WO2010120987A1 - Composés de morpholino-pyrimidine à pont uréidoaryle et carbamoylaryle, à cycles condensés, leur utilisation en tant qu'inhibiteurs de kinase mtor et de kinase pi3, et leurs synthèses - Google Patents

Composés de morpholino-pyrimidine à pont uréidoaryle et carbamoylaryle, à cycles condensés, leur utilisation en tant qu'inhibiteurs de kinase mtor et de kinase pi3, et leurs synthèses Download PDF

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WO2010120987A1
WO2010120987A1 PCT/US2010/031175 US2010031175W WO2010120987A1 WO 2010120987 A1 WO2010120987 A1 WO 2010120987A1 US 2010031175 W US2010031175 W US 2010031175W WO 2010120987 A1 WO2010120987 A1 WO 2010120987A1
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oxa
azabicyclo
phenyl
heteroaryl
aryl
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Arie Zask
Jeroen Cunera Verheijen
Joshua Aaron Kaplan
Kevin Joseph Curran
Semiramis Ayral-Kaloustian
David James Richard
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Wyeth Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • 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.
  • 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.
  • Phosphatidylinositol (hereinafter abbreviated as "Pl") is one of the phospholipids in cell membranes.
  • Pl 4,5 bisphosphate
  • PIP2 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)].
  • PI3K phosphatidylinositol-3 kinase
  • 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)].
  • class Ia PI3K subtype has been most extensively investigated to date. Within the class Ia subtype there are three isoforms ( ⁇ , ⁇ , & ⁇ ) 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.
  • 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.
  • RBD Ras binding domains
  • PI3K 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.
  • PI3K As a central component of the PI3K/Akt/mTOR signaling pathway PI3K (particularly the class Ia ⁇ isoform) has become a major therapeutic target in cancer drug discovery.
  • 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 10 ⁇ that is activated by interaction with G protein-coupled receptors. Interaction between p1 10 ⁇ 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 C2 ⁇ , C2 ⁇ and C2 ⁇ 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)py ⁇ do[3',2':4,5]furo[3,2-d]py ⁇ midin-2- yl)phenol) inhibits PI3K ⁇ and PI3K ⁇ as well as the mTOR enzymes with IC50 values of 2, 3, and 50-80 nM respectively.
  • 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 ⁇ and PI3K ⁇ 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
  • 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 ⁇ and PI3K ⁇ as well as the mTOR enzymes with IC50 values 4, 5, and "nanomolar".
  • 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.
  • PI3K Phosphatidylinositol 3-kinase
  • 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 PI3K ⁇ and ⁇ , TG-1001 15 is in phase I/I I trials for treatment of infarct following myocardial ischemia-reperfusion injury.
  • Cerylid's antithrombotic PI3K ⁇ inhibitor CBL-1309 (structure unknown) has completed preclinical toxicology studies.
  • PI3K 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., PI3K ⁇ 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.
  • targets in the PI3K/Akt pathway e.g., PI3K ⁇ and mTOR [mammalian target of rapamycin]
  • lipid kinase inhibitors may parallel protein kinase inhibitors in that nonselective inhibitors may also be brought forward to the clinic.
  • Mammalian Target of Rapamycin 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.
  • mTOR kinase 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.
  • mTOR inhibitors 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.
  • 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.
  • 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.
  • hSMG-1 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.
  • PTC premature translation termination codon
  • NMD nucleic acid deficiency virus
  • 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.
  • PI3K inhibitors and mTOR inhibitors are expected to be novel types of medicaments useful against cell proliferation disorders, especially as carcinostatic agents.
  • the instant invention is directed to these and other important ends.
  • the invention provides compounds of Formula I:
  • 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.
  • the invention provides compounds of Formula I:
  • T O, S or NR ,4.
