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WO2008148074A2 - Inhibiteurs de mtor et methodes de traitement mettant en œuvre ces inhibiteurs - Google Patents

Inhibiteurs de mtor et methodes de traitement mettant en œuvre ces inhibiteurs Download PDF

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WO2008148074A2
WO2008148074A2 PCT/US2008/064809 US2008064809W WO2008148074A2 WO 2008148074 A2 WO2008148074 A2 WO 2008148074A2 US 2008064809 W US2008064809 W US 2008064809W WO 2008148074 A2 WO2008148074 A2 WO 2008148074A2
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compound
aryl
alkyl
alkenyl
halo
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WO2008148074A3 (fr
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Richard Lin
Dale Drueckhammer
Jun Yong Choi
Lisa Ballou
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Research Foundation Of State University Of New York
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    • 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

Definitions

  • Rapamycin a bacterial macrolide
  • has immunosuppressant properties and is used in kidney transplantation. Rapamycin also has antiangiogenic properties that can have dramatic antineoplastic effects, demonstrated in an animal model of metastasis.
  • the mammalian target of rapamycin commonly known as mTOR, is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription.
  • mTOR also functions as a sensor of cellular nutrient and energy levels and redox status.
  • mTOR mammalian target of rapamycin
  • TSC tuberous sclerosis complex
  • Rapamycin binds to its intracellular receptor to form a complex that inhibits mTOR function. Rapamycin and its analogs, however, have two disadvantages: only some of the functions of mTOR are blocked, and Akt protein kinase, which promotes cell survival, is activated. Small molecules that can compete with ATP in the catalytic site of mTOR to inhibit the kinase-dependent functions without enhancing the cell survival functions would be very desirable to inhibit cancer growth. Thus, there remains a need for novel small molecule inhibitors of the mTOR kinase that do not have these disadvantages. These compounds may be useful for treating (TSC) as an initial treatment or in patients who are resistant to rapamycin treatment.
  • Tuberous sclerosis complex is a rare genetic disease estimated to affect 1 in 6,000 individuals and most commonly manifests itself in infants and small children. (Young, J. et al, Molecular Medicine Today 4, 313-319 (1998)). TSC is characterized by the development of benign tumors called hamartomas at multiple sites in the body. Development in the brain often leads to seizures and learning and behavioral problems. The kidney, lung, and heart are also commonly affected, sometimes causing failure of these organs, while severe skin rashes are also common.
  • TSC Three types of brain tumors are associated with TSC: cortical tubers, which generally form on the surface of the brain; subependymal nodules, which form in the walls of the ventricles (the fluid- filled cavities of the brain); and giant-cell astrocytomas, a type of tumor that can block the flow of fluids within the brain.
  • cortical tubers which generally form on the surface of the brain
  • subependymal nodules which form in the walls of the ventricles (the fluid- filled cavities of the brain)
  • giant-cell astrocytomas a type of tumor that can block the flow of fluids within the brain.
  • TSC is caused by mutations in either of the tumor suppressor genes tscl and tsc2.
  • TSCl 130 kDa
  • TSC2 200 kDa
  • the TSCl and TSC2 proteins form a heterodimer that negatively regulates the mammalian target of rapamycin (mTOR).
  • mTOR mammalian target of rapamycin
  • the direct target of the TSC1/TSC2 complex is the small G protein Rheb (Ras homolog enriched in brain), which is a positive regulator of mTOR signaling.
  • TSC1/TSC2 complex stimulates the GTPase activity of Rheb, converting it to its inactive GDP-bound state and thus inhibiting mTOR (See Fig. 2).
  • loss of the TSC1/TSC2 complex allows Rheb to accumulate in the active GTP-bound form, thus leading to constitutive activation of mTOR.
  • mTOR is a large multidomain protein kinase that is a key component of a signaling pathway that regulates cell growth, proliferation and survival.
  • rapamycin Fig. 1
  • Fig. 1 The natural compound rapamycin (Fig. 1) and its analogs inhibit mTOR function without directly inhibiting its kinase activity.
  • Fig. 1 The natural compound rapamycin (Fig. 1) and its analogs inhibit mTOR function without directly inhibiting its kinase activity.
  • Experiments using these drugs in animal models have already validated mTOR as a target for the treatment of TSC. (Kenerson, H., Dundon, et al., Pediatric Research 57, 67-75; Lee, L.
  • rapamycin is already being tested in clinical trials as a treatment for TSC. (Franz, D. N. et al., Annals of Neurology 59, 490-498 (2006).
  • Rapamycin (Fig. 1), a bacterial metabolite, binds to a domain of mTOR distinct from the kinase domain, resulting in inhibition of mTOR function by a mechanism that is not fully understood. Rapamycin inhibits the proliferation of many types of cells, including T cells, and is currently used as an immunosuppressant. An intact kinase domain is essential for mTOR function. The mTOR kinase domain is most closely related to the one found in phosphoinositide 3-kinases (PBKs) (see Fig. 3). (Crespo, J. L. et al., Microbiol MoI Biol Rev., 66, 579-591 (2002)).
  • PBKs phosphoinositide 3-kinases
  • mTOR phosphorylates proteins, not lipids.
  • the unusual mTOR kinase domain defines the PBK-related kinase (PIKK) family of protein kinases, which includes DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated protein kinase (ATM) and ATM- and Rad3 -related protein kinase (ATR) (see Fig. 3).
  • PIKK PBK-related kinase
  • DNA-PK DNA-dependent protein kinase
  • ATM ataxia telangiectasia mutated protein kinase
  • ATR ATM- and Rad3 -related protein kinase
  • the mTOR-Raptor complex (mTORCl) phosphorylates the translation repressor 4E-BP1 and T389 in S6K (ribosomal protein S6 kinase), and is rapamycin sensitive (Fig. 2).
  • the mTOR-Rictor complex (mTORC2) phosphorylates the protein kinase Akt at S473 and is insensitive to rapamycin. Rapamycin analogs are under clinical development as chemotherapeutic agents for a variety of cancers, and rapamycin has also been investigated for treatment of TSC. (Franz, D. N. et al., Annals of Neurology 59, 490-498 (2006); Vignot, S. et.
  • LY294002 (Fig.l) is a structurally simple small molecule that inhibits the kinase activity of both PBKs and PIKK family members, including mTOR (Vlahos, C. J. et al., J. Biol. Chem. 269, 5241-5248 (1994)).
  • PBKs regulate a wide range of cellular functions, including growth, glucose metabolism and motility (Katso, R., et al., Annual Review of Cellular and Developmental Biology 17, 615-675 (2001)).
  • PIKKs regulate processes such as cell cycle progression and genome maintenance.
  • LY294002 as a non-selective mTOR inhibitor might have undesirable toxic side effects. While the 3-D structure of mTOR has not been solved, the structures of the complexes of PBK ⁇ with ATP, LY294002, and four other inhibitors have been reported (Walker, E. H. et al., MoI. Cell. 6, 909-919 (2000); Walker, E. H. et al., Nature 402, 313-320 (1999)). The 8- phenyl group of LY294002 binds to PBK in space occupied by the ribose moiety of ATP.
