WO2010120987A1 - Ring fused, ureidoaryl- and carbamoylaryl-bridged morpholino-pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses - Google Patents

Abstract

The invention relates to ring fused, bridged 4-morpholino-pyhmidine compounds of Formula (I), their ring homologues and methods for making and using the compounds.

Description

RING FUSED, UREIDOARYL- AND CARBAMOYLARYL-BRIDGED MORPHOLINO-

PYRIMIDINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE

INHIBITORS, AND THEIR SYNTHESES

FIELD OF THE INVENTION

The invention relates to ring fused, ureidoaryl- and carbamoylaryl-bhdged morpholino-pyhmidine compounds, compositions comprising such a compound, methods of synthesizing such compounds, and methods for treating mTOR-related diseases comprising the administration of an effective amount of such a compound. In particular, the invention is directed to para-substituted ureidophenyl- and carbamoylphenyl-bhdged morpholino-pyrimidine compounds. The invention also relates to methods for treating PI3K-related diseases comprising the administration of an effective amount of such a compound. The invention also relates to methods for treating hSMG-1 kinase-related diseases comprising the administration of an effective amount of such a compound.

BACKGROUND OF THE INVENTION

Phosphatidylinositol (hereinafter abbreviated as "Pl") is one of the phospholipids in cell membranes. In recent years it has become clear that Pl plays an important role also in intracellular signal transduction. It is well recognized in the art that Pl (4,5) bisphosphate (PI(4,5)P2 or PIP2) is degraded into diacylglycerol and inositol (1 ,4,5) triphosphate by phospholipase C to induce activation of protein kinase C and intracellular calcium mobilization, respectively [M. J. Berridge et al., Nature, 312, 315 (1984); Y. Nishizuka, Science, 225, 1365 (1984)].

In the late 1980s, phosphatidylinositol-3 kinase ("PI3K") was found to be an enzyme that phosphorylates the 3-position of the inositol ring of phosphatidylinositol [D.

Whitman et al., Nature, 332, 664 (1988)]. When PI3K was discovered, it was originally considered to be a single enzyme. Recently however, it was clarified that a plurality of

PI3K subtypes exists. Three major subtypes of PI3Ks have now been identified on the basis of their in vitro substrate specificity, and these three are designated class I (a & b), class II, and class III [B. Vanhaesebroeck, Trend in Biol. Sci., 22, 267(1997)]. The class Ia PI3K subtype has been most extensively investigated to date. Within the class Ia subtype there are three isoforms (α, β, & δ) that exist as hetero dimers of a catalytic 1 10-kDa subunit and regulatory subunits of 50-85kDa. The regulatory subunits contain SH2 domains that bind to phosphorylated tyrosine residues within growth factor receptors or adaptor molecules and thereby localize PI3K to the inner cell membrane. At the inner cell membrane PI3K converts PIP2 to PIP3 (phosphatidylinositol-3,4,5-thsphosphate) that serves to localize the downstream effectors PDK1 and Akt to the inner cell membrane where Akt activation occurs. Activated Akt mediates a diverse array of effects including inhibition of apoptosis, cell cycle progression, response to insulin signaling, and cell proliferation. Class Ia PI3K subtypes also contain Ras binding domains (RBD) that allow association with activated Ras providing another mechanism for PI3K membrane localization. Activated, oncogenic forms of growth factor receptors, Ras, and even PI3K kinase have been shown to aberrantly elevate signaling in the PI3K/Akt/mTOR pathway resulting in cell transformation. As a central component of the PI3K/Akt/mTOR signaling pathway PI3K (particularly the class Ia α isoform) has become a major therapeutic target in cancer drug discovery.

Substrates for class I PI3Ks are Pl, PI(4)P and PI(4,5)P2, with PI(4,5)P2 being the most favored. Class I PI3Ks are further divided into two groups, class Ia and class Ib, because of their activation mechanism and associated regulatory subunits. The class Ib PI3K is p1 10γ that is activated by interaction with G protein-coupled receptors. Interaction between p1 10γ and G protein-coupled receptors is mediated by regulatory subunits of 1 10, 87, and 84 kDa.

Pl and PI(4)P are the known substrates for class Il PI3Ks; PI(4,5)P2 is not a substrate for the enzymes of this class. Class Il PI3Ks include PI3K C2α, C2β and C2γ isoforms, which contain C2 domains at the C terminus, implying that their activity is regulated by calcium ions.

The substrate for class III PI3Ks is Pl only. A mechanism for activation of the class III PI3Ks has not been clarified. Because each subtype has its own mechanism for regulating activity, it is likely that activation mechanism(s) depend on stimuli specific to each respective class of PI3K. The compound PM 03 (3-(4-(4-morpholinyl)pyπdo[3',2':4,5]furo[3,2-d]pyπmidin-2- yl)phenol) inhibits PI3K_α and PI3K_γ as well as the mTOR enzymes with IC50 values of 2, 3, and 50-80 nM respectively. I. P. dosing in mice of this compound in human tumor xenograft models of cancer demonstrated activity against a number of human tumor models, including the glioblastoma (PTEN null U87MG), prostate (PC3), breast (MDA- MB-468 and MDA-MB-435) colon carcinoma (HCT 1 16); and ovarian carcinoma (SKOV3 and IGROV-1 ); (Raynaud et al, Pharmacologic Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases, Cancer Res. 2007 67: 5840-5850).

The compound ZSTK474 (2-(2-difluoromethylbenzoimidazol-1 -yl)-4,6- dimorpholino-1 ,3,5-thazine) inhibits PI3K_α and PI3K_γ but not the mTOR enzymes with an IC50 values of 16, 4.6 and >10,000 nM respectively (Dexin Kong and Takao Yamori,

ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms, Cancer Science, 2007, 98:10 1638-1642). Chronic oral administration of

ZSTK474 in mouse human xenograft cancer models, completely inhibited growth which originated from a non-small-cell lung cancer (A549), a prostate cancer (PC-3), and a colon cancer (WiDr) at a dose of 400 mg/kg. (Yaguchi et al, Antitumor Activity of

ZSTK474, a New Phosphatidylinositol 3-Kinase Inhibitor, J. Natl. Cancer Inst. 98: 545-

556).

The compound NVP-BEZ-235 (2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)- 2,3-dihydro-1 H-imidazo[4,5-c]quinolin-1-yl)phenyl)propanenithle) inhibits both PI3K_α and PI3K_γ as well as the mTOR enzymes with IC50 values 4, 5, and "nanomolar".

Testing in human tumor xenograft models of cancer demonstrated activity against human tumor models of prostrate (PC-3) and glioblastoma (U-87) cancer. It entered clinical trials in December of 2006 (Verheijen, J. C. and Zask, A., Phosphatidylinositol 3- kinase (PI3K) inhibitors as anticancer drugs, Drugs Fut. 2007, 32(6): 537-547).

The compound SF-1 126 (a prodrug form of LY-294002, which is 2-(4- morpholinyl)-8-phenyl-4H-1 -benzopyran-4-one) is "a pan-PI3K inhibitor". It is active in preclinical mouse cancer models of prostrate, breast, ovarian, lung, multiple myeloma, and brain cancers. It began clinical trials in April, 2007 for the solid tumors endometrial, renal cell, breast, hormone refractory prostate, and ovarian cancers. (Verheijen, J. C. and Zask, A., Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer drugs, Drugs Fut. 2007, 32(6): 537-547). Exelixis Inc. (So. San Francisco, CA) recently filed INDs for XL-147 (a selective pan-PI3K inhibitor of unknown structure) and XL-765 (a mixed inhibitor of mTOR and PI3K of unknown structure) as anticancer agents. TargeGen's short-acting mixed inhibitor of PI3Kγ and δ, TG-1001 15, is in phase I/I I trials for treatment of infarct following myocardial ischemia-reperfusion injury. Cerylid's antithrombotic PI3Kβ inhibitor CBL-1309 (structure unknown) has completed preclinical toxicology studies.

According to Verheijen, J. C. and Zask, A., Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer drugs, Drugs Fut. 2007, 32(6): 537-547,

Although it seems clear that inhibition of the α isoform is essential for the antitumor activity of PI3K inhibitors, it is not clear whether a more selective inhibitor of a particular PI3K isoform may lead to fewer unwanted biological effects. It has recently been reported that non-PI3Kα class I isoforms (PI3Kβ, δ and Y) have the ability to induce oncogenic transformation of cells, suggesting that nonisoform- specific inhibitors may offer enhanced therapeutic potential over specific inhibitors.

Selectivity versus other related kinases is also an important consideration for the development of PI3K inhibitors. While selective inhibitors may be preferred in order to avoid unwanted side effects, there have been reports that inhibition of multiple targets in the PI3K/Akt pathway (e.g., PI3Kα and mTOR [mammalian target of rapamycin]) may lead to greater efficacy. It is possible that lipid kinase inhibitors may parallel protein kinase inhibitors in that nonselective inhibitors may also be brought forward to the clinic.

Mammalian Target of Rapamycin, mTOR, is a cell-signaling protein that regulates the response of tumor cells to nutrients and growth factors, as well as controlling tumor blood supply through effects on Vascular Endothelial Growth Factor, VEGF. Inhibitors of mTOR starve cancer cells and shrink tumors by inhibiting the effect of mTOR. All mTOR inhibitors bind to the mTOR kinase. This has at least two important effects. First, mTOR is a downstream mediator of the PI3K/Akt pathway. The PI3K/Akt pathway is thought to be over activated in numerous cancers and may account for the widespread response from various cancers to mTOR inhibitors. The over- activation of the upstream pathway would normally cause mTOR kinase to be over activated as well. However, in the presence of mTOR inhibitors, this process is blocked. The blocking effect prevents mTOR from signaling to downstream pathways that control cell growth. Over-activation of the PI3K/Akt kinase pathway is frequently associated with mutations in the PTEN gene, which is common in many cancers and may help predict what tumors will respond to mTOR inhibitors. The second major effect of mTOR inhibition is anti-angiogenesis, via the lowering of VEGF levels.

In lab tests, certain chemotherapy agents were found to be more effective in the presence of mTOR inhibitors. George, J. N., et al., Cancer Research, 61 , 1527-1532,

2001 . Additional lab results have shown that some rhabdomyosarcoma cells die in the presence of mTOR inhibitors. The complete functions of the mTOR kinase and the effects of mTOR inhibition are not completely understood.

There are three mTOR inhibitors, which have progressed into clinical trials. These compounds are Wyeth's Torisel, also known as 42-(3-hydroxy-2- (hydroxymethyl)-rapamycin 2-methylpropanoate, CCI-779 or Temsirolimus; Novartis' Everolimus, also known as 42-0-(2-hydroxyethyl)-rapamycin, or RAD 001 ; and Ariad's AP23573 also known as 42-(dimethylphopsinoyl)-rapamycin. The FDA has approved Torisel for the treatment of advanced renal cell carcinoma. In addition, Torisel is active in a NOS/SCID xenograft mouse model of acute lymphoblastic leukemia [Teachey et al, Blood, 107(3), 1 149-1 155, 2006]. Everolimus is in a phase Il clinical study for patients with Stage IV Malignant Melanoma. AP23573 has been given orphan drug and fast- track status by the FDA for treatment of soft-tissue and bone sarcomas.

The three mTOR inhibitors have non-linear, although reproducible pharmacokinetic profiles. Mean area under the curve (AUC) values for these drugs increase at a less than dose related way. The three compounds are all semi-synthetic derivatives of the natural macrolide antibiotic rapamycin. It would be desirable to find fully synthetic compounds, which inhibit mTOR that are more potent and exhibit improved pharmacokinetic behaviors.

The most recently described PI3K family member was identified in human cells and named human or hSMG-1. Yamashita (Genes Dev. 2001 15: 2215-2228) characterized two isoforms of hSMG-1 proteins, p430 and p400, which are expressed in various cell lines of human, monkey, rat, and mouse. Yamashita's p400 hSMG-1 isoform is a 3529-amino-acid protein of 396,040 Daltons. Brumbaugh (Molecular Cell, Volume 14, Issue 5, 4 June 2004, Pages 585-598) isolated a 3521 amino acid polypeptide with a deduced molecular mass of 395 kDa. Brumbaugh's hSMG-1 is eight amino acids shorter at the amino terminus than the protein isolated by Yamashita.

Both hllpfl and p53 are physiological targets for hSMG-1 in intact cells. Rapamycin in the presence of purified recombinant FKBP12 does not inhibit the kinase activity of hSMG-1. Wortmannin, the modified steroidal anti-infective agent, and the purine caffeine inhibit the kinase activity of hSMG-1 with IC50 values of -60 nM and 0.3 mM, respectively. However, these are non-specific protein kinase inhibitors.

