • R^N10a is selected from hydrogen or an optionally substituted C_1-10 alkyl group where the optional substituents are selected from cyano, halo, hydroxyl, C_1-7alkyloxy, C_1-7alkylamino and di-C_1-7alkylamino; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms, where the optional substituents are selected from cyano, halo, hydroxyl, C_1-7alkyloxy, C_1-7alkylamino and di-C_1-7alkylamino;
  • R^O3 is an unsubstituted C_1-3 alkyl group; and
  • R² is selected from NR^N5R^N6, an optionally substituted C_5-6 heteroaryl group, and an optionally substituted C₆ aryl group.

In another embodiment, there is provided a subset of compounds of formula (II) or (IIa), and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N, and the others are CH;
  • Z is H, F or OR^O3
  • R^N10 is selected from hydrogen, —C(O)CH₃, —C(O)CH₂OH, —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH(CH₃)₂, —CH₂CH₂OMe, —CH₂C(CH₃)₂, —CH₂CH₂C(CH₃)₂, —CH(CH₃)CH₂C(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, —CH₂cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, —CH₂imidazole;
  • R^N10a is hydrogen; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional substituents are selected from halo, hydroxyl, C_1-7alkyloxy;
  • R^O3 is a methyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 5 to 7 ring atoms which may be optionally be substituted, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C_1-7 saturated alkyl and C_1-7 saturated alkoxy (wherein the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl).

In a further embodiment, there is provided a subset of compounds of formula (II) or (IIa), and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N, and the others are CH;
  • Z is H, F or OR^O3
  • R^N10 is selected from hydrogen, —C(O)CH₃, —C(O)CH₂OH, —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH(CH₃)₂, —CH₂CH₂OMe, —CH₂C(CH₃)₂, —CH₂CH₂C(CH₃)₂, —CH(CH₃)CH₂C(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, —CH₂cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, —CH₂imidazole;
  • R^N10a is hydrogen; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional substituents are selected from halo, hydroxyl, C_1-7alkyloxy;
  • R^O3 is a methyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl, wherein optional N-substituents on the piperazinyl and homopiperazinyl groups include C_1-7alkyl groups or esters, in particular, esters bearing a C_1-7 alkyl group as an ester substituent, e.g. —C(═O)OCH₃, —C(═O)OCH₂CH₃ and —C(═O)OC(CH₃)₃, and optional C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C_1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.

In a further embodiment, there is provided a subset of compounds of formula (II) or (IIa), and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • Z is H, F or OR^O3
  • R^N10 is selected from hydrogen, —C(O)CH₃, —C(O)CH₂OH, —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH(CH₃)₂, —CH₂CH₂OMe, —CH₂C(CH₃)₂, —CH₂CH₂C(CH₃)₂, —CH(CH₃)CH₂C(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, —CH₂cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, —CH₂imidazole;
  • R^N10a is hydrogen; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional substituents are selected from halo, hydroxyl, C_1-7alkyloxy;
  • R^O3 is a methyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted morpholino, thiomorpholino, piperidinyl, homopiperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C_1-7 saturated alkyl and C_1-7 saturated alkoxy (wherein the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl).

In a further embodiment, there is provided a subset of compounds of formula (II) or (IIa), and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • Z is H, F or OR^O3
  • R^N10 is a R^N10 is selected from hydrogen, —C(O)CH₃, —C(O)CH₂OH, —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH(CH₃)₂, —CH₂CH₂OMe, —CH₂C(CH₃)₂, —CH₂CH₂C(CH₃)₂, —CH(CH₃)CH₂C(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, —CH₂cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, —CH₂imidazole;
  • R^N10a is hydrogen; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional substituents are selected from halo, hydroxyl, C_1-7alkyloxy;
  • R^O3 is a methyl group; and
  • R² is a group selected from

In an embodiment of the invention, there is provided a subset of compounds of Formula I(B), I(B)i or I(B)ii wherein the compound is a compound of formula (II), (IIa) or (IIb), and pharmaceutically acceptable salts thereof,

wherein:

• • only one of X⁵, X⁶ and X⁸ is N, and the others are CH;
  • Z is H, F or OR^O3;
  • R^N10 is selected from hydrogen, C(O)R^C2, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_5-20 aryl group, or an optionally substituted C_1-10 alkyl group where R^C2 are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heterocyclyl group, an optionally substituted C_1-7 alkyl group or NR^N11R^N12, where R^N11 and R^N12 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heterocycyl group, an optionally substituted C_5-20 aryl group or R^N11 and R^N12 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;
  • R^N10a is selected from hydrogen or an optionally substituted C_1-10 alkyl group; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms;
  • R^O3 is an optionally substituted C_1-6 alkyl group; and
  • R² is selected from NR^N5R^N6, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group.

In another embodiment, there is provided a subset of compounds of formula (II), (IIa) or (IIb), and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N, and the others are CH;
  • Z is H, F or OR^O3
  • R^N10 is R^N10 is selected from hydrogen, C(O)R^C2, an optionally substituted C_5-6 heteroaryl group, an optionally substituted C₆ aryl group, or an optionally substituted C_1-10 alkyl group where R^C2 are selected from CH₃ or CH₂OH where the optional substituents are selected from cyano, halo, hydroxyl, C_1-7alkyloxy, C_1-7alkylamino and di-C_1-7alkylamino;
  • R^N10a is selected from hydrogen or an optionally substituted C_1-10 alkyl group where the optional substituents are selected from cyano, halo, hydroxyl, C_1-7alkyloxy, C_1-7alkylamino and di-C_1-7alkylamino; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 3 and 8 ring atoms, where the optional substituents are selected from cyano, halo, hydroxyl, C_1-7alkyloxy, C_1-7alkylamino and di-C_1-7alkylamino;
  • R^O3 is an unsubstituted C_1-3 alkyl group; and
  • R² is selected from NR^N5R^N6, an optionally substituted C_5-6 heteroaryl group, and an optionally substituted C₆ aryl group.

In another embodiment, there is provided a subset of compounds of formula (II), (IIa) or (IIb), and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N, and the others are CH;
  • Z is H, F or OR^O3
  • R^N10 is selected from hydrogen, —C(O)CH₃, —C(O)CH₂OH, —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH(CH₃)₂, —CH₂CH₂OMe, —CH₂C(CH₃)₂, —CH₂CH₂C(CH₃)₂, —CH(CH₃)CH₂C(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, —CH₂cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, —CH₂imidazole;
  • R^N10a is hydrogen; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional substituents are selected from halo, hydroxyl, C_1-7alkyloxy;
  • R^O3 is a methyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 5 to 7 ring atoms which may be optionally be substituted, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C_1-7 saturated alkyl and C_1-7 saturated alkoxy (wherein the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl).

In a further embodiment, there is provided a subset of compounds of formula (II), (IIa) or (IIb), and pharmaceutically acceptable salts thereof, in which:

• • only one of X⁵, X⁶ and X⁸ is N, and the others are CH;
  • Z is H, F or OR^O3
  • R^N10 is selected from hydrogen, —C(O)CH₃, —C(O)CH₂OH, —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH(CH₃)₂, —CH₂CH₂OMe, —CH₂C(CH₃)₂, —CH₂CH₂C(CH₃)₂, —CH(CH₃)CH₂C(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, —CH₂cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, —CH₂imidazole;
  • R^N10a is hydrogen; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional substituents are selected from halo, hydroxyl, C_1-7alkyloxy;
  • R^O3 is a methyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl, wherein optional N-substituents on the piperazinyl and homopiperazinyl groups include C_1-7alkyl groups or esters, in particular, esters bearing a C_1-7 alkyl group as an ester substituent, e.g. —C(═O)OCH₃, —C(═O)OCH₂CH₃ and —C(═O)OC(CH₃)₃, and optional C-substituents for the imidazolyl, morpholino, thiomorpholino, piperadinyl, homopiperadinyl, piperazinyl, homopiperazinyl or pyrrolidinyl groups include phenyl, ester, amide and C_1-4 alkyl, preferably methyl, aminomethyl, hydroxymethyl or hydroxyethyl.

In a further embodiment, there is provided a subset of compounds of formula (II), (IIa) or (IIb), and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • Z is H, F or OR^O3
  • R^N10 is selected from hydrogen, —C(O)CH₃, —C(O)CH₂OH, —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH(CH₃)₂, —CH₂CH₂OMe, —CH₂C(CH₃)₂, —CH₂CH₂C(CH₃)₂, —CH(CH₃)CH₂C(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, —CH₂cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, —CH₂imidazole;
  • R^N10a is hydrogen; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional substituents are selected from halo, hydroxyl, C_1-7alkyloxy;
  • R^O3 is a methyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form an optionally substituted morpholino, thiomorpholino, piperidinyl, homopiperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl group, wherein the optional substituents are selected from cyano, halo, hydroxyl, and C_1-7 saturated alkyl and C_1-7 saturated alkoxy (wherein the saturated alkyl and alkoxy groups may be optionally substituted by one or more groups selected from halo, hydroxyl, C_1-7 alkoxy, amino and C_5-6 aryl).

In a further embodiment, there is provided a subset of compounds of formula (II), (IIa) or (IIb), and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • Z is H, F or OR^O3
  • R^N10 is a R^N10 is selected from hydrogen, —C(O)CH₃, —C(O)CH₂OH, —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH(CH₃)₂, —CH₂CH₂OMe, —CH₂C(CH₃)₂, —CH₂CH₂C(CH₃)₂, —CH(CH₃)CH₂C(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, —CH₂cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, —CH₂imidazole;
  • R^N10a is hydrogen; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional substituents are selected from halo, hydroxyl, C_1-7alkyloxy;
  • R^O3 is a methyl group; and
  • R² is a group selected from

In a further embodiment, there is provided a subset of compounds of formula (II), (IIa) or (IIb), and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • Z is H, F or OR^O3
  • R^N10 is selected from hydrogen, —C(O)CH₃, —C(O)CH₂OH, —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH(CH₃)₂, —CH₂CH₂OMe, —CH₂C(CH₃)₂, —CH₂CH₂C(CH₃)₂, —CH(CH₃)CH₂C(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, —CH₂cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, —CH₂imidazole;
  • R^N10a is hydrogen; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional substituents are selected from halo, hydroxyl, C_1-7alkyloxy;
  • R^O3 is a methyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a

In a further embodiment, there is provided a subset of compounds of formula (II), (IIa) or (IIb), and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • Z is H, F or OR^O3
  • R^N10 is selected from hydrogen, —C(O)CH₃, —C(O)CH₂OH, —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH(CH₃)₂, —CH₂CH₂OMe, —CH₂C(CH₃)₂, —CH₂CH₂C(CH₃)₂, —CH(CH₃)CH₂C(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, —CH₂cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, —CH₂imidazole;
  • R^N10a is hydrogen; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional substituents are selected from halo, hydroxyl, C_1-7alkyloxy;
  • R^O3 is a methyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a

In a further embodiment, there is provided a subset of compounds of formula (II), (IIa) or (IIb), and pharmaceutically acceptable salts thereof, in which:

• • X⁵ and X⁶ are each CH;
  • X⁸ is N;
  • Z is H, F or OR^O3
  • R^N10 is selected from hydrogen, —C(O)CH₃, —C(O)CH₂OH, —CH₃, —CH₂CH₃, —CH₂CH₂OH, —CH(CH₃)₂, —CH₂CH₂OMe, —CH₂C(CH₃)₂, —CH₂CH₂C(CH₃)₂, —CH(CH₃)CH₂C(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, —CH₂cyclopropyl, methylcyclohexyl, cyanocyclohexyl, pyrazolyl, hydroxypyrrolidinyl, —CH₂imidazole;
  • R^N10a is hydrogen; or
  • R^N10 and R^N10a together with the nitrogen to which they are bound form an optionally substituted heterocyclic ring containing between 5 or 6 ring atoms, where the optional substituents are selected from halo, hydroxyl, C_1-7alkyloxy;
  • R^O3 is a methyl group; and
  • R² is NR^N5R^N6 where R^N5 and R^N6 together with the nitrogen to which they are bound form a

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

Compounds of the present invention may be tested for enzyme and cell activity as described herein. Compounds may also be tested for a range of physical and pharmacokinetic properties by methods known in the art. Thus, compounds may be selected on the basis of one or more criteria such as enzyme activity, cell activity, solubility, protein binding, cyp inhibition, bio-availability, clearance and metabolism as measured in vivo and/or in vitro.

In a further aspect of the invention, particular compounds of the invention are any one of Examples 1a, 1b, 1d, 1e, 1f, 1g, 1i, 1k, 1l, 1m, 1n, 1o, 1p, 1q, 1bb, 1bc, 1bd, 1be, 1bf, 1bg, 1bh, 1bi, 1bj, 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 pharmaceutically acceptable salts thereof.

In a further aspect of the invention, there is provided a compound, or a pharmaceutical salt thereof, selected from Examples 11bu, 11ce, 22b, 28de, 28dg, 28j, 11ar, 29e, 29h, 29i, 29l, 29m, 29n, 29o, 28n, 28o, 28z, 28aa, 28ag, 28ai, 28al, 11v, 28az, 11ah, 17e, 17i, 17j, 15d, 15f, 14v, 14ab, 14aj, 15t, 15u, 15w, 15x, 15y, 15z, 13f, 13g, 28bp, 28bs, 28bv, 28by, 28cb, 28cv, 11aw, 13u, 11bf, 28ct, 29q, 29s, 29u, 29v, 29w, 11au, 15r, 14t, 28dj, 11cl, 12d, 12e, 11cs, 12h, 12j, 11cw, 11bo, 11bp, 11j, 11bx, 11by, 11cf, 11ci, 11cj, 14an, 14ap, 14av, 22d, 28dh, 28di, 16a, 11n, 11p, 11q, 28e, 28h, 29b, 29c, 29f, 29k, 28p, 11bd, 28w, 28ab, 28af, 28aj, 28aq, 28as, 28av, 28ay, 28bb, 28bc, 28bf, 28bl, 11ab, 14p, 19a, 11av, 13a, 15b, 15c, 15e, 15g, 14aa, 14ad, 14ah, 15v, 13e, 28bq, 28bt, 28bz, 28ca, 28cd, 28cg, 28ci, 28bx, 15n, 11am, 11ao, 28cn, 28cx, 11bk, 23b, 14g, 15s, 14q, 28dd, 11cp, 11cq, 12f, 12g, 23g, 11cv, 11ct, 11b, 11a, 11c, 11d, 11bl, 11bm, 11f, 11i, 11g, 11h, 11br, 11bs, 11bv, 11e, 11bz, 11cc, 11k, 11cg, 11l, 14al, 14am, 14ao, 14aq, 14as, 14at, 14au, 14aw, 14ax, 14ay, 14az, 14ba, 14bb, 14bc, 14bd, 14be, 14bf, 22c, 22a, 28a, 11as, 11s, 28c, 28d, 28f, 28g, 28i, 28k, 29j, 28m, 28q, 28r, 28s, 28t, 28u, 28v, 28x, 28y, 28ac, 28ad, 28ae, 28ah, 28ak, 28am, 28an, 28ap, 28ar, 28au, 28aw, 28ax, 28ba, 28bd, 28be, 28bg, 28bi, 28bk, 28bh, 28bj, 28bm, 11bg, 18b, 14h, 11ba, 18a, 11aa, 11ac, 11ae, 11af, 11ag, 24b, 11bc, 14i, 14j, 14k, 14l, 14m, 14n, 14o, 28bn, 28bo, 14u, 11bb, 11at, 17b, 17c, 17d, 17f, 17g, 17k, 15a, 14w, 14x, 14y, 14z, 14ac, 14af, 14ai, 28br, 28bw, 28cc, 28cf, 28ch, 28cj, 28ck, 28cl, 14ak, 28cm, 14a, 13i, 13y, 11ak, 11al, 11ap, 11be, 28co, 28cr, 28cs, 28db, 29p, 13l, 11u, 14b, 15q, 14c, 14e, 14f, 14d, 11az, 14r, 14s, 11cn, 11co, and 13ad

In a further aspect of the invention, there is provided a compound, or a pharmaceutical salt thereof, selected from Examples 11bu, 11ce, 28de, 28dg, 28j, 11ar, 29e, 29h, 29i, 29l, 29m, 29n, 29o, 28n, 28o, 28z, 28aa, 28ag, 28ai, 28al, 11v, 28az, 11ah, 17e, 17i, 17j, 15d, 15f, 14v, 14ab, 14aj, 15t, 15u, 15w, 15x, 15y, 15z, 13f, 13g, 28bp, 28bs, 28by, 28by, 28cb, 28cv, 11aw, 13u, 11bf, 28ct, 29q, 29s, 29u, 29v, 29w, 11au, 15r, 14t, 28dj, 11cl, 12d, 12e, 11cs, 12h, 12j, 11cw, 11bo, 11bp, 11j, 11bx, 11by, 11cf, 11ci, 11cj, 14an, 14ap, 14av, 28dh, 28di, 16a, 11n, 11p, 11q, 28e, 28h, 29b, 29c, 29f, 29k, 28p, 11bd, 28w, 28ab, 28af, 28aj, 28aq, 28as, 28av, 28ay, 28bb, 28bc, 28bf, 28bl, 11ab, 14p, 19a, 11av, 13a, 15b, 15c, 15e, 15g, 14aa, 14ad, 14ah, 15v, 13e, 28bq, 28bt, 28bz, 28ca, 28cd, 28cg, 28ci, 28bx, 15n, 11am, 11ao, 28cn, 28cx, 11bk, 23b, 14g, 15s, 14q, 28dd, 11cp, 11cq, 12f, 12g, 23g, 11cv, 11ct, 11b, 11a, 11c, 11d, 11bl, 11bm, 11f, 11i, 11g, 11h, 11br, 11bs, 11bv, 11e, 11bz, 11ce, 11k, 11cg, 11l, 14al, 14am, 14ao, 14aq, 14as, 14at, 14au, 14aw, 14ax, 14ay, 14az, 14ba, 14bb, 14bc, 14bd, 14be, 14bf, 28a, 11as, 11s, 28c, 28d, 28f, 28g, 28l, 28k, 29j, 28m, 28q, 28r, 28s, 28t, 28u, 28v, 28x, 28y, 28ac, 28ad, 28ae, 28ah, 28ak, 28am, 28an, 28ap, 28ar, 28au, 28aw, 28ax, 28ba, 28bd, 28be, 28bg, 28bi, 28bk, 28bh, 28bj, 28bm, 11bg, 18b, 14h, 11ba, 18a, 11aa, 11ac, 11ae, 11af, 11ag, 24b, 11bc, 14i, 14j, 14k, 14l, 14m, 14n, 14o, 28bn, 28bo, 14u, 11bb, 11at, 17b, 17c, 17d, 17f, 17g, 17k, 15a, 14w, 14x, 14y, 14z, 14ac, 14af, 14ai, 28br, 28bw, 28cc, 28cf, 28ch, 28cj, 28ck, 28cl, 14ak, 28cm, 14a, 13i, 13y, 11ak, 11al, 11ap, 11be, 28co, 28cr, 28cs, 28db, 29p, 13l, 11u, 14b, 15q, 14c, 14e, 14f, 14d, 11az, 14r, 14s, 11cn, 11co, 13ad, 11cr, 11cw, 11cy, 11dv, 25c, 11cl, 11cm, 11cn, 11cq, 11cv, 11cx, 11di, 11dj, 11cb, 11cj, 11ck, 11ct, 11cu, 11cz, 11db, 11dc, 11dd, 11de, 11dg, 11dh, 11dk, 11dl, 11dm, 11dn, 11do, 11dp, 11dq, 11dt, 11du, 11dw, 11dy, 11dz, 11ea, 11ec, 11ed, 11ee, 28dm, 28dn and 28do.

In a further aspect of the invention, there is provided a compound, or a pharmaceutical salt thereof, selected from Examples 11bu, 11ce, 22b, 28de, 28dg, 28j, 11ar, 29e, 29h, 29i, 29l, 29m, 29n, 29o, 28n, 28o, 28z, 28aa, 28ag, 28ai, 28al, 11v, 28az, 11ah, 17e, 17i, 17j, 15d, 15f, 14v, 14ab, 14aj, 15t, 15u, 15w, 15x, 15y, 15z, 13f, 13g, 28bp, 28bs, 28bv, 28by, 28cb, 28cv, 11aw, 13u, 11bf, 28ct, 29q, 29s, 29u, 29v, 29w, 11au, 15r, 14t, 28dj, 11cl, 12d, 12e, 11cs, 12h, 12j, 11cw, 11bo, 11bp, 11j, 11bx, 11by, 11cf, 11ci, 11cj, 14an, 14ap, 14av, 22d, 28dh, 28di, 16a, 11n, 11p, 11q, 28e, 28h, 29b, 29c, 29f, 29k, 28p, 11bd, 28w, 28ab, 28af, 28aj, 28aq, 28as, 28av, 28ay, 28bb, 28bc, 28bf, 28bl, 11ab, 14p, 19a, 11av, 13a, 15b, 15c, 15e, 15g, 14aa, 14ad, 14ah, 15v, 13e, 28bq, 28bt, 28bz, 28ca, 28cd, 28cg, 28ci, 28bx, 15n, 11am, 11ao, 28cn, 28ex, 11bk, 23b, 14g, 15s, 14q, 28dd, 11cp, 11cq, 12f, 12g, 23g, 11cv, 11ct, 11b, 11a, 11c, 11d, 11bl, 11bm, 11f, 11i, 11g, 11h, 11br, 11bs, 11bv, 11e, 11bz, 11cc, 11k, 11cg, 11l, 14al, 14am, 14ao, 14aq, 14as, 14at, 14au, 14aw, 14ax, 14ay, 14az, 14ba, 14bb, 14bc, 14bd, 14be, 14bf, 22c, 22a, 28a, 11as, 11s, 28c, 28d, 28f, 28g, 28i, 28k, 29j, 28m, 28q, 28r, 28s, 28t, 28u, 28v, 28x, 28y, 28ac, 28ad, 28ae, 28ah, 28ak, 28am, 28an, 28ap, 28ar, 28au, 28aw, 28ax, 28ba, 28bd, 28be, 28bg, 28bi, 28bk, 28bh, 28bj, 28bm, 11bg, 18b, 14h, 11ba, 18a, 11aa, 11ac, 11ae, 11af, 11ag, 24b, 11bc, 14i, 14j, 14k, 14l, 14m, 14n, 14o, 28bn, 28bo, 14u, 11bb, 11at, 17b, 17c, 17d, 17f, 17g, 17k, 15a, 14w, 14x, 14y, 14z, 14ac, 14af, 14ai, 28br, 28bw, 28cc, 28cf, 28ch, 28cj, 28ck, 28cl, 14ak, 28cm, 14a, 13i, 13y, 11ak, 11al, 11ap, 11be, 28co, 28cr, 28cs, 28 db, 29p, 13l, 11u, 14b, 15q, 14c, 14e, 14f, 14d, 11az, 14r, 14s, 11cn, 11co, 13ad, 11cr, 11cw, 11cy, 11dv, 25c, 11cl, 11cm, 11cn, 11cq, 11cv, 11cx, 11di, 11dj, 11eb, 11cj, 11ck, 11ct, 11cu, 11cz, 11db, 11dc, 11dd, 11de, 11dg, 11dh, 11dk, 11dl, 11dm, 11dn, 11do, 11dp, 11dq, 11dt, 11du, 11dw, 11dy, 11dz, 11ea, 11ec, 11ed, 11ee, 28dm, 28dn and 28do.

In a further aspect of the invention, there is provided a compound, or a pharmaceutical salt thereof, selected from Examples 11bo, 11bp, 11j, 11bx, 11by, 11cf, 11ci, 11cj, 14an, 14ap, 14av, 22d, 28dh, 28di, 16a, 11n, 11p, 11q, 28e, 28h, 29b, 29c, 29f, 29k, 28p, 11bd, 28w, 28ab, 28af, 28aj, 28aq, 28as, 28av, 28ay, 28bb, 28be, 28bf, 28bl, 11ab, 14p, 19a, 11av, 13a, 15b, 15c, 15e, 15g, 14aa, 14ad, 14ah, 15v, 13e, 28bq, 28bt, 28bz, 28ca, 28cd, 28cg, 28ci, 28bx, 15n, 11am, 11ao, 28en, 28cx, 11bk, 23b, 14g, 15s, 14q, 28dd, 11cp, 11cq, 12f, 12g, 23g, 11cv, 11ct, 11b, 11a, 11c, 11d, 11bl, 11bm, 11f, 11i, 11g, 11h, 11br, 11bs, 11bv, 11e, 11bz, 11cc, 11k, 11cg, 11l, 14al, 14am, 14ao, 14aq, 14as, 14at, 14au, 14aw, 14ax, 14ay, 14az, 14ba, 14bb, 14bc, 14bd, 14be, 14bf, 22c, 22a, 28a, 11as, 11s, 28c, 28d, 28f, 28g, 28i, 28k, 29j, 28m, 28q, 28r, 28s, 28t, 28u, 28v, 28x, 28y, 28ac, 28ad, 28ae, 28ah, 28ak, 28am, 28an, 28ap, 28ar, 28au, 28aw, 28ax, 28ba, 28bd, 28be, 28bg, 28bi, 28bk, 28bh, 28bj, 28bm, 11bg, 18b, 14h, 11ba, 18a, 11aa, 11ac, 11ae, 11af, 11ag, 24b, 11bc, 14i, 14j, 14k, 14l, 14m, 14n, 14o, 28bn, 28bo, 14u, 11bb, 11at, 17b, 17c, 17d, 17f, 17g, 17k, 15a, 14w, 14x, 14y, 14z, 14ac, 14af, 14ai, 28br, 28bw, 28cc, 28cf, 28ch, 28cj, 28ck, 28cl, 14ak, 28cm, 14a, 13i, 13y, 11ak, 11al, 11ap, 11be, 28co, 28cr, 28cs, 28db, 29p, 13l, 11u, 14b, 15q, 14c, 14e, 14f, 14d, 11az, 14r, 14s, 11cn, 11co and 13ad,

In a further aspect of the invention, there is provided a compound, or a pharmaceutical salt thereof, selected from Examples 11bo, 11bp, 11j, 11bx, 11by, 11cf, 11ci, 11cj, 14an, 14ap, 14av, 28dh, 28di, 16a, 11n, 11p, 11q, 28e, 28h, 29b, 29c, 29f, 29k, 28p, 11bd, 28w, 28ab, 28af, 28aj, 28aq, 28as, 28av, 28ay, 28bb, 28bc, 28bf, 28bl, 11ab, 14p, 19a, 11av, 13a, 15b, 15c, 15e, 15g, 14aa, 14ad, 14ah, 15v, 13e, 28bq, 28bt, 28bz, 28ca, 28cd, 28cg, 28ci, 28bx, 15n, 11am, 11ao, 28cn, 28cx, 11bk, 23b, 14g, 15s, 14q, 28dd, 11cp, 11cq, 12f, 12g, 23g, 11cv, 11ct, 11b, 11a, 11e, 11d, 11bl, 11bm, 11f, 11i, 11g, 11h, 11br, 11bs, 11bv, 11e, 11bz, 11cc, 11k, 11cg, 11l, 14al, 14am, 14ao, 14aq, 14as, 14at, 14au, 14aw, 14ax, 14ay, 14az, 14ba, 14bb, 14bc, 14bd, 14be, 14bf, 28a, 11as, 11s, 28c, 28d, 28f, 28g, 28i, 28k, 29j, 28m, 28q, 28r, 28s, 28t, 28u, 28v, 28x, 28y, 28ac, 28ad, 28ae, 28ah, 28ak, 28am, 28an, 28ap, 28ar, 28au, 28aw, 28ax, 28ba, 28bd, 28be, 28bg, 28bi, 28bk, 28bh, 28bj, 28bm, 11bg, 18b, 14h, 11ba, 18a, 11aa, 11ac, 11ae, 11af, 11ag, 24b, 11be, 14i, 14j, 14k, 14l, 14m, 14n, 14o, 28bn, 28bo, 14u, 11bb, 11at, 17b, 17c, 17d, 17f, 17g, 17k, 15a, 14w, 14x, 14y, 14z, 14ac, 14af, 14ai, 28br, 28bw, 28cc, 28cf, 28ch, 28cj, 28ck, 28cl, 14ak, 28cm, 14a, 13i, 13y, 11ak, 11al, 11ap, 11be, 28co, 28cr, 28cs, 28db, 29p, 13l, 11u, 14b, 15q, 14c, 14e, 14f, 14d, 11az, 14r, 14s, 11cn, 11co, 13ad, 11cl, 11cm, 11cn, 11cq, 11cv, 11cx, 11di, 11dj, 11eb, 11cj, 11ck, 11ct, 11cu, 11cz, 11db, 11dc, 11dd, 11de, 11dg, 11dh, 11dk, 11dl, 11dm, 11dn, 11do, 11dp, 11dq, 11dt, 11du, 11dw, 11dy, 11dz, 11ea, 11ec, 11ed, 11ee, 28dm, 28dn and 28do.

In a further aspect of the invention, there is provided a compound, or a pharmaceutical salt thereof, selected from Examples 11bo, 11bp, 11j, 11bx, 11by, 11cf, 11ci, 11cj, 14an, 14ap, 14av, 22d, 28dh, 28di, 16a, 11n, 11p, 11q, 28e, 28h, 29b, 29c, 29f, 29k, 28p, 11bd, 28w, 28ab, 28af, 28aj, 28aq, 28as, 28av, 28ay, 28bb, 28be, 28bf, 28bl, 11ab, 14p, 19a, 11av, 13a, 15b, 15c, 15e, 15g, 14aa, 14ad, 14ah, 15v, 13e, 28bq, 28bt, 28bz, 28ca, 28cd, 28cg, 28ci, 28bx, 15n, 11am, 11ao, 28cn, 28cx, 11bk, 23b, 14g, 15s, 14q, 28dd, 11cp, 11cq, 12f, 12g, 23g, 11cv, 11ct, 11b, 11a, 11e, 11d, 11bl, 11bm, 11f, 11i, 11g, 11h, 11br, 11bs, 11bv, 11e, 11bz, 11cc, 11k, 11cg, 11l, 14al, 14am, 14ao, 14aq, 14as, 14at, 14au, 14aw, 14ax, 14ay, 14az, 14ba, 14bb, 14bc, 14bd, 14be, 14bf, 22c, 22a, 28a, 11as, 11s, 28c, 28d, 28f, 28g, 28l, 28k, 29j, 28m, 28q, 28r, 28s, 28t, 28u, 28v, 28x, 28y, 28ac, 28ad, 28ae, 28ah, 28ak, 28am, 28an, 28ap, 28ar, 28au, 28aw, 28ax, 28ba, 28bd, 28be, 28bg, 28bi, 28bk, 28bh, 28bj, 28bm, 11bg, 18b, 14h, 11ba, 18a, 11aa, 11ac, 11ae, 11af, 11ag, 24b, 11bc, 14i, 14j, 14k, 14l, 14m, 14n, 14o, 28bn, 28bo, 14u, 11bb, 11at, 17b, 17c, 17d, 17f, 17g, 17k, 15a, 14w, 14x, 14y, 14z, 14ac, 14af, 14ai, 28br, 28bw, 28cc, 28cf, 28ch, 28cj, 28ck, 28cl, 14ak, 28cm, 14a, 13i, 13y, 11ak, 11al, 11ap, 11be, 28co, 28cr, 28cs, 28db, 29p, 13l, 11u, 14b, 15q, 14c, 14e, 14f, 14d, 11az, 14r, 14s, 11cn, 11co, 13ad, 11cl, 11cm, 11cn, 11cq, 11cv, 11cx, 11di, 11dj, 11eb, 11cj, 11ck, 11ct, 11cu, 11cz, 11db, 11dc, 11dd, 11de, 11dg, 11dh, 11dk, 11dl, 11dm, 11dn, 11do, 11dp, 11dq, 11dt, 11du, 11dw, 11dy, 11dz, 11ea, 11ec, 11ed, 11ee, 28dm, 28dn and 28do.

In a further aspect of the invention, there is provided a compound, or a pharmaceutical salt thereof, selected from Examples 11b, 11a, 11c, 11d, 11bl, 11bm, 11f, 11i, 11g, 11h, 11br, 11bs, 11bv, 11e, 11bz, 11cc, 11k, 11cg, 11l, 14al, 14am, 14ao, 14aq, 14as, 14at, 14au, 14aw, 14ax, 14ay, 14az, 14ba, 14bb, 14bc, 14bd, 14be, 14bf, 22c, 22a, 28a, 11as, 11s, 28c, 28d, 28f, 28g, 28i, 28k, 29j, 28m, 28q, 28r, 28s, 28t, 28u, 28v, 28x, 28y, 28ac, 28ad, 28ae, 28ah, 28ak, 28am, 28an, 28ap, 28ar, 28au, 28aw, 28ax, 28ba, 28bd, 28be, 28bg, 28bi, 28bk, 28bh, 28bj, 28bm, 11bg, 18b, 14h, 11ba, 18a, 11aa, 11ac, 11ae, 11af, 11ag, 24b, 11be, 14i, 14j, 14k, 14l, 14m, 14n, 14o, 28bn, 28bo, 14u, 11bb, 11at, 17b, 17c, 17d, 17f, 17g, 17k, 15a, 14w, 14x, 14y, 14z, 14ac, 14af, 14ai, 28br, 28bw, 28cc, 28cf, 28ch, 28cj, 28ck, 28cl, 14ak, 28cm, 14a, 13i, 13y, 11ak, 11al, 11ap, 11be, 28co, 28cr, 28cs, 28db, 29p, 13l, 11u, 14b, 15q, 14c, 14e, 14f, 14d, 11az, 14r, 14s, 11cn, 11co and 13ad.

In a further aspect of the invention, there is provided a compound, or a pharmaceutical salt thereof, selected from Examples 11b, 11a, 11c, 11d, 11bl, 11bm, 11f, 11i, 11g, 11h, 11br, 11bs, 11bv, 11e, 11bz, 11cc, 11k, 11cg, 11l, 14al, 14am, 14ao, 14aq, 14as, 14at, 14au, 14aw, 14ax, 14ay, 14az, 14ba, 14bb, 14bc, 14bd, 14be, 14bf, 22c, 22a, 28a, 11as, 11s, 28c, 28d, 28f, 28g, 28i, 28k, 29j, 28m, 28q, 28r, 28s, 28t, 28u, 28v, 28x, 28y, 28ac, 28ad, 28ae, 28ah, 28ak, 28am, 28an, 28ap, 28ar, 28au, 28aw, 28ax, 28ba, 28bd, 28be, 28bg, 28bi, 28bk, 28bh, 28bj, 28bm, 11bg, 18b, 14h, 11ba, 18a, 11aa, 11ac, 11ae, 11af, 11ag, 24b, 11bc, 14i, 14j, 14k, 14l, 14m, 14n, 14o, 28bn, 28bo, 14u, 11bb, 11at, 17b, 17c, 17d, 17f, 17g, 17k, 15a, 14w, 14x, 14y, 14z, 14ac, 14af, 14ai, 28br, 28bw, 28cc, 28cf, 28ch, 28cj, 28ck, 28cl, 14ak, 28cm, 14a, 13i, 13y, 11ak, 11al, 11ap, 11be, 28co, 28cr, 28cs, 28db, 29p, 13l, 11u, 14b, 15q, 14c, 14e, 14f, 14d, 11az, 14r, 14s, 11cn, 11co, 13ad, 11cj, 11ck, 11ct, 11cu, 11cz, 11db, 11dc, 11dd, 11de, 11dg, 11dh, 11dk, 11dl, 11dm, 11dn, 11do, 11dp, 11dq, 11dt, 11du, 11dw, 11dy, 11dz, 11ea, 11ec, 11ed, 11ce, 28dm, 28dn and 28do.

In a further aspect of the invention, there is provided a compound, or a pharmaceutical salt thereof, selected from Examples 11b, 11a, 11c, 11d, 11bl, 11bm, 11f, 11i, 11g, 11h, 11br, 11bs, 11bv, 11e, 11bz, 11cc, 11k, 11cg, 11l, 14al, 14am, 14ao, 14aq, 14as, 14at, 14au, 14aw, 14ax, 14ay, 14az, 14ba, 14bb, 14bc, 14bd, 14be, 14bf, 28a, 11as, 11s, 28c, 28d, 28f, 28g, 28i, 28k, 29j, 28m, 28q, 28r, 28s, 28t, 28u, 28v, 28x, 28y, 28ac, 28ad, 28ae, 28ah, 28ak, 28am, 28an, 28ap, 28ar, 28au, 28aw, 28ax, 28ba, 28bd, 28be, 28bg, 28bi, 28bk, 28bh, 28bj, 28bm, 11bg, 18b, 14h, 11ba, 18a, 11aa, 11ac, 11ae, 11af, 11ag, 24b, 11bc, 14i, 14j, 14k, 14l, 14m, 14n, 14o, 28bn, 28bo, 14u, 11bb, 11at, 17b, 17c, 17d, 17f, 17g, 17k, 15a, 14w, 14x, 14y, 14z, 14ac, 14af, 14ai, 28br, 28bw, 28cc, 28cf, 28ch, 28cj, 28ck, 28cl, 14ak, 28cm, 14a, 13i, 13y, 11ak, 11al, 11ap, 11be, 28co, 28cr, 28cs, 28db, 29p, 13l, 11u, 14b, 15q, 14c, 14e, 14f, 14d, 11az, 14r, 14s, 11cn, 11co, 13ad, 11cj, 11ck, 11ct, 11cu, 11cz, 11db, 11dc, 11dd, 11de, 11dg, 11dh, 11dk, 11dl, 11dm, 11dn, 11do, 11dp, 11dq, 11dt, 11du, 11dw, 11dy, 11dz, 11ea, 11ec, 11ed, 11ee, 28dm, 28dn and 28do.

In a further aspect of the invention, there is provided a compound, or a pharmaceutical salt thereof, selected from Examples 11a, 11u, 11al, 11ap, 11at, 11az, 11co, 11de, 11dg, 11dh, 11dk, 11dl, 11dp, 11dq, 11dr, 11ds, 11dt, 11du, 11dy, 11ec, 11ee, 22d, 14b, 28dn and 28do.

In a further aspect of the invention, there is provided a compound, or a pharmaceutical salt thereof, selected from Examples 11a, 11u, 11al, 11ap, 11at, 11az, 11co, 11de, 11dg, 11dh, 11dk, 11dl, 11dp, 11dq, 11dr, 11ds, 11dt, 11du, 11dy, 11ec, 11ee, 14b, 28dn and 28do.

Includes Other Forms

Included in the above are the well known isomers, ionic, salt, solvate, protected forms and prodrugs of these compounds and substituents. For example, a reference to carboxylic acid (—COOH) also includes the anionic (carboxylate) form (—COO⁻), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (—N⁺HR¹R²), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (—O⁻), a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group.

Isomers, Salts, Solvates, Protected Forms, and Prodrugs

Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (−) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”).

If the compound is in crystalline form, it may exist in a number of different polymorphic forms. For example, for Example 11a was isolated as Form A: 2-Theta° 6.9 (46%), 8.53 (100%), 10.1 (21%), 10.86 (24%), 11.65 (11%), 13.31 (14%), 13.75 (7%), 14.37 (54%), 15.21 (5%), 16.19 (13%), 16.81 (39%), 17.19 (40%), 17.97 (21%), 18.41 (65%), 18.78 (80%), 20.66 (8%), 21.07 (89%), 22.05 (19%), 22.36 (42%), 24 (7%), 24.36 (33%), 25.25 (31%), 25.54 (16%), 26.92 (18%), 27.26 (8%), 28.03 (8%), 28.39 (21%), 29 (8%), 29.91 (13%), 30.62 (23%), 31.48 (9%), 32.72 (5%), 33.27 (11%), 34.88 (4%), 35.48 (5%), 36.16 (4%), 36.88 (4%), 37.37 (4%), 37.91 (6%), 38.65 (4%) and 39.83 (4%). A less stable form, Form B, has also been isolated from water/THF: 2-Theta° 3.67 (7%), 7.28 (7%), 8.52 (7%), 9.22 (30%), 11.42 (78%), 12.69 (24%), 13 (15%), 13.41 (44%), 13.6 (26%), 14.51 (19%), 15.56 (13%), 16.25 (9%), 17.11 (13%), 17.55 (18%), 18.24 (64%), 18.59 (56%), 19.51 (33%), 19.85 (26%), 20.32 (13%), 21.49 (17%), 21.79 (13%), 22.23 (18%), 22.84 (26%), 23.72 (23%), 25.46 (74%), 26.1 (100%), 26.72 (43%), 27.94 (16%), 28.35 (8%), 34.74 (10%), 35.34 (6%), 36.72 (9%) and 38.55 (4%).