  • A is selected from
  • each ring optionally substituted with 1-4 substituents selected from NR 6 R 7 , OR 8 , halogen, C r C 6 alkyl, C r C 6 heteroalkyl, C 6 -Ci 4 aryl, C r C 9 heteroaryl, Cs-Cs cycloalkyl, and Cs-Cs cycloheteroalkyl;
  • W is a bond, a substituted or unsubstituted C 2 -C6 alkenyl, or a substituted or unsubstituted C 2 -C 6 alkynyl;
  • Ar is C 6 -Ci 4 aryl or C 1 -C 9 heteroaryl ring, each of which may or may not be further substituted;
  • R is independently selected from H (provided that U is NH), d-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C6 alkynyl, CrC 6 heteroalkyl, C 6 -Ci 4 aryl, C 1 -C9 heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, and C3-C8 cycloheteroalkenyl, each of which may or may not be substituted; and
  • A is further substituted with one or more bridged morpholinyl of formula
  • A when A is further substituted with one or more substituents selected from NR 6 R 7 , OR 8 , halogen, C r C 6 alkyl, CrC 6 heteroalkyl, C 6 -Ci 4 aryl, C r C 9 heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloheteroalkyl.
  • substituents selected from NR 6 R 7 , OR 8 , halogen, C r C 6 alkyl, CrC 6 heteroalkyl, C 6 -Ci 4 aryl, C r C 9 heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloheteroalkyl.
  • the invention provides a compound of formula:
  • fused 5-membered carbocyclic ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, CrC 6 alkyl, CrC 6 heteroalkyl, C 6 -Ci 4 aryl, CrC 9 heteroaryl, C 3 -C 8 cycloalkyl, and C 8 -C 8 cycloheteroalkyl; T, U, W, Ar, R and R 1"4 are as defined above.
  • W is a bond and Ar is C 6 -Ci 4 aryl or C 1 -C9 heteroaryl, T is O or S, U is NH and R is C 6 -Ci 4 aryl or C 1 -C 9 heteroaryl.
  • W is a bond and Ar is a 4-substituted C 6 aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C 6 aryl or C 5 heteroaryl.
  • the invention provides a compound of formula:
  • fused 6-membered heterocyclic ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, CrC 6 alkyl, CrC 6 heteroalkyl, C 6 -Ci 4 aryl, CrC 9 heteroaryl, C 3 -C 8 cycloalkyl, and C 8 -C 8 cycloheteroalkyl; T, U, W, Ar, R and R 1"4 are as defined above.
  • W is a bond and Ar is C 6 -Ci 4 aryl or C 1 -C9 heteroaryl, T is O or S, U is NH and R is C 6 -Ci 4 aryl or C 1 -C9 heteroaryl.
  • W is a bond and Ar is a 4-substituted C 6 aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C 6 aryl or C 5 heteroaryl.
  • the invention provides a compound of formula:
  • fused aryl ring is optionally substituted with 1-4 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, CrC 6 alkyl, Ci-C 6 heteroalkyl, C 6 - Ci 4 aryl, Ci -Cg heteroaryl, C 3 -C 8 cycloalkyl, and C 8 -C 8 cycloheteroalkyl; T, U, W, Ar, R and R 1"4 are as defined above.
  • W is a bond and Ar is C 6 -Ci 4 aryl or d-C 9 heteroaryl, T is O or S, U is NH and R is C 6 -Ci 4 aryl or C r C 9 heteroaryl.
  • W is a bond and Ar is a 4-substituted C 6 aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4-substituted C 6 aryl or C5 heteroaryl.
  • the invention provides a compound of formula:
  • fused 5-membered heteroaryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, d-C 6 alkyl, CrC 6 heteroalkyl, C 6 -Ci 4 aryl, CrC 9 heteroaryl, C 3 -C 8 cycloalkyl, and C 8 -C 8 cycloheteroalkyl; T, U, W, Ar, R and R 1"4 are as defined above.
  • W is a bond and Ar is C 6 -Ci 4 aryl or C1-C9 heteroaryl, T is O or S, U is NH and R is C 6 -Ci 4 aryl or C 1 -C 9 heteroaryl.
  • W is a bond and Ar is a 4-substituted C 6 aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C 6 aryl or C 5 heteroaryl.
  • the invention provides a compound of formula:
  • either of the fused 5-membered heterocyclic or 6-membered heteroaryl ring is optionally substituted with 1 -3 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, CrC 6 alkyl, Ci-C 6 heteroalkyl, C 6 -Ci 4 aryl, Ci -C 9 heteroaryl, C 3 -C 8 cycloalkyl, and C 8 -C 8 cycloheteroalkyl; T, U, W, Ar, R and R 1"4 are as defined above.