Specific inhibition of hSMG-1 is a potential therapeutic strategy because inhibitors of hSMG-1 cause the accumulation of truncated p53 proteins from a premature translation termination codon (PTC) allele, as well as the increase in the level of mRNA with PTC, opening the possibility of the above strategy by specifically suppressing nonsense-mediated mRNA decay (NMD) through the inhibition of hSMG-1.

One-fourth of all mutations in human genetic diseases and cancers are of the type that can target the corresponding mRNA for NMD. Although NMD protects cells against deleterious gain-of-function mutations caused by the dominant negative effects of aberrant truncated proteins, there are some cases in which the truncated protein does not show such an effect, rather, it retains residual activity and can compensate for the normal gene function. Thus, the specific inhibition of NMD may provide a novel therapeutic strategy based on the type of mutation rather than on the gene in which the mutation resides.

The inhibitors of SMG-1 can rescue the synthesis of mature proteins through two independent mechanisms (i.e., the inhibition of NMD to increase the mRNA level and the suppression of translational termination that leads to the synthesis of a read-through mature protein product). In this sense, the specific inhibitors of hSMG-1 will be of potential therapeutic importance for all the genetic diseases associated with PTC mutations.

As explained above, PI3K inhibitors and mTOR inhibitors are expected to be novel types of medicaments useful against cell proliferation disorders, especially as carcinostatic agents. Thus, it would be advantageous to have new PI3K inhibitors and mTOR inhibitors as potential treatment regimens for mTOR- and PI3K-related diseases. The instant invention is directed to these and other important ends.

SUMMARY OF THE INVENTION

In one aspect, the invention provides compounds of Formula I:

I or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined below. The invention further provides a pharmaceutical composition comprising a compound of formula I and methods of treating PI3K, hSMG-1 , and mTOR related disorders comprising administering a compound of formula I to a mammal in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides compounds of Formula I:

or a pharmaceutically acceptable salt thereof wherein;

T = O, S or NR ,4.

U = NH, O or S;

A is selected from

, each ring optionally substituted with 1-4 substituents selected from NR⁶R⁷, OR⁸, halogen, C_rC₆ alkyl, C_rC₆ heteroalkyl, C₆-Ci₄ aryl, C_rC₉ heteroaryl, Cs-Cs cycloalkyl, and Cs-Cs cycloheteroalkyl;

W is a bond, a substituted or unsubstituted C₂-C6 alkenyl, or a substituted or unsubstituted C₂-C₆ alkynyl;

Ar is C₆-Ci₄ aryl or C₁-C₉ heteroaryl ring, each of which may or may not be further substituted; R is independently selected from H (provided that U is NH), d-C₆ alkyl, C₂-C₆ alkenyl, C₂-C6 alkynyl, CrC₆ heteroalkyl, C₆-Ci₄ aryl, C₁-C9 heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, and C3-C8 cycloheteroalkenyl, each of which may or may not be substituted; and

at least one of R¹ and R², or R³ and R⁴, or R² and R³, or R¹ and R⁴ together with the atoms that they bonded to join to form a ring, at each occurrence R¹, R², R³, R⁴ are independently selected from CrC₆ alkyl, substituted CrC₆ alkyl, CrC₆ alkoxy, substituted CrC₆ alkoxy, CrC₆ alkyl amine, and substituted CrC₆ alkyl amine, wherein R¹ - R², or R³ - R⁴ is one to four atoms in chain length and R² - R³, or R¹ - R¹ is one to three atoms in chain length.

According to one embodiment, A is further substituted with one or more bridged morpholinyl of formula

According to one embodiment, when A is further substituted with one or more substituents selected from NR⁶R⁷, OR⁸, halogen, C_rC₆ alkyl, CrC₆ heteroalkyl, C₆-Ci₄ aryl, C_rC₉ heteroaryl, C₃-C₈ cycloalkyl, and C₃-C₈ cycloheteroalkyl.

In another aspect, the invention provides a compound of formula:

wherein the fused 5-membered carbocyclic ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, CrC₆ alkyl, CrC₆ heteroalkyl, C₆-Ci₄ aryl, CrC₉ heteroaryl, C₃-C₈ cycloalkyl, and C₈-C₈ cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is C₆-Ci₄ aryl or C₁-C9 heteroaryl, T is O or S, U is NH and R is C₆-Ci₄ aryl or C₁-C₉ heteroaryl. According to one embodiment, W is a bond and Ar is a 4-substituted C₆ aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C₆ aryl or C₅ heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein the fused 6-membered heterocyclic ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, CrC₆ alkyl, CrC₆ heteroalkyl, C₆-Ci₄ aryl, CrC₉ heteroaryl, C₃-C₈ cycloalkyl, and C₈-C₈ cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is C₆-Ci₄ aryl or C₁-C9 heteroaryl, T is O or S, U is NH and R is C₆-Ci₄ aryl or C₁-C9 heteroaryl. According to one embodiment, W is a bond and Ar is a 4-substituted C₆ aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C₆ aryl or C₅ heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein the fused aryl ring is optionally substituted with 1-4 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, CrC₆ alkyl, Ci-C₆ heteroalkyl, C₆- Ci₄ aryl, Ci -Cg heteroaryl, C₃-C₈ cycloalkyl, and C₈-C₈ cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is C₆-Ci₄ aryl or d-C₉ heteroaryl, T is O or S, U is NH and R is C₆-Ci₄ aryl or C_rC₉ heteroaryl. According to one embodiment, W is a bond and Ar is a 4-substituted C₆ aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4-substituted C₆ aryl or C5 heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein the fused 5-membered heteroaryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, d-C₆ alkyl, CrC₆ heteroalkyl, C₆-Ci₄ aryl, CrC₉ heteroaryl, C₃-C₈ cycloalkyl, and C₈-C₈ cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is C₆-Ci₄ aryl or C1-C9 heteroaryl, T is O or S, U is NH and R is C₆-Ci₄ aryl or C₁-C₉ heteroaryl. According to one embodiment, W is a bond and Ar is a 4-substituted C₆ aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C₆ aryl or C₅ heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein either of the fused 5-membered heterocyclic or 6-membered heteroaryl ring is optionally substituted with 1 -3 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, CrC₆ alkyl, Ci-C₆ heteroalkyl, C₆-Ci₄ aryl, Ci -C₉ heteroaryl, C₃-C₈ cycloalkyl, and C₈-C₈ cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is C₆-Ci₄ aryl or C₁-C₉ heteroaryl, T is O or S, U is NH and R is C₆-Ci₄ aryl or C₁-C9 heteroaryl. According to one embodiment, W is a bond and Ar is a 4-substituted C₆ aryl or C₅ heteroaryl, T is O or S, U is NH and R is a 4-substituted C₆ aryl or C5 heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein the fused 6-membered heterocyclic ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, d-C₆ alkyl, Ci-C₆ heteroalkyl, C6-C-ι₄ aryl, Ci -Cg heteroaryl, C3-C₈ cycloalkyl, and Cs-Cs cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is C₆-Ci₄ aryl or C₁-C9 heteroaryl, T is O or S, U is NH and R is C₆-Ci₄ aryl or C₁-C₉ heteroaryl. According to one embodiment, W is a bond and Ar is a 4-substituted Ce aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted Ce aryl or C5 heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein the fused 5-membered heteroaryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, CrC₆ alkyl, Ci-C₆ heteroalkyl, C₆-Ci₄ aryl, Ci -C₉ heteroaryl, C₃-C₈ cycloalkyl, and C₈-C₈ cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is C₆-Ci₄ aryl or C₁-C9 heteroaryl, T is O or S, U is NH and R is C₆-Ci₄ aryl or C₁-C₉ heteroaryl. According to one embodiment, W is a bond and Ar is a 4-substituted C₆ aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C₆ aryl or C5 heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein the fused 5-membered heteroaryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, CrC₆ alkyl, Ci-C₆ heteroalkyl, C6-Ci₄ aryl, Ci -Cg heteroaryl, C3-C₈ cycloalkyl, and Cs-Cs cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is C₆-Ci₄ aryl or C₁-C9 heteroaryl, T is O or S, U is NH and R is C₆-Ci₄ aryl or C₁-C₉ heteroaryl. According to one embodiment, W is a bond and Ar is a 4-substituted C₆ aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted Ce aryl or C5 heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein the fused 5-membered aryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, C_rC₆ alkyl, C_rC₆ heteroalkyl, C₆-Ci₄ aryl, C_rC₉ heteroaryl, C₃-C₈ cycloalkyl, and C₈-C₈ cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is C₆-Ci₄ aryl or d-C₉ heteroaryl, T is O or S, U is NH and R is C₆-Ci₄ aryl or C₁-C₉ heteroaryl. According to one embodiment, W is a bond and Ar is a 4- substituted C₆ aryl or C₅ heteroaryl, T is O or S, U is NH and R is a 4-substituted C₆ aryl or C₅ heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein the fused 6-membered carbocyclic ring is optionally substituted with 1-4 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, CrC₆ alkyl, Ci-C₆ heteroalkyl, C₆-Ci₄ aryl, CrC₉ heteroaryl, C₃-C₈ cycloalkyl, and C₈-C₈ cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is C₆-Ci₄ aryl or C₁-C9 heteroaryl, T is O or S, U is NH and R is C₆-Ci₄ aryl or C₁-C9 heteroaryl. According to one embodiment, W is a bond and Ar is a 4-substituted C₆ aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C₆ aryl or C₅ heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein the fused 5-membered heteroaryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, CrC₆ alkyl, CrC₆ heteroalkyl, C₆-Ci₄ aryl, Ci -Cg heteroaryl, C3-C₈ cycloalkyl, and C₈-C₈ cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is C₆-Ci₄ aryl or C₁-C9 heteroaryl, T is O or S, U is NH and R is C₆-Ci₄ aryl or C₁-C₉ heteroaryl. According to one embodiment, W is a bond and Ar is a 4-substituted Ce aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C& aryl or C5 heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein the fused 5-membered heteroaryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, C-i-Cδ alkyl, C-i-Cδ heteroalkyl, C6-C-ι₄ aryl, Ci -Cg heteroaryl, C3-Cs cycloalkyl, and Cs-Cs cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is Cδ-Ci₄ aryl or C₁-C9 heteroaryl, T is O or S, U is NH and R is C_δ-Ci₄ aryl or C₁-C₉ heteroaryl. According to one embodiment, W is a bond and Ar is a 4-substituted Ce aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C₆ aryl or C₅ heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein the fused 5-membered heteroaryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, d-Cβ alkyl, Ci-Cβ heteroalkyl,

aryl, Ci -Cg heteroaryl, C3-Cs cycloalkyl, and Cs-Cs cycloheteroalkyl; T, U, W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is Cδ-Ci₄ aryl or C₁-C9 heteroaryl, T is O or S, U is NH and R is C_δ-Ci₄ aryl or C₁-C₉ heteroaryl. According to one embodiment, W is a bond and Ar is a 4-substituted C₆ aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C₆ aryl or C5 heteroaryl.

In another aspect, the invention provides a compound of formula:

wherein T, U₁ W, Ar, R and R^1"4 are as defined above. According to one embodiment, W is a bond and Ar is C₆-Ci₄ aryl or C_rC₉ heteroaryl, T is O or S, U is NH and R is C₆- Ci₄ aryl or C₁-C₉ heteroaryl. According to one embodiment, W is a bond and Ar is a A- substituted C₆ aryl or C₅ heteroaryl, T is O or S, U is NH and R is a 4-substituted C₆ aryl or C₅ heteroaryl.

In a separate embodiment, Ar is a substituted aryl or heteroaryl ring substituted with a urea or carbamate at the 4-position, a -OH at the 3- or 4-position, and a NH₂ at the A- position, when Ar is 3-pyridiyl or 3, 5 pyrimidinyl and a NH at the 3- or 4-position when Ar is indolyl.

In one embodiment, the bridged morpholine group,

is selected from 8-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 3-oxa-6- azabicyclo[3.1.1]heptane, 3-oxa-9-azabicyclo[3.3.1]nonane, 3,7-dioxa-9- azabicyclo[3.3.1]nonane, 7-methyl-3-oxa-7,9-diazabicyclo[3.3.1 ]nonane, 3-oxa-7,9- diazabicyclo[3.3.1 ]nonane, 7-ethyl-3-oxa-7,9-diazabicyclo[3.3.1 ]nonane, 9-oxa-3- azabicyclo[3.3.1]nonane, 3,9-dioxa-7-azabicyclo[3.3.1 ]nonane, 9-oxa-3,7- diazabicyclo[3.3.1]nonane, 3-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane, 3-ethyl-9- oxa-3,7-diazabicyclo[3.3.1]nonane, 6,8-dioxa-3-azabicyclo[3.2.1]octane, 2-oxa-5- azabicyclo[2.2.1]heptane, and 2-oxa-5-azabicyclo[2.2.2]octane.

