US20190336609A1 - C40-, C28-, and C-32-Linked Rapamycin Analogs as mTOR Inhibitors - Google Patents

C40-, C28-, and C-32-Linked Rapamycin Analogs as mTOR Inhibitors Download PDF

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US20190336609A1
US20190336609A1 US16/398,011 US201916398011A US2019336609A1 US 20190336609 A1 US20190336609 A1 US 20190336609A1 US 201916398011 A US201916398011 A US 201916398011A US 2019336609 A1 US2019336609 A1 US 2019336609A1
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compound
pharmaceutically acceptable
independently
acceptable salt
disease
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Jennifer Pitzen
Micah James Evans Gliedt
G. Leslie Burnett
James Bradley Aggen
Gert KISS
James Joseph Cregg
Christopher Michael Semko
Walter Won
Gang Wang
Julie Chu-Li Lee
Arun P. Thottumkara
Adrian Liam Gill
Kevin T. Mellem
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Revolution Medicines Inc
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Revolution Medicines Inc
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Priority to US16/398,011 priority Critical patent/US20190336609A1/en
Assigned to Revolution Medicines, Inc. reassignment Revolution Medicines, Inc. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WON, WALTER, MELLEM, KEVIN T., THOTTUMKARA, ARUN P., WANG, GANG, AGGEN, JAMES BRADLEY, BURNETT, G. Leslie, CREGG, James Joseph, GILL, ADRIAN LIAM, GLIEDT, Micah James Evans, KISS, Gert, LEE, Julie Chu-li, PITZEN, Jennifer, SEMKO, CHRISTOPHER MICHAEL
Publication of US20190336609A1 publication Critical patent/US20190336609A1/en
Priority to US16/831,579 priority patent/US10980889B1/en
Priority to US17/083,172 priority patent/US11364300B2/en
Priority to US17/733,755 priority patent/US20230055672A1/en
Abandoned legal-status Critical Current

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    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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Definitions

  • the present disclosure relates to mTOR inhibitors. Specifically, the embodiments are directed to compounds and compositions inhibiting mTOR, methods of treating diseases mediated by mTOR, and methods of synthesizing these compounds.
  • mTOR The mammalian target of rapamycin (mTOR) is a serine-threonine kinase related to the lipid kinases of the phosphoinositide 3-kinase (PI3K) family.
  • PI3K phosphoinositide 3-kinase
  • mTOR exists in two complexes, mTORC1 and mTORC2, which are differentially regulated, have distinct substrate specificities, and are differentially sensitive to rapamycin.
  • mTORC1 integrates signals from growth factor receptors with cellular nutritional status and controls the level of cap-dependent mRNA translation by modulating the activity of key translational components such as the cap-binding protein and oncogene eIF4E.
  • Rapamycin is a selective mTORC1 inhibitor through the binding to the FK506 Rapamycin Binding (FRB) domain of mTOR kinase with the aid of FK506 binding protein 12 (FKBP12).
  • FRB domain of mTOR is accessible in the mTORC1 complex, but less so in the mTORC2 complex.
  • the potency of inhibitory activities against downstream substrates of mTORC1 by the treatment of Rapamycin is known to be diverse among the mTORC1 substrates.
  • Rapamycin strongly inhibits phosphorylation of the mTORC1 substrate S6K and, indirectly, phosphorylation of the downstream ribosomal protein S6 which control ribosomal biogenesis.
  • Rapamycin shows only partial inhibitory activity against phosphorylation of 4E-BP1, a major regulator of eIF4E which controls the initiation of CAP-dependent translation. As a result, more complete inhibitors of mTORC1 signaling are of interest.
  • TORi ATP site TOR inhibitor
  • the molecules compete with ATP, the substrate for the kinase reaction, in the active site of the mTOR kinase (and are therefore also mTOR active site inhibitors). As a result, these molecules inhibit downstream phosphorylation of a broader range of substrates.
  • mTOR inhibition may have the effect of blocking 4E-BP1 phosphorylation, these agents may also inhibit mTORC2, which leads to a block of Akt activation due to inhibition of phosphorylation of Akt S473.
  • mTOR inhibitors Disclosed herein, inter alia, are mTOR inhibitors. In some embodiments, compounds disclosed herein are more selective inhibitors of mTORC1 versus mTORC2. In some embodiments, compounds disclosed herein are more selective inhibitors of mTORC2 versus mTORC1. In some embodiments, compounds disclosed herein exhibit no selectivity difference between mTORC1 and mTORC2.
  • the present disclosure relates to compounds capable of inhibiting the activity of mTOR.
  • the present disclosure further provides a process for the preparation of compounds of the present disclosure, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders mediated by mTOR.
  • R 32 is —H, ⁇ O, —OR 3 , —N 3 , or —O—C( ⁇ Z 1 )—R 32a ;
  • R 28 is —H, (C 1 -C 6 )alkyl, or —C( ⁇ Z 1 )—R 28a ;
  • R 40 is —H or —C( ⁇ Z 1 )—R 40a ;
  • each Z 1 is independently O or S;
  • R 28a , R 32a ; and R 40a are independently -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; -L 2 -A 1 -L 1 -A 2 -L 3 -B; —O—(C 1 -C 6 )alkyl; or —O—(C 6 -C 10 )aryl; wherein the aryl of —O—(C 6 -C 10 )aryl is unsubstituted or substituted with 1-5 substituents selected from —NO 2 and halogen;
  • a 1 and A 2 are independently absent or are independently selected from
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X 1 is independently a heteroarylene or heterocyclylene ring
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each W 1 is independently a heteroarylene or heterocyclylene ring
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each G 1 and G 2 are independently heteroarylene or heterocyclylene ring;
  • each L 1 is independently selected from
  • L 2 and L 3 are independently absent or are independently selected from
  • each B is independently selected from
  • each B 1 is independently selected from
  • heteroarylene, heterocyclylene, and arylene are each independently optionally substituted with alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, or hydroxyl;
  • each R 3 is independently H or (C 1 -C 6 )alkyl
  • each R 4 is independently H, (C 1 -C 6 )alkyl, halogen, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, (C 6 -C 10 )aryl, wherein the heteroaryl, heterocyclyl, and aryl are each independently optionally substituted with —N(R 3 ) 2 , —OR 3 , halogen, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-CN, —C(O)NR 3 -heteroaryl, or —C(O)NR 3 -heterocyclyl;
  • each R 5 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is each independently optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 6 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is each independently optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 7 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is each independently optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 8 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is each independently optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each Y is independently —C(R 3 ) 2 or a bond
  • each n is independently an integer from one to 12;
  • each o is independently an integer from zero to 30;
  • each p is independently an integer from zero to 12;
  • each q is independently an integer from zero to 30;
  • each r is independently an integer from one to 6.
  • R 32 is —H, ⁇ O, —OR 3 , —N 3 , or —O—C( ⁇ Z 1 )—R 32a ;
  • R 28 is —H, (C 1 -C 6 )alkyl, or —C( ⁇ Z 1 )—R 28a ;
  • R 40 is —H or —C( ⁇ Z 1 )—R 40a ;
  • R 28 and R 40 are H, then R 32 is not ⁇ O;
  • each Z 1 is independently O or S;
  • R 28a , R 32a , and R 40a are independently -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; -L 2 -A 1 -L 1 -A 2 -L 3 -B; —O—(C 1 -C 6 )alkyl; or —O—(C 6 -C 10 )aryl; wherein the aryl of —O—(C 6 -C 10 )aryl is unsubstituted or substituted with 1-5 substituents selected from —NO 2 and halogen;
  • a 1 and A 2 are independently absent or are independently selected from
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X 1 independently is a heteroarylene or heterocyclylene ring
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each W 1 independently is a heteroarylene or heterocyclylene ring
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each G 1 and G 2 are independently heteroarylene or heterocyclylene ring;
  • each L 1 is independently selected from
  • L 2 and L 3 are independently absent or are independently selected from
  • each B is independently selected from
  • each B 1 is independently selected from
  • heteroarylene, heterocyclylene, and arylene are each independently optionally substituted with alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, or hydroxyl;
  • each R 3 is independently H or (C 1 -C 6 )alkyl
  • each R 4 is independently H, (C 1 -C 6 )alkyl, halogen, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, (C 6 -C 10 )aryl, wherein the heteroaryl, heterocyclyl, and aryl are each independently optionally substituted with —N(R 3 ) 2 , —OR 3 , halogen, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-CN, —C(O)NR 3 -heteroaryl, or —C(O)NR 3 -heterocyclyl;
  • each R 5 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is each independently optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 6 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is each independently optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 7 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is each independently optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 8 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is each independently optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each Y is independently —C(R 3 ) 2 or a bond
  • each n is independently an integer from one to 12;
  • each o is independently an integer from zero to 30;
  • each p is independently an integer from zero to 12;
  • each q is independently an integer from zero to 30;
  • each r is independently an integer from one to 6.
  • R 32 is —H, ⁇ O, or —OR 3 ;
  • R 28 is —H or —C( ⁇ Z 1 )—R 28a ;
  • R 40 is —H or —C( ⁇ Z 1 )—R 40a ;
  • Z 1 is independently O or S
  • R 28a and R 40a are independently -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; —O—(C 1 -C 6 )alkyl; or —O—(C 6 -C 10 )aryl; wherein the aryl of —O—(C 6 -C 10 )aryl is unsubstituted or substituted with 1-5 substituents selected from —NO 2 and halogen;
  • a 1 and A 2 are independently absent or are independently selected from
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X 1 is independently a heteroarylene or heterocyclylene ring
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each W 1 independently is a heteroarylene or heterocyclylene ring
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each G 1 and G 2 are independently heteroarylene or heterocyclylene ring;
  • each L 1 is independently selected from
  • L 2 and L 3 are independently absent or are independently selected from
  • each B is independently selected from
  • each B 1 is independently selected from
  • heteroarylene, heterocyclylene, and arylene are each independently optionally substituted with alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, or hydroxyl;
  • each R 3 is independently H or (C 1 -C 6 )alkyl
  • each R 4 is independently H, (C 1 -C 6 )alkyl, halogen, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, (C 6 -C 10 )aryl, wherein the heteroaryl, heterocyclyl, and aryl are each independently optionally substituted with —N(R 3 ) 2 , —OR 3 , halogen, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-CN, —C(O)NR 3 -heteroaryl, or —C(O)NR 3 -heterocyclyl;
  • each R 5 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 6 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl is of (C 1 -C 6 )alkyl optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 7 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 8 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each Y is independently —C(R 3 ) 2 or a bond
  • each n is independently an integer from one to 12;
  • each o is independently an integer from zero to 30;
  • each p is independently an integer from zero to 12;
  • each q is independently an integer from zero to 30;
  • each r is independently an integer from one to 6.