Note that, except as discussed below for tautomeric forms, specifically excluded from the term “isomers”, as used herein, are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, —OCH₃, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, —CH₂OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C_1-7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain 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, N-nitroso/hyroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including ¹H, ²H (D), and ³H (T); C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof. Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g. fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.

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

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

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

If the compound is cationic, or has a functional group which may be cationic (e.g., —NH₂ may be —NH₃⁺), then a salt may be formed 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, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: acetic, propionic, succinic, gycolic, stearic, palmitic, lactic, malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, aspartic, benzoic, cinnamic, pyruvic, salicyclic, sulfanilic, 2-acetyoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, isethionic, valeric, and gluconic. Examples of suitable polymeric anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term “solvate” is used herein in the conventional sense to refer to a complex of solute (e.g. active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a 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, pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, ref. 26.

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

For example, an aldehyde or ketone group may be protected as an acetal or ketal, respectively, in which 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 readily regenerated by hydrolysis using a large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide or a urethane, for example, as: a methyl amide (—NHCO—CH₃); a benzyloxy amide (—NHCO—OCH₂C₆H₅, —NH-Cbz); as a t-butoxy amide (—NHCO—OC(CH₃)₃, —NH-Boc); a 2-biphenyl-2-propoxy amide (—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethoxy amide (—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a 2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxy amide (—NH-Troc), as an allyloxy amide (—NH-Alloc), as a 2-(phenylsulphonyl)ethyloxy amide (—NH-Psec); or, in suitable cases, as an N-oxide (>NO.).

For example, a carboxylic acid group may be protected as an ester for example, as: an C_1-7 alkyl ester (e.g. a methyl ester; a t-butyl ester); a C_1-7 haloalkyl ester (e.g. a C_1-7 trihaloalkyl ester); a triC_1-7 alkylsilyl-C_1-7 alkyl ester; or a C_5-20 aryl-C_1-7 alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.

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

It may be convenient or desirable to prepare, purify, and/or handle the active compound in the form of a prodrug. The term “prodrug”, as used herein, pertains to a compound which, when metabolised (e.g. in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties.

For example, some prodrugs are esters of the active compound (e.g. 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 esterification, for example, of any of the carboxylic acid groups (—C(═O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required. Examples of such metabolically labile esters include those wherein R is C_1-20 alkyl (e.g. -Me, -Et); C_1-7 aminoalkyl (e.g. aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C_1-7 alkyl (e.g. acyloxymethyl; acyloxyethyl; e.g. pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; 1-(4-tetrahydropyranyloxy)carbonyloxyethyl; (4-tetrahydropyranyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonyloxyethyl).

Further suitable prodrug forms include phosphonate and glycolate salts. In particular, hydroxy groups (—OH), can be made into phosphonate prodrugs by reaction with chlorodibenzylphosphite, followed by hydrogenation, to form a phosphonate group —O—P(═O)(OH)₂. Such a group can be cleared by phosphotase enzymes during metabolism to yield the active drug with the hydroxy group.

Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound. For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

Acronyms

For convenience, many chemical moieties are represented using well known abbreviations, including but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (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 dimethylsulfoxide (DMSO).

General Synthesis

Compounds of formula I can be represented by Formula 1:

wherein R⁴ represents NR^N3R^N4.

Compounds of Formula 1 can be synthesised from compounds of Formula 2:

When R⁷ is NR^N1R^N2, this is by reaction with R⁷H. When R⁷ is an optionally substituted C_3-20 heterocyclyl group or C_5-20 aryl group, this is by reaction with R⁷B(OAlk)₂, where each Alk is independently C_1-7 alkyl or together with the oxygen to which they are attached form a C_5-7 heterocyclyl group. When R⁷ is an amide, urea or sulfonamide group, this is by reaction with ammonia followed by reaction of the resulting primary amide with the appropriate acid chloride, isocyanate or sulfonyl chloride. When R⁷ is OR^O1 or SR^S1, this is by reaction with potassium carbonate in the appropriate alcohol or thiol solvent.

Therefore, according to a further aspect of the present invention there is provided a process for the preparation of a compound of formula I, from a compound of Formula 2:

wherein:R⁴ is NR^N3R^N4 where R^N3 and R^N4, together with the nitrogen to which they are bound, form a heterocyclic ring containing between 3 and 8 ring atoms;R² is selected from H, halo, OR^O2, SR^S2b, NR^N5R^N6, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group,wherein R^O2 and R^S2b are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, or an optionally substituted C_1-7 alkyl group, and R^N5 and R^N6 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heteroaryl group, and an optionally substituted C_5-20 aryl group, or R^N5 and R^N6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms,comprising

• • (a) when R⁷ is NR^N1R^N2, reaction of the compound of formula 2 with R⁷H; or
  • (b) when R⁷ is an optionally substituted C_3-20 heterocyclyl group or C_5-20 aryl group, reaction of the compound of formula 2 with R⁷B(OAlk)₂, where each Alk is independently C_1-7 alkyl or together with the oxygen to which they are attached form a C_5-7 heterocyclyl group, or
  • (c) when R⁷ is an amide, urea or sulfonamide group, reaction of a compound of formula 2 with ammonia followed by reaction of the resulting primary amine with the appropriate acid chloride, isocyanate or sulfonyl chloride, or
  • (d) when R⁷ is OR^O1 or SR^S1, by reaction of the compound of formula 1 in the presence of base in the appropriate alcohol or thiol solvent.

Compounds of formula I(A) can be synthesised by reaction a compound of Formula 1a:

wherein R⁴ represents NR^N3R^N4, and

wherein Lv is a leaving group, such as a halogen, for example chlorine, or an OSO₂R group, where R is alkyl or aryl, such as methyl,by reaction with R^N10NH₂.

Compounds of Formula 1a can be synthesised by reaction of a compound of Formula 1b

wherein R⁴ represents NR^N3R^N4, and

with an alkyl or aryl sulphonyl chloride in the presence of a base.

Compounds of Formula 1b can be synthesised by reacting a compound of Formula 2:

with R⁷B(OAlk)₂, where each Alk is independently C_1-7 alkyl or together with the oxygen to which they are attached form a C_5-7 heterocyclyl group.

Compounds of Formula 2 can be synthesised from compounds of Formula 3:

by reaction with HR⁴ (NR^N3R^N4) followed by reaction with HR².

Compounds of Formula 3 can be synthesised from compounds of Formula 4:

by treatment with POCl₃ and N,N-diisopropylamine, for example.

Compounds of Formula 4 can be synthesised from compounds of Formula 5:

by treatment with oxalyl chloride, for example.

Compounds of Formula 5 can be synthesised 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 synthesised from compounds of Formula 2A:

When R² is NR^N5R^N6, this is by reaction with R²H. When R² is an optionally substituted C_3-20 heterocyclyl group or C_5-20 aryl group, this is by reaction with R²B(OAlk)₂, where each Alk is independently C_1-7 alkyl or together with the oxygen to which they are attached form a C_5-7 heterocyclyl group. When R² is OR^O2 or SR^S2b, this is by reaction with potassium carbonate in the appropriate alcohol or thiol solvent.

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

whereinR⁴ is NR^N3R^N4 where R^N3 and R^N4, together with the nitrogen to which they are bound, form a heterocyclic ring containing between 3 and 8 ring atoms; andR⁷ is selected from halo, OR^O1, SR^S1, NR^N1R^N2, NR^N7aC(═O)R^C1, NR^N7bSO₂R^S2a, an optionally substituted C_5-20 heteroaryl group, or an optionally substituted C_5-20 aryl group,where R^O1 and R^S1 are selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, or an optionally substituted C_1-7 alkyl group; R^N1 and R^N2 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_5-20 aryl group or R^N1 and R^N2 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;R^C1 is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_1-7 alkyl group or NR^N8R^N9, where R^N8 and R^N9 are independently selected from H, an optionally substituted C_1-7 alkyl group, an optionally substituted C_5-20 heteroaryl group, an optionally substituted C_5-20 aryl group or R^N8 and R^N9 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms;R^S2a is selected from H, an optionally substituted C_5-20 aryl group, an optionally substituted C_5-20 heteroaryl group, or an optionally substituted C_1-7 alkyl group; andR^N7a and R^N7b are selected from H and a C_1-4 alkyl group;comprising

• • (a) when R² is NR^N5R^N6, reacting a compound of formula 2A with R²H, or
  • (b) when R² is an optionally substituted C_3-20 heterocyclyl group or C_5-20 aryl group, by reacting a compound of formula 2A with R²B(OAlk)₂, where each Alk is independently C_1-7 alkyl or together with the oxygen to which they are attached form a C_5-7 heterocyclyl group, or
  • (c) when R² is OR^O2 or SR^S2b, by reacting a compound of formula 2A in the presence of a base in the appropriate alcohol or thiol solvent.

Compounds of Formula 2A can be synthesised from compounds of Formula 3:

by reaction with HR⁴ (HNR^N3R^N4) followed by reaction with HR⁷ or HR⁷ equivalent. For example, when R⁷ is an optionally substituted C_3-20 heterocyclyl group or C_5-20 aryl group, this is by reaction with R⁷B(OAlk)₂, where each Alk is independently C_1-7 alkyl or together with the oxygen to which they are attached form a C_5-7 heterocyclyl group.

Compounds of formula I(B) can be represented by Formula 1.1:

wherein R⁴ represents

Compounds of Formula 1.1 can be synthesised from compounds of Formula 2.1:

wherein R⁴ represents

When R⁷ is NR^N1R^N2, this is by reaction with R⁷H. When R⁷ is an amide, urea or sulfonamide group, this is by reaction with ammonia followed by reaction of the resulting primary amide with the appropriate acid chloride, isocyanate or sulfonyl chloride. When R⁷ is OR^O1 or SR^S1, this is by reaction with potassium carbonate in the appropriate alcohol or thiol solvent. When R⁷ is an optionally substituted C_3-20 heterocyclyl group or C_5-20 aryl group, this is by reaction with R⁷B(OAlk)₂, where each Alk is independently C_1-7 alkyl or together with the oxygen to which they are attached form a C_5-7 heterocyclyl group.

Compounds of Formula 2.1 can be synthesised from compounds of Formula 3:

by reaction with HR⁴ (eg.

followed by reaction with HR².

Alternatively compounds of Formula 1 and Formula 1.1 can be synthesised from compounds of Formula 7:

by reaction with HR².

Compounds of Formula 7 can be synthesised from compounds of Formula 8:

When R⁷ is NR^N1R^N2, this is by reaction with R⁷H. When R⁷ is an amide, urea or sulfonamide group, this is by reaction with ammonia followed by reaction of the resulting primary amide with the appropriate acid chloride, isocyanate or sulfonyl chloride. When R⁷ is OR^O1 or SR^S1, this is by reaction with potassium carbonate in the appropriate alcohol or thiol solvent. When R⁷ is an optionally substituted C_3-20 heterocyclyl group or C_5-20 aryl group, this is by reaction with R⁷B(OAlk)₂, where each Alk is independently C_1-7 alkyl or together with the oxygen to which they are attached form a C_5-7 heterocyclyl group.

Compounds of Formula 8 can be synthesised from compounds of Formula 3:

by reaction with HR⁴ (eg.

When R⁷ is

the Compound of Formula II can be prepared by reaction a compound of Formula 1.2:

wherein R⁴ represents

R⁷ is

wherein Lv is a leaving group, such as a halogen, for example chlorine, or a OSO₂ group, where R is alkyl or aryl, such as methyl, by reaction with R^N10HN₂.

Compounds of Formula 1.2 can be synthesised by reaction of a compound of Formula 1.3

wherein R⁴ represents

and

R⁷ is

with an alkyl or aryl sulphonyl chloride in the presence of a base.

For Example:

Compounds of Formula 1.3 can be prepared by reaction with R⁷B(OAlk)₂, where each Alk is independently C_1-7 alkyl or together with the oxygen to which they are attached form a C_5-7 heterocyclyl group.

Use

The present invention provides active compounds, specifically, active in inhibiting the activity of mTOR.

The term “active” as used herein, pertains to compounds which are capable of inhibiting mTOR activity, and specifically includes both compounds with intrinsic activity (drugs) as well as prodrugs of such compounds, which prodrugs may themselves exhibit little or no intrinsic activity.

One assay which may conveniently be used in order to assess the mTOR inhibition offered by a particular compound is described in the examples below.

The present invention further provides a method of inhibiting the activity of mTOR in a cell, comprising contacting said cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable composition. Such a method may be practised in vitro or in vivo.

For example, a sample of cells may be grown in vitro and an active compound brought into contact with said cells, and the effect of the compound on those cells observed. As examples of “effect”, the inhibition of cellular growth in a certain time or the accumulation of cells in the G1 phase of the cell cycle over a certain time may be determined. Where the active compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.

The term “treatment”, as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e. prophylaxis) is also included.

The term “adjunct” as used herein relates to the use of active compounds in conjunction with known therapeutic means. Such means include cytotoxic regimes of drugs and/or ionising radiation as used in the treatment of different cancer types. Examples of adjunct anti-cancer agents that could be combined with compounds from 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), ethylenimine/methylmelamine, thriethylenemelamine (TEM), triethylene thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine): Alkyl sulfonates; busulfan; Triazines, 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, erythrohydroxynonyladenine (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; epipodophylotoxins, etoposide, teniposide: Antibiotics; actimomycin D, daunomycin (rubidomycin), doxorubicin (adriamycin), mitoxantrone, idarubicin, bleomycins, 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: Radiosensitizers, metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, RSU 1069, EO9, RB 6145, SR4233, nicotinamide, 5-bromodeozyuridine, 5-iododeoxyuridine, bromodeoxycytidine: Platinium coordination complexes; cisplatin, carboplatin: Anthracenedione; mitoxantrone, AQ4N Substituted urea, hydroxyurea; Methylhydrazine derivatives, N-methylhydrazine (MIH), procarbazine; Adrenocortical suppressant, mitotane (o.p′-DDD), aminoglutethimide: Cytokines; interferon (α, β, γ), interleukin; Hormones and antagonists; adrenocorticosteroids/antagonists, prednisone and equivalents, dexamethasone, aminoglutethimide; Progestins, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate; Estrogens, diethylstilbestrol, ethynyl estradiol/equivalents; Antiestrogen, tamoxifen; Androgens, testosterone propionate, fluoxymesterone/equivalents; Antiandrogens, flutamide, gonadotropin-releasing hormone analogs, leuprolide; Nonsteroidal antiandrogens, flutamide; EGFR inhibitors, VEGF inhibitors; Proteasome inhibitors.

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

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

Cancer

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

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

Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.

The anti cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:—

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

(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5*-reductase such as finasteride;

(iii) anti-invasion agents (for example c-Src kinase family inhibitors like 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 like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase);

(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)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, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) antiangiogenic agents such as those which 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 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 within 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 that work by other mechanisms (for example linomide, inhibitors of integrin avb3 function and angiostatin)];

(vi) vascular damaging 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 which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy; and

(ix) immunotherapy approaches, including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using anti idiotypic antibodies.

Administration

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

The subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orangutang, gibbon), or a human.

Formulations

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

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

The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, refs. 27 to 29.

The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.

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

A tablet may be made by conventional means, e.g. compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

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

Formulations suitable for topical administration in the mouth include losenges comprising the active compound in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising 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 carrier, especially an aqueous solvent for the active compound.

Formulations suitable for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid for administration as, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the active compound.

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

Formulations suitable for topical administration via the skin include ointments, creams, and emulsions. When formulated in an ointment, the active compound may optionally be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active compounds may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, 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 mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.

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

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

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

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration (e.g., by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal), include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or 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 ng/ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs.

Dosage

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

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

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

In addition to their use in therapeutic medicine, the compounds of Formula I, I(A), I(B), I(B)i or I(B)ii and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of mTor in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In the above other pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments of the compounds of the invention described herein also apply.

EXAMPLES

General Experimental Methods

Thin Layer chromatography was carried out using Merck Kieselgel 60 F₂₅₄ glass backed plates. The plates were visualized by the use of a UV lamp (254 nm). Silica gel 60 (particle sizes 40-63 μm) supplied by E.M.Merck was employed for flash chromatography. ¹H NMR spectra were recorded at 300 MHz on a Bruker DPX-300 instrument. Chemical shifts were referenced relative to tetramethylsilane.

Purification of Samples

The samples were purified on Gilson LC units. Mobile phase A—0.1% aqueous TFA, mobile phase B—Acetonitrile; flow rate 6 ml/min; Gradient—typically starting at 90% A/10% B for 1 minute, rising to 97% after 15 minutes, holding for 2 minutes, then back to the starting conditions. Column: Jones Chromatography Genesis 4 μm, C18 column, 10 mm×250 mm. Peak acquisition based on UV detection at 254 nm.

Identification of Samples

Mass spectra were recorded on a Finnegan LCQ instrument in positive ion mode. Mobile phase A—0.1% aqueous formic acid. Mobile phase B—Acetonitrile; Flowrate 2 ml/min; Gradient—starting at 95% A/5% B for 1 minute, rising to 98% B after 5 minutes and holding for 3 minutes before returning to the starting conditions. Column: Varies, but always C18 50 mm×4.6 mm (currently Genesis C18 4 μm. Jones Chromatography). PDA detection Waters 996, scan range 210-400 nm.

QC Method QC2-AQ

Mass spectra were recorded on a Waters ZQ instrument in Electrospray ionisation mode. Mobile phase A—0.1% aqueous formic acid. Mobile phase B—0.1% Formic acid in acetonitrile; Flowrate 2 ml/min; Gradient—starting at 100% A/0% B for 1 minute, rising to 95% B after 7 minutes and holding for 2 minutes before returning to the starting conditions. Column: Varies, currently Genesis AQ 120A 4u 50 mm×4.6 mm, Hichrom Ltd. PDA detection Waters 996, scan range 210-400 nm.

QC Method QC2-Long

Mass spectra were recorded on a Waters ZQ instrument in Electrospray ionisation mode. Mobile phase A—0.1% aqueous formic acid. Mobile phase B—0.1% Formic acid in acetonitrile; Flowrate 2 ml/min; Gradient—starting at 95% A/5% B, rising to 95% B after 20 minutes and holding for 3 minutes before returning to the starting conditions. Column: Varies, but always C18 50 mm×4.6 mm (currently Genesis C18 4u 50 mm×4.6 mm, Hichrom Ltd). PDA detection Waters 996, scan range 210-400 nm.

QC Method QC2-QC

Mass spectra were recorded on a Waters ZQ instrument in Electrospray ionisation mode. Mobile phase A—0.1% aqueous formic acid. Mobile phase B—0.1% Formic acid in acetonitrile; Flowrate 2 ml/min; Gradient—starting at 95% A/5% B, rising to 95% B after 5 minutes and holding for 5 minutes before returning to the starting conditions. Column: Varies, but always C18 50 mm×4.6 mm (currently Genesis C18 4 μm 50×4.6 mm, Hichrom Ltd). PDA detection Waters 996, scan range 210-400 nm.

QC Method QC3-AQ-Long

Mass spectra were recorded on a Waters ZQ instrument in Electrospray ionisation mode. Mobile phase A—0.1% aqueous formic acid. Mobile phase B—0.1% Formic acid in acetonitrile; Flowrate 2 ml/min; Gradient—starting at 100% A/0% B for 1 minute, rising to 95% B after 20 minutes and holding for 5 minutes before returning to the starting conditions. Column: Varies, currently Genesis AQ 4 μm 50 mm×4.6 mm, Hichrom Ltd. PDA detection Waters 996, scan range 210-400 nm.

Examples 11u, 19a, 28bs, 28by, 28bw, 28bx, 28by, 28bz, 28ca, 28cb, 28cc, 28cd, 28ce, 28cf, 28cg, 28ch, 28ci, 28cj, 28ck, 28cl, 28cm, 28dk, 28dl and 28dm were analysed using the QC Method QC2-AQ.

Examples 22c, 22d, 23c, 23e, 23g, 24b, 25b, 28aa, 28ab, 28ac, 28ad, 28ae, 28af, 28ag, 28ah, 28ai, 28aj, 28ak, 28al, 28am, 28an, 28ao, 28ap, 28aq, 28ar, 28as, 28at, 28au, 28az, 28bc, 28bl, 28bm, 28bt, 28bu, 28cn, 28co, 28cp, 28cq, 28cr, 28cs, 28ct, 28cu, 28cv, 28cw, 28cx, 28cy, 28cz, 28da, 28db, 28dc, 28df, 28dj, 28l, 28o, 28q, 28r, 28s, 28t, 28u, 28v, 28w, 28x, 28y, 28z, 29a, 29b, 29c, 29d, 29e, 29f, 29g, 29h, 29i, 29j, 29k, 29l, 29m, 29n, 29o, 11a, 11aa, 11ab, 11ac, 11ad, 11ae, 11af, 11ag, 11ah, 11ai, 11ak, 11as, 11au, 11az, 11bb, 11cq, 11ct, 11dg, 11ec, 11g, 11i, 11m, 11w, 11x, 11y, 11z, 31a, 13a, 13ac, 13b, 13c, 13d, 13e, 13f, 13g, 13h, 13i, 13j, 13v, 13w, 13x, 13y, 13z, 14j, 14k, 14l, 14m, 14n, 14o, 14p, 16a, comparative of Example 1c, comparative of Example 1j and comparative of Example 1k were analysed using the QC Method QC2-Long.

Examples 20a, 21a, 22a, 22b, 22e, 23a, 23b, 23d, 23f, 24a, 25a, 25c, 26a, 27a, 28a, 28av, 28aw, 28ax, 28ay, 28b, 28ba, 28bb, 28bd, 28be, 28bf, 28bg, 28bh, 28bi, 28bj, 28bk, 28bn, 28bo, 28bp, 28bq, 28br, 28c, 28d, 28dd, 28de, 28dg, 28dh, 28di, 28dn, 28do, 28e, 28f, 28g, 28h, 28i, 28j, 28k, 28m, 28n, 29p, 29q, 29r, 29s, 29t, 29u, 29v, 29w, 29x, 11aj, 11al, 11am, 11an, 11ao, 11ap, 11aq, 11ar, 11at, 11av, 11aw, 11ax, 11ay, 11b, 11ba, 11bc, 11be, 11bf, 11bg, 11bh, 11bi, 11bj, 11bk, 11bl, 11bm, 11bn, 11bo, 11bp, 11bq, 11br, 11bs, 11bt, 11bu, 11bv, 11bw, 11bx, 11by, 11bz, 11c, 11ca, 11cb, 11cc, 11cd, 11ce, 11cf, 11cg, 11ch, 11ci, 11cj, 11ck, 11cl, 11cm, 11cn, 11co, 11cp, 11cr, 11cs, 11cu, 11cv, 11cw, 11cx, 11cy, 11cz, 11d, 11da, 11db, 11dc, 11dd, 11de, 11df, 11dh, 11di, 11dj, 11dk, 11dl, 11dm, 11dn, 11do, 11dp, 11dq, 11dr, 11ds, 11dt, 11du, 11dv, 11dw, 11dx, 11dy, 11dz, 11e, 11ea, 11eb, 11ed, 11ee, 11f, 11h, 11j, 11k, 11l, 11n, 11o, 11p, 11q, 11r, 11s, 11t, 11v, 30a, 30b, 30c, 12a, 12b, 12c, 12d, 12e, 12f, 12g, 12h, 12i, 12j, 13aa, 13ab, 13ad, 13k, 13l, 13m, 13n, 13o, 13p, 13q, 13r, 13s, 13t, 13u, 14a, 14aa, 14ab, 14ac, 14ad, 14ae, 14af, 14ag, 14ah, 14ai, 14aj, 14ak, 14al, 14am, 14an, 14ao, 14ap, 14aq, 14ar, 14as, 14at, 14au, 14av, 14aw, 14ax, 14ay, 14az, 14b, 14ba, 14bb, 14bc, 14bd, 14be, 14bf, 14c, 14d, 14e, 14f, 14g, 14h, 14i, 14q, 14r, 14s, 14t, 14u, 14v, 14w, 14x, 14y, 14z, 15a, 15b, 15c, 15d, 15e, 15f, 15g, 15h, 15i, 15j, 15k, 15l, 15m, 15n, 15o, 15p, 15q, 15r, 15s, 15t, 15u, 15v, 15w, 15x, 15y, 15z, 17a, 17b, 17c, 17d, 17e, 17f, 17g, 17h, 17i, 17j, 17k, 18a, 18b, 18c, 18d, comparative of Example 1a, comparative of Example 1at, comparative of Example 1b, Example 10a and Example 10c were analysed using the QC Method QC2-QC.

Examples 28p and 11bd were analysed using the QC Method QC3-AQ-Long.

Microwave Synthesis

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

General Procedure for the Synthesis of 2,4,7-Substituted Pyridopyrimidine Derivatives

Synthesis of 2,4,7-Substituted Pyridopyrimidine Derivatives

Intermediates:

To the appropriate amino acid (1 equiv) was added liquid ammonia (sufficient to make a 0.6M solution of substrate in ammonia). The suspension was sealed in a pressure vessel which was then heated slowly to 130° C. It was noted that at this temperature a pressure of 18 bar was observed. This temperature and pressure was maintained for a further 16 hours whereupon the mixture was cooled to room temperature. The pressure vessel was opened and the reaction poured into ice cold water (1 reaction volume). The resulting solution was acidified to pH 1-2 using concentrated HCl which caused a precipitate to form. The acidic mixture was allowed to warm to room temperature and was stirred like this for a further 30 min The suspension was then extracted with diethyl ether (3×400 ml). The combined organic extracts were then filtered and the filtrate concentrated in vacuo to give a white solid which was dried further over P₂O₅ to give the title compound (typically 80-90% yield and 90%+ pure) in suitably pure form to be used without any further purification.

2-Amino-6-chloronicotinic acid (Inter. 2)

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

To a 0.3 M solution of amino acid (1 equiv) in anhydrous THF, under an inert atmosphere, was added thionyl chloride (3.3 equiv) in a dropwise fashion. The reaction mixture was stirred at room temperature for 2 hours. After this time the reaction was concentrated in vacuo to give a crude yellow solid residue. The crude solid was dissolved in THF (equal to initial reaction volume) and concentrated in vacuo again to give a yellow solid residue. The residue was dissolved once more in THF and concentrated as before to give a solid residue which was then dissolved in THF (to give a solution of 0.3M) and ammonia gas bubbled through the solution for 1 hour. The resultant precipitate was removed by filtration and the filtrate concentrated in vacuo to give a yellow precipitate which was triturated with water at 50° C. then dried to give the title compound (typically 90-95%) yield and suitably clean enough to be used without any further purification.

2-Amino-6-chloronicotinamide (Inter. 3)

To a 0.3 M solution of 2-amino-6-chloronicotinic acid (Inter. 2) (1 equiv) in anhydrous THF, under an inert atmosphere, was added thionyl chloride (3.3 equiv) in a dropwise fashion. The reaction mixture was stirred at room temperature for 2 hours. After this time the reaction was concentrated in vacuo to give a crude yellow solid residue. The crude solid was dissolved in THF (equal to initial reaction volume) and concentrated in vacuo again to give a yellow solid residue. The residue was dissolved once more in THF and concentrated as before to give a solid residue which was then dissolved in THF (to give a solution of 0.3M) and ammonia gas bubbled through the solution for 1 hour. The resultant precipitate was removed by filtration and the filtrate concentrated in vacuo to give a yellow precipitate which was triturated with water at 50° C. then dried to give the title compound (92% yield, 93% purity), suitably clean to be used without any further purification. m/z (LC-MS, ESP): 172 [M+H]⁺ R/T=3.19 mins

To a stirred solution (0.06 M) of substrate (1 equiv) in anhydrous toluene under an inert atmosphere was added oxalyl chloride (1.2 equiv) in a dropwise manner. The resulting mixture was then heated to reflux (115° C.) for 4 hours whereupon it was 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 suitably pure form to be used without any further purification.

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

To a stirred solution (0.06 M) of 2-amino-6-chloronicotinamide (Inter. 3) (1 equiv) in anhydrous toluene under an inert atmosphere was added oxalyl chloride (1.2 equiv) in a dropwise manner. The resulting mixture was then heated to reflux (115° C.) for 4 hours whereupon it was 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 suitably pure form (95% yield, 96% purity) to be used without any further purification. m/z (LC-MS, ESP): 196 [M−H]⁻ R/T 3.22 mins

To a stirred 0.5 M suspension of the appropriate dione (1 equiv) in anhydrous toluene under an inert atmosphere was slowly added diisopropylethylamine (3 equiv). The reaction mixture was then heated to 70° C. for 30 minutes and then cooled to room temperature prior to the addition of POCl₃ (3 equiv). The reaction was then heated to 100° C. for 2.5 hours before being cooled 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 over silica gel for 30 minutes. After this time the silica was removed by filtration, the filtrate concentrated and the crude residue purified by flash chromatography (SiO₂) to give the title compound in analytically pure form.

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

To a stirred 0.5 M suspension of the dione (Inter. 4) (1 equiv.) in anhydrous toluene under an inert atmosphere was slowly added diisopropylethylamine (3 equiv.). The reaction mixture was then heated to 70° C. for 30 minutes and then cooled to room temperature prior to the addition of POCl₃ (3 equivalents). The reaction was then heated to 100° C. for 2.5 hours before being cooled 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 over silica gel for 30 minutes. After this time the silica was removed by filtration, the filtrate concentrated and the crude residue 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 mins

To a cooled (0-5° C.) stirred solution (0.1 M) of the appropriate trichloro-substrate (1 equiv) in CH₂Cl₂ was added diisopropylethylamine (1 equiv) in a dropwise fashion. The appropriate amine (1 equiv) was then added to the reaction mixture portionwise over the period of 1 hour. The solution was maintained at room temperature with stirring for a further 1 hour before the mixture was washed with water (2×1 reaction volume). The aqueous extracts were combined and extracted with CH₂Cl₂ (2×1 reaction volume). The organic extracts were then combined, dried (sodium sulphate), filtered and concentrated in vacuo to give an oily residue which solidified upon prolonged drying. The solid was triturated with diethylether and then filtered and the cake washed with cold diethyl ether to leave the title compound in suitable clean form to be used without any further purification.

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

To a cooled (0-5° C.) stirred solution (0.1 M) of the trichloro substrate (Inter. 5) (1 equiv.) in CH₂Cl₂ was added diisopropylethylamine (1 equiv.) in a dropwise fashion. The appropriate amine (1 equiv.) was then added to the reaction mixture portionwise over the period of 1 hour. The solution was maintained at room temperature with stirring for a further 1 hour before the mixture was washed with water (2×1 reaction volume). The aqueous extracts were combined and extracted with CH₂Cl₂ (2×1 reaction volume). The organic extracts were then combined, dried (sodium sulphate), filtered and concentrated in vacuo to give an oily residue which solidified upon prolonged drying. The solid was triturated with diethylether and then filtered and the cake washed with cold diethyl ether to leave the title compound in suitable clean form to be used without any further purification.

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

Inter. 6b: 2,7-Dichloro-4-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine; R⁴=(2R,6S)-2,6-Dimethyl-morpholino; (99% yield, 90% purity) m/z (LC-MS, ESP): 313 [M+H]⁺ R/T=4.39 mins

Inter. 6c: 2,7-Dichloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine—R⁴=(S)-3-Methyl-morpholine, X=N, Y=C, Z=C: (87% yield, 92% purity) m/z (LC-MS, ESP): 301 [M+H]⁺ R/T=4.13 min

Inter. 6c: 2,7-Dichloro-4-((R)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine—R⁴=(R)-3-Methyl-morpholine: (99% yield, 94% purity) m/z (LC-MS, ESP): 301 [M+H]⁺ R/T=3.49 min

Alternatively, to a stirred 0.47 M suspension of the appropriate dione (1 equiv) in anhydrous anisole under an inert atmosphere was added POCl₃ (2.6 equiv). The mixture was heated to 55° C. and then diisopropylethylamine (2.6 equiv) was slowly added. The reaction mixture was then heated to 85-90° C. for 30 minutes. Water was added in portions (0.15 equiv), and the reaction mixture was held at 85-90° C. for a further 30 minutes. The reaction was cooled to 50° C., and then 15% of the anisole solvent was removed by vacuum distillation. The mixture was then cooled to −5° C. and diisopropylethylamine (1.1 equiv) was added. A 4.9M solution of the appropriate amine (1.05 equiv) in anisole was then added to the reaction mixture continuously over a period of 1 hour. The solution was then warmed to 30° C. and the reaction monitored by HPLC until reaction completion.

One third of the resulting mixture from the above reaction was then added over 10 min to a stirred mixture of 1.95M aqueous potassium hydroxide (3.9 equiv) and i-butanol (6.9 equiv) at 60° C. The stirring was stopped, the phases were allowed to separate, and the aqueous phase was removed. Stirring was resumed, and 1.95M aqueous potassium hydroxide (3.9 equiv) was added to the retained organic phase. The second third of the resulting reaction mixture from the reaction above was then added over 10 min at 60° C. Again, stirring was stopped, the phases were allowed to separate, and the aqueous phase was removed. Stirring was resumed, and 1.95M aqueous potassium hydroxide (3.9 equiv) was added to the retained organic phase. The remaining third of the resulting reaction mixture from the reaction above was then added over 10 min at 60° C. Again, stirring was stopped, the phases were allowed to separate, and the aqueous phase was removed. Water was then added to the organic phase with stirring, and the stirred mixture heated to 75° C. Stirring was stopped, the phases were allowed to separate, and the aqueous phase was removed. The resulting organic phase was stirred and allowed to cool to 30° C., and then as the mixture was heated to 60° C. heptane (11.5 equiv) was added over 20 min when the mixture was around 40° C. After being heated to 60° C., the mixture was cooled over 2.5 h to 10° C. After 30 min, the resulting slurry was filtered off, washed with a 10:1 heptane:anisole mixture (2×1.4 equiv) and then washed with heptane (2×1.4 equiv). The solid was then dried in a vacuum oven at 50° C. to leave the title compound in suitable clean form to be used without any further purification.

To a solution (0.2 M) of the appropriate dichloro-substrate (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 being cooled to ambient temperature. The reaction was diluted with CH₂Cl₂ (1 reaction volume) and then washed with water (3×1 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 solution before being dried (sodium sulphate) and concentrated in vacuo to give an oil. The crude residue was purified by flash chromatography (SiO₂, eluted with EtOAc:Hex (7:3) going to (1:1)) to give the title compound as a yellow solid that was suitably clean to be used without any further purification.

2,4-Diamino-7-chloropyridopyrimidines (Inter. 7)

To a solution (0.2 M) of the appropriate dichloro-substrate (Inter. 6a or 6b) (1 equiv) in anhydrous 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 being cooled to ambient temperature. The reaction was diluted with CH₂Cl₂ (1 reaction volume) and then washed with water (3×1 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 solution before being dried (sodium sulphate) and concentrated in vacuo to give an oil. The crude residue was purified by flash chromatography (SiO₂, eluted with EtOAc:Hex (7:3) going to (1:1)) to give the title compound as a yellow solid that was suitably clean to be used without any 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 mins

Inter. 7b: 7-Chloro-4-(2-methyl-piperidin-1-yl)-2-morpholin-4-yl-1-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 mins

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 mins

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-Methyl-morpholine; (70% yield, 97% purity) m/z (LC-MS, ESP): 350 [M+H]⁺ R/T=3.44 mins

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 mins

Inter. 7f: 7-Chloro-4-((S)-3-methyl-morpholin-4-yl)-2-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine—R⁴=(S)-3-Methyl-morpholine, R²=(S)-3-Methyl-morpholine, X=N, Y=C, Z=C: (71% yield, 90% purity) m/z (LC-MS, ESP): 364 [M+H]⁺ R/T=3.52 min

Inter. 7g: 7-Chloro-2-(2-ethyl-piperidin-1-yl)-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine—R⁴=(S)-3-Methyl-morpholine, R²=2-Ethyl-piperidine, X=N, Y=C, Z=C: (51% yield, 98% purity) m/z (LC-MS, ESP): 376 [M+H]⁺ R/T=3.88 min

Inter. 7h: 7-Chloro-4-((S)-3-methyl-morpholin-4-yl)-2-morpholin-4-yl-pyrido[2,3-d]pyrimidine, —R⁴=(S)-3-Methyl-morpholine, R²=morpholine, X=N, Y=C, Z=C: (72% yield, 96% purity) m/z (LC-MS. ESP): 350 [M+H]⁺ R/T=3.45 min

Inter. 7i: 7-Chloro-2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-4-((S)-3-methyl-morpholin-4-yl-pyrido[2,3-d]pyrimidine—R⁴=(S)-3-Methyl-morpholine, R²=cis-dimethylmorpholine: (33% yield) m/z (LC-MS, ESP): 378 [M+H]⁺ R/T=3.68 min

Inter. 7j: 7-Chloro-4-((R)-3-methyl-morpholin-4-yl)-2-((R)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine, —R⁴=R²=(R)-3-Methyl-morpholine: (48% yield, 100% purity) m/z (LC-MS, ESP): 364 [M+H]⁺ R/T=2.80 min

To a 0.33 M solution of 2,7-dichloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine (1 equiv) in N,N-dimethylacetamide was added Hunig's base (1 equiv) followed by the appropriate amine (1.1 equiv). The reaction mixture was heated 40° C. for 1 hour. After this time the reaction was allowed to cool, diluted with EtOAc (1 reaction volume) and then washed with water (1 reaction volume). The aqueous fraction was removed and extracted further with EtOAc (2×1 reaction volume). The combined organic extracts were dried (MgSO₄), filtered and concentrated in vacuo to give a crude oily residue which was purified by flash chromatography (SiO₂) using EtOAc/Hexanes as eluent which furnished the desired products in a suitably clean form.

Inter. 7k: 7-Chloro-4-((S)-3-methyl-morpholin-4-yl)-2-thiomorpholin-4-yl-pyrido[2,3-d]pyrimidine: (30% yield, 100% purity) m/z (LC-MS, ESP): 366.4 [M+H]⁺ R/T=3.00 min

Inter. 7l: 7-Chloro-4-((S)-3-methyl-morpholin-4-yl)-2-(4-methyl-piperazin-1-yl)-pyrido[2,3-d]pyrimidine: (32% yield, 95% purity) m/z (LC-MS, ESP): 363.4 [M+H]⁺ R/T=2.37 min

The appropriate chloro-substrate (1 equiv) was dissolved in a toluene/ethanol (1:1) solution (0.02 M). Sodium carbonate (2 equiv) and the appropriate pinacolate boron ester or boronic acid (1 equiv) were then added followed by tetrakis(triphenylphosphine) palladium⁰ (0.1 equiv). The reaction vessel was sealed and the mixture 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 give the desired products.