According to one embodiment, the invented compound is selected from: 1-(4-(7-(8-oxa-

3-azabicyclo[3.2.1]octan-3-yl)-3-(2,2,2-thfluoroethyl)-3H-[1 ,2,3]thazolo[4,5-d]pyhmidin-5- yl)phenyl)-3-(pyridin-4-yl)urea, 1 -(4-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(2,2,2- trifluoroethyl)-3H-[1 ,2,3]tnazolo[4,5-d]pynmidin-5-yl)phenyl)-3-(4-(4-methylpiperazin-1- yl)phenyl)urea, 1 -(4-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(2,2,2-trifluoroethyl)-3H- [1 ,2,3]triazolo[4,5-d]pyrirnidin-5-yl)phenyl)-3-(pyridin-3-yl)urea, 2-hydroxyethyl 4-(7-(8- oxa-3-azabicyclo[3.2.1 ]octan-3-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]triazolo[4,5- d]pyrimidin-5-yl)phenylcarbamate, 1-(4-(7-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3- (2,2,2-tπfluoroethyl)-3H-[1 ,2,3]tπazolo[4,5-d]pyrimidin-5-yl)phenyl)-3-(pyridin-4-yl)urea, 1-(4-(7-(3-oxa-8-azabicyclo[3.2.1 ]octan-8-yl)-3-(2,2,2-trifluoroethyl)-3H- [1 ,2,3]triazolo[4,5-d]pyrirnidin-5-yl)phenyl)-3-(4-(4-methylpiperazin-1 -yl)phenyl)urea, 1 - (4-(7-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]triazolo[4,5- d]pyrirnidin-5-yl)phenyl)-3-(pyridin-3-yl)urea, and 2-hydroxyethyl 4-(7-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-5- yl)phenylcarbamate, 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea, 1 -{4-[4-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]phenyl}-3-pyridin- 4-ylurea, 1-{4-[2-(dimethylamino)-ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1 ]oct- 8-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]phenyl}urea, 1 -methyl-3-{4-[4-(3-oxa-8- azabicyclo-[3.2.1]oct-8-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]phenyl}urea, 1 -{4- ^-(S-oxa-δ-azabicyclotS^.iloct-δ-yO^^-dihydro-SH-pyranoμ^-dlpyπmidin^- yl]phenyl}-3-pyridin-4-ylurea, 2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)- 7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]phenyl}carbamate, 1 -{4-[4-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]phenyl}-3-pyridin- 4-ylurea, 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8- yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]phenyl}urea, 2-hydroxyethyl {4-[4-(8-oxa- 3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl]phenyl}carbamate, 1 -{4-[4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea, 1-{4-[2-

(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro- 5H-pyrano[4,3-d]pyrimidin-2-yl]phenyl}urea, 1 -[4-(4-methylpiperazin-1 -yl)phenyl]-3-{4-[4- (3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl]phenyl}urea, 1 -methyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-7,8-dihydro-5H- pyrano[4,3-d]pyrimidin-2-yl]phenyl}urea, 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7,8- dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea, 1 -{4-[7-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-5- yl]phenyl}-3-pyridin-4-ylurea, 2-hydroxyethyl {4-[7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-3- (2,2,2-trifluoroethyl)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl]phenyl}carbamate, 1 -{4-[7-(3- oxa-8-azabicyclo[3.2.1]oct-8-yl)-3-(2,2,2-tπfluoroethyl)-3H-[1 ,2,3]triazolo[4,5-d]pyπmidin- 5-yl]phenyl}-3-pyridin-3-ylurea, 2-hydroxyethyl {4-[7-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl]phenyl}carbamate, 1 -{4-[7- (8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]triazolo[4,5- d]pyrirnidin-5-yl]phenyl}-3-pyridin-3-ylurea, 1 -(4-{[4-(1 -methylethyl)piperazin-1 - yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H- pyrano[4,3-d]pyrimidin-2-yl]phenyl}urea, 1 -[4-(4-methylpiperazin-1 -yl)phenyl]-3-{4-[7-(8- oxa-3-azabicyclo[3.2.1]oct-3-yl)-3-(2,2,2-tπfluoroethyl)-3H-[1 ,2,3]tπazolo[4,5-d]pyrimidin- 5-yl]phenyl}urea, 1-{4-[7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-3-(2,2,2-trifluoroethyl)-3H- [1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl]phenyl}-3-pyridin-4-ylurea, 1 -(4-(4-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)phenyl)-3-(4-(4- isopropylpiperazine-1-carbonyl)phenyl)urea, 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrirnidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1- yl)phenyl)urea, 1 -(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3- d]pyrirnidin-2-yl)phenyl)-3-(pyridin-4-yl)urea and pharmaceutically acceptable salts thereof

In other aspects, the invention provides pharmaceutical compositions comprising compounds or pharmaceutically acceptable salts of the compounds of the present Formula I. and a pharmaceutically acceptable carrier.

In other aspects, the invention provides a pharmaceutically acceptable carrier suitable for oral administration and the composition comprises an oral dosage form.

In other aspects, the invention provides pharmaceutical compositions comprising compound of claim 1 ; a second compound selected from the group consisting of a topoisomerase I inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L- asparaginase, doxorubicin, epirubicin, 5-fluorouracil, docetaxel, paclitaxel, leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogen mustards, BCNU, carmustine, lomustine, vinblastine, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, imatinib mesylate, Avastin (bevacizumab), hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin, and lavendustin A; and a pharmaceutically acceptable carrier.

In other aspects, the second compound is Avastin.

In other aspects, the invention provides a method of treating a PI3K-related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat a PI3K-related disorder.

In other aspects, the PI3K-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer.

In other aspects, the PI3K-related disorder is cancer.

In other aspects, the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.

In other aspects, the invention provides a method of treating an mTOR-related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat an mTOR-related disorder.

In other aspects, the mTOR-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer.

In other aspects, the mTOR-related disorder is cancer.

In other aspects, the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.

In other aspects, the invention provides a method of treating a cancer selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer comprising administering to a mammal in need thereof a composition comprising a compound of Formula I; a second compound selected from the group consisting of a topoisomerase I inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopuhne, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil, docetaxel, paclitaxel, leucovohn, levamisole, irinotecan, estramustine, etoposide, nitrogen mustards, BCNU, carmustine, lomustine, vinblastine, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, imatinib mesylate, Avastin (bevacizumab), hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin, and lavendustin A; and a pharmaceutically acceptable carrier, in an amount effective to treat the cancer.

In other aspects, the invention provides a method of inhibiting mTOR in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit mTOR.

In other aspects, the invention provides a method of inhibiting PI3K in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit PI3K.

In other aspects, the invention provides a method of inhibiting both mTOR and PI3K in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit both mTOR and PI3K.

Representative "pharmaceutically acceptable salts" include but are not limited to, e.g., water-soluble and water-insoluble salts, such as the acetate, aluminum, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzathine (N,N'-dibenzylethylenediamine), benzenesulfonate, benzoate, bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, choline, citrate, clavulariate, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate (camphorsulfonate), esylate (ethanesulfonate), ethylenediamine, fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, glutamate, hexafluorophosphate, hexylresorcinate, hydrabamine (N₁N'- bis(dehydroabietyl)ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, iodide, isothionate (2- hydroxyethanesulfonate), lactate, lactobionate, laurate, lauryl sulfate, lithium, magnesium, malate, maleate, mandelate, meglumine (1-deoxy-1 -(methylamino)-D- glucitol), mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate (4,4'- methylenebis-3-hydroxy-2-naphthoate, or embonate), pantothenate, phosphate, picrate, polygalacturonate, potassium, propionate, p-toluenesulfonate, salicylate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate (8-chloro-3,7-dihydro-1 ,3-dimethyl-1 H-puhne-2,6-dione), thethiodide, tromethamine (2-amino-2-(hydroxymethyl)-1 ,3-propanediol), valerate, and zinc salts.

Some compounds within the present invention possess one or more chiral centers, and the present invention includes each separate enantiomer of such compounds as well as mixtures of the enantiomers. Where multiple chiral centers exist in compounds of the present invention, the invention includes each combination as well as mixtures thereof. All chiral, diastereomeric, and racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials.

An "effective amount" when used in connection a compound of the present invention of this invention is an amount effective for inhibiting mTOR or PI3K in a subject.

The following definitions are used in connection with the compounds of the present invention unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated "C_x-Cy", where x and y are the lower and upper limits, respectively. For example, a group designated as "C_rC₆" contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.

"Alkenyl-" refer to a straight or branched chain unsaturated hydrocarbon containing at least one double bond. Examples of a C₂-Cioalkenyl- group include, but are not limited to, ethylene, propylene, 1 -butylene, 2-butylene, isobutylene, sec- butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, 4-octene, 1-nonene, 2- nonene, 3-nonene, 4-nonene, 1-decene, 2-decene, 3-decene, 4-decene and 5-decene. An alkenyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, (Ci-C₆alkyl)amino-, di(C_rC₆alkyl)amino-, (Ci-C₆alkyl)C(O)N(C_r C₃alkyl)-, (C_rC₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (C_rC₆alkyl)NHC(O)-, di(C_r C₆alkyl)NC(O)-, NC-, hydroxyl, C_rC₆alkoxy-, d-C₆alkyl-, HO₂C-, (C_r C₆alkoxy)carbonyl-, (CrC₆alkyl)C(O)-, C₆-Ci₄aryl-, Ci-Cgheteroaryl-, and C₃- Cscycloalkyl-.

"Alkoxy-" refers to the group R-O- where R is an alkyl group, as defined below. Exemplary C-i-Cδalkoxy- groups include but are not limited to methoxy, ethoxy, n- propoxy, 1-propoxy, n-butoxy and t-butoxy. An alkoxy group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, Ci-Cεalkoxy-, H₂N-, (Ci-C₆alkyl)amino-, di(C_rC₆alkyl)amino-, (Ci-C₆alkyl)C(O)N(CrC₃alkyl)-, (C_r C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (C_rC₆alkyl)NHC(O)-, di(C_r C₆alkyl)NC(O)-, NC-, C_rC₆alkoxy-, HO₂C-, (C_rC₆alkoxy)carbonyl- , (C_rC₆alkyl)C(O)-, C₆-C-ι₄aryl-, Ci-Cgheteroaryl-, Cs-Cscycloalkyl-, CrC_δhaloalkyl-, CrC_δaminoalkyl-, (Cr C6alkyl)carboxyl-, Ci-CδCarboxyamidoalkyl-, or O₂N-.

"(Alkoxy)carbonyl-" refers to the group alkyl-O-C(O)-. Exemplary (C_r C6alkoxy)carbonyl- groups include but are not limited to methoxy, ethoxy, n-propoxy, 1 - propoxy, n-butoxy and t-butoxy. An (alkoxy)carbonyl group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, H₂N-, (Cr C₆alkyl)amino-, di(C_rC₆alkyl)amino-, (CrC₆alkyl)C(O)N(Ci-C₃alkyl)-, (C_r C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (C_rC₆alkyl)NHC(O)-, di(C_r C₆alkyl)NC(O)-, NC-, C_rC₆alkoxy-, HO₂C-, (C_rC₆alkoxy)carbonyl- , (C_rC₆alkyl)C(O)-, C₆-Ci₄aryl-, C_rC₉heteroaryl-, Cs-Cscycloalkyl-, CrC₆haloalkyl-, CrC₆arninoalkyl-, (C_r C₆alkyl)carboxyl-, C-i-Cecarboxyamidoalkyl-, or O₂N-.

"Alkyl-" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a Ci-Cioalkyl- group may have from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, "alkyl" is a chain (straight or branched) having 1 to 6 (inclusive) carbon atoms in it. Examples of C-i-Cδalkyl- groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. An alkyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, (Ci-C6alkyl)amino-, di(d- C₆alkyl)amino-, (Ci-C₆alkyl)C(O)N(Ci-C₃alkyl)-, (Ci-C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (CrC₆alkyl)NHC(O)-, di(C_rC₆alkyl)NC(O)-, NC-, hydroxyl, C_rC₆alkoxy-, C_r C₆alkyh HO₂C-, (C_rC₆alkoxy)carbonyl-, (C_rC₆alkyl)C(O)-, C₆-Ci₄aryl-, C_rC₉heteroaryl- , Cs-Cscycloalkyl-, C_rC₆haloalkyl-, C_rC₆aminoalkyl-, (CrC₆alkyl)carboxyl-, C_r C_δCarboxyamidoalkyl-, or O₂N-.