  • R 32 is —H, ⁇ O or —OR 3 ;
  • R 28 is —H or —C( ⁇ Z 1 )—R 28a ;
  • R 40 is —H or —C( ⁇ Z 1 )—R 40a ;
  • Z 1 is independently O or S
  • R 28a and R 40a are independently -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; —O—(C 1 -C 6 )alkyl; or —O—(C 6 -C 10 )aryl; wherein the aryl of —O—(C 6 -C 10 )aryl is unsubstituted or substituted with 1-5 substituents selected from —NO 2 and halogen;
  • a 1 and A 2 are independently absent or are independently selected from
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X 1 is independently a heteroarylene or heterocyclylene ring
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each W 1 is independently a heteroarylene or heterocyclylene ring
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each G 1 and G 2 are independently heteroarylene or heterocyclylene ring;
  • each L 1 is independently selected from
  • each B is independently selected from
  • each B 1 is independently selected from
  • heteroarylene, heterocyclylene, and arylene are each independently optionally substituted with alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, or hydroxyl;
  • each R 3 is independently H or (C 1 -C 6 )alkyl
  • each R 4 is independently H, (C 1 -C 6 )alkyl, halogen, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, (C 6 -C 10 )aryl, wherein the heteroaryl, heterocyclyl, and aryl are each independently optionally substituted with —N(R 3 ) 2 , —OR 3 , halogen, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-CN, —C(O)NR 3 -heteroaryl, or —C(O)NR 3 -heterocyclyl;
  • each R 5 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 6 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 7 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 8 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each Y is independently C(R 3 ) 2 or a bond
  • each n is independently an integer from one to 12;
  • each o is independently an integer from zero to 30;
  • each p is independently an integer from zero to 12;
  • each q is independently an integer from zero to 30;
  • each r is independently an integer from one to 6.
  • a compound of Formula I or II is represented by the structure of Formula I-28:
  • a compound of Formula Ia, Ic, I, or II is represented by the structure of Formula I-28b:
  • a compound of Formula I or II is represented by the structure of Formula I-40:
  • a compound of Formula Ia, Ic, I or II is represented by the structure of Formula I-40b:
  • a compound of Formula Ia, Ic, I or II is represented by the structure of Formula I-32b:
  • the present disclosure provides a method of treating a disease or disorder mediated by mTOR comprising administering to the subject suffering from or susceptible to developing a disease or disorder mediated by mTOR a therapeutically effective amount of one or more disclosed compounds.
  • the present disclosure provides a method of preventing a disease or disorder mediated by mTOR comprising administering to the subject suffering from or susceptible to developing a disease or disorder mediated by mTOR a therapeutically effective amount of one or more disclosed compounds.
  • the present disclosure provides a method of reducing the risk of a disease or disorder mediated by mTOR comprising administering to the subject suffering from or susceptible to developing a disease or disorder mediated by mTOR a therapeutically effective amount of one or more disclosed compounds.
  • Another aspect of the present disclosure is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, Ia, Ib, Ic, II, or IIb, or a pharmaceutically acceptable salt or tautomer of any of the foregoing, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can further comprise an excipient, diluent, or surfactant.
  • the pharmaceutical composition can be effective for treating, preventing, or reducing the risk of a disease or disorder mediated by mTOR in a subject in need thereof.
  • Another aspect of the present disclosure relates to a compound of Formula I, Ia, Ib, Ic, II, or IIb, or a pharmaceutically acceptable salt or tautomer of any of the foregoing, for use in treating, preventing, or reducing the risk of a disease or disorder mediated by mTOR in a subject in need thereof.
  • Another aspect of the present disclosure relates to the use of a compound of Formula I, Ia, Ib, Ic, II, or IIb, or a pharmaceutically acceptable salt or tautomer of any of the foregoing, in the manufacture of a medicament for in treating, preventing, or reducing the risk of a disease or disorder mediated by mTOR in a subject in need thereof.
  • the present disclosure also provides compounds that are useful in inhibiting mTOR.
  • the present disclosure relates to mTOR inhibitors. Specifically, the embodiments are directed to compounds and compositions inhibiting mTOR, methods of treating diseases mediated by mTOR, and methods of synthesizing these compounds.
  • an optionally substituted group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein) of the substituents listed for that group in which said substituents may be the same or different.
  • an optionally substituted group has 1 substituent.
  • an optionally substituted group has 2 substituents.
  • an optionally substituted group has 3 substituents.
  • an optionally substituted group has 4 substituents.
  • an optionally substituted group has 5 substituents.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched non-cyclic carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di-and multivalent radicals, having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbons).
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, such as those groups having 10 or fewer carbon atoms.
  • alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Certain alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched may mean that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, and i-butenyl.
  • a C 2 -C 6 alkenyl group is an alkenyl group containing between 2 and 6 carbon atoms.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Certain alkynyl groups have 2 to about 4 carbon atoms in the chain. Branched may mean that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkynyl chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl.
  • a C 2 -C 6 alkynyl group is an alkynyl group containing between 2 and 6 carbon atoms.
  • alkynylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne.
  • cycloalkyl means a monocyclic or polycyclic saturated or partially unsaturated carbon ring containing 3-18 carbon atoms.
  • cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.
  • a C 3 -C 8 cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms.
  • a cycloalkyl group can be fused (e.g., decalin) or bridged (e.g., norbornane).
  • a “cycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl.
  • heterocyclyl or “heterocycloalkyl” or “heterocycle” refers to a monocyclic or polycyclic 3 to 24-membered ring containing carbon and at least one heteroatom selected from oxygen, phosphorous, nitrogen, and sulfur and wherein there is not delocalized 7E electrons (aromaticity) shared among the ring carbon or heteroatom(s).
  • Heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
  • a heterocyclyl or heterocycloalkyl ring can also be fused or bridged, e.g., can be a bicyclic ring.
  • heterocyclylene or “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a “heterocyclyl” or “heterocycloalkyl” or “heterocycle.”
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl may refer to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • arylene alone or as part of another substituent, means a divalent radical derived from an aryl.
  • heteroaryl refers to an aryl group (or rings) that contains at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atom(s) are optionally oxidized, and the nitrogen atom(s) is optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinoly
  • heteroaryl may also include multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below.
  • the term may also include multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, can be condensed with one or more rings selected from heteroaryls (to form for example a naphthyridinyl such as 1,8-naphthyridinyl), heterocycles, (to form for example a 1, 2, 3, 4-tetrahydronaphthyridinyl such as 1, 2, 3, 4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system.
  • heteroaryls to form for example a naphthyridinyl such
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heteroaryl) can be at any position of the multiple condensed ring system including a heteroaryl, heterocycle, aryl or carbocycle portion of the multiple condensed ring system and at any suitable atom of the multiple condensed ring system including a carbon atom and heteroatom (e.g., a nitrogen).
  • heteroarylene alone or as part of another substituent, means a divalent radical derived from a heteroaryl.
  • Non-limiting examples of aryl and heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimid
  • a heteroaryl moiety may include one ring heteroatom (e.g., O, N, or S).
  • a heteroaryl moiety may include two optionally different ring heteroatoms (e.g., O, N, or S).
  • a heteroaryl moiety may include three optionally different ring heteroatoms (e.g., O, N, or S).
  • a heteroaryl moiety may include four optionally different ring heteroatoms (e.g., O, N, or S).
  • a heteroaryl moiety may include five optionally different ring heteroatoms (e.g., O, N, or S).
  • An aryl moiety may have a single ring.
  • An aryl moiety may have two optionally different rings.
  • An aryl moiety may have three optionally different rings.
  • An aryl moiety may have four optionally different rings.
  • a heteroaryl moiety may have one ring.
  • a heteroaryl moiety may have two optionally different rings.
  • a heteroaryl moiety may have three optionally different rings.
  • a heteroaryl moiety may have four optionally different rings.
  • a heteroaryl moiety may have five optionally different rings.
  • halo or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” may include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl may include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, 1-fluoro-2-bromoethyl, and the like.
  • hydroxyl means —OH.
  • hydroxyalkyl as used herein, means an alkyl moiety as defined herein, substituted with one or more, such as one, two or three, hydroxy groups. In certain instances, the same carbon atom does not carry more than one hydroxy group.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy -1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl.
  • oxo means an oxygen that is double bonded to a carbon atom.
  • a substituent group as used herein, may be a group selected from the following moieties:
  • an “effective amount” when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.
  • carrier encompasses carriers, excipients, and diluents and may mean a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • treating refers to improving at least one symptom of the subject's disorder. Treating may include curing, improving, or at least partially ameliorating the disorder.
  • prevent refers to keeping a disease or disorder from afflicting the subject. Preventing may include prophylactic treatment. For instance, preventing can include administering to the subject a compound disclosed herein before a subject is afflicted with a disease and the administration will keep the subject from being afflicted with the disease.
  • disorder means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administer refers to either directly administering a disclosed compound or pharmaceutically acceptable salt or tautomer of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt or tautomer of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.
  • a “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.
  • a compound has the following formula:
  • R 32 is ⁇ O. In certain embodiments, R 32 is —OR 3 . In certain embodiments, R 32 is H. In certain embodiments, R 32 is —N 3 .
  • each R 3 is independently H or (C 1 -C 6 )alkyl. In certain embodiments, R 3 is H. In certain embodiments, R 3 is (C 1 -C 6 )alkyl. In certain embodiments, R 3 is methyl.
  • R 28 is H. In certain embodiments, R 28 is (C 1 -C 6 )alkyl. In certain embodiments, R 40 is H.
  • a compound is represented by the structure of Formula I-40b:
  • a compound is represented by the structure of Formula I-40:
  • R 40 is —C( ⁇ Z 1 )—R 40a .
  • Z 1 is O.
  • Z 1 is S.
  • R 40a is —O—(C 1 -C 6 )alkyl or —O—(C 6 -C 10 )aryl; wherein the aryl is unsubstituted or substituted with 1-5 substituents selected from NO 2 and halogen.
  • R 40a is -A 1 -L 1 -A 2 -B. In certain embodiments, R 40a is -A 1 -A 2 -B. In certain embodiments, R 40a is -L 2 -A 1 -L 1 -A 2 -L 3 -B.
  • R 40a is -A 1 -L 1 -A 2 -B, wherein A 1 and A 2 are absent. In certain embodiments, R 40a is -A 1 -L 1 -A 2 -B, wherein A 2 is absent. In certain embodiments, R 40a is -A 1 -L 1 -A 2 -B, wherein A 1 is absent. In certain embodiments, R 40a is -A 1 -L 1 -A 2 -B. In certain embodiments, R 40a is -A 1 -A 2 -B. In certain embodiments, R 40a is -L 2 -A 1 -L 1 -A 2 -L 3 -B, wherein L 2 and A 1 are absent.
  • R 40a is -L 2 -A 1 -L 1 -A 2 -L 3 -B, wherein L 2 is absent. In certain embodiments, R 40a is -L 2 -A 1 -L 1 -A 2 -L 3 -B, wherein L 3 is absent.
  • a compounds is represented by the structure of Formula I-28b:
  • R 32 and R 28 are described as above for Formula Ia, Ic, I, or II.
  • a compound is represented by the structure of Formula I-28:
  • R 28 is —C( ⁇ Z 1 )—R 28a .
  • Z 1 is O.
  • Z 1 is S.
  • R 28a is —O—(C 1 -C 6 )alkyl or —O—(C 6 -C 10 )aryl; wherein the aryl is unsubstituted or substituted with 1-5 substituents selected from NO 2 and halogen.
  • R 28a is In certain embodiments, R 28a is -A 1 -A 2 -B. In certain embodiments, R 28a is -L 2 -L 1 -A 2 -L 3 -B.
  • R 28a is -A 1 -L 1 -A 2 -B, wherein A 1 and A 2 are absent. In certain embodiments, R 28a is -A 1 -L 1 -A 2 -B, wherein A 2 is absent. In certain embodiments, R 28a is A 1 -L 1 -A 2 -B, wherein A 1 is absent. In certain embodiments, R 28a is -A 1 -L 1 -A 2 -B. In certain embodiments, R 28a is -A 1 -A 2 -B. In certain embodiments, R 28a is -L 2 -A 1 -L 1 -A 2 -L 3 -B, wherein L 2 and A 1 are absent.
