WO2017031427A1 - Composés et procédés d'inhibition de mtor - Google Patents

Composés et procédés d'inhibition de mtor Download PDF

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Publication number
WO2017031427A1
WO2017031427A1 PCT/US2016/047776 US2016047776W WO2017031427A1 WO 2017031427 A1 WO2017031427 A1 WO 2017031427A1 US 2016047776 W US2016047776 W US 2016047776W WO 2017031427 A1 WO2017031427 A1 WO 2017031427A1
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Prior art keywords
optionally substituted
compound
nrc
alkyl
heterocyclic ring
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PCT/US2016/047776
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English (en)
Inventor
Allan S. Wagman
Russell J. JOHNSON
Haiying CAI
Lily W. HU
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3-V Biosciences, Inc.
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Publication of WO2017031427A1 publication Critical patent/WO2017031427A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This invention relates to the field of protein kinases and inhibitors thereof.
  • the invention relates to inhibitors of mammalian target of rapamycin (mTOR) signaling pathways, and methods of their use.
  • mTOR mammalian target of rapamycin
  • mTOR The mammalian target of rapamycin, mTOR, is a protein kinase that integrates both extracellular and intracellular signals of cellular growth, proliferation, and survival. Given its central role in cellular growth, proliferation and survival, it is perhaps not surprising that mTOR signaling is frequently dysregulated in cancer and other diseases (Bjomsti and Houghton Rev Cancer 2004, 4(5), 335-48; Houghton and Huang Microbiol Immunol 2004, 279, 339-59; Inoki, Corradetti et al. Nat Genet 2005, 37(1), 19-24).
  • mTOR is a member of the PIKK (PI3K-related Kinase) family of atypical kinases which includes ATM, ATR, and DNAPK, and its catalytic domain is homologous to that of PI3K. Dysregulation of PI3K signaling is a common function of tumor cells. In general, mTOR inhibition may be considered as a strategy in many of the tumor types in which PI3K signaling is implicated.
  • PIKK PI3K-related Kinase
  • Inhibitors of mTOR may be useful in treating a number of cance s, including the following: breast cancer ( agata, Lan et al., Cancer Cell 2004, 6(2), 117-27: Pandolfi N. Engl, J. Med. 2004, 351(22), 2337-8; Nahta, Yu et al. Nat. Clin. Praci. Oncol. 2006, 3(5), 269-280); antle cell lymphoma (MCL) (Dal Col, Zancai et al. Blood 2008, 1 1 .1 (10), 5142-51); renal cell carcinoma (Thomas, Tran et al. Nat Med 2006, 12(1 ), 122-7; Atkins, Hidalgo et al. J. Clin.
  • NSCLC non small cell lung carcinoma
  • anaplastic large cell lymphoma ACL
  • hamartomas angiomyelo lipomas
  • T ' SC-associated and sporadic lymphangioleiomyomatosis Cowden's disease (multiple hamaratoma syndrome) (Bissler, McCormack et al. N. Engl. J. Med. 2008, 358(2), 140-151); sclerosing hemangioma (Randa M. S. Amin. Pathology International 2008, 58(1), 38-44); Peutz- Jeghers syndrome (PJS); head and neck cancer (Gupta, McKenna et al. Clin. Cancer Res.
  • ACL anaplastic large cell lymphoma
  • hamartomas angiomyelo lipomas
  • T ' SC-associated and sporadic lymphangioleiomyomatosis Cowden's disease (multiple hamaratoma syndrome) (Bissler, McCormack et al. N. Engl. J
  • neurofibromatosis (Ferner R.E. Eur. J. Hum. Genet. 2006, 15(2), 131-138; Sabatini Nat. Rev. Cancer 2006, 6(9), 729-734; Johannessen, Johnson et al. Current Biology 2008, 18(1), 56-62); macular degeneration; macular edema; myeloid leukemia; systemic lupus; and autoimmune lymphoproliferative syndrome (ALPS).
  • APS autoimmune lymphoproliferative syndrome
  • inhibitors of mTO may be useful in the treatment of viral infections and diseases associated therewith (US 2012/0190676; CA 2825825).
  • the present invention is directed to compounds having activity as mTOR inhibitors, including mTORCl and mTORC2, including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and the use of such compounds to inhibit mTOR and to tliereby treat any of a variety of conditions or diseases in which modulation of the rapamycin signaling pathway provides a therapeutic benefit .
  • R 1 is Ci-ealkyl optionally substituted with one or more R ', C2- 6 alkenyl optionally substituted with one or more R', Ci-ealkynyl optionally substituted with one or more R', N(R 5 )(R 6 ), OR 5 , a 3 to 8 membered carbocyclic ring optionally substituted with one or more R', or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R 7 ;
  • R 5 and R 6 are each independently H, C h alky! optionally substituted with one or more R 7 , Ci-ealkenyl optionally substituted with one or more R 7 , C 2 . 6 alkyny3 optionally substituted with one or more R', a 3 to 8 membered carbocyclic ring optionally substituted with one or more R 7 , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R', heteroaryi optionally substituted with one or more R', or aryl optionally substituted with one or more R 7 , or
  • R 5 and R b together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R' ;
  • R is Ci- 6 alky3, Ci-ealkenyl, i " >., ⁇ ..'3 ⁇ 4ikyn> !.
  • R 2 is Ci- 6 alkyl optionally substituted with one or more R'°, C 2 - 6 alkenyl optionally substituted with one or more R lU , N(R 8 )(R ), a 3 to 8 membered carbocyclic ring optionally substituted with one or more R 10 , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R lU , heteroaryl optionally substituted with one or more R 10 , or aryl optionally substituted with one or more R 10 ;
  • R 5 and R 9 are each independently H, d-ealky! optionally substituted with one or more R'°, Cj-ealkenyl optionally substituted with one or more R i0 , C ⁇ alkynyl optionally substituted with one or more R 10 .
  • a 3 to 8 membered carbocyclic ring optionally substituted with one or more R l0 a 3 to 8 membered heterocyclic ring optionally substituted with one or more R" J , heteroaryl optionally substituted with one or more R 10 , or aiyl optionally substituted with one or more R 10 , or
  • R K and R 9 together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R 1 ";
  • R 10 is C 2 .. 6 alkenyl, Ci-ealkyny!, halogen, -CN, oxo, -OR, -N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R -C(0)N(R) 2 , -NRC(0)R
  • R 3 is H, halogen, -CN, Ci-ealkyl, Ci-ehaloalkyi, or -OR;
  • R 4 is H, halogen, -CN, C f .alk> !.
  • Ci_ 6 haloalkyl, -N(R) 2 , -OR, -C(0)N(R) 2 , -Ci-ealkyl-OR, 3 to 8 membered carbocyclic ring, or 3 to 8 membered heterocyclic ring;
  • A is aiyl or heteroaryl, wherein A is optionally substituted by one or more R 1 1 ;
  • R" is Ci-ealkyl, C 2 . 6 alkenyi, C 2 .. 6 alkynyl, Ci-Jialoalkyl, halogen, -CN, oxo, -OR, -N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R -C(0)N(R) 2 , -NRC(0)R
  • R " are each independently H, Ci-ealkyl optionally substituted with one or more R', Ci-ealkeny] optionally substituted with one or more R', Ci-ealkynyl optionally- substituted with one or more R'', heteroaryl optionally substituted with one or more R ? , or aryi optionally substituted with one or more R', or
  • R 3 and R 6 together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R 7 ;
  • R 7 is ( " ; ..,a!kyl . C 2 . 6 alkenyl, C 2 . 6 alkynyl, Ci-ehaloalkyl, -OR, -N(R) 2 , -NRC(0)R -NRC(0)N(R) 2, -OC(0)N(R) 2 , -NRC(0)OR, -C ⁇ alkyl-OR, -C;_ 6 alkyl-N(R) 2 ,
  • R* 5 and R y together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R l0 ;
  • R i0 is C]- 4 alkyl, Ci. 4 haloalkyl, -OR, -N(R) 2 , -NRC(0)R -NRC(0)N(R) 2,
  • A is aryi or heteroaryl, wherein A is optionally substituted by one or more R 11 ;
  • R u is halogen, -CN, Ci-ealkyl, C 2 - 6 alkenyl, Ci-ealkynyi, Cj-ehaloalkyi, oxo, -OR, - (R) 2 , ⁇ C(Q)R, ⁇ C(Q)OR, -C(0)N(R) 2 , -NRC(0)R -NRC(0)N(R) 2 , -OC(0)N(R) 2 , -NRC(0)OR, -S(0) 2 R, -S(0) 2 N(R) 2 , -NRS(0) 2 R -Ci_ 6 alkyl-OR, -Ci- 6 alkyl-N(R) 2 ,
  • each R is independently H, Ci-ealkyl, Ci-ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.