"(Alkyl)amino-" refers to an -NH group, the nitrogen atom of said group being attached to an alkyl group, as defined above. Representative examples of an (C_r C6alkyl)amino- group include, but are not limited to CH₃NH-, CH₃CH₂NH-, CH₃CH₂CH₂NH-, CH₃CH₂CH₂CH₂NH-, (CH₃)₂CHNH-, (CH₃)₂CHCH₂NH-, CH₃CH₂CH(CH₃)NH- and (CH₃)₃CNH-. An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, (Ci-C6alkyl)amino-, di(Ci-C₆alkyl)amino-, (C_rC₆alkyl)C(O)N(CrC₃alkyl)-, (C-i-CealkyOcarboxyamido-, HC(O)NH-, H₂NC(O)-, (C_rC₆alkyl)NHC(O)-, di(C_rC₆alkyl)NC(O)-, NC-, hydroxyl, C_r C₆alkoxy-, Ci-C₆alkyl-, HO₂C-, (Ci-C₆alkoxy)carbonyl-, (C_rC₆alkyl)C(O)-, C₆-Ci₄aryl-, d-Cgheteroaryl-, C₃-CsCyClOaI kyl-, C-i-Cδhaloalkyl-, Ci-Cδaminoalkyl-, (Ci- C₆alkyl)carboxyl-, C-i-Cecarboxyamidoalkyl-, or O₂N-.

"(Alkyl)carboxyamido-" refers to a -NHC(O)- group in which the carbonyl carbon atom of said group is attached to an alkyl group, as defined above. Representative examples of a

group include, but are not limited to, - NHC(O)CH₃, -NHC(O)CH₂CH₃, -NHC(O)CH₂CH₂CH₃, -NHC(O)CH₂CH₂CH₂CH₃, - NHC(O)CH₂CH₂CH₂CH₂CH₃, -NHC(O)CH(CH₃)₂, -NHC(O)CH₂CH(CH₃)₂, NHC(O)CH(CH₃)CH₂CH₃, -NHC(O)-C(CH₃)₃ and -NHC(O)CH₂C(CH₃)₃. "-Alkylene-", "-alkenylene-", and "-alkynylene-" refers to alkyl-, alkenyl- and alkynyl- groups, as defined above, having two points of attachment within a chemical structure. Examples of -d-C₆alkylene- include ethylene (-CH₂CH₂-), propylene (- CH₂CH₂CH₂-), and dimethylpropylene (-CH₂C(CHs)₂CH₂-). Likewise, examples of -C₂- Cεalkenylene- include ethenylene (-CH=CH- and propenylene (-CH=CH — CH₂-). Examples of -d-Cεalkynylene- include ethynylene (-C≡C-) and propynylene (-C≡C — CH₂-).

"Alkynyl-" refers to a straight or branched chain unsaturated hydrocarbon containing at least one triple bond. Examples of a C₂-Cioalkynyl- group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1 - pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne, isohexyne, 1 -heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne, 4-octyne, 1 -nonyne, 2-nonyne, 3- nonyne, 4-nonyne, 1 -decyne, 2-decyne, 3-decyne, 4-decyne and 5-decyne. An alkynyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, (C_rC₆alkyl)amino-, di(C_rC₆alkyl)amino-, (Ci-C₆alkyl)C(O)N(CrC₃alkyl)- , (C_rC₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (C_rC₆alkyl)NHC(O)-, CIi(C₁- C₆alkyl)NC(O)-, NC-, hydroxyl, C_rC₆alkoxy-, C_rC₆alkyl-, HO₂C-, (C_r C₆alkoxy)carbonyl-, (Ci-C₆alkyl)C(O)-, C₆-C-ι₄aryl-, d-Cgheteroaryl-, and C₃- Cscycloalkyl-.

"Aryl-" refers to an aromatic hydrocarbon group. Examples of an C6-d₄aryl- group include, but are not limited to, phenyl, 1 -naphthyl, 2-naphthyl, 3-biphen-1 -yl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl. An aryl group can be unsubstituted or substituted with one or more of the following groups: d- Cεalkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(Ci-C₆alkyl)-, H₂N-, aminoalkyl-, di(d- C₆alkyl)amino-, HO₂C-, (C_rC₆alkoxy)carbonyl-, (d-C₆alkyl)carboxyl-, di(d- C₆alkyl)amido-, H₂NC(O)-, (C_rC₆alkyl)amido-, or O₂N-.

"(Aryl)alkyl-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with an aryl group as defined above. (C₆-d₄Aryl)alkyl- moieties include benzyl, benzhydryl, 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. An (aryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, hydroxyl, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, (CrC₆alkyl)C(O)N(Ci-C₃alkyl)-, (Ci-C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (C_r C₆alkyl)NHC(O)-, di(C_rC₆alkyl)NC(O)-, NC-, hydroxyl, C_rC₆alkoxy-, C_rC₆alkyl-, HO₂C- , (CrC₆alkoxy)carbonyl-, (C_rC₆alkyl)C(O)-, C₆-Ci₄aryl-, C_rC₉heteroaryl-, C₃- Cscycloalkyl-, Ci-C₆haloalkyl-, Ci-C₆aminoalkyl-, (d-Cealky^carboxyl-, Cr C_δCarboxyainidoalkyl-, or O₂N-.

"Carboxyamidoalkyl-" refers to a primary carboxyamide (CONH₂), a secondary carboxyamide (CONHR') or a tertiary carboxyamide (CONR¹R"), where R' and R" are the same or different substituent groups selected from CrC_δalkyl-, C₂-C₆alkenyl, C₂- C₆alkynyl, C₆-Ci₄aryl-, C_rC₉heteroaryl-, or OrCscycloalkyl-, attached to the parent compound by an -CrCεalkylene- group as defined above. Exemplary Cr Cecarboxyamidoalkyl- groups include but are not limited to NH₂C(O)-CH₂-, CH₃NHC(O)- CH₂CH₂-, (CH₃)ZNC(O)-CH₂CH₂CH₂-, CH₂=CHCH₂NHC(O)-CH₂CH₂CH₂CH₂-,

HCCCH₂NHC(O)-CH₂CH₂CH₂CH₂CH₂-, C₆H₅NHC(O)-CH₂CH₂CH₂CH₂CH₂CH₂-, 3- PyHdVlNHC(O)-CH₂CH(CH₃)CH₂CH₂-, and cyclopropyl-CH₂NHC(0)-

"Cycloalkyl-" refers to a monocyclic, non-aromatic, saturated hydrocarbon ring. Representative examples of a C₃-C8cycloalkyl- include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl can be unsubstituted or independently substituted with one or more of the following groups: halogen, H₂N-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, (Cr C₆alkyl)C(O)N(CrC₃alkyl)-, (Ci-C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (C_r C₆alkyl)NHC(O)-, di(C_rC₆alkyl)NC(O)-, NC-, hydroxyl, C_rC₆alkoxy-, C_rC₆alkyl-, HO₂C- , (CrC₆alkoxy)carbonyl-, (C_rC₆alkyl)C(O)-, C₆-Ci₄aryl-, C_rC₉heteroaryl-, or C₃- Cscycloalkyl-, CrCεhaloalkyl-, CrCδaminoalkyl-, (CrC6alkyl)carboxyl-, Cr CδCarboxyamidoalkyl-, or O₂N-. Additionally, each of any two hydrogen atoms on the same carbon atom of the carbocyclic ring can be replaced by an oxygen atom to form an oxo (=0) substituent or the two hydrogen atoms can be replaced by an alkylenedioxy group so that the alkylenedioxy group, when taken together with the carbon atom to which it is attached, form a 5- to 7-membered heterocycle containing two oxygen atoms.

"Di(alkyl)amino-" refers to a nitrogen atom attached to two alkyl groups, as defined above. Each alkyl group can be independently selected. Representative examples of an di(CrC6alkyl)amino- group include, but are not limited to, -N(CH₃)₂, - N(CH₂CH₃)(CH₃), -N(CH₂CH₃)₂, -N(CH₂CH₂CH₃)₂, -N(CH2CH₂CH₂CH₃)2, N(CH(CH₃)₂)₂, -N(CH(CH₃)₂)(CH₃), -N(CH₂CH(CH₃)₂)2, -NH(CH(CH₃)CH₂CH₃)₂, - N(C(CH₃)₃)₂, -N(C(CHa)₃)(CH₃), and -N(CH₃)(CH₂CH₃). The two alkyl groups on the nitrogen atom, when taken together with the nitrogen to which they are attached, can form a 3- to 7- membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with -N(H)-, -N(d-C₆alkyl)-, -N(C₃- Cscycloalkyl)-, -N(C₆-d₄aryl)-, -N(C_rC₉heteroaryl)-, -N(C_rC₆aminoalkyl)-, -N(C₆- Ci₄arylamino)-, -O-, -S-, -S(O)-, Or -S(O)₂-.

"Halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

"Heteroaryl-" refers to 5-10-membered mono and bicyclic aromatic groups containing at least one heteroatom selected from oxygen, sulfur and nitrogen. Examples of monocyclic d-Cgheteroaryl- radicals include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, thiadiazoyl, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl, furazanyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, thazolyl, pyrimidinyl, N-pyridyl, 2-pyhdyl, 3-pyhdyl and 4-pyridyl. Examples of bicyclic d- Cgheteroaryl- radicals include but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl, and indazolyl. The contemplated heteroaryl- rings or ring systems have a minimum of 5 members. Therefore, for example, Ci heteroaryl- radicals would include but are not limited to tetrazolyl, C₂heteroaryl- radicals include but are not limited to thazolyl, thiadiazoyl, and tetrazinyl, Cgheteroaryl- radicals include but are not limited to quinolinyl and isoquinolinyl. A heteroaryl group can be unsubstituted or substituted with one or more of the following groups: d-Cealkyl-, halogen, d-C_δhaloalkyl-, hydroxyl, d- Cehydroxylalkyl-, H₂N-, Ci-C₆aminoalkyl-, di(Ci-C₆alkyl)amino-, -COOH, (Ci- C₆alkoxy)carbonyl-, (C_rC₆alkyl)carboxyl-, di(C_rC₆alkyl)amido-, H₂NC(O)-, (C_r C6alkyl)amido-, or O₂N-.

"(Heteroaryl)alkyl-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a heteroaryl- group as defined above. Examples of (d-Cgheteroaryl)alkyl- moieties include 2-pyridylmethyl,

2-thiophenylethyl, 3-pyhdylpropyl, 2-quinolinylmethyl, 2-indolylmethyl, and the like. A

(heteroaryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, hydroxyl, (CrC₆alkyl)amino-, di(CrC₆alkyl)amino-, (CrC₆alkyl)C(O)N(Ci-C₃alkyl)-, (CrC₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (d- C₆alkyl)NHC(O)-, di(C_rC₆alkyl)NC(O)-, NC-, hydroxyl, C_rC₆alkoxy-, C_rC₆alkyl-, HO₂C- , (Ci-C₆alkoxy)carbonyl-, (Ci-C₆alkyl)C(O)-, C₆-Ci₄aryl-, Ci-Cgheteroaryl-, C₃- Cscycloalkyl-, d-C_δhaloalkyl-, d-Ceaminoalkyl-, (Ci-C₆alkyl)carboxyl-, d- Cecarboxyamidoalkyl-, or O₂N-.

"Heteroatom" refers to a sulfur, nitrogen, or oxygen atom.

"Heterocycle" or "heterocyclyl-" refers to 3-10-membered monocyclic, fused bicyclic, and bridged bicyclic groups containing at least one heteroatom selected from oxygen, sulfur and nitrogen. A heterocycle may be saturated or partially saturated. Exemplary d-Cgheterocyclyl- groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1 ,2,3,6-tetrahydropyridine-1 -yl, tetrahydropyran, pyran, thiane, thiine, piperazine, oxazine, 5,6-dihydro-4H-1 ,3-oxazin-2- yl, 2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, 3,6- diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 6-oxa-3,8- diazabicyclo[3.2.1]octane, 7-oxa-2,5-diazabicyclo[2.2.2]octane, 2,7-dioxa-5- azabicyclo[2.2.2]octane, 2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxa-5- azabicyclo[2.2.2]octane, 3,6-dioxa-8-azabicyclo[3.2.1]octane, 3-oxa-6- azabicyclo[3.1.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 5,7-dioxa-2- azabicyclo[2.2.2]octane, 6,8-dioxa-3-azabicyclo[3.2.1]octane, 6-oxa-3- azabicyclo[3.1.1]heptane, 8-oxa-3-azabicyclo[3.2.1 ]octan-3-yl, 8-oxa-3- azabicyclo[3.2.1]octan-3-yl, 2-methyl-2,5-diazabicyclo[2.2.1 ]heptane-5-yl, 1 ,3,3- trimethyl-6-azabicyclo[3.2.1]oct-6-yl, S-hydroxy-δ-azabicycloβ^.iloctan-δ-yl-, 7-methyl- 3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl, 3-oxa-9- azabicyclo[3.3.1]nonan-9-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, 4-methyl-3,4- dihydro-2H-1 ,4-benzoxazin-7-yl, thiazine, dithiane, and dioxane. The contemplated heterocycle rings or ring systems have a minimum of 3 members. Therefore, for example, Ci heterocyclyl- radicals would include but are not limited to oxaziranyl, diazihdinyl, and diazirinyl, diheterocyclyl- radicals include but are not limited to azihdinyl, oxiranyl, and diazetidinyl, Cgheterocyclyl- radicals include but are not limited to azecanyl, tetrahydroquinolinyl, and perhydroisoquinolinyl. Ηeterocyclyl(alkyl)-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a heterocycle group as defined above. Heterocyclyl(C_rC₆alkyl)- moieties include 2-pyhdylmethyl, 1 - piperazinylethyl, 4-morpholinylpropyl, 6-piperazinylhexyl, and the like. A heterocyclyl(alkyl) group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, (Ci-C₆alkyl)amino-, di(C_rC₆alkyl)amino-, (d-

C₆alkyl)C(O)N(C_rC₃alkyl)-, (C_rC₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (C_r

C₆alkyl)NHC(O)-, di(C_rC₆alkyl)NC(O)-, NC-, hydroxyl, C_rC₆alkoxy-, C_rC₆alkyl-, HO₂C-

, (CrCδalkoxyJcarbonyl-, (CrC6alkyl)C(O)-, 4- to 7-membered monocyclic heterocycle, C₆-Ci₄aryl-, C_rC₉heteroaryl-, or Cs-Cscycloalkyk

"Hydroxylalkyl-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with hydroxyl groups.