  • R 28a is -L 2 -A 1 -L 1 -A 2 -L 3 -B, wherein L 2 is absent. In certain embodiments, R 28a is -L 2 -A 1 -L 1 -A 2 -L 3 -B, wherein L 3 is absent.
  • the compounds are represented by the structure of Formula I-32b:
  • R 32 is described as above for Formula Ia, Ic, I, or II.
  • R 32 is —O—C( ⁇ Z 1 )—R 32a .
  • Z 1 is O.
  • Z 1 is S.
  • R 32a is —O—(C 1 -C 6 )alkyl or —O—(C 6 -C 10 )aryl; wherein the aryl is unsubstituted or substituted with 1-5 substituents selected from NO 2 and halogen.
  • R 32a is -A 1 -L 1 -A 2 -B. In certain embodiments, R 32a is -A 1 -A 2 -B. In certain embodiments, R 32a is -L 2 -A 1 -L 1 -A 2 -L 3 -B.
  • R 32a is -A 1 -L 1 -A 2 -B, wherein A 1 and A 2 are absent. In certain embodiments, R 32a is -A 1 -L 1 -A 2 -B, wherein A 2 is absent. In certain embodiments, R 32a is -A 1 -L 1 -A 2 -B, wherein A 1 is absent. In certain embodiments, R 32a is -A 1 -L 1 -A 2 -B. In certain embodiments, R 32a is -A 1 -A 2 -B. In certain embodiments, R 32a is -L 2 -A 1 -L 1 -A 2 -L 3 -B, wherein L 2 and A 1 are absent.
  • R 32a is -L 2 -A 1 -L 1 -A 2 -L 3 -B, wherein L 2 is absent. In certain embodiments, R 32a is -L 2 -A 1 -L 1 -A 2 -L 3 -B, wherein L 3 is absent.
  • each L 1 is independently selected from
  • each L 1 is independently selected from
  • each L 1 is independently selected from
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 is
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 2 and L 3 are independently absent or are independently selected from
  • L 2 and L 3 are independently absent or are independently selected from
  • L 2 is absent. In certain embodiments, L 2 is
  • L 2 is
  • L 2 is
  • L 2 is
  • L 2 is
  • L is N
  • L 2 is
  • L 2 is
  • L 2 is
  • L 2 is
  • L 2 is
  • L 2 is
  • L 3 is absent. In certain embodiments, L 3 is
  • L 3 is
  • L 3 is
  • L 3 is
  • L 3 is
  • L 3 is
  • L 3 is
  • L 3 is
  • L 3 is In certain embodiments, L 2 is
  • L 2 is
  • L 2 is
  • L 3 is
  • L 3 is
  • L 3 is R 3
  • a 1 and A 2 are independently absent or are independently selected from
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X 1 is independently a heteroarylene or heterocyclylene ring
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each W 1 is independently a heteroarylene or heterocyclylene ring
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each G 1 and G 2 are independently heteroarylene or heterocyclylene ring.
  • a 1 and A 2 are independently absent or are independently selected from
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X 1 is independently a heteroarylene or heterocyclylene ring
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each W 1 is independently a heteroarylene or heterocyclylene ring
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each G 1 and G 2 are independently heteroarylene or heterocyclylene ring.
  • a 1 and A 2 are independently absent or are independently selected from
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X 1 is independently a heteroarylene or heterocyclylene ring
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each W 1 is independently a heteroarylene or heterocyclylene ring
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each G 1 and G 2 are independently heteroarylene or heterocyclylene ring;
  • the bond on the left side of A 1 , as drawn, is bound to —C( ⁇ Z 1 )— or L 2 ; and the bond on the right side of the A 2 moiety, as drawn, is bound to B or L 3 .
  • the bond on the left side of A 1 , as drawn is bound to —C( ⁇ Z 1 )—; and the bond on the right side of die A 2 moiety, as drawn, is bound to B.
  • the bond on the left side of A 1 , as drawn is bound to —C( ⁇ Z 1 )— or L 2 ; and wherein the bond CHI the right side of the A 2 moiety, as drawn, is bound to B or L 3 .
  • a 1 is absent. In certain embodiments, A 1 is
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene.
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene.
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; and each X 1 is a heteroarylene or heterocyclylene ring.
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; and each W 1 is a heteroarylene or heterocyclylene ring.
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; and each W 1 is a heteroarylene or heterocyclylene ring.
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene.
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; and each G 1 and G 2 are independently heteroarylene or heterocyclylene ring.
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 2 is absent. In certain embodiments, A 2 is
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene.
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene.
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; and each X 1 is independently a heteroarylene or heterocyclylene ring.
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; and each W 1 is independently a heteroarylene or heterocyclylene ring.
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; and each W 1 is independently a heteroarylene or heterocyclylene ring.
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene.
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; and each G 1 and G 2 are independently a heteroarylene or heterocyclylene ring.
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each B is independently selected from
  • B is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • B is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • B is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • B is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • each B 1 is independently selected from
  • heteroarylene, heterocyclylene, and arylene are each independently optionally substituted with alkyl, hydroxy alkyl, haloalkyl, alkoxy, halogen, or hydroxyl.
  • each B 1 is independently selected from
  • heterocyclylene, and arylene are each independently optionally substituted with alkyl, hydroxy alkyl, haloalkyl, alkoxy, halogen, or hydroxyl.
  • B 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • B 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • B 1 is
  • arylene is optionally substituted with haloalkyl.
  • B 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • B 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • B 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • B 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • B 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • B 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • B 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • B 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • B 1 is
  • the heteroaryl, heterocyclyl, and arylene are optionally substituted with alkyl, hydroxy alkyl, haloalkyl, alkoxy, halogen, or hydroxyl.
  • R 3 is H. In certain embodiments, R 3 is (C 1 -C 6 )alkyl.
  • R 4 is H. In certain embodiments, R 4 is (C 1 -C 6 )alkyl. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is 5-12 membered heteroaryl, 5-12 membered heterocyclyl, or (C 6 -C 10 )aryl, wherein the heteroaryl, heterocyclyl, and aryl are optionally substituted with —N(R 3 ) 2 , —OR 3 , halogen, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-CN, or —C(O)NR 3 -heteroaryl. In certain embodiments, R 4 is —C(O)NR 3 -heterocyclyl. In certain embodiments, R 4 is 5-12 membered heteroaryl, optionally substituted with —N(R 3 ) 2 or —OR 3
  • each R 5 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 .
  • R 5 is H.
  • R 5 is (C 1 -C 6 )alkyl, wherein the alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 .
  • R 5 is —C(O)OR 3 .
  • R 5 is —N(R 3 ) 2 .
  • each R 6 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 .
  • R 6 is H.
  • R 6 is (C 1 -C 6 )alkyl, wherein the alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 .
  • R 6 is —C(O)OR 3 .
  • R 6 is —N(R 3 ) 2 .
  • each R 7 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 .
  • R 7 is H.
  • R 7 is (C 1 -C 6 )alkyl, wherein the alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 .
  • R 7 is —C(O)OR 3 .
  • R 7 is —N(R 3 ) 2 .
  • each R 8 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 .
  • R 8 is H.
  • R 8 is (C 1 -C 6 )alkyl, wherein the alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 .
  • R 8 is —C(O)OR 3 .
  • R 8 is —N(R 3 ) 2 .
  • each Y is independently C(R 3 ) 2 or a bond. In certain embodiments, Y is C(R 3 >2. In certain embodiments, Y is CH 2 . In certain embodiments, Y is a bond.
  • n is 1, 2, 3, 4, 5, 6, 7, or 8, or any range derivable therein. In certain embodiments, n is 1, 2, 3, or 4. In certain embodiments, n is 5, 6, 7, or 8. In certain embodiments, n is 9, 10, 11, or 12.
  • o is an integer from zero to 10, or any range derivable therein. In certain embodiments, o is 0, 1, 2, 3, 4, or 5. In certain embodiments, o is 6, 7, 8, 9, or 10. In certain embodiments, o is one to 7. In certain embodiments, o is one to 8. In certain embodiments, o is one to 9. In certain embodiments, o is 3 to 8.
  • o is an integer from zero to 30, or any range derivable therein. In certain embodiments, o is an integer from zero to 30, 29, 28, 27, or 26. In certain embodiments, o is an integer from zero to 25, 24, 23, 22, or 21. In certain embodiments, o is an integer from zero to 20, 19, 18, 17, or 16. In certain embodiments, o is an integer from zero to 15, 14, 13, 12, or 11.
  • p is 0, 1, 2, 3, 4, 5, or 6, or any range derivable therein. In certain embodiments, p is 7, 8, 9, 10, 11, or 12. In certain embodiments, p is 0, 1, 2, or 3. In certain embodiments, p is 4, 5, or 6.
  • q is an integer from zero to 10, or any range derivable therein. In certain embodiments, q is 0, 1, 2, 3, 4, or 5. In certain embodiments, q is 6, 7, 8, 9, or 10. In certain embodiments, q is one to 7. In certain embodiments, q is one to 8. In certain embodiments, q is one to 9. In certain embodiments, q is 3 to 8.
  • q is an integer from zero to 30, or any range derivable therein. In certain embodiments, q is an integer from zero to 30, 29, 28, 27, or 26. In certain embodiments, q is an integer from zero to 25, 24, 23, 22, or 21. In certain embodiments, q is an integer from zero to 20, 19, 18, 17, or 16. In certain embodiments, q is an integer from zero to 15, 14, 13, 12, or 11.
  • r is an integer from one to 6. In certain embodiments, r is one. In certain embodiments, r is 2. In certain embodiments, r is 3. In certain embodiments, r is 4. In certain embodiments, r is 5. In certain embodiments, r is 6.
  • R 32 is not ⁇ O.
  • the compound is not rapamycin, as shown below:
  • R 32 is —O—C( ⁇ Z 1 )—R 32a . In certain embodiments, R 32 is —O—C( ⁇ Z 1 )—R 32a ; wherein R 32a is -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; or -L 2 -A 1 -L 1 -A 2 -L 3 -B. In certain embodiments, in Formula Ia or Ic, R 28 is-C( ⁇ Z 1 )—R 28a .
  • R 28 is-C( ⁇ Z 1 )—R 28a ; wherein R 28a is -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; or -L 2 -A 1 -L 1 -A 2 -L 3 -B.
  • R 40 is —C( ⁇ Z 1 )—R 40a .
  • R 40 is —C( ⁇ Z 1 )—R 40a . wherein R 40a is -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; or -L 2 -A 1 -L 1 -A 2 -L 3 -B.
  • the present disclosure provides a compound of Formula Ia or Ic, or a pharmaceutically acceptable salt or tautomer thereof, having one, two, or three of the following features:
  • R 32 is —O—C( ⁇ Z 1 )—R 32a ;
  • R 28 is-C( ⁇ Z 1 )—R 28a ;
  • R 40 is-C( ⁇ Z 1 )—R 40a .
  • the present disclosure provides a compound of Formula Ia or Ic, or a pharmaceutically acceptable salt or tautomer thereof, having one, two, or three of the following features:
  • the present disclosure provides a compound of Formula Ia or Ic, or a pharmaceutically acceptable salt or tautomer thereof, having one, two, or three of the following features:
  • the present disclosure provides a compound of Formula Ia or Ic, or a pharmaceutically acceptable salt or tautomer thereof, having one, two, three, or four of the following features:
  • R 28a , R 32a , and R 40a is -A 1 -L 1 -A 2 -B;
  • R 4 is 5-12 membered heteroaryl, optionally substituted with —N(R 3 ) 2 or —OR 3 .