  • PBK The active site of PBK (and presumably the PIKK family) is more open in this position compared to more typical protein kinases, which make more extensive use of interaction with the ribose moiety in binding ATP. This may explain why LY294002 is not an inhibitor of more typical protein kinases, an important consideration in the development of selective inhibitors of mTOR.
  • LY294002 has been used as a lead structure for the development of isoform- selective inhibitors of PBK (Camps, M. et al, Nat. Med. 11, 936-943 (2005); Knight, Z. A. et al, Bioorg Med Chem 12, 4749-4759 (2004)), while Griffin et al. have used LY294002 as a template for the design of DNA-PK inhibitors (Griffin, R. J. et al., J Med Chem 48, 569-585 (2005); Hardcastle, I. R. et al., J Med Chem 48, 7829-7846 (2205); Leahy, J. J. et al., Med Chem Lett 14, 6083-6087 (2004)).
  • the present invention provides novel compounds that are useful for inhibiting mTOR activity.
  • Compounds of the present invention include those having the formula:
  • A is selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, halo, aryl,
  • R 1 is selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, halo, aryl,
  • R 2 is selected from H, halo, amino, hydroxyl, lower alkyl, lower alkenyl, and lower alkynyl
  • R 3 is selected from H, halo, amino, hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, and cycloalkyl
  • R > 4 is selected from H, halo, amino, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl,
  • R 40 is selected from halo, hydroxyl, nitro, amino, CN, C(O)R 44 , alkyl, cycloalkyl, aralkyl, aryl, and a heterocyclic group;
  • R 41 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group
  • each R 42 and R 43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 42 and R 43 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R 44 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl,
  • R 1 is selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, halo, aryl, -(C 1-6 alkyl)-aryl, and -(C 2-6 alkenyl)-aryl;
  • R 2 is selected from H, halo, amino, hydroxyl, lower alkyl, lower alkenyl, and lower alkynyl;
  • R 3 is selected from H, halo, amino, hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, and cycloalkyl;
  • R 4 is selected from H, halo, amino, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl,
  • R 40 is selected from halo, hydroxyl, nitro, amino, CN, C(O)R 44 , alkyl, cycloalkyl, aralkyl, aryl, and a heterocyclic group;
  • R 41 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group
  • each R 42 and R 43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 42 and R 43 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R 44 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl,
  • A is selected from:
  • All A12 A13 A14 and B is selected from;
  • Particular embodiments of the invention include compounds of formula I in which B is Bl, and A is Al, A2, A3, A4, A5, A6, A7, A8, A8, or AlO, and compounds of formula II in which B is B2, B3, B4, B5, B6, B7, B8, B9, BlO, BI l, B12, B13, or B14.
  • the compounds inhibit mTOR with an IC 50 of less than about 2 ⁇ M. In certain embodiments, the compounds inhibit the kinase activity of PI3K to a lesser extent than mTOR. In certain embodiments of the invention, the compounds inhibit PI3K with an IC50 of more than about 25 ⁇ M.
  • the present invention also provides pharmaceutical compositions and kits comprising a compound of the present invention, and further provides methods of inhibiting mTOR activity in a cell or subject (including mammals and humans) wherein a compound of the present invention is provided to the cell or subject.
  • Figure 1 provides the structures of rapamycin, LY294002 and a related inhibitor.
  • LY294022 is a known inhibitor of the phosphoinositide 3-kinases (PBKs) and of the PI3K-related kinase (PIKK) family, of which mTOR is a member.
  • PBKs phosphoinositide 3-kinases
  • PIKK PI3K-related kinase
  • Compound 1 of figure 1 has been developed as an inhibitor of the related DNA-dependent protein kinase (DNA-PK) (Griffin et al 2005).
  • Figure 2 provides a schematic description of TSC-related cell signaling pathways.
  • Figure 3 provides an alignment of kinase domains of PBKs and PIKKs. The shading points out some of the most highly conserved amino acids among the six sequences. The diamonds point out two positions in which sequence differences are being exploited for selective inhibition of mTOR.
  • Figure 4 provides the structure and IC 50 values ( ⁇ M) for LY294002 and analogs for which mTOR inhibition data have been reported.
  • Figure 5 provides active site residues (tube structures) and LY294002 (space filling model) in the kinase domains of PBK ⁇ (left) and mTOR (right).
  • the mTOR structure was derived from homology modeling based on the crystal structure of PBK ⁇ using the MOE software package.
  • Figure 6 shows carbon-8 substituents of some compounds of structure I of the present invention. Also shown are approximate IC 50 values for mTOR (upper value) and PBK (lower, ⁇ or ⁇ isoform as indicated). When only one value is shown, it is for mTOR.
  • Figure 7 provides the results of in vitro kinase assays.
  • Figure 7A shows an autoradiograph where immunoprecipitated mTOR was assayed with increasing concentrations of compound 1 of Figure 1 in ⁇ M.
  • Figure 7B shows the results of a study where PBK ⁇ (represented by circles) and PBK ⁇ (represented by squares) was purified from baculovirus-infected insect cells and assayed in the presence of compound 1 of Figure 1 (closed) or LY294002 (open).
  • Figure 8 provides the results of in vivo assays.
  • Figure 8A shows the results of a study where serum- starved Ratl cells were pretreated with vehicle (Veh), 10 nM rapamycin (Rap), 5 ⁇ M compound 1 of Figure 1 or 5 ⁇ M LY294002 for 20 min. and then treated with or without 50 ng/ml PDGF (platelet-derived growth factor) for 10 min.
  • Figure 8B shows the results of a study where MCF7 cells growing in serum-containing medium were treated with vehicle, 10 nM rapamycin or 25 ⁇ M of compound 1 for 24 h. Cell lysates were analyzed by Western blotting using the indicated antibodies, including actin to show equal loading of proteins in each lane.
  • Figure 8C shows the results of a study where MCF7 cells were treated with increasing concentrations of compound 1 of figure 1 for 4 days and cell growth was measured by MTT assays.
  • Figure 9 provides compounds of the present invention with a quinoline or isoquinoline ring at C-8.
  • Figure 10 provides compounds of the present invention — acylthio and bromo analogs as C2243 -modifying inhibitors.
  • the present invention provides novel compounds that are useful in inhibiting mTOR activity.
  • a series of compounds based on a pyrimidoisoquinolineone ring system designed to discriminate between the active sites of mTOR and related kinases were synthesized and tested.
  • the compounds of the present invention were designed based primarily on the crystal structure of the PI3K ⁇ -LY294002 complex (Walker, E. H. et al, MoI. Cell. 6, 909-919 (2000); Walker, E. H. et al., Nature 402, 313-320 (1999)).
  • Fig. 3 shows an alignment of a portion of the active site sequences of selected PI3K and PIKK family members. Views of the PI3K ⁇ active site structure alongside the mTOR homology model are shown in Fig. 5. The results revealed two interesting differences in active site residues between these kinases (indicated by the diamonds in Figure 3).
  • the side chain indole of W812 in PI3K ⁇ is very close to the carbon-8 phenyl group of LY294002 in the crystal structure.
  • the equivalent residue is also W in the other PBKs but is K in mTOR (K2171) and ATR, R in DNA-PK, and I in ATM.
  • the 3-D models indicate that the active sites of mTOR and DNA-PK have additional space in this area that can accommodate expansion of the 8-phenyl ring of LY294002 due to the less bulky K and R side chains.
