WO2015154047A1 - Novel methods - Google Patents

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Publication number
WO2015154047A1
WO2015154047A1 PCT/US2015/024371 US2015024371W WO2015154047A1 WO 2015154047 A1 WO2015154047 A1 WO 2015154047A1 US 2015024371 W US2015024371 W US 2015024371W WO 2015154047 A1 WO2015154047 A1 WO 2015154047A1
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mtorc
mammalian target
rapamycin complex
inhibitor
free
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PCT/US2015/024371
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French (fr)
Inventor
David Sherris
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Restorgenex Corporation
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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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/559—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing hetero atoms other than oxygen
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/436—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 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines

Definitions

  • Hutchinson-Gilford Progeria Syndrome is a rare, fatal genetic disease characterized by premature aging. HGPS patients most often die of myocardial infarction or stroke in their early teens.
  • HGPS may be caused by a mutation in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11 producing a lamin A variant with an internal deletion of 50 amino acids termed progerin.
  • Progerin is defective in a post-translational processing step.
  • the normal processing of lamin A involves famesylation of the C terminus by farnesyltransferase which targets the protein to the inner nuclear membrane surface where it is cleaved to yield mature lamin A.
  • Progerin does not have the cleavage site resulting in permanent famesylation which is believed to cause progerin to remain anchored in the nuclear membrane with other proteins of the nuclear scaffold attached to it.
  • Progerin accumulation in dividing cells disrupts the nuclear scaffold leading to nuclear blebbing in cultured cells.
  • Progerin may also be produced in non-HGPS individuals. Progerin appears to accumulate with increasing age; a statistically significant increase in the amount of progerin- positive cells has been seen with age. HGPS shares many of the hallmarks of the normal aging process. Features common to HGPS and normal aging include alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and osteoporosis.
  • a method of increasing autophagy comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • a method of decreasing mRNA translation comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2
  • a method of decreasing mRNA translation comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6-one derivative.
  • a method of decreasing cellular progerin levels comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • a method of treatment or prophylaxis of an aging-related disorder comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • HGPS Progeria Syndrome
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • HGPS Progeria Syndrome
  • a method of treatment or prophylaxis of Parkinson's disease comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • a method of treatment or prophylaxis of Parkinson's disease comprising administering to a patient in need thereof an effective amount of a benzo[c]- chromen-6-one derivative.
  • a method of treatment or prophylaxis of Huntington's disease comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • a method of treatment or prophylaxis of alopecia comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • a method of treatment or prophylaxis of alopecia comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6-one derivative.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Figure 1 shows coimmunoprecipitation for mTOR with raptor and rictor to assess
  • Figure 2 shows detection of progerin and lamin A/C in normal and Hutchinson-
  • HGPS Gilford Progeria Syndrome
  • Figure 3 shows detection of progerin and lamin A/C at passage 16 in normal
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • compounds disclosed herein e.g., compounds of Formula I, e.g., 8-(l-hydroxyethyl)-2-methoxy-3-((4-methoxybenzyl)oxy)- 6H-benzo[c]chromen-6-one, are allosteric, dissociative inhibitors of both mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
  • mTORC-1 and mTORC-2 will activate autophagy, thereby reducing the accumulation of mutated or improperly processed protein such as progerin.
  • a compound which is an inhibitor of mTORC-1 and mTORC-2 e.g., an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2, has a different activity and/or improved safety profile compared to an mTORC-1 inhibitor, e.g., rapamycin, or a compound that inhibits mTORC-1 and mTORC-2 by inhibiting mTOR kinase.
  • an mTORC-1 inhibitor e.g., rapamycin
  • patient encompasses human and non-human (i.e., animal) patients.
  • the patient is human or non-human.
  • the patient is non-human.
  • the patient is human.
  • treatment encompass treatment and amelioration of symptoms of a disease or disorder, e.g., Hutchinson-Gilford Progeria Syndrome, as well as treatment of the cause of the disease or disorder.
  • treatment also encompass preventing or retarding progression of a disease or disorder, e.g., Hutchinson-Gilford Progeria Syndrome.
  • ⁇ ективное amount encompasses a therapeutically effective amount to treat a specific disease or disorder.
  • composition As used herein, “concurrently” means the compounds are administered simultaneously or within the same composition. In some embodiments, the compounds are administered simultaneously. In some embodiments, the compounds are administered within the same composition.
  • Alkyl as used herein may include a saturated or unsaturated hydrocarbon moiety, preferably saturated, e.g., one to eight, e.g., one to six, e.g., one to four carbon atoms in length, which may be linear or branched (e.g., n-butyl or tert-butyl) unless otherwise specified, and may be optionally substituted, e.g., mono-, di-, or tri-substituted on any one of the carbon atoms, e.g., with Ci_ 4 alkyl (e.g., methyl), Ci_ 4 alkoxy, halogen (e.g., chloro or fluoro), haloCi_ 4 alkyl (e.g., trifluoromethyl), hydroxy, and carboxy.
  • Ci_ 4 alkyl e.g., methyl
  • Ci_ 4 alkoxy e.g., halogen (e.g., chloro or fluoro)
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, 3-methylpentyl, 4-methylpentyl, n-pentyl, n-hexyl and n-heptyl.
  • Aryl as used herein may include a monocyclic or polycyclic aromatic hydrocarbon, preferably phenyl, optionally substituted, e.g., with Ci_ 4 alkyl (e.g., methyl), Ci_ 4 alkoxy, halogen (e.g., chloro or fluoro), haloCi_ 4 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, or an additional aryl or heteroaryl.
  • Ci_ 4 alkyl e.g., methyl
  • Ci_ 4 alkoxy e.g., methyl
  • halogen e.g., chloro or fluoro
  • haloCi_ 4 alkyl e.g., trifluoromethyl
  • Method 1 of increasing autophagy comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Rl H or alkyl
  • R2 H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
  • R5 Oxo, aryl, hydroxyl, alkyl, or O-alkyl
  • R7 H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1, 1.1, or 1.4 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is in free or pharmaceutically acceptable salt form.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is in free or pharmaceutically acceptable salt form, e.g., in free form.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula II
  • Rl H or alkyl
  • R2 H, O-alkyl, OH, amino, O-heterocyc, O-aryl, O-substituted alkyl where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, O-alkyl, O-substituted alkyl where substitution is aryl or heteroaryl, OH, O-acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
  • R5 H, Aryl, heteroaryl or substituted alkyl
  • R6 H, Alkyl, or Aryl
  • Method 1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula III
  • Rl alkyl or H
  • R2 alkyl or H
  • R3 Acetyl
  • R4 H or Alkyl
  • Method 1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula IV
  • Rl H or F
  • R2 H or nitro
  • R5 alkyl, substituted alkyl or aryl
  • any of methods 1, 1.1, or 1.24-1.26 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
  • Method 1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is selected from AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC- 0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU-0063794, and Tori 1.
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • an aging-related disorder e.g., alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, e.g., osteoporosis.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Any of methods 1 or 1.1-1.33 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) one, two, three, or four times daily or in sustained release form.
  • 0.01 to 500 mg/kg e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 1.35 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
  • the second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
  • mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) for increasing autophagy, e.g., for use in any of methods 1 or 1.1-1.40.
  • mTORC-1 mammalian target of rapamycin complex 2
  • mTORC-2 mammalian target of rapamycin complex 2
  • a pharmaceutical composition comprising an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), in combination with a pharmaceutically acceptable diluent or carrier, for use in increasing autophagy, e.g., for use in any of methods 1 or 1.1-1.40.
  • a method (Method 2) of increasing autophagy comprising administering to a patient in need thereof an effective amount of a benzo[c]- chromen-6-one derivative.
  • Rl H or alkyl
  • R2 H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
  • R5 Oxo, aryl, hydroxyl, alkyl, or O-alkyl
  • R7 H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • the benzo[c]-chromen-6-one derivative is an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2.
  • any of methods 2 or 2.1-2.29 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the benzo[c]-chromen-6-one derivative one, two, three, or four times daily or in sustained release form.
  • rapamycin complex 1 is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
  • rapamycin analog e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus.
  • a benzo[c]-chromen-6-one derivative in the manufacture of a medicament for increasing autophagy, e.g., for use in any of methods 2 or 2.1-2.36.
  • a pharmaceutical composition comprising a benzo[c]-chromen-
  • 6-one derivative in combination with a pharmaceutically acceptable diluent or carrier, for use in increasing autophagy, e.g., for use in any of methods 2 or 2.1-2.36.
  • Method 3 of decreasing mRNA translation comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC -2).
  • Rl H or alkyl
  • R2 H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
  • R5 Oxo, aryl, hydroxyl, alkyl, or O-alkyl
  • R7 H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
  • X O, N, or S, in free or pharmaceutically acceptable salt form.
  • Method 3 3.1, or 3.2 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 3 3.1, or 3.4 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is in free form.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is in free or pharmaceutically acceptable salt form.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 3 3.1, or 3.14 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is in free or pharmaceutically acceptable salt form, e.g., in free form.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 3 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula II
  • Rl H or alkyl
  • R2 H, O-alkyl, OH, amino, O-heterocyc, O-aryl, O-substituted alkyl where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, O-alkyl, O-substituted alkyl where substitution is aryl or heteroaryl, OH, O-acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
  • R5 H, Aryl, heteroaryl or substituted alkyl
  • R6 H, Alkyl, or Aryl
  • Method 3 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula III
  • Rl alkyl or H
  • R2 alkyl or H
  • R3 Acetyl
  • R4 H or Alkyl
  • Method 3 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula IV
  • Rl H or F
  • R2 H or nitro
  • R5 alkyl, substituted alkyl or aryl
  • any of methods 3, 3.1, or 3.24-3.26 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
  • Method 3 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is selected from AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC- 0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU-0063794, and Tori 1.
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • an aging-related disorder e.g., alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, e.g., osteoporosis.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • any of methods 3 or 3.1-3.33 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) one, two, three, or four times daily or in sustained release form.
  • 0.01 to 500 mg/kg e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 3.35 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
  • rapamycin analog e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus.
  • Method 3.37 wherein the second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
  • mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) for decreasing mRNA translation, e.g., for use in any of methods 3 or 3.1-3.40.
  • mTORC-1 mammalian target of rapamycin complex 2
  • mTORC-2 mammalian target of rapamycin complex 2
  • a pharmaceutical composition comprising an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), in combination with a pharmaceutically acceptable diluent or carrier, for use in decreasing mRNA translation, e.g., for use in any of methods 3 or 3.1-3.40.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 4 of decreasing mRNA translation comprising administering to a patient in need thereof an effective amount of a benzo [c] -chromen-6-one derivative.
  • Rl H or alkyl
  • R2 H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
  • R5 Oxo, aryl, hydroxyl, alkyl, or O-alkyl
  • R7 H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
  • Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is in free or pharmaceutically acceptable salt form, e.g., in free form.
  • Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is a benzo[c]-chromen- 6-one selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • an aging-related disorder e.g., alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, e.g., osteoporosis.
  • any of methods 4 or 4.1-4.29 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the benzo[c]-chromen-6-one derivative one, two, three, or four times daily or in sustained release form.
  • Method 4.31 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
  • rapalog a rapamycin analog
  • the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
  • composition comprising a benzo[c]-chromen-
  • 6-one derivative in combination with a pharmaceutically acceptable diluent or carrier, for use in decreasing mRNA translation, e.g., for use in any of methods 4 or 4.1-4.36.