  • R 4 is 5-12 membered heteroaryl, optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • R 32 is ⁇ O.
  • R 40a can be -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; or -L 2 -A 1 -L 1 -A 2 -L 3 -B.
  • R 4 is 5-12 membered heteroaryl, optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • R 32 is —OH.
  • R 40a can be -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; or -L 2 -A 1 -L 1 -A 2 -L 3 -B.
  • R 4 is 5-12 membered heteroaryl, optionally substituted with —N(R 3 ) 2 or —OR 3 ;
  • R 32 is ⁇ O.
  • R 40a can be -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; or -L 2 -A 1 -L 1 -A 2 -L 3 -B.
  • arylene is optionally substituted with alkyl, hydroxy alkyl, haloalkyl, alkoxy, halogen, or hydroxyl;
  • R 4 is 5-12 membered heteroaryl, optionally substituted with —N(R 3 ) 2 or —OR 3 ; and g) R 32 is —OH.
  • R 40a can be -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; or -L 2 -A 1 -L 1 -A 2 -L 3 -B.
  • arylene is optimally substituted with alkyl, hydroxy alkyl, haloalkyl, alkoxy, halogen, or hydroxyl;
  • R 4 is 5-12 membered heteroaryl, optimally substituted with —N(R 3 ) 2 or —OR 3 ;
  • R 32 is —OH.
  • R 40a can be -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; or -L 2 -A 1 -L 1 -A 2 -L 3 -B.
  • R 40a is any organic moiety, which may have a molecular weight (e.g. the sum of the atomic masses of the atoms of the substituent) of less than 15 g/mol, 50 g/mol, 100 g/mol, 150 g/mol, 200 g/mol, 250 g/mol, 300 g/mol, 350 g/mol, 400 g/mol, 450 g/mol, or 500 g/mol.
  • a molecular weight e.g. the sum of the atomic masses of the atoms of the substituent
  • the present disclosure provides for a compound selected from below or a pharmaceutically acceptable salt or tautomer thereof,
  • the present disclosure provides for a compound selected from below or a pharmaceutically acceptable salt or tautomer thereof,
  • the present disclosure provides for a compound selected from below or a pharmaceutically acceptable salt or tautomer thereof,
  • the compounds of the disclosure may include pharmaceutically acceptable salts of the compounds disclosed herein.
  • Representative “pharmaceutically acceptable salts” may include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iod
  • “Pharmaceutically acceptable salt” may also include both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” may refer to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which may be 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, capiylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-dis
  • “Pharmaceutically acceptable base addition salt” may refer to those salts that retain the biological effectiveness and properties of die free acids, which are not biologically or otherwise undesirable. These salts may be prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases may include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. For example, inorganic salts may include, but are not limited to, ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases may 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, dicyclohexylamine, 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.
  • basic ion exchange resins such
  • structures depicted herein may also include compounds which differ only in die presence of one or more isotopically enriched atoms.
  • compounds having the present structure except for the replacement of a hydrogen atom by deuterium or tritium, or the replacement of a carbon atom by 13 C or 14 C, or the replacement of a nitrogen atom by 15 N, or the replacement of an oxygen atom with 17 O or 18 O are within the scope of the disclosure.
  • Such isotopically labeled compounds are useful as research or diagnostic tools.
  • one or more deuterium atoms may be introduced into the PEG moiety of any compound of the present invention. Mechanisms for such modifications are known in the art starting from commercially available starting materials, such as isotopically enriched hydroxylamine building blocks.
  • a tritium or a deuterium may be introduced at the C32 position of compounds of the present invention using, for example, a commercially available isotopically pure reducing agent and methods known to those in the art.
  • 14 C may be introduced into the C40 carbamate moiety of compounds of the present invention using commercially available materials and methods known to those of skill in the art.
  • an isotope such as deuterium or tritium may be introduced into the R 40a substituent of a compound of Formula Ia, Ic, I or II, using commercially available starting materials and methods known to those of skill in the art.
  • the compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the schemes given below.
  • the compounds of any of the formulae described herein may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes and examples. In die schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of Formula I, Ia, Ib, II, or IIb, or a pharmaceutically acceptable salt or tautomer of any of the foregoing.
  • the compounds of any of the formulae described herein may be prepared by methods which avoid the use of metal-mediated cycloaddition reactions which require the use of azide-containing compounds.
  • Azide containing compounds present potential safety hazards associated with their preparation and storage (e.g., explosion due to high energy decomposition).
  • the reaction schemes herein can avoid the use of copper or ruthenium metals in the penultimate or ultimate synthetic steps, which can be advantageous. Avoiding the use of copper or ruthenium metals in the penultimate or ultimate synthetic steps reduces the potential for contamination of the final compounds with undesirable metal impurities.
  • reaction schemes herein provide better yields than other reaction schemes. In the reaction schemes herein, there is no need to alkylate at the C40-hydroxyl of rapamycin, which is advantageous for providing as much as a 5-fold improved overall yield in preparing bivalent compounds from rapamycin compared to other reaction schemes.
  • the present disclosure may include both possible stereoisomers (unless specified in the synthesis) and may include not only racemic compounds but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
  • the compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds of the disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. These methods may include but are not limited to those methods described below.
  • tautomers may refer to a set of compounds that have the same number and type of atoms, but differ in bond connectivity and are in equilibrium with one another.
  • a “tautomer” is a single member of this set of compounds. Typically a single tautomer is drawn but it may be understood that this single structure may represent all possible tautomers that might exist Examples may include enol-ketone tautomerism. When a ketone is drawn it may be understood that both the enol and ketone forms are part of the disclosure.
  • thermodynamic equilibrium position may vary between different members of compounds of Formula I, Ia, Ib, Ic, II, or IIb
  • both isomers are contemplated for the compounds of Formula I, Ia, Ib, Ic, II, or lib.
  • the pyran isomer form of all intermediates and compounds of Formula I, Ia, Ib, Ic, II, or IIb is shown.
  • rapamycin is Formula RAP
  • R 16 is —OCH 3 ; R 26 is ⁇ O; R 28 is —OH; R 32 is ⁇ O; and R 40 is —OH.
  • a “rapalog” refers to an analog or derivative of rapamycin.
  • a rapalog can be rapamycin that is substituted at any position, such as R 16 , R 26 , R 28 , R 32 , or R 40 .
  • An active site inhibitor is an active site mTOR inhibitor.
  • AS inhibitor is depicted by B, in Formula I, Ia, Ib, Ic, II, or IIb.
  • the linker amine can include substitutions, such as R ⁇ H and C1-C6 alkyl groups.
  • the carbamate moiety, where Z 1 ⁇ O or S, can be attached to the rapalog at R 40 or R 28 (Formula I, Ia, Ib, Ic, II, or IIb), including variations found in Table 1 in the Examples Section.
  • An mTOR active site inhibitor can attach to the linker via a primary or secondary amine, and may include variations found in Table 2 in the Examples Section.
  • the linker amine can include substitutions, such as R ⁇ H and C1-C6 alkyl groups.
  • the pre-linker amine can include substitutions, such as R 2 ⁇ H, C1-C6 alkyl groups, and cycloalkyl including 4 to 8-membered rings.
  • the carbamate moiety, where Z 1 ⁇ O or S, can be attached to the rapalog at R 40 or R 28 (Formula I, Ia, Ib, Ic, II, or IIb), including variations found in Table 1 in the Examples Section.
  • An mTOR active site inhibitor can attach to the linker via a primary or secondary amine, and may include variations found in Table 2 in the Examples Section.
  • the linker amine can include substitutions, such as R ⁇ H and C1-C6 alkyl groups.
  • the post-linker amine can include substitutions, such as R 2 ⁇ H, C1-C6 alkyl groups, and cycloalkyl including 4 to 8-membered rings.
  • the carbamate moiety, where Z 1 ⁇ O or S, can be attached to the rapalog at R 40 or R 28 (Formula I, Ia, Ib, Ic, II, or IIb), including variations found in Table 1 in the Examples Section.
  • An mTOR active site inhibitor can attach to the linker via a primary or secondary amine, and may include variations found in Table 2 in the Examples Section.
  • the linker amine can include substitutions, such as R ⁇ H and C1-C6 alkyl groups.
  • the pre- and post-linker amines can each include substitutions, such as R 2 ⁇ H, C1-C6 alkyl groups, and cycloalkyl including 4 to 8-membered rings.
  • the carbamate moiety where Z 1 ⁇ O or S, can be attached to the rapalog at R 40 or R 28 (Formula I, Ia, Ib, Ic, II, or lib), including variations found in Table 1 in the Examples Section.
  • An mTOR active site inhibitor can attach to the linker via a primary or secondary amine, and may include variations found in Table 2 in the Examples Section.
  • the pre-linker amine can include substitutions, such as R 2 ⁇ H, C1-C6 alkyl groups, and cycloalkyl including 4 to 8-membered rings.
  • the carbamate moiety, where Z 1 ⁇ O or S, can be attached to the rapalog at R 40 or R 28 (Formula I, Ia, Ib, Ic, II, or IIb), including variations found in Table 1 in the Examples Section.
  • An mTOR active site inhibitor can attach to the linker via a primary or secondary amine, and may include variations found in Table 2 in the Examples Section.
  • the linker amines can include substitutions, such as R ⁇ H and C1-C6 alkyl groups.
  • the post-linker amine can include substitutions, such as R 2 ⁇ H, C1-C6 alkyl groups, and cycloalkyl including 4 to 8-membered rings.
  • the carbamate moiety, where Z 1 ⁇ O or S, can be attached to the rapalog at R 40 or R 28 (Formula I, Ia, Ib, Ic, II, or IIb), including variations found in Table 1 in the Examples Section.
  • An mTOR active site inhibitor can attach to the linker via a primary or secondary amine, and may include variations found in Table 2 in the Examples Section.
  • the linker amine can include substitutions, such as R ⁇ H and C1-C6 alkyl groups.
  • the pre- and post-linker amines can each include substitutions, such as R 2 ⁇ H, C1-C6 alkyl groups, and cycloalkyl including 4 to 8-membered rings.
  • the carbamate moiety where Z 1 ⁇ O or S, can be attached to the rapalog at R 40 or R 28 (Formula I, Ia, Ib, Ic, II, or lib), including variations found in Table 1 in the Examples Section.
  • An mTOR active site inhibitor can attach to the linker via a primary or secondary amine, and may include variations found in Table 2 in the Examples Section.
  • the linker amine can include substitutions, such as R ⁇ H and C1-C6 alkyl groups.
  • the post-linker amine can include substitutions, such as R 2 ⁇ H, C1-C6 alkyl groups, and cycloalkyl including 4 to 8-membered rings.
  • the carbamate moiety, where Z 1 ⁇ O or S, can be attached to the rapalog at R 40 or R 28 (Formula I, Ia, Ib, Ic, II, or IIb), including variations found in Table 1 in the Examples Section.
  • An mTOR active site inhibitor can attach to the linker via a primary or secondary amine, and may include variations found in Table 2 in the Examples Section.
  • compositions including a pharmaceutically acceptable excipient and a compound of the present invention, or pharmaceutically acceptable salt or tautomer thereof.
  • a compound of the present invention may be included in a therapeutically effective amount.
  • Administration of the disclosed compounds or compositions can be accomplished via any mode of administration for therapeutic agents.