  • the W2239 side chain of mTOR equivalent to 1881 in PBK ⁇ and present as W in all of the PIKKs, extends into some of this space but still leaves room for expansion of the inhibitor (Figure 5).
  • the methyl side chain of A885 in PBK ⁇ is about 5A away from one of the methylene carbons attached to oxygen in the morpholine moiety of LY294002 (Fig. 5).
  • the equivalent amino acid is S or T in most of the other members of this family while mTOR is the only member that has C in this position.
  • C2243 in mTOR thus provides a potential site for covalent modification by a group on the morpholine moiety of the inhibitor that reacts with the thiol, which thus imparts additional selectivity for mTOR.
  • the compounds of the present invention exploit the structural differences described above, based on the LY294002 structure but with the arrangement of heteroatoms of the pyrimidoisoquinolineone ring system of 1 ( Figure 1).
  • the compounds of the present invention have the structure:
  • A is selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, halo, aryl,
  • R 1 is selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, halo, aryl,
  • R 2 is selected from H, halo, amino, hydroxyl, lower alkyl, lower alkenyl, and lower alkynyl
  • R 3 is selected from H, halo, amino, hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, and cycloalkyl
  • R > 4 is selected from H, halo, amino, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl,
  • R 40 is selected from halo, hydroxyl, nitro, amino, CN, C(O)R 44 , alkyl, cycloalkyl, aralkyl, aryl, and a heterocyclic group;
  • R 41 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group
  • each R 42 and R 43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 42 and R 43 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R 44 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl,
  • R 2 is selected from H, halo, amino, hydroxyl, methyl and trifluoromethyl. In particularly preferred embodiments R 2 is H.
  • R 3 is selected from H, halo, amino, hydroxyl, methyl and trifluoromethyl. In particularly preferred embodiments R 3 is H.
  • A is selected from aryl, -(C 1-6 alkyl)-aryl, -(C 2-6 alkenyl)-aryl.
  • R 1 is selected from H, halo, and alkyl. In particularly preferred embodiments R 1 is H.
  • R 4 is selected from halo, amino, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, -(CH 2 )O-O-R 41 , -(CH 2 ) ⁇ -N(R 42 )(R 43 ), -(CH 2 ) ⁇ -N(R 41 )-(CH 2 ),C(O)R 44 , -(CH 2 ) ⁇ -SR 41 , -(CH 2 ) ⁇ -C(O)R 44 , -(CH 2 ) ⁇ -C(O)-(CH 2 ),OR 41 , -(CH 2 ) ⁇ -C(O)-(CH 2 ),N(R 42 )(R 43 ), -(CH 2 ) ⁇ O-C(O)R 44 , -(CH 2 ) ⁇ S-C(O)R 44 , -(CH 2 ) ⁇ S-C(O)R 44 ,
  • the compounds of the present invention have the structure:
  • R 1 is selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, halo, aryl,
  • R 2 is selected from H, halo, amino, hydroxyl, lower alkyl, lower alkenyl, and lower alkynyl
  • R 3 is selected from H, halo, amino, hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, and cycloalkyl
  • R 4 is selected from H, halo, amino, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl,
  • R 40 is selected from halo, hydroxyl, nitro, amino, CN, C(O)R 44 , alkyl, cycloalkyl, aralkyl, aryl, and a heterocyclic group;
  • R 41 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group
  • each R 42 and R 43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 42 and R 43 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R 44 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl,
  • R 5 is selected H, halo, -OH, amino, alkyl, -O-alkyl, -O-aryl, -O-aralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, -(C 1-6 alkyl)-aryl, and -(C 2 _ 6 alkenyl)-aryl, and a heterocyclic group; a is O to 4; b is O to 4; m is 1 or 2; and
  • R 2 is selected from H, halo, amino, hydroxyl, methyl and trifluoromethyl. In particularly preferred embodiments R 2 is H.
  • R is selected from H, halo, amino, hydroxyl, methyl and trifluoromethyl.
  • R 3 is H.
  • R 4 is selected from halo, amino, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, -(CH 2 ) ⁇ -O-R 41 , -(CH 2 ) ⁇ -N(R 42 )(R 43 ), -(CH 2 ) ⁇ -N(R 41 )-(CH 2 ),C(O)R 44 , -(CH 2 ) ⁇ -SR 41 , -(CH 2 ) ⁇ -C(O)R 44 , -(CH 2 ) ⁇ -C(O)-(CH 2 ),OR 41 , -(CH 2 ) ⁇ -C(O)-(CH 2 ),OR 41 , -(CH 2 ) ⁇ -C(O)-(CH 2 ),OR 41 , -(CH
  • halo or halogen as used herein includes fluorine, chlorine, bromine and iodine.
  • alkyl as used herein contemplates substituted or unsubstituted, straight and branched chain alkyl radicals containing from one to eight carbon atoms.
  • lower alkyl as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
  • the alkyl group may be optionally substituted with one or more substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R, -SC(O)R, -OC(O)N(R)(R), SO 2 , -SOR, -SO 3 R, and -SO 2 N(R)(R).
  • substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R, -SC
  • alkenyl as used herein contemplates substituted or unsubstituted, straight and branched chain alkene radicals containing from two to eight carbon atoms.
  • lower alkenyl as used herein contemplates alkenyl radicals containing from two to six carbon atoms.
  • the alkenyl group may be optionally substituted with one or more substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R, -SC(O)R, -OC(O)N(R)(R), SO 2 , -SOR, -SO 3 R, and -SO 2 N(R)(R).
  • substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R, -
  • alkynyl as used herein contemplates substituted or unsubstituted, straight and branched carbon chain containing from two to 8 carbon atoms and having at least one carbon-carbon triple bond.
  • alkynyl includes, for example ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-methyl-l-butynyl, and the like.
  • lower alkynyl as used herein contemplates alkenyl radicals containing from two to six carbon atoms.
  • the alkynyl group may be optionally substituted with one or more substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R, -SC(O)R, -OC(O)N(R)(R), SO 2 , -SOR, -SO 3 R, and -SO 2 N(R)(R).
  • substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R,
  • cycloalkyl as used herein contemplates substituted or unsubstituted cyclic alkyl radicals containing form 3 to 7 carbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • a cycloalkyl group may be optionally substituted with one or more substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R, -SC(O)R, -OC(O)N(R)(R), SO 2 , -SOR, -SO 3 R, and -SO 2 N(R)(R).
  • substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R,
  • cycloalkenyl as used herein contemplates substituted or unsubstituted cyclic alkenyl radicals containing form 5 to 7 carbon atoms in which has a double bond between two of the ring carbons and includes cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkenyl group may be optionally substituted with one or more substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R, -SC(O)R, -OC(O)N(R)(R), SO 2 , -SOR, -SO 3 R, and -SO 2 N(R)(R).
  • substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R
  • aryl as used herein contemplates substituted or unsubstituted single-ring aromatic groups (for example, phenyl, pyridyl, pyrazole, etc.) and fused polycyclic ring systems (naphthyl, quinoline, dibenzothiophene, etc.), and unfused polycyclic ring systems (biphenyl, bipyridine, phenyl-pyridine, etc.).
  • the polycyclic rings may have two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls.