  • Method 5 of decreasing cellular progerin levels comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Rl H or alkyl
  • R2 H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
  • R5 Oxo, aryl, hydroxyl, alkyl, or O-alkyl
  • R7 H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is in free or pharmaceutically acceptable salt form.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is in free or pharmaceutically acceptable salt form, e.g., in free form.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 5 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula II
  • Rl H or alkyl
  • R2 H, O-alkyl, OH, amino, O-heterocyc, O-aryl, O-substituted alkyl where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, O-alkyl, O-substituted alkyl where substitution is aryl or heteroaryl, OH, O- acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
  • R5 H, Aryl, heteroaryl or substituted alkyl
  • R6 H, Alkyl, or Aryl
  • Method 5 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula III
  • Rl alkyl or H
  • R2 alkyl or H
  • R3 Acetyl
  • R4 H or Alkyl
  • Method 5 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula IV
  • Rl H or F
  • R2 H or nitro
  • R5 alkyl, substituted alkyl or aryl
  • any of methods 5, 5.1, or 5.24-5.26 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
  • Method 5 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is selected from AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC- 0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU-0063794, and Tori 1.
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • an aging-related disorder e.g., alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, e.g., osteoporosis.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • any of methods 5 or 5.1-5.31 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) one, two, three, or four times daily or in sustained release form.
  • 0.01 to 500 mg/kg e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 5.33 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
  • rapamycin analog e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus.
  • mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) for decreasing cellular progerin levels, e.g., for use in any of methods 5 or 5.1-5.38.
  • mTORC-1 mammalian target of rapamycin complex 2
  • mTORC-2 mammalian target of rapamycin complex 2
  • a pharmaceutical composition comprising an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), in combination with a pharmaceutically acceptable diluent or carrier, for use in decreasing cellular progerin levels, e.g., for use in any of methods 5 or 5.1-5.38.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 6 of decreasing cellular progerin levels comprising administering to a patient in need thereof an effective amount of a benzo [c] -chromen-6-one derivative.
  • Rl H or alkyl
  • R2 H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
  • R5 Oxo, aryl, hydroxyl, alkyl, or O-alkyl
  • R7 H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • an aging-related disorder e.g., alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, e.g., osteoporosis.
  • any of methods 6 or 6.1-6.27 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the benzo[c]-chromen-6-one derivative one, two, three, or four times daily or in sustained release form.
  • Method 6.29 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
  • rapalog a rapamycin analog
  • temsirolimus e.g., everolimus, ridaforolimus, or deforolimus.
  • benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
  • Method 6.31 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
  • a benzo[c]-chromen-6-one derivative in the manufacture of a medicament for decreasing cellular progerin levels, e.g., for use in any of methods 6 or 6.1- 6.34.
  • composition comprising a benzo[c]-chromen-
  • 6-one derivative in combination with a pharmaceutically acceptable diluent or carrier, for use in decreasing cellular progerin levels, e.g., for use in any of methods 6 or 6.1-6.34.
  • Method 7 of treatment or prophylaxis of an aging-related disorder comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Rl H or alkyl
  • R2 H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
  • R5 H, Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
  • R7 H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is in free or pharmaceutically acceptable salt form.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 or 7.1 the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is in free or pharmaceutically acceptable salt form, e.g., in free form.
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 7 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula II
  • Rl H or alkyl
  • R2 H, O-alkyl, OH, amino, O-heterocyc, O-aryl, O-substituted alkyl where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, O-alkyl, O-substituted alkyl where substitution is aryl or heteroaryl, OH, O- acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
  • R5 H, Aryl, heteroaryl or substituted alkyl
  • R6 H, Alkyl, or Aryl
  • Method 7 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula III
  • Rl alkyl or H
  • R2 alkyl or H
  • R3 Acetyl
  • R4 H or Alkyl
  • Method 7 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula IV
  • Rl H or F
  • R2 H or nitro
  • R5 alkyl, substituted alkyl or aryl
  • any of methods 7, 7.1, or 7.24-7.26 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
  • Method 7 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is selected from AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC- 0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU-0063794, and Tori 1.
  • any of methods 7 or 7.1-7.28 wherein the aging-related disorder is one or more of alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and osteoporosis, e.g., atherosclerosis, e.g., lipofuscin deposition, e.g., nail dystrophy, e.g., hypermelanosis, e.g., decreased adipose tissue, e.g., osteoporosis.
  • atherosclerosis e.g., lipofuscin deposition
  • nail dystrophy e.g., hypermelanosis
  • adipose tissue e.g., osteoporosis.
  • any of methods 7 or 7.1-7.29 wherein the aging-related disorder is one or more of alopecia, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and osteoporosis.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • any of methods 7 or 7.1-7.32 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) one, two, three, or four times daily or in sustained release form.
  • 0.01 to 500 mg/kg e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Any of methods 7 or 7.1-7.33 comprising administering the mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) in an amount effective to increase autophagy, decrease mRNA translation, and/or decrease cellular progerin levels, e.g., in an amount effective to increase autophagy, e.g., in an amount effective to decrease mRNA translation, e.g., in an amount effective to decrease cellular progerin levels.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 7.35 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
  • rapamycin analog e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus.
  • the second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
  • mTORC-1 mammalian target of rapamycin complex 2
  • mTORC-2 mammalian target of rapamycin complex 2
  • mTORC-1 mammalian target of rapamycin complex 2
  • mTORC-2 mammalian target of rapamycin complex 2
  • a pharmaceutical composition comprising an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), in combination with a pharmaceutically acceptable diluent or carrier, for treatment or prophylaxis of an aging-related disorder, e.g., for use in any of methods 7 or 7.1- 7.40.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 8 of treatment or prophylaxis an aging-related disorder comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6-one derivative.
  • Rl H or alkyl
  • R2 H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
  • R5 Oxo, aryl, hydroxyl, alkyl, or O-alkyl
  • R7 H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
  • Method 8 or 8.1 wherein the benzo[c]-chromen-6-one derivative is a benzo[c]-chromen- 6-one selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
  • any of methods 8 or 8.1-8.24 wherein the aging-related disorder is one or more of alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and osteoporosis, e.g, alopecia, e.g., atherosclerosis, e.g., lipofuscin deposition, e.g., nail dystrophy, e.g., hypermelanosis, e.g., decreased adipose tissue, e.g., osteoporosis.
  • alopecia e.g., atherosclerosis, e.g., lipofuscin deposition
  • nail dystrophy e.g., hypermelanosis
  • adipose tissue e.g., osteoporosis.
  • any of methods 8 or 8.1-8.25 wherein the aging-related disorder is one or more of alopecia, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and osteoporosis.
  • Any of methods 8 or 8.1-8.28 comprising administering 0.01 to 500 mg/kg, e.g., 25 to 500 mg/kg, of the benzo[c]-chromen-6-one derivative one, two, three, or four times daily or in sustained release form.
  • Any of methods 8 or 8.1-8.29 comprising administering the benzo[c]-chromen-6-one derivative in an amount effective to increase autophagy, decrease mRNA translation, and/or decrease cellular progerin levels, e.g., in an amount effective to increase autophagy, e.g., in an amount effective to decrease mRNA translation, e.g., in an amount effective to decrease cellular progerin levels.
  • Method 8.30 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
  • rapamycin analog e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 8.33 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
  • Any of methods 8 or 8.1-8.34 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of a stimulator of autophagy.
  • Method 8.35 wherein the stimulator of autophagy is trehalose, lithium, epigallocatechin- 3-gallate, or stromal cell-derived factor 1.
  • a benzo[c]-chromen-6-one derivative for treatment or prophylaxis of an aging-related disorder, e.g., for use in any of methods 8 or 8.1-8.36.
  • a benzo[c]-chromen-6-one derivative in the manufacture of a medicament for treatment or prophylaxis of an aging-related disorder, e.g., for use in any of methods 8 or 8.1-8.36.
  • a pharmaceutical composition comprising a benzo[c]- chromen-6-one derivative, in combination with a pharmaceutically acceptable diluent or carrier, for treatment or prophylaxis of an aging-related disorder, e.g., for use in any of methods 8 or 8.1- 8.36.
  • a method of treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, Huntington's disease, or alopecia comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC -2).
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • Parkinson's disease Huntington's disease
  • alopecia comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC -2).
  • Method 9 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula I
  • Rl H or alkyl
  • R2 H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
  • R5 Oxo, aryl, hydroxyl, alkyl, or O-alkyl
  • R7 H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
  • Method 9, 9.1, or 9.6 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is in free form.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 9 or 9.1 the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 9 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula II
  • Rl H or alkyl
  • R2 H, O-alkyl, OH, amino, O-heterocyc, O-aryl, O-substituted alkyl where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, O-alkyl, O-substituted alkyl where substitution is aryl or heteroaryl, OH, O- acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
  • R5 H, Aryl, heteroaryl or substituted alkyl
  • R6 H, Alkyl, or Aryl
  • Method 9 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula III
  • Rl alkyl or H
  • R2 alkyl or H
  • R3 Acetyl
  • R4 H or Alkyl
  • Method 9 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula IV
  • Rl H or F
  • R2 H or nitro
  • R5 alkyl, substituted alkyl or aryl
  • any of methods 9, 9.1, or 9.24-9.26 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
  • Method 9 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is selected from AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC- 0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU-0063794, and Tori 1.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • any of methods 9 or 9.1-9.29 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the inhibitor of mammalian target of rapamycin complex
  • mTORC-1 mammalian target of rapamycin complex 2
  • mTORC-2 mammalian target of rapamycin complex 2
  • Any of methods 9 or 9.1 -9.30 comprising treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS).
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • Any of methods 9 or 9.1-9.30 comprising treatment or prophylaxis of Parkinson's disease.
  • Any of methods 9 or 9.1-9.30 comprising treatment or prophylaxis of alopecia.
  • Any of methods 9 or 9.1-9.34 comprising administering the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex
  • mTORC-2 in an amount effective to increase autophagy, decrease mRNA translation, and/or decrease cellular progerin levels, e.g., in an amount effective to increase autophagy, e.g., in an amount effective to decrease mRNA translation, e.g., in an amount effective to decrease cellular progerin levels.
  • Method 9.36 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
  • rapamycin analog e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus.
  • Method 9.38 wherein the second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
  • mTORC-1 mammalian target of rapamycin complex 1
  • mTORC-2 mammalian target of rapamycin complex 2
  • Method 9.40 wherein the stimulator of autophagy is trehalose, lithium, epigallocatechin- 3-gallate, or stromal cell-derived factor 1.
  • a farnesyl transferase inhibitor HMG-CoA reductase inhibitor
  • farnesyl pyrophosphate synthetase inhibitor farnesyl pyrophosphate synthetase inhibitor
  • progerin expression inhibitor an antisense oligonucleotide that targets mutated LMNA mRNA or pre-mRNA transcript
  • mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) for treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease,
  • Huntington's disease or alopecia, e.g., for use in any of methods 9 or 9.1-9.45.
  • mTORC-1 mammalian target of rapamycin complex 2
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • Parkinson's disease Huntington's disease, or alopecia, e.g., for use in any of methods 9 or 9.1-
  • a pharmaceutical composition comprising an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), in combination with a pharmaceutically acceptable diluent or carrier, for treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, Huntington's disease, or alopecia, e.g., for use in any of methods 9 or 9.1-9.45.
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • Parkinson's disease Huntington's disease
  • alopecia e.g., for use in any of methods 9 or 9.1-9.45.
  • a method of treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, Huntington's disease, or alopecia comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6-one derivative.
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • Parkinson's disease Huntington's disease
  • alopecia comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6-one derivative.
  • Rl H or alkyl
  • R2 H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
  • R3 H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
  • R4 H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
  • R5 Oxo, aryl, hydroxyl, alkyl, or O-alkyl
  • R7 H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
  • Method 10 or 10.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 10 or 10.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
  • Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is a benzo[c]- chromen-6-one selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
  • Any of methods 10 or 10.1-10.25 comprising administering 0.01 to 500 mg/kg, e.g., 25 to 500 mg/kg, of the benzo[c]-chromen-6-one derivative one, two, three, or four times daily or in sustained release form.