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

To a solution (0.09 M) of the appropriate boronic acid or ester (1 equiv) in water (I volume) was added the appropriate 2,7-dichloro-4-amino pyridopyrimidine (1 equiv) (Inter. 6a or 6b) potassium carbonate (2.5 equiv) and acetonitrile (1 volume). The mixture was degassed by bubbling nitrogen through the solution while sonicating for 15 minutes before the addition of by tetrakis(triphenylphosphine) palladium (0.03 equiv). The mixture was degassed for a further 5 minutes before heating under an inter atmosphere at 95° C. for 2 hours. Upon completion, the reaction was cooled to room temperature and filtered under vacuum. The filtrate was concentrated in vacuo to give a solid residue which was dissolved in CH₂Cl₂ (1 volume) and washed with water (1 volume). The organic extract was then dried (MgSO₄), filtered and concentrated in vacuo to give an amorphous solid which was triturated with Et₂O to leave the desired product as a fine powder.

Inter. 8a (R⁴=Morpholine, R⁷=4-chlorophenyl) 2-Chloro-7-(4-chloro-phenyl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine; ¹H NMR (300 MHz, Solvent CDCl₃ δ ppm 8.29-7.96 (m, 2H), 7.75 (d, J=8.70 Hz, 1H), 7.54-7.21 (m, 2H), 5.29 (s, 1H), 3.91 (m, 8H).

Example 1

R⁷=Aryl

Examples 1a-bx

The appropriate 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 appropriate boronic acid (1 equiv.) were then added followed by tetrakis(triphenylphosphine) palladium (0.1 equiv). The reaction vessel was sealed and the mixture 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 give the compounds listed below.

TABLE 1
				Retention
				Time		Purity
	R7	R4	R2	(mins)	[m/z]	(%)
1a				7.66	466.6	89
1b				9.56	440.4	85
1c				8.57	406.5	88
1d				4.56	420.5	89
1e				4.41	436.5	98
1f				4.13	452.3	99
1g				4.82	424	99
1h				4.66	390.1	96
1i				8.12	412.3	93
1j				4.38	450.1	96
1k				7.75	482.5	89
1l				7.88	422.4	99
1m				9.08	478.4	99
1n				8.52	431.4	95
1o				3.89	456.4	93
1p				4.36	480.5	100
1q				4.09	436.4	100
1r				4.03	396.2	100
1s				10.19	404.2	97
1t				4.66	426.3	98
1u				4.67	420.1	95
1v				4.53	426.3	99
1w				9.11	454.4	100
1x				8.93	445.3	97
1y				4.72	426.4	99
1z				8.89	451.5	80
1aa				7.66	396.4	99
1ab				7.65	463.4	85
1ac				3.62	407.4	99
1ad				7.06	410.4	99
1ae				4.24	466.5	100
1af				4.33	484.4	96
1ag				4.44	454.3	98
1ah				8.43	466.4	97
1ai				6.98	449.4	100
1aj				9.06	420.4	90
1ak				8.95	450.4	96
1al				9.45	446.2	88
1am				8.92	464.4	99
1an				9.85	456.4	97
1ao				10.42	490.4	97
1ap				4.41	440.3	99
1aq				8.4	448.5	97
1ar				7.66	456.4	99
1as				8.46	491.5	99
1at				8.97	464.4	99
1au				8.35	431.5	93
1av				8.59	450.4	99
1aw				10.1	462.4	98
1ax				6.03	407.4	100
1ay				7.63	457.5	99
1az				6.4	408.4	99
1ba				9.08	478.4	99
1bb				3.95	452.3	95
1bc				9.01	464.4	99
1bd				4.69	464.3	98
1be				4.31	426.3	100
1bf				4.9	512.4	100
1bg				7.82	449.5	90
1bh				8.18	463.5	89
1bi				3.89	426.4	100
1bj				5.45	353.2	100
1bk				5.43	518.4	96
1bl				11.28	502.3	95
1bm				4.13	480.4	97
1bn				4.79	464.4	97
1bo				5.2	492.4	93
1bp				4.5	508.4	90
1bq				4.81	476.4	100
1br				9.44	450.3	98
1bs				4.65	424.3	99
1bt				9.26	506.3	98
1bu				4.78	438.4	99
1bv				11.43	526.3	99
1bw				11.54	548.3	98
1bx				5.37	506.4	95

Example 1bj:—1H NMR (300 MHz, Solvent CDCl₃) δ 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).

Example 2

R⁷=Substituted Amino

Examples 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 was sealed 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 give the compounds listed below.

	TABLE 2
				Purity	m/z	RT
	R4	R2	R7	%	[MH]+	(mins)
2a				95	421	4.65
2b				96	513	4.12
2c				95	451	3.6
2d				98	373.1	7.18
2e				83	389.2	3.73
2f				100	472.2	3.49
2g				96	479.5	8.81
2h				85	446.5	8.34
2i				91	405.5	9.41
2j				99	435.5	4.61
2k				86	455.5	9.68
2l				96	514.5	9.38
2m				100	525.6	10.46
2n				96	463.6	10.62
2o				92	472.5	9.44
2p				98	553.6	11.83
2q				97	486.6	10.22
2r				100	412.4	3.5
2s				92	538.2	10.59
2t				86	436.2	3.44
2u				81	459.4	4.26
2v				88	399.6	7.96
2w				90	442.6	5.13
2x				94	426.4	8.52
2y				95	515.6	8.71
2z				92	445.4	9.49
2aa				98	471.5	9.04
2ab				69	492.6	6.25
2ac				73	502.5	9.48
2ad				97	524.2	9.68
2ae				96	525.4	4.79
2af				98	427.5	4.55
2ag				100	413.4	4.36
2ah				95	385.3	3.88
2ai				89	399.5	8.13
2aj				94	399.5	8.18
2ak				91	378.4	7.81
2al				99	441.6	9.95
2am				92	385.5	7.46
2an				99	469.4	4.31
2ao				98	427.5	3.91
2ap				83	512.2	4.97
2aq				94	427.1	94
2ar				99	436.1	3.9
2as				98	482.1	4.36
2at				98	510.5	8.96
2au				98	463.6	4.03
2av				99	473.6	4.12
2aw				99	500.6	4.17
2ax				82	489.5	4.84
2ay				98	488.5	4.56
2az				100	422.5	3.73
2ba				100	422.5	3.6
2bb				99	423.5	3.94
2bc				97	423.5	4.11
2bd				100	436.5	4.00
2be				99	436.5	4.49
2bf				95	544.6	5.23
2bg				99	436.5	3.94
2bf				5.35	330.3	96

Example 2bf:—¹H NMR (300 MHz, Solvent CDCl₃) δ 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)

Example 3

R⁷=NH₂

Examples 3a-b

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

	TABLE 3
				Pur-
				ity	m/z	RT
	R4	R2	R7	%	[MH]+	(mins)
3a				95	345.2	3.86
3b				91	329.4	7.33

Example 4

R⁷=Urea

Examples 4a

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

	TABLE 4
				Purity	m/z	RT
	R4	R2	R7	%	[MH]+	(mins)
4a				99	416.5	3.8

Example 5

R⁷=Amido

Examples 5a-g

To a solution (0.02M) of the appropriate amine-substrate (Example 3a or 3b) (1 equiv) in anhydrous CH₂Cl₂ was added triethylamine (2 equivalents) and the appropriate acid chloride (2 equivalents). The mixture was stirred at room temperature for 1 hour whereupon the solvent was allowed to evaporate at atmospheric pressure and the crude residue purified by preparative HPLC to give the compounds below.

	TABLE 5
					m/z	RT
	R4	R2	R7	Purity %	[MH]+	(mins)
5a				95	402.2	4.49
5b				96	441.2	4.16
5c				100	413.2	3.89
5d				98	495.2	4.34
5e				83	501.2	4.28
5f				95	387.2	6.04
5g				99	454.5	3.85

Example 6

R⁷=Sulfonamido

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

	TABLE 6
				Purity	m/z	RT
	R4	R2	R7	%	[MH]+	(mins)
6				85	423.5	3.87

Example 7

R⁷=Alkoxy

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

	TABLE 7
				Purity	m/z	RT
	R4	R2	R7	%	[MH]+	(mins)
7				100	402.2	4.49

Example 8

R⁷=4-alkoxy-3-aminomethyl-phenyl

Examples 8a-8bh

To a 0.1 M solution of Example 1a (1 equiv.) in CH₂Cl₂ was added Et₃N (1 equiv.) followed by methanesulfonyl chloride (1.1 equiv.) which was added dropwise. The reaction was stirred under an inert atmosphere for 90 minutes whereupon it was quenched with water (2×1 volume), the organ is extract separated and dried (MgSO₄) filtered and concentrated in vacuo. The crude yellow gum was then diluted in diethyl ether and stirred vigorously. The resultant yellow precipitate was then collected by filtration to give the title compound (98%) in suitable clean form to be used without further purification.

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

To 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-pyrido[2,3-d]pyrimidine (1 equiv.) in dimethylformamide was added potassium carbonate (2.6 equiv.) followed by the triethylamine (1 equiv.) and finally the appropriate amine (1.1 equiv.). The reaction mixture was then heated to 40° C. for 16 hours whereupon it was purified by preparative HPLC to give the desired product.

	TABLE 8
		Retention
	Purity	time
	(%)	(mins)	[m/z]
8a		99	3.86	519.5
8b		77	6.32
8c		98	5.29	559.5
8d		98	5.96	509.4
8e		87	7.56	599.5
8f		100	6	479.5
8g		99	3.88	519.5
8h		99	3.57	578.5
8i		99	6.21	549.6
8j		95	6.97	561.5
8k		99	6.8	533.5
8l		99	3.95	521.5
8m		99	4.04	535.4
8n		99	4.18	575.5
8o		99	7.14	547.5
8p		75	7.75	561.5
8q		99	4.12	549.4
8r		93	6.36	507.6
8s		100	6.71	551.5
8t		99	4.11	549.5
8u		98	6.73	521.5
8v		99	6.25	523.4
8w		99	4.1	561.5
8x		99	4.14	571.4
8y		99	4.12	658.4
8z		99	4.07	615.5
8aa		99	3.73	577.4
8ab		99	3.81	591.4
8ac		99	3.92	619.4
8ad		99	3.55	569.3
8ae		99	3.42	662.3
8af		99	4.01	619.4
8ag		99	3.96	575.3
8ah		99	4.12	573.5
8ai		99	3.61	576.5
8aj		99	3.91	549.4
8ak		99	4.01	553.4
8al		83	4.81	531.4
8am
8an		92	4.10	575.4
8ao		97	4.17	613.4
8ap		99	3.64	584.5
8aq		99	3.79	523.4
8ar		98	4.10	629.5
8as		99	4.20	650.5
8at		99	4.11	600.4
8au		86	4.20	614.4
8av		94	4.20	581.5
8aw		99	4.33	623.4
8ax		99	4.17	589.4
8ay		83	4.22	626.5
8az		96	4.41	631.5
8ba		89	5.14	647.5
8bb		99	3.95	601.4
8bc		99	4.27	583.4
8bd		99	3.97	583.4
8be		99	4.29	613.5
8bf		74	10.36	627.6
8bg		93	7.13	599.2

Example 9

R²=aryl; R⁷=aryl

Examples 9a-9ae

To the appropriate 2-chloro-pyridopyrimidine (Inter. 8a) (1 equiv) in acetonitril/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 whereupon it was cooled to room temperature. The reaction was then filtered through a thin silica pad, which was washed with 1:1 mixture MeOH/CH₂Cl₂ (1 volume), concentrated in vacuo and then purified by preparative HPLC to give the desired product (9a-9ae)

	TABLE 9
		Retention
	Purity	time
	(%)	(mins)	[m/z]
9a		92	7.17	488.3
9b		86	10.16	518.3
9c		95	10.72	474.3
9d		99	4.58	443.4
9e		95	4.53	459.4
9f		97	7.21	419.3
9g		83	4.35	457.3
9h		97	4.42	473.5
9i		97	4.01	445.3
9j		91	4.70	454.3
9k		79	7.19	472.3
9l		89	7.24	444.3
9m		98	4.45	433.2
9n		99	3.54	458.3
9o		96	11.05	505.3
9p		98	7.49	471.2
9q		92	4.63	489.3
9r		99	11.32	497.3
9s
9t		94	5.20	404.2
9u		96	5.24	433.2
9v		99	7.18	448.2
9w		83	6.25	431.2
9x		99	5.18	393.2
9y		81	5.83	417.2
9z		80	2.71	447.2
9aa		97	6.27	479.4
9ab		96	6.20	428.3
9ac		97	2.11	446.2
9ad		95	6.51	461.2
9ae		87	7.28	459.3

Example 10

Example 10a

7-Chloro-2-((S)-3-methyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine was reacted with 2-aminopyridine-5-boronic acid using Suzuki coupling conditions I (Example 11 procedures).

5-[2-((S)-3-Methyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine: (76% yield, 96% purity) m/z (LC-MS, ESP): 408.2 [M+H]⁺ R/T=3.29 min

NMR Data for Example 10a

¹H NMR (300 MHz, CDCl₃ δ ppm 8.77 (ArH, d, J=1.86 Hz, 1H), 8.34 (ArH, dd, J=8.65, 2.40 Hz, 1H), 7.93 (ArH, d, J=8.48 Hz, 1H), 7.32 (ArH, d, J=8.49 Hz, 1H), 6.54 (ArH, dd, J=8.66, 0.62 Hz, 1H), 4.97-4.84 (CH₂, m, 1H), 4.70-4.52 (CH₂, +NH, m, 3H), 4.00-3.61 (CH₂, m, 11H), 3.57-3.45 (CH₂, m, 1H), 3.40-3.26 (CH₂, m, 1H), 1.30 (CH₃, d, J=6.81 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.77, 162.88, 160.52, 159.97, 159.37, 148.25, 137.62, 134.71, 125.05, 112.06, 108.21, 104.17, 71.29, 67.28, 66.66, 50.27, 46.87, 39.34 and 14.40.

Example 10b

N-{3-[2-((S)-3-Methyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-phenyl}-methanesulfonamide

7-Chloro-2-((S)-3-methyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine was reacted with (3-methylsulfonylaminophenyl)boronic acid using Suzuki coupling conditions G (Example 11 procedures). The resultant crude residue was purified by flash chromatography (SiO₂) using 0-10% MeOH in CH₂Cl₂ to provide a yellow solid which corresponded to the title compound.

N-{3-[2-((S)-3-Methyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-phenyl}-methanesulfonamide: (95% yield, 100% purity) m/z (LC-MS, ESP): 490.2 [M+H]⁺ R/T=3.49 min

Example 10c

2-Methoxy-N-methyl-5-[2-((S)-3-methyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzamide

The appropriate 7-chloropyridopyrimidine was reacted with 2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester according to conditions E described in Example 11 procedures to give 2-methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-thiomorpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid methyl ester as the desired product (1 equiv) which was in then diluted in MeOH to give a 0.03M solution. NaOH (5 equiv of 1 M solution) was then added and the resultant mixture stirred at room temperature for 5 days. After this time the reaction was filtered and neutralized with 1M HCl before being concentrated in vacuo to give a crude yellow residue which was diluted in CH₂Cl₂. The mixture was filtered and the resulting filtrate concentrated to give the desired products as a oil.

2-Methoxy-5-[2-((S)-3-methyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid: (91% yield, 92% purity) m/z (LC-MS, ESP): 466.4 [M+H]⁺ R/T=2.67 min

To a 0.06M solution of 2-methoxy-5-[2-((S)-3-methyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid (1 equiv) in anhydrous THF was added HBTU (1.5 equiv) followed by methylamine (1M in THF, 15 equiv) and then triethylamine (2 equiv). The mixture was allowed to stir at room temperature for 2 hours whereupon it was concentrated in vacuo and re-diluted in CH₂Cl₂ (2 reaction volumes) and washed with saturated brine solution (2 reaction volumes). The organic fraction was removed, dried (Na₂SO₄), filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO₂) using Hexanes:EtOAc—100:0 going to 0:100 as eluent to give the desire product as a yellow solid.

2-Methoxy-N-methyl-5-[2-((S)-3-methyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzamide: (33% yield, 92% purity) m/z (LC-MS, ESP): 479.2 [M+H]⁺ R/T=3.96 min

    TABLE 10
    [m/z]
10a 408.2
10b 490.2
10c 479.2

Example 11

Preparation of 2,4,7-Substituted Pyridopyrimidine Intermediates

Procedures for the Synthesis of 2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-7-aryl]-pyrido[2,3-d]pyrimidine Derivatives

To a (0.1 M) solution of 2,7-dichloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine (1 equiv) in MeCN/H₂O (1:1 mixture) was added the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and potassium carbonate (3 equiv). The mixture was degassed with nitrogen for 20 minutes before the addition of tetrakis(triphenylphosphine)palladium⁰ (0.05 equiv). The reaction was degassed for a further 5 minutes before being heated to reflux under an inert atmosphere for 3 hours. Whereupon, it was concentrated in vacuo and the crude residue partitioned between CH₂Cl₂/H₂O. The organic fraction was dried (MgSO₄), filtered and concentrated in vacuo to give an oil which was further purified by flash chromatography (SiO₂) using 5% MeOH in CH₂Cl₂ as eluent.

3-[2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzamide: (27% yield, 99% purity) m/z (LC-MS,ESP): 384.3 [M+H]⁺ R/T=3.13 min)

5-[2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine: (93% yield, 89% purity) m/z (LC-MS,ESP): 357 [M+H]⁺, R/T=2.53 min)

2-Chloro-7-(4-chloro-phenyl)-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine: (80% yield, 85% purity) m/z (LC-MS,ESP): 357.5 [M+H]⁺, R/T=4.26 min)

{5-[2-Chloro-4-((R)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl}-methanol: (97% yield, 93% purity) m/z (LC-MS,ESP): 401 [M+H]⁺, R/T=3.42 min)

Procedures for the Synthesis of Boronic Ester:

5-bromo-2-methoxybenzoic acid methyl ester (1 equiv) was dissolved in dioxane (0.1 M). Bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv) were added and the mixture was degassed with nitrogen for 20 minutes. (1,1′-Bis(diphenylphosphino)ferrocene-dichloropalladium (0.05 equiv) was added and the mixture was degassed for a further 5 minutes. The reaction mixture was heated to 120° C. for 2 hours under nitrogen. After cooling to room temperature, the reaction mixture was diluted with CH₂Cl₂ and filtered through Celite™. The filtrate was concentrated in vacuo to give a dark oil. The residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate and the aqueous layer further extracted with EtOAc. The combined organic phases were dried (MgSO₄), filtered and the filtrate was concentrated in vacuo to give a dark residue which was purified by flash column chromatography onto silica gel eluting with 0 to 30% ethyl acetate in hexane.

2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester: (77% yield, 100% purity) m/z (LC-MS, ESP): 293.5 [M+H]⁺ R/T=4.24 min

Procedures for the Synthesis of Tetrazolyl Boronic Acids

The appropriate cyanophenylpinacolate boron ester or boronic acid (1 equiv) was dissolved in DMF (0.67 M). Sodium azide (6 equiv) and ammonium chloride (6 equiv) were added. The reaction mixture was heated to 120° C. for 2.5 hours. After cooling down, the reaction mixture was poured into a mixture of ice water and EtOAc. Sodium nitrite was added and the aqueous phase was acidified by 6N HCl until pH 2. The mixture was allowed to stir at room temperature for 30 min and then was extracted with EtOAc and n-butanol. Organic fractions were collected, dried over sodium sulphate, filtered off and concentrated in vacuo, to yield a crude residue which was further purified accordingly:

The crude residue was recrystallized from CH₂Cl₂/hexane, obtaining the desired product as a white solid.

[3-(1H-tetrazol-5-yl)phenyl]boronic acid: (15% yield, 100% purity) m/z (LC-MS, ESP): 191 [M+H]⁺ R/T=2.49 min

The crude residue was recrystallized from CH₂Cl₂/hexane, to give the desired product as a white solid.

[4-(1H-tetrazol-5-yl)phenyl]boronic acid: (64% yield, 100% purity) m/z (LC-MS, ESP): 191 [M+H]⁺ R/T=2.49 min

The residue was purified by reverse phase column using a gradient from 5% to 20% acetonitrile in 0.1% formic acid/water solution, yielding the desired product.

[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]boronic acid: (18% yield, 100% purity) m/z (LC-MS, ESP): 207 [M−H]⁻ R/T=2.51 min

Procedure for the Synthesis of Methanesulfonylamido Boronic Acid

3-Amino-4-fluorophenylboronic acid (1 equiv) was dissolved in THF (0.1 M). Methane sulphonyl chloride (10 equiv) and pyridine (1 equiv) were added. The reaction mixture was heated to 70° C. for 30 minutes. After cooling down, the reaction mixture was concentrated in vacuo, to yield a crude residue which was used without further purification.

3-(Methanesulfonylamino)-4-fluoro-phenylboronic acid: (51% yield, 90% purity) m/z (LC-MS, ESP): 232 [M−H]⁻ R/T=2.50 min

Procedure for the Synthesis of 3-hydroxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ol

To a 0.18 M solution of 5-bromo-2-hydroxybenzyl alcohol (1 equiv) in dioxane was added bis(pinacolato)diboron (1.2 equiv) and potassium acetate (3.5 equiv) followed by 1,1′-bis(diphenylphosphino)ferrocene (0.05 equiv). The mixture was degassed with nitrogen for 20 minutes. PdCl₂(dppf) (0.05 equiv) was added and the mixture degassed for a further 5 minutes. The reaction was then heated to reflux under an inert atmosphere for 2 hours. Upon completion, the reaction was cooled, filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO₂) using EtOAc/Hexanes—1:1 as eluent to give the desired product.

3-Hydroxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ol 6-Bromo-3H-pyrido[2,3-d]pyrimidin-4-one: (67% yield, 94% purity) m/z (LC-MS,ESP): 251 [M−H]⁻ R/T=3.32 minutes)

Procedure for the Synthesis of 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

To a 0.05 M solution of 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (1 equiv) in dioxane was added bis(pinacolato)diboron (1.2 eqiv) and potassium acetate (1.5 equiv) followed by 1,1′-bis(diphenylphosphino)ferrocene (0.05 equiv). The mixture was degassed with nitrogen for 20 minutes. PdCl₂(dppf) (0.05 equiv) was added and the mixture degassed for a further 5 minutes. The reaction was then heated to 120° C. under an inert atmosphere for 8 hours. Upon completion, the reaction was cooled, filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO₂) using EtOAc/Hexanes—4:1 as eluent to give the desired product.

5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one: (68% yield, 92% purity) m/z (LC-MS,ESP): 260 [M−H]⁻ R/T=3.52 minutes)

Procedure for the Synthesis of 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one boronic ester

To a 1.2 M solution of 5-bromoanthranilic acid (1 equiv) in N,N-dimethylformamide was added formamidine acetate (1 equiv). The mixture was heated to reflux and stirred at this temperature for 16 hours. After this time, the reaction was cooled and NaHCO₃ solution (5% in H₂O) (3 volumes) were carefully added and the mixture stirred vigorously. The resulting precipitate was collected by filtration and then washed with water (2×1 volume) and then t-butyl methylether (2×1 volume) before being dried in a vacuum oven to give the desired product which required no further purification.

6-Bromo-3H-pyrido[2,3-d]pyrimidin-4-one: (91% yield, insert) m/z (LC-MS,ESP): 225 [M−H]⁻ R/T=2.31 minutes)

To a (0.35M) solution of 6-bromo-3H-pyrido[2,3-d]pyrimidin-4-one (1 equiv) in dioxane was added bis(pinacolato)diboron (1.2 eqiv) and potassium acetate (1.5 equiv) followed by 1,1′-bis(diphenylphosphino)ferrocene (0.05 equiv). The mixture was degassed with nitrogen for 20 minutes. PdCl₂(dppf) (0.05 equiv) was added and the mixture degassed for a further 5 minutes. The reaction was then heated to reflux under an inert atmosphere for 16 hours. After this time, the mixture was cooled, filtered through Celite™ and then partitioned between CH₂Cl₂/NaHCO_3(aq). The organic fraction was removed, dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO₂) 1:1—Hexanes:EtOAc going to neat EtOAc. The purified material was then dissolved in the minimum volume of CH₂Cl₂ and hexane added in order to precipitate the desired product as a whiter crystalline solid

6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one (15% yield, 96% purity) m/z (LC-MS,ESP): Mass ion not observable, R/T=3.30 min)

Procedure for the Synthesis of 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrido[2,3-b][1,4]oxazin-2-one

To a 0.3 M solution of 7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2-one (1 equiv) were added bis(pinacolato)diboron (1.10 equiv), potassium acetate (3.5 equiv) and 1,1′-bis(diphenylphosphino)ferrocene (0.05 equiv). The mixture was degassed with nitrogen for 20 minutes before the addition of PdCl₂(dppf) (0.05 equiv) and degassing for a further 5 minutes. A condenser was attached to the reaction vessel and the mixture heated to reflux under an inert atmosphere for 16 hours. After this time, the reaction was cooled, filtered through Celite™. The cake was washed CH₂Cl₂ and the filtrate concentrated in vacuo before being re-dissolved in EtOAc and washed with H₂O and then saturated brine. The organic fraction was separated, dried (MgSO₄) and concentrated in vacuo to give a crude residue which was further purified by flash chromatography (SiO₂) using 1:1—EtOAc:Hexanes going to neat EtOAc as eluent to give the desired product.

7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrido[2,3-b][1,4]oxazin-2-one: (97% yield, 90% purity) m/z (LC-MS,ESP): 317 [M+H+MeCN]⁺, R/T=3.72 min)

Procedure for the Synthesis of 2-Methoxynicotinonitrile-5-boronic acid

To a cooled (−78° C.) solution (0.25 M) of 5-bromo-2-methoxybenzonitrile in THF was added n-BuLi (1.10 equiv of a 2.5 M solution in hexanes) dropwise. The mixture was maintained at this temperature with stirring for 45 minutes before the addition of triisopropylborate (1.25 equiv). The reaction was then warmed to −20° C. before the addition of 1N HCl (0.5 reaction volumes). The mixture was allowed to warm to room temperature and stirred like this for a further 20 minutes. After this time the mixture was diluted with H₂O and then extracted with Et₂O (3×4 reaction volumes). The combined organic fractions were then dried (MgSO₄), filtered and concentrated in vacuo to give an off white solid which corresponded to the title compound

2-Methoxynicotinonitrile-5-boronic acid: (44% yield, 90% purity) m/z (LC-MS,ESP): 177.0 [M+H]⁺, R/T=2.87 min)

Procedure for the Synthesis of 2-Ethoxynicotinonitrile-5-boronic acid

To a cooled (−78° C.) solution (0.25 M) of 5-bromo-2-ethoxybenzonitrile in THF was added n-BuLi (11.10 equiv of a 2.5 M solution in hexanes) dropwise. The mixture was maintained at this temperature with stirring for 45 minutes before the addition of triisopropylborate (1.25 equiv). The reaction was then warmed to −20° C. before the addition of 1N HCl (0.5 reaction volumes). The mixture was allowed to warm to room temperature and stirred like this for a further 20 minutes. After this time the mixture was diluted with H₂O and then extracted with Et₂O (3×4 reaction volumes). The combined organic fractions were then dried (MgSO₄), filtered and concentrated in vacuo to give an off white solid which corresponded to the title compound.

2-Ethoxynicotinonitrile-5-boronic acid: (23% yield, 97% purity) m/z (LC-MS,ESP): 191.0 [M+H]⁺, R/T=3.09 min)

Procedure for the Synthesis of 2-Isopropoxynicotinonitrile-5-boronic acid

To a cooled (−78° C.) solution (0.25 M) of 5-bromo-2-isopropoxy-nicotinonitrile in THF was added n-BuLi (1.10 equiv of a 2.5 M solution in hexanes) dropwise. The mixture was maintained at this temperature with stirring for 45 minutes before the addition of triisopropylborate (1.25 equiv). The reaction was then warmed to −20° C. before the addition of 1N HCl (0.5 reaction volumes). The mixture was allowed to warm to room temperature and stirred like this for a further 20 minutes. After this time the mixture was diluted with H₂O and then extracted with Et₂O (3×4 reaction volumes). The combined organic fractions were then dried (MgSO₄), filtered and concentrated in vacuo to give an off white solid which was triturated with CH₂Cl₂ to give the desired compound.

2-Isopropoxy-nicotinonitrile-5-boronic acid: (100% yield, 97% purity) m/z (LC-MS,ESP): 204.2 [M+H]⁻, R/T=3.25 min)

Procedure for the Synthesis of 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-phthalazin-1-one

To a 3M solution of 5-bromo-2-formyl benzoic acid (1 equiv) in water was added hydrazine hydrate (5 equivs). The reaction was heated to 95° C. for 4 hours whereupon a white precipitate had formed in the mixture. The reaction was cooled, and filtered. The white solid material was washed with cold methanol and dried to give the desired product.

7-Bromo-2H-phthalazin-1-one: (73% yield, 95% purity) m/z (LC-MS,ESP): 225.2 [M+H]⁺, R/T=2.99 min)

Bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and 1,1′-bis(diphenylphosphino)ferrocene (0.05 equiv) were dissolved in dioxane. The mixture was degassed with nitrogen for 20 minutes before the addition of PdCl₂(dppf) (0.05 equiv). The mixture was degassed for a further 5 minutes. The mixture was heated to reflux for 16 hours and then allowed to cool to room temperature. Water was added to the mixture before it was extracted with EtOAc (2×2 reaction volumes). The combined organic fractions were dried (MgSO₄), filtered and concentrated in vacuo before being purified by flash chromatography (SiO₂) neat hexanes going to 1:1—Hexanes:EtOAc then neat EtOAc to give the desire product as a white crystalline solid.

7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-phthalazin-1-one: (86% yield, 92% purity) m/z (LC-MS,ESP): 191.3 [M+H]⁺, R/T=2.29 min)

Procedure for the Synthesis of 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one

5-Bromo-2-methylbenzoic acid (1 equiv) was dissolved in a 1:9 MeOH/toluene mixture (0.1 M). The reaction mixture was cooled to 0° C. and a trimethylsilyldiazomethane (1.05 equiv) solution in diethylether (2M) was added slowly until a persistent yellow tinge was observed. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The resulting residue was sonicated in hexane, collected by vacuum filtration over a sintered funnel, dried and used without further purification.

5-Bromo-2-methyl-benzoic acid methyl ester: (99% yield, 100% purity) m/z (LC-MS, ESP): no ionisation R/T=4.43 min

To a solution of 5-Bromo-2-methyl-benzoic acid methyl ester (1 equiv) in chloroform (0.1 M) were added N-bromosuccinimide (1.2 equiv) and benzoyl peroxide (0.05 equiv). The reaction mixture was stirred at reflux for 16 hours. It was then diluted with chloroform and a precipitate was collected by vacuum filtration on a sintered funnel. The filtrate was concentrated in vacuo. The subsequent residue was purified by flash column chromatography onto silica gel eluting with DCM in hexane (0 to 20%) to yield the desired product as a clear colourless oil.

5-Bromo-2-bromomethyl-benzoic acid methyl ester: 80% yield, 100% purity) m/z (LC-MS, ESP): no ionisation R/T=4.40 min

A solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1 equiv) in a 1:1 THF/MeOH mixture was treated by gentle bubbling of ammonia gas for 40 minutes at room temperature. The reaction mixture was concentrated in vacuo. The residue was sonicated in CH₂Cl₂ for 15 minutes then filtered to give the desired product as a white solid.

6-Bromo-2,3-dihydro-isoindol-1-one: (98% yield, 90% purity) m/z (LC-MS, ESP): 212.3/214.3 [M+H]⁺ R/T=2.98 min

To a solution of 6-bromo-2,3-dihydro-isoindol-1-one (1 equiv) in dry dioxan (0.1 M) were added bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv). The reaction mixture was degassed with nitrogen for 20 minutes. PdCl₂(dppf) (0.05 equiv) was added to the reaction mixture, which was degassed for a further 5 minutes. The reaction mixture was heated to 70° C. for 2 hours under nitrogen then heated to 120° C. for 16 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic phases dried (MgSO₄), filtered and concentrated in vacuo. The residue was sonicated in EtOAc, the suspension was filtered onto a sintered funnel and the collected grey solid was dried and used without further purification.

6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one: (82% yield, 29% purity, main impurity being the boronic acid 43%) m/z (LC-MS, ESP): 519.5 [2M+H]⁺ R/T=3.38 min

Procedure for the Synthesis of 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione

To a solution of 5-bromoisatoic anhydride (1 equiv) in water (1 M) was added glycine (1.4 equiv) and triethylamine (1 equiv) at room temperature. The reaction mixture was stirred at room temperature for 4 hours to give a cloudy solution. The reaction mixture was concentrated in vacuo. Acetic acid was added and the reaction mixture was stirred at 140° C. for 4.5 hours. The reaction mixture was cooled down slowly to room temperature. A precipitate was formed. The reaction mixture was diluted with diethyl ether then filtered through a sintered funnel to yield the desired product.

7-Bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione: (75% yield, 100% purity) m/z (LC-MS, ESP): 255.2/257.2 [M+H]⁺R/T=2.67 min

To a solution of 7-bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (1 equiv) in dry dioxan (0.1 M) were added bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv). The reaction mixture was degassed with nitrogen for 20 minutes. PdCl₂(dppf) (0.05 equiv) was added to the reaction mixture, which was degassed for a further 5 minutes. The reaction was heated to 120° C. for 16 hours under nitrogen. The reaction mixture was partitioned between CH₂Cl₂/MeOH and water. The aqueous phase was further extracted with CH₂Cl₂/MeOH. The combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The residue was sonicated in hexane/CH₂Cl₂, filtered, sonicated in CH₂Cl₂ and filtered to yield the desired product.

7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione: (63% yield, 85% purity main impurity being the boronic acid 15%) m/z (LC-MS, ESP): 303.4 [M+H]⁺ R/T=3.08 min

To a solution of 2-amino-4-bromobenzoic acid (1 equiv) in DMA (0.23 M), were added ammonium chloride (7 equiv), HBTU (1 equiv) and diisopropylethylamine (2 equiv). The reaction mixture was stirred for 24 hours at room temperature. DMA was evaporated and the residue was purified by flash column chromatography onto silica gel eluting with a gradient of TBME/hexane to yield the desired product as a white solid.

2-Amino-4-bromo-benzamide: 40% yield, 100% purity) m/z (LC-MS, ESP): 215 [M+H]⁺ R/T=3.00 min

To a solution of 2-amino-4-bromo-benzamide (1 equiv) in DMA (0.14 M) were added triethyl orthoformate (10 equiv) and trifluoroacetic acid (1 equiv). The reaction vessel was sealed and exposed to microwave radiation (160° C., medium absorption setting) for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was filtered through a silica pad with 10% methanol in ethyl acetate yielding the required product as a pale yellow solid.

7-Bromo-3H-quinazolin-4-one: (71% yield, 100% purity) m/z (LC-MS, ESP): 268 [M+H]⁺ R/T=2.94 min

To a solution of 7-bromo-3H-quinazolin-4-one (1 equiv) in dioxane (0.04 M) were added bispinacolato diboron (2.2 equiv), potassium acetate (1.5 equiv), dppf (0.1 equiv) and PdCl₂(dppf) (0.1 equiv). The reaction mixture was degassed with nitrogen for 5 minutes, sonicated and stirred at 120° C. for 3 hours. The reaction mixture was concentrated in vacuo. The residue was filtered through a Celite™ pad topped with silica with ethyl acetate. The mother liquor was concentrated in vacuo yielding a brown solid which was further purified by flash column chromatography onto silica gel eluting with a gradient of methanol/diethyl ether (0 to 5%) to yield the desired product as a white solid.

7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-quinazolin-4-one: (53% yield, 61% purity main impurity being the boronic acid 39%) m/z (LC-MS, ESP): [M+H]⁺ R/T=min

To a solution of 6-bromo-2-oxindole (1 equiv) in NMP (0.05 M) were added bispinacolato diboron (2.4 equiv), potassium acetate (1.5 equiv), dppf (0.05 equiv) and PdCl₂(dppf) (0.05 equiv). The reaction mixture was stirred at 130° C. for 3 hours and then concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel eluting with EtOAc/hexane (9/1), yielding the desired product as a red solid.

6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one: (22% yield, 51% purity main impurity being the boronic acid 28%) m/z (LC-MS, ESP): 260 [M+H]⁺ R/T=3.51 min

Procedure for the Synthesis of 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one

4-Bromo-2-bromomethyl-benzoic acid methyl ester was prepared according to literature.

A solution of 4-bromo-2-bromomethyl-benzoic acid methyl ester (1 equiv) in a 1:1 THF/MeOH mixture was treated by gentle bubbling of ammonia gas for 4 hours at room temperature. The reaction mixture was concentrated in vacuo. The residue was sonicated in water, filtered, then sonicated in diethylether and filtered to give the desired product as a white solid.

5-Bromo-2,3-dihydro-isoindol-1-one: (81% yield, 100% purity) m/z (LC-MS, ESP): 212.3/214.3 [M+H]⁺ R/T=3.06 min

To a solution of 5-bromo-2,3-dihydro-isoindol-1-one (1 equiv) in dry dioxan (0.1 M) were added bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv). The reaction mixture was degassed with nitrogen for 20 minutes. PdCl₂(dppf) (0.05 equiv) was added to the reaction mixture, which was degassed for a further 5 minutes. The reaction mixture was heated to 70° C. for 2 hours under nitrogen then heated to 120° C. for 16 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic phases dried (MgSO₄), filtered and concentrated in vacuo. The residue was dissolved in CH₂Cl₂ and hexane was added. The resulting suspension was filtered and the collected brown powder was dried and used without further purification.

5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one: (94% yield, 76% purity, main impurity being the boronic acid 13%) m/z (LC-MS, ESP): 260.4 [2M+H]⁺ R/T=3.51 min

Procedures for the Preparation of Examples 11a to 11du

• R⁴=(S)-3-methyl-morpholine
• R²=(S)-3-methyl-morpholine or cis-dimethylmorpholine or 2-Ethyl-piperidine or morpholine or thiomorpholine or 4-methylpiperazine
• R⁷=aryl or heteroaryl

Procedures for the Suzuki Coupling:

The synthesis of the appropriate chloro-substrate has been described in the present document as intermediates. The appropriate pinacolate boron ester or boronic acids were prepared according to synthesis described in the present document (as intermediates) or commercially available, typically from the following suppliers:

Sigma-Aldrich, Lancaster, Frontier Scientific, Boron Molecular, Interchim, Asymchem, Combi-blocks, Apollo Scientific, Fluorochem, ABCR, Digital Speciality Chemicals.

Conditions A:

The appropriate chloro-substrate (1 equiv) was dissolved in a toluene/ethanol (1:1) solution (0.02 M). Sodium carbonate (2 equiv) and the appropriate pinacolate boron ester or boronic acid (1 equiv) were then added followed by tetrakis(triphenylphosphine) palladium⁰ (0.1 equiv). The reaction vessel was sealed and the mixture 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 give the desired products.

Conditions B:

A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.4 equiv), the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) in n-butanol (0.03 M of chloro-substrate) was stirred at 120° C. for 2 hours. Upon completion the samples were filtered through a silica cartridge, washed through with CH₂Cl₂ and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions C:

To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.4 equiv), and the appropriate pinacolate boron ester or boronic acid (1.1 equiv) in acetonitrile/water (1:1) (0.041 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium) (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (150° C., medium absorption setting) for 30 minutes under nitrogen atmosphere. Upon completion the samples were filtered through a silica cartridge, washed with CH₂Cl₂ and methanol and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions D:

To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (1.2 equiv), and the appropriate pinacolate boron ester or boronic acid (1.2 equiv) in acetonitrile/water (1:1) (0.083 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 25 minutes under nitrogen atmosphere. Upon completion the sample was purified by column chromatography on silica gel using a gradient MeOH/CH₂Cl₂ to afford the desired product which was recrystallised from diethyl ether.