Examples of C-i-C_δhydroxylalkyl- moieties include, for example, -CH₂OH, -CH₂CH₂OH, -

CH₂CH₂CH₂OH, -CH₂CH(OH)CH₂OH, -CH₂CH(OH)CH₃, -CH(CH₃)CH₂OH and higher homologs.

"Leaving group" refers an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction. For example, in the heterolytic solvolysis of benzyl bromide in acetic acid: the leaving group is bromide. In the reaction of N,N,N-trimethyl- 1-phenylmethanaminium ion with methanethiolate, the leaving group is trimethylamine. In the electrophilic nitration of benzene, it is H⁺. The term has meaning only in relation to a specified reaction. Examples of leaving groups include, for example, carboxylates {i.e. CH₃COO^", CF₃CO₂ ^"), F^", water, Cl^", Br^", I^", N₃ ^", SCN^", trichloroacetimidate, thiopyridyl, tertiary amines (i.e. trimethylamine), phenoxides (i.e. nitrophenoxide), and sulfonates (/. e. tosylate, mesylate, triflate).

"Perfluoroalkyl-" refers to alkyl group, defined above, having two or more fluorine atoms. Examples of a Ci-C_δperfluoroalkyl- group include CF₃, CH₂CF₃, CF₂CF₃ and CH(CF₃)₂.

The term "optionally substituted", unless otherwise specified, as used herein means that at least one hydrogen atom of the optionally substituted group has been substituted with halogen, H₂N-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, (Ci- C₆alkyl)C(O)N(C_rC₃alkyl)-, (C_rC₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (C_r C₆alkyl)NHC(O)-, di(C_rC₆alkyl)NC(O)-, NC-, hydroxyl, C_rC₆alkoxy-, C_rC₆alkyl-, HO₂C- , (CrC₆alkoxy)carbonyl-, (C_rC₆alkyl)C(O)-, C₆-Ci₄aryl-, C_rC₉heteroaryl-, or C₃- Cscycloalkyl-.

A "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or gorilla.

The compounds of the present invention exhibit an mTOR inhibitory activity and, therefore, can be utilized to inhibit abnormal cell growth in which mTOR plays a role. Thus, the compounds of the present invention are effective in the treatment of disorders with which abnormal cell growth actions of mTOR are associated, such as restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, cancer, etc. In particular, the compounds of the present invention possess excellent cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas, and especially, leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, advanced renal cell carcinoma, acute lymphoblastic leukemia, malignant melanoma, soft-tissue or bone sarcoma, etc.

The compounds of the present invention exhibit a PI3 kinase inhibitory activity and, therefore, can be utilized in order to inhibit abnormal cell growth in which PI3 kinases play a role. Thus, the compounds of the present invention are effective in the treatment of disorders with which abnormal cell growth actions of PI3 kinases are associated, such as restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, cancer, etc. In particular, the compounds of the present invention possess excellent cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas, and especially, leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, advanced renal cell carcinoma, acute lymphoblastic leukemia, malignant melanoma, soft-tissue or bone sarcoma, etc.

For therapeutic use, the pharmacologically active compounds of Formula I will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in association with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjutants and excipients employing standard and conventional techniques.

The pharmaceutical compositions of this invention include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous) bronchial or nasal administration. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The solid carrier may contain conventional excipients such as binding agents, fillers, tableting lubricants, disintegrants, wetting agents and the like. The tablet may, if desired, be film coated by conventional techniques. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring agents. For parenteral administration, a vehicle normally will comprise sterile water, at least in large part, although saline solutions, glucose solutions and like may be utilized. Injectable suspensions also may be used, in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and the like also may be added to the parenteral dosage forms. Particularly useful is the administration of a compound of Formula I directly in parenteral formulations. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula I according to the invention. See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition. Baltimore, MD: Lippincott Williams & Wilkins, 2000.

The dosage of the compounds of Formula I to achieve a therapeutic effect will depend not only on such factors as the age, weight and sex of the patient and mode of administration, but also on the degree of potassium channel activating activity desired and the potency of the particular compound being utilized for the particular disorder of disease concerned. It is also contemplated that the treatment and dosage of the particular compound may be administered in unit dosage form and that one skilled in the art would adjust the unit dosage form accordingly to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect.

A suitable dose of a compound of Formula I or pharmaceutical composition thereof for a mammal, including man, suffering from, or likely to suffer from any condition as described herein is an amount of active ingredient from about 0.01 mg/kg to 10 mg/kg body weight. For parenteral administration, the dose may be in the range of 0.1 mg/kg to 1 mg/kg body weight for intravenous administration. For oral administration, the dose may be in the range about 0.1 mg/kg to 5 mg/kg body weight. The active ingredient will preferably be administered in equal doses from one to four times a day. However, usually a small dosage is administered, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.

However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound of be administered, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

The amount of the compound of the present invention or a pharmaceutically acceptable salt thereof that is effective for inhibiting mTOR or PI3K in a subject. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, the condition, the seriousness of the condition being treated, as well as various physical factors related to the individual being treated, and can be decided according to the judgment of a health-care practitioner. Equivalent dosages may be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months. The number and frequency of dosages corresponding to a completed course of therapy will be determined according to the judgment of a health-care practitioner. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one compound of the present invention or a pharmaceutically acceptable salt thereof is administered, the effective dosage amounts correspond to the total amount administered.

In one embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered concurrently with another therapeutic agent.

In one embodiment, a composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and an effective amount of another therapeutic agent within the same composition can be administered.

Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective amount range. The compound of the present invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent can act additively or, in one embodiment, synergistically. In one embodiment, of the invention, where another therapeutic agent is administered to an animal, the effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof is less than its effective amount would be where the other therapeutic agent is not administered. In this case, without being bound by theory, it is believed that the compound of the present invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent act synergistically.

In another embodiment, a method of treating advanced renal cell carcinoma, comprising administering to a mammal in need thereof the compounds or a pharmaceutically acceptable salt of the compounds of the present Formula I in an amount effective to treat advanced renal cell carcinoma. In another embodiment, a method of treating acute lymphoblastic leukemia, comprising administering to a mammal in need thereof the compounds or a pharmaceutically acceptable salt of the compounds of any of the present Formula I in an amount effective to treat acute lymphoblastic leukemia.

In another embodiment, a method of treating acute lymphoblastic leukemia, comprising administering to a mammal in need thereof the compounds or a pharmaceutically acceptable salt of the compounds of any of the present Formula I in an amount effective to treat malignant melanoma.

In another embodiment, a method of treating acute lymphoblastic leukemia, comprising administering to a mammal in need thereof the compounds or a pharmaceutically acceptable salt of the compounds of any of the present formula I in an amount effective to treat soft-tissue or bone sarcoma.

Procedures used to synthesize the compounds of the present invention are described in Schemes 1-5 and are illustrated in the examples. Reasonable variations of the described procedures are intended to be within the scope of the present invention:

Scheme 1

One synthetic route to 4-ureidophenyl- or 4-carbamophenyl-4-bridged morpholino quinazoline compounds of the present invention is summarized in Scheme 1. Reaction of 2,4-dichloroquinazoline (1 ) with an equivalent of a bridged morpholine, 8-oxa-3- azabicyclo[3.2.1]octane (2), provided the bridged morpholino-quinazoline compound of formula 3. The bridged morpholino-quinazoline compound is substituted with an anilino group by a metal catalyzed Suzuki coupling reaction using 4-aminophenylboronic to provide the bridged morpholino-quinazoline compound of formula 4. Subsequent treatment of the compound of formula 4 with thphosgene followed by a primary amine, gave access to the invented ureidoaryl-bhdged morpholine quinazoline compounds of formula 5.

Scheme 2

Scheme 2 summarizes a method for preparing ureidoaryl-substituted fused ring, bridged morpholino-pyrimidine compounds of the present invention. Reaction of 2- chlorobenzonitrile with methyl oxalate and cesium carbonate in dimethylformamide solvent provided the fused ring compound of formula 6, methyl 3-aminobenzofuran-2- carboxylate. Reaction of the fused ring compound of formula 6 with p- nitrophenylbenzoyl chloride and triethylamine followed by DMAP in methylene chloride solvent provided the nitrophenyl substituted benzofuran compound of formula 7. The compound of formula 7 was reacted with ammonia in methanol and tetrahydrofuran and provided the carboxamido substituted benzofuran compound of formula 8. Ring closure of the compound of formula 8 was accomplished using sodium hydroxide in alcohol solvent and provided the tricyclic pyrimidine-4(3H)-one compound of formula 9. Reaction of the compound of formula 9 with phosphorus oxychloride in DMF provided the chloro derivative of the tricyclic pyhmidine-4(3H)-one compound of formula 10. The compound of formula 10, reacted with an equivalent of a bridged morpholine, 8-oxa-3- azabicyclo[3.2.1]octane (2), to provide the bridged morpholino compound of formula 1 1. The nitrophenyl group of the compound of formula 1 1 upon reduction using iron and ammonium chloride provided the compound of formula 12. Fused, tricyclic carbamophenyl-bhdged morpholino pyrimidines of the formula 12 were converted into compounds of this invention by treatment with thphosgene followed by addition of the required amine or alcohol, as previously described.

Scheme 3

X = O, NH Scheme 3 summarizes methods for preparing compounds of the present invention. Ureidophenyl bridged morpholino triazolo pyrimidine compounds were prepared by the following synthetic methods. The dichloropyrimidine compound was reacted with an equivalent of a bridged morpholine pyrimidine to provide the bridged morpholino pyrimidine compound. Reaction of the bridged morpholino pyrimidine compound with an alkyl amino compound provided the substituted bridged morpholino pyrimidine compound. Reduction of the nitro group substituted on the pyridine core of the substituted bridged morpholino pyrimidine compound using Raney nickel and hydrogen provided the amino group substituted on the pyrimidine core. Cyclization of the amino derivative of the bridged morpholino pyrimidine compound using sodium nitrite in acetic acid provided the ring fused thazolopyhmidine compound. The aniline boronate was substituted on the pyrimidine core using a palladium catalyzed Suzuki coupling reaction and provided the anilino derivative. Reaction of the anilino derivative with thphosgene followed by addition of the required amine or alcohol, as previously described, provided the invented Ureidophenyl- or carbamophenyl bridged morpholino thazolopyhmidine compounds.

Scheme 4

Scheme 4 summarizes methods for preparing ring fused ureidophenyl- or carbamophenyl-bhdged morpholino pyranopryrimidine compounds of the present invention. Reaction of 2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyhmidine (14) with an equivalent of a bridged morpholine provided the bridged 4-bhdged morpholino-7,8- dihydro-5H-pyrano[4,3-d]pyhmidine compound of formula 15. A palladium catalyzed Suzuki coupling of a 4-anilinoboronate to the compound of formula 15 provided the coupled product of formula 16. Reaction of the anilino derivative with thphosgene followed by addition of the required amine or alcohol, as previously described, provided the invented ureidophenyl- or carbamophenyl bridged morpholino-7,8-dihydro-5H- pyrano[4,3-d]pyrimidine compounds of formula 17.