  • the aryl group may be optionally substituted with one or more substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R, -SC(O)R, -OC(O)N(R)(R), SO 2 , -SOR, -SO 3 R, and -SO 2 N(R)(R).
  • substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R, -SC
  • heterocyclic group or "heterocyclic ring” as used herein contemplates substituted or unsubstituted aromatic and non-aromatic cyclic radicals having at least one heteroatom as a ring member.
  • Preferred heterocyclic groups are those containing 5 or 6 ring atoms which includes at least one hetero atom, and includes cyclic amines such as morpholino, piperidino, pyrrolidino, and the like, and cyclic ethers, such as tetrahydrofuran, tetrahydropyran, and the like.
  • Aromatic heterocyclic groups also termed "heteroaryl” groups contemplates single-ring hetero-aromatic groups that may include from one to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.
  • heterocyclic group also includes polycyclic ring systems having two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is a heterocycle, e.g., the other ring(s) can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls.
  • polycyclic heteroaromatic systems include quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, quinaxoline, benzimidazole, benzofuran, purine, imidazopyridine, benzotriazole, and the like.
  • a heterocyclic group may be optionally substituted with one or more substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -0-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R, -SC(O)R, -OC(O)N(R)(R), SO 2 , -SOR, -SO 3 R, and -SO 2 N(R)(R).
  • substituents selected from halo, oxo, CN, NO 2 , CO 2 R, C(O)R, -0-R, -N(R)(R), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R)(R), -OC(O)R, -SC(O
  • aralkyl as used herein contemplates a lower alkyl group which has as a substituent an aryl group
  • each R is independently selected from H, Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, C 2 _ 6 alkenyl, aryl, and aralkyl.
  • heteroatom particularly as a ring heteroatom, refers to N, O, and S.
  • Preferred compounds of the present invention have structure I:
  • A is selected from:
  • B is selected from B2-B18.
  • the compound is structure I, wherein A is Al and B is Bl . [0058] In one embodiment, the compound is structure I, wherein A is A2 and B is Bl .
  • the compound is structure I, wherein A is A3 and B is Bl .
  • the compound is structure I, wherein A is A4 and B is Bl .
  • the compound is structure I, wherein A is A5 and B is Bl .
  • the compound is structure I, wherein A is A6 and B is Bl .
  • the compound is structure I, wherein A is A7 and B is Bl .
  • the compound is structure I, wherein A is A8 and B is Bl .
  • the compound is structure I, wherein A is A9 and B is Bl .
  • the compound is structure I, wherein A is AlO and B is Bl.
  • the compound is structure II and B is B2.
  • the compound is structure II and B is B3.
  • the compound is structure II and B is B4.
  • the compound is structure II and B is B5.
  • the compound is structure II and B is B6.
  • the compound is structure II and B is B7.
  • the compound is structure II and B is B8.
  • the compound is structure II and B is B9.
  • the compound is structure II and B is BlO.
  • the compound is structure II and B is Bl 1.
  • the compound is structure II and B is B 12.
  • the compound is structure II and B is B13.
  • the compound is structure II and B is B 14.
  • the compound is structure II and B is B15.
  • the compound is structure II and B is B 16.
  • the compound is structure II and B is B 17. [0083] In one embodiment, the compound is structure II and B is B 18.
  • Compounds of the invention are mTOR inhibitors.
  • the IC50 for mTOR inhibition is less than about 10 ⁇ M, or less than about 5 ⁇ M, or less that about 2 ⁇ M.
  • a compound of the invention is a more effective inhibitor of mTOR than of a related kinase.
  • certain mTOR inhibitors have an IC50 for mTOR that is at least about 2 fold, or at least about 5 fold, or at least about 10 fold lower than the IC50 for PBK ⁇ .
  • the IC 50 for PBK ⁇ is greater than about 10 ⁇ M or greater than about 25 ⁇ M.
  • Preferred compounds of the present invention include, but are not limited to, compounds where the structure is structure I and wherein A is A2 or A6. Another preferred compound is a compound having structure II wherein B is B9.
  • aryl A1-A5 or Al 1 -Al 4
  • Suzuki coupling reaction to provide compounds of formula I, wherein A is aryl.
  • Compound 4 can be prepared by the following synthetic scheme:
  • the A group is then introduced into compound 6 by either the Suzuki coupling reaction or the Heck reaction as described above.
  • the hydroxyl of the resulting compound can be converted into a leaving group (for example, a tosylate or mesylate, by reaction with toluenesulfonyl chloride or methanesulfonyl chloride in the presence of diethylamine, respectively) to provide a compound of formula 7.
  • compound 5 is depicted above as the racemic mixture, the individual isomers of compound 5, i.e., the (R) isomer substantially free of the (S) isomer and (S) isomer substantially free of the (R) isomer are also within the scope of the invention. Accordingly, compounds of structure I and II wherein B is an individual isomer of B2-B5, B9, or B 12 are also within the scope of invention. Individual isomers of compound 5 will be prepared as described in the literature. (See, Berg, S., Larsson, L. G., Renyi, L., Ross, S.B., Thorberg, S.O. and Thorell-Scantesson, G.
  • Compound 7 can be reacted with Cl “ or Br " (for example, NaCl or NaBr) to provide the compound of structure I wherein B is B2 or B3, respectively.
  • Compound 7 can also be reacted with CH 3 -C(O)SH in the presence of NaH in dimethyl formamide to provide the compound of structure I wherein B is B4.
  • Hydrolysis of the compounds of structure I wherein B is B4, for example, with sodium hydroxide in methanol provides the compound of structure I wherein B is B9.
  • Reaction of the compound of structure I wherein B is B9 with an acid chloride of formula R-C(O)Cl, wherein R is an alkyl group provides a thioester. For example if R in R-C(O)Cl is -CH(CH 3 ) 2 the resulting compound is the compound of structure I wherein B is B5.
  • the hydroxyl of compound 11 can be functionalized as described above.
  • the hydroxyl of compound 11 can be converted into a leaving group and then converted into -Cl, -Br, or -SH, i.e., compounds of structure I wherein B is B6, B7, or B 13, using the methods described above.
  • the compounds of structure I wherein B is -SC(O)CH3, or -SC(O)CH(CHs) 2 i.e., compounds of structure I wherein B is BlO or BI l, respectively, are also prepared from compound 11 using the methods described above.
  • Oxidation of the hydroxyl of compound 11 (Swern oxidation (i.e., oxalyl chloride, dimethyl sulfoxide, and triethyl amine) or TEMPO oxidation (i.e., TCIA and NaHCOs) provides the compound structure I wherein B is B8.
  • compound 9 is depicted above as the racemic mixture, the individual isomers of compound 9, i.e., the (R) isomer substantially free of the (S) isomer and (S) isomer substantially free of the (R) isomer are also within the scope of the invention. Accordingly, compounds of structures I and II wherein B is an individual isomer of B6-B8 or B 10-Bl 3 are also within the scope of invention.
  • Compounds of structure II are prepared by reacting a compound of formula 12 with a compound of formula 5 or 9 and then functionalizing the hydroxyl of the resulting compound as described above.
  • Compound 12 is a known compound:
  • the present invention further provides methods of inhibiting mTOR activity in a cell or subject wherein a compound of the present invention is provided to the cell or subject.