Conditions E:

To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.4 equiv), and the appropriate pinacolate boron ester or boronic acid (1.3 equiv) in acetonitrile/water (1:1) (0.041 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The reaction vessel was sealed and heated at 95° C. for 16 hours. Upon completion the reaction mixture was partitioned between aqueous HCl and CH₂Cl₂ and washed with aqueous HCl. Combined aqueous phase were extracted with CH₂Cl₂ (2×), neutralised with aqueous NaOH (2N) to give a cloudy solution that was extracted with CH₂Cl₂. Combined organic phases were washed with brine, dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 4% MeOH in CH₂Cl₂ to give the desired product.

Conditions F:

To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.0 equiv), and the appropriate pinacolate boron ester or boronic acid (1.5 equiv) in acetonitrile/water (1:1) (0.028 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The reaction vessel was sealed and heated at 120° C. for 2 hours under nitrogen atmosphere. Upon completion the reaction mixture was partitioned between water and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 4% MeOH in CH₂Cl₂ to give the desired product which was recrystallised from hexane/diethyl ether.

Conditions G:

To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), and the appropriate pinacolate boron ester or boronic acid (1.05 equiv) in acetonitrile/water (1:1) (0.068 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The reaction vessel was sealed and heated at 100° C. for 5 hours under nitrogen atmosphere. Upon completion the reaction mixture was partitioned between brine and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 4% MeOH in CH₂Cl₂ to give the desired products which were recrystallised from hexane/CH₂Cl₂.

Conditions H:

A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 8 hours. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

Conditions I:

Conditions I were similar to conditions H apart form the heating method: 100° C. for 2 hours.

Conditions J:

A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (1.2 equiv), the appropriate pinacolate boron ester or boronic acid (1.2 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) in acetonitrile/water (0.03 M of chloro-substrate) was stirred at 100° C. for 2 hours. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

Conditions K:

Conditions K were similar to conditions G apart form the heating method: 100° C. for 16 hours.

Conditions L:

To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), and the appropriate pinacolate boron ester or boronic acid (1.10 equiv) in acetonitrile/water (1:1) (0.041 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (100° C., medium absorption setting) for 90 minutes. Upon completion the reaction mixture was partly concentrated. The residue was partitioned between water and ethyl acetate and extracted with ethyl acetate and n-butanol. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 30 to 10% hexane in ethyl acetate to give the desired product which was recrystallised from hexane/CH₂Cl₂.

Conditions M:

A mixture of the appropriate chloro-substrate (1 equiv), cesium fluoride (3.0 equiv), the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) in acetonitrile/water (0.09 M of chloro-substrate) was stirred at 115° C. for 48 hours. Upon completion the sample was concentrated in vacuo to half original volume. The residue was partitioned between water and CH₂Cl₂. Organic phase was dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexane to give the desired product.

Conditions N:

A mixture of the appropriate chloro-substrate (1 equiv), tripotassium phosphate (1.5 equiv), the appropriate pinacolate boron ester or boronic acid (1.05 equiv) and bis(tri-t-butylphosphine) palladium (0.05 equiv) was suspended in dioxane (0.16 M of chloro-substrate). The reaction vessel was sealed and exposed to microwave radiation (170° C. medium absorption setting) for 45 minutes. Upon completion the sample was concentrated in vacuo. The residue was partitioned between water and CH₂Cl₂. The organic phase was dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 40 to 100% ethyl acetate in hexane to give the desired product.

Conditions O:

A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) in n-butanol (0.068 M of chloro-substrate) was stirred at 95° C. for 15 minutes. Upon completion, the residue was partitioned between ethyl acetate and brine. Organic phase was dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 30 to 100% ethyl acetate in hexane to give the desired product which was recrystallised from ethyl acetate/hexane.

Conditions P:

To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.0 equiv), and the appropriate pinacolate boron ester or boronic acid (2.0 equiv) in acetonitrile/water (1:1) (0.041 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (120° C., medium absorption setting) for 10 minutes under nitrogen atmosphere. Upon completion the samples were filtered through a silica cartridge, washed through with CH₂Cl₂ and the concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

Conditions Q:

A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) were dissolved in n-butanol (0.056 M of chloro-substrate). The reaction vessel was sealed and exposed to microwave radiation (150° C., medium absorption setting) for 30 minutes. Upon completion the samples were filtered through a silica cartridge, washed with CH₂Cl₂ and methanol and then concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with ethyl acetate and then 5% MeOH in CH₂Cl₂ to give the desired product.

Conditions R:

A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), the appropriate pinacolate boron ester or boronic acid (1.2 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) in acetonitrile/water (0.05 M of chloro-substrate) was stirred at 115° C. for 1.5 hours. Upon completion the crude reaction was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 5 to 20% MeOH in CH₂Cl₂ to give the desired product.

Conditions S:

A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (10.0 equiv), the appropriate pinacolate boron ester or boronic acid (1.2 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 2 hours. Upon completion the reaction mixture was partitioned between water and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% MeOH in CH₂Cl₂ to give the desired product which was recrystallised from hexane/CH₂Cl₂.

Conditions T:

A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.0 equiv), the appropriate pinacolate boron ester or boronic acid (2.0 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) was dissolved in acetonitrile/water (0.02 M of chloro-substrate). The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 30 minutes. Upon completion the sample was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% MeOH in CH₂Cl₂ to give the desired product.

Conditions U:

A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), the appropriate pinacolate boron ester or boronic acid (1.0 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 110° C. for 8 hours. Upon completion the reaction mixture was partitioned between water and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were washed with brine, dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 2% MeOH in CH₂Cl₂ to give the desired product which was recrystallised from hexane/CH₂Cl₂.

Conditions V:

A mixture of the appropriate chloro-substrate (1 equiv), cesium fluoride (3.0 equiv), the appropriate pinacolate boron ester or boronic acid (1 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 16 hours. The reaction mixture was partitioned between water and CH₂Cl₂, and extracted with CH₂Cl₂. The organic phase was dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% MeOH in CH₂Cl₂ to give the desired product which was recrystallised from hexane/CH₂Cl₂.

Conditions W:

A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), the appropriate pinacolate boron ester or boronic acid (1 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) was dissolved in acetonitrile/water (0.04 M of chloro-substrate). The reaction vessel was sealed and exposed to microwave radiation (110° C., medium absorption setting) for 10 minutes. The crude residue was purified by column chromatography on silica gel eluting with 0 to 2% MeOH in TBME to give the desired product.

	TABLE 11
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Conditions	Example Structure
11a	96	7.66	466.6	A
11b	99	4.31	480.4	A
11c	98	4.67	478.4	A
11d	99	4.13	406.2	A
11e	99	3.94	422.3	A
11f	99	4.32	420.3	A
11g	99	3.83	436.3	A
11h	89	3.99	422.2	A
11i	96	3.85	436.3	A
11j	99	4.5	420.3	A
11k	98	4.49	426.3	A
11l	100	3.91	452.3	A
11m	99	3.99	437.4	B
11n	99	4.2	437.4	B
11o	99	4.23	437.4	B
11p	99	4.16	425.4	B
11q	98	4.1	492.5	B
11r	98	1.09	438.4	B
11s	99	3.98	410.4	B
11t	100	4.04	468.5	B
11u	100	4.95	422.3	B
11v	98	4.32	441.4	B
11w	91	6.46	441.3	B
11x	98	7.16	439.3	B
11y	97	6.54	441.4	B
11z	95	5.92	425.5	B
11aa	100	8.28	424.4	B
11ab	99	6.67	467.4	B
11ac	100	8.01	509.5	B
11ad	100	7.23	468.4	B
11ae	100	6.99	481.4	B
11af	99	7.55	495.4	B
11ag	100	6.51	511.4	B
11ah	99	6.95	425.2	B
11ai	89	7.52	465.2	B
11aj	80	4.5	459.3	B
11ak	97	6.79	463.2	C
11al	99	4.07	491.4	C
11am	99	3.94	484.3	C
11an	99	3.95	484.3	C
11ao	97	3.75	449.3	C
11ap	99	3.86	463.3	C
11aq	99	3.87	529.4	D
11ar	99	3.41	407.3	E
11as	98	6.59	449.4	F
11at	97	4.05	499.3	G
11au	96	7	425.3	G
11av	99	4.28	449.4	H
11aw	97	4.33	431.3	I
11ax	99	3.99	450.5	J
11ay	98	4.19	443.3	K
11az	100	8.94	421.2	L
11ba	100	4.28	464.5	M
11bb	98	8.16	450.3	N
11bc	99	3.99	454.4	O
11bd	90	8.4	485.3	P
11be	99	3.91	507.4	C
11bf	99	3.39	532.4	C
11bg	97	4.19	494.4	M
11bh	98	4.15	474.3	Q
11bi	96	4.13	474.4	R
11bj	94	3.99	492.3	R
11bk	98	4.04	517.4	S
11bl	98	4.13	431.2	B
11bm	98	4.27	445.3	B
11bn	97	4.27	451.2	B
11bo	99	4.21	436.3	B
11bp	99	4.40	440.2	B
11bq	87	4.22	420.3	B
11br	93	4.40	420.3	B
11bs	94	4.30	454.2	B
11bt	95	4.32	436.3	B
11bu	99	3.53	407.3	B
11bv	99	3.94	396.3	B
11bw	85	4.49	445.3	B
11bx	99	4.59	450.3	B
11by	98	4.20	450.3	B
11bz	87	4.30	436.3	B
11ca	99	4.62	434.4	B
11cb	99	4.74	434.4	B
11cc	92	4.67	463.0	B
11cd	99	4.63	450.4	B
11ce	85	3.71	421.3	B
11cf	98	4.35	410.3	B
11cg	97	4.34	436.3	B
11ch	98	4.48	459.3	B
11ci	87	4.49	465.3	B
11cj	100	4.50	450.3	B
11ck	99	4.14	466.5	T
11cl	100	3.8	474.4	P
11cm	99	4.01	477.3	T
11cn	99	4.73	474.3	E
11co	99	4.08	477.3	D
11cp	87	4.48	461.3	D
11cq	84	7.44	493.4	L
11cr	97	3.85	475.3	T
11cs	100	4.63	450.4	D
11ct	99		464.3	S
11cu	100	3.89	436.2	B
11cv	100	3.89		J

Note:

The following examples were synthesized from the corresponding boronic acids: 11aa, 11ab, 11ac, 11ad, 11ae, 11af, 11ag, 11ah, 11ai, 11aj, 11ak, 11al, 11am, 11an, 11ao, 11ap, 11aq, 11as, 11at, 11au, 11av, 11aw, 11ax, 11ay, 11az, 11ba, 11bb, 11bd, 11be, 11bk, 11bl, 11bm, 11bn, 11bo, 11bp, 11bq, 11br, 11bs, 11bt, 11bu, 11bv, 11bw, 11bx, 11by, 11bz, 11ca, 11cb, 11cc, 11cd, 11cf, 11eg, 11ch, 11ci, 11cj, 11d, 11e, 11f, 11g, 11h, 11i, 11j, 11k, 11n, 11o, 11p, 11r, 11t, 11w, 11x, 11y, 11cn, 11co, 11cp, 11cs, 11cv and 11z.

The following Examples were synthesized from the corresponding pinacolate boron esters: 11a-c, 11ck, 11cl, 11cm, 11cq, 11cr, 11ct, 11cu, 11ar, 11bf, 11ce, 11m, 11q, 11s, 11u and 11v.

NMR Data for Example 11n

¹H NMR (300 MHz, CDCl₃) δ ppm 8.88 (ArH, d, J=2.20 Hz, 1H), 8.55 (ArH, dd, J=8.70, 2.45 Hz, 1H), 8.04 (ArH, d, J=8.43 Hz, 1H), 7.42 (ArH, d, J=8.44 Hz, 1H), 6.88 (ArH, d, J=8.70 Hz, 1H), 5.01-4.90 (CH, m, 1H), 4.65 (CH, d, J=13.12 Hz, 1H), 4.40 (CH, d, J=6.68 Hz, 1H), 4.04 (OCH₃+CH₂, s, 5H), 3.96-3.69 (CH₂, m, 7H), 3.60 (CH, dt, J=11.86, 11.60, 2.67 Hz, 1H), 3.40 (CH, dt, J=13.01, 12.73, 3.60 Hz, 1H), 1.50 (CH₃, d, J=6.78 Hz, 3H), 1.39 (CH₃, d, J=6.81 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.41, 165.29, 162.98, 160.10, 160.01, 146.58, 138.51, 134.81, 128.05, 112.42, 110.84, 104.75, 71.29, 70.92, 67.26, 66.92, 53.75, 52.87, 46.94, 44.43, 39.33, 14.73 and 14.36.

NMR Data for Example 11u

¹H NMR (300 MHz, CDCl₃) δ ppm 8.80 (ArH, d, J=1.91 Hz, 1H), 8.39 (ArH, dd, J=8.66, 2.39 Hz, 1H), 7.96 (ArH, d, J=8.48 Hz, 1H), 7.35 (ArH, d, J=8.49 Hz, 1H), 6.59 (ArH, d, J=8.66 Hz, 1H), 4.91 (CH, dd, J=4.15, 1.62 Hz, 1H), 4.78 (NH₂, s, 2H), 4.67-4.55 (CH, m, 1H), 4.34 (CH, d, J=6.88 Hz, 1H), 4.04-3.91 (CH₂, m, 2H), 3.90-3.64 (CH₂, m, 7H), 3.62-3.49 (CH₂, m, 1H), 3.44-3.29 (CH₂, m, 1H), 1.45 (CH₃, d, J=6.77 Hz, 3H), 1.34 (CH₃, d, J=6.82 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.54, 163.10, 160.45, 160.13, 159.45, 148.10, 137.82, 134.76, 125.17, 112.16, 108.45, 104.59, 71.44, 71.06, 67.41, 67.07, 52.98, 47.05, 44.56, 36.46, 14.84 and 14.75.

NMR Data for Example 11ag

¹H NMR (300 MHz, CDCl₃) δ ppm 8.59 (ArH, dd, J=7.33, 2.43 Hz, 1H), 8.40 (ArH, ddd, J=8.53, 5.03, 2.47 Hz, 1H), 7.97 (ArH, d, J=8.42 Hz, 1H), 7.42 (ArH, d, J=8.46 Hz, 1H), 7.20-7.10 (ArH, m, 1H), 4.84 (CH, dd, J=3.67, 2.96 Hz, 1H), 4.53 (CH, d, J=12.77 Hz, 1H), 4.33 (CH₂, d, J=6.83 Hz, 1H), 3.99-3.89 (CH₂, m, 2H), 3.86-3.77 (CH₂, m, 4H), 3.75-3.65 (CH₂, m, 5H), 3.67-3.32 (CH₂, m, 3H), 3.57-3.45 (CH₂, m, 1H), 3.36-3.26 (CH₂, m, 1H), 1.42 (CH₃, d, J=6.78 Hz, 3H), 1.30 (CH₃, d, J=6.82 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.26, 164.26, 162.74, 160.29, 159.93, 135.52, 135.11, 133.47, 133.34, 130.89, 116.84, 116.51, 113.11, 105.11, 71.26, 70.91, 67.11, 66.91, 62.20, 52.79, 47.02, 44.46, 43.02, 39.36, 14.77 and 14.37.

NMR Data for Example 11aq

¹H NMR (300 MHz, CDCl₃) δ ppm 8.61 (ArH, t, J=1.46, 1.46 Hz, 1H), 8.33 (ArH, d, J=7.84 Hz, 1H), 8.06 (ArH, d, J=8.37 Hz, 1H), 7.90 (ArH, s, 1H), 7.62 (ArH, d, J=7.84 Hz, 1H), 7.44 (ArH, d, J=8.38 Hz, 1H), 5.30 (CH₂, s, 1H), 4.97-4.84 (CH₂, m, 1H), 4.64-4.52 (CH₂, m, 1H), 4.45-4.34 (CH₂, m, 1H), 4.06-3.94 (CH₂, m, 2H), 3.93-3.64 (CH₂, m, 8H), 3.61-3.51 (CH₂, m, 1H), 3.45-3.30 (CH₂, m, 1H), 3.19 (CH₂, d, J=4.84 Hz, 2H), 1.49 (CH₃, d, J=6.78 Hz, 3H), 1.36 (CH₃, d, J=6.82 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ ppm 160.22, 140.70, 140.01, 134.25, 131.82, 129.24, 128.02, 126.34, 113.12, 105.41, 104.65, 71.23, 70.87, 66.88, 61.03, 52.85, 47.04, 45.34, 44.42, 39.35, 14.78 and 14.38.

NMR Data for Example 11ar

¹H NMR (300 MHz, CDCl₃) δ ppm 8.81-8.73 (ArH, m, 2H), 8.14-7.99 (ArH, m, 3H), 7.48 (ArH, d, J=8.35 Hz, 1H), 5.02-4.89 (CH, m, 1H), 4.69-4.59 (CH₂, m, 1H), 4.41 (CH, d, J=6.84 Hz, 1H), 4.08-3.96 (CH₂, m, 2H), 3.82 (H2, dddd, J=19.69, 14.05, 6.26, 3.77 Hz, 7H), 3.65-3.53 (CH₂, m, 1H), 3.48-3.31 (CH₂, m, 1H), 1.51 (CH₃, d, J=6.78 Hz, 3H), 1.38 (CH₃, d, J=6.83 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.29, 162.96, 160.03, 159.82, 150.36, 145.80, 135.20, 121.83, 113.02, 105.93, 71.24, 70.87, 67.21, 66.87, 52.88, 46.99, 44.45, 39.35, 14.76 and 14.41.

NMR Data for Example 11as

¹H NMR (300 MHz, CDCl₃) δ ppm 8.67 (ArH, t, J=1.54, 1.54 Hz, 1H), 8.29 (ArH, dd, J=6.60, 1.28 Hz, 1H), 8.07 (ArH, d, J=8.41 Hz, 1H), 8.03-7.98 (ArH, m, 2H), 7.62-7.49 (ArH, m, 2H), 4.98-4.89 (CH, m, br, 1H), 4.67-4.59 (CH, m, br, 1H), 4.41 (CH, d, J=6.78 Hz, 1H), 4.05-3.66 (CH₂, m, 10H), 3.64-3.34 (CH₂, m, 3H), 1.75 (s, 1.5H), 1.50 (CH₃, d, J=6.78 Hz, 3H), 1.38 (CH₃, d, J=6.82 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ ppm 168.86, 165.34, 162.90, 161.21, 160.01, 138.97, 135.00, 133.74, 131.09, 129.23, 128.98, 126.52, 113.20, 105.20, 100.00, 71.23, 70.89, 67.22, 66.90, 52.82, 46.97, 44.45, 39.34, 14.75 and 14.36

NMR Data for Example 11at

¹H NMR (300 MHz, CDCl₃) δ ppm 8.06 (ArH, d, J=2.05 Hz, 1H), 7.98 (ArH, d, J=8.41 Hz, 1H), 7.86-7.79 (ArH, m, 1H), 7.46-7.33 (ArH, m, 3H), 7.23 (NH, s, 1H), 4.83 (CH, dd, J=3.58, 2.50 Hz, 1H), 4.56-4.46 (CH, m, 1H), 4.32 (CH, d, J=6.74 Hz, 1H), 3.93-3.89 (CH₂, m, 2H), 3.88-3.77 (CH₂, m, 2H), 3.76-3.58 (CH₂, m, 5H), 3.49 (CH₂, dt, J=11.76, 11.38, 2.76 Hz, 1H), 3.35-3.20 (CH₂, m, 1H), 2.89 (SCH₃, s, 3H), 1.42 (CH₃, d, J=6.78 Hz, 3H), 1.27 (CH₃, d, J=5.25, Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.32, 162.87, 161.30, 159.96, 140.41, 137.57, 135.01, 129.92, 124.55, 122.25, 120.57, 113.32, 105.24, 71.25, 70.90, 67.22, 66.91, 52.86, 46.99, 44.42, 39.40, 31.60, 22.66, 14.77 and 14.12.

NMR Data for Example 11ax

¹H NMR (300 MHz, CDCl₃) δ ppm 8.88 (ArH, t, J=1.52, 1.52 Hz, 1H), 8.32-8.25 (ArH, m, 1H), 8.13-8.06 (ArH, m, 1H), 7.99 (ArH, d, J=8.42 Hz, 1H), 7.53-7.39 (ArH, m, 2H), 4.90-4.80 (CH, m, 1H), 4.58-4.48 (CH, m, 1H), 4.33 (CU, d, J=6.90 Hz, 1H), 3.95-3.65 (CH₂, +OH m, 8H), 3.64 (CH₂, d, J=2.85 Hz, 2H), 3.56-3.45 (CH, m, 1H), 3.31 (CH, d, J=3.67 Hz, 1H), 1.42 (CH₃, d, J=6.79 Hz, 3H), 1.29 (CH₃, d, J=6.81 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 169.20, 165.22, 161.32, 159.85, 139.91, 135.01, 131.39, 129.70, 128.71, 113.31, 70.90, 67.10, 52.80, 47.07, 44.42, 39.36, 14.77 and 14.37.

NMR Data for Example 11az

¹H NMR (300 MHz, CDCl₃) δ ppm 8.04-7.95 (ArH, m, 2H), 7.87 (ArH, d, J=8.54 Hz, 1H), 7.32 (ArH, d, J=8.55 Hz, 1H), 6.71-6.64 (ArH, m, 2H), 4.92-4.81 (CH, m, 1H), 4.57 (CH, d, br, 1H), 4.29 (CH₂, d, J=7.10 Hz, 1H), 3.91 (CH₂, m, 2H), 3.82-3.58 (CH₂+NH₂, m, 9H), 3.48 (CH₂, dd, J=11.36, 2.76 Hz, 1H), 3.33 (CH₂, dd, J=13.48, 3.61 Hz, 1H), 1.39 (CH₃, d, J=6.78 Hz, 3H), 1.28 (CH₃, d, J=6.82 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.28, 162.18, 148.68, 135.36, 129.54, 119.67, 114.75, 112.63, 104.43, 104.00, 71.29, 70.94, 67.27, 67.12, 66.95, 52.78, 44.45, 39.15, 14.74 and 14.37.

NMR Data for Example 11ba

¹H NMR (300 MHz, CDCl₃) δ ppm 8.69 (ArH, t, J=1.58, 1.58 Hz, 1H), 8.44-8.33 (ArH, m, 1H), 8.11-8.03 (ArH, m, 1H), 7.99 (ArH, d, J=8.42 Hz, 1H), 7.57-7.38 (ArH, m, 2H), 4.87 (CH₂, dd, J=4.84, 0.43 Hz, 1H), 4.57 (CH, d, J=12.80 Hz, 1H), 4.31 (CH₂, t, J=6.72, 6.72 Hz, 1H), 3.94 (CH₂, dd, J=11.15, 3.26 Hz, 2H), 3.90 (OCH₃, d, J=6.23 Hz, 3H), 3.83-3.62 (CH₂, m, 7H), 3.57-3.45 (CH₂, m, 1H), 3.39-3.24 (CH₂, m, 1H), 1.42 (CH₃, d, J=6.78 Hz, 3H), 1.30 (CH₃, d, J=6.81 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 166.92, 165.41, 162.93, 161.43, 161.01, 139.13, 134.91, 132.51, 130.87, 130.57, 128.87, 113.26, 105.16, 71.29, 70.91, 67.25, 66.91, 52.86, 52.18, 46.96, 44.45, 14.77 and 14.37.

NMR Data for Example 11bc

¹H NMR (300 MHz, DMSO) δ ppm 8.37 (ArH, dd, J=7.40, 2.26 Hz, 1H), 8.20 (ArH, d, J=8.50 Hz, 1H), 8.14-8.05 (ArH, m, 1H), 7.62 (ArH, d, J=8.51 Hz, 1H), 7.29 (ArH, dd, J=9.77, 8.71 Hz, 1H), 5.42 (CH, t, J=5.76, 5.76 Hz, 1H), 4.77 (CH, dd, J=6.57, 1.98 Hz, 1H), 4.65 (CH₂OH, d, J=5.67 Hz, 2H), 4.51-4.37 (CH₂, m, 2H), 3.98-3.83 (CH₂, m, 3H), 3.80-3.70 (CH₂, m, 2H), 3.69-3.56 (CH₂, m, 4H), 3.45 (CH₂, dt, J=11.86, 11.77, 2.75 Hz, 1H), 3.30-3.16 (CH₂, m, 3H), 1.38 (CH₃, d, J=6.75 Hz, 3H), 1.25 (CH₃, d, J=6.75 Hz, 3H)

¹³C NMR (75 MHz, DMSO) δ ppm 164.91, 162.60, 160.18, 159.82, 136.10, 134.86, 130.19, 129.99, 128.61, 128.27, 128.15, 115.85, 115.57, 113.00, 104.80, 70.89, 70.66, 66.84, 66.67, 52.29, 46.76, 44.34, 14.84 and 14.34.

NMR Data for Example 11bd

¹H NMR (300 MHz, DMSO) δ ppm 8.63 (ArH, t, J=1.49, 1.49 Hz, 1H), 8.26 (ArH, d, J=7.95 Hz, 1H), 8.17 (ArH, d, J=8.46 Hz, 1H), 7.91-7.80 (ArH, m, 1H), 7.62 (ArH, dd, J=14.96, 8.10 Hz, 2H), 7.37 (NH₂, s, 2H), 4.69 (CH, dd, J=6.21, 1.34 Hz, 1H), 4.35 (CH₂, d, J=13.74 Hz, 2H), 3.91-3.74 (CH₂, m, 3H), 3.73-3.46 (CH₂, m, 6H), 3.36 (CH₂, dt, J=11.82, 11.71, 2.49 Hz, 1H), 2.41 (CH₉, td, J=3.46, 1.69, 1.69 Hz, 1H), 1.30 (CH₃, d, J=6.74 Hz, 3H), 1.17 (CH₃, d, J=6.75 Hz, 3H)

¹³C NMR (75 MHz) δ ppm 164.85, 162.63, 159.86, 159.49, 145.34, 139.35, 136.44, 130.73, 129.98, 127.34, 124.96, 113.18, 105.38, 79.87, 79.43, 78.99, 70.89, 70.67, 66.85, 66.67, 52.29, 46.79, 44.37, 14.88 and 14.41.

NMR Data for Example 11bk

¹H NMR (300 MHz, CDCl₃) δ ppm 8.19 (ArH, dd, J=7.62, 2.22 Hz, 1H), 8.12 (ArH, ddd, J=8.54, 5.03, 2.25 Hz, 1H), 8.01 (ArH, d, J=8.41 Hz, 1H), 7.38 (ArH, d, J=8.43 Hz, 1H), 7.24-7.19 (ArH, m, 1H), 6.83 (NH, s, br, 1H), 4.98-4.85 (CH, m, 1H), 4.67-4.55 (CH, m, 1H), 4.36 (CH₂, d, J=6.95 Hz, 1H), 4.06-3.93 (CH₂, m, 2H), 3.91-3.65 (CH₂, m, 1H), 3.53 (CH—, dd, J=11.40, 2.69 Hz, 1H), 3.44-3.28 (CH₂, m, 1H), 3.07 (SCH3, s, 3H), 1.47 (CH₃, d, J=6.77 Hz, 3H), 1.34 (CH₃, d, J=6.81 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.45, 162.93, 160.61, 160.12, 157.28, 153.99, 136.32, 135.15, 123.51, 116.31, 116.05, 113.26, 105.18, 71.39, 71.01, 67.36, 67.01, 53.00, 47.07, 44.51, 39.44, 31.71, 22.77, 14.86, and 14.95.

Compounds were also synthesized according to the following procedures:

Procedure for the Synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-isopropoxy-benzamide (Example 11cw)

5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-isopropoxy-benzonitrile (1 equiv) was added portionwise to concentrated H₂SO₄ (0.1 M substrate in acid). The reaction was heated to 90° C. and maintained at this temperature until all starting material had dissolved to give a bright red solution. The mixture was cooled and water (2 reaction volumes) added dropwise, then the solution was neutralized by careful addition of solid NaOH until pH 4-5 was attained. The mixture was cooled and neutralised by addition of 2N NaOH and then extracted using EtOAc (2×10 reaction volumes). The combined extracts were dried (MgSO₄), filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO₂) using MeOH/DCM—0:100 going to 5:95 as eluent to give the desire product as a yellow powder.

5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-isopropoxy-benzamide: (53% yield, 100% purity) m/z (LC-MS,ESP): 507.5 [M+H]⁻, R/T=3.01 min)

Procedure for the Synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-hydroxy-benzamide (Example 11cx)

5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-isopropoxy-benzonitrile (1 equiv) was added portionwise to concentrated H₂SO₄ (0.1 M substrate in acid). The reaction was heated to 90° C. and maintained at this temperature until all starting material had dissolved to give a bright red solution. The mixture was cooled and water (2 reaction volumes) added dropwise, then the solution was neutralized by careful addition of solid NaOH until pH 4-5 was attained. The mixture was cooled and neutralised by addition of 2N NaOH and then extracted using EtOAc (2×10 reaction volumes). The combined extracts were dried (MgSO₄), filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO₂) using MeOH/DCM—0:100 going to 5:95 as eluent to give the desire product as a yellow powder.

5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-hydroxy-benzamide: (44% yield, 100% purity) m/z (LC-MS,ESP): 465.4 [M+H], R/T=2.70 min)

Procedure for the Synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridine-2-carboxylic acid amide (Example 11cy)

Synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridine-2-carbonitrile was carried out as follows:—

To the appropriate chloro-substrate (1 equiv), potassium carbonate (3 equiv) and the appropriate boronic acid or pinacolate boron ester (1.1 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) which were dissolved in N,N-dimethylacetamide (0.17 M of chloro-substrate). The mixture was degassed with nitrogen, sealed and exposed to microwave radiation (130° C., medium absorption setting) for 5 minutes. The mixture was concentrated in vacuo and then suspended in t-butylmethyl ether, filtered and dried to give the desired product.

5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridine-2-carbonitrile: (84% yield, 93% purity) m/z (LC-MS,ESP): 191.3 [M+H]⁺, R/T=2.29 min)

To a suspension of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridine-2-carbonitrile (1 equiv) in concentrated H₂SO₄. The mixture was heated to 90° C. until a pale brown solution formed. The mixture was allowed to cool and then basified with 50% w/w NaOH solution. The aqueous mixture was extracted using EtOAc (3×2 reaction volumes). The combined organic fractions were dried (MgSO₄), filtered and concentrated in vacuo to give a pale yellow solid which was triturated with EtOAc to give the desire product.

5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridine-2-carboxylic acid amide: 93% yield, 96% purity) m/z (LC-MS,ESP): 450.4 [M+H]⁺, R/T=3.72 min)

Procedure for the Synthesis of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine (Example 11cz)

To a 1.2 M solution of compound 1au (1 equiv) in THF was added hydrazine hydrate (9 reaction volumes). The reaction vessel was sealed and exposed to microwave radiation (115° C., medium absorption setting) for 2 hours. Upon completion, the reaction mixture was extracted with EtOAc (2×1 reaction volume). The organic fractions were combined, dried (MgSO₄), filtered and concentrated in vacuo to give the desired product in suitably clean form for use in subsequent reactions.

{4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-hydrazine 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-phthalazin-1-one: (77% yield, 84% purity) m/z (LC-MS,ESP): 437.4 [M+H]⁺, R/T=2.23 min)

A 0.12 M solution of {4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-hydrazine 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-phthalazin-1-one (1 equiv) in EtOH was added to a glass lined autoclave which contained activated Ra—Ni. The reaction was maintained under 5 bar H₂ for 30 hours. Upon completion, the mixture was filtered through a pad of Celite™ and the filtrate concentrated in vacuo. The resulting crude residue was purified by reverse phase flash chromatography using 5:95-0.1% TFA/MeCN:0.1% TFA/H₂O as eluent to give the desire product as a yellow powder.

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine: (70% yield, 100% purity) m/z (LC-MS,ESP): 422 [M+H], R/T=2.25 min)

Procedure for the Synthesis of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzamide (Example 11da)

To the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv) and the appropriate boronic acid or pinacolate boron ester (1.1 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) which were dissolved in MeCN/H₂O (0.03 M of chloro-substrate). The mixture was degassed with nitrogen, sealed and exposed to microwave radiation (110° C., medium absorption setting) for 25 minutes. The mixture filtered and the precipitate collected, and recrystallised from MeCN/H₂O to give the desired product.

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile: (49% yield, 87% purity) m/z (LC-MS,ESP): 449 [M+H]⁺, R/T=2.93 min)

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile (1 equiv) was dissolved concentrated sulfuric acid (0.15 M substrate in acid). The reaction was heated rapidly to 90° C. for 5 minutes before cooling the mixture and quenched, carefully, with solid NaOH until the solution was basic. The mixture was extracted with EtOAc/nBuOH (2×1 reaction volume—1:1 ratio). The organic extracts were combined, dried (MgSO₄), filtered and concentrated in vacuo to give a residue which was further purified using flash chromatography (SiO₂) with TBME going to TBME/MeOH (95:5) as eluent, the give the title compound as a yellow solid.

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzamide Synthesis: (71% yield, 99% purity) m/z (LC-MS,ESP): 467 [M+H]⁺, R/T=2.60 min)

Procedure for the Synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1H-pyridin-2-one (Example 11db)

To a 0.2 M solution of compound 1ah (1 equiv) in DMA was added a 1.6 M aqueous solution of sodium hydroxide (5 equiv). The reaction vessel was sealed and exposed to microwave radiation (110° C., medium absorption setting) for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was suspended in water and sonicated to give a turbid solution, washed with TBME then cooled and neutralised with 2M HCl, forming a yellow precipitate. The precipitate was filtered and washed with water and TBME and dried to give the desired product.

5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1H-pyridin-2-one: (69% yield, 96% purity) m/z (LC-MS,ESP): 423 [M+H]⁺, R/T=3.60 min)

Procedure for the Synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1H-pyridin-2-one (Example 11dc)

To the compound 1ah (1 equiv) was added a solution of 40% methylamine in methanol (100 equiv). The reaction vessel was sealed and exposed to microwave radiation (115° C., medium absorption setting) for 30 minutes. The solution was concentrated in vacuo to yield a yellow solid. The crude residue was then purified by preparative HPLC to give the desired product.

{5-[2,4-Bis-(3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-methyl-amine: (61% yield, 99% purity) m/z (LC-MS,ESP): 436 [M+H]⁺, R/T=3.34 min)

NMR Data for Example 11dc

¹H NMR (300 MHz, CDCl₃ δ ppm 8.69 (ArH, d, J=2.06 Hz, 1H), 8.56 (ArH, dd, J=9.02, 2.32 Hz, 1H), 7.97 (ArH, d, J=8.47 Hz, 1H), 7.33 (ArH, d, J=8.48 Hz, 1H), 6.59 (ArH, d, J=9.03 Hz, 1H), 5.92 (NH, s, br, 1H), 4.90 (CH₂, dd, J=5.85, 0.41 Hz, 1H), 4.59 (CH₂, d, J=12.53 Hz, 1H), 4.41-4.29 (CH₂, m, 1H), 4.05-3.93 (CH₂, m, 2H), 3.90-3.62 (CH₂, m, 8H), 3.62-3.50 (CH₂, m, 1H), 3.43-3.31 (CH₂, m, 1H), 3.00 (NCH₃, s, 3H), 1.47 (CH₃, d, J=6.78 Hz, 3H), 1.35 (CH₃, d, J=6.82 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃ δ ppm 167.59, 165.30, 162.90, 159.99, 158.84, 144.22, 139.19, 134.85, 123.35, 111.65, 106.51, 104.57, 71.28, 70.91, 67.24, 66.92, 52.83, 46.96, 44.42, 39.34, 29.05, 14.73 and 14.34.

Procedure for the Synthesis of {5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-dimethyl-amine (Example 11dd)

To a solution of compound 1ah (1 equiv) in THF (0.05 M) was added a solution of 33% dimethylamine in ethanol (200 equiv). The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 40 minutes. The solution was concentrated in vacuo to yield a yellow solid. The crude residue was then purified by preparative HPLC to give the desired product.

{5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-dimethyl-amine: (54% yield, 97% purity) m/z (LC-MS,ESP): 450 [M+H], R/T=3.52 min)

Procedure for the Synthesis of 8-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (Example 11de)

The appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), 3-methoxy-4-methoxycarbonylphenylboronic acid, pinacol ester (1.1 equiv) were suspended in (1:1) acetonitrile/water (0.1 M of chloro-substrate). The mixture was sonicated and degassed for 15 minutes with nitrogen. Tetrakistriphenylphosphine (0.05 equiv) was then added and the mixture was sonicated for a further 5 minutes with nitrogen. The mixture was heated to 100° C. for 3 hours under nitrogen. The reaction was cooled and the insoluble residue was filtered off. The filtrate was concentrated to half the original volume and the remaining water mixture was extracted with CH₂Cl₂. The organic layers were washed with water and brine, combined and dried with magnesium sulphate, filtered and concentrated in vacuo to yield an oil which was purified by flash column chromatography eluting with 50% to 100% EtOAc/Hexane.

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid methyl ester: (67% yield, 100% purity) m/z (LC-MS,ESP): 494 [M+H]⁺, R/T=2.86 min)

A solution of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid methyl ester (1 equiv) in ethylenediamine (0.35 M) was stirred at room temperature for 24 hours. DMA was added to the solution (ethylenediamine/DMA 1:1.25). The reaction vessel was sealed and exposed to microwave radiation (180° C., medium absorption setting) for 1 hour. The reaction mixture was diluted with CH₂Cl₂ and extracted with water and washed with brine. The organic layer was dried with magnesium sulphate, filtered and concentrated in vacuo to yield a yellow solid which was then purified by preparative HPLC to give the desired product.

8-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one: (49% yield, 99% purity) m/z (LC-MS,ESP): 490 [M+H]⁺, R/T=3.52 min)

NMR Data for Example 11de

¹H NMR (300 MHz, CDCl₃ δ ppm 8.65 (NH, s, br, 1H), 8.01 (ArH, d, J=8.38 Hz, 1H), 7.78 (ArH, s, 1H), 7.68 (ArH, s, 1H), 7.44 (ArH, dd, J=18.50, 8.20 Hz, 2H), 4.93-4.77 (CH₂, m, 1H), 4.50 (CH₂, s, 1H), 4.46-4.32 (CH₂, m, 1H), 4.05-3.61 (CH₂, m, 14H), 3.53 (CH₂, d, J=2.04 Hz, 1H), 3.41-3.26 (CH₂, m, 1H), 1.47 (CH₃, d, J=6.76 Hz, 3H), 1.33 (CH₃, d, J=6.78 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃ δ ppm 165.11, 165.07, 165.00, 163.41, 162.64, 161.07, 159.90, 144.87, 135.18, 129.50, 118.02, 116.80, 113.87, 109.20, 105.45, 71.20, 70.89, 67.14, 66.89, 52.77, 47.04, 44.76, 44.40, 39.33, 14.78 and 13.32.

Procedure for the Synthesis of 7-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (Example 11df)

A solution of the compound 1bg (1 equiv) in ethylenediamine (0.35 M) was stirred at room temperature for 24 hours. DMA was added to the solution (ethylenediamine/DMA 1:1.25). The reaction vessel was sealed and exposed to microwave radiation (180° C., medium absorption setting) for 1 hour. The reaction mixture was diluted with ethyl acetate and extracted with water. The organic layer was dried with magnesium sulphate, filtered and concentrated in vacuo to yield a residue which was then purified by flash column chromatography eluting with 0% to 20% MeOH/CH₂Cl₂.