  • W is a bond and Ar is C 6 -Ci 4 aryl or C 1 -C 9 heteroaryl, T is O or S, U is NH and R is C 6 -Ci 4 aryl or C 1 -C9 heteroaryl.
  • W is a bond and Ar is a 4-substituted C 6 aryl or C 5 heteroaryl, T is O or S, U is NH and R is a 4-substituted C 6 aryl or C5 heteroaryl.
  • the invention provides a compound of formula:
  • fused 6-membered heterocyclic ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, d-C 6 alkyl, Ci-C 6 heteroalkyl, C6-C- ⁇ 4 aryl, Ci -Cg heteroaryl, C3-C 8 cycloalkyl, and Cs-Cs cycloheteroalkyl; T, U, W, Ar, R and R 1"4 are as defined above.
  • W is a bond and Ar is C 6 -Ci 4 aryl or C 1 -C9 heteroaryl, T is O or S, U is NH and R is C 6 -Ci 4 aryl or C 1 -C 9 heteroaryl.
  • 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.
  • the invention provides a compound of formula:
  • fused 5-membered heteroaryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, CrC 6 alkyl, Ci-C 6 heteroalkyl, C 6 -Ci 4 aryl, Ci -C 9 heteroaryl, C 3 -C 8 cycloalkyl, and C 8 -C 8 cycloheteroalkyl; T, U, W, Ar, R and R 1"4 are as defined above.
  • W is a bond and Ar is C 6 -Ci 4 aryl or C 1 -C9 heteroaryl, T is O or S, U is NH and R is C 6 -Ci 4 aryl or C 1 -C 9 heteroaryl.
  • W is a bond and Ar is a 4-substituted C 6 aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C 6 aryl or C5 heteroaryl.
  • the invention provides a compound of formula:
  • fused 5-membered heteroaryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, CrC 6 alkyl, Ci-C 6 heteroalkyl, C6-Ci 4 aryl, Ci -Cg heteroaryl, C3-C 8 cycloalkyl, and Cs-Cs cycloheteroalkyl; T, U, W, Ar, R and R 1"4 are as defined above.
  • W is a bond and Ar is C 6 -Ci 4 aryl or C 1 -C9 heteroaryl, T is O or S, U is NH and R is C 6 -Ci 4 aryl or C 1 -C 9 heteroaryl.
  • W is a bond and Ar is a 4-substituted C 6 aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted Ce aryl or C5 heteroaryl.
  • the invention provides a compound of formula:
  • fused 5-membered aryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, C r C 6 alkyl, C r C 6 heteroalkyl, C 6 -Ci 4 aryl, C r C 9 heteroaryl, C 3 -C 8 cycloalkyl, and C 8 -C 8 cycloheteroalkyl; T, U, W, Ar, R and R 1"4 are as defined above.
  • W is a bond and Ar is C 6 -Ci 4 aryl or d-C 9 heteroaryl, T is O or S, U is NH and R is C 6 -Ci 4 aryl or C 1 -C 9 heteroaryl.
  • W is a bond and Ar is a 4- substituted C 6 aryl or C 5 heteroaryl, T is O or S, U is NH and R is a 4-substituted C 6 aryl or C 5 heteroaryl.
  • the invention provides a compound of formula:
  • fused 6-membered carbocyclic ring is optionally substituted with 1-4 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, CrC 6 alkyl, Ci-C 6 heteroalkyl, C 6 -Ci 4 aryl, CrC 9 heteroaryl, C 3 -C 8 cycloalkyl, and C 8 -C 8 cycloheteroalkyl; T, U, W, Ar, R and R 1"4 are as defined above.
  • W is a bond and Ar is C 6 -Ci 4 aryl or C 1 -C9 heteroaryl, T is O or S, U is NH and R is C 6 -Ci 4 aryl or C 1 -C9 heteroaryl.
  • W is a bond and Ar is a 4-substituted C 6 aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C 6 aryl or C 5 heteroaryl.
  • the invention provides a compound of formula:
  • fused 5-membered heteroaryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, CrC 6 alkyl, CrC 6 heteroalkyl, C 6 -Ci 4 aryl, Ci -Cg heteroaryl, C3-C 8 cycloalkyl, and C 8 -C 8 cycloheteroalkyl; T, U, W, Ar, R and R 1"4 are as defined above.