  • R 1 is Ci-eaikyl optionally substituted with one or more R' , C 2 _ 6 aikenyl optionally substituted with one or more R 7 , C 2 .ealkyny3 optionally substituted with one or more R 7 , N(R 5 )(R 6 ), OR 3 , a 3 to 8 membered carbocyclic ring optionally substituted with one or more R'', or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R 7 ;
  • R and R 6 are each independently H, ' : ...nlk% i optionally substituted with one or more R 7 , C 2 _ 6 alkenyl optionally substituted with one or more R 7 , C 2 _ 6 alkynyl optionally substituted with one or more R', a 3 to 8 membered carbocyclic ring optionally substituted with one or more R ' , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R', heteroarv'l optionally substituted with one or more R 7 , or aryi optionally substituted with one or more R 7 , or
  • R 5 and R 6 together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R' ;
  • R' is Ci-ealkyl, C 2-6 alkenyl, C 2 _ 6 alkynyl, Ci-ehaloalkyi, halogen, -CN, oxo, -OR, - (R) 2 , -C(0)R, -C(0)OR, OC(0)R -C(G)N(R) 2 , -NRC(0)R
  • R 2 is Ci -eaikyl optionally substituted with one or more R'°, C -ealkenyl optionally substituted with one or more R 10 , N(R 8 )(R 9 ), a 3 to 8 membered earbocyclie ring optionally substituted with one or more R 10 , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R" J , heteroaryl optionally substituted with one or more R 10 , or aiyl optionally substituted with one or more R 10 ;
  • R K and R are each independently H, optionally substituted with one or more R l0 , Ci-ealkenyl optionally substituted with one or more R'", C 2 - 6 alkynyl optionally substituted with one or more R 10 , a 3 to 8 membered earbocyclie ring optionally substituted with one or more R'°, a 3 to 8 membered heterocyclic ring optionally substituted with one or more R lU , heteroaryl optionally substituted with one or more R k ', or aiyl optionally substituted with one or more R 10 , or
  • R 9 and R 9 together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R l0 ;
  • R lC" is Ci-ealkyi, C 2- ealkenyl, C 2 _ 6 alkynyl, Ci -ehaloalkyl, halogen, -CN, oxo, -OR, -N(R) 2 , -C(0)R, -C(0)OR, OC(0)R -C(0)N(R) 2 , -NRC(0)R
  • R 3 is H, halogen, -CN, C h alky!, C;. 6 haloalkyl, or -OR;
  • R 4 is H, halogen, -CN, CV 6 aikyi, Ci-ehaloalkyi, -N(R) 2 , -OR, -C(0)N(R) 2 ,
  • A is ary] or heteroaiyl, wherein A is optionally substituted by one or more R 11 ;
  • R 11 is Ci-eaikyi, C 2-6 alkenyl, C 2-6 alkynyl, Ci-ehaloalkyl, halogen, -CN, oxo, -OR, -N(R) 2 , -C(0)R, -C(0)OR, OC(0)R -C(0)N(R) 2 , -NRC(0)R , -NRC(0)N(R) 2, -QC(Q)N(R) 2 , -NRC(Q)QR, -S(i)) .R. -S(0) 2 N(R) 2 , -NRS(0) >R.
  • each R is independently H, Ci- 6 alkyl, ( ' ...haloalk) !. 3 to 6 mem be red carbocyclic ring, or 3 to 6 membered heterocyclic ring.
  • R 3 and R D are each independently H, C h alky! optionally substituted with one or more R', C 2 .. 6 alkenyl optionally substituted with one or more R', C 2 .. 6 alkynyl optionally substituted with one or more R', heteroaryl optionally substituted with one or more R 7 , or aryi optionally substituted with one or more R 7 , or
  • R 5 and R 6 together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R' ;
  • R 7 is Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C ]-6 haloalkyl, -OR, -N(R) 2 , -NRC(0)R -NRC(0)N(R) 2i -OC(0)N(R) 2 , -NRC(0)OR, -Ci.. 6 aikyl ⁇ OR, -( : .,.aik> 1- N(R) 2 , -C(0)N(R) 2 , -C 1 . 6 alkyl-C(O)N(R) 2 , -C 1 .
  • R i0 is C, . 4 alkyL Ci.Aaloalkyl, -OR, -N(R) 2 , -NRC(0)R -NRC(0)N(R) 2, -OC(0)N(R) 2 , -NRC(0)OR, -( '• ...aikyl-OK . -( ⁇ ...a!kyl Ai K) -. -C(0)N(R) 2 ,
  • A is aryl or heteroaryl, wherein A is optionally substituted by one or more R 11 ;
  • R 1 1 is halogen, -CN, Ci-ealkyl, C 2 -6alkenyi, C 2 .&alkynyi, Ci-ehaloalkyl, oxo, -OR, -N(R) 2 , -C(0)R, -C(0)OR, -C(0)N(R) 2 , -NRC(0)R -NRC(0)N(R) 2,
  • each R is independently H, C h alky!, Ci -ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.
  • a pharmaceutical composition comprising a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a compound having the structure of Formula ⁇ -a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition further comprises one or more additional biologically active agents.
  • the additionally biologically active agents is selected from the group consisting of anticancer drugs; cyctotoxins, cell cycle arresting drugs; and cytostatic drugs, or a combination of these agents.
  • the one or more additional biologically active agents is selected from the group consisting of antiviral drags; DNA gyrase inhibitors, protease inhibitors, polymerase inhibitors, or a combination of these agents.
  • the one or more additional biologically active agents is selected from the group consisting of immunomodulator drugs; interferon, steroid, cox inhibitor, or a combination of these agents.
  • the additionally biologically active agent is an anticancer drug selected from, the group consisting of paclitaxel, doxorubicin, vincristine, actinomycin D, altretamine, asparaginase, bleomycin, busulphan, cabazitaxel, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicm, docetaxel, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarabicin, ifosfamide, irinotecan, lomustine, melphalan, mercaptopurine, methotre
  • agents targeting DNA repair deficiency e.g. olaparib
  • agents targeting receptor tyrosine kinases such as EGFR, ERBB2, c-MET, VEGFR2, and IGFR1, e.g. erlotinib, necitumumab, traztuzamab, pertuzamab, lapatsnib, crizotinib, cabozantinib, onartuamab, ramucirumab, or bevacizumab
  • agents tarting hormone receptors such as the androgen and estrogen receptors, e.g.
  • enzalutamide, abiraterone, or tamoxifen agents targeting the MAP kinase or PI3K-AKT pathways, e.g. cobimetinib, vemurafenib, and everolimus; Her2 (ErbB2) pathway blockers such as lapatinib, trastuzumab, and Kadyzla; rnTOR blockers such as raiapogs ⁇ e.g., sirolimus); mTORC l/mTORCl inhibitors; Angiogenesis or VEGFR pathway blockers such as avastin, nexavar or sutent; Aromatase modulators such as exemtesane or femora; Androgen signaling modulators such as enzalutamide, bicalutamide; and B-RAF blockers such as Tafinlar or Zelboraf.
  • Her2 (ErbB2) pathway blockers such as lapatinib, trastu
  • a method of inhibiting mTOR in a warm-blooded animal comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of inhibiting mTOR in a warm-blooded animal comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of inhibiting mTOR in a warm-blooded animal comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of inhibiting mTOR in a warm-blooded animal comprising administering to the animal an effective amount of a compound having the structure of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating cancer in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating cancer in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating cancer in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating cancer in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing a respirator ⁇ ' vims infection in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing a respirator ⁇ - virus infection in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing a respiratory virus infection in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing a respirator],' virus infection in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing inflammation in a warmblooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing inflammation in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Fonnula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing inflammation in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing inflammation in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Fonnula Il-a, or a stereoisomer, pharmaceutically acceptable sale or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • Amino refers to the -NH 2 radical .
  • Niro refers to the -NO?, radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), having from one to twelve carbon atoms -12 alkyl), preferably one to eight carbon atoms (Cj-Cg alkyl) or one to six carbon atoms (Ci-Ce alkyl), and which is attached to the rest of the molecule by a single bond, e.g.
  • an alkyl group may be optionally substituted.
  • Alkylene or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, which is saturated or unsaturated (i.e. , contains one or more double and/or triple bonds), and having from one to twelve carbon atoms, e.g. , methylene, ethylene, propylene, H-butylene, ethenylene, propenylene, tt-butenylene, propynylene, w-butynylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or double bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain may be optionally substituted.
  • Alkoxy refers to a radical of the formula -OR 3 where R a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted.
  • Alkylamino refers to a radical of the formula -NHR a or -NRaR a where each R, is, independently, an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted.
  • Thioalkyl refers to a radical of the formula -SR 3 where R a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group may be optionally substituted.
  • Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • the aryi radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system., which may include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, and radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, os-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • 'Aralkyl refers to a radical of the fonnula -R b ⁇ R G where R is an alkylene chain as defined above and R is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.
  • Cycloalkyl or “carbocyclic ring” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
  • Monocyclic radicals include, for example, cyclopropyi, cyclobutyl, cyclopentyi, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic radicals include, for example, adamantyi, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1Jheptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.
  • Cycloalkylalkyl refers to a radical of the formula -3 ⁇ 43 ⁇ 4 where 3 ⁇ 4 is an alkylene chain as defined above and R g is a cycloalkyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally substituted.
  • fused refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention.
  • the fused ring is a heterocyclyl ring or a heteroaryl ring
  • any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.
  • Halo refers to bromo, chioro, fluoro or iodo.
  • Haloaikyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyL and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.
  • Heterocyclyl or “heterocyclic ring” refers to a stable 3- to 18-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyciic, tricyclic or tetracyclic ring system, which may include fused, bridged, or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized; and the heterocyclyl radical may be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, dioxolanyi, thienyl[l ,3]dithianyl, decahydroisoquinolyl, imidazo!inyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuciidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiarnorpholimyl, 1-oxox
  • N-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical .
  • a N-heterocyclyl group may be optionally substituted.
  • Heterocyclyl alkyl refers to a radical of the formula -3 ⁇ 4 e where 3 ⁇ 4 is an alkylene chain as defined above and 3 ⁇ 4 is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxoiyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazoiyi, benzo [ )][!, 4] dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxoiyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothioph
  • N-heteroaryi refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group may be optionally substituted.
  • Heteroarylalkyl refers to a radical of the formula -R 3 ⁇ 4 R f where R 3 ⁇ 4 is an alkvlene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted.
  • substituted means any of the above groups (i.e., alkyi, alkvlene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, CL Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups: a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as
  • “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g. , a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • R g and Rh are the same or different and independently hydrogen, alkyi, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl .
  • Substituted further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyi, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cvcloalkyL cvcloalkylalkvl, haloaikyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group.
  • non-hydrogen groups are generally referred to herein as "substituents" or “non-hydrogen substituents”.
  • substituents may also be optionally substituted with one or more of the above substituents.
  • Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologicaliy active compound of the invention.