8-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one: (40% yield, 100% purity) m/z (LC-MS,ESP): 490 [M+H]⁺, R/T=3.49 min)

NMR Data for Example 11df

¹H NMR (300 MHz, CDCl₃ δ ppm 8.60 (ArH, d, J=2.23 Hz, 1H), 7.93-7.83 (ArH, m, 2H), 7.34 (ArH, d, J=8.56 Hz, 1H), 6.89 (ArH, d, J=8.97 Hz, 1H), 4.82-4.71 (CH₂, m, 1H), 4.47 (CH₂, dd, J=7.28, 6.58 Hz, 1H), 4.30 (CH₂, d, J=6.93 Hz, 1H), 3.95-3.55 (CH₂, m, 13H), 3.55-3.42 (CH₂, m, 1H), 3.35-3.21 (CH₂, m, 1H), 1.40 (CH₃, d, J=6.77 Hz, 3H), 1.26 (CH₃, d, J=6.80 Hz, 3H).

Procedure for the Synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-difluoromethoxy-benzamide (Example 11dg)

To a solution of 5-bromo-2-difluoromethoxy-benzoic acid (1 equiv) in THF (0.1 M) was added dropwise thionyl chloride (5 equiv) at room temperature. The reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was suspended in dry THF (0.04 M) and ammonia gas was slowly bubbled into the reaction mixture for 45 minutes. The reaction mixture was concentrated in vacuo. The residue was dissolved in minimum CH₂Cl₂ and hexane was added to give a white precipitate that was collected by vacuum filtration in suitably clean form for use in subsequent reactions.

5-Bromo-2-difluoromethoxy-benzamide: (45% yield, 73% purity) m/z (LC-MS, ESP): 266/268 [M+H]⁺, R/T=3.42 min)

To a solution of 5-bromo-2-difluoromethoxy-benzamide (1 equiv) in dioxan (0.1 M) were added bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv). The reaction mixture was degassed with nitrogen for 15 minutes. PdCl₂(dppf) (0.05 equiv) was added to the reaction mixture, which was degassed for a further 5 minutes. The reaction mixture was stirred at 110° C. for 12 hours under nitrogen. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with water, dried with magnesium sulphate, filtered and concentrated in vacuo to give the desired product for use in subsequent reactions

2-Difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide: (71% yield, crude taken forward without further analysis)

A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), 2-difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (1.1 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 4 hours. Upon completion the reaction mixture was partitioned between water and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were washed with brine, dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.

5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-difluoromethoxy-benzamide: (14% yield, 100% purity) m/z (LC-MS, ESP): 515 [M+H]⁺, R/T=7.40 min

Procedure for the Synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-difluoromethoxy-N-methyl-benzamide (Example 11dh)

To a solution of 5-bromo-2-difluoromethoxy-benzoic acid (1 equiv) in DMF (0.1 M) was added triethylamine (4 equiv). The reaction mixture was cooled to 0° C. and HBTU (1.2 equiv) was added. The reaction mixture was allowed to reach room temperature over 1 hour and methylamine hydrochloride (2 equiv) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between EtOAc and water and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with water, dried with magnesium sulphate, filtered and concentrated under in vacuo to give the desired product in suitably clean form for use in subsequent reactions.

5-Bromo-2-difluoromethoxy-N-methyl-benzamide: (100% yield, 75% purity) m/z (LC-MS, ESP): 280/282 [M+H]⁺, R/T=3.55 min)

2-Difluoromethoxy-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide was prepared in a similar way as 2-Difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide using 5-bromo-2-difluoromethoxy-N-methyl-benzamide as the starting material.

2-Difluoromethoxy-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide: (100% yield, crude taken forward without further analysis)

A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), 2-difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (1.1 equiv) and tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 2 hours. Upon completion the reaction mixture was partitioned between water and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were washed with brine, dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.

5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-difluoromethoxy-N-methyl-benzamide: (53% yield, 87% purity) m/z (LC-MS, ESP): 421 [M+H]⁺, R/T=4.06 min)

Procedure for the Synthesis of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzamide (Example 11di)

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid methyl ester (1 equiv) was dissolved in methanol (0.2 M). 1M Sodium hydroxide aqueous solution (5.0 equiv) was added. The reaction mixture was stirred at room temperature for 3 hours. Upon completion the reaction mixture was neutralised with 1M aqueous HCl and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 10% MeOH in CH₂Cl₂ to give the desired product.

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid: (100% yield, 100% purity) m/z (LC-MS, ESP): 480 [M+H]⁺, R/T=2.69 min)

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid (1 equiv) was suspended in THF (0.05 M). Thionyl chloride was added dropwise at 40° C. The reaction mixture was then heated for an hour at 40° C. Ammonia gas was then slowly bubbled into the reaction mixture. THF was then added for further dilution (0.025 M) and the reaction mixture was heated for an hour at 40° C. Upon completion the reaction mixture was cooled down and concentrated in vacuo. The residue was partitioned between water and CH₂Cl₂. The aqueous phase was extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% MeOH in CH₂Cl₂ to give the desired product.

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzamide: (88% yield, 99% purity) m/z (LC-MS, ESP): 479 [M+H]⁺, R/T=3.92 min)

NMR Data for Example 11di

¹H NMR (300 MHz, CDCl₃ δ ppm 8.30 (ArH, d, J=8.17 Hz, 1H), 8.04 (ArH, dd, J=6.21, 4.98 Hz, 2H), 7.80 (NH, br, s, 1H), 7.67 (ArH, dd, J=8.21, 1.49 Hz, 1H), 7.49 (ArH, d, J=8.44 Hz, 1H), 5.96 (NH, s, br, 1H), 4.98-4.85 (CH₂, m, 1H), 4.61 (CH₂, d, J=12.90 Hz, 1H), 4.39 (CH₂, d, J=6.89 Hz, 1H), 4.13 (OCH₃, s, 3H), 4.05-3.64 (CH₂, m, 9H), 3.64-3.51 (CH₂, m, 1H), 3.41 (CH₂, dd, J=13.34, 3.62 Hz, 1H), 1.49 (CH₃, d, J=6.79 Hz, 3H), 1.36 (CH₃, d, J=6.82 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) 0 ppm 166.78, 165.32, 162.81, 160.99, 160.02, 158.15, 143.57, 134.98, 132.76, 121.80, 120.15, 113.62, 111.30, 105.44, 71.27, 70.89, 67.23, 66.90, 56.42, 52.88, 47.01, 44.41, 39.36, 14.77 and 14.40.

Procedure for the synthesis of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-N-methyl-benzamide (Example 11dj)

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid (1 equiv) was dissolved in THF (0.1 M) and HBTU (1.5 equiv) was added. Methylamine in THF (15 equiv) was added dropwise followed by triethylamine (1.5 equiv) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and CH₂Cl₂. The aqueous phase was extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-N-methyl-benzamide: (56% yield, 96% purity) m/z (LC-MS, ESP): 493 [M+H]⁺, R/T=4.00 min)

NMR Data for Example 11dj

¹H NMR (300 MHz, CDCl₃ δ ppm 8.26 (ArH, d, J=8.16 Hz, 1H), 7.98 (ArH, dd, J=8.74, 4.91 Hz, 2H), 7.91-7.81 (NH, m, br, 1H), 7.60 (ArH, dd, J=8.21, 1.52 Hz, 1H), 7.43 (ArH, d, J=8.45 Hz, 1H), 4.93-4.81 (CH₂, m, 1H), 4.62-4.51 (CH₂, m, 1H), 4.39-4.28 (CH₂, m, 1H), 4.07 (OCH₃, s, 3H), 4.00-3.58 (CH₂, m, 9H), 3.57-3.45 (CH₂, m, 1H), 3.40-3.27 (CH₂, m, 1H), 2.99 (NHCH₃, d, J=4.82 Hz, 3H), 1.43 (CH₃, d, J=6.78 Hz, 3H), 1.31 (CH₃, d, J=6.81 Hz, 3H).

Procedure for the Synthesis of 2-methoxy-N-methyl-5-[4-((S)-3-methyl-morpholin-4-yl)-2-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzamide (Example 11dk)

To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), and 2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.05 equiv) in acetonitrile/water (1:1) (0.028 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 20 minutes. Upon completion the reaction mixture was partitioned between water and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 20% MeOH in CH₂Cl₂ to give the desired product.

2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid: (91% yield, 100% purity) m/z (LC-MS, ESP): 466.4 [M+H]⁺, R/T=2.68 min)

2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid (1 equiv) was dissolved in DMF (0.1 M) and DIPEA (8 equiv) was added. HBTU (1.2 equiv) was added at 0° C. and the reaction mixture was stirred for 30 minutes. Methylamine hydrochloride (5 equiv) was added and the reaction mixture was stirred 0° C. for 30 minutes and at room temperature for 1 hour. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. Combined organic phases were washed with water and brine, dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography to give the desired product.

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-N-methyl-benzamide: (73% yield, 97% purity) m/z (LC-MS, ESP): 479.2 [M+H]⁺, R/T=3.97 min)

NMR Data for Example 11dk

¹H NMR (300 MHz, CDCl₃ δ ppm 8.71 (ArH, d, J=2.45 Hz, 1H), 8.45 (ArH, dd, J=8.75, 2.48 Hz, 1H), 7.97 (ArH, d, J=8.52 Hz, 1H), 7.78 (NH, s, br, 1H), 7.51 (ArH, d, J=8.56 Hz, 1H), 7.01 (ArH, d, J=8.84 Hz, 1H), 4.39 (CH₂, d, J=6.69 Hz, 1H), 3.96 (OCH₃, s, 3H), 3.95-3.77 (CH₂, m, 7H), 3.76-3.58 (CH₂, m, 7H), 2.98 (NCH₃, d, J=4.81 Hz, 3H), 1.42 (CH₃, d, J=6.78 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.74, 164.71, 161.22, 160.99, 159.11, 159.04, 135.09, 132.93, 131.23, 131.16, 121.32, 119.02, 113.63, 111.84, 104.61, 70.90, 66.90, 56.27, 52.70, 44.70, 44.48, 26.70 and 14.85.

Procedure for the Synthesis of 6-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1H-indazol-3-ylamine (Example 11dl)

To a mixture of 7-chloro-4-((S)-3-methyl-morpholin-4-yl)-2-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine (1 equiv), potassium carbonate (2.5 equiv), and 4-cyano-3-fluorophenylboronic acid (1.2 equiv) in acetonitrile/water (1:1) (0.03 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (110° C., medium absorption setting) for 25 minutes under nitrogen atmosphere. Upon completion the precipitate was collected by vacuum filtration, which was in suitably pure form to be used with no further purification.

4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile: (49% yield, 96% purity) m/z (LC-MS, ESP): 449.2 [M+H]⁺ R/T=2.93 min

To a 0.2 M solution of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile (1 equiv) in n-BuOH was added 0.2 reaction volumes of hydrazine hydrate. A reflux condenser was attached to the mixture which was then heated to 140° C. for 2 hours whereupon it was cooled, and concentrated in vacuo to give an orange residue which was purified by flash chromatography (SiO₂) using Et₂O:MeOH—94:6 as eluent which allowed a yellow solid which was then recrystallised from CH₂Cl₂/Hexanes to furnish the title compound as a yellow solid.

6-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1H-indazol-3-ylamine: (90% yield, 97% purity) m/z (LC-MS, ESP): 461.2 [M+H]⁺ R/T=3.77 min

NMR Data for Example 11di

(¹H NMR (300 MHz, CD₃SOCD₃ δ ppm 11.6 (1H, s, formate), 8.31-8.01 (ArH, m, 2H), 7.74 (ArH, ddd, J=18.90, 15.23, 8.49 Hz, 3H), 5.42 (NH₂, s, 2H), 4.88-4.70 (NH, m, 1H), 4.44 (CH₂, d, J=10.93 Hz, 2H), 3.91 (CH₂, m, 3H), 3.81-3.54 (CH₂, m, 6H), 3.46 (CH₂, dt, J=11.82, 11.67, 2.52 Hz, 1H), 3.38-3.13 (CH₂, m, 1H), 2.51 (CH, td, J=3.52, 1.73, 1.73 Hz, 1H), 1.38 (CH₃, d, J=6.75 Hz, 3H), 1.26 (CH₃, d, J=6.79 Hz, 3H).

¹³C NMR (75 MHz, CD₃SOCD₃) δ ppm 164.43, 162.05, 161.20, 159.29, 149.19, 141.79, 136.12, 135.32, 120.42, 116.81, 114.78, 113.13, 108.47, 104.30, 70.39, 70.15, 66.34, 66.15, 51.81, 46.24, 43.81, 30.89, 22.0, 14.31 and 13.89.

Procedure for the Synthesis of N-{4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-acetamide (Example 11dm)

To a 0.1 M solution of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine (example 11cz) (1 equiv) in pyridine was added acetic anhydride (3 equiv). A reflux condenser was attached to the reaction vessel which was then heated to 70° C. or 2 days. Upon completion, the reaction was purified, in its crude for by preparative HPLC give the title compound as a white solid.

N-{4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-acetamide: (95% yield, 99% purity) m/z (LC-MS, ESP): 464.1 [M+H]⁺ R/T=3.77 min

NMR Data for Example 11dm

¹H NMR (300 MHz, CDCl₃δ ppm 8.70 (NH, s, 1H), 8.37-8.29 (ArH, m, 2H), 8.01 (ArH, d, J=8.36 Hz, 1H), 7.94 (ArH, dd, J=5.26, 1.54 Hz, 1H), 7.49 (ArH, d, J=8.39 Hz, 1H), 4.87 (CH₂, ddd, J=2.90, 1.56, 0.64 Hz, 1H), 4.56 (CH₂, d, J=13.43 Hz, 1H), 4.33 (CH₂, d, J=6.86 Hz, 1H), 3.99-3.58 (CH₂, m, 10H), 3.57-3.45 (CH₂, m, 1H), 3.39-3.25 (CH₂, m, 1H), 2.19 (CH₃, s, 3H), 1.43 (CH₃, d, J=6.78 Hz, 3H), 1.31 (CH₃, d, J=6.82 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃ δ ppm 168.79, 165.32, 162.82, 160.00, 159.87, 151.94, 148.64, 148.15, 135.18, 118.86, 113.66, 111.94, 106.03, 71.27, 70.89, 67.23, 66.89, 52.89, 46.98, 44.46, 39.35, 24.81, 14.77 and 14.41.

Procedure for the Synthesis of Examples 11dn to 11dp

The appropriate 7-chloropyridopyrimidine was reacted with 2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester according to conditions E to give 2-methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-thiomorpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid methyl ester as the desired product (1 equiv) which was then diluted in MeOH to give a 0.03M solution. NaOH (5 equiv of 1 M solution) was then added and the resultant mixture stirred at room temperature for 5 days. After this time the reaction was filtered and neutralized with 1 M HCl before being concentrated in vacuo to give a crude yellow residue which was diluted in CH₂Cl₂. The mixture was filtered and the resulting filtrate concentrated to give the desired product as an oil.

2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-thiomorpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid: (99% yield, 95% purity) m/z (LC-MS, ESP): 482.2 [M+H]⁺ R/T=2.78 min

2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-(4-methyl-piperazin-1-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid: (88% yield, 96% purity) m/z (LC-MS, ESP): 479.5 [M+H]⁺ R/T=2.26 min

2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid: (91% yield, 100% purity) m/z (LC-MS, ESP): 466.4 [M+H]⁺ R/T=2.68 min

To a warmed (40° C.) 0.06 M solution of the appropriate benzoic acid derivative (1 equiv) in anhydrous THF was added thionyl chloride (2.5 equiv) in a dropwise fashion. The reaction was maintained at this temperature and stirred for a further 1 hour. After this time the mixture was evaporated to give a brown oil, which was diluted in dry THF (sufficient to make 0.06 M solution) before ammonia gas was bubble through the mixture, which was accompanied by an exotherm. Upon completion, addition of ammonia was stopped and the mixture concentrated in vacuo to give a yellow oily residue which was dissolved in CH₂Cl₂ (1 reaction volume) and washed with water (2×1 reaction volume). The organic extract was removed, dried (MgSO₄), filtered and concentrated in vacuo to give the title compound.

2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-thiomorpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzamide: (30% yield, 97% purity) m/z (LC-MS, ESP): 481.1 [M+H]⁺ R/T=4.02 min

NMR Data for Example 11dn

¹H NMR (300 MHz, CDCl₃ δ ppm 8.83 (ArH, d, J=2.46 Hz, 1H), 8.61 (ArH, dd, J=8.75, 2.48 Hz, 1H), 8.00 (ArH, d, J=8.47 Hz, 1H), 7.72 (NH, d, J=0.76 Hz, 1H), 7.56 (ArH, d, J=8.50 Hz, 1H), 7.13 (ArH, d, J=8.82 Hz, 1H), 5.88 (NH, d, J=0.98 Hz, 1H), 4.42-4.23 (CH2, m, 4), 4.05 (CH₃O, s, 3H), 4.03-3.94 (CH₂, m, 1H), 3.85 (CH₂, ddd, J=14.51, 8.58, 5.82 Hz, 2H), 3.78-3.62 (CH₂, m, 3H), 2.75-2.65 (CH₂, m, 3H), 1.46 (CH₃, d, J=6.76 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃ δ ppm 166.60, 165.41, 162.87, 161.09, 159.89, 159.23, 134.73, 133.71, 131.82, 131.68, 120.56, 113.16, 111.89, 104.63, 70.95, 66.91, 56.29, 52.81, 46.70, 44.54, 27.45 and 14.70.

2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-(4-methyl-piperazin-1-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzamide: (12% yield, 98% purity) m/z (LC-MS, ESP): 481.1 [M+H]⁺ R/T=43.28 min

NMR Data for Example 11do

¹H NMR (300 MHz, CDCl₃ δ ppm 8.78 (ArH, d, J=2.48 Hz, 1H), 8.57 (ArH, dd, J=8.76, 2.52 Hz, 1H), 8.28 (NH, s, br, 1H), 7.96 (ArH, d, J=8.50 Hz, 1H), 7.68 (NH, s, br, 1H), 7.54 (ArH, d, J=8.55 Hz, 1H), 7.08 (ArH, d, J=8.84 Hz, 1H), 4.42-4.28 (CH₂, m, 1H), 4.09 (CH₂, s, br, 2H), 4.01 (OCH₃, s, 3H), 3.77 (CH₂, ddd, J=36.04, 19.80, 10.87 Hz, 9H), 2.76 (CH₂, t, J=5.05, 5.05 Hz, 4H), 2.47 (NCH₃, s, 3H), 1.42 (CH₃, d, J=6.77 Hz, 3H).

2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzamide: (61% yield, 97% purity) m/z (LC-MS, ESP): 465.4 [M+H]⁺ R/T=2.69 min

(NMR Data for Example 11dp

¹H NMR (300 MHz, CDCl₃ δ ppm 8.77 (ArH, d, J=2.44 Hz, 1H), 8.58 (ArH, dd, J=8.76, 2.47 Hz, 1H), 7.94 (ArH, d, J=8.48 Hz, 1H), 7.65 (NH, s, br, 1H), 7.51 (ArH, d, J=8.53 Hz, 1H), 7.06 (ArH, d, J=8.84 Hz, 1H), 5.91 (NH, s, br, 1H), 4.32 (CH₂, d, J=6.79 Hz, 1H), 3.98 (OCH₃, s, 3H), 3.95-3.86 (CH₂, m, 5H), 3.84-3.55 (CH₂, m, 9H), 1.40 (CH₃, d, J=6.77 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃ δ ppm 166.63, 165.31, 162.78, 160.96, 160.31, 159.29, 134.76, 133.68, 131.69, 131.60, 120.56, 113.09, 111.88, 104.76, 70.94, 67.04, 66.91, 56.28, 52.76, 44.58, 44.45 and 14.75.

Procedure for the Synthesis of Example 11dq

To a (0.1 M) solution of example 11at (1 equiv) in CHCl₃ was added m-CPBA (5.5 equiv). A reflux condenser was added to the apparatus and the mixture heated to 60° C. for 17 hours. After this time the reaction was concentrated in vacuo and purified by flash chromatography (SIO₂) using CH₂Cl₂:MeOH—95:5 as eluent to furnish the desired product.

N-{3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-8-oxy-pyrido[2,3-d]pyrimidin-7-yl]-phenyl}-methanesulfonamide: (39% yield, 100% purity) m/z (LC-MS, ESP): 515.5 [M+H]⁺ R/T=2.95 min.

NMR Data for Example 11dq

¹H NMR (300 MHz, CDCl₃ δ ppm 10.04 (NH, s, br, 1H), 8.42 (ArH, s, 1H), 7.55-7.25 (ArH, m, 4H), 6.96 (ArH, d, J=8.67 Hz, 1H), 4.80 (CH₂, s, br, 1H), 4.51 (CH₂, s, br, 1H), 4.31 (CH₂, d, J=6.71 Hz, 1H), 4.00-3.51 (CH₂, m, 9H), 3.49-3.34 (CH₂, m, 1H), 3.24 (CH₂, dd, J=13.22, 3.30 Hz, 1H), 2.80 (SCH₃, s, 3H), 1.42 (CH₃, d, J=6.78 Hz, 1H), 1.19 (CH₃, d, J=6.69 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃ δ ppm 165.58, 159.69, 158.28, 149.96, 138.59, 134.47, 129.53, 125.86, 123.35, 123.30, 116.17, 107.52, 71.33, 71.11, 67.32, 67.10, 53.39, 47.62, 44.87, 39.79, 38.68, 31.90, 22.97 and 15.16.

Procedure for the Synthesis of Example 11dr

7-Chloro-2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine was couple with 3-nitrobenzoic acid using Suzuki conditions D to give the desire product as a yellow powder.

2,4-Bis-((S)-3-methyl-morpholin-4-yl)-7-(3-nitro-phenyl)-pyrido[2,3-d]pyrimidine: (90% yield, 100% purity) m/z (LC-MS, ESP): 451.6 [M+H]⁺ R/T=3.41 min

To a 0.1M solution of 2,4-bis-((S)-3-methyl-morpholin-4-yl)-7-(3-nitro-phenyl)-pyrido[2,3-d]pyrimidine (1 equiv) in EtOH/H₂O—1:1 was added ammonium chloride (8 equiv) and iron powder (8 equiv). The reaction mixture was heated to 100° C. for 1 hour before cooling and filtering through a thin Celite™ pad. The cake was washed with EtOH (1 reaction volume). The filtrate was concentrated in vacuo and then partitioned between water and CH₂Cl₂ (1 reaction volume of each). The organic phase was removed, dried (MgSO₄), filtered and concentrated in vacuo and then purified by flash chromatography (SiO₂) using MeOH:CH₂Cl₂ (0:100-5:95-10-90) as eluent to give the title compound as a yellow solid.

3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-phenylamine: (88% yield, 98% purity) m/z (LC-MS, ESP): 421.1 [M+H]⁺ R/T=3.76 min

NMR Data for Example 11dr

¹H NMR (300 MHz, CDCl₃ δ ppm 7.93 (ArH, d, J=8.45 Hz, 1H), 7.62-7.55 (ArH, m, 1H), 7.41-7.32 (m, 1H), 7.20 (ArH, d, J=7.32 Hz, 2H), 6.71 (ArH, ddd, J=7.88, 2.40, 0.86 Hz, 1H), 4.87 (ArH, dd, J=3.54, 1.66 Hz, 1H), 4.57 (NH, d, J=13.25 Hz, 1H), 4.30 (NH, s, br, 1H), 3.98-3.56 (CH₂, m, 11H), 3.56-3.44 (CH₂, m, 1H), 3.37-3.24 (CH₂, m, 1H), 1.40 (CH₃, d, J=6.77 Hz, 3H), 1.29 (CH₃, d, J=6.81 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃ δ ppm 165.46, 162.87, 162.60, 159.96, 146.80, 139.75, 134.48, 129.35, 117.99, 116.69, 114.74, 113.48, 104.92, 71.32, 70.93, 67.28, 66.94, 52.80, 46.90, 44.49, 39.33, 14.71 and 14.33.

Procedure for the Synthesis of Example 11ds

To a 0.3M solution of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile (example 11av) (1 equiv) in EtOH was added hydrazine hydrate (5 equiv). The mixture was refluxed for 90 minutes whereupon it was cooled and partitioned between CH₂Cl₂ and water (1 reaction volume of each). The organic extract was removed. The aqueous phase was further extracted with CH₂Cl₂ (2×1 reaction volume). The combined organic extracts were then dried (MgSO₄), filtered and concentrated in vacuo to give a yellow slurry which was further purified by flash chromatography (SiO₂) using EtOAC/Hexanes as eluent to give the title compound as a yellow powder.

5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1H-indazol-3-ylamine: (52% yield, 100% purity) m/z (LC-MS, ESP): 461.6 [M+H]⁺ R/T=2.85 min

NMR Data for Example 11ds

¹H NMR (300 MHz, CDCl₃ δ ppm 8.52 (ArH, s, 1H), 8.06 (ArH, dd, J=8.84, 1.50 Hz, 1H), 7.94 (ArH, d, J=8.49 Hz, 1H), 7.42 (ArH, d, J=8.50 Hz, 1H), 7.29 (ArH, d, J=8.79 Hz, 2H), 4.87 (CH₂, dd, J=3.99, 1.99 Hz, 1H), 4.60 (CH₂, s, br, 1H), 4.32 (CH₂, d, J=6.78 Hz, 1H), 3.98-3.58 (CH₂, m, 9H), 3.51 (CH₂, dt, J=11.78, 11.46, 2.71 Hz, 1H), 3.39-3.25 (CH₂, m, 1H), 1.42 (CH₃, d, J=6.77 Hz, 3H), 1.29 (CH₃, d, J=6.81 Hz, 3H) (NH's not clearly seen)

¹³C NMR (75 MHz, CDCl₃ δ ppm 165.43, 162.97, 162.33, 160.01, 142.86, 134.62, 130.11, 127.06, 120.17, 115.21, 112.98, 109.71, 104.51, 71.32, 70.94, 67.28, 66.95, 52.80, 46.95, 44.48, 39.36, 27.01, 14.79 and 14.33.

		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Conditions	Example Structure
11dt	96	3.96	461.2	U
11du	97	4.10	513.1	I
11dv	99	4.04	495.0	J
11dw	98	3.70	504.1	V
11dx	99	3.79	474.1	I
11dy	99	3.79	474.1	W
11dz	99	4.06	499.2	D
11ea	99	4.16	451.2	D
11eb	98	3.96	446.2	P
11ec	99	7.55	466.2	J
11ed	98	3.86	461.2	D
11ee	98	4.04	485.2	D

Note:

The following examples were synthesized from the corresponding boronic acids: 11du, 11dv, 11dz and 11ee.

The following examples were synthesized from the corresponding pinacolate boron esters: 11dw, 11dx, 11ea, 11eb and 11ec.

The following Examples were synthesized from a mixture of the corresponding boronic acids and pinacolate boron esters: 11dt, 11dy, and 11ed.

NMR Data for Example 11ec

¹H NMR (300 MHz, CDCl₃ δ ppm 8.15 (ArH, d, J=7.5 Hz, 2H), 7.97 (ArH, d, J=8.46 Hz, 1H), 7.42 (ArH, d, J=8.46 Hz, 1H), 6.98 (ArH, d, J=9.24 Hz, 1H), 4.91 (CH₂, d, J=5.55 Hz, 1H), 4.77 (CH₂OH, s, 2H), 4.61 (CH₂, d, J=12.42 Hz, 1H), 4.36-4.34 (CH₂, m, 1H), 4.00-3.70 (OCH₃+CH₂, m, 9H), 3.69-3.51 (CH₂, m, 1H), 3.41-3.31 (CH₂, m, 1H), 1.46 (CH₃, d, J=6.69 Hz, 3H), 1.35 (CH₃, d, J=6.87 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.42, 162.88, 161.87, 159.95, 159.16, 134.54, 131.13, 129.25, 128.89, 128.44, 112.85, 110.27, 104.49, 71.30, 70.92, 67.26, 66.93, 61.98, 55.56, 52.78, 46.91, 44.45, 39.32, 14.69 and 14.31.

NMR Data for Example 11ed

¹H NMR (300 MHz, CDCl₃ δ ppm 8.34 (ArH, s, 1H), 8.11 (ArH, d, J=8.02 Hz, 1H), 8.00 (ArH, d, J=8.41 Hz, 1H), 7.90 (ArH, d, J=7.98 Hz, 1H), 7.43 (ArH, d, J=8.42 Hz, 1H), 7.10 (NH, br, s, 1H), 4.95-4.81 (CH₂, m, 1H), 4.57 (CH₂, d, J=13.37 Hz, 1H), 4.47 (NHCH₂, s, 2H), 4.33 (CH₂, d, J=6.68 Hz, 1H), 3.99-3.58 (CH₂, m, 9H), 3.51 (CH₂, dt, J=11.81, 11.45, 2.72 Hz, 1H), 3.31 (CH₂, dt, J=12.91, 12.52, 3.57 Hz, 1H), 1.42 (CH₃, d, J=6.78 Hz, 3H), 1.30 (CH₃, d, J=6.81 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ ppm 171.32, 165.36, 162.94, 161.42, 160.04, 144.06, 142.31, 135.01, 133.20, 127.63, 123.83, 123.08, 113.49, 105.35, 71.27, 70.91, 67.24, 66.91, 52.85, 46.96, 45.70, 44.48, 39.35, 14.76 and 14.39.

NMR Data for Example 11ef

¹H NMR (300 MHz, CDCl₃ δ ppm 8.08 (ArH, d, J=1.95 Hz, 1H), 8.01-7.94 (ArH, m, 1H), 7.82 (ArH, td, J=6.63, 1.80, 1.80 Hz, 1H), 7.48 (NH, br, s, 1H), 7.39 (ArH, dd, J=12.99, 5.20 Hz, 3H), 4.34 (CH₂, q, J=6.63, 6.56, 6.56 Hz, 1H), 3.97-3.76 (CH₂, m, 7H), 3.75-3.57 (CH₂, m, 7H), 2.87 (SO₂CH₃, s, 3H), 1.42 (CH₃, d, J=6.78 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.21, 162.77, 161.34, 160.28, 140.30, 137.69, 135.07, 129.91, 124.53, 122.37, 120.57, 113.44, 105.22, 70.91, 66.97, 66.89, 52.84, 44.58, 44.39, 39.32 and 14.79.

NMR Data for Example 11dz

¹H NMR (300 MHz, CDCl₃ δ ppm 8.11-8.03 (ArH, m, 2H), 7.96 (ArH, d, J=8.44 Hz, 1H), 7.38-7.31 (ArH, m, 1H), 7.32-7.24 (ArH, m, 2H), 4.85 (CH₂, d, J=5.45 Hz, 1H), 4.54 (CH₂, d, J=12.83 Hz, 1H), 4.32 (CH₂, d, J=6.78 Hz, 1H), 3.97-3.57 (CH₂, m, 9H), 3.50 (CH₂, dt, J=11.75, 11.35, 2.73 Hz, 1H), 3.37-3.24 (CH₂, m, 1H), 2.95 (SO₂CH₃, s, 3H), 1.42 (CH₃, d, J=6.78 Hz, 1H), 1.29 (CH₃, d, J=6.81 Hz, 3H) (NH not seen).

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.36, 162.93, 161.33, 160.00, 138.73, 135.29, 134.86, 129.34, 119.66, 112.95, 104.90, 71.27, 70.92, 67.24, 66.93, 52.82, 46.97, 44.45, 39.58, 33.35, 14.75 and 14.36.

NMR Data for Example 11ea

¹H NMR (300 MHz, CDCl₃ δ ppm 7.87 (ArH, d, J=8.55 Hz, 1H), 7.81 (ArH, d, J=1.80 Hz, 1H), 7.47 (ArH, dd, J=8.17, 1.85 Hz, 1H), 7.35 (ArH, d, J=8.57 Hz, 1H), 6.69 (ArH, d, J=8.14 Hz, 1H), 4.85 (CH₂, d, J=5.96 Hz, 1H), 4.62-4.52 (CH₂, m, 1H), 4.28 (CH₂, d, J=6.77 Hz, 1H), 4.02 (NH₂, s, br, 2H), 3.95 (d, J=6.54 Hz, 1H), 3.93 (CH₃, s, 3H), 3.92-3.57 (CH₂, m, 9H), 3.55-3.45 (CH₂, m, 1H), 3.38-3.25 (CH₂, m, 1H), 1.39 (CH₃, d, J=6.77 Hz, 3H), 1.29 (CH₃, d, J=6.81 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.48, 162.91, 162.45, 159.98, 147.22, 138.70, 134.14, 128.92, 121.24, 113.97, 112.74, 110.15, 104.11, 71.35, 70.95, 67.32, 66.96, 55.83, 52.79, 46.89, 44.44, 39.31, 31.60, 22.66 and 14.30.

NMR Data for Example 11eb

¹H NMR (300 MHz, CD₃COCD₃ δ ppm 11.83 (ArH, s, 1H), 9.06 (ArH, d, J=2.07 Hz, 1H), 8.75 (ArH, d, J=2.09 Hz, 1H), 8.30-8.10 (ArH, m, 1H), 7.72 (ArH, d, J=8.55 Hz, 1H), 7.54 (ArH, s, 1H), 6.59 (NH, s, 1H), 4.77 (CH₂, dd, J=6.66, 1.89 Hz, 1H), 4.49-4.34 (CH₂, m, 2H), 4.03-3.83 (CH₂, m, 3H), 3.81-3.55 (CH₂, m, 6H), 3.54-3.38 (CH₂, m, 1H), 3.23 (CH₂, dd, J=13.19, 3.46 Hz, 1H), 1.37 (CH₃, d, J=6.74 Hz, 3H), 1.25 (CH₃, d, J=6.75 Hz, 3H).

¹³C NMR (75 MHz, CD₃COCD₃) δ ppm 165.41, 163.09, 161.32, 160.22, 150.21, 143.45, 136.25, 128.14, 128.09, 126.99, 120.44, 113.54, 104.90, 101.82, 71.32, 71.09, 67.27, 67.09, 52.78, 47.17, 44.79 and 15.25.

NMR Data for Example 11dy

¹H NMR (300 MHz, CD₃SOCD₃ δ ppm 8.40 (ArH, d, J=1.37 Hz, 1H), 8.33 (ArH, dd, J=8.38, 1.63 Hz, 1H), 8.25 (ArH, d, J=8.45 Hz, 2H), 8.17 (ArH, s, 1H), 7.79 (ArH, d, J=8.48 Hz, 1H), 4.84-4.73 (CH, m, 1H), 4.45 (CH₂, d, J=13.67 Hz, 2H), 4.00-3.84 (CH₂, m, 3H), 3.81-3.57 (CH₂, m, 6H), 3.46 (CH₂, dt, J=11.84, 11.73, 2.61 Hz, 1H), 3.23 (CH₂, dt, J=13.16, 12.92, 3.65 Hz, 1H), 1.39 (CH₃, d, J=6.75 Hz, 3H), 1.26 (CH₃, d, J=6.75 Hz, 3H)

¹³C NMR (75 MHz, CD₃SOCD₃ δ ppm 164.30, 162.06, 160.45, 159.32, 159.03, 149.10, 145.91, 143.53, 135.86, 126.40, 125.73, 125.30, 123.33, 113.30, 105.06, 70.35, 70.14, 66.31, 66.14, 51.79, 46.27, 43.81, 30.38, 14.35 and 13.89.

NMR Data for Example 11dv

¹H NMR (300 MHz, CD₃SOCD₃ δ ppm 8.39 (ArH, dd, J=5.45, 3.65 Hz, 1H), 8.23 (ArH, d, J=8.47 Hz, 1H), 8.14-8.03 (ArH, m, 2H), 7.81-7.69 (ArH+NH, m, 2H), 4.77 (CH₂, dd, J=6.52, 2.00 Hz, 1H), 4.43 (CH₂, d, J=13.75 Hz, 2H), 3.99-3.83 (CH₂, m, 2H), 3.80-3.56 (CH₂, m, 6H), 3.52-3.15 (CH₂, m, 5H), 2.50 (CH₂, td, J=3.67, 1.83, 1.83 Hz, 2H), 1.38 (CH₃, d, J=6.75 Hz, 3H), 1.25 (CH₃, d, J=6.75 Hz, 3H), 1.19-1.10 (CH₃, m, 3H).

¹³C NMR (75 MHz, CD₃SOCD₃ δ ppm 164.80, 163.51, 162.52, 159.84, 158.73, 158.27, 142.53, 142.43, 136.38, 131.02, 125.84, 123.52, 123.48, 115.08, 114.76, 113.45, 105.57, 70.87, 70.64, 66.83, 66.65, 52.32, 46.79, 44.32, 34.59, 15.10, 14.87 and 14.42.

NMR Data for Example 11dy

¹H NMR (300 MHz, CD₃SOCD₃ δ ppm 10.52 (H, s, 1H), 8.19 (ArH, d, J=8.50 Hz, 1H), 7.79-7.68 (ArH, m, 2H), 7.61 (ArH, d, J=8.52 Hz, 1H), 7.35 (ArH, d, J=7.66 Hz, 1H), 4.84-4.69 (CH₂, m, 1H), 4.42 (CH₂, dd, J=7.38, 5.30 Hz, 2H), 3.91 (CH₂, dd, J=14.30, 7.97 Hz, 3H), 3.82-3.52 (CH₂, m, 8H), 3.45 (CH₂, d, J=2.42 Hz, 1H), 3.26-3.15 (CH₂, m, 1H), 1.37 (CH₃, d, J=6.74 Hz, 3H), 1.25 (CH₃, d, J=6.76 Hz, 3H).

¹³C NMR (75 MHz, CD₃SOCD₃ δ ppm 176.84, 164.89, 162.55, 160.83, 159.82, 144.90, 138.19, 135.98, 128.66, 125.02, 120.94, 113.09, 108.05, 104.92, 70.90, 70.67, 66.84, 66.67, 52.32, 46.76, 44.30, 36.29, 14.85 and 14.35.

NMR Data for Example 11dt

¹H NMR (300 MHz, CDCl₃ δ ppm 8.58 (ArH, d, J=7.97 Hz, 1H), 8.49 (ArH, d, J=45.95 Hz, 1H), 7.99 (ArH, d, J=8.42 Hz, 1H), 7.50 (ArH, dd, J=17.31, 8.21 Hz, 1H), 7.24 (ArH, d, J=17.82 Hz, 1H), 5.01-4.86 (CH₂, s, br, 1H), 4.65-4.39 (CH₂, m, 3H), 4.33 (CH₂, d, J=6.25 Hz, 1H), 4.04-3.58 (CH₂, m, 8H), 3.49 (CH₂, d, J=11.36 Hz, 1H), 3.31 (CH₂, d, J=2.99 Hz, 1H), 1.41 (CH₃, d, J=6.72 Hz, 3H), 1.29 (CH₃, d, J=6.76 Hz, 3H) (1 proton missing, lots of overlap seen, NH not seen either)

¹³C NMR (75 MHz, CDCl₃ δ ppm 171.52, 165.39, 162.90, 161.33, 160.01, 145.14, 139.06, 135.02, 132.17, 123.57, 122.56, 113.20, 105.21, 71.29, 70.92, 67.25, 66.93, 52.78, 46.95, 45.68, 44.51, 39.34, 27.00, 14.74 and 14.35.

NMR Data for Example 11du

¹H NMR (300 MHz, CDCl₃ δ ppm 8.12 (ArH, d, J=8.32 Hz, 2H), 8.03 (ArH, d, J=8.43 Hz, 1H), 7.51-7.39 (ArH, m, 3H), 5.08 (CH₂, br, s, 1H), 4.89 (CH₂, d, J=4.91 Hz, 1H), 4.58 (CH₂, d, J=12.59 Hz, 1H), 4.40 (CH₂NH, br, s, 2H), 4.22 (NH, br, s, 1H), 4.04-3.64 (CH₂, m, 9H), 3.56 (CH₂, dt, J=11.80, 11.45, 2.75 Hz, 1H), 3.44-3.30 (CH₂, m, 1H), 2.87 (SO₂CH₃s, 3H), 1.48 (CH₃, d, J=6.78 Hz, 3H), 1.35 (CH₃, d, J=6.81 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃ δ ppm 165.16, 163.70, 162.51, 159.71, 138.71, 138.33, 134.99, 128.40, 128.15, 113.45, 105.20, 71.23, 70.89, 67.18, 66.90, 52.82, 47.07, 46.90, 44.21, 41.25, 39.41, 14.78 and 14.38.