  • Any of methods 10 or 10.1-10.26 comprising treatment or prophylaxis of Hutchinson- Gilford Progeria Syndrome (HGPS).
  • HGPS Hutchinson- Gilford Progeria Syndrome
  • Any of methods 10 or 10.1-10.26 comprising treatment or prophylaxis Parkinson's disease.
  • Any of methods 10 or 10.1-10.26 comprising treatment or prophylaxis Huntington's disease.
  • Any of methods 10 or 10.1-10.26 comprising treatment or prophylaxis alopecia.
  • any of methods 10 or 10.1-10.30 comprising administering the benzo[c]-chromen-6-one derivative in an amount effective to increase autophagy, decrease mRNA translation, and/or decrease cellular progerin levels, e.g., in an amount effective to increase autophagy, e.g., in an amount effective to decrease mRNA translation, e.g., in an amount effective to decrease cellular progerin levels.
  • mTORC-1 an inhibitor of mammalian target of rapamycin complex 1
  • Method 10.32 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
  • Method 10.34 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
  • a benzo[c]-chromen-6-one derivative for treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, Huntington's disease, or alopecia, e.g., for use in any of methods 10 or 10.1-10.41.
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • Parkinson's disease Huntington's disease
  • alopecia e.g., for use in any of methods 10 or 10.1-10.41.
  • a benzo[c]-chromen-6-one derivative in the manufacture of a medicament for treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, Huntington's disease, or alopecia, e.g., for use in any of methods 10 or 10.1-10.41.
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • Parkinson's disease Huntington's disease
  • alopecia e.g., for use in any of methods 10 or 10.1-10.41.
  • a pharmaceutical composition comprising a benzo[c]- chromen-6-one derivative, in combination with a pharmaceutically acceptable diluent or carrier, for treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, Huntington's disease, or alopecia, e.g., for use in any of methods 10 or 10.1-10.41.
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • Parkinson's disease Huntington's disease
  • alopecia e.g., for use in any of methods 10 or 10.1-10.41.
  • Dosages employed in practicing the present invention will of course vary depending, e.g., on the particular disease or condition to be treated, the particular compound used, the mode of administration, and the therapy desired.
  • the compounds disclosed herein e.g., the inhibitors of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), the benzo[c]-chromen-6-one derivatives, and the compounds of Formula I, Formula II, Formula III, and Formula IV, may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, but are preferably administered orally. In general, satisfactory results, e.g.
  • an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 to 150 mg, conveniently administered once, or in divided doses 2, 3, or 4 times daily or in sustained release form.
  • Unit dosage forms for oral administration thus, for example, may comprise from about 0.2 to 75 or 150 mg, e.g.
  • a compound disclosed herein e.g., an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), a benzo[c]- chromen-6-one derivative, or a compound of Formula I, Formula II, Formula III, or Formula IV, together with a pharmaceutically acceptable diluent or carrier therefor.
  • a compound disclosed herein e.g., an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), a benzo[c]- chromen-6-one derivative, or a compound of Formula I, Formula II, Formula III, or Formula IV, together with a pharmaceutically acceptable diluent or carrier therefor.
  • compositions comprising a compound disclosed herein, e.g., an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), a benzo[c]-chromen-6-one derivative, or a compound of Formula I, Formula II, Formula III, or Formula IV, may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus oral dosage forms may include tablets, capsules, solutions, suspensions and the like. [0095] Compounds of Formula I, Formula II, Formula III, and Formula IV may be synthesized as described in U.S. Patent No. 8,475,776 and U.S. Patent Application Publication No. 2006/0257337, the contents of which are hereby incorporated by reference.
  • Example 1 Anti-angiogenic activity (antiproliferative for endothelial cells) measured in vitro
  • HUVECs is shown as one measure of anti-angiogenic activity.
  • HUVECS and the required media complements are purchased from Cascade Biologies (Portland, OR) and the growth and maintenance of the cultures is as described by the manufacturer.
  • the proliferation assay is carried out by seeding the HUVECs in 96-well plates at a density of 1 ,000 cells/well in complete medium. Following a 24 h plating period, the cells are starved for 24 h in 0.5% serum before being treated with SG ("Signal Gene" now "Palomid”) angiogenic inhibitors in the presence of 10 ng/ml b-FGF or dosing ranging presence of either b-FGF or VEGF in complete medium.
  • Non-proliferating endothelial cells are assayed by growing HUVECs to quiescence in 96-well plates and treating with angiogenic inhibitors for 48 h. Initially, 5,000 cells/well are seeded and confluence is achieved the next day. The plates are incubated another 24 h to ensure growth arrest before treatment with angiogenic inhibitors. Cell number is determined as outlined above. The results are shown in Table II. The compounds show anti-angiogenic activity through inhibition of the proliferation of angiogenic cytokine stimulated endothelial cells.
  • na no activity; HUVECp, HUVEC proliferating; HUVECq, HUVEC quiescent; nd, not determined
  • Reagent Buffer containing 1 mmol/L phenylmethylsulfonyl fluoride, 1 mmol/L Na 3 V0 4 , 1 mmol/L EGTA, 1 g/mL leupeptin, 0.5% aprotinin, and 2 ⁇ g/mL pepstatin A and from cultured cells using cell lysis buffer [20 mmol/L Tris-HCl (pH 7.5), 0.15 mol/L NaCl, 1% Triton X-100, 1 mmol/L phenylmethylsulfonyl fluoride, 1 mmol/L Na 3 V0 4 , 1 mmol/L EGTA, 1 ⁇ g/mL leupeptin, 0.5%> aprotinin, and 2 ⁇ g/mL pepstatin A].
  • Equal amounts of protein are separated by NuPAGE No vex Bis-Tris Gels (Invitrogen Corp.) and transferred into nitrocellulose membranes (Invitrogen). Membranes are incubated with primary antibodies overnight at 4°C after blocking with 5% milk in TBS-Tween 20 and then detected using horseradish peroxidase-conjugated anti- rabbit or anti-mouse secondary antibodies (Amersham Biosciences UK), respectively, and SuperSignal West Pico Chemiluminescent Substrate system (Pierce). All experiments are carried out independently at least thrice. For immunoprecipitations, C6 glioma cells are serum starved for 24 h.
  • IGF-I stimulation Before insulin-like growth factor (IGF)-I stimulation, cells are pretreated with P529 (also known as SG00529) (20 ⁇ /L) for 2 or 24 h.
  • Cell lysis buffer consisted of 20 mmol/L Tris (pH 7.5), 150 mmol/L NaCl, 1 mmol/L EDTA, 0.3% CHAPS, 25 mmol/L sodium pyrophosphate, 1 mmol/L ⁇ -glycerophosphate, 1 mmol/L Na 3 V0 4 , and 1 g/mL leupeptin. Protein (1.5 mg) diluted to 1 mL with cell lysis buffer is centrifuged at 10,000 x g for 10 min at 4°C to remove cellular debris.
  • mTOR (1 : 100) antibody is added and immune complexes are allowed to form by incubating with rotation overnight at 4°C.
  • a 50% slurry (25 mL) of protein G-Sepharose is then added and the incubation is continued for 3 h.
  • Immunoprecipitates are captured with protein G-Sepharose, washed four times with cell lysis buffer, and analyzed by immunoblotting. Results are shown in Figure 1 indicating that P529 (SG00529) inhibits both mTORCl and mTORC2 complexes.
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • P529 also known as SG00529) for 1 week.
  • Detection of progerin and lamin AJC is shown in the top graph in Figure 2.
  • the bottom graph in Figure 2 represents quantification analysis of Western Blot band intensities for progerin by image analysis.
  • the y-axis is labeled "Relative band intensity” and the left band on the x-axis is labeled "HGPS control” and the right band on the x-axis is "HGPS+P529.”
  • HGPS+P529 Decrease in levels of progerin protein shown in P529 (SG00529) treated HGPS cells.
  • HGPS Hutchinson-Gilford Progeria Syndrome
  • FIG. 3 a represents quantification analysis of Western Blot band intensities for progerin by image analysis.
  • the y-axis is labeled "Relative progerin band intensity” and the left bar on the x-axis is labeled "HGPS control" and the right bar on the x-axis is "HGPS+P529.”
  • HGPS control the left bar on the x-axis
  • HGPS+P529 the right bar on the x-axis
  • the intensity values are quantified and normalized by the band intensities of ⁇ -actin loading control.

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Abstract

Provided are novel methods comprising administering an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).

Description

NOVEL METHODS
[0001] This application claims priority to U.S. Provisional Application No. 61/974,938, filed April 3, 2014, the contents of which are hereby incorporated by reference.
BACKGROUND
[0002] Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal genetic disease characterized by premature aging. HGPS patients most often die of myocardial infarction or stroke in their early teens.
[0003] HGPS may be caused by a mutation in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11 producing a lamin A variant with an internal deletion of 50 amino acids termed progerin. Progerin is defective in a post-translational processing step. The normal processing of lamin A involves famesylation of the C terminus by farnesyltransferase which targets the protein to the inner nuclear membrane surface where it is cleaved to yield mature lamin A. Progerin does not have the cleavage site resulting in permanent famesylation which is believed to cause progerin to remain anchored in the nuclear membrane with other proteins of the nuclear scaffold attached to it. Progerin accumulation in dividing cells disrupts the nuclear scaffold leading to nuclear blebbing in cultured cells.
[0004] Progerin may also be produced in non-HGPS individuals. Progerin appears to accumulate with increasing age; a statistically significant increase in the amount of progerin- positive cells has been seen with age. HGPS shares many of the hallmarks of the normal aging process. Features common to HGPS and normal aging include alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and osteoporosis.
[0005] Accumulation of mutated or improperly processed protein may also play a role in other diseases such as Parkinson's and Huntington's diseases.
[0006] There is an ongoing need for treatments for HGPS, as well as Parkinson's and
Huntington's diseases. BRIEF SUMMARY
[0007] The problems set forth above as well as further and other problems are solved by the present teachings. These solutions and other advantages are achieved by the various embodiments of the teachings described herein below.
[0008] Provided is a method of increasing autophagy comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
[0009] Further provided is a method of increasing autophagy comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6-one derivative.
[0010] Further provided is a method of decreasing mRNA translation comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2
(mTORC-2).
[0011] Further provided is a method of decreasing mRNA translation comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6-one derivative.
[0012] Further provided is a method of decreasing cellular progerin levels comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
[0013] Further provided is a method of decreasing cellular progerin levels comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6-one derivative.
[0014] Further provided is a method of treatment or prophylaxis of an aging-related disorder comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
[0015] Further provided is a method of treatment or prophylaxis of an aging-related disorder comprising administering to a patient in need thereof an effective amount of a benzo[c]- chromen-6-one derivative. [0016] Further provided is a method of treatment or prophylaxis of Hutchinson-Gilford
Progeria Syndrome (HGPS) comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
[0017] Further provided is a method of treatment or prophylaxis of Hutchinson-Gilford
Progeria Syndrome (HGPS) comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6-one derivative.
[0018] Further provided is a method of treatment or prophylaxis of Parkinson's disease comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
[0019] Further provided is a method of treatment or prophylaxis of Parkinson's disease comprising administering to a patient in need thereof an effective amount of a benzo[c]- chromen-6-one derivative.
[0020] Further provided is a method of treatment or prophylaxis of Huntington's disease comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
[0021] Further provided is a method of treatment or prophylaxis of Huntington's disease comprising administering to a patient in need thereof an effective amount of a benzo[c]- chromen-6-one derivative.