Scheme 5

Scheme 5 summarizes methods for preparing ring fused ureidophenyl- or carbamophenyl-bhdged morpholino cyclopenta[d]pryrimidine compounds of the present invention. Reaction of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyhmidine (18) with an equivalent of a bridged morpholine provided the bridged 4-bhdged morpholino-6,7- dihydro-5H-cyclopenta[d]pyhmidine compound of formula 19. A palladium catalyzed Suzuki coupling of a 4-anilinoboronate to the compound of formula 19 provided the coupled product of formula 20. Reaction of the anilino derivative with thphosgene followed by addition of the required amine or alcohol, as previously described, provided the invented ureidophenyl- or carbamophenyl bridged morpholino-6,7-dihydro-5H- cyclopenta[d]pyhmidine compounds of formula 21 .

EXAMPLES

The following abbreviations are used herein and have the indicated definitions: ATP is adenosine triphosphate, βME is 2-mercaptoethanol, BSA is Bovine Serum Albumin, CHAPS is (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid, DELFIA is Dissociation-Enhanced Lanthanide Fluorescent Immunoassay, DME is 1 ,2- dimethoxyethane, DMF is N,N-dimethylformamide, DMSO is dimethylsulfoxide, DPBS is Dulbecco's Phosphate Buffered Saline Formulation. DTT is (2S,3S)-1 ,4-bis- sulfanylbutane-2,3-diol or dithiothreitol, EDTA is ethylenediaminetetraacetic acid, EGTA is ethylene glycol tetraacetic acid, EtOAc is ethyl acetate, FLAG-TOR is a FLAG-tagged TOR protein, HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, and HPLC is high-pressure liquid chromatography. Magnesol™ is a hydrated, synthetic, amorphous magnesium silicate. Magnesol™ is a registered trademark of the Dallas Group of America Inc. Microcrystin LR is a cyclic heptapeptide hepatotoxin produced Microcystis aeruginosa containing the amino acids leucine (L) and arginine (R) in the variable positions, MS is mass spectrometry, mTOR is Mammalian Target of Rapamycin (a protein), MTS is 3-(4, 5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-( 4-sulfophenyl)-2H-tetrazolium, inner salt, PBS is phosphate- buffered saline (pH 7.4), PI3K is phosphoinositide 3-kinase (an enzyme), RPMI 1640 is a buffer (Sigma-Aldhch Corp., St. Louis, MO, USA), RT is retention time, SDS is dodecyl sulfate (sodium salt), SRB is Sulforhodamine B, TAMRA is tetramethyl-6- carboxyrhodamine, TFA is thfluoroacetic acid, THF is tetrahydrofuran, and TRIS is ths(hydroxymethyl)aminomethane.

The following exemplary compounds illustrate, but are not meant to limit the scope of the invented compounds, as summarized in Schemes 1-5.

Example 1 : Preparation of 4-Ureidophenyl-or 4-carbamophenyl-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)quinazolin-2-yl) compounds

3-(2-chloroquinazolin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (3) To 2,4-dichloroquinazoline (1 , 500 mg, 2.5 mmol) and 8-oxa-3-aza- bicyclo[3.2.1]octane HCI (2, 390 mg, 2.6 mmol) in dichloromethane (15 mL) was added thethylamine (0.98 mL, 7.5 mmol). After 18 hours, the reaction mixture was concentrated in vacuo to give compound 3 as a white powder (1 .3 g).

4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)quinazolin-2-yl)aniline (4)

3-(2-Chloroquinazolin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (2) (1.0 g), 4- aminophenylboronic acid, pinacol ester (660 mg), toluene (7.5 mL), EtOH (7.5 mL), 2M aqueous Na₂COs and tetrakis(thphenylphosphine) palladium (230 mg) were heated by microwave irradiation (1 hour, 120° C). After cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic extracts were washed with brine and dried over MgSO₄ and concentrated in vacuo to result in a dark syrup. Purification by RP HPLC gave the title compound as a yellow foam (0.52 g). A mixture of 2,4-dichloro-pyhdo[2,3-d]pyrimidine (200 mg, 1.00 mmol), morpholine (104mg, 1.20mmol) and triethyl amine (120 mg, 1.20 mmol) in 4 mL of THF was stirred at room temperature for 6 hours. Then the reaction mixture was diluted with 200 mL of ethyl acetate and the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer then was collected and dried over anhydrous sodium sulfate and concentrated to give 2-chloro-4-morpholin-4-yl-pyrido [2, 3-d] pyrimidine (4, 250mg, 100% yield) as a light yellow solid. HPLC: RT = 0.27 min; MS 251 , 253 [M+H].

Urea or carbamate formation (5)

4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)quinazolin-2-yl)aniline (0.52 g, 1.6 mmol) in dichloromethane (24 mL) was divided evenly among eight 20 mL vials. A solution of thphosgene (0.24 g, 0.8 mmol) in dichloromethane (8 mL) was divided evenly among the vials followed by addition of thethylamine (300 μL) to each vial. After 20 minutes, an excess of amine, aniline or alcohol was added to give the corresponding urea or carbamate, after purification by RP HPLC. MS m/z = 342.0 (M+H).

Example 2: Preparation of 4-ureidophenyl- or 4-carbamophenyl-4-(8-oxa-3- azabicycloIS^.Iloctan-S-ylJpyridoIS'^'^.SlfuroIS^-dlpyrimidin^-yl) compounds Methyl 3-aminobenzofuran-2-carboxylate (6)

CS₂CO3 (47g, 144 mmol) was added to a solution of methyl oxalate (7.8g, 87 mmol) in DMF (40 ml_). 2-Chloronicotinitrile (1 Og, 72 mmol) was added as a solution in DMF (40 ml_). The reaction mixture was heated at 85° C for 2 hours. After cooling, dichlormethane was added (100 ml_). Filtration through a sintered glass funnel and concentration in vacuo gave a residue that was dissolved in CH₂CI₂ and filtered through a short column of silica gel. Elution with CH₂CI₂/acetone provided compound 6 as a pale yellow solid (1 1 .2 g). 1 .76 g of this material was purified by RP HPLC to give 0.46 g of compound 6 as an off white solid.

Methyl 3-(4-nitrobenzamido)furo[2,3-b]pyridine-2-carboxylate (7)

Methyl 3-aminobenzofuran-2-carboxylate (6, 0.46g, 2.4 mmol) in dichloromethane (20 ml.) was treated with p-nitrobenzoyl chloride (0.67g, 3.6 mmol). Thethylamine (1 mL) was added, followed by DMAP (30 mg) and additional p-nitrobenzoyl chloride (200 mg). After 18 hours, the reaction mixture was concentrated. Pyridine (50 mL) was added followed by water (5 mL) and concentrated aqueous NH₄OH. Filtration and washing with water, THF, and methanol gave, after drying in vacuo, the compound 7 as a white solid.

^(^(δ-oxa-S-azabicycloia^.iloctan-a-yOpyridoia'^'^.Slfuroia^-dlpyrimidin^- yl)aniline (12).

A stream of NH₃ gas was bubbled into a mixture of MeOH (10 mL) and THF (20 mL) at -78° C for 10 minutes in a sealable tube. Methyl 3-(4-nitrobenzamido)furo[2,3- b]pyhdine-2-carboxylate (0.54 g, 1.6 mmol) was then added as a solid. The tube was sealed and allowed to warm to room temperature. After 18 hours, the reaction mixture was concentrated in vacuo to give 3-(4-Nitrobenzamido)furo[2,3-b]pyridine-2- carboxamide (8) as a solid. MS m/z = 327.0 (M+H) To this solid was added iPrOH (40 mL) and aqueous NaOH (2.5 M, 20 mL). The reaction mixture was heated at reflux for 1.5 hours, then allowed to cool to ambient temperature. After 18 hours, the precipitate was collected by filtration, washed with water and dried in vacuo to give 2-(4- nitrophenyl)-pyrido[3',2':4,5]furo[3,2-d]pyhmidin-4(3H)-one, (9) as a solid (600 mg); MS m/z = 309.0 (M+H). The solid was treated with POCI₃ (5 mL) and one drop of DMF and heated at 190° C for 1 hour. The reaction mixture was concentrated in vacuo, CH₃CN and Et₃N were added and then removed in vacuo to give the chloride 10 as a solid; MS m/z = 327.0, 329.0 (M+H) To the chloride compound 10 in EtOH (12 ml.) was added 8- oxa-3-aza-bicyclo[3.2.1 ]octane.HCI (2, 100 mg) and thethylamine (1 ml_). The reaction mixture was heated at 160° C for 10 minutes. After allowing the reaction mixture to cool, water was added and the solid compound (11 ) was collected by filtration (507 mg). MS m/z = 374.2 (M+H) Compound 11 (0.48 g), Fe (0) (0.67 g), and NH₄CI (32 mg) in 4:1 EtOH:H₂O (5 mL) was heated at reflux for 1 hour and then allowed to cool. Concentration in vacuo and addition of 4:1 EtOAc:Et₃N (10 mL) resulted in a suspension, which was applied to a short column of silica gel. Elution with additional 4:1 EtOAc:Et₃N followed by elution with 20%Et₃N/THF gave, after concentration in vacuo, the aniline (12) as an orange brown solid (290 mg). MS m/z = 374.2 (M+H).

Urea or carbamate formation (13)

4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyhdo[3',2':4,5]furo[3,2-d]pyrimidin-2-yl)aniline (12, 0.15 g) in 20% Et3N/THF (18 mL) was divided into 3 vials. A solution of triphosgene (90 mg) in THF (6 mL) was divided evenly into each vial. After 5 minutes, an amine or alcohol was added. Concentration in vacuo and purification by RP HPLC gave the desired invented compounds.

The following examples were prepared using the synthetic methods:

Example 3: 1-(4-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(2,2,2-thfluoroethyl)-3H- [1 ,2,3]thazolo[4,5-d]pyhmidin-5-yl)phenyl)-3-(pyridin-4-yl)urea

Example 4: 1-(4-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(2,2,2-thfluoroethyl)-3H- [1 ,2,3]triazolo[4,5-d]pyhmidin-5-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Example s: 1-(4-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(2,2,2-thfluoroethyl)-3H- [1 ,2,3]thazolo[4,5-d]pyhmidin-5-yl)phenyl)-3-(pyridin-3-yl)urea

Example 6: 2-hydroxyethyl 4-(7-(8-oxa-3-azabicyclo[3.2.1 ]octan-3-yl)-3-(2,2,2- trifluoroethyl)-3H-[1 , 2, 3]triazolo[4,5-d]pyrimidin-5-yl)phenyl carbamate

Example 7: 1-(4-(7-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(2,2,2-thfluoroethyl)-3H- [1 ,2,3]thazolo[4,5-d]pyhmidin-5-yl)phenyl)-3-(pyridin-4-yl)urea Example 8: 1 -(4-(7-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(2,2,2-trifluoroethyl)-3H- [1 ,2,3]triazolo[4,5-d]pynmidin-5-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Example 9: 1 -(4-(7-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(2,2,2-trifluoroethyl)-3H- [1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl)phenyl)-3-(pyridin-3-yl)urea

Example 10: 2-hydroxyethyl 4-(7-(3-oxa-8-azabicyclo[3.2.1 ]octan-8-yl)-3-(2,2,2- trifluoroethyl)-3H-[1 , 2, 3]triazolo[4,5-d]pyιϊmidin-5-yl)phenyl carbamate

Preparation of 4-ureidophenyl- or 4-carbamophenyl-4-(3-oxa-8- azabicycloIS^.Iloctan-δ-yO-y.δ-dihydro-SH-pyrano^S-dlpyrimidine compounds

4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloro-7,8-dihydro-5H-pyrano[4,3- djpyrimidine

To 2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (500 mg, 2.4 mmol) and 3-oxa- 8-aza-bicyclo[3.2.1]octane.HCI (401 mg) in dichloromethane (4 ml.) and ethanol (4 ml.) was added thethylamine (0.68 ml_, 4.88 mmol). After 72 hours, the reaction mixture was subjected to an aqueous workup and chromatographed on silica gel (EtOAc/hexanes) to give the title compound as a white solid (360 mg).

4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin- 2-yl)aniline

4-(3-oxa-8-azabicyclo[3.2.1 ]octan-8-yl)-2-chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (0.36 g), 4-aminophenylboronic acid, pinacol ester (336 mg), toluene (2.5 ml_), EtOH (2.5 ml_), 2M aqueous Na2CO3 (0.64 ml.) and tetrakis(thphenylphosphine) palladium (148 mg) were heated by microwave irradiation (20 min, 140C). After cooling, the reaction mixture was subjected to an aqueous workup and filtered through Magnesol™ to give the title compound as a yellow solid (290 mg).