Tested in the Biological Assay: Ex. (11b) 0.00185 μM; Ex. (11c) 0.00184 μM Ex. (11d) 0.00245 μM; Ex. (11az) 0.006865 μM.

Tested in Alternative Enzyme Assay: Ex. (11a) 0.0089 μM; Ex. (11e) 0.0044 μM; Ex. (11f) 0.005 μM; Ex. (11g) 0.011 μM; Ex. (11h) 0.0021 μM; Ex. (11i) 0.0056 μM; Ex. (11j) 0.035 μM; Ex. (11k) 0.015 μM; Ex. (11l) 0.0057 μM; Ex. (11m) 0.31 μM; Ex. (11n) 0.085 μM; Ex. (11o) 0.14 μM; Ex. (11p) 0.038 μM; Ex. (11q) 0.39 μM; Ex. (11r) 0.23 μM; Ex. (11s) 0.028 μM; Ex. (11t) 0.34 μM; Ex. (11u) 0.015 μM; Ex. (11v) 0.18 μM; Ex. (11w) 0.26 μM; Ex. (11x) 0.53 μM; Ex. (11y) 0.33 μM; Ex. (11z) 0.37 μM; Ex. (11aa) 0.025 μM; Ex. (11ab) 0.029 μM; Ex. (11ac) 0.14 μM; Ex. (11ad) 0.0069 μM; Ex. (11ae) 0.38 μM; Ex. (11af) 0.054 μM; Ex. (11ag) 0.029 μM; Ex. (11ah) 0.012 μM; Ex. (11ai) 1.1 μM; Ex. (11aj) 0.49 μM; Ex. (11ak) 0.017 μM; Ex. (11al) 0.23 M; Ex. (11am) 0.21 μM; Ex. (11an) 0.14 μM; Ex. (11ao) 0.0083 μM; Ex. (11ap) 0.02 μM; Ex. (11aq) 0.084 μM; Ex. (11ar) 0.006 μM; Ex. (11as) 0.013° M; Ex. (11at) 0.031 μM; Ex. (1au) 0.09 μM; Ex. (1av) 0.29 μM; Ex. (1aw) 0.062 μM; Ex. (1ax) 0.0092 μM; Ex. (11ay) 0.15 μM; Ex. (11ba) 0.44 μM; Ex. (11bb) 0.14 μM; Ex. (11bc) 0.083 μM; Ex. (11bd) 0.011 μM; Ex. (11be) 0.18 μM; Ex. (11bf) 0.06 μM; Ex. (11bg) 0.17 μM; Ex. (11bh) 0.014 μM; Ex. (11bi) 0.032 μM; Ex. (11bj) 0.035 μM; Ex. (11bk) 0.039 μM; Ex. (11bl) 0.0027 μM; Ex. (11bm) 0.055 μM; Ex. (11bn) 0.04 μM; Ex. (11bo) 0.018 μM; Ex. (11bp) 0.1 μM; Ex. (11bq) 0.14 μM; Ex. (11br) 0.056 μM; Ex. (11bs) 0.039 μM; Ex. (11bt) 0.11 μM; Ex. (11bu) 0.016 μM; Ex. (11bv) 0.0051 μM; Ex. (11bw) 0.036 μM; Ex. (11bx) 0.038 μM; Ex. (11by) 0.0046 μM; Ex. (11bz) 0.018 μM; Ex. (11ca) 0.35 μM; Ex. (11cb) 0.5 μM; Ex. (11cc) 0.0064 μM; Ex. (11cd) 0.46 μM; Ex. (11ce) 0.091 μM; Ex. (11cf) 0.073 μM; Ex. (11cg) 0.00026 μM; Ex. (11ch) 0.22 μM; Ex. (11ci) 0.15 μM; Ex. (11cj) 0.09 μM; Ex. (11ck) 0.065 μM; Ex. (11cl) 0.2 μM; Ex. (11cm) 0.16 μM; Ex. (11cn) 0.31 μM; Ex. (11co) 2.5 μM; Ex. (11cp) 1 μM; Ex. (11cq) 0.25 μM; Ex. (11cr) 0.69 μM; Ex. (11cs) 7.5 μM; Ex. (11ct) 0.024 μM; Ex. (11cu) 0.042 μM; Ex. (11cv) 0.3 μM; Ex. (11cw) 0.49 μM; Ex. (11cx) 0.12 μM; Ex. (11cy) 0.72 μM; Ex. (11cz) 0.066 μM; Ex. (11da) 1.8 μM; Ex. (11db) 0.03 μM; Ex. (11dc) 0.02 μM; Ex. (11dd) 0.073 μM; Ex. (11de) 0.0049 μM; Ex. (11dg) 0.014 μM; Ex. (11dh) 0.041 μM; Ex. (11di) 0.23 μM; Ex. (11dj) 0.25 μM; Ex. (11dk) 0.02 μM; Ex. (11dl) 0.018 μM; Ex. (11dm) 0.0075 μM; Ex. (11dn) 0.0055 μM; Ex. (11do) 0.03 μM; Ex. (11dp) 0.0067 μM; Ex. (11dq) 0.037 μM; Ex. (11dt) 0.0026 μM; Ex. (11du) 0.00039 μM; Ex. (11dv) 0.72 μM; Ex. (11dw) 0.021 μM; Ex. (11dx) 0.035 μM; Ex. (11dy) 0.0035 μM; Ex. (11dz) 0.099 μM; Ex. (11ea) 0.057 μM; Ex. (11eb) 0.17 μM; Ex. (11ec) 0.013 μM; Ex. (11ed) 0.016 μM; Ex. (11ee) 0.0048 μM.

Tested in phospho-Ser473 Akt assay: Ex. (11df) 0.3813 μM; Ex. (11dr) 0.01415 μM; Ex. (11ds) 0.06066 μM.

Example 12

R⁷=Aryl or hetero aryl

To a solution (0.2 M) of the appropriate chloro-substrate (1 equiv) in dioxane was added diisopropylethylamine (2 equiv). To this mixture was then added the appropriate amine (2 equiv). The reaction was then heated under the influence of microwave radiation (120° C., medium absorption setting) for 10 minutes. Upon completion the sample was concentrated in vacuo and the resulting residue dissolved in CH₂Cl₂ and washed with H₂O. The organic fraction was removed, dried (MgSO₄). The crude residue was purified by flash chromatography (SiO₂) to give the desired products.

	TABLE 12
		Retention
	Purity	time	M/z
	(%)	(min)	[M + H}+	Example Structure
12a	97	3.28	448.3
12b	99	3.78	439.3
12c	99	3.31	462.4
12d	100	3.76	463.3
12e	99	3.11	483.3
12f	99	3.82	463.4
12g	100	3.39	436.5
12h	100	3.68	463.4
12i	98	3.26	448.4
12j	100	3.38	450.3

Tested in Alternative Enzyme Assay: Ex. (12a) 0.7 μM; Ex. (12b) 0.56 μM; Ex. (12c) 0.6 μM; Ex. (12d) 0.27 μM; Ex. (12e) 0.35 μM; Ex. (12f) 0.17 μM; Ex. (12g) 0.064 μM; Ex. (12h) 0.29 μM; Ex. (12i) 0.64 μM; Ex. (12j) 0.2 μM.

Example 13

Compounds 13a to 13ab

R⁴=(S)-3-methyl-morpholineR²=(S)-3-methyl-morpholineAr=aryl

Carboxy-substrates are reported in Example 11.

Method: Amide Formation

Conditions A:

The appropriate carboxy-substrate (1 equiv) was dissolved in DMF (0.067 M). HBTU (1.2 equiv) and appropriate amines (1.05 equiv) were added along with 3 drops of triethylamine at 0° C. The reaction vessels were sealed and the mixtures were stirred between 1 and 12 hours at room temperature. Upon completion the samples were concentrated in vacuo. The crude residues were then purified by preparative HPLC to give the desired products.

	TABLE 13
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Conditions	Example Structure
13a	98	7.36	515.3	A
13b	82	5.31	518.4	A
13c	96	7.2	477.3	A
13d	96	6.95	533.4	A
13e	95	7.33	495.3	A
13f	95	8.34	531.3	A
13g	98	6.61	519.4	A
13h	98	6.64	519.4	A
13i	99	7.32	533.4	A
13j	99	8.19	505.4	A
13k	98	4.15	521.5	A
13l	99	4.27	513.4	A
13m	90	4.22	491.3	A
13n	98	4.35	505.5	A
13o	95	4.2	493.4	A
13p	98	4.36	503.4	A
13q	98	4.31	501.4	A
13r	95	4.62	519.5	A
13s	99	4.19	517.3	A
13t	99	3.97	507.4	A
13u	99	4.07	521.4	A
13v	96	7.38	495.4	A
13w	91	8.42	523.3	A
13x	97	8.44	523.4	A
13y	97	7.69	511.3	A
13z	92	8.33	521.3	A
13aa	86	4.12	509.3	A
13ab	83	4.19	519.3	A
13ac	100	7.13	477.4	A
13ad	100	4.00	493.4	A

Tested in Alternative Enzyme Assay: Ex. (13a) 0.048 μM; Ex. (13b) 0.32 μM; Ex. (13c) 0.09 μM; Ex. (13d) 0.28 μM; Ex. (13e) 0.0047 μM; Ex. (13f) 0.28 μM; Ex. (13g) 0.0052 μM; Ex. (13h) 0.18 μM; Ex. (13i) 0.14 μM; Ex. (13j) 0.17 μM; Ex. (13k) 0.23 μM; Ex. (131) 0.044 μM; Ex. (13m) 0.32 μM; Ex. (13n) 0.23 μM; Ex. (13o) 0.37 μM; Ex. (13p) 0.56 μM; Ex. (13q) 0.12 μM; Ex. (13r) 0.5 μM; Ex. (13s) 0.38 μM; Ex. (13t) 0.042 μM; Ex. (13u) 0.13 μM; Ex. (13v) 0.16M; Ex. (13w) 0.5 μM; Ex. (13x) 0.24 μM; Ex. (13y) 0.74 μM; Ex. (13z) 0.34 μM; Ex. (13aa) 0.026 μM; Ex. (13ab) 0.14 μM; Ex. (13ac) 1.6 μM; Ex. (13ad) 0.066 μM.

Example 14

Benzyl alcohol substrates are reported in Example 11.

The appropriate benzyl alcohol (1 equiv) was dissolved in CH₂Cl₂ (0.08 M). Triethylamine (1 equiv) was added at room temperature, followed by the addition of thionyl chloride (2 equiv). The reaction mixture was stirred at 30° C. for 45 minutes. Upon completion the reaction mixture was partitioned between brine and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 10 to 70% ethyl acetate in hexane.

7-(3-Chloromethyl-phenyl)-2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine: (72% yield, 90% purity) m/z (LC-MS, ESP): 454 [M+H]⁺ R/T=3.15 min

The appropriate benzyl alcohol (1 equiv) was dissolved in CH₂Cl₂ (0.052 M). Thionyl chloride (3.3 equiv) was added. The reaction mixture was heated up to 55° C. and a solution of triethylamine (1.7 equiv) in CH₂Cl₂ (0.044 M) was added dropwise over 10 minutes. The reaction mixture was allowed to stir at 30° C. for 10 minutes. Upon completion the reaction mixture was partitioned between brine and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 10 to 50% ethyl acetate in hexane.

7-(4-Chloromethyl-phenyl)-2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine: (65% yield, 90% purity) m/z (LC-MS, ESP): 454 [M+H]⁺ R/T=3.15 min

The appropriate benzyl alcohol (1 equiv) was dissolved in CH₂Cl₂ (0.044 M). Thionyl chloride (3.3 equiv) was added. The reaction mixture was heated up to 55° C. and a solution of triethylamine (1.7 equiv) in CH₂Cl₂ (0.044 M) was added dropwise over 10 minutes. The reaction mixture was allowed to stir at 30° C. for 30 minutes. Upon completion the reaction mixture was partitioned between brine and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was used without further purification.

7-(3-Chloromethyl-4-fluoro-phenyl)-2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine: (96% yield, 90% purity) m/z (LC-MS, ESP): 472 [M+H]⁺ R/T=3.96 min

The appropriate benzyl alcohol (1 equiv) was dissolved in CH₂Cl₂ (0.086 M). Triethylamine (2.5 equiv) and thionyl chloride (2.5 equiv) were added. The reaction mixture was heated up to 45° C. afor 3 hours. Upon completion the reaction mixture was partitioned between water and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 10 to 50% ethyl acetate in hexane.

7-(3-Chloromethyl-4-methoxy-phenyl)-2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine: (37% yield, 90% purity) m/z (LC-MS, ESP): 484 [M+H]⁺ R/T=3.21 min

Compounds 14a to 14ak

R⁴=(S)-3-methyl-morpholineR²=(S)-3-methyl-morpholineR⁷=aryl

Method: Benzylamines, Benzylethers and Benzylsulfones Formation

Conditions A:

The appropriate chlorobenzyl-substrate (1 equiv) was dissolved in THF (0.067 M). The appropriate amine (80 equiv) as well as triethylamine (1 equiv) was added. The reaction vessels were sealed and the mixtures were stirred for 3 to 5 hours at 95° C. Upon completion the samples were concentrated in vacuo. The crude residues were then purified by preparative HPLC to give the desired products.

Conditions B:

The appropriate chlorobenzyl-substrate (1 equiv) was dissolved in an aqueous ammonia/n-butanol (1.5:1) solution (0.011 M). The reaction vessel was sealed and the mixture was stirred for 10 minutes at 140° C. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions C:

The appropriate chlorobenzyl-substrate (1 equiv) and sodium hydroxide (1 equiv) were dissolved in ethanol (0.011 M). The reaction vessel was sealed and the mixture was stirred for 3 hours at 50° C. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions D:

The appropriate chlorobenzyl-substrate (1 equiv) was dissolved in DMF (0.022 M). Imidazole (3 equiv) and potassium tert-butoxide (3 equiv) were added. The reaction vessel was sealed and the mixture was stirred for 2 hours at room temperature. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

Conditions E:

The appropriate chlorobenzyl-substrate (1 equiv) was dissolved in DMF (0.066 M). Sodium sulfinate (1.3 equiv) was added. The mixture was stirred for 2 hours at 125° C. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

Conditions F:

The appropriate chlorobenzyl-substrate (1 equiv), potassium carbonate (2.6 equiv) triethylamine (1 equiv) and the appropriate amine (1.1 equiv) were suspended in DMF (0.028 M). The reaction vessel was sealed and the mixture was stirred for 16 hours at 40° C. Upon completion the sample was filtered through a silica cartridge, washed with CH₂Cl₂ and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

	TABLE 14
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Conditions	Example Structure
14a	87	3.61	449.3	A
14b	95	3.41	435.2	B
14c	99	3.4	505.5	A
14d	100	3.42	505.5	A
14e	100	3.44	519.5	A
14f	100	3.39	479.4	A
14g	95	4.36	464.4	C
14h	96	3.4	479.4	A
14i	95	3.4	435.4	B
14j	92	5.6	475.4	A
14k	94	5.65	477.4	A
14l	97	5.39	449.4	A
14m	90	5.6	519.5	A
14n	96	5.83	489.5	A
14o	95	5.56	493.4	A
14p	26,69	6.63,6.78	501.4	A
14q	99	3.43	486.4	D
14r	94	3.44	505.5	A
14s	97	3.44	505.3	A
14t	94	6.06	498.7	E
14u	98	3.42	453.4	B
14v	99	3.63	493.4	A
14w	99	3.62	495.4	A
14x	96	3.55	467.4	A
14y	99	3.6	537.4	A
14z	99	3.67	507.4	A
14aa	97	3.59	511.4	A
14ab	91	3.58	499.4	A
14ac	99	3.55	497.4	A
14ad	99	3.4	523.4	A
14ae	99	3.47	522.4	A
14af	99	3.42	481.4	A
14ag	99	3.49	536.4	A
14ah	98	3.43	537.5	A
14ai	99	3.48	509.4	A
14aj	99	3.46	525.5	A
14ak	99	3.42	523.5	A
14al	99	3.55	505.4	F
14am	99	3.60	507.4	F
14an	99	3.66	533.4	F
14ao	99	3.77	547.5	F
14ap	99	3.70	561.4	F
14aq	99	3.52	549.5	F
14ar	99	3.85	571.5	F
14as	99	3.85	549.5	F
14at	99	3.76	535.5	F
14au	99	3.83	549.5	F
14av	96	3.32	578.5	F
14aw	99	3.82	561.5	F
14ax	99	3.59	519.4	F
14ay	99	3.66	521.4	F
14az	99	3.65	521.4	F
14ba	99	3.46	509.4	F
14bb	99	3.52	523.4	F
14bc	99	3.84	561.5	F
14bd	99	3.81	599.5	F
14be	93	3.29	559.4	F
14bf	99	3.91	575.5	F

NMR Data for example 14h

¹H NMR (300 MHz, DMSO) δ ppm 8.21 (ArH, d, J=8.39 Hz, 2H), 8.08-8.01 (ArH, m, 1H), 7.65 (ArH, d, J=8.49 Hz, 1H), 7.49 (ArH, d, J=4.85 Hz, 2H), 4.82-4.72 (CH₂, m, 1H), 4.45 (CH₂, +NH m, 3H), 3.99-3.82 (CH₂, m, 7H), 3.69 (CH₂, ddd, J=19.97, 8.86, 5.32 Hz, 8H), 3.53 (CH₂, t, J=5.65, 5.65 Hz, 2H), 3.29-3.15 (CH₂, m, 2H), 1.38 (CH₃, d, J=6.75 Hz, 3H), 1.25 (CH₃, d, J=6.75 Hz, 3H)

NMR Data for Example 14r

¹H NMR (300 MHz, CDCl₃ δ ppm 8.19 (ArH, s, 1H), 8.03 (ArH, ddd, J=8.43, 5.31, 3.28 Hz, 2H), 7.54-7.37 (ArH, m, 3H), 5.00-4.85 (CH, m, 1H), 4.68-4.56 (CH₂, m, 1H), 4.36 (CH₂, ddd, J=6.83, 4.79, 2.16 Hz, 2H), 4.07-3.92 (CH₂, m, 2H), 3.91-3.66 (CH₂, m, 11H), 3.63-3.49 (CH₂, m, 1H), 3.39 (CH₂, dd, J=13.37, 3.58 Hz, 1H), 3.04-2.92 (CH₂, m, 1H), 2.80 (CH₂, d, J=10.30 Hz, 1H), 2.65 (CH₂, dd, J=10.23, 4.92 Hz, 1H), 2.52-2.39 (CH₂, m, 1H), 2.21 (CH₂, d, J=7.02 Hz, 1H), 1.89-1.73 (CH₂, m, 1H), 1.46 (CH₃, d, J=6.77 Hz, 3H), 1.35 (CH₃, d, J=6.81 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.57, 163.03, 162.50, 160.11, 139.06, 134.83, 130.62, 128.81, 127.10, 113.70, 105.06, 71.44, 71.06, 67.41, 67.25, 67.07, 62.87, 60.08, 52.98, 52.49, 47.07, 44.58, 39.47, 35.02, 14.86 and 14.90.

NMR Data for Example 14s

¹H NMR (300 MHz, CDCl₃) δ ppm 8.22 (ArH, s, 1H), 8.11-7.96 (ArH, m, 2H), 7.48 (ArH, dd, J=10.85, 7.98 Hz, 3H), 4.99-4.86 (CH, m, 1H), 4.68-4.55 (CH, m, 1H), 4.44-4.30 (CH₂, m, 2H), 4.06-3.92 (CH₂, m, 2H), 3.93-3.65 (CH₂, m, 10H), 3.62-3.50 (CH₂, m, 1H), 3.39 (CH₂, dd, J=13.39, 3.57 Hz, 1H), 3.14-3.01 (CH₂, m, 1H), 2.88 (CH₂, d, J=10.59 Hz, 1H), 2.77-2.67 (CH₂, m, 1H), 2.63-2.43 (CH₂, m, 1H), 2.31-2.14 (CH₂, m, 1H), 1.92-1.79 (CH₂, m, 1H), 1.47 (CH₃, d, J=6.77 Hz, 3H), 1.35 (CH₃, d, J=6.81 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃)) δ ppm 165.56, 163.03, 162.34, 160.12, 139.16, 134.89, 130.80, 128.94, 128.91, 127.39, 113.69, 105.11, 71.44, 71.21, 71.06, 67.40, 67.06, 62.61, 59.93, 52.98, 52.42, 47.08, 44.58, 39.47, 34.88, 31.73, 22.80, 14.86 and 14.91.

Tested in the Biological Assay: Ex. (14f) 0.001967 μM.

Tested in Alternative Enzyme Assay: Ex. (14a) 0.0016 μM; Ex. (14b) 0.025 μM; Ex. (14c) 0.093 μM; Ex. (14d) 0.013 μM; Ex. (14e) 0.0019 μM; Ex. (14f) <0.0027 μM; Ex. (14g) 0.13 μM; Ex. (14h) 0.031 μM; Ex. (14i) 0.027 μM; Ex. (14j) 0.054 μM; Ex. (14k) 0.016 μM; Ex. (14l) 0.0091 μM; Ex. (14m) 0.015 μM; Ex. (14n) 0.0071 μM; Ex. (14o) 0.021 μM; Ex. (14p) 0.17 μM; Ex. (14q) 0.13 μM; Ex. (14r) 0.04 μM; Ex. (14s) 0.029 μM; Ex. (14t) 0.09 μM; Ex. (14u) 0.027 μM; Ex. (14v) 0.14 μM; Ex. (14w) 0.028 μM; Ex. (14x) 0.12 μM; Ex. (14y) 0.13 μM; Ex. (14z) 0.13 μM; Ex. (14aa) 0.2 μM; Ex. (14ab) 1.1 μM; Ex. (14ac) 0.087 μM; Ex. (14ad) 0.081 μM; Ex. (14ae) 0.16 μM; Ex. (14af) 0.58 μM; Ex. (14ag) 0.54 μM; Ex. (14ah) 0.2 μM; Ex. (14ai) 0.22 μM; Ex. (14aj) 0.46 μM; Ex. (14ak) 0.015 μM; Ex. (14al) 0.064 μM; Ex. (14am) 0.024 μM; Ex. (14an) 0.095 μM; Ex. (14ao) 0.064 μM; Ex. (14ap) 0.11 μM; Ex. (14aq) 0.012 μM; Ex. (14ar) 0.06 μM; Ex. (14as) 0.091 μM; Ex. (14at) 0.12 μM; Ex. (14au) 0.096 μM; Ex. (14av) 0.0038 μM; Ex. (14aw) 0.11 μM; Ex. (14ax) 0.1 μM; Ex. (14ay) 0.14 μM; Ex. (14az) 0.038 μM; Ex. (14ba) 0.013 μM; Ex. (14bb) 0.032 μM; Ex. (14bc) 0.076 μM; Ex. (14bd) 0.12 μM; Ex. (14be) 0.049 μM; Ex. (14bf) 0.059 μM.

Example 15

Benzyl chloride substrates are reported in Example 14.

The appropriate benzyl chloride (1 equiv) was dissolved in an ammonium hydroxide and n-butanol (1.5:1) solution (0.01 M). The reaction vessel was sealed and the mixture exposed to microwave radiation (140° C., medium absorption setting) for 10 minutes. Upon completion the reaction mixture was partitioned between brine and ethyl acetate and extracted with ethyl acetate. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% methanol in CH₂Cl₂.

3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzylamine: (81% yield, 100% purity) m/z (LC-MS, ESP): 435 [M+H]⁺ R/T=2.44 min

5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzylamine: (85% yield, 98% purity) m/z (LC-MS, ESP): 453 [M+H]⁺ R/T=3.21 min

4-[2,4-Bis-(3-methyl-morpholin-4-yl)-pyrido[2,9-d]pyrimidin-7-yl]-benzylamine: (95% yield, 97% purity) m/z (LC-MS, ESP): 435 [M+H]⁺ R/T=2.36 min

The appropriate benzyl chloride (1 equiv) was dissolved in a 2 M solution of methylamine in THF (80 equiv). Triethylamine (1 equiv) was added. The reaction mixture was stirred at 95° C. for 2.5 hours. Upon completion the reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and n-butanol and the organic phase was washed with brine, dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 7% methanol in CH₂Cl₂.

{3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzyl}-methyl-amine: (77% yield, 94% purity) m/z (LC-MS, ESP): 449 [M+H]⁺ R/T=2.44 min

{4-[2,4-Bis-(3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzyl}-methyl-amine: (93% yield, 87% purity) m/z (LC-MS, ESP): 449 [M+H]⁺ R/T=2.40 min

Procedures for the Synthesis of Examples 15a to 15z

R⁴=(S)-3-methyl-morpholineR²=(S)-3-methyl-morpholine

Conditions A:

The appropriate aminobenzyl-substrate (1 equiv) was dissolved in CH₂Cl₂ (0.035 M). The appropriate acyl chloride or acid anhydride (2 equiv) as well as triethylamine (1 equiv) was then added. The mixtures were stirred for 2 hours at room temperature. Upon completion the samples were concentrated in vacuo. The crude residues were then purified by preparative HPLC to give the desired products.

Conditions B:

The appropriate methylaminobenzyl-substrate (1 equiv) was dissolved in CH₂Cl₂ (0.035 M). The appropriate acyl chloride or acid anhydride (2 equiv) as well as triethylamine (1 equiv) were added. The mixtures were stirred for 12 hours at 95° C. Upon completion the samples were concentrated in vacuo. The crude residues were then purified by preparative HPLC to give the desired products.

	TABLE 15
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Conditions	Example Structure
15a	98	4.02	477.4	A
15b	99	4.12	507.4	A
15c	99	4.22	503.4	A
15d	99	4.27	505.4	A
15e	99	4.34	517.4	A
15f	99	4.41	519.4	A
15g	99	4.51	531.3	A
15h	98	4.17	491.4	B
15i	99	4.17	521.5	B
15j	98	4.39	517.4	B
15k	98	4.48	519.5	B
15l	99	4.58	531.5	B
15m	99	4.64	533.5	B
15n	98	4.73	545.4	B
15o	100	4.38	527.4	C
15p	99	4.51	541.4	C
15q	99	3.8	477.4	A
15r	98	3.93	491.4	B
15s	99	3..93	521.4	B
15t	100	3.94	495.4	A
15u	100	4.02	525.4	A
15v	100	4.16	521.4	A
15w	100	4.19	523.4	A
15x	100	4.27	535.4	A
15y	100	4.32	537.5	A
15z	98	4.38	549.5	A

Tested in Alternative Enzyme Assay: Ex. (15a) 0.023 μM; Ex. (15b) 0.054 μM; Ex. (15c) 0.12 μM; Ex. (15d) 0.12 μM; Ex. (15e) 0.12 μM; Ex. (15f) 0.37 μM; Ex. (15g) 0.12 μM; Ex. (15h) 0.19 μM; Ex. (15i) 0.2 μM; Ex. (15j) 0.31 μM; Ex. (15k) 0.89 μM; Ex. (15l) 0.049 μM; Ex. (15m) 1.4 μM; Ex. (15n) 0.64 μM; Ex. (15o) 0.12 μM; Ex. (15p) 0.5 μM; Ex. (15q) 0.091 μM; Ex. (15r) 0.56 μM; Ex. (15s) 0.67 μM; Ex. (15t) 0.057 μM; Ex. (15u) 0.16 μM; Ex. (15v) 0.14 μM; Ex. (15w) 0.16 μM; Ex. (15x) 0.29 μM; Ex. (15y) 0.44 μM; Ex. (15z) 1.4 μM.

Example 16

The chloro-substrate was reported in Example 11.

The appropriate chloro-substrate (1 equiv) was dissolved in n-butanol (0.055 M). 2-formylfuran-3-boronic acid (1.0 equiv), potassium carbonate (1.2 equiv), and tetrakis(triphenylphosphine)palladium⁰ (0.05 equiv) were added. The reaction vessel was sealed and exposed to microwave radiation (110° C. medium absorption setting) for 15 minutes. Upon completion the reaction mixture was filtered through a silica cartridge and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 40% ethyl acetate in hexane to give the desired product.

3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-furan-2-carbaldehyde: (26% yield, 90% purity) m/z (LC-MS, ESP): 424 [M+H]⁺ R/T=2.81 min

The above product was dissolved in THF (0.018 M) and sodium borohydride (2 equiv) was added. This mixture was allowed to stir at room temperature for 5 minutes. Upon completion the reaction mixture was filtered through a silica cartridge and the filtrate was concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.

	TABLE 16
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Example Structure
16a	96	6.89	426.3

Tested in Alternative Enzyme Assay: Ex. (16a) 0.013 μM.

Example 17

The chloro-substrate was reported in Example 11.

The appropriate chloro-substrate (1 equiv) was dissolved in dioxane (0.16 M). 5-formyl-2-furylboronic acid (1.05 equiv), tripotassium phosphate (1.5 equiv) and bis(tri-t-butylphosphine)palladium (0.05 equiv) were added. The reaction vessel was sealed and exposed to microwave radiation (170° C., medium absorption setting) for 45 minutes. Upon completion the reaction mixture was partitioned between water and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 40 to 100% ethyl acetate in hexane to give the desired product.

5-[2,4-Bis-(3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-furan-2-carboxaldehyde: (100% yield, 100% purity) m/z (LC-MS, ESP): 424 [M+H]⁺ R/T=2.75 min

The appropriate formylfuran-substrate (1 equiv) was dissolved in a THF/CH₂Cl₂ (1:1) solution (0.036 M). The appropriate amines (2.2 equiv) sodium borohydride (2.4 equiv) and acetic acid (0.03 equiv) were added. The reaction mixture was stirred at room temperature for 24 hours. Upon completion the samples were filtered through a silica cartridge, washed with methanol and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

	TABLE 17
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Example Structure
17a	97	3.2	496.4
17b	99	3.32	469.4
17c	99	3.49	439.4
17d	99	3.51	453.4
17e	99	3.58	465.4
17f	97	3.53	509.4
17g	98	3.61	479.4
17h	99	3.56	483.4
17i	95	3.86	491.4
17j	98	3.46	482.4
17k	99	3.54	467.4

Tested in Alternative Enzyme Assay: Ex. (17a) 0.59 μM; Ex. (17b) 0.13 μM; Ex. (17c) 0.091 μM; Ex. (17d) 0.097 μM; Ex. (17e) 0.15 μM; Ex. (17f) 0.12 μM; Ex. (17g) 0.17 μM; Ex. (17h) 0.33 μM; Ex. (17i) 0.079 μM; Ex. (17j) 0.12 μM; Ex. (17k) 0.14 μM.

Example 18

The methylbenzoic ester substrates were reported in Example 11.

Conditions A:

Example 11ba (1 equiv) was dissolved in dioxane (0.16 M). Ethanolamine (51.0 equiv) was added. The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 50 minutes. Upon completion the reaction mixture was concentrated in vacuo. The crude residue was then purified by column chromatography on silica gel using a gradient 0 to 5% MeOH in CH₂Cl₂ to afford the desired product.

Conditions B:

Example 11bg (1 equiv) was dissolved in dioxane (0.05 M). Ethanolamine (2.0 equiv) was added. The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 2×20 minutes. Upon completion the reaction mixture was concentrated in vacuo. The reaction mixture was partitioned between water and CH₂Cl₂ and extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was then purified by column chromatography on silica gel using a gradient 0 to 5% MeOH in CH₂Cl₂ to afford the desired product.

Conditions C:

To a solution of the appropriate carboxylic acid derivative (1 equiv) suspended in CH₂Cl₂ was added HBTU (1.3 equiv) followed by diisopropylethylamine (3 equiv). The mixture was cooled (−78° C.) and the appropriate amine added (1.1 equiv). The mixture was stirred for 3 hrs before being concentrated to dryness and purified by preparative HPLC to give the desire products.

	TABLE 18
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Conditions	Example Structure
18a	100	3.75	493.5	A
18b	99	3.86	523.5	B
18c	97	3.79	465.3	C
18d	98	3.70	507.4	C

NMR Data for Example 18a

¹H NMR (300 MHz, CDCl₃) δ ppm 8.55 (ArH, s, 1H), 8.09 (ArH, d, J=7.85 Hz, 1H), 7.95 (ArH, d, J=8.42 Hz, 1H), 7.86 (ArH, d, J=7.86 Hz, 1H), 7.49-7.33 (ArH, m, 2H), 4.89-4.75 (CH, m, 1H), 4.56-4.46 (CH, m, 1H), 4.38-4.26 (CH₂, m, 1H), 3.97-3.87 (CH₂, m, 2H), 3.85-3.75 (CH₂, m, 4H), 3.72-3.55 (CH₂, m, 7H), 3.53-3.44 (CH₂, m, 1H), 3.34-3.24 (CH₂, m, 1H), 1.41 (CH₃, d, J=6.77 Hz, 3H), 1.28 (CH₃, d, J=6.82 Hz, 3H).

Tested in Alternative Enzyme Assay: Ex. (18a) 0.028 μM; Ex. (18b) 0.079 μM; Ex. (18c) 0.13 μM; Ex. (18d) 2 μM.

Example 19

The benzyl alcohol substrate was reported in Example 11.

Example 11bc (1 equiv) was dissolved in THF (0.022 M). Sodium tert-butoxide (3.0 equiv) and iodomethane (10.0 equiv) were added. The reaction vessel was stirred at room temperature for 48 hours. Upon completion the sample was filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

	TABLE 19
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Example Structure
19a	100	2.87	468.4

Tested in Alternative Enzyme Assay: Ex. (19a) 0.088 μM.

Example 20

The pyridinone substrate was reported in Example 23.

Example 23c (1 equiv) was dissolved in DMF (0.1 M). Potassium carbonate (1.1 equiv) and iodomethane (1.1 equiv) were added. The reaction vessel was stirred at 100° C. for 2 hours. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

	TABLE 20
		Retention
	Purity	time	m/zz
	(%)	(min)	[M + H]+	Example Structure
20a	100	3.67	437.2

Tested in Alternative Enzyme Assay: Ex. (20a) 0.11 μM.

Example 21

The sulfonamide substrate was reported in Example 11.

Example 11at (1 equiv) was dissolved in DMF (0.1 M). Potassium carbonate (2.0 equiv) and iodomethane (1.5 equiv) were added. The reaction vessel was heated at 100° C. for 2 hours. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

	TABLE 21
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Example Structure
21a	87	4.11	513.3

Tested in Alternative Enzyme Assay: Ex. (21a) 0.37 μM.

Example 22

To a solution of the appropriate 7-substituted-1H-pteridine-2,4-dione (1 equiv) in anhydrous toluene (sufficient to make a 0.1 M solution) was added Hunig's base (3 equiv). A reflux condenser was attached to the reaction vessel and the mixture heated, under an inert atmosphere) to 70° C. for 30 minutes. After this time, the reaction was cooled to 40° C. whereupon POCl₃ (3 equiv) was added. The mixture was then heated, with stirring, to 110° C. for 3 hrs. Upon completion, the reaction was cooled and concentrated in vacuo to give a tarry residue which was dissolved in the minimum volume of CH₂Cl₂ and filtered through a thick silica pad. The resulting filtrate was concentrated in vacuo to give the desired 2,4-dichloro-7-substituted-pteridine product (typically 65-99% yield) in suitably pure form to be used without any further purification.

2,4-Dichloro-7-p-tolyl-pteridine; R⁷=toluoyl, R²=Cl, R⁴=Cl, X=N, Y=C, Z=N: (61% yield, 99% purity) m/z (LC-MS, ESP): Did not ionize, R/T=3.27 min

2,4-Dichloro-7-phenyl-pteridine; R⁷=phenyl, R²=Cl, R⁴=Cl, X=N, Y=C, Z=N: (66% yield, 99% purity) m/z (LC-MS, ESP): Did not ionize, R/T=3.10 min

To a cooled (−5° C.) solution of the appropriate amine (1 equiv=R⁴) in N,N-dimethylacetamide (sufficient to make 0.2 M solution) was added the appropriate 2,4-dichloro-7-substituted-pteridine (1 equiv added as a 0.04 M solution in N,N-dimethylacetamide). After approx 10 minutes Hunig's base was added (1 equiv) and the resultant mixture stirred at −5° C. for 30 minutes. After this time, the reaction was allowed to warm to room temperature, whereupon the appropriate amine (1 equiv=R²) and Hunig's base (1 equiv) were then added. The resultant mixture was heated to 60° C. and maintained at this temperature, with stirring, for 16 hours. Upon completion, the mixture was allowed to cool to room temperature before being purified by preparative HPLC to give the desired product.

	TABLE 22
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Example Structure
22a	99	5.33	421.5
22b	96	5.55	435.4
22c	95	10.29	421.3
22d	94	9.48	407.2
22e	94	9.48	356.2

Tested in Alternative Enzyme Assay: Ex. (22a) 0.02669 μM; Ex. (22b) 0.2147 μM; Ex. (22c) 0.04872 μM; Ex. (22d) 0.0263 μM; Ex. (22e) 0.5414 μM.

Example 23

Compounds 23a to 23f

The pyridine substrates were reported in Example 11.

Conditions A:

Example 11w (1 equiv) was dissolved in a dry THF/methanol (1:1) solution (0.057 M). Sodium hydride (4.5 equiv) was added. The reaction mixture was stirred at room temperature for 15 minutes under nitrogen. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 40 minutes. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

Conditions B:

Example 11w (1 equiv) was dissolved in dry THF (0.057 M). Dimethylethanolamine (10.0 equiv) and sodium hydride (5.0 equiv) were added. The reaction mixture was stirred at room temperature for 15 minutes under nitrogen. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 20 minutes. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

Conditions C:

Example 11au (1 equiv) was dissolved in DMSO (0.59 M). 8N aqueous sodium hydroxide solution (50.0 equiv) was added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 20 minutes. Upon completion concentrated aqueous HCl was added carefully. The mixture was neutralized with 2N aqueous sodium hydroxide solution. The suspension was diluted with methanol then filtered through a sintered funnel. The filtrate was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions D:

Example 11au (1 equiv) was dissolved in NMP (0.1 M). Potassium cyanide (20.0 equiv) was added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 46 hours. Upon completion the reaction mixture was partitioned between water and CH₂Cl₂. The aqueous phase was extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 50 to 100% ethyl acetate in hexane to give the desired product.

Conditions E:

Example 11au (1 equiv) was dissolved in NMP (0.1 M). Potassium cyanide (20.0 equiv) was added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 46 hours. Upon completion the reaction mixture was partitioned between water and CH₂Cl₂. The aqueous phase was extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 50 to 100% ethyl acetate in hexane first, then eluting with 10% methanol in CH₂Cl₂. The crude fractions were then further purified by preparative HPLC to give the desired product.

Conditions F:

Example 11ah (1 equiv) was dissolved in NMP (0.1 M). Potassium cyanide (8.0 equiv) was added. The reaction vessel was sealed and the mixture exposed to microwave radiation (180° C., medium absorption setting) for 40 minutes. Upon completion the sample was filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

	TABLE 23
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Conditions	Example Structure
23a	99	4	437.3	A
23b	99	3.42	494.4	B
23c	97	5.77	423.4	C
23d	97	3.96	432.4	D
23e	98	6.62	450.2	E
23f	99	3.93	432.3	F
23g	89	5.03	478.4

Tested in Alternative Enzyme Assay: Ex. (23a) 0.2 μM; Ex. (23b) 0.33 μM; Ex. (23c) 0.14 μM; Ex. (23d) 0.48 μM; Ex. (23e) 0.19 μM; Ex. (23f) 0.16 μM; Ex. (23g) 0.11 μM.

Example 24

The ester substrate was reported in Example 11.