[0022] Further provided is a method of treatment or prophylaxis of alopecia comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
[0023] Further provided is a method of treatment or prophylaxis of alopecia comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6-one derivative.
[0024] Further provided is use of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) in diseases or disorders that may be ameliorated through enhancement of autophagy and/or decreasing mRNA translation.
[0025] Further provided is use of a benzo[c]-chromen-6-one derivative in diseases or disorders that may be ameliorated through enhancement of autophagy and/or decreasing mRNA translation.
[0026] Further provided is use of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) for treatment or prophylaxis of diseases or disorders related to autophagy and/or mRNA translation.
[0027] Further provided is use of a benzo[c]-chromen-6-one derivative for treatment or prophylaxis of diseases or disorders related to autophagy and/or mRNA translation.
[0028] Further areas of applicability of the present disclosure will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of this disclosure, are intended for purposes of illustration only and are not intended to limit the scope of this disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The present disclosure will become more fully understood from the detailed description and the accompanying drawings, wherein:
[0030] Figure 1 shows coimmunoprecipitation for mTOR with raptor and rictor to assess
TORC1 and TORC2 complex inhibition.
[0031] Figure 2 shows detection of progerin and lamin A/C in normal and Hutchinson-
Gilford Progeria Syndrome (HGPS) cells treated with 5 μιη P529 (also known as SG00529) (top graph) and quantification analysis of Western Blot band intensities for progerin by image analysis (bottom graph).
[0032] Figure 3 shows detection of progerin and lamin A/C at passage 16 in normal and
Hutchinson-Gilford Progeria Syndrome (HGPS) cells treated with 5 μιη P529 (also known as SG00529) (Figure 3a) and quantification analysis of Western Blot band intensities for progerin by image analysis (Figure 3b). DETAILED DESCRIPTION
[0033] The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit this disclosure, its application, or uses.
[0034] As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are hereby incorporated by reference in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.
[0035] Without being bound by theory, it is believed that compounds disclosed herein, e.g., compounds of Formula I, e.g., 8-(l-hydroxyethyl)-2-methoxy-3-((4-methoxybenzyl)oxy)- 6H-benzo[c]chromen-6-one, are allosteric, dissociative inhibitors of both mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2). In addition, without being bound by theory, it is believed that an inhibitor of both mTORC-1 and mTORC-2 will activate autophagy, thereby reducing the accumulation of mutated or improperly processed protein such as progerin. Further, without being bound by theory, it is believed that a compound which is an inhibitor of mTORC-1 and mTORC-2, e.g., an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2, has a different activity and/or improved safety profile compared to an mTORC-1 inhibitor, e.g., rapamycin, or a compound that inhibits mTORC-1 and mTORC-2 by inhibiting mTOR kinase.
[0036] As used herein, "patient" encompasses human and non-human (i.e., animal) patients. In some embodiments, the patient is human or non-human. In other embodiments, the patient is non-human. In other embodiments, the patient is human.
[0037] As used herein, "treatment" and "treating" encompass treatment and amelioration of symptoms of a disease or disorder, e.g., Hutchinson-Gilford Progeria Syndrome, as well as treatment of the cause of the disease or disorder. As used herein, "treatment" and "treating" also encompass preventing or retarding progression of a disease or disorder, e.g., Hutchinson-Gilford Progeria Syndrome.
[0038] As used herein, "effective amount" encompasses a therapeutically effective amount to treat a specific disease or disorder.
[0039] As used herein, "concurrently" means the compounds are administered simultaneously or within the same composition. In some embodiments, the compounds are administered simultaneously. In some embodiments, the compounds are administered within the same composition.
[0040] "Alkyl" as used herein may include a saturated or unsaturated hydrocarbon moiety, preferably saturated, e.g., one to eight, e.g., one to six, e.g., one to four carbon atoms in length, which may be linear or branched (e.g., n-butyl or tert-butyl) unless otherwise specified, and may be optionally substituted, e.g., mono-, di-, or tri-substituted on any one of the carbon atoms, e.g., with Ci_4 alkyl (e.g., methyl), Ci_4 alkoxy, halogen (e.g., chloro or fluoro), haloCi_4 alkyl (e.g., trifluoromethyl), hydroxy, and carboxy. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, 3-methylpentyl, 4-methylpentyl, n-pentyl, n-hexyl and n-heptyl.
[0041] "Aryl" as used herein may include a monocyclic or polycyclic aromatic hydrocarbon, preferably phenyl, optionally substituted, e.g., with Ci_4 alkyl (e.g., methyl), Ci_4 alkoxy, halogen (e.g., chloro or fluoro), haloCi_4 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, or an additional aryl or heteroaryl.
[0042] Unless otherwise indicated, language such as "an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC- 2)," "a benzo[c]-chromen-6-one derivative," or "a compound of Formula I, Formula II, Formula III, or Formula IV," is to be understood as embracing the compounds in any form, for example free or pharmaceutically acceptable form.
[0043] In one embodiment, provided is a method (Method 1) of increasing autophagy comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
[0044] Further provided is Method 1 as follows:
1.1 Method 1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula I
Figure imgf000008_0001
R4
Formula I
wherein,
Rl = H or alkyl;
R2 = H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6 = H;
R7 = H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
R8 = H; and
X = O, N, or S,
in free or pharmaceutically acceptable salt form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000008_0002
in free or pharmaceutically acceptable salt form.
Method 1, 1.1, or 1.2 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000009_0001
in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000009_0002
in free or pharmaceutically acceptable salt form.
Method 1, 1.1, or 1.4 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000009_0003
in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000010_0001
in free or pharmaceutically acceptable salt form.
Method 1, 1.1, or 1.6 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000010_0002
in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000010_0003
in free or pharmaceutically acceptable salt form.
Method 1, 1.1, or 1.8 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000010_0004
in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000011_0001
in free or pharmaceutically acceptable salt form.
Method 1, 1.1, or 1.10 wherein the inhibitor of mammalian target of rapamycin complex 1 mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000011_0002
in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000011_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000012_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000012_0002
in free or pharmaceutically acceptable salt form.
Method 1, 1.1, or 1.14 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000012_0003
in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000012_0004
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000013_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000013_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000013_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000014_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000014_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 1 or 1.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000014_0003
SG00292 in free or pharmaceutically acceptable salt form.
Method 1 , 1.1 , or 1.22 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000015_0001
SG00292 in free form.
Method 1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula II
Figure imgf000015_0002
R4
Formula II
wherein,
Rl = H or alkyl;
R2 = H, O-alkyl, OH, amino, O-heterocyc, O-aryl, O-substituted alkyl where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, O-alkyl, O-substituted alkyl where substitution is aryl or heteroaryl, OH, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = H, Aryl, heteroaryl or substituted alkyl; and
R6 = H, Alkyl, or Aryl,
in free or pharmaceutically acceptable salt form. Method 1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula III
Figure imgf000016_0001
Formula III
wherein,
Rl = alkyl or H;
R2 = alkyl or H;
R3 = Acetyl; and
R4 = H or Alkyl,
in free or pharmaceutically acceptable salt form.
Method 1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula IV
Figure imgf000016_0002
wherein,
Rl = H or F;
R2 = H or nitro;
R3 = H;
R4 = H; and
R5 = alkyl, substituted alkyl or aryl,
in free or pharmaceutically acceptable salt form. Any of methods 1, 1.1, or 1.24-1.26 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
Method 1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is selected from AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC- 0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU-0063794, and Tori 1.
Any of methods 1 or 1.1-1.28 wherein the patient has Hutchinson-Gilford Progeria Syndrome (HGPS).
Any of methods 1 or 1.1-1.28 wherein the patient has Parkinson's disease.
Any of methods 1 or 1.1-1.28 wherein the patient has Huntington's disease.
Any of methods 1 or 1.1-1.28 wherein the patient has an aging-related disorder, e.g., alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and/or osteoporosis, e.g., alopecia, e.g., atherosclerosis, e.g., lipofuscin deposition, e.g., nail dystrophy, e.g., hypermelanosis, e.g., decreased adipose tissue, e.g., osteoporosis.
Any of methods 1 or 1.1-1.32 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2.
Any of methods 1 or 1.1-1.33 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) one, two, three, or four times daily or in sustained release form.
Any of methods 1 or 1.1-1.34 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one of more of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1). 1.36 Method 1.35 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
1.37 Any of methods 1, 1.1-1.27, or 1.29-1.36 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of a second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
1.38 Method 1.37 wherein the second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
1.39 Any of methods 1 or 1.1-1.38 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of a stimulator of autophagy.
1.40 Method 1.39 wherein the stimulator of autophagy is trehalose, lithium, epigallocatechin- 3-gallate, or stromal cell-derived factor 1.
[0045] Also provided is use of an inhibitor of mammalian target of rapamycin complex 1
(mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) for increasing autophagy, e.g., for use in any of methods 1 or 1.1-1.40.
[0046] Also provided is use of an inhibitor of mammalian target of rapamycin complex 1
(mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) in the manufacture of a medicament for increasing autophagy, e.g., for use in any of methods 1 or 1.1-1.40.
[0047] Also provided is a pharmaceutical composition comprising an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), in combination with a pharmaceutically acceptable diluent or carrier, for use in increasing autophagy, e.g., for use in any of methods 1 or 1.1-1.40. [0048] In another embodiment, provided is a method (Method 2) of increasing autophagy comprising administering to a patient in need thereof an effective amount of a benzo[c]- chromen-6-one derivative.
[0049] Further provided is Method 2 as follows:
2.1 Method 2 wherein the benzo[c]-chromen-6-one derivative is a compound of Formula I
Figure imgf000019_0001
Formula I
wherein,
Rl = H or alkyl;
R2 = H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6 = H;
R7 = H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
R8 = H; and
X = O, N, or S,
in free or pharmaceutically acceptable salt form.
Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000020_0001
in free or pharmaceutically acceptable salt form.
Method 2, 2.1, or 2.2 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000020_0002
in free form.
Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000020_0003
in free or pharmaceutically acceptable salt form.
Method 2 2.1, or 2.4 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000020_0004
in free form.
Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000021_0001
in free or pharmaceutically acceptable salt form.
Method 2 2.1 , or 2.6 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000021_0002
in free form.
Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative
Figure imgf000021_0003
in free or pharmaceutically acceptable salt form.
Method 2, 2.1 , or 2.8 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000021_0004
in free form.
Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative
Figure imgf000022_0001
in free or pharmaceutically acceptable salt form.
Method 2, 2.1 , or 2.10 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000022_0002
in free form.
Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative
Figure imgf000022_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000022_0004
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000023_0001
in free or pharmaceutically acceptable salt form.
Method 2, 2.1, or 2.14 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000023_0002
in free form.
Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative
Figure imgf000023_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000023_0004
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000024_0001
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000024_0002
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000024_0003
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000024_0004
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000025_0001
SG00292 in free or pharmaceutically acceptable salt form.
Method 2, 2.1 , or 2.22 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000025_0002
SG00292 in free form.
Method 2 or 2.1 wherein the benzo[c]-chromen-6-one derivative is a benzo[c]-chromen- 6-one selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
Any of methods 2 or 2.1-2.24 wherein the patient has Hutchinson-Gilford Progeria Syndrome (HGPS).
Any of methods 2 or 2.1-2.24 wherein the patient has Parkinson's disease.
Any of methods 2 or 2.1-2.24 wherein the patient has Huntington's disease.
Any of methods 2 or 2.1-2.24 wherein the patient has an aging-related disorder, e.g., alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and/or osteoporosis, e.g., alopecia, e.g., atherosclerosis, e.g., lipofuscin deposition, e.g., nail dystrophy, e.g., hypermelanosis, e.g., decreased adipose tissue, e.g., osteoporosis. 2.29 Any of methods 2 or 2.1-2.28 wherein the benzo[c]-chromen-6-one derivative is an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2.