  • These modes may include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, topical, intrathecal, or intracranial administration modes.
  • administering can include oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
  • Administration can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • the compositions of the present disclosure can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • the compositions of the present disclosure may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates.
  • compositions of the present disclosure can also be delivered as microspheres for slow release in the body.
  • microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Set Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res.
  • the formulations of the compositions of the present disclosure can be delivered by the use of liposomes which fuse with die cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis.
  • liposomes particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo.
  • compositions of the present disclosure can also be delivered as nanoparticles.
  • the disclosed compounds or pharmaceutical compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • injectables tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • they can also be administered in intravenous (both bolus and infusion), intraperitoneal, intrathecal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.
  • Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
  • the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
  • Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.
  • the disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as die carrier.
  • the disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described for instance in U.S. Pat. No. 5,262,564, the contents of which are hereby incorporated by reference.
  • Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled.
  • the disclosed compounds can also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, poly lactic acid, poly epsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, poly cyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a polymer e.g., a polycarboxylic acid polymer, or a polyacrylate.
  • Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • compositions comprising a compound, or a pharmaceutically acceptable salt or tautomer thereof, of the present disclosure and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can further include an excipient, diluent, or surfactant.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.
  • the compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer, autoimmune disease, inflammatory disease, metabolic disease, neurodegenerative disease, fungal infection, or transplant rejection, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
  • the compounds described herein can be used in combination with other active agents known to be longevity agents or anti-aging agents.
  • the pharmaceutical composition may include a second agent (e.g., therapeutic agent).
  • the pharmaceutical composition may include a second agent (e.g., therapeutic agent) in a therapeutically effective amount.
  • the second agent is an anti-cancer agent.
  • the second agent is an immunotherapeutic agent.
  • the second agent is an immune-oncological agent.
  • the second agent is an anti-autoimmune disease agent.
  • the second agent is an anti-inflammatory disease agent.
  • the second agent is an anti-neurodegenerative disease agent.
  • the second agent is an anti-metabolic disease agent.
  • the second agent is an anti-cardiovascular disease agent. In certain embodiments, the second agent is an anti-aging agent. In certain embodiments, the second agent is a longevity agent. In certain embodiments, the second agent is an agent for treating or preventing transplant rejection. In certain embodiments, the second agent is an agent for treating or preventing fungal infection. In certain embodiments, the second agent is immune system repressor. In certain embodiments, the second agent is an mTOR modulator. In certain embodiments, the second agent is an mTOR inhibitor. In certain embodiments, the second agent is an active site mTOR inhibitor. In certain embodiments, the second agent is a rapamycin. In certain embodiments, the second agent is a rapamycin analog. In certain embodiments, the second agent is an mTOR pathway inhibitor. In certain embodiments, the second agent is CDK4/6 inhibitor; anti-PD1/PD-L1, PI3K inhibitor; or Ras inhibitor.
  • Anti-cancer agent or “anti-cancer drug” is used in accordance with its plain ordinary meaning and refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.
  • an anti-cancer agent is a chemotherapeutic.
  • an anticancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer.
  • anti-cancer agents include, but are not limited to, rapamycin, rapamycin analog, bevacizumab, PP242, FN 128, MLN0128, anti-androgens (e.g., Casodex, Flutamide, MDV3100, or ARN-509), MEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g.
  • alkylating agents e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan),
  • gefitinib IressaTM
  • erlotinib TarcevaTM
  • cetuximab ErbituxTM
  • lapatinib TykerbTM
  • panitumumab VectibixTM
  • vandetanib CaprelsaTM
  • afatinib/BIBW2992 CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD 153035, BMS-599626), sorafenib, imatinib, sunitinib, dasat
  • tomaymycin carboplatin
  • CC-1065 and CC-1065 analogs including amino-CBIs, nitrogen mustards (such as chlorambucil and melphalan), dolastatin and dolastatin analogs (including auristatins: eg. monomethyl auristatin E), anthracycline antibiotics (such as doxorubicin, daunorubicin, etc.), duocarmycins and duocarmycin analogs, enediynes (such as neocarzinostatin and calicheamicins), leptomycin derivaties, maytansinoids and maytansinoid analogs (e.g.
  • mertansine methotrexate
  • mitomycin C taxoids
  • vinca alkaloids such as vinblastine and vincristine
  • epothilones e.g. epothilone B
  • camptothecin and its clinical analogs topotecan and irinotecan FNK128, PP242, PP121, MLN0128, AZD8055, AZD2014, VP-BEZ235, BGT226, SF1 126, Torin 1, Torin 2, WYE 687, WYE 687 salt (e.g., hydrochloride), PF04691502, PI-103, CC-223, OSI-027, XL388, KU-0063794, GDC-0349, PKI-587, rapamycin, deforolimus (AP23573, MK-8669, ridaforolimus), temsirolimus (CCI-779), ABT478, everolimus (RAD001) or the like.
  • mTOR refers to the protein “mechanistic target of rapamycin (serine/threonine kinase)” or “mammalian target of rapamycin.”
  • the term “mTOR” may refer to the nucleotide sequence or protein sequence of human mTOR (e.g., Entrez 2475, Uniprot P42345, RefSeq NM_004958, or RefSeq NP_004949) (SEQ ID NO: 1).
  • the term “mTOR” may include both die wild-type form of the nucleotide sequences or proteins as well as any mutants thereof. In some embodiments, “mTOR” is wild-type mTOR.
  • mTOR is one or more mutant forms.
  • the term “mTOR” XYZ may refer to a nucleotide sequence or protein of a mutant mTOR wherein the Y numbered amino acid of mTOR that normally has an X amino acid in the wildtype, instead has a Z amino acid in the mutant.
  • an mTOR is the human mTOR.
  • the mTOR has the nucleotide sequence corresponding to reference number GL206725550 (SEQ ID NO:2).
  • the mTOR has the nucleotide sequence corresponding to RefSeq NM_004958.3 (SEQ ID NO:2).
  • the mTOR has the protein sequence corresponding to reference number GL4826730 (SEQ ID NO: 1). In embodiments, the mTOR has the protein sequence corresponding to RefSeq NP_004949.1 (SEQ ID NO: 1). In embodiments, the mTOR has the following amino acid sequence:
  • the mTOR is a mutant mTOR.
  • the mutant mTOR is associated with a disease that is not associated with wildtype mTOR.
  • the mTOR may include at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any range derivable therein) compared to the sequence above.
  • mTORC1 refers to the protein complex including mTOR and Raptor (regulatory-associated protein of mTOR). mTORC1 may also include MLST8 (mammalian lethal with SEC 13 protein 8), PRAS40, and/or DEPTOR. mTORC1 may function as a nutrient/energy/redox sensor and regulator of protein synthesis.
  • mTORC1 pathway or “mTORC 1 signal transduction pathway” may refer to a cellular pathway-including mTORC1. An mTORC1 pathway includes the pathway components upstream and downstream from mTORC1. An mTORC1 pathway is a signaling pathway that is modulated by modulation of mTORC1 activity.
  • an mTORC1 pathway is a signaling pathway that is modulated by modulation of mTORC1 activity but not by modulation of mTORC2 activity. In embodiments, an mTORC1 pathway is a signaling pathway that is modulated to a greater extent by modulation of mTORC1 activity than by modulation of mTORC2 activity.
  • mTORC2 refers to the protein complex including mTOR and RICTOR (rapamycin-insensitive companion of mTOR). mTORC2 may also include G ⁇ L, mSIN1 (mammalian stress-activated protein kinase interacting protein 1), Protor 1/2, DEPTOR, TTI1, and/or TEL2. mTORC2 may regulate cellular metabolism and the cytoskeleton.
  • mTORC2 pathway or “mTORC2 signal transduction pathway” may refer to a cellular pathway including mTORC2.
  • An mTORC2 pathway includes the pathway-components upstream and downstream from mTORC2.
  • An mTORC2 pathway is a signaling pathway that is modulated by modulation of mTORC2 activity.
  • an mTORC2 pathway is a signaling pathway that is modulated by modulation of mTORC2 activity but not by modulation of mTORC1 activity.
  • an mTORC2 pathway is a signaling pathway that is modulated to a greater extent by modulation of mTORC2 activity than by modulation of mTORC1 activity.
  • Rapamycin refers to a macrolide produced by the bacteria Streptomyces hygroscopicus . Rapamycin may prevent the activation of T cells and B cells. Rapamycin has the IUPAC name (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-oxaazacycl
  • Analog is used in accordance with its plain ordinary meaning within chemistry and biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or die replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound, including isomers thereof.
  • rapamycin analog or “rapalog” refers to an analog or derivative (e.g., a prodrug) of rapamycin.
  • active site mTOR inhibitor and “ATP mimetic” refers to a compound that inhibits the activity of mTOR (e.g., kinase activity) and binds to the active site of mTOR (e.g., the ATP binding site, overlapping with the ATP binding site, blocking access by ATP to the ATP binding site of mTOR).
  • mTOR e.g., kinase activity
  • ATP mimetic refers to a compound that inhibits the activity of mTOR (e.g., kinase activity) and binds to the active site of mTOR (e.g., the ATP binding site, overlapping with the ATP binding site, blocking access by ATP to the ATP binding site of mTOR).
  • active site mTOR inhibitors include, but are not limited to, TNK128, PP242, PP121, MLN0128, AZD8055, AZD2014, NVP-BEZ235, BGT226, SF1126, Torin 1, Torin 2, WYE 687, WYE 687 salt (e.g., hydrochloride), PF04691502, PI-103, CC-223, OSI-027, XL388, KU-0063794, GDC-0349, and PKI-587.
  • an active site mTOR inhibitor is an asTORi.
  • active site inhibitor may refer to “active site mTOR inhibitor.”
  • FKBP refers to the protein Peptidyl-prolyl cis-trans isomerase. For non-limiting examples of FKBP, see Cell Mol Life Sci. 2013 September; 70(18):3243-75.
  • FKBP may refer to “FKBP-12” or “FKBP 12” or “FKBP 1 A.”
  • FKBP may refer to the human protein. Included in the term “FKBP” is the wildtype and mutant forms of the protein.
  • FKBP may refer to the wildtype human protein.
  • FKBP may refer to the wildtype human nucleic acid.
  • the FKBP is a mutant FKBP.
  • the mutant FKBP is associated with a disease that is not associated with wildtype FKBP.
  • the FKBP includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any range derivable therein) compared to wildtype FKBP.
  • FKBP-12 or “FKBP 12” or “FKBP 1 A” may refer to the protein “Peptidyl-prolyl cis-trans isomerase FKBP 1 A.” In embodiments, “FKBP-12” or “FKBP 12” or “FKBP 1 A” may refer to the human protein. Included in the term “FKBP-12” or “FKBP 12” or “FKBP 1 A” are the wildtype and mutant forms of the protein.
  • FKBP-12 or “FKBP 12” or “FKBP 1 A” may refer to the protein associated with Entrez Gene 2280, OMIM 186945, UniProt P62942, and/or RefSeq (protein) NP_000792 (SEQ ID NO:3).
  • the reference numbers immediately above may refer to the protein, and associated nucleic acids, known as of the date of filing of this application.
  • “FKBP-12” or “FKBP 12” or “FKBP 1 A” may refer to the wildtype human protein.
  • FKBP-12 or “FKBP 12” or “FKBP 1 A” may refer to the wildtype human nucleic acid.
  • the FKBP-12 is a mutant FKBP-12.
  • the mutant FKBP-12 is associated with a disease that is not associated with wildtype FKBP-12.