  • prodrug refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).
  • prodrugs are provided in Higuchi, T., et al., A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the invention and the like.
  • the invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabelled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism, to occur, and isolating its conversion products from the urine, blood or other biological samples.
  • an animal such as rat, mouse, guinea pig, monkey, or to human
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • Mammal' 1 includes humans and both domestic animals such as laboratory animals and household pets (e.g. , cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
  • domestic animals such as laboratory animals and household pets (e.g. , cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
  • Optional or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means thai the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyS sulfuric acid, ethane- 1 ,2-disulfonic acid
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamme, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are iso
  • solvate refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent.
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
  • a “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g. , humans.
  • a medium includes all pharmaceutically acceptable earners, diluents or excipients therefor.
  • Effective amount refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to inhibit mTOR.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Treating covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:
  • disease and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
  • the compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomenc forms that may be defined, in terms of absolute stereochemistry, as (R) ⁇ or (S)- or, as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and ($)-, or (D)- and (L) ⁇ isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the present invention includes tautomers of any said compounds.
  • R 1 is C j-ealkyl optionally substituted with one or more R 7 , C ⁇ -ealkenyl optionally substituted with one or more R 7 , C j-eaikynyl optionally substituted with one or more R ? , N(R 3 )(R D ), OR '1 , a 3 to 8 membered carbocvclic ring optionally substituted with one or more R ', or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R 7 ;
  • R “ and R° are each independently H, Ci-ealkyl optionally substituted with one or more R', C 2 - 6 alkenyl optionally substituted with one or more R', C 2 - 6 alkynyl optionally substituted with one or more R 7 , a 3 to 8 membered carbocvclic ring optionally substituted with one or more R', or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R 7 , heteroaryl optionally substituted with one or more R 7 , or aryl optionally substituted with one or more R , or
  • R 3 and R 6 together with the nitrogen to which they are attached, fonn an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ';
  • R' is Ci-ealkyl, Ci-ealkenyl, C 2 - 6 alkynyl, Ci-ghaloalkyl, halogen, -CN, oxo, -OR, -N(R) 2 , -C(())R, -C(0)OR, ()C(())R -C(0)N(R) 2 , -NRC(0)R
  • R 2 is Ci-ealkyl optionally substituted with one or more R l0 , C 2 - 6 alkenyl optionally substituted with one or more R llj , N(R 8 )(R ), a 3 to 8 membered carbocvclic ring optionally substituted with one or more R 10 , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R'°, heteroaryl optionally substituted with one or more R 10 , or aryl optionally substituted with one or more R 10 ;
  • R 5 and R 9 are each independently H, C h alky 1 optionally substituted with one or more R'°, C 2 - 6 alkenyl optionally substituted with one or more R i0 , C 2 _ 6 alkynyl optionally substituted with one or more R 10 .
  • a 3 to 8 membered carbocyclic ring optionally substituted with one or more R l0 a 3 to 8 membered heterocyclic ring optionally substituted with one or more R'°, heteroaryl optionally substituted with one or more R 10 , or aryl optionally substituted with one or more R 10 , or R 8 and R 9 , togettier with the nitrogen to which they are attached, form an
  • R llj is Ci- 6 alkyl, C 2 _ 6 alkenyl, Ci-ealkynyl, Ci-ehaloalkyl, halogen, -CN, oxo, -OR, -N(R) 2 , -C(0)R, ⁇ ( ( O)OR. OC(0)R -C(0)N(R) 2 , -NRC(0)R
  • R 3 is H, halogen, -CN, C h alky!, Ci-ehaloalkyi, or -OR;
  • R 4 is H, halogen, -CN, C h alky!, ( •• ,.haloalk> I. -N(R) 2 , -OR, -C(0)N(R) 2 , ⁇ Ci-6alky3-OR, 3 to 8 membered carbocycSic ring, or 3 to 8 membered heterocyclic ring;
  • A is aryl or heteroarv'l, wherein A is optionally substituted by one or more R 1 1 ;
  • R i J is Ci-ealkyi, C 2-6 alkenyl, C 2 _ 6 alkynyl, Ci -ehaloalkyl, halogen, -CN, oxo, -OR, -N(R_) 2 , -C(0)R, -C(0)OR, OC(0)R -C(0)N(R) 2 , -NRC(0)R
  • each R is independently H, Ci-ealkyl, Ci-ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.
  • R 1 is Ci-jalkyl optionally substituted with one or more R 7 , C 2 .. 3 alkenyl optionally substituted with one or more R ', C 2 .. 3 alkynyl optionally substituted with one or more R', N(R 5 )(R 6 ), OR 5 , a 3 to 6 membered carbocyclic ring optionally substituted with one or more R ' ', or a 3 to 6 membered heterocyclic ring optionally substituted with one or more R' ;
  • R and R 6 are each independently H, C - >alkyi optionally substituted with one or more R 7 , C >. a!kein ! optionally substituted with one or more R 7 , Cj-nalkynyl optionally substituted with one or more R' , a 3 to 6 membered carbocyclic ring optionally substituted with one or more R', or a 3 to 6 membered heterocyclic ring optionally substituted with one or more R', heteroaryi optionally substituted with one or more R', or and optionally substituted with one or more R 7 , or
  • R 5 and R b together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R';
  • Ci-4alkyl is Ci-4alkyl, C 2- 4alkenyl, Cwhaloalkyl, -OR, -N(R) 2 ,
  • R 1 is optionally substituted with one or more
  • R C 2 - 3 alkenyl optionally substituted with one or more R', C 2 . 3 alkynyl optionally substituted with one or more R 7 , N(R 5 )(R t> ), OR 3 , a 4 to 6 membered carbocyclic ring optionally substituted with one or more R', or a 4 to 6 membered heterocyclic ring optionally substituted with one or more R';
  • R 5 and R 6 are each independently H, Ci_ 3 alkyl optionally substituted with one or more R', C 2 _ 3 alkenyl optionally substituted with one or more R', C 2 _ 3 alkynyl optionally substituted with one or more R 7 , a 4 to 6 membered carbocyclic nng optionally substituted with one or more R 7 , or a 4 to 6 membered heterocyclic ring optionally substituted with one or more R , heteroaryi optionally substituted with one or more R', or aryl optionally substituted with one or more R', or
  • R 5 and R 6 together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 4 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R';
  • R 7 is Ci_ 3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, -OR, -N(R) 2 , -C(0)N(R) 2 , -NRC(0)R -NRC(G)N(R) 3 ⁇ 4 ⁇ C.. 2 alkyl-OR, -C.. 2 alky3-N(R) 2 , -C I .. 2 alkyl-C(0) (R) 2 ,
  • R ! is Ci-3alkyl optionally substituted with one or more R', C 2- 3alkenyl optionally substituted with one or more R', C 2- 3alkynyl optionally substituted with one or more R 7 , N(R 3 )(R 6 ), OR 1 , a 6 membered carbocyclic ring optionally substituted with one or more R ', or a 6 membered heterocyclic ring optionally substituted with one or more R 7 ;
  • R 3 and R D are each independently H, C h alky! optionally substituted with one or more R 7 , C 2-3 aikenyl optionally substituted with one or more R 7 , C 2-3 aikynyl optionally substituted with one or more R', a 5 to 6 membered carbocyclic ring optionally substituted with one or more R , or a 5 to 6 membered heterocyclic ring optionally substituted with one or more R', heteroarv'l optionally substituted with one or more R 7 , or aryi optionally substituted with one or more R 7 , or
  • R 5 and R 6 together with the nitrogen to which they are attached, form an N- heteroeyclic ring containing 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R';
  • R 7 is methyl, -OR, -N(R) 2 , -C(0)N(R) 2 , -NRC(0)R -NRC(0)N(R) 2 ,
  • R 2 is N(R 8 )(R 9 ), a 4 to 6 membered carbocyclic ring optionally substituted with one or more R 10 , or a 4 to 6 membered heterocyclic ring optionally substituted with one or more R 10 ;
  • R 8 and R 9 together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 4 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R lC' ;
  • R l0 is Ci_ 6 alkyl, C 2 remedy 6 aikenyl, C 2 - 6 alkynyL Ci- 6 haloalkyL oxo, -OR, -N(R) 2 , -C(0)N(R) 2 , -NRC(0)R -NRC(0)N(R) 2, -OC(0)N(R) 2 , -NRC(0)OR,
  • R 2 is N(R 8 )(R 9 ), a 5 to 6 membered carbocyclic ring optionally substituted with one or more R 10 , or a 5 to 6 membered heterocyclic ring optionally substituted with one or more R 10 ;
  • R 8 and R 9 together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 5 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R lC' ;
  • R l0 is Ci_ 6 alkyl, C 2 remedy 6 aikenyl, C 2 - 6 aikyny3, Ci- 6 haloalkyL oxo, -OR, -N(R) 2 , -C(0)N(R) 2 , -NRC(0)R -NRC(0) (R) 2i -OC(0)N(R) 2 , ⁇ NRC(0)OR,
  • R 2 is N(R 8 )(R 9 ), a 6 membered carbocyclic ring optionally substituted with one or more R 10 , or 6 membered heterocyclic ring optionally substituted with one or more R 10 ;
  • R 10 is Ci-ealkyl, C;. 6 haloalkyl, oxo, -OR, -N(R) 2 , -C(0)N(R) 2 , -NRC(0)R -NRC(0)N(R)2, -OC(0)N(R) 2 , -NRC(0)OR, •• ( ' ; . i ,aik> i- R. -C . ,.aik> l- ⁇ (R)...
  • R 10 is Ci-ealkyl, oxo, -OR, -N(R) 2 .
  • R 3 is H or halogen. In further embodiments R 3 is H or F. In still further embodiments R 3 is H. In other embodiments, R 4 is H, halogen, Ci ⁇ alkyl, Ci-chaloalkyl, -OR,
  • R 4 is H, F, CI, Br, methyl, ethyl, -CH 2 OH, -OR, or -CH 2 OR, -C(0)N(R) 2 .