Urea or carbamate formation

To a solution of triphosgene (127 mg) in dichloromethane (1 mL) was added a suspension of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-5H-pyrano[4,3- d]pyhmidin-2-yl)aniline (290 mg) and thethylamine (0.358 mL) in dichloromethane dropwise over 2 min. The reaction mixture was divided evenly among several vials. To the vials was added an amine or alcohol to give the following ureas and carbamates after purification by RP HPLC:

Example 12: 1-[4-(4-methylpiperazin-1 -yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct- 8-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]phenyl}urea

Example 13: 1-methyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H- pyrano[4,3-d]pyrimidin-2-yl]phenyl}urea

Example 14: 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyhmidin-2-yl]phenyl}urea

Example 15: 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H-pyrano[4,3- d]pyhmidin-2-yl]phenyl}-3-pyhdin-3-ylurea

Example 16: 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H-pyrano[4,3- d]pyhmidin-2-yl]phenyl}-3-pyhdin-4-ylurea

Example 17: 2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-5H- pyrano[4,3-d]pyrimidin-2-yl]phenyl}carbamate

Preparation of 4-ureidophenyl- or 4-carbamophenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane compounds

3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-8-oxa-3- azabicyclo[3.2.1]octane

To 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (500 mg, 2.64 mmol) and 3-oxa- 8-aza-bicyclo[3.2.1]octane.HCI (435 mg) in dichloromethane (4 ml.) and ethanol (4 ml.) was added thethylamine (0.737 ml_, 5.29 mmol). After 72 hours, the reaction mixture was subjected to an aqueous workup and chromatographed on silica gel (EtOAc/hexanes) to give the title compound as a white solid (495 mg).

4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 2-yl)aniline 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1 ]octane (0.495 g, 1 .86 mmol), 4-aminophenylboronic acid, pinacol ester (490 mg), toluene (3.7 ml_), EtOH (3.7 ml_), 2M aqueous Na2CO3 (0.93 mL) and tetrakis(thphenylphosphine) palladium (215 mg) were heated by microwave irradiation (20 minutes, 140° C). After cooling, the reaction mixture was subjected to an aqueous workup and filtered through Magnesol™. The resulting solid was triturated with ether/hexanes to give the title compound as a white solid (417 mg).

Urea formation

To a solution of triphosgene (138 mg) in dichloromethane (1 mL) was added a suspension of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)aniline (300 mg) and triethylamine (0.389 mL) in dichloromethane dropwise over 2 min. The reaction mixture was divided evenly among several vials. To the vials was added an amine to give the corresponding ureas or after purification by RP HPLC:

Example 18: 1-[4-(4-methylpiperazin-1 -yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct- 8-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]phenyl}urea

Example 19: 2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H- cyclopentatdjpyhmidin^-yljphenyljcarbamate

Example 20: 1-methyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H- cyclopenta[d]pyhmidin-2-yl]phenyl}urea

Example 21 : 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-cyclopenta[d]pyhmidin-2-yl]phenyl}urea

Example 22: 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]phenyl}-3-pyhdin-3-ylurea

Example 23: 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]phenyl}-3-pyhdin-4-ylurea Example 24: 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-cyclopenta[d]pyrirnidin-2-yl]phenyl}urea

Example 25: 1-methyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]phenyl}urea

Example 26: 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H-pyrano[4,3- d]pyrirnidin-2-yl]phenyl}-3-pyridin-4-ylurea

Example 27: 2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-5H- pyrano[4,3-d]pyrimidin-2-yl]phenyl}carbamate

Example 28: 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H- cyclopenta[d]pyrirnidin-2-yl]phenyl}-3-pyridin-4-ylurea

Example 29: 1-[4-(4-methylpiperazin-1 -yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct- 8-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]phenyl}urea

Example 30: 2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H- cyclopentatdlpyrimidin^-yllpheny^carbamate

Example 31 : 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea

Example 32: 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]phenyl}urea

Example 33: 1-[4-(4-methylpiperazin-1 -yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct- 8-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]phenyl}urea

Example 34: 1-methyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H- pyrano[4,3-d]pyrimidin-2-yl]phenyl}urea

Example 35: 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H-pyrano[4,3- d]pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea Example 36: 1-{4-[7-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-3-(2,2,2-trifluoroethyl)-3H- [1 ,2,3]tπazolo[4,5-d]pyπrnidin-5-yl]phenyl}-3-pyridin-4-ylurea

Example 37: 2-hydroxyethyl {4-[7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-3-(2,2,2- tπfluoroethyl)-3H-[1 ,2,3]tπazolo[4,5-d]pyrirnidin-5-yl]phenyl}carbamate

Example 38: 1-{4-[7-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-3-(2,2,2-trifluoroethyl)-3H- [1 ,2,3]triazolo[4,5-d]pynrnidin-5-yl]phenyl}-3-pyridin-3-ylurea

Example 39: 2-hydroxyethyl {4-[7-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-3-(2,2,2- tnfluoroethyl)-3H-[1 ,2,3]tnazolo[4,5-d]pyrimidin-5-yl]phenyl}carbamate

Example 40: 1-{4-[7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-3-(2,2,2-trifluoroethyl)-3H- [1 ,2,3]triazolo[4,5-d]pynmidin-5-yl]phenyl}-3-pyridin-3-ylurea

Example 41 : 1-(4-{[4-(1-methylethyl)piperazin-1 -yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]phenyl}urea

Example 42: 1-[4-(4-methylpiperazin-1 -yl)phenyl]-3-{4-[7-(8-oxa-3-azabicyclo[3.2.1]oct- 3-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]tnazolo[4,5-d]pynmidin-5-yl]phenyl}urea

Example 43: 1-{4-[7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-3-(2,2,2-trifluoroethyl)-3H- [1 ,2,3]triazolo[4,5-d]pynmidin-5-yl]phenyl}-3-pyridin-4-ylurea

Example 44: 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3- d]pyrimidin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea

Example 45: 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3- d]pyrimidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Example 46: 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3- d]pyrimidin-2-yl)phenyl)-3-(pyridin-4-yl)urea BIOLOGICAL EVALUATION

PI3K-alpha and PI3K-qamma Fluorescence Polarization Assay Protocols

The reaction buffer was 20 mM HEPES, pH 7.5, 2 mM MgCI₂, 0.05% CHAPS; and 0.01 % βME (added fresh). The Stop/Detection Buffer was 100 mM HEPES, pH 7.5, 4 mM EDTA, 0.05% CHAPS; ATP 20 mM in water; PIP2 (diC8, Echelon, Salt Lake

City Utah cat # P-4508) 1 mM in water (MW=856.5). The GST-GRP was 1 .75 mg/mL or

1.4 mg/mL in 10% glycerol. The Red detector (TAMRA) was 2.5 μM. Nunc 384-well black polypropylene fluorescent plates were used for PI3K assays.

The assay is run by placing 5 μL of diluted enzyme per well, then 5 μL of diluted compound (or 9.5 μL enzyme then 0.5 μL compound in DMSO) is added and mixed.

Then, 10 μL of substrate is added to start the reaction. The samples are incubated 30-

60 minutes, then the reaction is stopped by adding 20 μL stop/detector mix. PI3K is diluted with reaction buffer (e.g., 5 μL or 7.5 μL PI3K into 620 μL reaction buffer), and 5 μL of diluted enzyme is used per well. 5 μL reaction buffer or drug diluted in buffer (e.g., 4 μL/100 so final DMSO is 1 % in reaction) is added to each. Pipetting up and down mixes the samples. Alternatively, the enzyme can be diluted to 1215 μL. In this case 9.8 μL is added per well and 0.2 μL compound is added in DMSO.

To prepare 1 mL of substrate solution, 955 μL reaction buffer, 40 μL PIP2, and

2.5 μL ATP are mixed. 10 μL of substrate is added to each well to start the reaction. This results in 20 μM PIP2, and 25 μM ATP per reaction. The stop/detector mix is prepared by mixing 4 μL Red detector and 1.6 μL or 2.0 μL GST-GRP with 1 mL stop buffer, which results in 10 nM probe and 70 nM GST-GRP. 20 μL of the stop/detector mix is added to each well to stop the reaction. The plates are read after 30-90 minutes keeping the red probe solutions dark. For the zero time point, stop/detector mix is added to the enzyme just before adding substrate. For an extra control, stop/detector mix is added to buffer (no enzyme) and substrate or to just buffer (no substrate). Pooled PI3K preparations had a protein concentration of 0.25 mg/mL. The recommended reaction has 0.06 μL per 20 μL (0.015 μg/20 μL) or 0.01 125 μg/15 μL or 0.75 μg/mL. Plates are read on machines with filters for TAMRA. The units are mP with no enzyme controls reading app 190-220 mP units. Fully active enzyme reduces fluorescence polarization down to 70-100 mP after 30 minutes. An active cpd raises the mP values halfway to control or to 120-150 mP units. Compounds of the invention had IC₅₀S against PI3K-alpha ranging from 7 nM to 2,858 nM.

mTOR Enzyme Assay

(See Toral-Barza, et al. Biochem Biophys. Res. Commun. 2005 June 24;332(1 ):304-10) The routine human TOR assays with purified enzyme were performed in 96-well plates by DELFIA format as follows. Enzymes were first diluted in kinase assay buffer (10 mM HEPES (pH 7.4), 50 mM NaCI, 50 mM β-glycerophosphate, 10 mM MnCI₂, 0.5 mM DTT, 0.25 _μM microcystin LR, and 100 μg/mL BSA). To each well, 12 μL of the diluted enzyme were mixed briefly with 0.5 μL test inhibitor or the control vehicle DMSO. The kinase reaction was initiated by adding 12.5 μL kinase assay buffer containing ATP and His6-S6K to give a final reaction volume of 25 μL containing 800 ng/mL FLAG-TOR, 100 _μM ATP and 1.25 _μM His6-S6K. The reaction plate was incubated for 2 hours (linear at 1-6 hours) at room temperature with gentle shaking and then terminated by adding 25 μL stop buffer (20 mM HEPES (pH 7.4), 20 mM EDTA, 20 mM EGTA). The DELFIA detection of the phosphorylated (Thr-389) His6-S6K was performed at room temperature using a monoclonal anti-P(T389)- p70S6K antibody (1A5, Cell Signaling) labeled with Europium-N1-ITC (Eu) (10.4 Eu per antibody, PerkinElmer). The DELFIA Assay buffer and Enhancement solution were purchased from PerkinElmer. 45 μL of the terminated kinase reaction mixture was transferred to a MaxiSorp plate (Nunc) containing 55 μL PBS. The His6-S6K was allowed to attach for 2 hours after which the wells were aspirated and washed once with PBS. 100 _μL of DELFIA Assay buffer with 40 ng/mL Eu-P(T389)-S6K antibody was added. The antibody binding was continued for 1 hour with gentle agitation. The wells were then aspirated and washed 4 times with PBS containing 0.05% Tween-20 (PBST). 100 μL of DELFIA enhancement solution was added to each well and the plates were read in a PerkinElmer Victor model plate reader. Data obtained were used to calculate enzymatic activity and enzyme inhibition by potential inhibitors. Compounds of the invention had IC50 activities ranging from <1 nM to 580 nM. hSMG-1 kinase assay

The human SMG-1 (hSMG-1 ) kinase assay employs the recombinant hSMG-1 protein prepared from transiently transfected HEK293 cells and a GST-p53 (aa 1-70) fusion substrate protein derived from cellular tumor suppressor gene p53. The routine assay is performed in a 96-well plate format as follows. Enzymes were first diluted in kinase assay buffer (10 mM HEPES, pH 7.4, 50 mM NaCI, 0.2 mM DTT, 50 mM β- glycerophosphate, 0.5 μM microcystin LR, 10 mM MnCI₂). To each well, 12 μL of the diluted enzyme were mixed briefly with 0.5 μL test inhibitor or control vehicle DMSO. The kinase reaction was initiated by adding 12.5 μL kinase assay buffer containing ATP and GST-p53 to give a final reaction volume of 25 μL containing 400-800 ng/mL FLAG- hSMG-1 , 0.5 μg GST-p53, 10 μM ATP. The reaction was carried out at room temperature for 1.0 hour before terminated by addition of 25 μl stop solution. The assay mixture was then transferred to FluoroNunc Plates with MaxiSorp Surface (Nunc #439454). The plates were incubated at room temperature for 2 hr (4 ⁰C for overnight) to achieve efficient binding of substrate protein to the plate. The plates were aspirated, washed with PBS. Phospho-substrate proteins were detected by incubating for 1 hour with 125 ng of europium-labeled anti-mouse secondary antibody (PerkinElmer AD2027) and the primary phospho(S15)-p53 monoclonal antibody (Cell Signal #9286) in 100 μL DELFIA assay buffer (PerkinElmer #1244-1 1 1 ). Plates were then washed and incubated for 0.5 hour with 100 μl of DELFIA enhancement solution (PerkinElmer #1244-105). DELFIA assay results are recorded in a Victor Plate Reader (PerkinElmer). Data obtained were used to calculate enzymatic activity and enzyme inhibition by potential inhibitors.