  • the FKBP-12 may include at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any range derivable therein) compared to wildtype FKBP-12.
  • the FKBP-12 has the protein sequence corresponding to reference number GL206725550.
  • the FKBP-12 has the protein sequence corresponding to RefSeq NP_000792.1 (SEQ ID NO:3).
  • 4E-BP1 refers to the protein “Eukaryotic translation initiation factor 4E-binding protein 1.”
  • 4E-BP1 or “4EBP1” or “EIF4EBP 1” may refer to the human protein. Included in the term “4E-BP 1” or “4EBP 1” or “EIF4EBP1” are the wildtype and mutant forms of the protein.
  • “4E-BP1” or “4EBP1” or “EIF4EBP1” may refer to the protein associated with Entrez Gene 1978, OMIM 602223, UniProt Q13541, and/or RefSeq (protein) NP_004086 (SEQ ID NO:4).
  • the reference numbers immediately above may refer to the protein, and associated nucleic acids, known as of the date of filing of this application.
  • “4E-BP 1” or “4EBP1” or “EIF4EBP1” may refer to the wildtype human protein.
  • “4E-BP1” or “4EBP1” or “EIF4EBP1” may refer to the wildtype human nucleic acid.
  • the 4EBP1 is a mutant 4EBP1.
  • the mutant 4EBP1 is associated with a disease that is not associated with wildtype 4EBP1.
  • the 4EBP1 may include at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any range derivable therein) compared to wildtype 4EBP1.
  • the 4EBP1 has the protein sequence corresponding to reference number GL4758258.
  • the 4EBP1 has the protein sequence corresponding to RefSeq NP_004086.1 (SEQ ID NO:4).
  • Akt refers to the serine/threonine specific protein kinase involved in cellular processes such as glucose metabolism, apoptosis, proliferation, and other functions, also known as “protein kinase B” (PKB) or “Akt1.”
  • PPKB protein kinase B
  • the reference numbers immediately above may refer to the protein, and associated nucleic acids, known as of the date of filing of this application.
  • Akt or “Akt1” or “PKB” may refer to the wildtype human protein.
  • Akt or “Akt1” or “PKB” may refer to the wildtype human nucleic acid.
  • the Akt is a mutant Akt.
  • the mutant Akt is associated with a disease that is not associated with wildtype Akt
  • the Akt may include at least one amino acid mutation (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any range derivable therein) compared to wildtype Akt.
  • the Akt has the protein sequence corresponding to reference number GI: 62241011.
  • the Akt has the protein sequence corresponding to RefSeq NP 005154.2 (SEQ ID NO:5).
  • the present disclosure provides a method of treating a disease or disorder mediated by mTOR comprising administering to the subject suffering from or susceptible to developing a disease or disorder mediated by mTOR a therapeutically effective amount of one or more disclosed compositions or compounds.
  • the present disclosure provides a method of preventing a disease or disorder mediated by mTOR comprising administering to the subject suffering from or susceptible to developing a disease or disorder mediated by mTOR a therapeutically effective amount of one or more disclosed compositions or compounds.
  • the present disclosure provides a method of reducing the risk of a disease or disorder mediated by mTOR comprising administering to the subject suffering from or susceptible to developing a disease or disorder mediated by mTOR a therapeutically effective amount of one or more disclosed compositions or compounds.
  • the disease is cancer or an immune-mediated disease.
  • the cancer is selected from brain and neurovascular tumors, head and neck cancers, breast cancer, lung cancer, mesothelioma, lymphoid cancer, stomach cancer, kidney cancer, renal carcinoma, liver cancer, ovarian cancer, ovary endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neuro cancers, spleen cancers, pancreatic cancers, blood proliferative disorders, lymphoma, leukemia, endometrial cancer, cervical cancer, vulva cancer, prostate cancer, penile cancer, bone cancers, muscle cancers, soft tissue cancers, intestinal or rectal cancer, anal cancer, bladder cancer, bile duct cancer, ocular cancer, gastrointestinal stromal tumors, and neuro-endocrine tumors.
  • the disorder is liver cirrhosis.
  • the immune-mediated disease is selected from resistance by transplantation of heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum *** , limb, muscle, nerves, duodenum, small-bowel, or pancreatic-islet-cell; graft-versus-host diseases brought about by medulla ossium transplantation; rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis.
  • the disease is tuberous sclerosis complex (TSC).
  • TSC tuberous sclerosis complex
  • the disease is pancreatic neuroendocrine tumor (PNET), mantle cell lymphoma (MCL), colorectal cancer or bowel cancer (CRC), uterine cancer, ovarian cancer, bladder cancer, genitourinary tract cancer, or renal cell carcinoma (RCC).
  • PNET pancreatic neuroendocrine tumor
  • MCL mantle cell lymphoma
  • CRCC renal cell carcinoma
  • the present disclosure provides a method of treating cancer comprising administering to the subject a therapeutically effective amount of one or more disclosed compositions or compounds.
  • the cancer is selected from brain and neurovascular tumors, head and neck cancers, breast cancer, lung cancer, mesothelioma, lymphoid cancer, stomach cancer, kidney cancer, renal carcinoma, liver cancer, ovarian cancer, ovary endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neuro cancers, spleen cancers, pancreatic cancers, blood proliferative disorders, lymphoma, leukemia, endometrial cancer, cervical cancer, vulva cancer, prostate cancer, penile cancer, bone cancers, muscle cancers, soft tissue cancers, intestinal or rectal cancer, anal cancer, bladder cancer, bile duct cancer, ocular cancer, gastrointestinal stromal tumors, and neuro-endocrine tumors.
  • the disorder is liver cirrhosis.
  • the disease is tuberous sclerosis complex (TSC).
  • TSC tuberous sclerosis complex
  • the disease is pancreatic neuroendocrine tumor (PNET), mantle cell lymphoma (MCL), colorectal cancer or bowel cancer (CRC), uterine cancer, ovarian cancer, bladder cancer, genitourinary tract cancer, or renal cell carcinoma (RCC).
  • PNET pancreatic neuroendocrine tumor
  • MCL mantle cell lymphoma
  • CRCC renal cell carcinoma
  • cancer includes human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.
  • the disease is multiple myeloma.
  • the disease is breast cancer.
  • the disease is triple negative breast cancer.
  • cancer includes cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, carcinomas and sarcomas.
  • exemplary cancers that may be treated with a compound or method provided herein include cancer of the prostate, thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreatic cancer.
  • Additional examples may include, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalign ant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.
  • the disease is leukemia.
  • leukemia refers broadly to progressive, malignant diseases of die blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow.
  • Leukemia is generally clinically classified CHI the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in die number of aberrant cells in the blood-leukemic or aleukemic (subleukemic).
  • Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,
  • the disease is sarcoma.
  • sarcoma generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botrvoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorr
  • the disease is melanoma.
  • melanoma is taken to mean a tumor arising from the melanocyte system of the skin and other organs.
  • Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
  • the disease is carcinoma.
  • carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum , cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryon
  • the present disclosure provides a method of treating an immune-mediated disease comprising administering to the subject a therapeutically effective amount of one or more disclosed compositions or compounds.
  • the immune-mediated disease is selected from resistance by transplantation of heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum *** , limb, muscle, nerves, duodenum, small-bowel, or pancreatic-islet-cell; graft-versus-host diseases brought about by medulla ossium transplantation; rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis.
  • the disease is autoimmune disease.
  • autoimmune disease refers to a disease or condition in which a subject's immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject.
  • autoimmune diseases examples include Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Auto
  • ADAM Acute Disseminated Encephalomye
  • the present disclosure provide a method of treating an age related condition comprising administering to the subject a therapeutically effective amount of one or more disclosed compositions or compounds.
  • the age related condition is selected from sarcopenia, skin atrophy, muscle wasting, brain atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, high blood pressure, erectile dysfunction, dementia, Huntington's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, diminished life expectancy, impaired kidney function, and age-related hearing loss, aging-related mobility disability (e.g., frailty), cognitive decline, age-related dementia, memory impairment, tendon stiffness, heart dysfunction such as cardiac hypertrophy and systolic and diastolic dysfunction, immunosenescence, cancer, obesity, and diabetes.
  • sarcopenia skin atrophy, muscle wasting, brain atrophy, atherosclerosis, arteriosclerosis, pulmonary em
  • the disclosed compositions or compounds can be used with regard to immunosenescence.
  • Immunosenescence may refer to a decrease in immune function resulting in impaired immune response, e.g., to cancer, vaccination, infectious pathogens, among others. It involves both the host's capacity to respond to infections and the development of long-term immune memory, especially by vaccination. This immune deficiency is ubiquitous and found in both long- and short-lived species as a function of their age relative to life expectancy rather than chronological time. It is considered a major contributory factor to the increased frequency of morbidity and mortality among the elderly. Immunosenescence is not a random deteriorative phenomenal, rather it appears to inversely repeat an evolutionary pattern and most of the parameters affected by immunosenescence appear to be under genetic control.
  • Immunosenescence can also be sometimes envisaged as the result of die continuous challenge of the unavoidable exposure to a variety of antigens such as viruses and bacteria. Immunosenescence is a multifactorial condition leading to many pathologically significant health problems, e.g., in the aged population. Age-dependent biological changes such as depletion of hematopoietic stem cells, an increase in PD1+lymphocytes, a decline in the total number of phagocytes and NK cells and a decline in humoral immunity contribute to the onset of immunosenescence.
  • immunosenescence can be measured in an individual by measuring telomere length in immune cells (See, e.g., U.S. Pat. No. 5,741,677).
  • Immunosenescence can also be determined by documenting in an individual a lower than normal number of naive CD4 and/or CD8 T cells, T cell repertoire, the number of PD 1-expressing T cells, e.g., a lower than normal number of PD-1 negative T cells, or response to vaccination in a subject greater than or equal to 65 years of age.
  • mTOR selective modulation of certain T-cell populations may improve vaccine efficacy in the aging population and enhance effectiveness of cancer immunotherapy.
  • the present disclosure provides a method of treating immunosenescence comprising administering to the subject a therapeutically effective amount of one or more disclosed compositions or compounds.
  • a disease that may be treated with a compound, pharmaceutical composition, or method described herein is organ or tissue transplant rejection (e.g. heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or comeal transplants; graft-versus-host disease), restenosis, Hamartoma syndromes (e.g., tuberous sclerosis or Cowden Disease), Lymphangioleiomyomatosis, Retinitis pigmentosis, encephalomyelitis, insulin-dependent diabetes mellitus, lupus, dermatomyositis, arthritis, rheumatic diseases, Steroid-resistant acute Lymphoblastic Leukemia, fibrosis, scleroderma, pulmonary fibrosis, renal fibrosis, cystic fibrosis, Pulmonary hypertension, Multiple sclerosis, VHL syndrome, Carney complex, Familial adenonamtous polyposis, Juvenile polyposis syndrome, Birt-Hogg-Duke syndrome, Fa
  • the disease is neurodegenerative disease.
  • the term “neurodegenerative disease” refers to a disease or condition in which the function of a subject's nervous system becomes impaired.
  • Examples of neurodegenerative diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar at
  • the disease is metabolic disease.
  • the term “metabolic disease” refers to a disease or condition in which a subject's metabolism or metabolic system (e.g., function of storing or utilizing energy) becomes impaired.
  • Examples of metabolic diseases that may be treated with a compound, pharmaceutical composition, or method described herein include diabetes (e.g., type I or type II), obesity, metabolic syndrome, or a mitochondrial disease (e.g., dysfunction of mitochondria or aberrant mitochondrial function).