2.30 Any of methods 2 or 2.1-2.29 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the benzo[c]-chromen-6-one derivative one, two, three, or four times daily or in sustained release form.
2.31 Any of methods 2 or 2.1-2.30 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1).
2.32 Method 2.31 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
2.33 Any of methods 2 or 2.1-2.32 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
2.34 Method 2.33 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
2.35 Any of methods 2 or 2.1-2.34 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of a stimulator of autophagy.
2.36 Method 2.35 wherein the stimulator of autophagy is trehalose, lithium, epigallocatechin- 3-gallate, or stromal cell-derived factor 1.
[0050] Also provided is use of a benzo[c]-chromen-6-one derivative for increasing autophagy, e.g., for use in any of methods 2 or 2.1-2.36.
[0051] Also provided is use of a benzo[c]-chromen-6-one derivative in the manufacture of a medicament for increasing autophagy, e.g., for use in any of methods 2 or 2.1-2.36. [0052] Also provided is a pharmaceutical composition comprising a benzo[c]-chromen-
6-one derivative, in combination with a pharmaceutically acceptable diluent or carrier, for use in increasing autophagy, e.g., for use in any of methods 2 or 2.1-2.36.
[0053] In another embodiment, provided is a method (Method 3) of decreasing mRNA translation comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC -2).
[0054] Further provided is Method 3 as follows:
3.1 Method 3 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula I
Figure imgf000027_0001
Formula I
wherein,
Rl = H or alkyl;
R2 = H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6 = H;
R7 = H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
R8 = H; and
X = O, N, or S, in free or pharmaceutically acceptable salt form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000028_0001
in free or pharmaceutically acceptable salt form.
Method 3, 3.1, or 3.2 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000028_0002
in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000028_0003
in free or pharmaceutically acceptable salt form.
Method 3, 3.1, or 3.4 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000029_0001
in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000029_0002
in free or pharmaceutically acceptable salt form.
Method 3, 3.1, or 3.6 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000029_0003
in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000030_0001
in free or pharmaceutically acceptable salt form.
Method 3, 3.1, or 3.8 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000030_0002
in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000030_0003
in free or pharmaceutically acceptable salt form.
Method 3, 3.1, or 3.10 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is SG00528
,0 in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000031_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000031_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000031_0003
in free or pharmaceutically acceptable salt form. Method 3, 3.1, or 3.14 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000032_0001
in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000032_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000032_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000033_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000033_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000033_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000034_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 3 or 3.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000034_0002
SG00292 in free or pharmaceutically acceptable salt form.
Method 3, 3.1, or 3.22 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000034_0003
SG00292 in free form.
Method 3 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula II
Figure imgf000035_0001
R4
Formula II
wherein,
Rl = H or alkyl;
R2 = H, O-alkyl, OH, amino, O-heterocyc, O-aryl, O-substituted alkyl where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, O-alkyl, O-substituted alkyl where substitution is aryl or heteroaryl, OH, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = H, Aryl, heteroaryl or substituted alkyl; and
R6 = H, Alkyl, or Aryl,
in free or pharmaceutically acceptable salt form.
Method 3 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula III
Figure imgf000035_0002
Formula III
wherein,
Rl = alkyl or H;
R2 = alkyl or H;
R3 = Acetyl; and R4 = H or Alkyl,
in free or pharmaceutically acceptable salt form.
Method 3 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula IV
Figure imgf000036_0001
Formula IV
wherein,
Rl = H or F;
R2 = H or nitro;
R3 = H;
R4 = H; and
R5 = alkyl, substituted alkyl or aryl,
in free or pharmaceutically acceptable salt form.
Any of methods 3, 3.1, or 3.24-3.26 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
Method 3 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is selected from AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC- 0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU-0063794, and Tori 1.
Any of methods 3 or 3.1-3.28 wherein the patient has Hutchinson-Gilford Progeria Syndrome (HGPS).
Any of methods 3 or 3.1-3.28 wherein the patient has Parkinson's disease. Any of methods 3 or 3.1 -3.28 wherein the patient has Huntington' s disease.
Any of methods 3 or 3.1-3.28 wherein the patient has an aging-related disorder, e.g., alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and/or osteoporosis, e.g., alopecia, e.g., atherosclerosis, e.g., lipofuscin deposition, e.g., nail dystrophy, e.g., hypermelanosis, e.g., decreased adipose tissue, e.g., osteoporosis.
Any of methods 3 or 3.1-3.32 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2.
Any of methods 3 or 3.1-3.33 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) one, two, three, or four times daily or in sustained release form.
Any of methods 3 or 3.1-3.34 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1).
Method 3.35 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
Any of methods 3, 3.1-3.27, or 3.29-3.36 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of a second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
Method 3.37 wherein the second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1. 3.39 Any of methods 3 or 3.1-3.38 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of a stimulator of autophagy.
3.40 Method 3.39 wherein the stimulator of autophagy is trehalose, lithium, epigallocatechin- 3-gallate, or stromal cell-derived factor 1.
[0055] Also provided is use of an inhibitor of mammalian target of rapamycin complex 1
(mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) for decreasing mRNA translation, e.g., for use in any of methods 3 or 3.1-3.40.
[0056] Also provided is use of an inhibitor of mammalian target of rapamycin complex 1
(mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) in the manufacture of a medicament for decreasing mRNA translation, e.g., for use in any of methods 3 or 3.1-3.40.
[0057] Also provided is a pharmaceutical composition comprising an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), in combination with a pharmaceutically acceptable diluent or carrier, for use in decreasing mRNA translation, e.g., for use in any of methods 3 or 3.1-3.40.
[0058] In another embodiment, provided is a method (Method 4) of decreasing mRNA translation comprising administering to a patient in need thereof an effective amount of a benzo [c] -chromen-6-one derivative.
[0059] Further provided is Method 4 as follows:
4.1 Method 4 wherein the benzo [c]-chromen-6-one derivative is a compound Formula I
Figure imgf000038_0001
Formula I
wherein,
Rl = H or alkyl; R2 = H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6 = H;
R7 = H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
R8 = H; and
X = O, N, or S,
in free or pharmaceutically acceptable salt form.
Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000039_0001
in free or pharmaceutically acceptable salt form.
Method 4 4.1, or 4.2 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000039_0002
in free form.
Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000040_0001
in free or pharmaceutically acceptable salt form.
Method 4, 4.1 , or 4.4 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000040_0002
in free form.
Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative
Figure imgf000040_0003
in free or pharmaceutically acceptable salt form.
Method 4 4.1 , or 4.6 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000040_0004
in free form.
Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative
Figure imgf000041_0001
in free or pharmaceutically acceptable salt form.
Method 4, 4.1 , or 4.8 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000041_0002
in free or pharmaceutically acceptable salt form.
Method 4 4.1 , or 4.10 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000041_0003
in free form.
Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative
Figure imgf000042_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000042_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000042_0003
in free or pharmaceutically acceptable salt form.
Method 4, 4.1, or 4.14 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000042_0004
in free form.
Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative
Figure imgf000043_0001
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000043_0002
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000043_0003
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000043_0004
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000044_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000044_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000044_0003
SG00292 in free or pharmaceutically acceptable salt form.
Method 4, 4.1 , or 4.22 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000045_0001
SG00292 in free form.
Method 4 or 4.1 wherein the benzo[c]-chromen-6-one derivative is a benzo[c]-chromen- 6-one selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
Any of methods 4 or 4.1-4.24 wherein the patient has Hutchinson-Gilford Progeria Syndrome (HGPS).
Any of methods 4 or 4.1-4.24 wherein the patient has Parkinson's disease.
Any of methods 4 or 4.1-4.24 wherein the patient has Huntington's disease.
Any of methods 4 or 4.1-4.24 wherein the patient has an aging-related disorder, e.g., alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and/or osteoporosis, e.g., alopecia, e.g., atherosclerosis, e.g., lipofuscin deposition, e.g., nail dystrophy, e.g., hypermelanosis, e.g., decreased adipose tissue, e.g., osteoporosis.
Any of methods 4 or 4.1-4.28 wherein the benzo[c]-chromen-6-one derivative is an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2.
Any of methods 4 or 4.1-4.29 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the benzo[c]-chromen-6-one derivative one, two, three, or four times daily or in sustained release form.
Any of methods 4 or 4.1-4.30 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1).
Method 4.31 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus). 4.33 Any of methods 4 or 4.1-4.32 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
4.34 Method 4.33 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
4.35 Any of methods 4 or 4.1-4.34 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of a stimulator of autophagy.
4.36 Method 4.35 wherein the stimulator of autophagy is trehalose, lithium, epigallocatechin- 3-gallate, or stromal cell-derived factor 1.
[0060] Also provided is use of a benzo[c]-chromen-6-one derivative for decreasing mRNA translation, e.g., for use in any of methods 4 or 4.1-4.36.
[0061] Also provided is use of a benzo[c]-chromen-6-one derivative in the manufacture of a medicament for decreasing mRNA translation, e.g., for use in any of methods 4 or 4.1-4.36.
[0062] Also provided is a pharmaceutical composition comprising a benzo[c]-chromen-
6-one derivative, in combination with a pharmaceutically acceptable diluent or carrier, for use in decreasing mRNA translation, e.g., for use in any of methods 4 or 4.1-4.36.
[0063] In another embodiment, provided is a method (Method 5) of decreasing cellular progerin levels comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
[0064] Further provided is Method 5 as follows:
5.1 Method 5 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula I
Figure imgf000047_0001
R4
Formula I
wherein,
Rl = H or alkyl;
R2 = H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6 = H;
R7 = H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
R8 = H; and
X = O, N, or S,
in free or pharmaceutically acceptable salt form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000047_0002
in free or pharmaceutically acceptable salt form.
Method 5, 5.1, or 5.2 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000048_0001
in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000048_0002
in free or pharmaceutically acceptable salt form.
Method 5, 5.1, or 5.4 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000048_0003
in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000049_0001
in free or pharmaceutically acceptable salt form.
Method 5, 5.1, or 5.6 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000049_0002
in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000049_0003
in free or pharmaceutically acceptable salt form.
Method 5, 5.1, or 5.8 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000049_0004
in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000050_0001
in free or pharmaceutically acceptable salt form.
Method 5, 5.1, or 5.10 wherein the inhibitor of mammalian target of rapamycin complex 1 mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000050_0002
in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000050_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000051_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000051_0002
in free or pharmaceutically acceptable salt form.
Method 5, 5.1, or 5.14 wherein the inhibitor of mammalian target of rapamycin compli 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000051_0003
in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000051_0004
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000052_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000052_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000052_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000053_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000053_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 5 or 5.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000053_0003
SG00292 in free or pharmaceutically acceptable salt form.
Method 5, 5.1, or 5.22 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000054_0001
SG00292 in free form.
Method 5 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula II
Figure imgf000054_0002
R4
Formula II
wherein,
Rl = H or alkyl;
R2 = H, O-alkyl, OH, amino, O-heterocyc, O-aryl, O-substituted alkyl where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, O-alkyl, O-substituted alkyl where substitution is aryl or heteroaryl, OH, O- acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = H, Aryl, heteroaryl or substituted alkyl; and
R6 = H, Alkyl, or Aryl,
in free or pharmaceutically acceptable salt form. Method 5 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula III
Figure imgf000055_0001
Formula III
wherein,
Rl = alkyl or H;
R2 = alkyl or H;
R3 = Acetyl; and
R4 = H or Alkyl,
in free or pharmaceutically acceptable salt form.