In vitro cell growth assay

The cell lines used were human prostate lines LNCap and PC3MM2, human breast lines MDA468 and MCF7, human renal line HTB44 (A498), human colon line HCT1 16, and human ovarian line OVCAR3. Cells were plated in 96-well culture plates. One day following plating, the inhibitors were added to cells. Three days after drug treatment, viable cell densities were determined by metabolic conversion (by viable cells) of the dye MTS, a well-established cell proliferation assay. The assays were performed using an assay kit purchased from Promega Corp. (Madison, Wl) following the protocol supplied with the kit. The MTS assay results were read in a 96-well plate reader by measuring absorbance at 490 nm. The effect of each treatment was calculated as percent of control growth relative to the vehicle-treated cells grown in the same culture plate. The drug concentration that conferred 50% inhibition of growth was determined as IC50. Compounds of the invention had IC50 activities against LNCAP cells ranging from 6 nM to >60 uM.

TABLE 1

PI3gamma mTOR PTEN Screen PTEN Screen PI3Kalpha

Mean Mean Mean Mean Mean

EXAMPLE IC₅₀ (nM) IC₅₀ (nM) IC₅₀ LNCap (nM) IC₅₀ MDA468 (nM) IC₅₀ (nM)

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention.

It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:

I or a pharmaceutically acceptable salt thereof wherein;

T = O, S or NR⁴

U = NH, O or S;

A is selected from

each ring is optionally substituted with 1-4 substituents selected from NR⁶R⁷, OR⁸, halogen, C_rC₆ alkyl, d-C₆ heteroalkyl, C₆-Ci₄ aryl, d-Cg heteroaryl, Cs-Cs cycloalkyl, and Cs-Cs cycloheteroalkyl;

W is a bond, a substituted or unsubstituted C₂-C6 alkenyl, or a substituted or unsubstituted C^-Cε alkynyl;

Ar is C₆-Ci₄ aryl or C_rC₉ heteroaryl ring, each of which may or may not be further substituted; R is independently selected from H (provided that U is NH), d-C₆ alkyl, C₂-C₆ alkenyl, C₂-C6 alkynyl, C-i-Cδ heteroalkyl, Cδ-Ci₄ aryl, C₁-C9 heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, and C3-C8 cycloheteroalkenyl, each of which may or may not be substituted; and

at least one of R¹ and R², or R³ and R⁴, or R² and R³, or R¹ and R⁴ together with the atoms that they bonded to join to form a ring, at each occurrence R¹, R², R³, R⁴ are independently selected from CrC₆ alkyl, substituted CrC₆ alkyl, CrC₆ alkoxy, substituted C-i-Cδ alkoxy, C-i-Cδ alkyl amine, and substituted C-i-Cδ alkyl amine, wherein R¹ - R², or R³ - R⁴ is one to four atoms in chain length and R² - R³, or R¹ - R¹ is one to three atoms in chain length.

2. The compound according to claim 1 of formula:

wherein the fused carbocyclic ring is optionally substituted with 1-4 substituents selected from morpholino, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, C-i-Cδ alkyl, C-i-Cδ heteroalkyl, C₆-Ci₄ aryl, C_rC₉ heteroaryl, C₃-C₈ cycloalkyl, and C₃-C₈ cycloheteroalkyl; W is a bond and Ar is Cδ-Ci₄ aryl or C₁-C9 heteroaryl, T is O or S, U is NH and R is Ce- Cu aryl or CrC₉ heteroaryl.

3. The compound according to claim 1 of formula:

wherein the fused 6-membered heterocyclic ring is optionally substituted with 1-4 substituents selected from morpholino, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, CrC₆ alkyl, d-C₆ heteroalkyl, C₆-Ci₄ aryl, CrC₉ heteroaryl, C₃-C₈ cycloalkyl, and C₃-C₈ cycloheteroalkyl; W is a bond and Ar is C₆-Ci₄ aryl or C-i-Cg heteroaryl, T is O or S, U is NH and R is C₆-C-ι₄ aryl or C-i-Cg heteroaryl.

4. The compound according to claim 1 of formula:

wherein the fused 5-membered heteroaryl ring is optionally substituted with 1-4 substituents selected from morpholino, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, Cr C₆ alkyl, CrC₆ heteroalkyl, C₆-Ci₄ aryl, CrC₉ heteroaryl, C₃-C₈ cycloalkyl, and C₃-C₈ cycloheteroalkyl; W is a bond and Ar is C₆-Ci₄ aryl or C₁-C9 heteroaryl, T is O or S, U is NH and R is C₆-Ci₄ aryl or C_rC₉ heteroaryl.

5. The compound according to claim 1 of formula:

wherein the fused 6-membered heteroaryl ring is optionally substituted with 1-4 substituents selected from morpholino, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, CrC₆ alkyl, d-C₆ heteroalkyl, C₆-Ci₄ aryl, CrC₉ heteroaryl, C₃-C₈ cycloalkyl, and C₃-C₈ cycloheteroalkyl; W is a bond and Ar is C₆-Ci₄ aryl or C-i-Cg heteroaryl, T is O or S, U is NH and R is C6-Ci₄ aryl or C₁-C9 heteroaryl.

6. The compound according to any one of claims 1 -5, wherein W is a bond and Ar is a 4-substituted C₆ aryl or Cs heteroaryl, T is O or S, U is NH and R is a 4-substituted C₆ aryl or C₅ heteroaryl.

7. The compound according to any one of claims 1 -6, wherein the A, the fused carbocyclic, the fused 6-membered heterocyclic, the fused 5-membered heteroaryl, or the fused 6-membered heterocyclic ring is substituted with 1-3 substituents selected from morpholino, tetrahydropyranyl, NR⁶R⁷, OR⁸, halogen, CrC₆ alkyl, CrC₆ heteroalkyl, C₆-Ci₄ aryl, C₁-C9 heteroaryl, C3-C₈ cycloalkyl, and C3-C₈ cycloheteroalkyl.

8. The compound of any one of claims 1 -7, wherein the bridged morpholinyl is selected from 8-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 3-oxa- 6-azabicyclo[3.1 .1]heptane, 3-oxa-9-azabicyclo[3.3.1]nonane, 3,7-dioxa-9- azabicyclo[3.3.1]nonane, 7-methyl-3-oxa-7,9-diazabicyclo[3.3.1 ]nonane, 3-oxa-7,9- diazabicyclo[3.3.1]nonane, 7-ethyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane, 9-oxa-3- azabicyclo[3.3.1]nonane, 3,9-dioxa-7-azabicyclo[3.3.1 ]nonane, 9-oxa-3,7- diazabicyclo[3.3.1 ]nonane, 3-methyl-9-oxa-3,7-diazabicyclo[3.3.1 ]nonane, 3-ethyl-9- oxa-3,7-diazabicyclo[3.3.1]nonane, 6,8-dioxa-3-azabicyclo[3.2.1]octane, 2-oxa-5- azabicyclo[2.2.1]heptane, and 2-oxa-5-azabicyclo[2.2.2]octane.

9. The compound of claim 1 , selected from 1-(4-(7-(8-oxa-3-azabicyclo[3.2.1]octan- 3-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]tnazolo[4,5-d]pyrimidin-5-yl)phenyl)-3-(pyridin-4- yl)urea, 1 -(4-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(2,2,2-trifluoroethyl)-3H- [1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl)phenyl)-3-(4-(4-methylpiperazin-1 -yl)phenyl)urea, 1 - (4-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]triazolo[4,5- d]pyrimidin-5-yl)phenyl)-3-(pyridin-3-yl)urea, 2-hydroxyethyl 4-(7-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-5- yl)phenylcarbamate, 1 -(4-(7-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(2,2,2- trifluoroethyl)-3H-[1 ,2,3]tπazolo[4,5-d]pyπmidin-5-yl)phenyl)-3-(pyridin-4-yl)urea, 1 -(4-(7- (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]triazolo[4,5- d]pyrimidin-5-yl)phenyl)-3-(4-(4-methylpiperazin-1 -yl)phenyl)urea, 1 -(4-(7-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-5- yl)phenyl)-3-(pyridin-3-yl)urea, and 2-hydroxyethyl 4-(7-(3-oxa-8-azabicyclo[3.2.1]octan- 8-yl)-3-(2,2,2-thfluoroethyl)-3H-[1 ,2,3]thazolo[4,5-d]pyrimidin-5-yl)phenylcarbamate, 1 - {4-[4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-6,7-dihydro-5H-cyclopenta[d]pyhmidin-2- yl]phenyl}-3-pyhdin-4-ylurea, 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H- cyclopenta[d]pyhmidin-2-yl]phenyl}-3-pyhdin-4-ylurea, 1-{4-[2-(dimethylamino)- ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]phenyl}urea, 1-methyl-3-{4-[4-(3-oxa-8-azabicyclo-[3.2.1]oct- 8-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]phenyl}urea, 1 -{4-[4-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyhmidin-2-yl]phenyl}-3-pyridin- 4-ylurea, 2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-5H- pyrano[4,3-d]pyrimidin-2-yl]phenyl}carbamate, 1 -{4-[4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8- yO-ej-dihydro-δH-cyclopentatdlpyhmidin^-yllphenylϊ-S-pyridin^-ylurea, 1-[4-(4- methylpiperazin-1 -yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-7,8-dihydro-5H- pyrano[4,3-d]pyrimidin-2-yl]phenyl}urea, 2-hydroxyethyl {4-[4-(8-oxa-3- azabicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyhmidin-2-yl]phenyl}carbamate, 1-{4-[4-(3-oχa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl]phenyl}-3-pyhdin-3-ylurea, 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyhmidin-2-yl]phenyl}urea, 1-[4- (4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6,7-dihydro- 5H-cyclopenta[d]pyhmidin-2-yl]phenyl}urea, 1-methyl-3-{4-[4-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyhmidin-2-yl]phenyl}urea, 1-{4- ^-(S-oxa-δ-azabicycloIS^.IJoct-δ-yO-Z.δ-dihydro-SH-pyrano^.S-dlpyrimidin^- yl]phenyl}-3-pyhdin-3-ylurea, 1-{4-[7-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-3-(2,2,2- tπfluoroethyl)-3H-[1 ,2,3]tπazolo[4,5-d]pyπrnidin-5-yl]phenyl}-3-pyridin-4-ylurea, 2- hydroxyethyl {4-[7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-3-(2,2,2-trifluoroethyl)-3H- [1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl]phenyl}carbamate, 1 -{4-[7-(3-oxa-8- azabicyclo[3.2.1]oct-8-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]tπazolo[4,5-d]pyrimidin-5- yl]phenyl}-3-pyridin-3-ylurea, 2-hydroxyethyl {4-[7-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-3- (2,2,2-trifluoroethyl)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl]phenyl}carbamate, 1 -{4-[7-(8- oxa-3-azabicyclo[3.2.1]oct-3-yl)-3-(2,2,2-tπfluoroethyl)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin- 5-yl]phenyl}-3-pyridin-3-ylurea, 1 -(4-{[4-(1 -methylethyl)piperazin-1 -yl]carbonyl}phenyl)-3- {4-[4-(3-oχa-8-azabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2- yl]phenyl}urea, 1 -[4-(4-methylpiperazin-1 -yl)phenyl]-3-{4-[7-(8-oxa-3- azabicyclo[3.2.1]oct-3-yl)-3-(2,2,2-trifluoroethyl)-3H-[1 ,2,3]tπazolo[4,5-d]pyrimidin-5- yl]phenyl}urea, 1-{4-[7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-3-(2,2,2-trifluoroethyl)-3H- [1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl]phenyl}-3-pyridin-4-ylurea, 1 -(4-(4-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)phenyl)-3-(4-(4- isopropylpiperazine-1-carbonyl)phenyl)urea, 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrirnidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1- yl)phenyl)urea, 1 -(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3- d]pyrirnidin-2-yl)phenyl)-3-(pyridin-4-yl)urea and pharmaceutically acceptable salts thereof.

10. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

1 1. A composition comprising a compound of claim 1 ; a second compound selected from the group consisting of a topoisomerase I inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopuhne, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil, docetaxel, paclitaxel, leucovohn, levamisole, ihnotecan, estramustine, etoposide, nitrogen mustards, BCNU, carmustine, lomustine, vinblastine, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, imatinib mesylate, Avastin (bevacizumab), hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin, and lavendustin A; and a pharmaceutically acceptable carrier.

12. The composition of claim 1 1 , wherein the second compound is Avastin.

13. A compound for use in treating a PI3K-related disorder, wherein a compound of claim 1 is administered to a mammal in need thereof in an amount effective to treat a PI3K-related disorder.

14. The compound of claim 13, wherein the PI3K-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer.

15. The compound of claim 14, wherein the PI3K-related disorder is cancer.

16. The compound of claim 15 wherein the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.