  • R 4 is H, F, CI, methyl, ethyl, -CH 2 OH, CH 2 OMe, or -OCH 3 .
  • R 4 is H or F.
  • R 4 is H.
  • R 3 and R 6 are each independently H, i " ;., ⁇ .a!kyi optionally substituted with one or more R 7 , C 2 - 6 alkenyl optionally substituted with one or more R 7 , C 2 - 6 alkynyl optionally substituted with one or more R', heteroaryi optionally substituted with one or more R', or aryl optionally substituted with one or more R 7 , or
  • R 5 and R ⁇ together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R' ;
  • R 7 is Ci-ealkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci- 6 haloalkyl, -OR, -N(R) 2 , -NRC(0)R ⁇ RC(0)N(R) 2 . -OC(0) (R) 2 , -NRC(0)OR, -C ⁇ alkyl-OR, -Ci- 6 alkyl- (R) 2 ,
  • R is d_ 4 alkyl, C ' : . ,haloalk> I. -OR, -N(R) 2 , -NRC(0)R -NRC(0)N(R) 2, -OC(0)N(R) 2 , ⁇ NRC(G)QR, -C ,,aik U ⁇ i)R. -C 1 - 6 alkyl-N(R) 2 , -C(0)N(R) 2 ,
  • A is aryl or heteroaryi, wherein A is optionally substituted by one or more R i J ;
  • R u is halogen, -CN, C 2 - 6 alkenyl, C 2 .. 6 alkynyl, Ci-rJialoalkyl, oxo, -OR, -N(R) 2 , -C(0)R, -C(0)OR, -C(0)N(R) 2 , -NRC(0)R -NRC(0)N(R) 2,
  • each R is independently H, Ci-ealkyl, Ci-ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.
  • A is phenyl optionally substituted by one or more R 1 ' , benzimidazolyl optionally substituted by one or more R a , indolyl optionally substituted by one or more R 11 , pyridiny] optionally substituted by one or more R 11 , pyrimidinyl optionally substituted by one or more R 11 , indazoiyl optionally substituted by one or more R 11 , thiazolyl optionally substituted by one or more R 1 1 , imidazolyl optionally substituted by one or more R 1 ' , pyrazolyl optionally substituted by one or more R n , triazolyl optionally substituted by one or more R 11 , tetrazoiyi optionally substituted by one or more R !
  • A is phenyl optionally substituted by one or more R u , pyridinyl optionally substituted by one or more R 1 ! , pyrimidinyl optionally substituted by one or more R 11 , or indazolyi optionally substituted by one or more R L L .
  • R 2 is -N(R 8 )(R 9 ) and I s and R 9 , together with the nitrogen to which they are attached, form an N-heterocyclic ring selected from the group consisting of:
  • each N -heterocyclic ring is independently optionally substituted by one or more R
  • R 2 is selected from the group consisting of:
  • R" is selected from “oup consisting of:
  • R ⁇ is an optionally substituted 3 to 8 membered heterocyclic ring selected from the group consisting of:
  • R 2 is selected from the group consisting of:
  • R 7 is selected from the group consisting of:
  • R " is N(R )(R ) and R and are each independently H, i " ; ., ⁇ .a!kyi optionally substituted with one or more R 10 , a 3 to 8 membered carbocvclic ring optionally substituted with one or more R'°, or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R'°.
  • R 2 is selected from the group consisting of:
  • R is ⁇ (K )(R") and R and R 6 , together with the nitrogen to which they are attached, form an N-heterocyclic ring selected from the group consisting of:
  • R 1 is selected from the group consisting of:
  • each N-heterocyclic ring is independently optionally substituted by one or more R ? ,
  • R 1 is selected from the group consisting of:
  • each N-heterocyclic ring is independently optionally substituted by one or more R' .
  • R 1 is an optionally substituted 3 to 8 membered heterocyclic ring selected from the group consisting of:
  • R 1 is -N(R J )(R b ) and 1 ⁇ and R 6 are each independently H, Ci-ealkyi optionally substituted with one or more R 7 , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R 7 , wherein R 1 is selected from the group consisting of:
  • R 1 is C h alky] optionally substituted with one or more R ? , wherein R 1 is selected from the group consisting of:
  • the compound having the structure of Formula I or Formula I-a is selected from the group consisting of compounds 1 to 31.
  • R ! is C h alky! optionally substituted with one or more R , C 2 - 6 alkenyl optionally substituted with one or more R', Ci-ealkynyl optionally substituted with one or more R', N(R 3 )(R 6 ), OR 5 , a 3 to 8 membered carbocyclic ring optionally substituted with one or more R', or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R 7 :
  • R 5 and R 6 are each independently H, Ci-ealkyl optionally substituted with one or more R , C 2 - 6 aikenyl optionally substituted with one or more R , C 2 _ 6 aikynyl optionally substituted with one or more R 7 , a 3 to 8 membered carbocyclic ring optionally substituted with one or more R 7 , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R , heteroaryl optionally substituted with one or more R' , or aryl optionally substituted with one or more R', or
  • R 5 and R 6 together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ' ;
  • R 7 is Cj-eaikyl, Cj-ealkenyl, Ca-ealkynyl, Ci-ehaloalkyi, halogen, -CN, oxo, -OR, ⁇ N(R) 2 , -C(0)R, -C(())()R . OC(0)R -C(0)N(R) 2 , -NRC(0)R
  • R 2 is Ci-ealkyl optionally substituted with one or more R 10 , C 2-6 aikenyl optionally substituted with one or more R'°, N(R S )(R 9 ), a 3 to 8 membered carbocyclic ring optionally substituted with one or more R 10 , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R lC" , heteroaryl optionally substituted with one or more R 10 , or aryl optionally substituted with one or more R ! 0 ;
  • R 8 and R 9 are each independently H, Ci-ealkyl optionally substituted with one or more R l0 , C 2-6 alkenyl optionally substituted with one or more R'°, C 2 _ealkynyl optionally substituted with one or more R ! ", a 3 to 8 membered carbocyclic ring optionally substituted with one or more R i0 , a 3 to 8 membered heterocyclic ring optionally substituted with one or more R lC' , heteroaryl optionally substituted with one or more R 10 , or aryl optionally substituted with one or more R K ', or
  • R 8 and R 9 together with the nitrogen to winch they are attached, form an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'";
  • R'° is Ci-eaikyi, C 2-6 alkenyl, C 2-6 alkynyl, Ci-ehaloalkyl, halogen, -CN, oxo, -OR, ( ! ⁇ )... -C(0)R, -C(())()R . OC(0)R -C(0)N(R) 2 , -NRC(0)R , -NRC(0)N(R) 2, -OC(0)N(R) 2 , -NRC(Q)QR, -SiO hR. -S(0) 2 N(R) 2 , -NRS(0) >R.
  • R 3 is H, halogen, -CN, d-ealkyl, d-ehaloalkyl, or -OR;
  • R 4 is H, halogen, -CN, d-ealkyl, d-ehaloalkyl, -N(R) 2 , -OR, -C(0)N(R) 2 , -Ci-ealkyl-OR, 3 io 8 membered carbocyclic ring, or 3 to 8 membered heterocyclic ring:
  • A is aryl or heteroaryl, wherein A is optionally substituted by one or more R 11 ;
  • R 11 is d-ealkyl, d-ealkenyl, d-ealkynyl, d-ehaloalkyl, halogen, -CN, oxo, -OR, -N(R) 2 , -C(())R, -C(0)OR, ()C(())R -C(0)N(R) 2 , -NRC(0)R
  • each R is independently H, d-ealkyl, d-ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.
  • R ! is d ⁇ alkyl optionally substituted with one or more R', Cj-nalkenyl optionally substituted with one or more R', d-salkynyl optionally substituted with one or more R ? , N(R 3 )(R D ), OR 3 , a 3 to 6 membered carbocyclic ring optionally substituted with one or more R', or a 3 to 6 membered heterocyclic ring optionally substituted with one or more R';
  • R 5 and R 6 are each independently H, C h alky! optionally substituted with one or more R', d-salkenyl optionally substituted with one or more R', d-salkynyl optionally substituted with one or more R', a 3 to 6 membered carbocyclic ring optionally substituted with one or more R 7 , or a 3 to 6 membered heterocyclic ring optionally substituted with one or more R', heteroaryl optionally substituted with one or more R', or aryl optionally substituted with one or more R', or
  • R 5 and R 6 together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R';
  • R is Ci-ealkyl, C 2 ⁇ alkenyl, C 2 -»alkynyl, Ci. 4 haloalkyl, -OR, ⁇ N(R) 2 , -C(0)N(R) 2 , -NRC(0)R -S RC( 0)N( R ) . - ⁇ Ri (O sOR. -OC(0)N(R) 2 , -i : . ,a!k> i- OR . -C 1 . 2 a3kyl-N(R) 2 , -C 1 .3alky3-C(0)N(R) 2 , -C : . :a!ky!-N RC(0)R. :uy k or lieterocyciyl.