  • W is a bond and Ar is C 6 -Ci 4 aryl or C 1 -C9 heteroaryl, T is O or S, U is NH and R is C 6 -Ci 4 aryl or C 1 -C 9 heteroaryl.
  • 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.
  • the invention provides a compound of formula:
  • fused 5-membered heteroaryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, C-i-C ⁇ alkyl, C-i-C ⁇ heteroalkyl, C6-C- ⁇ 4 aryl, Ci -Cg heteroaryl, C3-Cs cycloalkyl, and Cs-Cs cycloheteroalkyl; T, U, W, Ar, R and R 1"4 are as defined above.
  • W is a bond and Ar is C ⁇ -Ci 4 aryl or C 1 -C9 heteroaryl, T is O or S, U is NH and R is C ⁇ -Ci 4 aryl or C 1 -C 9 heteroaryl.
  • 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 6 aryl or C 5 heteroaryl.
  • the invention provides a compound of formula:
  • fused 5-membered heteroaryl ring is optionally substituted with 1-3 substituents selected from morpholinyl, tetrahydropyranyl, NR 6 R 7 , OR 8 , halogen, d-C ⁇ alkyl, Ci-C ⁇ 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.
  • W is a bond and Ar is C ⁇ -Ci 4 aryl or C 1 -C9 heteroaryl, T is O or S, U is NH and R is C ⁇ -Ci 4 aryl or C 1 -C 9 heteroaryl.
  • W is a bond and Ar is a 4-substituted C 6 aryl or C5 heteroaryl, T is O or S, U is NH and R is a 4- substituted C 6 aryl or C5 heteroaryl.
  • the invention provides a compound of formula:
  • W is a bond and Ar is C 6 -Ci 4 aryl or C r C 9 heteroaryl
  • T is O or S
  • U is NH and R is C 6 - Ci 4 aryl or C 1 -C 9 heteroaryl
  • W is a bond and Ar is a A- substituted C 6 aryl or C 5 heteroaryl
  • T is O or S
  • U is NH and R is a 4-substituted C 6 aryl or C 5 heteroaryl.
  • 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 NH 2 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.
  • 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, azabicyclo
  • the invented compound is selected from: 1-(4-(7-(8-oxa-
  • the invention provides pharmaceutical compositions comprising compounds or pharmaceutically acceptable salts of the compounds of the present Formula I. and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutically acceptable carrier suitable for oral administration and the composition comprises an oral dosage form.
  • 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,
  • the second compound is Avastin.
  • 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.
  • 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.
  • the PI3K-related disorder is cancer.
  • 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.
  • 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.
  • 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.
  • the mTOR-related disorder is cancer.
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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,
  • 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 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.
  • a group designated as “C r C 6 " 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 C 2 -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, H 2 N-, (Ci-C 6 alkyl)amino-, di(C r C 6 alkyl)amino-, (Ci-C 6 alkyl)C(O)N(C r C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, d-C 6 alkyl-, HO 2 C-, (C r C 6 alkoxy)carbonyl-, (CrC 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, Ci-Cgheteroaryl-, and C 3 - C
  • Alkoxy- refers to the group R-O- where R is an alkyl group, as defined below.
  • Exemplary C-i-C ⁇ alkoxy- 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-C ⁇ alkoxy-, H 2 N-, (Ci-C 6 alkyl)amino-, di(C r C 6 alkyl)amino-, (Ci-C 6 alkyl)C(O)N(CrC 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, C r C 6 alkoxy-, HO 2 C-, (C r C 6 alkoxy)carbonyl- , (C r C 6 alkyl)C(O)-, C 6 -C- ⁇ 4 aryl-, Ci-Cgheteroaryl-, Cs-Cscyclo
  • (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, H 2 N-, (Cr C 6 alkyl)amino-, di(C r C 6 alkyl)amino-, (CrC 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, C r C 6 alkoxy-, HO 2 C-, (C r C 6 alkoxy)carbonyl- , (C r C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, C r C 9 heteroaryl-, Cs-Cscycloalkyl-, CrC
  • 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.