Method 5 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula IV
Figure imgf000055_0002
wherein,
Rl = H or F;
R2 = H or nitro;
R3 = H;
R4 = H; and
R5 = alkyl, substituted alkyl or aryl,
in free or pharmaceutically acceptable salt form. Any of methods 5, 5.1, or 5.24-5.26 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
Method 5 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is selected from AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC- 0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU-0063794, and Tori 1.
Any of methods 5 or 5.1-5.28 wherein the patient has Hutchinson-Gilford Progeria Syndrome (HGPS).
Any of methods 5 or 5.1-5.28 wherein the patient has an aging-related disorder, e.g., alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and/or osteoporosis, e.g., alopecia, e.g., atherosclerosis, e.g., lipofuscin deposition, e.g., nail dystrophy, e.g., hypermelanosis, e.g., decreased adipose tissue, e.g., osteoporosis.
Any of methods 5 or 5.1-5.30 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2.
Any of methods 5 or 5.1-5.31 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) one, two, three, or four times daily or in sustained release form.
Any of methods 5 or 5.1-5.32 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1).
Method 5.33 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus). 5.35 Any of methods 5, 5.1-5.27, or 5.29-5.34 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of a second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
5.36 Method 5.35 wherein the second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
5.37 Any of methods 5 or 5.1-5.36 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of a stimulator of autophagy.
5.38 Method 5.37 wherein the stimulator of autophagy is trehalose, lithium, epigallocatechin- 3-gallate, or stromal cell-derived factor 1.
[0065] Also provided is use of an inhibitor of mammalian target of rapamycin complex 1
(mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) for decreasing cellular progerin levels, e.g., for use in any of methods 5 or 5.1-5.38.
[0066] Also provided is use of an inhibitor of mammalian target of rapamycin complex 1
(mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) in the manufacture of a medicament for decreasing cellular progerin levels, e.g., for use in any of methods 5 or 5.1-5.38.
[0067] Also provided is a pharmaceutical composition comprising an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), in combination with a pharmaceutically acceptable diluent or carrier, for use in decreasing cellular progerin levels, e.g., for use in any of methods 5 or 5.1-5.38.
[0068] In another embodiment, provided is a method (Method 6) of decreasing cellular progerin levels comprising administering to a patient in need thereof an effective amount of a benzo [c] -chromen-6-one derivative.
[0069] Further provided is Method 6 as follows:
6.1 Method 6 wherein the benzo [c]-chromen-6-one derivative is a compound of Formula I
Figure imgf000058_0001
R4
Formula I
wherein,
Rl = H or alkyl;
R2 = H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6 = H;
R7 = H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
R8 = H; and
X = O, N, or S,
in free or pharmaceutically acceptable salt form.
Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000058_0002
in free or pharmaceutically acceptable salt form.
Method 6, 6.1, or 6.2 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000059_0001
in free form.
Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000059_0002
in free or pharmaceutically acceptable salt form.
Method 6 6.1, or 6.4 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000059_0003
in free form.
Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000059_0004
in free or pharmaceutically acceptable salt form.
Method 6, 6.1, or 6.6 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000060_0001
in free form.
Method 6 or 6.1 the benzo[c]-chromen-6-one derivative
Figure imgf000060_0002
in free or pharmaceutically acceptable salt form.
Method 6, 6.1 , or 6.8 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000060_0003
in free or pharmaceutically acceptable salt form.
Method 6, 6.1 , or 6.10 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000061_0001
in free form.
Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000061_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000061_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000061_0004
in free or pharmaceutically acceptable salt form.
Method 6, 6.1, or 6.14 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000062_0001
in free form.
Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000062_0002
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000062_0003
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000062_0004
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000063_0001
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000063_0002
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000063_0003
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000063_0004
SG00292 in free or pharmaceutically acceptable salt form. Method 6, 6.1 , or 6.22 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000064_0001
SG00292 in free form.
Method 6 or 6.1 wherein the benzo[c]-chromen-6-one derivative is a benzo[c]-chromen- 6-one selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
Any of methods 6 or 6.1-6.24 wherein the patient has Hutchinson-Gilford Progeria Syndrome (HGPS).
Any of methods 6 or 6.1-6.24 wherein the patient has an aging-related disorder, e.g., alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and/or osteoporosis, e.g., alopecia, e.g., atherosclerosis, e.g., lipofuscin deposition, e.g., nail dystrophy, e.g., hypermelanosis, e.g., decreased adipose tissue, e.g., osteoporosis.
Any of methods 6 or 6.1-6.26 wherein the benzo[c]-chromen-6-one derivative is an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2.
Any of methods 6 or 6.1-6.27 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the benzo[c]-chromen-6-one derivative one, two, three, or four times daily or in sustained release form.
Any of methods 6 or 6.1-6.28 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1).
Method 6.29 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus). 6.31 Any of methods 6 or 6.1-6.30 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
6.32 Method 6.31 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
6.33 Any of methods 6 or 6.1-6.32 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of a stimulator of autophagy.
6.34 Method 6.33 wherein the stimulator of autophagy is trehalose, lithium, epigallocatechin- 3-gallate, or stromal cell-derived factor 1
[0070] Also provided is use of a benzo[c]-chromen-6-one derivative for decreasing cellular progerin levels, e.g., for use in any of methods 6 or 6.1-6.34.
[0071] Also provided is use of a benzo[c]-chromen-6-one derivative in the manufacture of a medicament for decreasing cellular progerin levels, e.g., for use in any of methods 6 or 6.1- 6.34.
[0072] Also provided is a pharmaceutical composition comprising a benzo[c]-chromen-
6-one derivative, in combination with a pharmaceutically acceptable diluent or carrier, for use in decreasing cellular progerin levels, e.g., for use in any of methods 6 or 6.1-6.34.
[0073] In another embodiment, provided is a method (Method 7) of treatment or prophylaxis of an aging-related disorder comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
[0074] Further provided is Method 7 as follows:
7.1 Method 7 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula I
Figure imgf000066_0001
R4
Formula I
wherein,
Rl = H or alkyl;
R2 = H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = H, Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6 = H;
R7 = H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
R8 = H; and
X = O, N, or S,
in free or pharmaceutically acceptable salt form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000066_0002
in free or pharmaceutically acceptable salt form.
Method 7, 7.1, or 7.2 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000067_0001
in free form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000067_0002
in free or pharmaceutically acceptable salt form.
Method 7, 7.1, or 7.4 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000067_0003
in free form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000068_0001
in free or pharmaceutically acceptable salt form.
Method 7, 7.1, or 7.6 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000068_0002
in free form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000068_0003
in free or pharmaceutically acceptable salt form.
Method 7, 7.1, or 7.8 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000068_0004
in free form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000069_0001
in free or pharmaceutically acceptable salt form.
Method 7, 7.1, or 7.10 wherein the inhibitor of mammalian target of rapamycin complex 1 mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000069_0002
in free form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000069_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000070_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000070_0002
in free or pharmaceutically acceptable salt form.
Method 7, 7.1, or 7.14 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000070_0003
in free form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000070_0004
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000071_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000071_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 7 or 7.1 the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000071_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000072_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000072_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 7 or 7.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000072_0003
SG00292 in free or pharmaceutically acceptable salt form.
Method 7, 7.1, or 7.22 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000073_0001
SG00292 in free form.
Method 7 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula II
Figure imgf000073_0002
R4
Formula II
wherein,
Rl = H or alkyl;
R2 = H, O-alkyl, OH, amino, O-heterocyc, O-aryl, O-substituted alkyl where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, O-alkyl, O-substituted alkyl where substitution is aryl or heteroaryl, OH, O- acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = H, Aryl, heteroaryl or substituted alkyl; and
R6 = H, Alkyl, or Aryl,
in free or pharmaceutically acceptable salt form. Method 7 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula III
Figure imgf000074_0001
Formula III
wherein,
Rl = alkyl or H;
R2 = alkyl or H;
R3 = Acetyl; and
R4 = H or Alkyl,
in free or pharmaceutically acceptable salt form.
Method 7 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula IV
Figure imgf000074_0002
wherein,
Rl = H or F;
R2 = H or nitro;
R3 = H;
R4 = H; and
R5 = alkyl, substituted alkyl or aryl,
in free or pharmaceutically acceptable salt form. Any of methods 7, 7.1, or 7.24-7.26 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
Method 7 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is selected from AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC- 0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU-0063794, and Tori 1.
Any of methods 7 or 7.1-7.28 wherein the aging-related disorder is one or more of alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and osteoporosis, e.g., atherosclerosis, e.g., lipofuscin deposition, e.g., nail dystrophy, e.g., hypermelanosis, e.g., decreased adipose tissue, e.g., osteoporosis.
Any of methods 7 or 7.1-7.29 wherein the aging-related disorder is one or more of alopecia, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and osteoporosis.
Any of methods 7 or 7.1-7.30 wherein the aging-related disorder is alopecia.
Any of methods 7 or 7.1-7.31 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2.
Any of methods 7 or 7.1-7.32 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) one, two, three, or four times daily or in sustained release form.
Any of methods 7 or 7.1-7.33 comprising administering the mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) in an amount effective to increase autophagy, decrease mRNA translation, and/or decrease cellular progerin levels, e.g., in an amount effective to increase autophagy, e.g., in an amount effective to decrease mRNA translation, e.g., in an amount effective to decrease cellular progerin levels.
7.35 Any of methods 7 or 7.1-7.34 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1).
7.36 Method 7.35 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
7.37 Any of methods 7, 7.1-7.27, or 7.29-7.36 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of a second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
7.38 Method 7.37 wherein the second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
7.39 Any of methods 7 or 7.1-7.38 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of a stimulator of autophagy.
7.40 Method 7.39 wherein the stimulator of autophagy is trehalose, lithium, epigallocatechin- 3-gallate, or stromal cell-derived factor 1.
[0075] Also provided is use of an inhibitor of mammalian target of rapamycin complex 1
(mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) for treatment or prophylaxis of an aging-related disorder, e.g., for use in any of methods 7 or 7.1-7.40.
[0076] Also provided is use of an inhibitor of mammalian target of rapamycin complex 1
(mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) in the manufacture of a medicament for treatment or prophylaxis of an aging-related disorder, e.g., for use in any of methods 7 or 7.1-7.40.
[0077] Also provided is use of a pharmaceutical composition comprising an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), in combination with a pharmaceutically acceptable diluent or carrier, for treatment or prophylaxis of an aging-related disorder, e.g., for use in any of methods 7 or 7.1- 7.40.
[0078] In another embodiment, provided is a method (Method 8) of treatment or prophylaxis an aging-related disorder comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6-one derivative.
[0079] Further provided is Method 8 as follows:
8.1 Method 8 wherein the benzo[c]-chromen-6-one derivative is a compound of Formula I
Figure imgf000077_0001
Formula I
wherein,
Rl = H or alkyl;
R2 = H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6 = H;
R7 = H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
R8 = H; and X = O, N, or S,
in free or pharmaceutically acceptable salt form.
Method 8 or 8.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000078_0001
in free or pharmaceutically acceptable salt form.
Method 8 8.1, or 8.2 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000078_0002
in free form.
Method 8 or 8.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000078_0003
in free or pharmaceutically acceptable salt form.
Method 8, 8.1, or 8.4 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000079_0001
in free form.
Method 8 or 8.1 wherein the benzo[c]-chromen-6-one derivative
Figure imgf000079_0002
in free or pharmaceutically acceptable salt form.
Method 8 8.1, or 8.6 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000079_0003
in free form.
Method 8 or 8.1 wherein the benzo[c]-chromen-6-one derivative
Figure imgf000079_0004
in free or pharmaceutically acceptable salt form.