  • R 1 is C h alky! optionally substituted with one or more R', C 2 -3aikenyl optionally substituted with one or more R', C 2 -3alkynyl optionally substituted with one or more R' , N(R 5 )(R t '), OR 3 , a 4 to 6 mem be red carbocyclic ring optionally substituted with one or more R ', or a 4 to 6 membered heterocyclic ring optionally substituted with one or more R 7 ;
  • R and R " are each independently H, ( ' ;. -.all-. ⁇ i optionally substituted with one or more R', C 2-3 alkenyl optionally substituted with one or more R', C 2-3 alkynyl optionally substituted with one or more R ? , a 4 to 6 membered carbocyclic ring optionally substituted with one or more R' , or a 4 to 6 membered heterocyclic ring optionally substituted with one or more R , heteroaryl optionally substituted with one or more R', or aryl optionally substituted with one or more R ', or
  • R 5 and R 6 together with the nitrogen to winch they are attached, form an N- heterocyclic ring containing between 4 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R';
  • R 7 is C M alkyl, C 2-3 alkenyl, C 2-3 alkynyl, -OR, -N(R) 2 , -C(0)N(R) 2 , -NRC(0)R ⁇ NRC(0)N(R)2, •• ( '• . • aiky! -OR. • ( '• . • alky! -Ni R ; .. -C 1 _ 2 aikyl ⁇ C(0)N(R)2,
  • R 1 is optionally substituted with one or more R 7 , C 2 .. 3 aikenyl optionally substituted with one or more R 7 , C 2 .. 3 aikynyl optionally substituted with one or more R 7 , N(R 5 )(R t> ), OR 3 , a 6 membered carbocyclic ring optionally substituted with one or more R 7 , or a 6 membered heterocyclic ring optionally substituted with one or more R' :
  • R and R 6 are each independently H, ( " i . ⁇ lkyi optionally substituted with one or more R 7 , C 2 _ 3 alkenyl optionally substituted with one or more R 7 , C 2 _ 3 alkynyl optionally substituted with one or more R', a 5 to 6 membered carbocyclic ring optionally substituted with one or more R', or a 5 to 6 membered heterocyclic ring optionally substituted with one or more R', heteroaryl optionally substituted with one or more R 7 , or aryl optionally substituted with one or more R 7 , or
  • R 5 and R D together with the nitrogen to which they are attached, form an N- heterocyclic ring containing 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'; and R. is methyl, -OR, -N(R) 2 , -C(0)N ⁇ R ) .. -NRC(0)R -NRC(0)N(R) 2,
  • R 2 is N(R 8 )(R 9 ), a 4 to 6 membered carbocyclic ring optionally substituted with one or more R 10 , or a 4 to 6 membered heterocyclic ring optionally substituted with one or more R 10 ;
  • R 8 and R 9 together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 4 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'";
  • R i0 is Ci- 6 alkyl, C 2 . 6 alkenyl, C 2-6 alkynyl, Ci. 6 haloalkyl, oxo, -OR, -N(R) 2 ,
  • R 2 is N(R )(R 9 ), a 5 to 6 membered carbocyclic ring optionally substituted with one or more R 10 , or a 5 to 6 membered heterocyclic ring optionally substituted with one or more R 10 ;
  • R 8 and R 9 together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 5 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R " : and
  • R i0 is Ci- 6 alkyl, C 2 _ 6 alkenyl, C 2 - 6 alkynyl, Ci- 6 haloalkyl, oxo, -OR, -N(R) 2 , -C(0)N(R) 2 , -NRC(())R -NRC(0)N(R) 2, -OC(0)N(R) 2 , -NRC(0)OR,
  • R 2 is N(R°)(R 9 ), a 6 membered carbocyclic ring optionally substituted with one or more R 10 , or 6 membered heterocyclic ring optionally substituted with one or more R 10 ;
  • R 8 and R 9 together with the nitrogen to which they are attached, form an N- heterocyclic ring containing 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R 10 ;
  • R i0 is Ci- 6 alkyl, d-ehaloalkyl, oxo, -OR, -N(R) 2 , -C(0)N(R) 2 , -NRC(0)R -NRC(0)N(R) 2 , -OC(0)N(R) 3 ⁇ 4 -NRC(0)OR, -Ci-ealkyl-OR, -Ci- 6 alkyl-N(R) 2 ,
  • R 1 " is C h alky!, oxo, -OR, -N(R) 2 .
  • R 3 is H or halogen.
  • R' is H or F.
  • R' is H.
  • R 4 is H, halogen, Ci -eaikyl, Ci-ehaloaikyl, -OR,
  • R 4 is H, F, CI, Br, methyl, ethyl, ( I i ⁇ ! i. -OR, or -CH 2 OR, -C(0)N(R) 2 .
  • R 4 is H, F, CI, methyl, ethyl, -CH 2 OH, CH 2 OMe, or -OCH3.
  • R 4 is H or F.
  • R 1 is H.
  • compound having activity as mTOR inhibitors are provided, the compounds having the following structure of Formula Il-a:
  • R 3 and R 6 are each independently H, Ci-ealkyl optionally substituted with one or more R 7 , Ci-ealkenyl optionally substituted with one or more R 7 , Ci-ealkynyl optionally substituted with one or more R', heteroaryi optionally substituted with one or more R', or and optionally substituted with one or more R 7 , or
  • R 5 and R 6 together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R' ;
  • R 7 is Ci-ealkyl, C 2-6 alkenyl, C 2-6 a]kyny], C 1-6 haloalky], -OR, ⁇ N(R) 2 , -NRC(0)R -NRC(0)N(R) 2. -OC(0)N(R) 2 , -NRC(0)OR, -C ⁇ alkyl-OR, -Ci- 6 aikyl-N(R) 2 ,
  • R 8 and R 9 together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'";
  • R 10 is Ci. 4 alkyl, C ⁇ haloalkyl, -OR, -N(R) 2 , -NRC(0)R -NRC(0)N(R) 2,
  • A is aryl or heteroaiyl, wherein A is optionally substituted by one or more R 11 ;
  • R i J is halogen, -CN, Cj-ealkyl, C ⁇ alkenyi, C 2 _ 6 alkynyl, Ci-ehaloalkyi, oxo, -OR, -N(R) 2 , -C(0)R, -( (O)OR. -C(0)N(R) 2 , -NRC(0)R -NRC(0)N(R) 2, -OC(0)N(R) 2 , -NRC(0)OR, -S(0) 2 R, -S(0) 2 N(R) 2 , -NRS(0) 2 R -Ci_ 6 alkyl-OR, -Ci- 6 alkyl-N(R) 2 ,
  • each R is independently H, Ci-ealkyl, Ci-ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.
  • A is phenyl optionally- substituted by one or more R n , benzimidazolyl optionally substituted by one or more R' 1 , indoiyi optionally substituted by one or more R 11 , pyridinyl optionally substituted by one or more R 11 , pyrimidinyl optionally substituted by one or more R 11 , indazolyl optionally substituted by one or more R 1 !
  • thiazolyl optionally substituted by one or more R 11 , imidazolyl optionally substituted by one or more R n , pyrazolyl optionally substituted by one or more R u , triazolyl optionally substituted by one or more R 1 ', tetrazolyl optionally substituted by one or more R a , oxazolyl optionally substituted by one or more R 11 , furanyl optionally substituted by one or more R 11 , thiophenyl optionally substituted by one or more R", thiaziazoiyl optionally substituted by one or more R 1 1 , or pyrrolyl optionally substituted by one or more R".
  • A is phenyl optionally substituted by one or more R 1 ! , pyridinyl optionally substituted by one or more R 11 , pyrimidinyl optionally substituted by one or more R i ! , or indazolyl optionally substituted by one or more R".
  • A is:
  • R 2 is -N(R 8 )(R 9 ) and R 8 and R 9 , together with the nitrogen to which they are attached, form an N-heterocyclic ring selected from the group consisting of:
  • each N-heterocyclic ring is independently optionally substituted by one
  • R " is selected from the group consisting of:
  • R is selected from the group consisting of:
  • R" is an optionally substituted 3 to 8 membered heterocyclic ring selected from the group consisting of:
  • R is selected from the group consisting of:
  • R " is an optionally substituted 3 to 8 membered carbocyclic ring selected from the group consisting of:
  • R 2 is N(R 8 )(R 9 ) and R 8 and R 9 are each independently H, C h alky! optionally substituted with one or more R l0 , a 3 to 8 membered carbocyclic ring optionally substituted with one or more R'°, or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R 10 .
  • R 2 is selected from the group consisting of:
  • R J is -N(R 5 )(R 6 ) and R and R° ' ,, ttooggeetthheerr wwiitthh tthhee nniittrrooggeenn ttoo wwhhkich they are attached, form an N-heterocyclic ring selected from the group consisting of:
  • R 1 is selected from, th
  • each N -heterocyclic ring is independently optionally substituted by one or more R' .
  • R ! is selected from the group consisting of:
  • each N-heterocyciic ring is independently optionally substituted by one or more R' .
  • R 1 is an optionally substituted 3 to 8 mernbered heterocyclic ring selected from the group consisting of:
  • each 3 to 8 mernbered heterocyclic ring is independently optionally substituted by one or more R 7 .
  • R 1 is N( '" )( K i- ) and R 5 and R 6 are each independently H, Cj-ealkyl optionally substituted with one or more R 7 , or a 3 to 8 mernbered heterocyclic ring optionally substituted with one or more R ? , wherein R 1 is selected from the group consisting of:
  • R ! is selected from the group consisting of:
  • the compound having the structure of Formula II or Formula Il-a is selected from the group consisting of compounds 32 to 39.
  • Formula I, I-a, II, or Il-a as set forth above, and any specific substituent set forth herein for a A, R', R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , or R ! 1 group in the compounds of structure I, I-a, II, or II -a, respectively, as set forth above, may be independently- combined with oilier embodiments and/or substituents of compounds of structure I, I-a, II, or Il-a, respectively, to form embodiments of the inventions not specifically set forth above.
  • the compounds of the present invention may be administered to a patient or subject as a raw chemical or may be formulated as pharmaceutical compositions.
  • Pharmaceutical compositions of the present invention generally comprise a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compound is present in the composition in an amount which is effective to treat a particular disease or condition of interest, as described herein, and preferably with acceptable toxicity to the patient.
  • the activity of compounds can be determined by one skilled in the art, for example, as described in the Example below. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
  • a pharmaceutical composition comprising a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition is provided comprising a compound having the structure of Formula IT, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a compound having the structure of Formula Tl-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition further comprises one or more additional biologically active agents.
  • the additionally biologically active agents is selected from the group consisting of anticancer drugs; cyctotoxins, cell cycle arresting drags; and cytostatic drags, or a combination of these agents.