Ester Hydrolysis:

Conditions A

Example 11bg (1 equiv) was dissolved in methanol (0.2 M). 1M Sodium hydroxide aqueous solution (5.0 equiv) was added. The reaction mixture was stirred at room temperature for 3 hours. Upon completion the reaction mixture was neutralised with 1M aqueous HCl and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 10% MeOH in CH₂Cl₂ to give the desired product.

Amide Formation:

Conditions B

Example 11bg (1 equiv) was suspended in THF (0.05 M). Thionyl chloride (2.5 equiv) was added dropwise at 40° C. The reaction mixture was then heated for an hour at 40° C. Ammonia gas was then slowly bubbled into the reaction mixture. THF was then added for further dilution (0.025 M) and the reaction mixture was heated for an hour at 40° C. Upon completion the reaction mixture was cooled down and concentrated in vacuo. The residue was partitioned between water and CH₂Cl₂. The aqueous phase was extracted with CH₂Cl₂. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% MeOH in CH₂Cl₂ to give the desired product.

	TABLE 24
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Conditions	Example Structure
24a	98	3.95	480.5	A
24b	98	7.09	479.4	B

NMR Data for Example 24a

¹H NMR (300 MHz, CDCl₃) δ ppm 8.82-8.69 (ArH, m, 1H), 8.68-8.56 (ArH, m, 1H), 8.03-7.90 (ArH, m, 1H), 7.52-7.39 (ArH, m, 1H), 7.18-7.05 (ArH, m, 1H), 4.92-4.80 (CH, m, 1H), 4.61-4.47 (CH, m, 1H), 4.37-4.27 (CH₂, m, 1H), 4.07 (OCH₃, s, 3H), 4.00-3.87 (CH₂, m, 2H), 3.85-3.60 (CH₂, m, 6H), 3.57-3.24 (CH₂, m, 3H), 1.41 (CH₃, d, J=6.65 Hz, 3H), 1.30 (CH₃, d, J=6.74 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.33, 134.98, 134.96, 132.64, 132.61, 132.58, 119.77, 112.83, 112.11, 100.01, 71.29, 70.90, 67.24, 66.91, 52.80, 46.96, 44.44, 39.34 and 14.74.

NMR Data for Example 24b

¹H NMR (300 MHz, CDCl₃) δ ppm 8.83 (ArH, d, J=2.46 Hz, 1H), 8.64 (ArH, dd, J=8.76, 2.49 Hz, 1H), 8.01 (ArH, d, J=8.47 Hz, 1H), 7.71 (NH, s, br, 1H), 7.57 (ArH, d, J=8.50 Hz, 1H), 7.13 (ArH, d, J=8.83 Hz, 1H), 5.79 (NH, s, br, 1H), 5.00-4.84 (CH, m, 1H), 4.62 (CH, dd, J=13.82, 0.70 Hz, 1H), 4.37 (CH₂, d, J=6.77 Hz, 1H), 4.05 (OCH₃, s, 3H), 4.03-3.94 (CH₂, m, 2H), 3.91-3.79 (CH₂, m, 3H), 3.79-3.63 (CH₂, m, 4H), 3.64-3.51 (CH₂, m, 1H), 3.44-3.30 (CH₂, m, 1H), 1.47 (CH₃, d, J=6.78 Hz, 3H), 1.35 (CH₃, d, J=6.81 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 166.58, 165.45, 162.87, 159.99, 159.22, 134.71, 133.75, 131.84, 131.65, 120.52, 113.07, 111.87, 104.80, 102.94, 71.33, 70.94, 67.29, 66.94, 56.28, 52.80, 46.93, 44.49, 39.33, 14.72 and 14.34.

Tested in Alternative Enzyme Assay: Ex. (24a) 0.00015 μM; Ex. (24b) 0.0032 μM.

Example 25

The chloro-substrate was reported in Example 11.

To a mixture of 7-chloro-4-((S)-3-methyl-morpholin-4-yl)-2-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine (1 equiv), potassium carbonate (1.2 equiv), and 3-BOC-aminophenylboronic acid (1.2 equiv) in acetonitrile/water (1:1) (0.08 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 10 minutes under nitrogen atmosphere. Upon completion the samples were filtered through a silica cartridge, washed with ethyl acetate and then concentrated in vacuo. The crude residue was used as such in the next reaction.

{3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-phenyl}-carbamic acid tert-butyl ester: (95% yield, 100% purity) m/z (LC-MS, ESP): 520.9 [M+H]⁺ R/T=3.23 min

The above product (1 equiv) was dissolved in a TFA/CH₂Cl₂ solution (1:20) (0.018 M). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then concentrated in vacuo. The residue was partitioned between water and CH₂Cl₂. The aqueous phase was neutralized with 1N aqueous sodium hydroxide. Combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was used as such in the next reaction.

3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-phenylamine: (100% yield, 100% purity) m/z (LC-MS, ESP): 520.9 [M+H]⁺ R/T=2.72 min

The above product (1 equiv) was dissolved in THF (0.013 M). Chloroethanesulfonyl chloride (3.5 equiv) was gently added to the reaction mixture at 0° C. and the reaction mixture was stirred at room temperature for 15 hours. 8N Aqueous sodium hydroxide (50 equiv) was then added and the reaction mixture was heated at 40° C. for 12 hours. The reaction mixture was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% MeOH in CH₂Cl₂ to give the desired product.

3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-phenylamine (1 equiv) was dissolved in THF (0.1 M). Pyridine (10 equiv) and isopropylsulfonyl chloride (10 equiv) were added to the reaction mixture at room temperature. The reaction mixture was then stirred at 90° C. for 4 hours. The reaction mixture was partitioned between CH₂Cl₂ and water. Organic phase was dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 60% EtOAc in hexane to give the desired product.

3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-phenylamine (1 equiv) was dissolved in CH₂Cl₂ (0.24 M). Tetrahydro-2-furoic acid (1.1 equiv), HBTU (2.0 equiv) and triethylamine (2 equiv) were added and the reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was partitioned between CH₂Cl₂ and water. Organic phase was dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 4% MeOH in TBME to give the desired product.

	TABLE 25
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Example Structure
25a	98	3.99	529.4
25b	96	8.28	527.3
25c	99	4.19	519.3

NMR Data for Example 25b

¹H NMR (300 MHz), CDCl₃ δ ppm 8.00-7.94 (ArH, m, 2H), 7.81 (ArH, td, J=7.12, 1.52, 1.52 Hz, 1H), 7.45-7.32 (ArH, m, 3H), 6.84 (NH, s, br, 1H), 4.93-4.80 (CH₂, m, 1H), 4.55 (CH₂, d, J=12.97 Hz, 1H), 4.38-4.25 (CH₂, m, 1H), 4.01-3.57 (CH₂, m, 9H), 3.57-3.45 (CH₂, m, 1H), 3.36-3.32 (CH₂, m, 2H), 1.42 (CH₃, d, J=6.78 Hz, 3H), 1.37-1.26 (3×CH₃, m, 9H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.36, 162.85, 161.36, 159.98, 140.27, 137.89, 134.92, 129.80, 124.03, 121.31, 119.64, 113.30, 105.19, 71.28, 70.91, 67.25, 66.91, 52.89, 52.87, 44.42, 39.33, 31.60, 22.66, 16.60, 14.75 and 14.36.

NMR Data for Example 25c

¹H NMR (300 MHz, CD₃COCD₃ δ ppm 8.52 (ArH, s, 1H), 8.24 (ArH, d, J=8.48 Hz, 1H), 7.91-7.80 (ArH, m, 2H), 7.62 (ArH, d, J=8.47 Hz, 1H), 7.46 (ArH, t, J=7.94, 7.94 Hz, 1H), 6.48 (NH, br, s, 1H), 4.84-4.70 (CH₂, m, 1H), 4.53-4.33 (CH₂, m, 3H), 4.09-3.79 (CH₂, m, 5H), 3.80-3.56 (CH₂, m, 5H), 3.49-3.40 (CH₂, m, 1H), 3.23-3.28 (CH₂, m, 1H), 2.20 (CH₂, d, J=6.66 Hz, 1H), 2.11-1.81 (CH₂, m, 4H), 1.39 (CH₃, d, J=6.75 Hz, 3H), 1.26 (CH₃, d, J=6.75 Hz, 3H).

¹³C NMR (75 MHz, CD₃COCD₃) δ ppm 171.66, 160.37, 147.37, 145.71, 138.93, 138.46, 135.69, 128.98, 126.26, 126.11, 122.52, 121.58, 118.91, 118.37, 104.46, 77.93, 70.31, 70.13, 68.81, 66.28, 66.15, 51.77, 46.41, 43.85, 29.98, 25.06, 14.39 and 13.92.

Tested in Alternative Enzyme Assay: Ex. (25a) 0.0043 μM; Ex. (25c) 0.33 μM.

Tested in phospho-Ser473 Akt assay: Ex. (25b) 0.5051 μM.

Example 26

The aminopyridine substrate was reported in Example 11.

Example 11u (1 equiv) was dissolved in pyridine (0.11 M). Acetic anhydride (5.0 equiv) was added and the reaction mixture was heated at 70° C. for 6 hours. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

	TABLE 26
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Example Structure
26a	100	3.8	464.4

NMR Data for Example 26a

¹H NMR (300 MHz, CDCl₃) δ ppm 8.18-8.12 (ArH, m, 2H), 8.05 (ArH, d, J=8.42 Hz, 1H), 7.52-7.40 (ArH, m, 3H), 4.96 (CH, d, br, J=4.93 Hz, 1H), 4.66 (CH, d, br, J=12.90 Hz, 1H), 4.40 (d, br, J=6.71 Hz, 1H), 4.07-3.54 (CH₂, m, 11H), 3.47-3.35 (CH, m, 1H), 1.51 (CH₃, d, J=6.79 Hz, 3H), 1.39 (CH₃, d, J=6.82 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.41, 162.93, 161.83, 160.02, 137.14, 136.13, 134.84, 129.19, 128.77, 112.99, 105.03, 71.29, 70.91, 67.26, 66.91, 52.85, 46.95, 44.46, 39.34, 14.73 and 14.37.

Tested in Alternative Enzyme Assay: Ex. (26a) 0.034 μM.

Example 27

The chloro-substrate was reported in Example 11.

The appropriate chloro-substrate (1 equiv) was dissolved in toluene (0.07 M). Phenol (1.0 equiv), palladium acetate (0.05 equiv), BINAP (0.05 equiv) and tripotassium phosphate (1.0 equiv) were added. The reaction vessel was sealed and exposed to microwave radiation (140° C., medium absorption setting) for 10 minutes. Upon completion the samples was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

	TABLE 27
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Example Structure
27a	93	4.70	436.4

Tested in Alternative Enzyme Assay: Ex. (27a) 0.52 μM.

Example 28

The chloro-substrate was reported in Example 11.

To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), and the appropriate boronic acid (1.1 equiv) in acetonitrile/water (1:1) (0.033 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The suspension was sonicated while degassed with nitrogen for 5 minutes then heated to 95° C. for 2 hours. Upon completion the reaction mixture was allowed to cool down to room temperature. The reaction mixture was concentrated in vacuo to half original volume. The crude residue was extracted with CH₂Cl₂ and the combined organic phases were washed with brine, dried (MgSO₄), filtered and concentrated in vacuo to give a yellow solid. The residue was sonicated in diethyl ether, collected by vacuum filtration to give the desired product as a yellow powder.

{5-[2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl}-methanol: (78% yield, 100% purity) m/z (LC-MS, ESP): 401 [M+H]⁺ R/T=3.47 min

{3-[2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-phenyl}-methanol: (90% yield, 90% purity) m/z (LC-MS, ESP): 371 [M+H]⁺ R/T=4.06 min

Alternatively, to a stirred mixture of bis(pinacolato)diboron (1.05 equiv) and potassium acetate (3 equiv) in N-methylpyrrolidine (13.5 equiv), purged with nitrogen, was added the corresponding bromobenzylalcohol (1 equiv) followed by PdCl₂(dppf) (0.02 equiv). The mixture was then heated to 60° C. and held for 10 min, then heated to 70° C. and held for 15 min and finally heated to 80° C. and held for 1 h. The appropriate chloro-substrate (1 equiv) was then added followed by PdCl₂(dppf) (0.02 equiv) and N-methylpyrrolidine (4.5 equiv). The temperature was then held at 75° C., then 4.3M aqueous potassium carbonate (3.5 equiv) was added over 13 min, then water (12 equiv) was added and the reaction was stirred at 75° C. for 90 min. Water (144 equiv) was then added slowly over 70 min with stirring while the temperature was reduced to 66° C. The temperature of the stirred mixture was then kept at 64° C. for 30 min, then cooled to 20° C. over 2.5 h, and held at 20° C. overnight. The resulting slurry was filtered, and the solid washed first with a 3:1 water:N-methylpyrrolidone mixture (18 equiv of water), then washed with water (24 equiv) and then washed with ethyl actetate (4×4.4 equiv). The solid was then dried in a vacuum oven at 50° C. to leave the title compound in suitable clean form to be used without any further purification. For example, {5-[2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl}-methanol: (73% yield)

Conditions A:

The appropriate chloro-substrate (1 equiv) was dissolved in DMA (0.04 M). Tripotassium phosphate (1.5 equiv) and the appropriate nucleophile (secondary amine) (1.5 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (200° 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 give the desired products.

Conditions B:

The appropriate chloro-substrate (1 equiv) was suspended in a propan-2-ol and aqueous ammonia (1:3) solution (0.02 M). The reaction vessel was sealed and the mixture exposed to microwave radiation (140° C., medium absorption setting) for 20 minutes. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions C:

The appropriate chloro-substrate (1 equiv) was dissolved in dioxane (0.04 M). Diisopropylethylamine (5.0 equiv) and the appropriate nucleophile (secondary amine) (1.5 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 20 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions D:

The appropriate chloro-substrate (1 equiv) was dissolved in dioxane (0.04 M). Tripotassium phosphate (3.0 equiv), xantphos (0.05 equiv), palladium acetate (0.05 equiv) and the appropriate nucleophile (amine) (1.5 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (150° C., medium absorption setting) for 20 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 give the desired products.

Conditions E:

The appropriate chloro-substrate (1.0 equiv) was dissolved in dioxane (0.04 M). Diisopropylethylamine (5.0 equiv) and the appropriate nucleophile (secondary amine, with BOC-protected amino side chain) (1.5 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 20 minutes. Upon completion the samples were concentrated in vacuo. To the crude residue was then added a 4 M solution of HCl in dioxane (0.15 M). The reaction mixtures were stirred at room temperature for 3 hours. Upon completion the samples were basified with a 2 N sodium hydroxide solution. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions F:

The appropriate nucleophile (substituted imidazole) (10.0 equiv) was dissolved in DMF (0.4 M). Sodium hydride (5.0 equiv) was then added. The reaction mixture was stirred at room temperature for 10 minutes under nitrogen and a solution of the appropriate chloro-substrate (1.0 equiv) in DMF (0.075 M) was added. The reaction vessel was sealed and the mixture exposed to microwave radiation (150° C., medium absorption setting) for 30 minutes. Upon completion the samples were filtered through a silica cartridge, eluted with CH₂Cl₂ and then concentrated in vacuo. The crude residue were then purified by preparative HPLC to give the desired products.

Conditions G:

The appropriate chloro-substrate (1 equiv) was dissolved in dioxane (0.04 M). Diisopropylethylamine (5.0 equiv) and the appropriate nucleophile (secondary amine) (4.5 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 40 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions H:

The appropriate chloro-substrate (1 equiv) was dissolved in dioxane (0.04 M). Diisopropylethylamine (5.0 equiv) and the appropriate nucleophile (secondary amine) (10.0 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 60 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions I:

The appropriate chloro-substrate (1 equiv) was dissolved in a solution of 1% DMA in dioxane (0.04 M). Diisopropylethylamine (5.0 equiv) and the appropriate nucleophile (secondary amine) (10.0 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (180° C., medium absorption setting) for 60 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions J:

The appropriate chloro-substrate (1 equiv) was dissolved in a solution of 1% DMA in dioxane (0.04 M). Diisopropylethylamine (7.0 equiv) and the appropriate nucleophile (secondary amine) (3.0 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (150° C., medium absorption setting) for 60 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions K:

The appropriate chloro-substrate (1 equiv) was dissolved in DMF (0.075 M). Potassium carbonate (5.0 equiv) and the appropriate nucleophile (alcohol) (10.0 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (120° C., medium absorption setting) for 20 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions L:

The appropriate chloro-substrate (1 equiv) was dissolved in DMF (0.075 M). Potassium carbonate (5.0 equiv) and the appropriate nucleophile (alcohol) (20.0 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (150° C., medium absorption setting) for 40 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions M:

The appropriate chloro-substrate (1 equiv) was dissolved in DMA (0.13 M). Diisopropylethylamine (2.0 equiv) and the appropriate nucleophile (amine) (2.0 equiv) were then added. The reaction vessel was heated to 100° C. for 3 hours. Upon completion, the reaction mixture was partitioned between dichloromethane and water and the aqueous layer further extracted with dichloromethane. The combined organic phases were dried (MgSO₄), filtered and the filtrate was concentrated in vacuo to give a yellow residue which was purified by recrystallisation from diethyl ether.

Conditions N:

5-[2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine (1 equiv) was dissolved in DMA (0.21 M). Diisopropylethylamine (1.0 equiv) and the appropriate nucleophile (amine) (1.1 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 10 minutes. Upon completion, the reaction mixture was partitioned between dichloromethane and water and the aqueous layer further extracted with CH₂Cl₂. The combined organic phases were dried (MgSO₄), filtered and the filtrate was concentrated in vacuo to give a yellow residue which was purified by column chromatography on silica gel eluting with 0% to 10% MeOH in CH₂Cl₂ to give the desired product.

Conditions O:

The appropriate chloro-substrate (1 equiv) was dissolved in DMA (0.16 M). Diisopropylethylamine (1.0 equiv) and the appropriate nucleophile (amine) (1.2 equiv) were then added. The reaction vessel was heated to 80° C. for 48 hours. Upon completion, the reaction mixture was partitioned between ethyl acetate and water and the organic layer washed with brine. The combined organic phases were dried (MgSO₄), filtered and the filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC to give the desired product.

Conditions P:

The appropriate chloro-substrate (1 equiv) was dissolved in anisole (0.25 M) (10 vol). Diisopropylethylamine (1.3 equiv) and the appropriate nucleophile (amine) (1.3 equiv) were then added. The reaction vessel was heated to 125° C. and stirred for 11 h. Upon completion, the reaction mixture was allowed to cool to 50° C. Aqueous 20% citric acid solution (7 vol) was added, stirred for 5 min and then allowed to separate partitioned. The aqueous layer was removed and retained. The organic layer was then extracted with a further aliquot of aqueous 20% citric acid solution (3 vol). The organic layer discarded, and the aqueous layers combined. The combined aqueous layers were washed first with anisole (5 vol), then 50% aqueous sodium hydroxide solution (1.23 vol) was added slowly. The resulting aqueous phase was extracted with ethyl acetate (10 vol). The aqueous layer was discarded and the organic layer was washed first with 10% aqueous sodium hydroxide solution (5 vol) and then water (5 vol). The organic layer was then slurried with silicycle Si-thiourea scavenger at 50° C. for 2 h, then the scavenger was filtered off and washed with ethyl actetate (2×1 vol). The organic phase was cooled to 20° C., seeded to start crystallization and stirred until a slurry obtained. The slurry was heated to 50° C. under vacuum and ethyl acetate (3 vol) was removed by vacuum distillation. 2-Methylpentane (3.4 vol) was added and the mixture heated to 60° C. and then slowly cooled to 20° C. over 2 h. The resulting slurry was filtered, and the solid washed with 1:1 ethyl actetate:pentane (2×0.5 vol). The solid was then dried in a vacuum oven at 50° C. to leave the desired product. For example, compound 1a was obtained (50.4% yield). The crude product (1 equiv) was dissolved in DMSO (5 vol based on product weight) at 50° C. Water (2 vol) was added and the mixture stirred at 50° C. until product crystallizes. The slurry was heated to 60° C. and then water (3 vol) was added slowly over 30 min so that the temperature was maintained at 60° C. The mixture was slowly cooled to 20° C. over 2h, and then held at 20° C. for 30 min. The resulting slurry was filtered, and the solid washed with 2:1 water:DMSO (0.5:1 vol), and then water (3×2 vol). The solid was then dried in a vacuum oven at 50° C. to leave the desired product.

	TABLE 28
	Purity	Retention	m/z
	(%)	time (min)	[M + H]+	Conditions	Example Structure
28a	91	4.43	464.5	A
28b	98	3.89	382.4	B
28c	96	4.36	450.4	C
28d	97	4.48	464.4	C
28e	93	3.56	479.4	C
28f	97	4.45	542.4	C
28g	97	4.11	494.4	C
28h	98	4.60	518.4	C
28i	96	4.54	464.4	C
28j	98	4.83	526.4	C
28k	93	3.96	466.4	C
28l	79	8.73	559.5	D
28m	94	4.28	458.5	D
28n	99	3.86	460.5	D
28o	92	6.48	459.3	D
28p	91	9.79	459.3	D
28q	91	8.03	436.3	C
28r	86	8.77	522.4	C
28s	81	5.59	479.4	C
28t	88	9.14	464.4	C
28u	91	8.76	522.4	C
28v	92	6.73	493.4	C
28w	87	9.69	584.5	C
28x	80	7.26	480.4	C
28y	85	7.41	480.4	C
28z	95	5.67	533.4	C
28aa	88	6.79	510.3	C
28ab	93	6.81	452.3	C
28ac	93	5.44	535.4	C
28ad	99	5.40	465.5	E
28ae	94	9.86	478.4	C
28af	94	9.11	518.3	C
28ag	72, 25	10.37,10.81	504.4	C
28ah	94	7.56	494.3	C
28ai	96	5.55	519.4	C
28aj	99	7.82	480.4	C
28ak	96	10.49	588.4	C
28al	96	10.92	540.4	C
28am	97	8.84	542.4	C
28an	95	9.74	551.4	C
28ao	96	6.18	479.3	C
28ap	92	8.46	450.3	C
28aq	97	10.99	560.4	C
28ar	89	8.12	532.4	C
28as	91	5.71	507.4	C
28at	99	10.88	679.4	C
28au	85	5.37	465.4	E
28av	98	4.54	466.6	C
28aw	98	4.30	450.5	C
28ax	99	4.02	454.5	C
28ay	100	3.83	433.4	F
28az	92	9.32	491.4	F
28ba	93	4.54	475.4	F
28bb	100	5.06	511.4	F
28bc	97	10.48	525.3	F
28bd	10, 89	4.70,4.77	492.5,492.5	C
28be	99	4.67	526.6	C
28bf	99	4.48	528.5	C
28bg	98	4.38	464.5	C
28bh	98	4.37	464.5	C
28bi	100	3.56	527.5	C
28bj	99	3.84	466.4	C
28bk	99	3.83	466.4	C
28b1	95	9.06	500.5	C
28bm	98	7.65	480.5	C
28bn	97	3.78	452.5	C
28bo	95	4.03	454.4	C
28bp	98	4.01	396.4	H
28bq	99	4.14	410.4	G
28br	99	4.30	424.4	H
28bs	93	5.27	426.4	C
28bt	94	7.18	428.3	H
28bu	84	5.95	439.3	I
28bv	91	4.91	439.4	C
28bw	94	5.38	440.4	G
28bx	94	5.40	440.4	G
28by	92	5.44	440.4	C
28bz	97	5.52	446.3	H
28ca	90	4.92	451.4	C
28cb	93	4.95	453.4	C
28cc	96	5.50	454.4	H
28cd	92	5.18	456.4	H
28ce	96	5.37	463.4	G
28cf	91	5.31	465.4	G
28cg	92	4.95	465.4	C
28ch	93	5.73	468.3	C
28ci	99	4.95	495.4	C
28cj	97	5.79	498.4	G
28ck	91	5.28	470.3	G
28cl	93	5.57	466.3	C
28cm	92	5.58	466.3	C
28cn	97	6.87	447.3	F
28co	93	6.70	479.2	C
28cp	92	6.18	453.2	J
28cq	92	6.18	453.1	J
28cr	92	6.72	440.2	C
28cs	97	7.84	468.3	I
28ct	98	5.38	467.3	I
28cu	98	6.63	397.2	K
28cv	88	7.17	411.2	L
28cw	100	6.24	427.2	K
28cx	83	6.87	441.2	L
28cy	93	5.45	454.2	K
28cz	97	5.72	468.3	K
28da	98	7.96	489.3	K
28db	98	6.73	440.3	K
28dc	96	8.26	436.2	K
28dd	95	4.05	452.4	J
28de	93	5.36	438.2	A
28df	93	11.22	452.3	A
28dg	96	4.86	438.4	A
28dh	100	4.66	454.4	A
28di	100	4.37	426.4	A
28dj	98	7.86	467.4	M
28dk	97	4.77	463.2	N
28dl	99	4.78	408.1	N
28dm	97	4.89	477.3	N
28dn	97	4.03	466.2	O
28do	99	3.99	466.2	O

NMR Data for Example 28b

¹H NMR (300 MHz, CDCl₃) δ ppm 8.85 (ArH, d, J=2.46 Hz, 1H), 8.64 (ArH, dd, J=8.75, 2.48 Hz, 1H), 8.30 (OH, s, br, 1H), 8.04 (ArH, d, J=8.47 Hz, 1H), 7.59 (ArH, d, J=8.54 Hz, 1H), 7.14 (ArH, d, J=8.83 Hz, 1H), 5.03-4.91 (CH₂, m, 1H), 4.66 (CH₂, dd, J=13.05, 0.77 Hz, 1H), 4.41 (CH₂, d, J=6.75 Hz, 1H), 4.07 (OCH₃, s, 3H), 4.04-3.98 (CH₂, m, 1H), 3.97-3.68 (CH₂, m, 11H), 3.60 (CH₂, d, J=2.75 Hz, 1H), 3.41 (CH₂, s, 1H), 1.50 (CH₃, d, J=6.77 Hz, 3H), 1.39 (CH₃, d, J=6.81 Hz, 3H)

NMR Data for Example 28k

¹H NMR (300 MHz, CHCl₃) δ ppm 10.59-10.51 (OH, m, 1H), 8.18 (ArH, dd, J=4.42, 2.17 Hz, 2H), 7.99 (ArH, d, J=8.45 Hz, 1H), 7.44 (ArH, d, J=8.48 Hz, 1H), 7.01 (ArH, d, J=9.22 Hz, 1H), 4.81 (CH₂OH, s, 2H), 4.37-4.11 (CH₂, m, 3H), 4.09-3.65 (OCH₃+CH₂, m, 13H), 2.02-1.94 (CH₂, m, 1H), 1.73-1.38 (CH₂, m, 1H), 1.50 (CH₃, d, J=6.77 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 162.05, 161.84, 161.81, 159.16, 150.47, 134.52, 129.29, 128.68, 128.43, 127.47, 117.04, 112.75, 110.28, 104.93, 104.30, 70.96, 67.12, 66.95, 66.77, 61.97, 55.57, 52.75, 50.99, 44.48 and 14.72.

NMR Data for Example 28v

¹H NMR (300 MHz, CDCl₃) δ ppm 8.07 (ArH, dd, J=7.09, 2.14 Hz, 2H), 7.89 (ArH, d, J=8.47 Hz, 1H), 7.33 (ArH, d, J=8.49 Hz, 1H), 6.91 (ArH, d, J=9.31 Hz, 1H), 6.88 (NH, S, Br, 1H), 5.34 (NH, s, Br, 1H), 4.95 (CH₂, dd, J=12.22, 0.66 Hz, 2H), 4.70 (CH₂OH, s, 2H), 4.34-4.20 (CH, m, 1H), 3.93-3.53 (OCH₃, +CH₂, m, 10H), 2.91 (CH₂, d, J=12.29 Hz, 2H), 2.38 (CH₂, s, 2H), 1.89 (CH₂, dd, J=6.92, 6.38 Hz, 2H), 1.76-1.54 (CH₂, m, 3H), 1.38 (CH₃, d, J=6.76 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 176.91, 165.39, 162.98, 161.80, 160.14, 159.13, 134.52, 131.20, 129.28, 128.84, 128.44, 119.99, 112.70, 110.26, 104.34, 70.97, 67.10, 66.94, 61.97, 55.57, 52.76, 44.52, 43.73, 43.69, 43.16, 26.88, and 14.70.

NMR Data for Example 28ab

¹H NMR (300 MHz, CDCl₃) δ ppm 8.19 (ArH, d, J=7.14 Hz, 2H), 8.00 (ArH, d, J=8.47 Hz, 1H), 7.43 (ArH, d, J=8.42 Hz, 1H), 7.01 (ArH, d, J=9.13 Hz, 1H), 4.82 (CH₂OH, s, 2H), 4.71-4.59 (CH₂, m, 1H), 4.47-4.35 (CH₂, m, 1H), 3.97 (OCH₃, s, 3H), 3.85 (CH₂, ddd, J=17.63, 13.74, 9.24 Hz, 8H), 2.12 (CH₂, s, Br, 5H), 1.50 (CH₃ d, J=6.75 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) ppm 159.35, 159.10, 134.61, 131.26, 129.22, 128.89, 128.54, 112.41, 110.21, 104.39, 71.06, 66.95, 61.99, 55.56, 52.80, 44.51, 27.01 and 14.78.

NMR Data for Example 28ax

¹H NMR (300 MHz, CDCl₃) δ ppm 8.27-8.17 (ArH, m, 2H), 8.00 (ArH, d, J=8.50 Hz, 1H), 7.45 (ArH, d, J=8.51 Hz, 1H), 7.01 (ArH, d, J=8.65 Hz, 1H), 5.40 (NH, br, s, 1H), 4.81 (CH₂OH, s, 2H), 4.49-4.35 (CH₂, m, 1H), 3.97 (OCH₃, s, 3H), 3.93-3.64 (CH₂, m, 6H), 3.58-3.48 (CH₂, m, 2H), 3.43 (OCH₃, s, 3H), 1.49 (CH₃, d, J=6.71 Hz, 3H), 1.34 (CH₃, d, J=6.68 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.67, 161.56, 160.64, 159.19, 134.53, 129.27, 128.83, 128.39, 112.53, 110.30, 76.23, 70.98, 67.00, 62.02, 59.18, 55.57, 52.73, 44.31, 18.23, 18.20 and 14.85.

NMR Data for Example 28bn

¹H NMR (300 MHz, CDCl₃) δ ppm 8.23-8.15 (ArH, m, 2H), 7.99 (ArH, d, J=8.45 Hz, 1H), 7.42 (ArH, d, J=8.46 Hz, 1H), 7.00 (ArH, d, J=8.35 Hz, 1H), 4.81 (CH₂OH, s, 2H), 4.65 (CH, s, br, 1H), 4.05-3.64 (OCH₃+CH₂, m, 13H), 3.24 (OH, s, 1H), 1.50 (CH₃, d, J=6.73 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.18, 162.87, 159.34, 159.06, 134.57, 131.25, 129.26, 128.84, 128.47, 112.36, 110.20, 104.35, 71.00, 70.97, 66.94, 61.91, 55.55, 52.82, 44.43, 27.01 and 14.87.

NMR Data for Example 28bo

¹H NMR (300 MHz, CDCl₃) δ ppm 8.28-8.17 (ArH, m, 2H), 8.00 (ArH, d, J=8.49 Hz, 1H), 7.45 (ArH, d, J=8.50 Hz, 1H), 7.02 (ArH, d, J=8.60 Hz, 1H), 5.51-5.34 (CH, m, 1H), 4.81 (CH₂OH, s, 2H), 4.47-4.34 (CH, m, 1H), 4.00 (CH₂, d, J=1.94 Hz, 1H), 3.97 (OCH₃, s, 3H), 3.93-3.89 (CH₂, m, 2H), 3.83-3.63 (CH₂, m, 4H), 3.53 (CH₂, d, br, J=4.02 Hz, 2H), 3.43 (OCH₃, s, 3H), 1.50 (CH₃, d, J=6.73 Hz, 3H), 1.34 (CH₃, d, J=6.69 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.69, 161.55, 160.67, 159.19, 134.52, 131.15, 129.26, 128.84, 128.41, 119.72, 112.58, 110.30, 70.98, 67.12, 67.00, 62.05, 59.18, 55.58, 52.73, 44.32, 18.20 and 14.84.

NMR Data for Example 28dj

¹H NMR (300 MHz, CDCl₃) δ ppm 8.10-8.03 (ArH, m, 2H), 7.95 (ArH, d, J=8.41 Hz, 1H), 7.42-7.30 (ArH, m, 3H), 5.52-5.27 (NH₂, m, br, 2H), 4.98 (CH₂, dd, J=12.74, 0.96 Hz, 2H), 4.31-4.29 (CH, m, 1H), 3.97-3.55 (CH₂, m, 8H), 3.07-2.86 (CH₂, m, 2H), 2.45-2.35 (CH₂, m, 1H), 1.99-1.88 (CH₂, m, br, 2H), 1.70 (CH₂, m, 2H), 1.41 (CH₃, d, J=6.76 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 176.75, 170.03, 165.35, 162.99, 161.12, 160.17, 137.17, 136.10, 134.83, 129.19, 128.76, 112.81, 104.86, 100.00, 70.95, 67.12, 66.91, 52.83, 44.50, 43.72, 43.68, 43.10, 28.88 and 14.73.

NMR Data for Example 28dk

¹H NMR (300 MHz, CDCl₃ δ ppm 8.67 (ArH, d, J=1.86 Hz, 1H), 8.38 (ArH, dd, J=8.76, 2.36 Hz, 1H), 8.29 (NH, s, weak signal, 1H), 7.91 (ArH, d, J=8.45 Hz, 1H), 7.27 (ArH, d, J=8.46 Hz, 1H), 6.58 (ArH, d, J=8.75 Hz, 1H), 5.54-5.45 (CH₂, m, 1H), 4.97 (NH₂, br, s, 2H), 4.37-4.24 (CH₂, m, 1H), 3.97-3.54 (CH₂, m, 6H), 3.09-2.87 (CH₂, m, 2H), 2.77 (NHCH₃, d, J=4.82 Hz, 3H), 2.42-2.24 (CH₂, m, 1H), 1.87 (CH₂, d, J=0.84 Hz, 2H), 1.79-1.59 (CH₂, m, 2H), 1.40 (CH₃, d, J=6.76 Hz, 3H).

NMR Data for Example 28dl

¹H NMR (300 MHz, CDCl₃ δ ppm 8.68 (ArH, d, J=1.98 Hz, 1H), 8.49 (ArH, dd, J=8.87, 2.32 Hz, 1H), 8.38 (NH, s, br, weak signal 1H), 7.99 (ArH, d, J=8.47 Hz, 1H), 7.34 (ArH, d, J=8.49 Hz, 1H), 6.67 (ArH, d, J=8.85 Hz, 1H), 4.38 (CH₂, d, J=6.77 Hz, 1H), 4.05-3.82 (CH₂, m, 7H), 3.81-3.62 (CH₂, m, 7H), 1.47 (CH₃, d, J=6.77 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ ppm 165.16, 162.79, 160.31, 159.09, 158.45, 143.98, 139.12, 135.00, 124.48, 111.80, 110.03, 104.70, 70.92, 67.00, 66.90, 52.81, 44.57, 44.40 and 14.78.

NMR Data for Example 28dm

¹H NMR (300 MHz, CDCl₃ δ ppm 8.67 (ArH, d, J=2.05 Hz, 1H), 8.36 (ArH, dd, J=8.76, 2.27 Hz, 1H), 7.90 (ArH, dd, J=8.45, 2.12 Hz, 1H), 7.26 (ArH, dd, J=8.47, 0.73 Hz, 1H), 6.57 (ArH, d, J=8.76 Hz, 1H), 5.10-4.87 (NH₂, m, 2H), 4.37-4.22 (CH₂, m, 1H), 3.96-3.51 (CH₂, m, 6H), 3.08 (NCH₃+CH₂, s, 4H), 2.95-2.91 (NCH₃, s, 3H), 2.80-2.59 (CH₂, m, 11H), 1.76 (CH₂, d, J=2.61 Hz, 3H), 1.64-1.44 (CH, m, 1H), 1.38 (CH₃, t, J=6.34, 6.34 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ ppm 173.59, 165.46, 165.31, 163.03, 160.17, 158.89, 145.99, 138.35, 134.76, 124.89, 111.71, 109.15, 104.41, 70.96, 66.96, 52.81, 46.85, 44.38, 39.43, 37.26, 35.56, 28.06, 24.95 and 14.71.

NMR Data for Example 28dn

¹H NMR (300 MHz, CDCl₃ δ ppm 8.10 (ArH, d, J=7.89 Hz, 2H), 7.97 (ArH, d, J=8.49 Hz, 1H), 7.42 (ArH, d, J=8.46 Hz, 1H), 6.98 (ArH, d, J=8.55 Hz, 1H), 4.88 (CH₂, d, J=5.25 Hz, 1H), 4.77 (CH₂OH, s, 2H), 4.56 (CH₂, d, J=13.38 Hz, 1H), 4.38-4.36 (CH₂, m, 1H), 4.02-3.51 (OCH₃+CH₂, m, 1H), 3.43-3.33 (CH₂, m, 1H), 1.47 (CH₃, d, J=6.77 Hz, 3H), 1.35 (CH₃, d, J=6.78 Hz, 3H).

¹³C NMR (75 MHz, CD₃COCD₃) δ ppm 165.11, 162.27, 161.87, 159.54, 159.23, 134.74, 130.76, 129.41, 128.86, 128.39, 113.09, 110.32, 104.45, 71.20, 70.95, 67.17, 66.91, 61.80, 55.57, 52.82, 47.05, 44.44, 39.45, 14.74 and 14.44.

NMR Data for Example 28do

¹H NMR (300 MHz, CDCl₃ δ ppm 8.10 (ArH, d, J=8.76 Hz, 2H), 7.98 (ArH, d, J=8.49 Hz, 1H), 7.42 (ArH, d, J=8.46 Hz, 1H), 6.97 (ArH, d, J=8.37 Hz, 1H), 4.88 (CH₂, d, J=5.46 Hz, 1H), 4.77 (CH₂OH, s, 2H), 4.58-4.49 (CH₂, m, 1H), 4.39-4.36 (CH₂, d J=7.41 Hz, 1H), 4.02-3.51 (OCH₃+CH₂, m, 11H), 3.43-3.33 (CH₂, m, 1H), 1.48 (CH₃, d, J=6.78 Hz, 3H), 1.35 (CH₃, d, J=6.78 Hz, 3H).

¹³C NMR (75 MHz, CD₃COCD₃) δ ppm 165.05, 161.87, 159.45, 159.24, 134.78, 130.70, 129.44, 128.86, 128.38, 113.14, 110.33, 104.43, 71.19, 70.95, 67.16, 66.90, 61.77, 55.57, 52.82, 47.08, 44.44, 39.47, 14.76 and 14.44.