  • the subject can be a mammal such as a human.
  • Preferable compounds inhibit mTOR activity, including both mTOR-Raptor (mTORCl) and mTOR-Rictor (mTORC2). More preferred compounds also are selective inhibitors of mTOR, that inhibit the kinase activity of PBK and/or other PIKK family members to a lesser extent than mTOR. Preferred compounds do not reactivate or activate the protein kinase Akt. Inhibit means reduce, decrease or completely eliminate activity.
  • the present invention also provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier is one that does not cause an adverse physical reaction upon administration and one in which compounds of the present invention are sufficiently soluble and retain their activity to deliver a therapeutically effective amount of the compound.
  • the therapeutically effective amount and method of administration of compounds of the invention may vary based on the individual patient, the indication being treated and other criteria evident to one of ordinary skill in the art.
  • a therapeutically effective amount of a compound of the invention is one sufficient to inhibit mTOR activity without causing significant adverse side effects.
  • the route(s) of administration useful in a particular application are apparent to one of ordinary skill in the art.
  • a salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • pharmaceutically acceptable counterion is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para ⁇
  • inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid
  • organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, bes
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzo
  • hydrate means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • solvate means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
  • the present invention provides a method of treatment for a disease (disorder or condition) affected by aberrant activity of mTOR.
  • ameliorate and “treat” are used interchangeably and include both therapeutic and prophylactic treatment. Treating or treatment can mean complete treatment so the subject does not possess any symptoms of the disease or can also mean reducing the symptoms of the disease. Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein).
  • Methods of treatment comprise administering a compound of the invention to a subject in need thereof (suffering from a condition or disorder caused by aberrant activity of mTOR).
  • mTOR inhibitors of the invention are particularly effective against tumors that are PTETV-deficient and/or have abnormalities in the PBK/ AKT pathway, which include certain melanomas, renal cell carcinomas, chronic and acute myeloid leukemias, endometrial cancers, myelomas, and tumors of the prostate, breast, lung, bladder, ovary, pancreas, colon, thyroid and brain.
  • EGFR epidermal growth factor receptor
  • PDGFR platelet derived growth factor receptor
  • IGF-R insulin-like growth factor 1 receptor
  • mTOR inhibitors of the invention are particularly useful for treatment of neoplastic disease when administered with one or more other cancer therapies, including but not limited to surgery, radiation therapy, chemotherapy, endocrine therapy, hyperthermia, and cryotherapy.
  • mTOR inhibitors of the invention can be administered with other agents that are inhibitors of signal transduction, including small molecules and biological agents.
  • small molecules include proteins, polypeptides, and nucleic acids, and have molecular weights greater than 2000 Daltons.
  • an mTOR inhibitor of the invention is used in combination with another agent that is a signal transduction inhibitor.
  • a signal transduction inhibitor is a receptor tyrosine kinase (RTK) antagonist that neutralizes or reduces that signal transduction activity of a receptor such as an epidermal growth factor receptor (EGFR, HER2) or insulin like growth factor receptor (IGF-R).
  • RTK receptor tyrosine kinase
  • Such agents include antigen-binding proteins that bind to the extracellular domain of the receptor or to a ligand of the receptor and block binding of the ligand.
  • Ligands for EGFR include, for example, EGF, TGF- ⁇ , amphiregulin, heparin-binding EGF (HB-EGF) and betacellulin.
  • EGF and TGF- ⁇ are thought to be the main endogenous ligands that result in EGFR-mediated stimulation.
  • EGFR antagonists that bind EGFR include, without limitation, biological agents such as antibodies (and functional equivalents thereof) specific for EGFR (e.g., cetuximab) or HER2 (e.g., trastuzumab), and chemical agents (small molecules), such as synthetic kinase inhibitors that act directly on the cytoplasmic domain of EGFR (e.g., gef ⁇ tinib, erlotinib).
  • An example of an antibody that binds to IGF-R is IMC-Al 2.
  • growth factor receptors involved in tumorigenesis are the receptors for vascular endothelial growth factor (VEGFR-I and VEGFR-2), platelet-derived growth factor (PDGFR), nerve growth factor (NGFR), fibroblast growth factor (FGFR).
  • VEGFR-I and VEGFR-2 vascular endothelial growth factor
  • PDGFR platelet-derived growth factor
  • NGFR nerve growth factor
  • FGFR fibroblast growth factor
  • inhibitors include sorefenib, which blocks the enzyme RAF kinase, a component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation and blocks the VEGFR-2/PDGFR ⁇ signaling cascade, and bevacizumab, a monoclonal antibody which binds to VEGF and inhibits signaling through VEFGR.
  • an mTOR inhibitor described herein is used in combination with another chemotherapeutic drug such as an alkylating agent or an anti-metabolite.
  • alkylating agents include, but are not limited to, cisplatin, carboplatin, cyclophosphamide, melphalan, and dacarbazine.
  • anti-metabolites include, but not limited to, methotrexate, doxorubicin, daunorubicin, and paclitaxel, gemcitabine.
  • Useful chemotherapeutic agents also include mitotic inhibitors, such as taxanes docetaxel and paclitaxil.
  • Topoisomerase inhibitors are another class of antineoplastic agents that can be used in combination with antibodies of the invention. These include inhibitors of topoisomerase I or topoisomerase II.
  • Topoisomerase I inhibitors include irinotecan (CPT-I l), aminocamptothecin, camptothecin, DX-8951f, and topotecan.
  • Topoisomerase II inhibitors include etoposide (VP- 16), and teniposide (VM -26).
  • hormones e.g., tamoxifen, leuprolide, flutamide
  • proteosome inhibitors e.g., bortezomib
  • antibiotics e.g., bleomycin, mitomycin.
  • the classes and chemotherapeutic agents identified above are illustrative and non-limiting.
  • mTOR antagonist therapy is administered before, during, or after commencing therapy with another agent, as well as any combination thereof, i.e., before and during, before and after, during and after, or before, during and after commencing therapy with the other agent.
  • the combination may provide increased, additive, or synergistic effect. Increased efficiency of the combination often allows for the use of a lower dosage of either or both of the agents than when used alone.
  • Treatable tumors include primary and secondary, or metastatic, tumors.
  • the compounds can also be used to treat refractory tumors.
  • Refractory tumors include tumors that fail or are resistant to treatment with chemotherapeutic agents alone, radiation alone or combinations thereof.
  • the mTOR inhibitory compounds are also useful to inhibit growth of recurring tumors, e.g., tumors that appear to be inhibited by treatment with chemotherapeutic agents and/or radiation but recur up to five years, sometimes up to ten years or longer after treatment is discontinued.
  • TSC tuberous sclerosis complex
  • LAM lymphangioleiomyomatosis
  • pulmonary cysts characterized by pulmonary cysts, recurrent pneumothorax, lymphadenopathy, cystic lymphatic masses, or other manifestations.
  • Proliferative conditions also include organ hypertrophy, such as familial cardiac hypertrophy, and smooth muscle thickening after vascular injury, such as occurs after placement of a vascular stent, and which can lead to vascular plaque occlusion and atherosclerosis.
  • organ hypertrophy such as familial cardiac hypertrophy
  • smooth muscle thickening after vascular injury such as occurs after placement of a vascular stent, and which can lead to vascular plaque occlusion and atherosclerosis.