  • C-i-C ⁇ alkyl- 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, H 2 N-, (Ci-C6alkyl)amino-, di(d- C 6 alkyl)amino-, (Ci-C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (Ci-C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (CrC 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyh HO 2 C-, (C r C 6 alkoxy)carbonyl-, (C r C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, C r C 9 heteroaryl- , Cs-Cscycloalkyl
  • (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 CH 3 NH-, CH 3 CH 2 NH-, CH 3 CH 2 CH 2 NH-, CH 3 CH 2 CH 2 CH 2 NH-, (CH 3 ) 2 CHNH-, (CH 3 ) 2 CHCH 2 NH-, CH 3 CH 2 CH(CH 3 )NH- and (CH 3 ) 3 CNH-.
  • An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (Ci-C6alkyl)amino-, di(Ci-C 6 alkyl)amino-, (C r C 6 alkyl)C(O)N(CrC 3 alkyl)-, (C-i-CealkyOcarboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, Ci-C 6 alkyl-, HO 2 C-, (Ci-C 6 alkoxy)carbonyl-, (C r C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, d-Cgheteroaryl-, C 3
  • (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)CH 3 , -NHC(O)CH 2 CH 3 , -NHC(O)CH 2 CH 2 CH 3 , -NHC(O)CH 2 CH 2 CH 2 CH 3 , - NHC(O)CH 2 CH 2 CH 2 CH 2 CH 3 , -NHC(O)CH(CH 3 ) 2 , -NHC(O)CH 2 CH(CH 3 ) 2 , NHC(O)CH(CH 3 )CH 2 CH 3 , -NHC(O)-C(CH 3 ) 3 and -NHC(O)CH 2 C(CH 3 ) 3 .
  • alkylene- refers to alkyl-, alkenyl- and alkynyl- groups, as defined above, having two points of attachment within a chemical structure.
  • Examples of -d-C 6 alkylene- include ethylene (-CH 2 CH 2 -), propylene (- CH 2 CH 2 CH 2 -), and dimethylpropylene (-CH 2 C(CHs) 2 CH 2 -).
  • Examples of -d-C ⁇ alkynylene- include ethynylene (-C ⁇ C-) and propynylene (-C ⁇ C — CH 2 -).
  • Alkynyl- refers to a straight or branched chain unsaturated hydrocarbon containing at least one triple bond.
  • Examples of a C 2 -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,
  • An alkynyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (C r C 6 alkyl)amino-, di(C r C 6 alkyl)amino-, (Ci-C 6 alkyl)C(O)N(CrC 3 alkyl)- , (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, CIi(C 1 - C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C-, (C r C 6 alkoxy)carbonyl-, (Ci-C 6 alkyl)C(O)-, C 6 -C- ⁇ 4 aryl-, d-Cgheteroaryl-,
  • Aryl- refers to an aromatic hydrocarbon group.
  • Examples of an C6-d 4 aryl- 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- C ⁇ alkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(Ci-C 6 alkyl)-, H 2 N-, aminoalkyl-, di(d- C 6 alkyl)amino-, HO 2 C-, (C r C 6 alkoxy)carbonyl-, (d-C 6 alkyl)carboxyl-, di(d- C 6 alkyl)amido-, H 2 NC(O)-, (C r C 6 alkyl)amido-, or O 2 N-.
  • (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.
  • (C 6 -d 4 Aryl)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, H 2 N-, hydroxyl, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, (CrC 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (Ci-C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C- , (CrC 6 alkoxy)carbonyl-, (C r C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, C r C 9 heteroaryl-, C
  • Carboxyamidoalkyl- refers to a primary carboxyamide (CONH 2 ), a secondary carboxyamide (CONHR') or a tertiary carboxyamide (CONR 1 R"), where R' and R" are the same or different substituent groups selected from CrC ⁇ alkyl-, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 6 -Ci 4 aryl-, C r C 9 heteroaryl-, or OrCscycloalkyl-, attached to the parent compound by an -CrC ⁇ alkylene- group as defined above.
  • Cycloalkyl- refers to a monocyclic, non-aromatic, saturated hydrocarbon ring.