Tested in Alternative Enzyme Assay: Ex. (28a) 0.03 μM; Ex. (28b) 0.1 μM; Ex. (28c) 0.066 μM; Ex. (28d) 0.15 μM; Ex. (28e) 0.039 μM; Ex. (28f) 0.038 μM; Ex. (28g) 0.031 μM; Ex. (28h) 0.23 μM; Ex. (28i) 0.03 μM; Ex. (28j) 0.088 μM; Ex. (28k) 0.019 μM; Ex. (28l) 0.097 μM; Ex. (28m) 0.042 μM; Ex. (28n) 0.31 μM; Ex. (28o) 0.51 μM; Ex. (28p) 0.25 μM; Ex. (28q) 0.11 μM; Ex. (28r) 0.18 μM; Ex. (28s) 0.037 μM; Ex. (28t) 0.054 μM; Ex. (28u) 0.073 μM; Ex. (28v) 0.014 μM; Ex. (28w) 0.25 μM; Ex. (28x) 0.014 μM; Ex. (28y) 0.023 μM; Ex. (28z) 0.088 μM; Ex. (28aa) 0.019 μM; Ex. (28ab) 0.012 μM; Ex. (28ac) 0.014 μM; Ex. (28ad) 0.078 μM; Ex. (28ae) 0.034 μM; Ex. (28af) 0.23 μM; Ex. (28ag) 0.25 μM; Ex. (28ah) 0.03 μM; Ex. (28ai) 0.063 μM; Ex. (28aj) 0.022 μM; Ex. (28ak) 0.42 μM; Ex. (28al) 0.36 μM; Ex. (28am) 0.077 μM; Ex. (28an) 0.14 μM; Ex. (28ao) 0.073 μM; Ex. (28ap) 0.013 μM; Ex. (28aq) 0.19 μM; Ex. (28ar) 0.079 μM; Ex. (28as) 0.08 μM; Ex. (28at) 0.78 μM; Ex. (28au) 0.11 μM; Ex. (28av) 0.27 μM; Ex. (28aw) 0.058 μM; Ex. (28ax) 0.026 μM; Ex. (28ay) 0.087 μM; Ex. (28az) 0.092 μM; Ex. (28ba) 0.16 μM; Ex. (28bb) 0.65 μM; Ex. (28bc) 0.043 μM; Ex. (28bd) 0.19 μM; Ex. (28be) 0.79 μM; Ex. (28bf) 0.077 μM; Ex. (28bg) 0.047 μM; Ex. (28bh) 0.04 μM; Ex. (28bi) 0.32 μM; Ex. (28bj) 0.024 μM; Ex. (28bk) 0.022 μM; Ex. (28bl) 0.61 μM; Ex. (28bm) 0.025 μM; Ex. (28bn) 0.01 μM; Ex. (28bo) 0.058 μM; Ex. (28 bp) 0.049 μM; Ex. (28bq) 0.072 μM; Ex. (28br) 0.03 μM; Ex. (28bs) 0.042 μM; Ex. (28bt) 0.062 μM; Ex. (28bu) 0.047 μM; Ex. (28bv) 0.11 μM; Ex. (28bw) 0.031 μM; Ex. (28bx) 0.035 μM; Ex. (28by) 0.039 μM; Ex. (28bz) 0.01 μM; Ex. (28ca) 0.0026 μM; Ex. (28cb) 0.25 μM; Ex. (28cc) 0.018 μM; Ex. (28cd) 0.025 μM; Ex. (28ce) 0.37 μM; Ex. (28cf) 0.013 μM; Ex. (28cg) 0.067 μM; Ex. (28ch) 0.078 μM; Ex. (28ci) 0.068 μM; Ex. (28cj) 0.055 μM; Ex. (28ck) 0.0095 μM; Ex. (28cl) 0.023 μM; Ex. (28cm) 0.029 μM; Ex. (28cn) 0.013 μM; Ex. (28co) 0.0052 μM; Ex. (28 cp) 0.0057 μM; Ex. (28cq) 0.027 μM; Ex. (28cr) 0.0063 μM; Ex. (28cs) 0.0047 μM; Ex. (28ct) 0.097 μM; Ex. (28cu) 0.08 μM; Ex. (28cv) 0.043 μM; Ex. (28cw) 0.034 μM; Ex. (28cx) 0.024 μM; Ex. (28cy) 0.12 μM; Ex. (28cz) 0.079 μM; Ex. (28da) 0.71 μM; Ex. (28db) 0.0031 μM; Ex. (28dc) 0.21 μM; Ex. (28dd) 0.028 μM; Ex. (28de) 0.26 μM; Ex. (28df) 0.4 μM; Ex. (28dg) 0.3 μM; Ex. (28dh) 0.15 μM; Ex. (28di) 0.15 μM; Ex. (28dj) 0.052 μM; Ex. (28dm) 0.061 μM; Ex. (28dn) 0.0094 μM; Ex. (28do) 0.026 μM.

Tested in phospho-Ser473 Akt assay: Ex. (28dk) 0.6821 μM; Ex. (28dl) 0.2951 μM.

Example 29

The chloro-substrates were reported in Example 28.

(Compounds 29a to 29x)

Conditions A:

To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.5 equiv), and the appropriate boronic acid (1.0 equiv) in acetonitrile/water (1:1) (0.026 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The reaction vessel was sealed and heated at 95° C. for 2 hours. Upon completion the samples were filtered through a silica cartridge, washed with CH₂Cl₂ and methanol and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions B:

To a mixture of the appropriate chloro-substrate (1 equiv), cesium fluoride (3.5 equiv), and the appropriate boronic acid (1.0 equiv) in acetonitrile (0.026 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The reaction vessel was sealed and heated at 95° C. for 2 hours. Upon completion the samples were filtered through a silica cartridge, washed with CH₂Cl₂ and methanol and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions C:

To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), and the appropriate pinacolate boron ester or boronic acid (1.1 equiv) in acetonitrile/water (1:1) (0.041 M of chloro-substrate) was added tetrakis(triphenylphosphine) palladium⁰ (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (150° C., medium absorption setting) for 30 minutes under nitrogen atmosphere. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

	TABLE 29
	Purity	Retention	m/z
	(%)	time (min)	[M + H]+	Conditions	Example Structure
29a	93	7.66	433.2	A
29b	88	8.95	471.3	A
29c	79	7.54	473.3	A
29d	92	11.14	519.3	A
29e	99	6.14	472.3	A
29f	90	7.43	458.3	A
29g	84	10.52	532.3	A
29h	75	9.58	501.3	B
29i	94	11.13	488.3	A
29j	84	7.36	444.3	A
29k	88	7.33	486.3	A
29l	88	8.75	487.3	A
29m	93	11.64	511.3	A
29n	87	9.26	457.3	A
29o	89	9.05	473.3	A
29p	97	4.31	444.3	C
29q	95	4.13	414.2	C
29r	94	4.14	414.2	C
29s	97	4.43	444.2	C
29t	98	4.28	444.2	C
29u	87	4.41	432.2	C
29v	98	4.07	417.2	C
29w	96	4.12	445.3	C
29x	99	5.66	418.2	A

NMR Data for Example 29j

¹H NMR (300 MHz, DMSO) δ ppm 9.63 (ArH, d, J=1.49 Hz, 1H), 8.84-8.69 (ArH, m, 2H), 8.49-8.37 (ArH, m, 1H), 8.19 (ArH, dd, J=8.61, 2.35 Hz, 1H), 8.00 (ArH, d, J=8.76 Hz, 1H), 7.57 (ArH, ddd, J=7.99, 4.81, 0.71 Hz, 1H), 7.15 (ArH, d, J=8.71 Hz, 1H), 5.23 (ArH, dd, J=2.03, 1.13 Hz, 1H), 5.23 (CH, m, 1H), 4.78 (CH, d, J=6.83 Hz, 1H), 4.61 (CH₂OH, s, 2H), 4.22 (CH₂, d, J=13.08 Hz, 1H), 4.03-3.92 (CH₂, m, 1H), 3.98 (OCH₃, s, 3H), 3.88-3.61 (CH₂, m, 3H), 2.50 1.49 (CH₃, d, J=6.79 Hz, 3H)

¹³C NMR (75 MHz, DMSO) δ ppm 164.91, 161.77, 161.25, 160.36, 158.71, 151.75, 149.97, 136.10, 133.86, 131.45, 129.97, 127.92, 126.79, 124.08, 117.24, 110.92, 108.15, 70.77, 66.83, 66.80, 58.39, 56.04, 52.15, 44.39 and 15.24.

NMR Data for Example 29x

¹H NMR (300 MHz, CDCl₃) δ ppm 9.86-9.80 (ArH, m, 1H), 9.00-8.91 (ArH, m, 1H), 8.77 (ArH, dd, J=4.80, 1.71 Hz, 3H), 8.28 (ArH, ddd, J=9.24, 8.03, 5.57 Hz, 1H), 7.83 (ArH, d, J=8.64 Hz, 2H), 7.60-7.53 (ArH, m, 2H), 7.53-7.43 (CH, m, 1H), 4.72 (CH₂, d, J=6.93 Hz, 1H), 4.33-4.23 (CH₂, m, 1H), 4.00-3.80 (CH₂, m, 4H), 1.65 (CH₃, d, J=6.81 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ ppm 164.55, 161.73, 161.53, 151.52, 150.66, 136.99, 136.34, 134.91, 133.42, 129.34, 129.12, 123.19, 119.66, 117.15, 108.64, 106.49, 70.98, 67.02, 52.92, 44.49 and 15.16.

Tested in Alternative Enzyme Assay: Ex. (29a) 0.048 μM; Ex. (29b) 0.018 μM; Ex. (29c) 0.052 μM; Ex. (29d) 0.25 μM; Ex. (29e) 0.11 μM; Ex. (29f) 0.096 μM; Ex. (29g) 0.0087 μM; Ex. (29h) 0.77 μM; Ex. (29i) 0.28 μM; Ex. (29j) 0.057 μM; Ex. (29k) 0.077 μM; Ex. (29l) 0.12 μM; Ex. (29m) 0.41 μM; Ex. (29n) 0.22 μM; Ex. (29o) 0.19 μM; Ex. (29p) 0.24 μM; Ex. (29q) 0.14 μM; Ex. (29r) 0.012 μM; Ex. (29s) 2 μM; Ex. (29t) 0.097 μM; Ex. (29u) 0.055 μM; Ex. (29v) 0.07 μM; Ex. (29w) 0.086 μM; Ex. (29x) 0.81 μM.

Example 30

The amino substrate was reported in Example 28.

(Compounds 30a to 30c)

Conditions A:

The appropriate amino-substrate (1 equiv) was suspended in THF (0.04 M). The appropriate sulfonyl chloride (2.0 equiv) was added. The reaction vessel was sealed and exposed to microwave radiation (140° C., medium absorption setting) for 10 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions B:

The appropriate amino-substrate (1 equiv) was suspended in DMF (0.04 M). The appropriate acyl chloride (1.2 equiv) and potassium carbonate (2.4 equiv) were added. The reaction vessel was sealed and exposed to microwave radiation (140° C., medium absorption setting) for 10 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Conditions C:

The appropriate amino-substrate (1 equiv) was suspended in DMF (0.09 M). The appropriate acyl chloride (3.0 equiv) was added. The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 15 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

	TABLE 30
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Conditions	Example Structure
30a	93	4.67	536.5	A
30b	97	4.58	486.4	B
30c	85	4.56	436.3	C

Tested in Alternative Enzyme Assay: Ex. (30a) 1.4 μM; Ex. (30b) 0.67 μM; Ex. (30c) 0.024 μM.

Example 31

The chloro-substrate was reported in Example 28.

(Compound 31a)

The appropriate chloro-substrate (1 equiv) was dissolved in ethanol (0.025 M). Sodium formate (11.0 equiv) and palladium on carbon (0.5 equiv) were added. The reaction vessel was sealed and heated at 100° C. for 12 hours. Upon completion the sample was filtered through Celite™, and the filtrate was concentrated in vacuo. The crude residue was then purified by reverse phase chromatography eluting with a gradient of 5 to 95% acetonitrile in 0.1% formic acid/water, to give the desired product.

	TABLE 31
		Retention
	Purity	time	m/z
	(%)	(min)	[M + H]+	Example Structure
31a	97	5.94	367.3

NMR Data for Example 31a

¹H NMR (300 MHz, DMSO) δ ppm 8.70 (ArH, s, 1H), 8.42-18.37 (ArH, m, 2H), 8.16 (ArH, dd, J=8.59, 2.34 Hz, 1H), 8.01 (ArH, d, J=8.79 Hz, 1H), 7.14 (ArH, d, J=8.69 Hz, 1H), 5.20 (CH, t, J=5.67, 5.67 Hz, 1H), 4.59 (CH₂, d, J=5.61 Hz, 2H), 4.05-3.93 (CH₂, m, 2H), 3.89 (OCH₃, s, 3H), 3.80-3.59 (CH₂, m, 4H), 3.57 (s, 1H), 3.31 (s, 1H), 2.50 (td, J=3.64, 1.80, 1.80 Hz, 1H), 1.42 (CH₃, d, J=6.79 Hz, 3H)

¹³C NMR (75 MHz, DMSO) δ ppm 164.04, 161.48, 160.52, 158.69, 157.38, 136.11, 131.43, 129.96, 127.87, 126.77, 117.33, 110.93, 109.11, 70.71, 66.83, 58.37, 56.03, 52.14, 44.28 and 15.17.

Tested in Alternative Enzyme Assay: Ex. (31a) 0.2 μM.

Comparative Example 1

Using the method of Example 11, to a cooled (0-5° C.) stirred solution (0.1 M) of the appropriate trichloro substrate (1 equiv) in CH₂Cl₂ was added diisopropylethylamine (1 equiv) in a dropwise fashion. The appropriate amine (1 equiv) was then added to the reaction mixture portionwise over the period of 1 hour. The solution was maintained at room temperature with stirring for a further 1 hour before the mixture was washed with water (2×1 reaction volume). The aqueous extracts were combined and extracted with CH₂Cl₂ (2×1 reaction volume). The organic extracts were then combined, dried (sodium sulphate), filtered and concentrated in vacuo to give an oily residue which solidified upon prolonged drying. The solid was triturated with diethylether and then filtered and the cake washed with cold diethyl ether to leave the title compound in a suitably clean form to be used without any further purification.

2,7-Dichloro-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine —R¹=morpholine: (92% yield, 90% purity) m/z (LC-MS, ESP): 285 [M+H]⁺ R/T=3.90 min

To a solution (0.2 M) of the appropriate dichloro-substrate (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 being cooled to ambient temperature. The reaction was diluted with CH₂Cl₂ (I reaction volume) and then washed with water (3×1 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 solution before being dried, filtered (sodium sulphate) and concentrated in vacuo to give an oil. The crude residue was purified by flash chromatography (SiO₂, eluted with EtOAc:Hex (7:3) going to (1:1)) to give the title compound as a yellow solid that was suitably clean to be used without any further purification.

7-Chloro-2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine—R1=morpholine, R2=cis-dimethylmorpholine: (42% yield, 100% purity) m/z (LC-MS, ESP): 364 [M+H]⁺ R/T=2.96 min

7-Chloro-2-((S)-3-methyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine R1=morpholine, R2=(S)-3-Methyl-morpholine: (70% yield, 97% purity) m/z (LC-MS, ESP): 350 [M+H]⁺ R/T=3.44 min

7-Chloro-2-(2-ethyl-piperidin-1-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine R1=morpholine, R2=2-Ethyl-piperidine: (56% yield, 95% purity) m/z (LC-MS, ESP): 362 [M+H]⁺ R/T=3.78 min

Comparative Examples 1a, 1b, 1c, 1j, and 1k

R⁴=morpholineR²=(S)-3-methyl-morpholine or cis-dimethylmorpholine or 2-Ethyl-piperidineR⁷=aryl or heteroaryl

The appropriate chloro-substrate (1 equiv) was dissolved in a toluene/ethanol (1:1) solution (0.02 M). Sodium carbonate (2 equiv) and the appropriate pinacolate boron ester or boronic acid (1 equiv) were then added followed by tetrakis(triphenylphosphine) palladium⁰ (0.1 equiv). The reaction vessel was sealed and the mixture 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 give the desired comparative examples.

The following Comparative Examples were prepared

		Retention
	Purity	time	m/z	Comparative Example
	(%)	(min)	[M + H]+	Structure
1a	99	4.13	452.3
1b	95	3.95	452.3
1c	99	9.01	464.4
1j	88	8.57	406.5
1k	93	8.12	412.3

Example 32

Biological Assay

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

The following compounds were tested in this assay:—1a, 1b, 1c, 1d, 1e, 1f, 1g, 1 h, 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, 2l, 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, 8l, 8m, 8n, 8o, 8p, 8q, 8r, 8s, 8t, 8u, 8v, 8w, 8x, 8y, 8z, 8aa, 8ab, 8ac, 8ad, 8ae, 8af, 8ag, 8ah, 8ai, 8aj, 8ak, 8al, 8am, 8an, 8ao, 8ap, 8aq, 8ar, 8as, 8at, 8au, 8av, 8aw, 8ax, 8az, 8ba, 8bb, 8bc, 8bd, 8be, 8bf and 8bg. All these 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, 8v, 8w, 8x, 8y, 8ae, 8af, 8am, 8ao, 8at, 8au, 8ay, 8az, 8ba, 8bd and 8bf, with the following compounds exhibiting IC₅₀ values against mTOR of less than 100 nM: 1a, 1b, 1d, 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, 8l, 8m, 8n, 8o, 8aa, 8ab, 8ac, 8ad, 8ag, 8ah, 8ai, 8aj, 8ak, 8al, 8an, 8ap, 8aq, 8ar, 8as, 8av, 8aw, 8ax, 8bb, 8bc, 8be, 8bg. For example, Compound 1k has an IC₅₀ of 0.043 μM

For compounds of Formula I(B), Examples 11a-11l, 11ak, 11al, 11ap, 11at, 11az, 13l, 14a, 14c, 14d, 14f, 14l, 14w, 14x, 15q were tested and exhibited IC₅₀ values against mTOR of less than 200 nM. For example 15q was measured to have an IC50 of 46 nm.

The comparative Examples were also tested and when compared to the corresponding Examples, the exhibited IC₅₀ values for the Comparative Examples were higher than those of the corresponding Examples (ie IC50 Comparative Example 1a>IC50 Example 11a). For example Example 11k was measured to have an IC50 of 5 nm whereas Comparative Example 1k was measured to have an IC50 of 33 nm. Therefore, compounds of the present invention are more active in the mTOR assay.

Example 33

Alternative Enzyme Assay

The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant mTOR.

A C-terminal truncation of mTOR encompassing amino acid residues 1362 to 2549 of mTOR (EMBL Accession No. L34075) was stably expressed as a FLAG-tagged fusion in HEK293 cells as described by 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 up to a confluency of 70-90% in Dulbecco's modified Eagle's growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalogue No. 41966-029) containing 10% heat-inactivated foetal calf serum (FCS; Sigma, Poole, Dorset, UK, Catalogue No. F0392), 1% L-glutamine (Gibco, Catalogue No. 25030-024) and 2 mg/ml Geneticin (G418 sulphate; Invitrogen Limited, UK Catalogue No. 10131-027). Following expression in the mammalian HEK293 cell line, expressed protein was purified using the FLAG epitope tag using standard purification techniques.

Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 μl) of each compound dilution were placed into a well of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one). A 10 μl mixture of recombinant purified mTOR enzyme, 1 μM biotinylated peptide substrate (Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-Tyr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH₂: Bachem UK Ltd), ATP (20 μM) in a buffer solution [comprising Tris-HCl pH7.4 buffer (50 mM), EGTA (0.1 mM), bovine serum albumin (0.5 mg/ml), DTT (1.25 mM) and manganese chloride (10 mM)] were added to the assay plates and incubated with compound for 2 hours at room temperature.

Each reaction was stopped by the addition of 5 μl of a mixture of EDTA (50 mM), bovine serum albumin (BSA; 0.5 mg/ml) and Tris-HCl pH7.4 buffer (50 mM) containing p70 S6 Kinase (T389) 1A5 Monoclonal Antibody (Cell Signalling Technology, Catalogue No. 9206B) and AlphaScreen Streptavidin donor and Protein A acceptor beads (200 ng/well Perkin Elmer, Catalogue No. 6760002B and 6760137R respectively). Assay plates were left for approx 16 hours at room temperature before measurement. The resultant signals arising from laser light excitation at 680 nm were measured using a Packard Envision instrument. Phosphorylated biotinylated peptide is formed in situ as a result of mTOR mediated phosphorylation. The phosphorylated biotinylated peptide that is associated with AlphaScreen Streptavidin donor beads forms a complex with the p70 S6 Kinase (T389) 1A5 Monoclonal Antibody that is associated with Alphascreen Protein A acceptor beads. Upon laser light excitation at 680 nm, the donor bead: acceptor bead complex produces a signal that can be measured. Accordingly, the presence of mTOR kinase activity results in an assay signal. In the presence of an mTOR kinase inhibitor, signal strength is reduced.

Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound. Control wells that produced a minimum signal corresponding to fully inhibited enzyme were created by adding EDTA (83 mM) instead of test compound.

mTOR enzyme inhibition for a given test compound was expressed as an IC₅₀ value.

The compounds tested in this assay exhibited IC₅₀ values against mTOR of less than 40 μm.

The following compounds were screened in this assay:—1bd, 1be, 1bk, 1bl, 1bm, 1bn, 1bo, 1bp, 1bq, 1br, 1bs, 1bt, 1bu, 1bv, 1bw, 1bx, 2bf, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9i, 9j, 9m, 9n, 9o, 9p, 9q, 9r, 9s, 9t, 9u, 9v, 9w, 9x, 9y, 9z, 9aa, 9ab, 9ac, 9ad and 9ae—all these compounds 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 exhibiting IC₅₀ values against mTOR of less than 300 nM: 1bd, 1be, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9ae, 9l, 9j, 9k, 9i, 9h, 1bj, 1bi, 1bh, 1bg and 1bf. For example, Compound 1b has an IC₅₀ of 0.057 μM.

For compounds of Formula I(B), the following compounds exhibited IC₅₀ values against mTOR of less than 1 μm: 11bp, 11ca, 11cb, 11cd, 22e, 28df, 11m, 11q, 11r, 27, 29h, 29m, 28n, 28o, 28ak, 28al, 28at, 11t, 28bb, 28be, 28bi, 28bl, 11x, 11y, 11ba, 11z, 30b, 11ae, 17a, 17h, 28ce, 15f, 14af, 14ag, 14aj, 15y, 13b, 15j, 15k, 15p, 13w, 13y, 13z, 21a, 28da, 13m, 13o, 13p, 13r, 13s, 11aj, 15r, 15s, 11cn, 12a, 12b, 11cq, 11cr, 12d, 13ad, 12h, 11cw and 11dd, with the following compounds exhibiting IC₅₀ values against mTOR of less than 300 nM: 11c, 11bq, 11bt, 11ch, 11ci, 14ap, 14at, 14aw, 14ax, 14ay, 14bd, 22b, 28de, 28dh, 28di, 28dg, 31a, 11o, 28b, 28d, 28h, 29d, 29e, 29i, 29l, 29n, 29o, 28p, 28q, 28r, 28w, 28af, 28ag, 28an, 28aq, 28au, 28av, 11v, 28ay, 28ba, 28bd, 11bg, 11w, 11ac, 14p, 19a, 11bb, 11av, 17b, 17e, 17f, 17g, 17k, 17j, 15c, 15d, 15e, 15g, 14v, 14x, 14y, 14z, 14aa, 14ae, 14ah, 14ai, 15u, 15v, 15w, 15x, 13d, 13f, 28bv, 28cb, 13h, 15h, 15i, 15l, 15o, 13i, 13j, 13v, 13x, 13u, 13ab, 11al, 11am, 11an, 11be, 28cy, 28dc, 23a, 29p, 29q, 13k, 13n, 13q, 23f, 23b, 14g, 11au, 15q, 11ay, 28dj, 23c, 23e, 20a, 11cl, 12c, 12e, 11cs, 12i, 18d, 23g and 11cu, with the following compounds exhibiting IC₅₀ values against mTOR of less than 100 nM: 11b, 11a, 11d, 11bl, 11bm, 11bn, 11f, 11bo, 11i, 11g, 11h, 11br, 11bs, 11bu, 11bv, 11e, 11j, 11bw, 11bx, 11by, 11bz, 11cc, 11ce, 11k, 11cf, 11cg, 11l, 11cj, 14al, 14am, 14an, 14ao, 14aq, 14ar, 14as, 14au, 14av, 14az, 14ba, 14bb, 14bc, 14be, 14bf, 22c, 22d, 22a, 28a, 16a, 11as, 11ax, 11n, 11p, 11s, 11ck, 28c, 28e, 28f, 28g, 28i, 28j, 28k, 11ar, 29a, 29b, 29c, 29f, 29g, 29j, 29k, 28l, 28m, 11bd, 11aq, 28s, 28t, 28u, 28v, 28x, 28y, 28z, 28aa, 28ab, 28ac, 28ad, 28ae, 28ah, 28ai, 28aj, 28am, 28ao, 28ap, 28ar, 28as, 28aw, 28ax, 28az, 28bc, 28bf, 28bg, 28bk, 28bh, 28bj, 25a, 28bm, 18b, 14h, 24a, 18a, 11aa, 11ab, 11ad, 11af, 11ag, 24b, 11bc, 14i, 11ah, 14j, 14l, 14m, 14n, 14o, 28bn, 28bo, 14u, 11bh, 26a, 11at, 17c, 17d, 17i, 13a, 13c, 15a, 15b, 14w, 14ac, 14ad, 15t, 13e, 13g, 28bp, 28bq, 28br, 28bs, 28bt, 28bu, 28bw, 28by, 28bz, 28ca, 28cc, 28cd, 28cf, 28cg, 28ch, 28ci, 28cj, 28ck, 28cl, 14ak, 28bx, 18cm, 28cv, 11bi, 11bj, 14a, 11aw, 13t, 13aa, 11ap, 11bf, 28cn, 28co, 28cp, 28cs, 28ct, 28cu, 28cw, 28cx, 28cz, 28cq, 29r, 29t, 13l, 29u, 29v, 29w, 30c, 11u, 14b, 14q, 14t, 14c, 14e, 14f, 28dd, 14d, 11az, 14r, 14s, 12f, 12g, 12j and 11cv. For example, Compound 14aa has an IC₅₀ of 151 nM.

The Comparative Examples were also tested and when compared to the corresponding Examples, the exhibited IC₅₀ values for the Comparative Examples were higher than those of the corresponding Examples. For example Example 1k was measured to have an IC50 of 15 nm whereas Comparative Example 1k was measured to have an IC50 of 225 nm. Therefore, compounds of the present invention are more active in reducing cell growth.

Example 34

Cell Proliferation Assay (GI₅₀)

Cell growth was assessed using the sulforhodamine B (SRB) assay (A). T47D (ECACC, 85102201) cells were routinely passaged in RPMI (Invitrogen, 42401018) plus 10% foetal calf serum (FCS), 1% L-glutamine (Gibco BRL, 25030) to a confluence not greater than 80%. To undertake the assay, T47D cells were seeded at 2.5×10³ cells/well in 9011 RPMI plus 10% foetal calf serum, 1% L-glutamine in 96 well plates (Costar, 3904) and incubated at 37° C. (+5% CO₂) in a humidified incubator. Once the cells had fully adhered (typically following 4-5 hours incubation) the plate was removed from the incubator and 10 μL of the diluent added to the control wells (A1-12 and B1-12). Compound was prepared in a six point semi-log dilution at 10× the final concentration required e.g. for a 6 point range of 30 μM to 100 nM in semi-log steps dilution started at 300 μM in stock plate. Dosing was completed by addition of 10 μL of compound at highest concentration to C1-12 through to the lowest concentration in H1-12. The plates were then incubated for 120 hours prior to SRB analysis.

Upon completion of incubation, media was removed and the cells fixed with 1001 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 well of cells was then stained with 100 μl of 0.4% (w/v) SRB (Sulforhodamine B, Sigma, Poole, Dorset, UK, Catalogue number S-9012) in 1% acetic acid for 20 minutes before washing four times with 1% acetic acid. Plates were then dried for 2 hours at room temperature. The dye from the stained cells was solubilized by the addition of 100 μl of 10 mM Tris Base into each well. Plates were gently shaken and left at room temperature for 30 minutes before measuring the optical density at 564 nM on a Microquant microtiter plate reader. The concentration of inhibitor eliciting a 50% reduction in growth (GI₅₀) was determined by analysis of staining intensity of the treated cells as a percentage of the 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. and Boyd, M. R. (1990) New calorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 82, 1107-1112.

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

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

For compounds of Formula I(B), Examples 11a-11l were tested and exhibited GI₅₀ values of less than 300 nM.

The Comparative Examples were also tested and when compared to the corresponding Examples, the exhibited GI₅₀ values for the Comparative Examples were higher than those of the corresponding Examples (ie GI₅₀ Comparative Example 1a>GI₅₀ Example 11a). For example Example 11k was measured to have a GI50 of 32 nm whereas Comparative Example 1k was measured to have an GI50 of 268 nm. Therefore, compounds of the present invention are more active in reducing cell growth.

Example 35

In Vitro phospho-Ser473 Akt Assay

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 quantitate features of images generated by laser-scanning.

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

For the assay, the cells were detached from the culture flask using ‘Accutase’ (Innovative Cell Technologies Inc., San Diego, Calif., USA; Catalogue No. AT104) using standard tissue culture methods and resuspended in media to give 1.7×10⁵ cells per ml. Aliquots (90 μl) were seeded into each of the inner 60 wells of a black Packard 96 well plate (PerkinElmer, Boston, Mass., USA; Catalogue No. 6005182) to give a density of 15000 cells per well. Aliquots (90 μl) of culture media were placed in the outer wells to prevent edge effects. The cells were incubated overnight at 37° C. with 5% CO₂ to allow them to adhere.

On day 2, the cells were treated with test compounds and incubated for 2 hours at 37° C. with 5% CO₂. Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required with growth media to give a range of concentrations that were 10-fold the required final test concentrations. Aliquots (10 μl) of each compound dilution were placed in a well (in triplicate) to give the final required concentrations. As a minimum response control, each plate contained wells having a final concentration of 100 μM LY294002 (Calbiochem, Beeston, UK, Catalogue No. 440202). As a maximum response control, wells contained 1% DMSO instead of test compound. Following incubation, the contents of the plates were fixed by treatment with a 1.6% aqueous formaldehyde solution (Sigma, Poole, Dorset, UK, Catalogue No. F1635) at room temperature for 1 hour.

All subsequent aspiration and wash steps were carried out using a Tecan 96 well plate washer (aspiration speed 10 mm/sec). The fixing solution was removed and the contents of the plates were washed with phosphate-buffered saline (PBS; 50 μl; Gibco, Catalogue No. 10010015). The contents of the plates were treated for 10 minutes at room temperature with an aliquot (50 μl) of a cell permeabilisation buffer consisting of a mixture of PBS and 0.5% Tween-20. The ‘permeabilisation’ buffer was removed and non-specific binding sites were blocked by treatment for 1 hour at room temperature of an aliquot (50 μl) of a blocking buffer consisting of 5% dried skimmed milk [‘Marvel’ (registered trade mark); 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 rabbit anti phospho-Akt (Ser473) antibody solution (50 μl per well; Cell Signalling, Hitchin, Herts, U.K., Catalogue No 9277) that had been diluted 1:500 in ‘blocking’ buffer. Cells were washed three times in a mixture of PBS and 0.05% Tween-20. Subsequently, cells were incubated for 1 hour at room temperature with Alexafluor488 labelled goat anti-rabbit IgG (50 μl per well; Molecular Probes, Invitrogen Limited, Paisley, UK, Catalogue No. A11008) that had been diluted 1:500 in ‘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 sealed with black plate sealers and the fluorescence signal was detected and analysed.

Fluorescence dose response data obtained with each compound were analysed and the degree of inhibition of Serine 473 in Akt was expressed as an IC₅₀ value.

The following compounds were tested and exhibited a cellular IC₅₀, measured by pAkt, of less than 25 μM: 1bj, 1bd, 1bh, 1bi, 9j, 9a, 9aa, 9r, 9d, 9f, 9e with the following compounds exhibiting a cellular IC₅₀, measured by pAkt, of less than 2.5 μM: 1br, 1bg, 1be, 9l, 9n, 9k, 9h, 9g, 9m and 9i. For example, compound 91 has a pAkt IC₅₀ of 2.2 uM For the compounds of Formula I(B), the compounds tested in this assay exhibited IC₅₀ values against mTOR of less than 10 μm.

The following compounds exhibited IC₅₀ values against mTOR of less than 11 μm: 11bu, 11ce, 22b, 28de, 28dg, 28j, 11ar, 29e, 29h, 29i, 29l, 29m, 29n, 29o, 28n, 28o, 28z, 28aa, 28ag, 28ai, 28al, 11v, 28az, 11ah, 17e, 17i, 17j, 15d, 15f, 14v, 14ab, 14aj, 15t, 15u, 15w, 15x, 15y, 15z, 13f, 13g, 28bp, 28bs, 28bv, 28by, 28cb, 28cv, 11aw, 13u, 11bf, 28ct, 29q, 29s, 29u, 29v, 29w, 11au, 15r, 14t, 28dj, 11cl, 12d, 12e, 11cs, 12h, 12j and 11cw, with the following compounds exhibiting IC₅₀ values against mTOR of less than 300 nM: 11bo, 11bp, 11j, 11bx, 11by, 11cf, 11ci, 11cj, 14an, 14ap, 14av, 22d, 28dh, 28di, 16a, 11n, 11p, 11q, 28e, 28h, 29b, 29c, 29f, 29k, 28p, 11bd, 28w, 28ab, 28af, 28aj, 28aq, 28as, 28av, 28ay, 28bb, 28bc, 28bf, 28bl, 2ab, 14p, 19a, 11av, 13a, 15b, 15c, 15e, 15g, 14aa, 14ad, 14ah, 15v, 13e, 28bq, 28bt, 28bz, 28ca, 28cd, 28cg, 28ci, 28bx, 15n, 11am, 11ao, 28cn, 28cx, 11bk, 23b, 14g, 15s, 14q, 28dd, 11cp, 11cq, 12f, 12g, 23g, 11cv and 11ct, with the following compounds exhibiting IC₅₀ values against mTOR of less than 100 nM: 11b, 11a, 11c, 11d, 11bl, 11bm, 11f, 11i, 11g, 11h, 11br, 11bs, 11bv, 11e, 11bz, 11cc, 11k, 11cg, 11l, 14al, 14am, 14ao, 14aq, 14as, 14at, 14au, 14aw, 14ax, 14ay, 14az, 14ba, 14bb, 14bc, 14bd, 14be, 14bf, 22c, 22a, 28a, 11as, 11s, 28c, 28d, 28f, 28g, 28i, 28k, 29j, 28m, 28q, 28r, 28s, 28t, 28u, 28v, 28x, 28y, 28ac, 28ad, 28ae, 28ah, 28ak, 28am, 28an, 28ap, 28ar, 28au, 28aw, 28ax, 28ba, 28bd, 28be, 28bg, 28bi, 28bk, 28bh, 28bj, 28bm, 11bg, 18b, 14h, 11ba, 18a, 11aa, 11ac, 11ae, 11af, 11ag, 24b, 11bc, 14i, 14j, 14k, 14l, 14m, 14n, 14o, 28bn, 28bo, 14u, 11bb, 11at, 17b, 17c, 17d, 17f, 17g, 17k, 15a, 14w, 14x, 14y, 14z, 14ac, 14af, 14ai, 28br, 28bw, 28cc, 28cf, 28ch, 28cj, 28ck, 28cl, 14ak, 28cm, 14a, 13i, 13y, 11ak, 11al, 11ap, 11be, 28co, 28cr, 28cs, 28 db, 29p, 13l, 11u, 14b, 15q, 14c, 14e, 14f, 14d, 11az, 14r, 14s, 11cn, 11co and 13ad. For example, Compound 28di has an IC₅₀ of 151 nM

The Comparative Examples were also tested and when compared to the corresponding Examples, the exhibited IC₅₀ values for the Comparative Examples were higher than those of the corresponding Examples. For example, Example 11k was measured to have an IC₅₀ of 83 nm whereas Comparative Example 1k was measured to have an IC50 of 412 nm. Therefore, compounds of the present invention are more active in reducing cell growth.

REFERENCE LIST

The following documents are all herein incorporated by reference.

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Claims

1-63. (canceled)

64. A compound of formula I:

65. The compound according to claim 64 wherein the compound is a compound of formula I(B)

66. The compound according to claim 65 wherein X5 and X6 are CH and X8 is N.

67. The compound according to claim 66 wherein the compound is a compound of formula I(B)i or I(B)ii:

68. The compound according to claim 66, wherein R7 is selected from an optionally substituted C5-20 aryl group, ORO1, NRN1RN2, NRN7aC(═O)RC1 and NRN7bSO2RS2a.

69. The compound according to claim 66, wherein R7 is an optionally substituted C5-6 aryl group.

70. The compound according to claim 66, wherein R7 is an optionally substituted phenyl group, wherein the optional substituents are selected from halo, hydroxyl, C1-7 alkyl, C1-7 alkoxy, C5-6arylamino and C1-7alkylamino and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C1-7 alkyl, C1-7 alkoxy, C5-6aryl, C5-6arylamino and C1-7alkylamino.

71. The compound according to claim 66, whereinR7 is an optionally substituted phenyl group selected from

72. The compound according to claim 66, wherein R7 is a pyridinyl group optionally substituted by halo, hydroxyl, cyano, C1-7 alkyl, C1-7alkoxy, aryl, amino or amido and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C1-7 alkyl, C1-7 alkoxy, C5-6aryl, C5-6arylamino, di-(C1-7alkyl)amino and C1-7alkylamino.

73. The compound according to claim 66, wherein R7 is selected from

74. The compound according to claim 66, wherein R2 is NRN5RN6, wherein RN5 and RN6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, which may optionally be substituted.

75. The compound according to claim 66, wherein R2 is selected from optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl, homopiperazinyl and pyrrolidinyl.

76. The compound according to claim 66 wherein R2 is selected from

77. The compound according to claim 66, wherein R7 is selected from

78. A pharmaceutical composition comprising a compound according to claim 64 and a pharmaceutically acceptable carrier or diluent.

79. A compound of formula (I):

80. The compound according to claim 79 wherein X5 and X6 are CH and X8 is N.

81. The compound according to claim 80, wherein R7 is selected from an optionally substituted C5-20 aryl group, ORO1, NRN1RN2, NRN7aC(═O)RC1 and NRN7bSO2RS2a.

82. The compound according to claim 80, wherein R7 is an optionally substituted C5-6 aryl group.

83. The compound according to claim 80, wherein R7 is an optionally substituted phenyl, wherein the optional substituents are selected from halo, hydroxyl, C1-7alkyl and C1-7alkoxy.

84. The compound according to claim 80, wherein R7 is a phenyl group optionally substituted by one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl.

85. The compound according to claim 80, wherein R7 is an optionally substituted C5-20 aryl group or an optionally substituted 5 to 20 membered heteroaryl group, wherein the optional substituents are selected from halo, hydroxyl, cyano, C1-7 alkyl, C1-7alkoxy, sulfonamino, amino, and amido and wherein the substitutent alkyl, alkoxy, or aryl groups may be further optionally substituted by one or more groups selected from halo, hydroxyl, C1-7 alkyl, C1-7 alkoxy, C5-6aryl, —NHS(═O)2C1-7alkyl, C5-6arylamino, di-(C1-7alkyl)amino and C1-7alkylamino.

86. The compound according to claim 80, wherein R7 is selected from

87. The compound according to claim 80, wherein R2 is NRN5RN6, wherein RN5 and RN6 together with the nitrogen to which they are bound form a heterocyclic ring containing between 3 and 8 ring atoms, which may optionally be substituted.

88. The compound according to claim 80, wherein R2 is selected from optionally substituted morpholino, thiomorpholino, piperidinyl, piperazinyl, homopiperazinyl and pyrrolidinyl.

89. The compound according to claim 80 wherein R2 is selected from

90. The compound according to claim 80, wherein R7 is selected from

91. A pharmaceutical composition comprising a compound according to claim 80 and a pharmaceutically acceptable carrier or diluent.

92. A method for producing a mTOR inhibitory effect in a warm-blooded animal, in need of such treatment, comprising administering to said animal an effective amount of a compound according to claim 64 or claim 79, or a pharmaceutically acceptable salt thereof.

93. A method for producing an anti-cancer effect in a warm-blooded animal in need of such treatment, comprising administering to said animal an effective amount of a compound according to claim 64 or claim 79, or a pharmaceutically acceptable salt thereof.