  • Inhibitors of mTOR are effective as immunosuppressors. Rapamycin has been approved for use as an immunosuppressant in kidney, liver and heart transplantation. Accordingly, the mTOR inhibitors described herein are used to treat autoimmune diseases, such as autoimmune lymphoproliferative disease.
  • the mTOR inhibitors described herein are used to delay or inhibit an acquired resistance to another drug therapy. Accordingly, an mTOR inhibitor of the invention is coadministered with a drug when resistance to that drug develops, or coadministered throughout treatment with the drug in order to delay or prevent progression to drug resistance.
  • acquired resistance is a major problem limiting the benefits of endocrine or hormone-dependent therapy of breast and prostate cancer.
  • Most prostate cancer is initially androgen dependent (AD).
  • Prostate cancer cells initially require androgen for continued proliferation.
  • ADT androgen deprivation therapy
  • GnRH agonists or estrogens leads to rapid induction of apoptosis of sensitive prostate cancer cells.
  • the positive response is followed by a period of growth arrest in which remaining cells tend not to die.
  • growth recurs in 90% of cases.
  • surviving cancer cells become androgen independent or unresponsive, and androgen- independent (AI) tumor growth follows.
  • the mTOR inhibitors of the invention are inhibitors of signal transduction pathways that are implicated in resistance to endocrine or hormone-dependent therapy.
  • the invention provides a method of delaying or inhibiting resistance to hormone-dependent therapy of prostate and breast cancer, as well as other cancers in signal transduction through pathways that involve mTOR is implicated.
  • an mTOR inhibitor of the invention is administered in combination with an anti-cancer drug (e.g., a gonadotropin- releasing hormone antagonist for prostate cancer; an anti-estrogen for breast cancer) once resistance to that drug has arisen.
  • the mTOR inhibitor is coadministered with the anti-cancer drug to delay or prevent progression to drug resistance.
  • compounds of the present invention can be administered as a pharmaceutical composition containing, for example, a compound and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil or injectable organic esters.
  • a pharmaceutically acceptable carrier including a physiologically acceptable compound, depends, for example, on the route of administration of the composition.
  • a pharmaceutical composition containing a compound of the present invention can be administered to a subject by various routes including, for example, oral administration; intramuscular administration; intravenous administration; anal administration; vaginal administration; parenteral administration; nasal administration; intraperitoneal administration; subcutaneous administration and topical administration.
  • the composition can be administered by injection or by incubation.
  • the pharmaceutical composition also can be a compound of the invention linked to a liposome or other polymer matrix. Liposomes, for example, which consist of phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • kits which comprise a pharmaceutical composition of the invention, wherein said pharmaceutical composition is in a container, and optionally, instructions describing a method of using the pharmaceutical composition for treatment.
  • the included compositions may be lyophilized and packaged with a diluent.
  • kits of this invention may comprise separate dosage forms of a compound of this invention and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent are associated with one another.
  • association with one another means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).
  • kits of this invention may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition.
  • a device to administer or to measure out a unit dose of the pharmaceutical composition may include a syringe and needle if said composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if said composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit.
  • Example 1 In Vitro and Cellular Testing of mTOR Inhibitors
  • the mTORCl complex is immunoprecipitated from FreeStyle 293 (Invitrogen, Carlsbad, CA) cell lysates using a Raptor antibody (Bethyl Laboratories, Montgomery, TX). Immunocomplexes are incubated with a compound of the present invention, added as a solution in dimethylsulfoxide (DMSO) for 30 min. prior to initiating the kinase reaction by adding ⁇ [ 32 P]ATP and glutathione-S-transferase (GST)-4E-BP1 as substrates. A control reaction in which the inhibitor solution is substituted with an equal volume of DMSO (hereafter called vehicle) is conducted in each series of assays to correct for any effect of solvent.
  • DMSO dimethylsulfoxide
  • SDS-polyacrylamide gel electrophoresis SDS-PAGE
  • GST-4E- BPl on the gel is visualized by Coomassie blue staining and autoradiography. Radioactive bands are then cut out of the gel and quantified by scintillation counting.
  • PBK ⁇ pi 10 ⁇ /p85 ⁇ complex
  • Sf9 cells are coinfected with baculoviruses expressing the human pi lO ⁇ catalytic subunit and p85 ⁇ regulatory subunits and the PBK ⁇ complex is purified as described for PBK ⁇ .
  • PBK Purified PBK is incubated with vehicle or compound for 10 min. prior to initiating the kinase reaction by adding ⁇ [ 32 P] ATP and phosphatidylinositol as substrates. After the reaction is stopped by adding acidified methanol/chloroform, the samples are subjected to thin layer chromatography (TLC). Radioactive spots corresponding to phosphatidylinositol 3 -phosphate are visualized by autoradiography, cut out of the TLC plate and quantified by scintillation counting. These results are used to calculate IC50 values against PBK ⁇ and PBK ⁇ for each compound.
  • TLC thin layer chromatography
  • PBK ⁇ and PBK ⁇ are further tested in vitro against the two other PBKs ( ⁇ and ⁇ ).
  • PBK proteins may be purchased from Upstate Biotechnology (Charlottesville, VA). The assays are performed as described above. The compounds are also tested against other PIKK family members (DNA-PK, ATM and ATR) using in vitro kinase assays as described in Chiang, G. G. et al, Methods MoI Biol 281, 125-141 (2004) with modifications.
  • Purified DNA-PK may be purchased from Promega (Madison, WI).
  • ATM and ATR may be obtained by immunoprecipitation from K562 cell lysates using Ab-3 antibody (Calbiochem, San Diego, CA) and ab2905 antibody (Novus Biological, Littleton, CO), respectively.
  • Ab-3 antibody Calbiochem, San Diego, CA
  • ab2905 antibody Novus Biological, Littleton, CO
  • the kinases are incubated with increasing concentrations of compound of the present invention and reactions are initiated by adding ⁇ [ 32 P]ATP and a GST-p53 (1-70 a.a.) fusion protein as substrates. After the reaction is stopped by boiling in SDS sample buffer, the samples are subjected to SDS-PAGE. GST-p53 is visualized by Coomassie blue staining and autoradiography. The radioactive bands are then cut out of the gel and quantified by scintillation counting. IC 50 values for each compound against each of these PI3K and PIKK enzymes are calculated.
  • Ratl fibroblasts are serum starved overnight and then incubated with vehicle or increasing concentrations of a compound of the present invention for 20 min. The cells are then stimulated for 10 min. without or with 50 ng/ml PDGF. Phosphorylation of sites modified by mTORCl (S6K T389) or mT0RC2 (Akt S473) is analyzed by Western blotting with phospho-specific antibodies. The blots are stripped and reprobed with general S6K and Akt antibodies to control for equal protein loading.
  • the Western blot bands are quantified using an Odyssey Infrared Imaging System (LI-COR Biosciences, Lincoln, NE) (Lu, Z. et al., J Biol. Chem. 250, 40347-40354 (2005)). IC 50 values are calculated for each phosphorylation site.
  • An effective mTOR kinase inhibitor should act like compound 1 of Figure 4 in suppressing S6K T389 and Akt S473 phosphorylation in vivo at low concentrations that are consistent with inhibition of mTOR in vitro (see Figures 7 A and 8A).