  • Representative examples of a C 3 -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, H 2 N-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, (Cr C 6 alkyl)C(O)N(CrC 3 alkyl)-, (Ci-C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C- , (CrC 6 alkoxy)carbonyl-, (C r C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, C r C 9 heteroaryl-, or C 3 - Cs
  • 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(CH 3 ) 2 , - N(CH 2 CH 3 )(CH 3 ), -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH2CH 2 CH 2 CH 3 )2, N(CH(CH 3 ) 2 ) 2 , -N(CH(CH 3 ) 2 )(CH 3 ), -N(CH 2 CH(CH 3 ) 2 )2, -NH(CH(CH 3 )CH 2 CH 3 ) 2 , - N(C(CH 3 ) 3 ) 2 , -N(C(CHa) 3 )(CH 3 ), and -N(CH 3 )(CH 2 CH 3 ).
  • 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-C 6 alkyl)-, -N(C 3 - Cscycloalkyl)-, -N(C 6 -d 4 aryl)-, -N(C r C 9 heteroaryl)-, -N(C r C 6 aminoalkyl)-, -N(C 6 - Ci 4 arylamino)-, -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.
  • 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.
  • 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.
  • Ci heteroaryl- radicals would include but are not limited to tetrazolyl
  • C 2 heteroaryl- 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 ⁇ haloalkyl-, hydroxyl, d- Cehydroxylalkyl-, H 2 N-, Ci-C 6 aminoalkyl-, di(Ci-C 6 alkyl)amino-, -COOH, (Ci- C 6 alkoxy)carbonyl-, (C r C 6 alkyl)carboxyl-, di(C r C 6 alkyl)amido-, H 2 NC(O)-, (C r C6alkyl)amido-, or O 2 N-.
  • (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,
  • (heteroaryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, hydroxyl, (CrC 6 alkyl)amino-, di(CrC 6 alkyl)amino-, (CrC 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (CrC 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (d- C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C- , (Ci-C 6 alkoxy)carbonyl-, (Ci-C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, Ci-Cgheteroaryl-, C
  • 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- diaza
  • 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.
  • ⁇ eterocyclyl(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 r C 6 alkyl)- 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, H 2 N-, (Ci-C 6 alkyl)amino-, di(C r C 6 alkyl)amino-, (d-
  • 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.
  • C-i-C ⁇ hydroxylalkyl- moieties include, for example, -CH 2 OH, -CH 2 CH 2 OH, -
  • 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.
  • the leaving group is bromide.
  • the leaving group is trimethylamine.
  • 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.
  • Perfluoroalkyl- refers to alkyl group, defined above, having two or more fluorine atoms.
  • Examples of a Ci-C ⁇ perfluoroalkyl- group include CF 3 , CH 2 CF 3 , CF 2 CF 3 and CH(CF 3 ) 2 .
  • optionally substituted means that at least one hydrogen atom of the optionally substituted group has been substituted with halogen, H 2 N-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, (Ci- C 6 alkyl)C(O)N(C r C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C- , (CrC 6 alkoxy)carbonyl-, (C r C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, C r C 9 heteroary
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • compositions of this invention include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous) bronchial or nasal administration.
  • parenteral including subcutaneous, intramuscular, intradermal and intravenous
  • nasal administration 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.
  • 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.
  • 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.
  • 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.
  • the dose may be in the range of 0.1 mg/kg to 1 mg/kg body weight for intravenous 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.
  • 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 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.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is administered concurrently with another therapeutic agent.
  • 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.
  • 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.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent act synergistically.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • ATP is adenosine triphosphate
  • ⁇ ME is 2-mercaptoethanol
  • BSA Bovine Serum Albumin
  • CHAPS is (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid
  • DELFIA Dissociation-Enhanced Lanthanide Fluorescent Immunoassay
  • DME is 1 ,2- dimethoxyethane
  • DMF is N,N-dimethylformamide
  • DMSO 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
  • HPLC high-pressure liquid chromatography.
  • MagnesolTM is a hydrated, synthetic, amorphous magnesium silicate. MagnesolTM 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.
  • RT retention time
  • SDS dodecyl sulfate (sodium salt)
  • SRB Sulforhodamine B
  • TAMRA is tetramethyl-6- carboxyrhodamine
  • TFA is thfluoroacetic acid
  • THF is tetrahydrofuran
  • TRIS is ths(hydroxymethyl)aminomethane.