  • the one or more additional biologically active agents is selected from, the group consisting of antiviral drugs; DNA gyrase inhibitors, protease inhibitors, polymerase inhibitors, or a combination of these agents.
  • the one or more additional biologically active agents is selected from the group consisting of immunomodulator drugs; interferon, steroid, cox inhibitor, or a combination of these agents.
  • a method of inhibiting mTOR in a warm-blooded animal comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of inhibiting mTOR in a warm-blooded animal comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of inhibiting mTOR in a warm-blooded animal comprising administering to the animai an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of inhibiting mTOR in a warm-blooded animai comprising administering to the animal an effective amount of a compound having the stracture of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating a disease state associated with dysregulation of the mTOR pathway comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating a disease state associated with dysregulation of the mTOR pathway comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating a disease state associated with dysregulation of the mTOR pathway comprising administering to the animal an effective amount of a compound having the stracture of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating a disease state associated with dysregulation of the mTOR pathway comprising administering to the animal an effective amount of a compound having the stracture of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • the disease state associated with dysregulation of the mTOR pathway is selected from the group consisting of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, infection, antiviral, antibacterial, vaccine adjuvant, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries.
  • the disease state associated with dysregulation of the mTOR pathway is a viral infection.
  • the viral infection is by a virus from the herpesviridae family of viruses.
  • the viral infection is by a herpesviridae viras selected from the group consisting of herpes simplex viras (HSV) types 1 and 2, varicella-zoster virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (variants A and B), human herpesvirus 7, human herpesvirus 8 (Kaposi's sarcoma - associated herpesvirus, KSHV), and cercopithecine herpesvirus 1 (B virus).
  • the viral infection is by a virus selected from human cytomegalovirus and herpes simplex virus- 1.
  • the viral infection is by a virus from the paramyxovindae family of viruses.
  • the viral infection is by a paramyxoviridae viras selected from the group consisting of Respiratory syncytial viras (RSV), mumps, measles, human parainfluenza viruses such as Parainfluenza Virus Type 3 (PIV3), Human metapneumovirus, Hendra viras (HeV), Nipah viras ( iV), and Cedar Virus.
  • RSV Respiratory syncytial viras
  • mumps mumps
  • measles measles
  • human parainfluenza viruses such as Parainfluenza Virus Type 3 (PIV3), Human metapneumovirus, Hendra viras (HeV), Nipah viras ( iV), and Cedar Virus.
  • PIV3 Parainfluenza Virus Type 3
  • HeV Hendra viras
  • the viral infection is by a viras from the picornaviridae family of viruses.
  • the viral infection is by a picornaviridae viras selected from the group consisting of Human rhino vims 16 (HRV-16), Human enterovirus. Hepatitis A viras, Coxsackie virus (including type A24 variant CA24v), Echovims, and Poliovirus.
  • the viral infection is by a virus from the orthomyxoviridae family of viruses.
  • the viral infection is by a orthomyxoviridae vims selected from the group consisting of Avian influenza (pathogenic strain (H5N1)), and Swine influenza including influenza C and the subtypes of influenza A known as HlNl , H1N2, H2N1, H3N1 , H3N2, and H2N3.
  • Avian influenza pathogenic strain (H5N1)
  • Swine influenza including influenza C and the subtypes of influenza A known as HlNl , H1N2, H2N1, H3N1 , H3N2, and H2N3.
  • the viral infection is by a viras from the retroviridae family of viruses. In one embodiment, the viral infection is by a retroviridae viras selected from the group consisting of human immunodeficiency virus (HTV-1).
  • HTV-1 human immunodeficiency virus
  • the viral infection is by a virus from the papiliomaviridae family of viruses. In one embodiment, the viral infection is by a papiliomaviridae viras selected from the group consisting of human papillomavirus (HPV).
  • HPV human papillomavirus
  • the viral infection is by a vims from the adenoviridae family of viruses. In one embodiment, the viral infection is by a adenoviridae viras selected from the group consisting of human adenovirus (Adenovirus serotype 14.)
  • the viral infection is by a viras from the poxviridae family of viruses.
  • the viral infection is by a poxviridae viras selected from the group consisting of Human orthopoxviruses, Monkeypox viras, Variola (VARV), including smallpox (Variola major virus) and Alastrim (Variola minor vims)), Cowpox (CPX), and Vaccinia (VACV or VV) vimses.
  • the viral infection is by a vims from the polyomaviridae family of vimses.
  • the viral infection is by a vims causing viral hemorrhagic fever.
  • the vims causing viral hemorrhagic fever is selected from the group consisting of Bundibugyo virus (BDBV), Sudan vims (SUDV), Tai ' Forest vims (TAFV) and Ebola vims (EBOV, formerly Zaire Ebola vims), Marburg, Lassa, Crimean-Congo, Seoul viruses, Lassa fever vims, Lujo vims and Argentine hemorrhagic fever.
  • BDBV Bundibugyo virus
  • SUDV Sudan vims
  • TAFV Tai ' Forest vims
  • EBOV formerly Zaire Ebola vims
  • Marburg Lassa
  • Lassa Crimean-Congo
  • Seoul viruses Lassa fever vims
  • Lassa fever vims Lujo vims and Argentine hemorrhagic fever.
  • the virus causing viral hemorrhagic fever is a South American Haemorrhagic Fever vims selected from the group consisting of Chapare, Guananto, Junin, Machupo, Sabia, Hantaviras hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS).
  • HFRS Hantaviras hemorrhagic fever with renal syndrome
  • HPS hantavirus pulmonary syndrome
  • the viral infection is by a virus from the flaviviridae family of vimses.
  • the viral infection is by a flaviviridae vims selected from the group consisting of Yellow fever, tick-borne encephalitis virus (TBEV), Kyasanur Forest disease virus, Omsk hemorrhagic fever vims, hepatitis B vims (HBV), hepatitis C vims (HCV), Dengue vimses (DEN-1, DEN-2, DEN- 3 and DEN-4), West Nile vims.
  • TBEV tick-borne encephalitis virus
  • HBV hepatitis B vims
  • HCV hepatitis C vims
  • DEN-1, DEN-2, DEN- 3 and DEN-4 Dengue vimses
  • the viral infection is by a vims from the togaviridae family of vimses. In one embodiment, the viral infection is by a togaviridae vims selected from the group consisting of Eastern. Equine Encephalitis vims, Venezuelan equine encephalitis vims, Western equine encephalitis vims, zoonotic alphaviruses (Chikungunya virus, Semiiki Forest virus complex), and arbovirus.
  • the viral infection is by a virus from the coronavindae family of vimses.
  • the viral infection is by a eoronaviridae vims selected from the group consisting of a SARS-associated coronavirus (SARS-CoV) and MERS (Middle East Respiratory Syndrome, MERS-CoV).
  • SARS-CoV SARS-associated coronavirus
  • MERS Middle East Respiratory Syndrome
  • the viral infection is by a virus from the bunyaviridae family of vimses. In one embodiment, the viral infection is by a bunyaviridae vims selected from the group consisting of Rift Valley fever. In another embodiment, the compounds of the present invention can be administered in combination with other antiviral drags, antiviral treatments, vaccines, or supportive, prophylactic or preventative measures.
  • the disease state associated with dysregulation of the mTOR pathway is associated with immunomodulation.
  • the immunomodulation is selected from the group consisting of immunosuppression, regulation of immune cells, including neutrophils, mast cells, natural killer cells, ⁇ T cells, macrophages, dendritic cells (DCs), T cells, and B cells.
  • the method of treating immunomodulation is associated with the reduction of inflammatory cytokine signaling, such as through the activation of the TLR pathways.
  • the method of treating immunomodulation is associated with the reduction of NF-KB, IF -a and - ⁇ and increasing of IL-10 and IL-12.
  • the method of treating immunomodulation is associated with the immunosuppressive treatment of solid and bone marrow transplantation, hematopoietic stem cell transplantation, organ transplantation, cell transplantation (e.g. islet grafts) and treatment of autoimmune disease.
  • the method of treating immunomodulation is associated with the improvement of memor ' T cell generation and enhanced vaccine responses.
  • a method of treating cancer in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating cancer in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating cancer in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating cancer in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • the cancer is associated with dysregulation of the PI3K pathway.
  • the cancer is selected from the group consisting of breast cancer; antle ceil lymphoma; renal cell carcinoma; acute myelogenous leukemia (AML); chronic myelogenous leukemia (CML); diffuse large B cell lymphoma (DLBCL); sarcoma; rhabdomyosarcoma; ovarian cancer; endometrial tumors; non small cell lung carcinoma (NSCLC); small cell, squamous, large cell and adenocarcinoma; lung cancer; colon cancer; colorectal tumors; KRAS-mutated colorectal tumors; gastric carcinomas; hepatocellular tumors; liver tumors; primary melanomas; pancreatic tumors; prostate carcinoma; thyroid carcinoma; follicular thyroid carcinoma; anaplastic large cell lymphoma (ALCL); hamaratomas, angiomyeloiipomas, TSC-
  • a method of treating or preventing a respiratory virus infection in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the staicture of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing a respiratory virus infection in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula I -a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing a respiratory virus infection in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing a respiratory virus infection in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula II-a, or a stereoisomer, pharmaceutically acceptabie sait or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing inflammation in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptabie salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing inflammation in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing inflammation in a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptabie sait or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • a method of treating or preventing inflammation i a warm-blooded animal in need thereof comprising administering to the animal an effective amount of a compound having the structure of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.
  • compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings of this invention.
  • a pharmaceutical composition of the invention may be in the form of a solid or liquid.
  • the carner(s) are particulate, so that the compositions are, for example, in tablet or powder form.
  • the carrier(s) may be liquid, with the compositions being, for example, an oral symp, injectable liquid or an aerosol, which is useful in, for example, mhaiatory administration.