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
  • Cells are plated in triplicate at 3,000 cells/well in 96-well plates and the next day they are treated with a compound of the present invention or vehicle. After 4 days the number of viable cells is determined using the MTT assay as previously described (Mosmann, T., Journal of Immunological Methods. 65, 55-63 (1983)). The results are read on a plate reader and the effect of the compound of the present invention expressed as the percentage of viable cells relative to vehicle-treated controls.
  • TdT -mediated dUTP nick end labeling TUNEL
  • flow cytometry As previously described in (Ballou, L. M. et al, Journal of Biological Chemistry 275, 4803-4809 (2000)).
  • TUNEL TdT -mediated dUTP nick end labeling
  • Akt activates survival pathways, it is expected that rapamycin-treated cells will exhibit a relatively low level of apoptosis.
  • the mTOR inhibitors of the present invention may induce a higher rate of cell death because of their suppression of mT0RC2 and Akt. A strong cytotoxic effect of the compound on TSC cells would be clinically more desirable than a cytostatic effect detected in the experiment above.
  • Compound 1 of Figure 4 and several compounds of the present invention, including those of structure I wherein B is Bl and A includes moieties shown in Figure 6 were tested for inhibition of the kinase activity of mTOR in vitro.
  • Results for compound 1 illustrate preferred properties for a selective mTOR kinase inhibitor.
  • compound 1 inhibits mTOR activity in a dose-dependent manner, which was confirmed using an in vitro kinase assay with ⁇ [ 32 P]ATP and GST-4E-BP1 as substrates (Figure 7A).
  • GST is glutathione-S-transferase and 4E-BP1 is eukaryotic initiation factor 4E binding protein.
  • Compound 1 is a poor inhibitor of PBKs as compared with LY294002 ( Figure 7B).
  • the PBKs were assayed using ⁇ [ 32 P]ATP and phosphatidylinositol as substrates. (Ballou, L. M., et al, Biochem. J. 394, 557-562 (2006)).
  • compound 1 of Figure 4 did not induce Akt phosphorylation because it inhibits both mTORCl and mT0RC2 (Figure 8B).
  • rapamycin and compound 1 of Figure 4 markedly reduced S6K T389 phosphorylation (Fig. 8B).
  • Compound 1 of Figure 4 also blocked MCF7 breast cancer cell proliferation by 50% at a concentration between 10 and 25 ⁇ M as measured by MTT assays ( Figure 8C). These results indicate that compound 1 of Figure 4 exhibits the expected properties of an mTOR kinase inhibitor both in vitro and in vivo.
  • compound 1 of Figure 4 and LY294002 were used as lead structures for the design of potent and selective inhibitors of mTOR, which are compounds of the present invention.
  • the compound having structure I wherein A is A5 exhibited the most potent inhibition of mTOR among this group, but also strongly inhibited PBK.
  • the compound having structure I wherein A is A2 is a compound of interest.
  • the compound having structure I wherein A is A6 exhibited potent inhibition of mTOR, similar to the compound having structure I wherein A is A2. It is noteworthy that while these compounds (having structure I wherein A is A2 or A6) exhibit similarly potent inhibition of mTOR, they are also structurally very similar, with compound (A6) simply lacking the 2-carbon bridge to form the second ring of compound (A2).
  • the compound having structure I wherein A is A7 showed the best activity of these three, and indeed this analog is predicted by computer modeling to have the ring nitrogen closest to the K2171 amine group. However, these three analogs also exhibited strong inhibition of PBK. Computer modeling suggests that the pyridine nitrogen atom of these analogs may form a hydrogen bond with the side chain hydroxyl group of T856 of PBK ⁇ (corresponds to T887 of PBK ⁇ ).
  • the amide isostere (the compound having structure I wherein A is AlO) of the olefin A6 (the compound having structure I wherein A is A6) exhibited potent inhibition.
  • the isomeric amide having the orientation of the nitrogen and carbonyl reversed was also prepared but showed minimal inhibition of mTOR. The results of these assays are shown in Table 1.

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Abstract

L'invention concerne de nouveaux composés inhibant l'activité de mTOR. L'invention concerne également des compositions, notamment des compositions pharmaceutiques, contenant ces composés. L'invention concerne encore des méthodes de traitement consistant à administrer ces compositions à un patient nécessitant un tel traitement.
PCT/US2008/064809 2007-05-24 2008-05-24 Inhibiteurs de mtor et methodes de traitement mettant en œuvre ces inhibiteurs WO2008148074A2 (fr)

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WO2011001113A2 (fr) 2009-07-02 2011-01-06 Sanofi-Aventis NOUVEAUX DERIVES DE 1,2,3,4-TETRAHYDRO-PYRIMIDO{1,2-a}PYRIMIDIN-6-ONE,LEUR PREPARATION ET LEUR UTILISATION PHARMACEUTIQUE
WO2011001115A1 (fr) 2009-07-02 2011-01-06 Sanofi-Aventis Nouveaux derives de 6-morpholin-4-yl-pyrimidin-4- ( 3h ) -one, leur preparation pharmaceutique comme inhibiteurs de phos phorylat i on d ' akt ( pkb )
WO2011001112A1 (fr) 2009-07-02 2011-01-06 Sanofi-Aventis NOUVEAUX DERIVES DE 2,3-DIHYDRO-1H-IMIDAZO{1,2-a}PYRIMIDIN-5-ONE, LEUR PREPARATION ET LEUR UTILISATION PHARMACEUTIQUE
FR2947550A1 (fr) * 2009-07-02 2011-01-07 Sanofi Aventis Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt (pkb)
FR2947551A1 (fr) * 2009-07-02 2011-01-07 Sanofi Aventis Nouveaux derives de 1,2,3,4-tetrahydro-pyrimido{1,2-a)pyrimidin-6-one, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt (pkb)
FR2951173A1 (fr) * 2009-10-09 2011-04-15 Sanofi Aventis Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
FR2951174A1 (fr) * 2009-10-09 2011-04-15 Sanofi Aventis Nouveaux derives de 1,2,3,4-tetrahydro-pyrimido{1,2-a}pyrimidin-6-one, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
WO2011109833A2 (fr) 2010-03-05 2011-09-09 President And Fellows Of Harvard College Compositions de cellules dendritiques induites et utilisations associées
WO2012085244A1 (fr) 2010-12-23 2012-06-28 Sanofi Derives de pyrimidinone, leur preparation et leur utilisation pharmaceutique