  • 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 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 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 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 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 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 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]t ⁇ azolo[4,5-d]py ⁇ rnidin-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- t ⁇ fluoroethyl)-3H-[1 ,2,3]t ⁇ azolo[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 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
  • the reaction buffer was 20 mM HEPES, pH 7.5, 2 mM MgCI 2 , 0.05% CHAPS; and 0.01 % ⁇ ME (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
  • the GST-GRP was 1 .75 mg/mL or
  • TAMRA Red detector
  • the assay is run by placing 5 ⁇ L of diluted enzyme per well, then 5 ⁇ L of diluted compound (or 9.5 ⁇ L enzyme then 0.5 ⁇ L compound in DMSO) is added and mixed.
  • reaction is stopped by adding 20 ⁇ L stop/detector mix.
  • PI3K is diluted with reaction buffer (e.g., 5 ⁇ L or 7.5 ⁇ L PI3K into 620 ⁇ L reaction buffer), and 5 ⁇ L of diluted enzyme is used per well.
  • 5 ⁇ L reaction buffer or drug diluted in buffer e.g., 4 ⁇ L/100 so final DMSO is 1 % in reaction
  • the enzyme can be diluted to 1215 ⁇ L. In this case 9.8 ⁇ L is added per well and 0.2 ⁇ L compound is added in DMSO.
  • reaction buffer 955 ⁇ L reaction buffer, 40 ⁇ L PIP2, and
  • ATP 2.5 ⁇ L ATP are mixed. 10 ⁇ L of substrate is added to each well to start the reaction. This results in 20 ⁇ M PIP2, and 25 ⁇ M ATP per reaction.
  • the stop/detector mix is prepared by mixing 4 ⁇ L Red detector and 1.6 ⁇ L or 2.0 ⁇ L GST-GRP with 1 mL stop buffer, which results in 10 nM probe and 70 nM GST-GRP. 20 ⁇ L 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.
  • PI3K preparations had a protein concentration of 0.25 mg/mL.
  • the recommended reaction has 0.06 ⁇ L per 20 ⁇ L (0.015 ⁇ g/20 ⁇ L) or 0.01 125 ⁇ g/15 ⁇ L or 0.75 ⁇ g/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 IC 50 S against PI3K-alpha ranging from 7 nM to 2,858 nM.
  • kinase reaction was initiated by adding 12.5 ⁇ L kinase assay buffer containing ATP and His6-S6K to give a final reaction volume of 25 ⁇ L containing 800 ng/mL FLAG-TOR, 100 ⁇ M ATP and 1.25 ⁇ M 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 ⁇ L 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 ⁇ L of the terminated kinase reaction mixture was transferred to a MaxiSorp plate (Nunc) containing 55 ⁇ L PBS.
  • the His6-S6K was allowed to attach for 2 hours after which the wells were aspirated and washed once with PBS.
  • 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 ⁇ - glycerophosphate, 0.5 ⁇ M microcystin LR, 10 mM MnCI 2 ).
  • kinase reaction was initiated by adding 12.5 ⁇ L kinase assay buffer containing ATP and GST-p53 to give a final reaction volume of 25 ⁇ L containing 400-800 ng/mL FLAG- hSMG-1 , 0.5 ⁇ g GST-p53, 10 ⁇ M ATP. The reaction was carried out at room temperature for 1.0 hour before terminated by addition of 25 ⁇ l 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 0 C 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 ⁇ L DELFIA assay buffer (PerkinElmer #1244-1 1 1 ). Plates were then washed and incubated for 0.5 hour with 100 ⁇ l 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.
  • 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.

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Abstract

La présente invention concerne des composés de 4-morpholino-pyrimidine pontés, à cycles condensés de formule (I), leurs homologues cycliques et des procédés pour préparer et utiliser les composés.