  • the disease is fungal disease.
  • the term “fungal disease” refers to a disease or condition associated with a fungus infection of the subject.
  • fungal diseases that may be treated with a compound, pharmaceutical composition, or method described herein include infection with Mucor circinelloides , zygomycetes, Cryptococcus neoformans, Candida albicans , yeast, and Saccharomyces cerevisiae among others.
  • the disease is inflammatory disease.
  • inflammatory disease refers to a disease or condition characterized by aberrant inflammation (e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease).
  • inflammatory diseases include traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic
  • the disease is cardiovascular disease.
  • cardiovascular disease refers to a disease or condition in which the function of a subject's cardiovascular system becomes impaired.
  • cardiovascular diseases include congestive heart failure; arrhythmogenic syndromes (e.g., paroxysomal tachycardia, delayed after depolarizations, ventricular tachycardia, sudden tachycardia, exercise-induced arrhythmias, long QT syndromes, or bidirectional tachycardia); thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, or thromboembolic disorders in the chambers of the heart); atherosclerosis; restenosis; peripheral arterial disease; coronary bypass grafting surgery; carotid artery disease; arteritis; myocarditis; cardiovascular inflammation; vascular inflammation; coronary heart disease (CHD); unstable angina
  • a method of treating a disease associated with an aberrant level of mTOR activity in a subject in need of such treatment may be caused by an upregulation of mTOR.
  • the method may include administering to the subject one or more compositions or compounds described herein.
  • the method may include administering to the subject a therapeutically effective amount of one or more compositions or compounds described herein (e.g., an mTOR modulator (e.g., inhibitor) as described above).
  • compositions or compounds as described herein for use as a medicament.
  • the medicament is useful for treating a disease caused by an upregulation of mTOR.
  • the use may include administering to the subject one or more compositions or compounds described herein.
  • the use may include administering to the subject a therapeutically effective amount of one or more compositions or compounds described herein (e.g., an mTOR modulator (e.g., inhibitor) as described above).
  • an mTOR modulator e.g., inhibitor
  • compositions or compounds as described herein for use in the treatment of a disease caused by aberrant levels of mTORC1 activity in a subject in need of such treatment.
  • the disease may be caused by an upregulation of mTORC1.
  • the use may include administering to the subject one or more compositions or compounds described herein.
  • the use may include administering to the subject a therapeutically effective amount of one or more compositions or compounds described herein (e.g., an mTORC1 modulator (e.g., inhibitor) as described above).
  • Upregulation of mTOR can result in an increased amount of mTOR activity compared to normal levels of mTOR activity in a particular subject or a population of healthy subjects.
  • the increased amount of mTOR activity may result in, for example, excessive amounts of cell proliferation thereby causing the disease state.
  • the subject of treatment for the disease is typically a mammal.
  • the mammal treated with the compound e.g., compound described herein, mTOR modulator (e.g., inhibitor)
  • mTOR modulator e.g., inhibitor
  • the mammal treated with the compound may be a human, nonhuman primate, and/or non-human mammal (e.g., rodent, canine).
  • a method of treating an mTOR activity-associated disease in a subject in need of such treatment including administering one or more compositions or compounds as described herein, including embodiments (e.g., a claim, embodiment, example, table, figure, or claim) to the subject.
  • compositions or compounds as described herein for use as a medicament.
  • the medicament may be useful for treating an mTORC1 activity-associated disease in a subject in need of such treatment.
  • the use may include administering one or more compositions or compounds as described herein, including embodiments (e.g., an aspect, embodiment, example, table, figure, or claim) to the subject.
  • compositions or compounds for use in the treatment of an mTOR activity-associated disease in a subject in need of such treatment may include administering one or more compositions or compounds as described herein, including embodiments (e.g., an aspect, embodiment, example, table, figure, or claim) to the subject.
  • the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is cancer. In embodiments, the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is an autoimmune disease. In embodiments, the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is an inflammatory disease. In embodiments, the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is a neurodegenerative disease. In embodiments, the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is a metabolic disease. In embodiments, the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is transplant rejection. In embodiments, the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is fungal infection. In embodiments, the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is a cardiovascular disease.
  • the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is aging. In embodiments, the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is dying of an age-related disease. In embodiments, the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is an age-related condition.
  • the age related condition is selected from the group consisting of sarcopenia, skin atrophy, muscle wasting, brain atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, high blood pressure, erectile dysfunction, dementia, Huntington's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, diminished life expectancy, impaired kidney function, and age-related hearing loss, aging-related mobility disability (e.g., frailty), cognitive decline, age-related dementia, memory impairment, tendon stiffness, heart dysfunction such as cardiac hypertrophy and systolic and diastolic dysfunction, immunosenescence, cancer, obesity, and diabetes.
  • sarcopenia skin atrophy, muscle wasting, brain atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, high blood pressure, erectile dysfunction, dementia, Huntington's
  • mTOR selective modulation of certain T-cell populations may improve vaccine efficacy in the aging population and enhance effectiveness of cancer immunotherapy.
  • the present disclosure provides a method of treating immunosenescence comprising administering to the subject a therapeutically effective amount of one or more disclosed compounds.
  • the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is cancer (e.g., carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, solid cancers, lymphoid cancers; cancer of the kidney, breast, lung, bladder, colon, gastrointestinal, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, esophagus, liver; testicular cancer, glioma, hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), multiple myeloma, and breast cancer (e.g., triple negative breast cancer)).
  • cancer e.g., carcinomas, sarcomas
  • the mTOR activity-associated disease or disease associated with aberrant levels of mTOR activity is Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Anti phospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid
  • a method of treating a disease including administering an effective amount of one or more compositions or compounds as described herein.
  • one or more compositions or compounds as described herein for use as a medicament e.g., for treatment of a disease.
  • one or more compositions or compounds as described herein for use in the treatment of a disease e.g., including administering an effective amount of one or more compositions or compounds as described herein.
  • the disease is cancer.
  • the disease is an autoimmune disease.
  • the disease is an inflammatory disease.
  • the disease is a neurodegenerative disease.
  • the disease is a metabolic disease.
  • the disease is fungal infection.
  • the disease is transplant rejection.
  • the disease is a cardiovascular disease.
  • the disease is cancer (e.g., carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, solid cancers, lymphoid cancers; cancer of the kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, esophagus, liver; testicular cancer, glioma, hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), multiple myeloma, and breast cancer (e.g., triple negative breast cancer)).
  • cancer e.g., carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, solid cancers
  • the disease is Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Anti phospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal or neuronal
  • the disease is a polycystic disease. In embodiments, the disease is polycystic kidney disease. In embodiments, the disease is stenosis. In embodiments, the disease is restenosis. In embodiments, the disease is neointimal proliferation. In embodiments, the disease is neointimal hyperplasia.
  • a method of treating aging in a subject in need of such treatment including administering one or more compositions or compounds as described herein, including embodiments (e.g., a claim, embodiment, example, table, figure, or claim) to the subject.
  • the present disclosure provides a method of treating immunosenescence comprising administering to the subject a therapeutically effective amount of one or more disclosed compounds or compositions.
  • compositions or compounds as described herein for use as a medicament.
  • the medicament may be useful for treating aging in a subject in need of such treatment.
  • the use may include administering one or more compositions or compounds as described herein, including embodiments (e.g., an aspect, embodiment, example, table, figure, or claim) to the subject.
  • compositions or compounds disclosed herein for use in the treatment of aging in a subject in need of such treatment
  • the use may include administering one or more compositions or compounds as described herein, including embodiments (e.g., an aspect embodiment example, table, figure, or claim) to the subject.
  • a method of extending life span or inducing longevity in a subject in need of such treatment including administering one or more compositions or compounds as described herein, including embodiments (e.g., a claim, embodiment example, table, figure, or claim) to the subject.
  • compositions or compounds as described herein for use as a medicament.
  • the medicament may be useful for extending life span or inducing longevity in a subject in need of such treatment.
  • the use may include administering one or more compositions or compounds as described herein, including embodiments (e.g., an aspect embodiment example, table, figure, or claim) to the subject.
  • compositions or compounds for use in extending life span or inducing longevity in a subject in need of such treatment may include administering one or more compositions or compounds as described herein, including embodiments (e.g., an aspect, embodiment, example, table, figure, or claim) to the subject.
  • a method of treating a polycystic disease in a subject in need of such treatment may be polycystic kidney disease.
  • the method may include administering to the subject one or more compositions or compounds described herein.
  • the method may include administering to the subject a therapeutically effective amount of one or more compositions or compounds described herein (e.g., an mTOR modulator (e.g., inhibitor) as described above).
  • an mTOR modulator e.g., inhibitor
  • compositions or compounds as described herein for use as a medicament.
  • the medicament is useful for treating a polycystic disease.
  • the polycystic disease may be polycystic kidney disease.
  • the use may include administering to the subject one or more compositions or compounds described herein.
  • the use may include administering to the subject a therapeutically effective amount of one or more compositions or compounds described herein (e.g., an mTOR modulator (e.g., inhibitor) as described above).
  • compositions or compounds as described herein for use in the treatment of a polycystic disease in a subject in need of such treatment.
  • the polycystic disease may be polycystic kidney disease.
  • the use may include administering to the subject one or more compositions or compounds described herein.
  • the use may include administering to the subject a therapeutically effective amount of one or more compositions or compounds described herein (e.g., an mTOR modulator (e.g., inhibitor) as described above).
  • a method of treating stenosis in a subject in need of such treatment may be restenosis.
  • the method may include administering to the subject one or more compositions or compounds described herein.
  • the one or more compositions or compounds are administered in a drug eluting stent.
  • the method may include administering to the subject a therapeutically effective amount of one or more compositions or compounds described herein (e.g., an mTOR modulator (e.g., inhibitor) as described above).
  • an mTOR modulator e.g., inhibitor
  • compositions or compounds as described herein for use as a medicament.
  • the medicament is useful for treating stenosis.
  • the stenosis may be restenosis.
  • the use may include administering to the subject one or more compositions or compounds described herein.
  • the compound is administered in a drug eluting stent.
  • the use may include administering to the subject a therapeutically effective amount of one or more compositions or compounds described herein (e.g., an mTOR modulator (e.g., inhibitor) as described above).
  • an mTOR modulator e.g., inhibitor
  • compositions or compounds as described herein for use in the treatment of stenosis in a subject in need of such treatment.
  • the stenosis may be restenosis.
  • the use may include administering to the subject one or more compositions or compounds described herein.
  • the one or more compositions or compounds are administered in a drug eluting stent.
  • the use may include administering to the subject a therapeutically effective amount of one or more compositions or compounds described herein (e.g., an mTOR modulator (e.g., inhibitor) as described above).
  • the disease is a disease described herein and die compound is a compound described herein and the composition is a composition described herein.
  • compounds disclosed herein are more selective inhibitors of mTORC1 versus mTORC2. In some embodiments, compounds disclosed herein are more selective inhibitors of mTORC2 versus mTORC1. In some embodiments, compounds disclosed herein exhibit no selectivity difference between mTORC 1 and mTORC2.
  • a method of modulating mTORC1 activity in a subject in need thereof including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the method includes inhibiting mTORC1 activity.
  • the method includes inhibiting mTORC1 activity and not inhibiting mTORC2 activity.
  • the method includes inhibiting mTORC1 activity more than inhibiting mTORC2 activity. In embodiments, the method includes inhibiting mTORC1 activity at least 1.1 fold as much as inhibiting mTORC2 activity (e.g., at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300.400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 100000, 200000, 300000, 400000, 500000, 600000, 700000, 800000, 900000, or 1000000 fold).