FR2969608A1 (fr) * 2010-12-28 2012-06-29 Sanofi Aventis Nouveaux derives de (5-halo-6-oxo-1,6-dihydro-pyrimidin-2-yl)-amide, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
FR2969614A1 (fr) * 2010-12-28 2012-06-29 Sanofi Aventis Nouveaux derives de pyrimidinones, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
FR2969613A1 (fr) * 2010-12-23 2012-06-29 Sanofi Aventis Nouveaux derives de 1,2,3,4-tetrahydro-pyrimido{1,2-a}pyrimidin-6-one, leur preparation et leur utilisation pharmaceutique
FR2969610A1 (fr) * 2010-12-28 2012-06-29 Sanofi Aventis Nouveaux derives de (6-oxo-1,6-dihydro-pyrimidin-2-yl)-indolinamide, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
FR2969607A1 (fr) * 2010-12-28 2012-06-29 Sanofi Aventis Nouveaux derives de thiopyrimidinones, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
FR2969612A1 (fr) * 2010-12-23 2012-06-29 Sanofi Aventis Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one, leur preparation et leur utilisation pharmaceutique
WO2012089633A1 (fr) 2010-12-28 2012-07-05 Sanofi Nouveaux derives de pyrimidines, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
US20130004436A1 (en) * 2010-03-18 2013-01-03 Steven Lehrer Compositions and Methods of Treating and Preventing Lung Cancer and Lymphangioleiomyomatosis
WO2013190510A2 (fr) 2012-06-22 2013-12-27 Sanofi Nouveaux dérivés de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one et de 1,2,3,4-tétrahydropyrimido{1,2-a}pyrimidin-6-one comprenant une morpholine substituée, leur procédé de préparation et leur utilisation pharmaceutique
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9284275B2 (en) 2007-01-11 2016-03-15 Critical Outcome Technologies Inc. Inhibitor compounds and cancer treatment methods
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US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
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WO2011001114A1 (fr) 2009-07-02 2011-01-06 Sanofi-Aventis Nouveaux derives de (6-oxo-1,6-dihydro-pyrimidin-2-yl)-amide, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
FR2947550A1 (fr) * 2009-07-02 2011-01-07 Sanofi Aventis Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt (pkb)
FR2947551A1 (fr) * 2009-07-02 2011-01-07 Sanofi Aventis Nouveaux derives de 1,2,3,4-tetrahydro-pyrimido{1,2-a)pyrimidin-6-one, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt (pkb)
WO2011001113A3 (fr) * 2009-07-02 2011-02-24 Sanofi-Aventis NOUVEAUX DERIVES DE 1,2,3,4-TETRAHYDRO-PYRIMIDO{1,2-a}PYRIMIDIN-6-ONE,LEUR PREPARATION ET LEUR UTILISATION PHARMACEUTIQUE
JP2012531462A (ja) * 2009-07-02 2012-12-10 サノフイ 新規２，３−ジヒドロ−１Ｈ−イミダゾ｛１，２−ａ｝ピリミジン−５−オン誘導体、これらの調製およびこれらの薬学的使用
JP2012531463A (ja) * 2009-07-02 2012-12-10 サノフイ 新規１，２，３，４−テトラヒドロピリミド｛１，２−ａ｝ピリミジン−６−オン誘導体、これらの調製およびこれらの医薬的使用
US8828997B2 (en) 2009-07-02 2014-09-09 Sanofi 2,3-dihydro-1H-imidazo(1,2-a)pyrimidin-5-one derivatives, preparation thereof, and pharmaceutical use thereof
US8846670B2 (en) 2009-07-02 2014-09-30 Sanofi 1,2,3,4-tetrahydro-pyrimido(1,2-a)pyrimidin-6-one derivatives, preparation thereof, and pharmaceutical use thereof
WO2011001115A1 (fr) 2009-07-02 2011-01-06 Sanofi-Aventis Nouveaux derives de 6-morpholin-4-yl-pyrimidin-4- ( 3h ) -one, leur preparation pharmaceutique comme inhibiteurs de phos phorylat i on d ' akt ( pkb )
WO2011001113A2 (fr) 2009-07-02 2011-01-06 Sanofi-Aventis NOUVEAUX DERIVES DE 1,2,3,4-TETRAHYDRO-PYRIMIDO{1,2-a}PYRIMIDIN-6-ONE,LEUR PREPARATION ET LEUR UTILISATION PHARMACEUTIQUE
CN102482286B (zh) * 2009-07-02 2015-07-15 赛诺菲 新型1,2,3,4-四氢嘧啶并{1,2-a}嘧啶-6-酮衍生物、其制备以及其医药用途
RU2554868C2 (ru) * 2009-07-02 2015-06-27 Санофи НОВЫЕ ПРОИЗВОДНЫЕ 2,3-ДИГИДРО-1Н-ИМИДАЗО[1,2-а]ПИРИМИДИН-5-ОНА, СПОСОБ ИХ ПОЛУЧЕНИЯ И ПРИМЕНЕНИЕ В ФАРМАЦИИ
WO2011001112A1 (fr) 2009-07-02 2011-01-06 Sanofi-Aventis NOUVEAUX DERIVES DE 2,3-DIHYDRO-1H-IMIDAZO{1,2-a}PYRIMIDIN-5-ONE, LEUR PREPARATION ET LEUR UTILISATION PHARMACEUTIQUE
FR2951174A1 (fr) * 2009-10-09 2011-04-15 Sanofi Aventis Nouveaux derives de 1,2,3,4-tetrahydro-pyrimido{1,2-a}pyrimidin-6-one, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
FR2951173A1 (fr) * 2009-10-09 2011-04-15 Sanofi Aventis Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
WO2011109833A2 (fr) 2010-03-05 2011-09-09 President And Fellows Of Harvard College Compositions de cellules dendritiques induites et utilisations associées
US9248110B2 (en) * 2010-03-18 2016-02-02 Steven Lehrer Compositions and methods of treating and preventing lung cancer and lymphangioleiomyomatosis
US20130004436A1 (en) * 2010-03-18 2013-01-03 Steven Lehrer Compositions and Methods of Treating and Preventing Lung Cancer and Lymphangioleiomyomatosis
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
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US8815853B2 (en) 2010-12-23 2014-08-26 Sanofi Pyrimidinone derivatives, preparation thereof and pharmaceutical use thereof
FR2969612A1 (fr) * 2010-12-23 2012-06-29 Sanofi Aventis Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one, leur preparation et leur utilisation pharmaceutique
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WO2012085244A1 (fr) 2010-12-23 2012-06-28 Sanofi Derives de pyrimidinone, leur preparation et leur utilisation pharmaceutique
WO2012089633A1 (fr) 2010-12-28 2012-07-05 Sanofi Nouveaux derives de pyrimidines, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
FR2969607A1 (fr) * 2010-12-28 2012-06-29 Sanofi Aventis Nouveaux derives de thiopyrimidinones, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
FR2969610A1 (fr) * 2010-12-28 2012-06-29 Sanofi Aventis Nouveaux derives de (6-oxo-1,6-dihydro-pyrimidin-2-yl)-indolinamide, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
FR2969614A1 (fr) * 2010-12-28 2012-06-29 Sanofi Aventis Nouveaux derives de pyrimidinones, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
US9133168B2 (en) 2010-12-28 2015-09-15 Sanofi Pyrimidine derivatives, preparation thereof, and pharmaceutical use thereof as akt(pkb) phosphorylation inhibitors
FR2969608A1 (fr) * 2010-12-28 2012-06-29 Sanofi Aventis Nouveaux derives de (5-halo-6-oxo-1,6-dihydro-pyrimidin-2-yl)-amide, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb)
JP2015525236A (ja) * 2012-06-22 2015-09-03 サノフイ 置換モルホリンを含む新規な２，３−ジヒドロ−１Ｈ−イミダゾ｛１，２−ａ｝ピリミジン−５−オンおよびこの１，２，３，４−テトラヒドロピリミド｛１，２−ａ｝ピリミジン−６−オン誘導体、その調製およびその製薬学的使用
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