  • the pharmaceutical composition When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
  • the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
  • a solid composition will typically contain one or more inert diluents or edible carriers.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, com starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
  • excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, com starch and the like
  • lubricants such as magnesium stearate or Sterotex
  • glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin
  • a flavoring agent such as peppermint,
  • the pharmaceutical composition when in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
  • a liquid carrier such as polyethylene glycol or oil.
  • the pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension.
  • the liquid may be for oral administration or for deliver ⁇ ' by injection, as two examples.
  • preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
  • the liquid pharmaceutical compositions of the invention may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Physiological saline is a preferred adjuvant.
  • a liquid pharmaceutical composition of the invention intended for either parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage will be obtained.
  • the pharmaceutical composition of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Thickening agents may be present in a pharmaceutical composition for topical administration.
  • the composition may include a transdermal patch or iontophoresis device.
  • the pharmaceutical composition of the invention may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drag.
  • the composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient.
  • bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
  • the pharmaceutical composition of the in v ention may include various materials, which modify the physical form, of a solid or liquid dosage unit.
  • the composition may include materials that form a coating shell around the active ingredients.
  • the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredients may be encased in a gelatin capsule.
  • the pharmaceutical composition of the invention in solid or liquid form may include an agent that binds to the compound of the invention and thereby assists in the delivery of the compound.
  • Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.
  • the pharmaceutical composition of the invention may consist of dosage units that can be administered as an aerosol.
  • aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Deiiveiy may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Deiiveiy of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols.
  • compositions of the invention may be prepared by methodology well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous deliver ⁇ ' system.
  • the compounds of the invention are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy.
  • a typical dosage of the substantially impermeable or substantially systemicaily non-bioavailable, compound may be between about 0.2 nig per day and about 2 g per day, or between about I mg and about 1 g per day, or between about 5 mg and about 500 mg, or between about 10 mg and about 250 mg per day, or between about 50 mg and about 200 mg, or between about 100 mg and about 150 mg, which is administered to a subject in need of treatment.
  • the frequency of administration of the compounds and compositions described herein may vary from once-a-day (QD) to twice-a-day (BID) or thrice-a-day (TID), etc., the precise frequency of administration varying with, for example, the patient's condition, the dosage, etc.
  • Compounds of the invention, or pharmaceutically acceptable derivatives thereof, may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents.
  • Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each active agent in its own separate pharmaceutical dosage formulation.
  • a compound of the invention and the other active agent can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations.
  • the compounds of the invention and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.
  • Suitable protecting groups include hydroxy, amino, rnercapto and carboxylic acid.
  • Suitable protecting groups for hydroxy include trialkyisilyl or diary lalkylsilyl (for example, f-butyldimethylsilyl, f-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Suitable protecting groups for rnercapto include -C(0)-R" (where R" is alkyl, aryl or arylalkyl), >-methoxybenzyl, trityl and the like.
  • Suitable protecting groups for car oxyiic acid include alkyl, aryl or arylalkyl esters.
  • Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley.
  • the protecting group may also be a polymer resin such as a Wang resin. Rink resin or a 2-chlorotrityl-chloride resin.
  • Compound 2 (3-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2-yl)phenyl) methanol.
  • Compound 2 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of using (3-(hydroxymethyl)phenyl)boronic acid in place of (2-methoxy-5 ⁇ (4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol in the Suzuki reaction, m/z (ES+) 435 (M i l s .
  • Compound 3. (35,3 3 ⁇ 4 7 )-4,4'-(7-(pyridin-4-yl)-l,8-naphthyridine-2,4-diyl)bis(3- methylmorpholine).
  • Compound 3 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of using pyridin-4-ylboronic acid in place of (2-methoxy-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2- ⁇ 'l)phenyl)methanol in the Suzuki reaction, m/z (ES+) 406 ( M i l) .
  • Compound 5 3-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2-yl)-N- methylbenzamide.
  • Compound 5 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of using (3-(methylcarbamoyl)phenyl)boronic acid in place of (2-methoxy-5-(4,4,5,5- tetramethyl-L3,2"dioxaborolan ⁇ 2-yl)phenyl)methanol in the Suzuki reaction, m/z (ES+) 462 ( M - ! 1) .
  • Compound 6 6-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2- yl ⁇ isoindolm ⁇ l-one.
  • Compound 6 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of 6-(4,4,5,5 ⁇ tetraniethyi-l,3,2-dioxaboroiaii-2-yi)isoindolin-l-one in place of (2- methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol in the Suzuki reaction, m/z (ES+) 460 (M+H) + .
  • Compound 7 (i?)-4-(7-(4-metho.xyphenyl)-2-((S)-3-methylmorpholino)-l,8- naphthyridin-4-yl)-3-methylmorpholine.
  • Compound 7 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of using (4-methoxyphenyl)boronic acid in place of (2- methoxy-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)methanol in the Suzuki reaction, m/z (ES+) 435 ( ⁇ + ⁇ ) " .
  • Compound 8 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 1 with the exception of using (3- (hydroxymethyl)phenyl)boronic acid in place of (2-methoxy-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)methanol in the Suzuki reaction and 8 ⁇ oxa ⁇ 3 ⁇ azabicyclo[3.2.1 ]octane in place of ( ⁇ S)-3-methylmorpholine in the Buchwald coupling reaction, m/z (ES+) 447 (M+H) + .
  • Compound 9 (5-(5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-((S)-3- methylmorpholino)-l,8-naphthyridin-2-yl)-2-methoxyphenyl)methanol.
  • Compound 9 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 1 with the exception of using 8-oxa-3- azabicyclo[ 3.2.1] octane in place of (S)-3-methylmorpholine in the Buchwald coupling reaction, m/z (ES+) 477 (M+H) + .
  • Compound 10 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 1 with the exception of using (4-methoxyphenyl)boronic acid in place of (2-methoxy-5-(4,4,5,5-tetrame1hy]-l,3,2-dioxaboro]an-2-yl)pheny])metlianol in the Suzuki reaction and 8-oxa-3-azabicyclo[3.2.1]octane in place of (S)-3- methylmorpholine in the Buchwaid coupling reaction, m/z (ES+) 447 ( ⁇ + ⁇ ) " .
  • Compound 11 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 1 with the exception of using (4-methoxyphenyl)boronic acid in place of (2-methoxy-5 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl)methanol in the Suzuki reaction and (l i,5 ⁇ S)-3-oxa-8-azabicyclo[3.2.1]octane in place of ( ⁇ S)-3- methylmorpholine in the Buchwald coupling reaction, nvz (ES+) 447 (M+H) + .
  • Compound 12 (5-(5,7-dimorphoIino-l,8-naphthyridin-2-yI)-2- methoxyphenyl)methanol.
  • Compound 12 was prepared using standard chemical manipulations and procedures similar to those used for preparation of 1 with the exception of using morpholine in place of (S)-3-methylmorpholine.
  • Compound 13 4,4'-(7-phenyl-l ,8-naphthyridine-2,4-diyl)dimorphoIine.
  • Compound 13 was prepared using standard chemical manipulations and procedures similar to those used for preparation of 1 with the exception of using morpholine in place of (S)-3- methylmorpholine and phenyl boronic acid instead of (2-methoxy-5-(4,4,5,5- tetramethyi-L3,2"dioxaboroian ⁇ 2-yl)phenyi)methaiiol in the Suzuki reaction, m/z (ES+) 377 ( M - ! 1) .
  • Compound 14.1. (4-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2- yl)phenyl)methanol.
  • Compound 14.1 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 1 with the exception of using (4-(hydroxymethyl) phenyl) boronic acid instead of (2-methoxy-
  • Compound 16 (4-(5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-((S)-3- methylmorpholino)-l,8-naphthyridin-2-yl)pheny])methanol.
  • Compound 16 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 14,1 with the exception of using 8-oxa-3- azahicyelo [3.2.1] octane in place of ( ⁇ S)-3-methylmorpholine in the Buchwald coupling reaction, m/z (ES+) 447 (M+H) + .
  • Compound 17 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 14 with the exception of using 8-oxa- 3-azabicycloj 3.2.1 joctane in place of (5)-3-methylmorpholine in the Buchwald coupling reaction and 2-methoxyethanamine in place of ethanolamine in the reductive animation, nv'z (ES+) 504 (M+H) + .
  • Compound 20 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 1 with the exception of using 6-(4,4,5,5-tetramethyl-l,3,2- dioxabofolan-2-yl)isoindolin-l-one in place of (2-methoxy-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)methanol in the Suzuki reaction and 8-oxa-3- azahicyelo [3.2.1] octane in place of ( ⁇ S)-3-methylmorpholine in the Buchwald coupling reaction, m/z (ES+) 472 (M+H) + .
  • Compound 21 (5-(7-((2i?,6 i S T )-2,6-diniethy!niorpho!ino)-5-(( 1 y)-3- methylmorpholino)-l,8-naphthyridin-2-y])-2-methoxypheny])methanol.
  • Compound 21 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of using (3- (hydroxymethyl)-4-meilioxyp3ienyi)boronic acid in place of (2-methoxy-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)memanol in the Suzuki reaction.
  • Compound 23.2 4,7-dichloro-2-(piperazin-l-yl)-l,8-naphthyridine.
  • Compound 23.2 was prepared from compound 23.1 using standard chemical manipulations starting and procedures were similar to those used for preparation of compound 1.5.
  • Compound 24.1 7-Methoxy-l ,8-naphthyridine-2,4-diol.
  • the mixture was cooled and additional dimethyl malonate (4.8 mL, 42 mrnol) was added and then the mixture heated at 170 °C for an additional 2.5 hours.
  • the mixture was cooled and additional dimethyl malonate (2.4 mL, 21 mrnol) was added and the mixture was heated at 170 °C for an additional 2 hours.