  • a method of modulating mTORC2 activity in a subject in need thereof including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the method includes inhibiting mTORC2 activity.
  • the method includes inhibiting mTORC2 activity and not inhibiting mTORC1 activity.
  • the method includes inhibiting mTORC2 activity more than inhibiting mTORC1 activity. In embodiments, the method includes inhibiting mTORC2 activity at least 1.1 fold as much as inhibiting mTORC1 activity (e.g., at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300.400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 100000, 200000, 300000, 400000, 500000, 600000, 700000, 800000, 900000, or 1000000 fold).
  • the mTOR is in a cell.
  • the cell is a mammalian cell, such as a human cell.
  • the cell may be isolated in vitro, form part of a tissue in vitro, or may form part of an organism.
  • Embodiment I As follows:
  • R 32 is —H, ⁇ O or —OR 3 ;
  • R 28 is —H or —C( ⁇ Z 1 )—R 28a ;
  • R 40 is —H or —C( ⁇ Z 1 )—R 40a ;
  • Z 1 is O or S
  • R 28a and R 40a are independently -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; -L 2 -A 1 -L 1 -A 2 -L 3 -B; —O—(C 1 -C 6 )alkyl; or —O—(C 6 -C 10 )aryl; wherein the aryl is unsubstituted or substituted with 1-5 substituents selected from —NO 2 and halogen;
  • a 1 and A 2 are independently absent or are independently selected from
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X 1 is a heteroarylene or heterocyclylene ring
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each W 1 is a heteroarylene or heterocyclylene ring
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each G 1 and G 2 are independently heteroarylene or heterocyclylene ring;
  • L 1 is selected from
  • L 2 and L 3 are independently absent or are independently selected from
  • each R 3 is independently H or (C 1 -C 6 )alkyl
  • each R 4 is independently H, (C 1 -C 6 )alkyl, halogen, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, (C 6 -C 10 )aryl, wherein the heteroaryl, heterocyclyl, and aryl are optimally substituted with —N(R 3 ) 2 , —OR 3 , halogen, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-CN, —C(O)NR 3 -heteroaryl; or —C(O)NR 3 -heterocyclyl; each R 5 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl is optimally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 6 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl is optimally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 7 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl is optimally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R® is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl is optimally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each Y is independently C(R 3 ) 2 or a bond
  • each n is independently a number from one to 12;
  • each o is independently a number from zero to 30;
  • each p is independently a number from zero to 12;
  • each q is independently a number from zero to 30;
  • each r is independently a number from one to 6.
  • R 32 is —H, ⁇ O or —OR 3 ;
  • R 28 is —H or —C( ⁇ Z 1 )—R 28a ;
  • R 40 is —H or —C( ⁇ Z 1 )—R 40 *;
  • Z 1 is O or S
  • R 28a and R 40a are independently -A 1 -L 1 -A; -A 1 -A 2 -B; —O—(C 1 -C 6 )alkyl; or —O—(C 6 -C 10 )aryl; wherein the aryl is unsubstituted or substituted with 1-5 substituents selected from —NO 2 and halogen;
  • a 1 and A 2 are independently absent or are independently selected from
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X 1 is a heteroarylene or heterocyclylene ring
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each W 1 is a heteroarylene or heterocyclylene ring
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each G 1 and G 2 are independently heteroarylene or heterocyclylene ring;
  • L 1 is selected from
  • each R 3 is independently H or (C 1 -C 6 )alkyl
  • each R 4 is independently H, (C 1 -C 6 )alkyl, halogen, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, (C 6 -C 10 )aryl, wherein the heteroaryl, heterocyclyl, and aryl are optionally substituted with —N(R 3 ) 2 , —OR 3 , halogen, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-CN, —C(O)NR 3 -heteroaryl; or —C(O)NR 3 -heterocyclyl;
  • each R 5 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl is optimally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 6 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl is optimally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 7 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl is optimally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each R 8 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl is optimally substituted with —N(R 3 ) 2 or —OR 3 ;
  • each Y is independently C(R 3 ) 2 or a bond
  • each n is independently a number from one to 12;
  • each o is independently a number from zero to 30;
  • each p is independently a number from zero to 12;
  • each q is independently a number from zero to 30;
  • each r is independently a number from one to 6.
  • R 40a is —O—(C 1 -C 6 )alkyl or —O—(C 6 -C 10 )aryl; wherein the aryl is unsubstituted or substituted with 1-5 substituents selected from —NO 2 and halogen.
  • R 28a is —O—(C 1 -C 6 )alkyl or —O—(C 6 -C 10 )aryl; wherein the aryl is unsubstituted or substituted with 1-5 substituents selected from —NO 2 and halogen.
  • Embodiment I-37 The compound of any one of Embodiments I-1 to I-7, I-9, I-11 to I-12, I-14 to I-15, I-17 to I-19, I-21, I-23 to I-24, I-26 to I-27, and I-29 to I-35, wherein A 1 is
  • Embodiment I-46 The compound of any one of Embodiments I-1 to I-7, I-10 to I-15, I-17 to I-19, I-22 to I-27 and I-29 to I-44, wherein A 2 is
  • Embodiment I-56 The compound of any one of Embodiments I-1 to I-53, wherein B 1 is
  • Embodiment I-57 The compound of any one of Embodiments I-1 to I-53, wherein B 1 is
  • R 4 is 5-12 membered heteroaryl, optionally substituted with —N(R 3 ) 2 , —OR 3 , halogen, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-CN, or —C(O)NR 3 -heteroaryl.
  • a pharmaceutical composition comprising a compound of any one of Embodiments I-1 to I-60, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
  • a method of treating a disease or disorder mediated by mTOR comprising administering to the subject suffering from or susceptible to developing a disease or disorder mediated by mTOR a therapeutically effective amount of one or more compounds of any one of Embodiments I-1 to I-60, or a pharmaceutically acceptable salt thereof.
  • a method of preventing a disease or disorder mediated by mTOR comprising administering to the subject suffering from or susceptible to developing a disease or disorder mediated by mTOR a therapeutically effective amount of one or more compounds of any one of Embodiments I-1 to I-60, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the risk of a disease or disorder mediated by mTOR comprising administering to the subject suffering from or susceptible to developing a disease or disorder mediated by mTOR a therapeutically effective amount of one or more compounds of any one of Embodiments I-1 to I-60, or a pharmaceutically acceptable salt thereof.
  • Embodiment I-66 The method of Embodiment I-65, wherein the cancer is selected from brain and neurovascular tumors, head and neck cancers, breast cancer, lung cancer, mesothelioma, lymphoid cancer, stomach cancer, kidney cancer, renal carcinoma, liver cancer, ovarian cancer, ovary endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neuro cancers, spleen cancers, pancreatic cancers, blood proliferative disorders, lymphoma, leukemia, endometrial cancer, cervical cancer, vulva cancer, prostate cancer, penile cancer, bone cancers, muscle cancers, soft tissue cancers, intestinal or rectal cancer, anal cancer, bladder cancer, bile duct cancer, ocular cancer, gastrointestinal stromal tumors, and neuro-endocrine tumors.
  • the cancer is selected from brain and neurovascular tumors, head and neck cancers, breast cancer, lung cancer, mesot
  • die immune-mediated disease is selected from resistance by transplantation of heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum *** , limb, muscle, nerves, duodenum, small-bowel, or pancreatic-islet-cell; graft-versus-host diseases brought about by medulla ossium transplantation; rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis.
  • a method of treating cancer comprising administering to the subject a therapeutically effective amount of one or more compounds of any one of Embodiments I-1 to I-60, or a pharmaceutically acceptable salt thereof.
  • Embodiment I-68 wherein the cancer is selected from brain and neurovascular tumors, head and neck cancers, breast cancer, lung cancer, mesothelioma, lymphoid cancer, stomach cancer, kidney cancer, renal carcinoma, liver cancer, ovarian cancer, ovary endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neuro cancers, spleen cancers, pancreatic cancers, blood proliferative disorders, lymphoma, leukemia, endometrial cancer, cervical cancer, vulva cancer, prostate cancer, penile cancer, bone cancers, muscle cancers, soft tissue cancers, intestinal or rectal cancer, anal cancer, bladder cancer, bile duct cancer, ocular cancer, gastrointestinal stromal tumors, and neuro-endocrine tumors.
  • the cancer is selected from brain and neurovascular tumors, head and neck cancers, breast cancer, lung cancer, mesothelioma, lymphoid cancer,
  • a method of treating an immune-mediated disease comprising administering to the subject a therapeutically effective amount of one or more compounds of any one of Embodiments I-1 to I-60, or a pharmaceutically acceptable salt thereof.
  • die immune-mediated disease is selected from resistance by transplantation of heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum *** , limb, muscle, nerves, duodenum, small-bowel, or pancreatic-islet-cell; graft-versus-host diseases brought about by medulla ossium transplantation; rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis.
  • a method of treating an age related condition comprising administering to the subject a therapeutically effective amount of one or more compounds of any one of Embodiments I-1 to I-60, or a pharmaceutically acceptable salt thereof.
  • die age related condition is selected from sarcopenia, skin atrophy, muscle wasting, brain atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, high blood pressure, erectile dysfunction, dementia, Huntington's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, diminished life expectancy, impaired kidney function, and age-related hearing loss, aging-related mobility disability (e.g., frailty), cognitive decline, age-related dementia, memory impairment, tendon stiffness, heart dysfunction such as cardiac hypertrophy and systolic and diastolic dysfunction, immunosenescence, cancer, obesity, and diabetes.
  • sarcopenia sarcopenia
  • skin atrophy muscle wasting
  • brain atrophy atherosclerosis
  • arteriosclerosis arteriosclerosis
  • pulmonary emphysema pulmonary emphysema
  • osteoporosis osteoarthriti
  • Embodiment I-81 Use of a compound of any one of Embodiments I-1 to I-60, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an age related condition.
  • Embodiment II As follows:
  • R 32 is —H, ⁇ O, —OR 3 , —N 3 , or —O—C( ⁇ Z 1 )—R 32a ;
  • R 28 is —H, (C 1 -C 6 )alkyl, or —C( ⁇ Z 1 )—R 28a ;
  • R 40 is —H or —C( ⁇ Z 1 )—R 40a ;
  • each Z 1 is independently O or S;
  • R 28a , R 32a , R 40a are independently -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; -L 2 -A 1 -L 1 -A 2 -L 3 -B; —O—(C 1 -C 6 )alkyl; or —O—(C 6 -C 10 )aryl; wherein the aryl of —O—(C 6 -C 10 )aryl is unsubstituted or substituted with 1-5 substituents selected from —NO 2 and halogen;
  • a 1 and A 2 are independently absent or are independently selected from
  • each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each X 1 is independently a heteroarylene or heterocyclylene ring
  • each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each W 1 is independently a heteroarylene or heterocyclylene ring
  • each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
  • each G 1 and G 2 are independently heteroarylene or heterocyclylene ring;
  • each L 1 is independently selected from
  • L 2 and L 3 are independently absent or are independently selected from

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US17/083,172 US11364300B2 (en) 2018-05-01 2020-10-28 C40-, C28-, and C-32-linked rapamycin analogs as mTOR inhibitors
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US11685749B2 (en) 2018-05-01 2023-06-27 Revolution Medicines, Inc. C26-linked rapamycin analogs as mTOR inhibitors
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