PCT/US2010/031175 2009-04-17 2010-04-15 Composés de morpholino-pyrimidine à pont uréidoaryle et carbamoylaryle, à cycles condensés, leur utilisation en tant qu'inhibiteurs de kinase mtor et de kinase pi3, et leurs synthèses WO2010120987A1 (fr)

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EP2307414A2 (fr) * 2008-07-07 2011-04-13 Xcovery Holding Company LLC Inhibiteurs sélectifs des isoformes de la pi3 kinase
WO2012136622A1 (fr) 2011-04-04 2012-10-11 Cellzome Limited Dérivés de dihydropyrrolopyrimidine en tant qu'inhibiteurs de la mtor
US8415376B2 (en) 2008-05-30 2013-04-09 Amgen Inc. Inhibitors of PI3 kinase
WO2013152717A1 (fr) 2012-04-10 2013-10-17 上海昀怡健康管理咨询有限公司 Composé de pyrimidine condensé, et procédé de préparation, intermédiaire, composition et utilisations dudit composé
JP2014528436A (ja) * 2011-10-07 2014-10-27 セルゾーム リミテッド Ｍｔｏｒ阻害剤としてのモルホリノ置換二環式ピリミジン尿素またはカルバメート誘導体
WO2015043398A1 (fr) 2013-09-30 2015-04-02 上海璎黎药业有限公司 Composé de pyrimidine condensée, intermédiaire, procédé de préparation s'y rapportant et composition et application correspondantes
WO2015055071A1 (fr) 2013-10-16 2015-04-23 上海璎黎药业有限公司 Composé hétérocyclique condensé, son procédé de préparation, composition pharmaceutique et leurs utilisations
JP2016510042A (ja) * 2013-03-04 2016-04-04 中国科学院上▲海▼▲藥▼物研究所 ピリドピリミジンまたはピリミドピリミジン系化合物、その製造方法、薬剤組成物及びその用途
US9593123B2 (en) 2013-09-06 2017-03-14 Hoffmann-La Roche Inc. Triazolo[4,5-D]pyrimidine derivatives
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CN112707907A (zh) * 2019-10-24 2021-04-27 张飞 新型嘌呤衍生物及其中间体与制备抗癌症药物的应用

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WO2012136622A1 (fr) 2011-04-04 2012-10-11 Cellzome Limited Dérivés de dihydropyrrolopyrimidine en tant qu'inhibiteurs de la mtor
JP2014528436A (ja) * 2011-10-07 2014-10-27 セルゾーム リミテッド Ｍｔｏｒ阻害剤としてのモルホリノ置換二環式ピリミジン尿素またはカルバメート誘導体
WO2013152717A1 (fr) 2012-04-10 2013-10-17 上海昀怡健康管理咨询有限公司 Composé de pyrimidine condensé, et procédé de préparation, intermédiaire, composition et utilisations dudit composé
US9499561B2 (en) 2012-04-10 2016-11-22 Shanghai Yingli Pharmaceutical Co., Ltd. Fused pyrimidine compound, and preparation method, intermediate, composition, and uses thereof
JP2016510042A (ja) * 2013-03-04 2016-04-04 中国科学院上▲海▼▲藥▼物研究所 ピリドピリミジンまたはピリミドピリミジン系化合物、その製造方法、薬剤組成物及びその用途
US9593123B2 (en) 2013-09-06 2017-03-14 Hoffmann-La Roche Inc. Triazolo[4,5-D]pyrimidine derivatives
WO2015043398A1 (fr) 2013-09-30 2015-04-02 上海璎黎药业有限公司 Composé de pyrimidine condensée, intermédiaire, procédé de préparation s'y rapportant et composition et application correspondantes
US9745321B2 (en) 2013-09-30 2017-08-29 Shanghai Yingli Pharmaceutical Co., Ltd Fused pyrimidine compound, intermediate, preparation method therefor, and composition and application thereof
WO2015055071A1 (fr) 2013-10-16 2015-04-23 上海璎黎药业有限公司 Composé hétérocyclique condensé, son procédé de préparation, composition pharmaceutique et leurs utilisations
US9656996B2 (en) 2013-10-16 2017-05-23 Shanghai Yingli Pharmaceutical Co., Ltd. Fused heterocyclic compound, preparation method therefor, pharmaceutical composition, and uses thereof
JP2018525345A (ja) * 2015-07-01 2018-09-06 ノースウェスタン ユニバーシティ 置換キナゾリン化合物及びグルコセレブロシダーゼ活性の調節のためのその使用
US10934270B2 (en) 2015-07-01 2021-03-02 Northwestern University Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
CN112707907A (zh) * 2019-10-24 2021-04-27 张飞 新型嘌呤衍生物及其中间体与制备抗癌症药物的应用
WO2021078141A1 (fr) * 2019-10-24 2021-04-29 苏州锐明新药研发有限公司 Nouveau dérivé de purine, intermédiaire et application de celui-ci dans la préparation d'un médicament anticancéreux
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