Method 8, 8.1, or 8.8 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000080_0001
in free form.
Method 8 or 8.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000080_0002
in free or pharmaceutically acceptable salt form.
Method 8 , 8.1 , or 8.10 wherein the benzo [c] -chromen-6-one derivative is
Figure imgf000080_0003
in free form.
Method 8 or 8.1 wherein the benzo [c]-chromen-6-one derivative is
Figure imgf000080_0004
in free form.
Method 8 or 8.1 wherein the benzo [c]-chromen-6-one derivative is
Figure imgf000081_0001
in free form.
Method 8 or 8.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000081_0002
in free or pharmaceutically acceptable salt form.
Method 8 , 8.1 , or 8.14 wherein the benzo [c] -chromen-6-one derivative is
Figure imgf000081_0003
in free form.
Method 8 or 8.1 wherein benzo [c]-chromen-6-one derivative
Figure imgf000081_0004
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 8 or 8.1 wherein benzo [c]-chromen-6-one derivative is
Figure imgf000082_0001
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 8 or 8.1 wherein benzo[c]-chromen-6-one derivative is
Figure imgf000082_0002
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 8 or 8.1 the benzo[c]-chromen-6-one derivative is
Figure imgf000082_0003
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 8 or 8.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000082_0004
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 8 or 8.1 wherein benzo[c]-chromen-6-one derivative is
Figure imgf000083_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 8 or 8.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000083_0002
SG00292 in free or pharmaceutically acceptable salt form.
Method 8, 8.1 , or 8.22 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000083_0003
SG00292 in free form.
Method 8 or 8.1 wherein the benzo[c]-chromen-6-one derivative is a benzo[c]-chromen- 6-one selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
Any of methods 8 or 8.1-8.24 wherein the aging-related disorder is one or more of alopecia, scleroderma, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and osteoporosis, e.g, alopecia, e.g., atherosclerosis, e.g., lipofuscin deposition, e.g., nail dystrophy, e.g., hypermelanosis, e.g., decreased adipose tissue, e.g., osteoporosis.
Any of methods 8 or 8.1-8.25 wherein the aging-related disorder is one or more of alopecia, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and osteoporosis.
Any of methods 8 or 8.1-8.26 wherein the aging-related disorder is alopecia.
Any of methods 8 or 8.1-8.27 wherein the benzo[c]-chromen-6-one derivative is an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2.
Any of methods 8 or 8.1-8.28 comprising administering 0.01 to 500 mg/kg, e.g., 25 to 500 mg/kg, of the benzo[c]-chromen-6-one derivative one, two, three, or four times daily or in sustained release form.
Any of methods 8 or 8.1-8.29 comprising administering the benzo[c]-chromen-6-one derivative in an amount effective to increase autophagy, decrease mRNA translation, and/or decrease cellular progerin levels, e.g., in an amount effective to increase autophagy, e.g., in an amount effective to decrease mRNA translation, e.g., in an amount effective to decrease cellular progerin levels.
Any of methods 8 or 8.1-8.30 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1).
Method 8.30 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
Any of methods 8 or 8.1-8.32 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
Method 8.33 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1. 8.35 Any of methods 8 or 8.1-8.34 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of a stimulator of autophagy.
8.36 Method 8.35 wherein the stimulator of autophagy is trehalose, lithium, epigallocatechin- 3-gallate, or stromal cell-derived factor 1.
[0080] Also provided is use of a benzo[c]-chromen-6-one derivative for treatment or prophylaxis of an aging-related disorder, e.g., for use in any of methods 8 or 8.1-8.36.
[0081] Also provided is use of a benzo[c]-chromen-6-one derivative in the manufacture of a medicament for treatment or prophylaxis of an aging-related disorder, e.g., for use in any of methods 8 or 8.1-8.36.
[0082] Also provided is use of a pharmaceutical composition comprising a benzo[c]- chromen-6-one derivative, in combination with a pharmaceutically acceptable diluent or carrier, for treatment or prophylaxis of an aging-related disorder, e.g., for use in any of methods 8 or 8.1- 8.36.
[0083] In another embodiment, provided is a method (Method 9) of treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, Huntington's disease, or alopecia comprising administering to a patient in need thereof an effective amount of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC -2).
[0084] Further provided is Method 9 as follows:
9.1 Method 9 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula I
Figure imgf000085_0001
Formula I
wherein, Rl = H or alkyl;
R2 = H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6 = H;
R7 = H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
R8 = H; and
X = O, N, or S,
in free or pharmaceutically acceptable salt form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000086_0001
in free or pharmaceutically acceptable salt form.
Method 9, 9.1, or 9.2 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000086_0002
in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000087_0001
in free or pharmaceutically acceptable salt form.
Method 9, 9.1, or 9.4 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000087_0002
in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1 and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000087_0003
in free or pharmaceutically acceptable salt form.
Method 9, 9.1, or 9.6 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000088_0001
in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin compli (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000088_0002
in free or pharmaceutically acceptable salt form.
Method 9, 9.1, or 9.8 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000088_0003
in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000089_0001
in free or pharmaceutically acceptable salt form.
Method 9, 9.1, or 9.10 wherein the inhibitor of mammalian target of rapamycin complex 1 mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000089_0002
in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000089_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000089_0004
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000090_0001
in free or pharmaceutically acceptable salt form.
Method 9, 9.1, or 9.14 wherein the inhibitor of mammalian target of rapamycin compli 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000090_0002
in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000090_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000091_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000091_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 9 or 9.1 the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000091_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000092_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000092_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 9 or 9.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000092_0003
SG00292 in free or pharmaceutically acceptable salt form.
Method 9, 9.1, or 9.22 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000093_0001
SG00292 in free form.
Method 9 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula II
Figure imgf000093_0002
R4
Formula II
wherein,
Rl = H or alkyl;
R2 = H, O-alkyl, OH, amino, O-heterocyc, O-aryl, O-substituted alkyl where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, O-alkyl, O-substituted alkyl where substitution is aryl or heteroaryl, OH, O- acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = H, Aryl, heteroaryl or substituted alkyl; and
R6 = H, Alkyl, or Aryl,
in free or pharmaceutically acceptable salt form. Method 9 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula III
Figure imgf000094_0001
Formula III
wherein,
Rl = alkyl or H;
R2 = alkyl or H;
R3 = Acetyl; and
R4 = H or Alkyl,
in free or pharmaceutically acceptable salt form.
Method 9 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound of Formula IV
Figure imgf000094_0002
wherein,
Rl = H or F;
R2 = H or nitro;
R3 = H;
R4 = H; and
R5 = alkyl, substituted alkyl or aryl,
in free or pharmaceutically acceptable salt form. Any of methods 9, 9.1, or 9.24-9.26 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is a compound selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form.
Method 9 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC- 1) and mammalian target of rapamycin complex 2 (mTORC-2) is selected from AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC- 0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU-0063794, and Tori 1.
Any of methods 9 or 9.1-9.28 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2.
Any of methods 9 or 9.1-9.29 comprising administering 0.01 to 500 mg/kg, e.g., 0.01 to 2 mg/kg, e.g., 25 to 500 mg/kg, of the inhibitor of mammalian target of rapamycin complex
1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) one, two, three, or four times daily or in sustained release form.
Any of methods 9 or 9.1 -9.30 comprising treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS).
Any of methods 9 or 9.1-9.30 comprising treatment or prophylaxis of Parkinson's disease.
Any of methods 9 or 9.1-9.30 comprising treatment or prophylaxis of Huntington's disease.
Any of methods 9 or 9.1-9.30 comprising treatment or prophylaxis of alopecia.
Any of methods 9 or 9.1-9.34 comprising administering the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex
2 (mTORC-2) in an amount effective to increase autophagy, decrease mRNA translation, and/or decrease cellular progerin levels, e.g., in an amount effective to increase autophagy, e.g., in an amount effective to decrease mRNA translation, e.g., in an amount effective to decrease cellular progerin levels. Any of methods 9 or 9.1-9.35 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1).
Method 9.36 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
Any of methods 9, 9.1-9.27, or 9.29-9.37 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of a second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
Method 9.38 wherein the second inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
Any of methods 9 or 9.1-9.39 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of a stimulator of autophagy.
Method 9.40 wherein the stimulator of autophagy is trehalose, lithium, epigallocatechin- 3-gallate, or stromal cell-derived factor 1.
Any of methods 9, 9.1-9.31, or 9.35-9.41 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is administered concurrently or sequentially, in any order, with one or more of a farnesyl transferase inhibitor, HMG-CoA reductase inhibitor, farnesyl pyrophosphate synthetase inhibitor, progerin expression inhibitor, an antisense oligonucleotide that targets mutated LMNA mRNA or pre-mRNA transcripts, and a bisphosphonate.
Method 9.42 wherein the farnesyl transferase inhibitor is lonafarnib.
Method 9.42 wherein the bisphosphonate is zoledronic acid. 9.45 Method 9.42 wherein the HMG-CoA reductase inhibitor is pravastatin.
[0085] Also provided is use of an inhibitor of mammalian target of rapamycin complex 1
(mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) for treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease,
Huntington's disease, or alopecia, e.g., for use in any of methods 9 or 9.1-9.45.
[0086] Also provided is use of an inhibitor of mammalian target of rapamycin complex 1
(mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) in the manufacture of a medicament for treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS),
Parkinson's disease, Huntington's disease, or alopecia, e.g., for use in any of methods 9 or 9.1-
9.45.
[0087] Also provided is use of a pharmaceutical composition comprising an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), in combination with a pharmaceutically acceptable diluent or carrier, for treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, Huntington's disease, or alopecia, e.g., for use in any of methods 9 or 9.1-9.45.
[0088] In another embodiment, provided is a method (Method 10) of treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, Huntington's disease, or alopecia comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6-one derivative.
[0089] Further provided is Method 10 as follows:
10.1 Method 10 wherein the benzo[c]-chromen-6-one derivative is a compound of Formula I
Figure imgf000097_0001
Formula I
wherein,
Rl = H or alkyl; R2 = H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6 = H;
R7 = H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
R8 = H; and
X = O, N, or S,
in free or pharmaceutically acceptable salt form.
Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000098_0001
in free or pharmaceutically acceptable salt form.
Method 10 10.1, or 10.2 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000098_0002
in free form.
Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000099_0001
in free or pharmaceutically acceptable salt form.
Method 10, 10.1, or 10.4 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000099_0002
in free form.
Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000099_0003
in free or pharmaceutically acceptable salt form.
Method 10 10.1, or 10.6 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000099_0004
in free form.
Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000100_0001
in free or pharmaceutically acceptable salt form.
Method 10, 10.1, or 10.8 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000100_0002
in free form.
Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000100_0003
in free or pharmaceutically acceptable salt form.
Method 10 10.1 , or 10.10 wherein the benzo[c]-chromen-6-one derivative
Figure imgf000100_0004
in free form.
Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000101_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000101_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative
Figure imgf000101_0003
in free or pharmaceutically acceptable salt form.
Method 10, 10.1, or 10.14 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000101_0004
in free form.
Method 10 or 10.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000102_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000102_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 10 or 10.1 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is
Figure imgf000102_0003
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 10 or 10.1 the benzo [c] -chromen-6-one derivative is
Figure imgf000102_0004
in free or pharmaceutically acceptable salt form, e.g., in free form. Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000103_0001
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000103_0002
in free or pharmaceutically acceptable salt form, e.g., in free form.
Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000103_0003
SG00292 in free or pharmaceutically acceptable salt form.
Method 10, 10.1, or 10.22 wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000104_0001
SG00292 in free form.