  • the mixture was cooled and additional dimethyl malonate (2.4 mL, 21 mrnol) was added and then the mixture was heated at 180 °C for 1 hour and 190 °C for 2 hours.
  • the vial containing the suspension was rinsed with dioxane (2.5 mL) and phosphoryl chloride (10 mL, 107 mmol) and added to the reaction.
  • the mixture was stirred at 60 °C for an 1 hour after scaffold addition. Additional phosphoryl chloride ( 15 mL, 161mmol) was added and the mixture heated at 60 °C for 1.5 hours, then at 70 °C for 1 hour.
  • the mixture was cooled and concentrated under reduced pressure. The residue was carefully quenched into ice water (250 mL) and then saturated sodium bicarbonate was added slowly until a pH ⁇ 7 was attained and diluted with dichloromethane (300 mL). The insoluble solids were removed by filtration through Celite®.
  • Compound 25 (4-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2- yl)p eny! ⁇ morpholino)methanone.
  • Compound 25 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 24, except (4-(moipholine-4-carbonyl)phenyl)boronic acid was used in place of (4-methoxy-2-methylphenyl)boronic acid in the Suzuki reaction, m/z (ES+) 518 ( M i l) .
  • Compound 26 (3-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2- yl)p eny!(morpholino)methanone.
  • Compound 26 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 24, except (3-(moipholine-4-carbonyl)phenyl)boronic acid was used in place of (4-methoxy-2-methylphenyl)boronic acid in the Suzuki reaction, m/z (ES+) 518 ( M i l) .
  • methoxyphenyPmethanol (compound 28, 50 mg, O i l mmol) in ethyl acetate (20 niL) under nitrogen was carefully added palladium/carbon (10 % Pd) (30 mg). The system was purged with nitrogen, then hydrogen was introduced to the system. The resulting solution was stirred for 2 hour at room temperature, then evacuated and purged with nitrogen. The solids were removed by filtration and the filtrate was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep Shield P18 QBD Column, 19* 150 mm, 5 ⁇ , 13 nm; mobile phase, water with 10 mmol NH4HCO3 and ACN (32.0% ACN up to 39.0% in 8 min); Detector, 254 nm . This yielded compound 31 as a yellow solid (2.1 mg, 4%). /z (ES+) 450 ⁇ M i l s .
  • Compound 33 (2-methoxy-5-(5-((S)-3-methylmorpholino)-7-((iS)-2- methylpiperidin-l-yl)-l,6-naphthyridin-2-yl)phenyl)methanol.
  • Compound 33 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 32, except ( ⁇ S)-2-methylpiperidine was used in place of (,S)-3-methylmorpholine in the Buchwaid coupling reaction, m/z (ES+) 463( ⁇ + ⁇ ) + .
  • Compound 34 (2-methoxy-5-(7-((S)-3-methylmorpholino)-5-((S)-2- inethySpiperid!n ⁇ l-yI) ⁇ l,6 ⁇ naphthyridin-2-yl)pheny! ⁇ methanoI.
  • Compound 34 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 32, except (5)-2-methylpiperidine was used in place of ( ⁇ S)-3-methylmorpholine in the S ⁇ Ar reaction, m/z (ES+) 463(M+H) "r .
  • Compound 35 (5-(5,7-bis((S)-2-methylpiperidin-l-yl)-l,6-naphthyridin-2-yl)-2- methoxyphenyl)methanol.
  • Compound 35 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 32, except ( ⁇ S)-2-methylpiperidine was used in place of (i.S) ⁇ 3 ⁇ 3 ⁇ 4mi:hy3rnorphoime in the 8 ⁇ and Buchwald reactions, m/z (ES+) 461(M+H) + .
  • Compound 36 (3S,3 'S)-4,4 ⁇ 2-(4-methoxyphenyl)-l,6-naphthyridine-5,7- diyl)bis(3-methyImorphoIine).
  • Compound 36 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 32, except (4-methoxyphenyi)boronic acid was used in place of (3-(hydroxymethyl)-4- methoxyphenyijboronic acid in the Suzuki reaction, m/z (ES+) 435 (M+H) + .
  • Compound 37 (3-(5,7-bis((S)-3-methylmorpholino)-l,6-naphthyridin-2- yl)phenyl)methanol.
  • Compound 37 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 32, except (3 ⁇ (hydroxymethyi)phenyi)boronic acid was used in place of (3- (hydroxymethyl)-4-methoxyphenyl)boronic acid in the Suzuki reaction, m/z (ES+) 435 (M+H) + .
  • EXAMPLE 38 (3-(5,7-bis((S)-3-methylmorpholino)-l,6-naphthyridin-2- yl)phenyl)methanol.
  • Compound 37 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 32, except (3 ⁇ (hydroxymethyi)phenyi)boronic acid was used in place of (3- (hydroxymethyl)-4-methoxyphenyl)boronic acid in the Suzuki reaction,
  • Half-maximal inhibitor ⁇ ' concentration (ICjo) of the mTOR human enzyme was determined for each compound by monitoring the extent of phosphorylation of human p70 S6 kinase residue Thr389 in the presence or absence of mTOR inhibitor.
  • the phosphorylation of Thr389 by mTOR was monitored through the use of a commercially available, europium-based, time-resolved fluorescence resonance energy transfer (TRFRET) assay, e.g. LANCE ® technology from Perkin Elmer or equivalent.
  • TRFRET time-resolved fluorescence resonance energy transfer
  • Recombinant human mTOR enzyme was pre-incubated across a range of mTOR- inhibitor concentrations to give a dose response curve for the inhibitor compound.
  • an appropriately emission dye labeled synthetic peptide containing the residues surrounding Thr38 of human p70 S6K e.g. the Ultra ULight' M ⁇ p7G S6K (Thr389) Peptide or equivalent was added to the compound/enzyme mix for 2 hours.
  • the extent of phosphorylation of Thr389 residues was then quantitated with an europium-anti-phospho-p70 S6K (Thr389) antibody, such as mouse monoclonal antibody labeled with the LANCE® Europium W1024-ITC chelate or equivalent.
  • the resulting fluorescent signal was obtained by using a TR- FRET reader, such as the Tecan Ml 000 Plate reader in TR-FRET mode (ex.
  • IC 50 values are summarized below in Table 1, wherein IC 50 less than 0.1 ⁇ are categorized as group A, IC50 between 0.1 and 1 ⁇ are categorized as group B, and IC 5 0 values above 1 ⁇ are categorized as group C.
  • the cellular half-maximal effective concentration (EC 50 ) was determined by monitoring the extent of mTOR phosphorylation of 4E-BP1 residues Thr37 Thr46 when human A549 ceils are incubated in the presence or absence of mTOR inhibitor compounds.
  • A549 cells are seeded in multi-well plates the day before compound treatment. Serial dilutions of the compounds in tissue culture medium are added to replicate wells of the cells and incubated for 1 hour. After compound treatment, the cells are lysed, and the lysate is transferred to a plate coated with a rabbit anti-4EBP phospho-Thr37/Thr46 capture antibody. Following a 2 hour mcubation, a matched 4E-BP1 mouse detection antibody is added for 1 hour.
  • EC50 values are summarized below in Table 2, wherein EC5 0 less than 0.1 ⁇ are categorized as group A, EC5 0 between 0.1 and 1 ⁇ are categorized as group B, and EC50 values greater than 1 ⁇ are categorized as group C.
  • mTor inhibitors as exemplified by the biochemical inhibition (IC 50 ) and cellular inhibition potency (EC 50 ) data presented in Table 3 for structures ID # 1 and #32.
  • IC 50 biochemical inhibition
  • EC 50 cellular inhibition potency
  • these compounds were found to have desirable biochemical kinase selectivity versus PI3K across important isoforms alpha, beta and delta as shown in Table 3 as IC5 0 S > 0.5 ⁇ . This selectivity is desirable to avoid potential off-target effects caused by inhibition of PI3K which might limit the therapeutic index and utility of mTor inhibitors.

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Abstract

Composés ayant une activité d'inhibition de mTOR. Composés, y compris leurs stéréoisomères, sels pharmaceutiquement acceptables et promédicaments, présentant la structure (I) suivante: Dans cette formule, R1, R2, R3, R4, et A sont tels que définis dans la description. L'invention concerne également des procédés associés à l'élaboration et à l'utilisation de tels composés, ainsi que des compositions pharmaceutiques comprenant de tels composés.
PCT/US2016/047776 2015-08-19 2016-08-19 Composés et procédés d'inhibition de mtor WO2017031427A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
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CN110016028A (zh) * 2019-04-17 2019-07-16 上海大学 萘啶二联吡咯化合物及其制备方法
WO2020025517A1 (fr) * 2018-07-31 2020-02-06 Merck Patent Gmbh Antagonistes de tlr7/8 et leurs utilisations
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11512069B2 (en) 2016-08-08 2022-11-29 Merck Patent Gmbh TLR7/8 antagonists and uses thereof
US11608344B2 (en) 2020-05-04 2023-03-21 Amgen Inc. Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use
US11629134B2 (en) 2015-12-17 2023-04-18 Merck Patent Gmbh TLR7/8 antagonists and uses thereof
US11718617B2 (en) 2020-05-04 2023-08-08 Amgen Inc. Heterocyclic compounds as triggering receptor expressed on myeloid cells2 agonists and methods of use
US11767321B2 (en) 2020-10-05 2023-09-26 Enliven Inc. 5- and 6-azaindole compounds for inhibition of BCR-ABL tyrosine kinases
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof
WO2024057013A1 (fr) * 2022-09-12 2024-03-21 Exscientia Ai Limited Modulateurs de nlrp3

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US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
TWI827641B (zh) * 2018-07-31 2024-01-01 德商默克專利有限公司 Tlr7/8拮抗劑及其用途
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JP7491900B2 (ja) 2018-07-31 2024-05-28 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｔｌｒ７／８アンタゴニストおよびそれらの使用
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US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof
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