Method 10 or 10.1 wherein the benzo[c]-chromen-6-one derivative is a benzo[c]- chromen-6-one selected from the compounds of Table I, in free or pharmaceutically acceptable salt form, e.g., in free form, e.g., in pharmaceutically acceptable salt form. Any of methods 10 or 10.1-10.24 wherein the benzo[c]-chromen-6-one derivative is an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2.
Any of methods 10 or 10.1-10.25 comprising administering 0.01 to 500 mg/kg, e.g., 25 to 500 mg/kg, of the benzo[c]-chromen-6-one derivative one, two, three, or four times daily or in sustained release form.
Any of methods 10 or 10.1-10.26 comprising treatment or prophylaxis of Hutchinson- Gilford Progeria Syndrome (HGPS).
Any of methods 10 or 10.1-10.26 comprising treatment or prophylaxis Parkinson's disease.
Any of methods 10 or 10.1-10.26 comprising treatment or prophylaxis Huntington's disease.
Any of methods 10 or 10.1-10.26 comprising treatment or prophylaxis alopecia.
Any of methods 10 or 10.1-10.30 comprising administering the benzo[c]-chromen-6-one derivative in an amount effective to increase autophagy, decrease mRNA translation, and/or decrease cellular progerin levels, e.g., in an amount effective to increase autophagy, e.g., in an amount effective to decrease mRNA translation, e.g., in an amount effective to decrease cellular progerin levels.
Any of methods 10 or 10.1-10.31 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1). 10.33 Method 10.32 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog) (e.g., temsirolimus, everolimus, ridaforolimus, or deforolimus).
10.34 Any of methods 10 or 10.1-10.33 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
10.35 Method 10.34 wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2) is AZD8055, PP242, INK128, AZD2014, NVP-BEZ235, NVP-BGT226, XL765, GDC-0980, SF-1126, PKI-587, PF-04691502, GSK2126458, VS5584, PI103, TORKiCC223, OSI027, KU- 0063794, or Tori 1.
10.36 Any of methods 10 or 10.1-10.35 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of a stimulator of autophagy.
10.37 Method 10.35 wherein the stimulator of autophagy is trehalose, lithium, epigallocatechin- 3-gallate, or stromal cell-derived factor 1.
10.38 Any of methods 10, 10.1-10.27, or 10.31-10.37 wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of a farnesyl transferase inhibitor, HMG-CoA reductase inhibitor, farnesyl pyrophosphate synthetase inhibitor, progerin expression inhibitor, an antisense oligonucleotide that targets mutated LMNA mRNA or pre-mRNA transcripts, a statin, and a bisphosphonate.
10.39 Method 10.38 wherein the farnesyl transferase inhibitor is lonafarnib.
10.40 Method 10.38 wherein the bisphosphonate is zoledronic acid.
10.41 Method 10.38 wherein the statin is pravastatin.
[0090] Also provided is use of a benzo[c]-chromen-6-one derivative for treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, Huntington's disease, or alopecia, e.g., for use in any of methods 10 or 10.1-10.41.
[0091] Also provided is use of a benzo[c]-chromen-6-one derivative in the manufacture of a medicament for treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, Huntington's disease, or alopecia, e.g., for use in any of methods 10 or 10.1-10.41.
[0092] Also provided is use of a pharmaceutical composition comprising a benzo[c]- chromen-6-one derivative, in combination with a pharmaceutically acceptable diluent or carrier, for treatment or prophylaxis of Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, Huntington's disease, or alopecia, e.g., for use in any of methods 10 or 10.1-10.41.
[0093] Dosages employed in practicing the present invention will of course vary depending, e.g., on the particular disease or condition to be treated, the particular compound used, the mode of administration, and the therapy desired. The compounds disclosed herein, e.g., the inhibitors of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), the benzo[c]-chromen-6-one derivatives, and the compounds of Formula I, Formula II, Formula III, and Formula IV, may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, but are preferably administered orally. In general, satisfactory results, e.g. for the treatment or prophylaxis of diseases and disorders as hereinbefore set forth are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 2.0 mg/kg. In larger mammals, for example humans, an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 to 150 mg, conveniently administered once, or in divided doses 2, 3, or 4 times daily or in sustained release form. Unit dosage forms for oral administration thus, for example, may comprise from about 0.2 to 75 or 150 mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg of a compound disclosed herein, e.g., an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), a benzo[c]- chromen-6-one derivative, or a compound of Formula I, Formula II, Formula III, or Formula IV, together with a pharmaceutically acceptable diluent or carrier therefor.
[0094] Pharmaceutical compositions comprising a compound disclosed herein, e.g., an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2), a benzo[c]-chromen-6-one derivative, or a compound of Formula I, Formula II, Formula III, or Formula IV, may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus oral dosage forms may include tablets, capsules, solutions, suspensions and the like. [0095] Compounds of Formula I, Formula II, Formula III, and Formula IV may be synthesized as described in U.S. Patent No. 8,475,776 and U.S. Patent Application Publication No. 2006/0257337, the contents of which are hereby incorporated by reference.
Table I. Structural formula of benzo[c]chromen-6-one derivatives
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
EXAMPLES
Example 1 - Anti-angiogenic activity (antiproliferative for endothelial cells) measured in vitro
[0096] Inhibition of the proliferation of human umbilical vein endothelial cells,
HUVECs, is shown as one measure of anti-angiogenic activity. HUVECS and the required media complements are purchased from Cascade Biologies (Portland, OR) and the growth and maintenance of the cultures is as described by the manufacturer. The proliferation assay is carried out by seeding the HUVECs in 96-well plates at a density of 1 ,000 cells/well in complete medium. Following a 24 h plating period, the cells are starved for 24 h in 0.5% serum before being treated with SG ("Signal Gene" now "Palomid") angiogenic inhibitors in the presence of 10 ng/ml b-FGF or dosing ranging presence of either b-FGF or VEGF in complete medium. After 48 h, cell number is determined using a calorimetric method as described by the supplier (Promega Corp., Madison, WI). The results are expressed as the percentage of the maximal b- FGF or VEGF response in the absence of angiogenic inhibitors. Non-proliferating endothelial cells are assayed by growing HUVECs to quiescence in 96-well plates and treating with angiogenic inhibitors for 48 h. Initially, 5,000 cells/well are seeded and confluence is achieved the next day. The plates are incubated another 24 h to ensure growth arrest before treatment with angiogenic inhibitors. Cell number is determined as outlined above. The results are shown in Table II. The compounds show anti-angiogenic activity through inhibition of the proliferation of angiogenic cytokine stimulated endothelial cells.
Table II.
Figure imgf000111_0001
na, no activity; HUVECp, HUVEC proliferating; HUVECq, HUVEC quiescent; nd, not determined
Example 2 - Immunoblotting and Immunoprecipitation
[0097] Proteins are extracted from mouse tissue using T-PER Tissue Protein Extraction
Reagent Buffer (Pierce) containing 1 mmol/L phenylmethylsulfonyl fluoride, 1 mmol/L Na3V04, 1 mmol/L EGTA, 1 g/mL leupeptin, 0.5% aprotinin, and 2 μg/mL pepstatin A and from cultured cells using cell lysis buffer [20 mmol/L Tris-HCl (pH 7.5), 0.15 mol/L NaCl, 1% Triton X-100, 1 mmol/L phenylmethylsulfonyl fluoride, 1 mmol/L Na3V04, 1 mmol/L EGTA, 1 μg/mL leupeptin, 0.5%> aprotinin, and 2 μg/mL pepstatin A]. Equal amounts of protein are separated by NuPAGE No vex Bis-Tris Gels (Invitrogen Corp.) and transferred into nitrocellulose membranes (Invitrogen). Membranes are incubated with primary antibodies overnight at 4°C after blocking with 5% milk in TBS-Tween 20 and then detected using horseradish peroxidase-conjugated anti- rabbit or anti-mouse secondary antibodies (Amersham Biosciences UK), respectively, and SuperSignal West Pico Chemiluminescent Substrate system (Pierce). All experiments are carried out independently at least thrice. For immunoprecipitations, C6 glioma cells are serum starved for 24 h. Before insulin-like growth factor (IGF)-I stimulation, cells are pretreated with P529 (also known as SG00529) (20 μιηοΙ/L) for 2 or 24 h. Cell lysis buffer consisted of 20 mmol/L Tris (pH 7.5), 150 mmol/L NaCl, 1 mmol/L EDTA, 0.3% CHAPS, 25 mmol/L sodium pyrophosphate, 1 mmol/L β-glycerophosphate, 1 mmol/L Na3V04, and 1 g/mL leupeptin. Protein (1.5 mg) diluted to 1 mL with cell lysis buffer is centrifuged at 10,000 x g for 10 min at 4°C to remove cellular debris. mTOR (1 : 100) antibody is added and immune complexes are allowed to form by incubating with rotation overnight at 4°C. A 50% slurry (25 mL) of protein G-Sepharose is then added and the incubation is continued for 3 h. Immunoprecipitates are captured with protein G-Sepharose, washed four times with cell lysis buffer, and analyzed by immunoblotting. Results are shown in Figure 1 indicating that P529 (SG00529) inhibits both mTORCl and mTORC2 complexes.
Example 3 - Protein immunoblot analysis of normal and HGPS human fibroblasts in early passage cells (passage 13)
[0098] Normal and Hutchinson-Gilford Progeria Syndrome (HGPS) cells are treated with
5 μΜ P529 (also known as SG00529) for 1 week. Detection of progerin and lamin AJC is shown in the top graph in Figure 2. The bottom graph in Figure 2 represents quantification analysis of Western Blot band intensities for progerin by image analysis. In the bottom graph in Figure 2, the y-axis is labeled "Relative band intensity" and the left band on the x-axis is labeled "HGPS control" and the right band on the x-axis is "HGPS+P529." Decrease in levels of progerin protein shown in P529 (SG00529) treated HGPS cells.
I l l Example 4 - Protein immunoblot analysis of normal and HGPS human fibroblasts in late passage cells (passage 16)
[0099] Normal and Hutchinson-Gilford Progeria Syndrome (HGPS) cells are treated with
5 μΜ P529 (also known as SG00529) for 2.5 weeks. Drug treatment is initiated at passage 13. Detection of progerin and lamin A/C at passage 16 is shown in Figure 3 a. Figure 3b represents quantification analysis of Western Blot band intensities for progerin by image analysis. In Figure 3b, the y-axis is labeled "Relative progerin band intensity" and the left bar on the x-axis is labeled "HGPS control" and the right bar on the x-axis is "HGPS+P529." Decrease in levels of progerin protein shown in P529 (SG00529) treated HGPS cells. The intensity values are quantified and normalized by the band intensities of β-actin loading control.

Claims

WHAT IS CLAIMED IS:
1. A method of treatment or prophylaxis of a disease characterized by accumulation of mutated or improperly processed protein selected from Hutchinson-Gilford Progeria Syndrome (HGPS), Parkinson's disease, and Huntington's disease comprising administering to a patient in need thereof an effective amount of a benzo[c]-chromen-6- one derivative.
2. The method of claim 1, wherein the benzo[c]-chromen-6-one derivative is a compound of Formula I
Figure imgf000114_0001
Formula I
wherein,
Rl = H or alkyl;
R2 = H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is e.g. halo, aryl, or heteroaryl, O-Ac, 0-P03, 0-S03, or OS02NH2;
R3 = H, OH, O-alkyl, 0-CH2Aryl, 0-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4 = H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl,
OCH2Heteroaryl, O-Acyl, OP03, OS03, or OS02NH2;
R5 = Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6 = H;
R7 = H, Acyl, substituted alkyl, where substitution is e.g. hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is 0-P03 or OS03;
R8 = H; and
X = O, N, or S,
in free or pharmaceutically acceptable salt form.
3. The method of claim 1 or 2, wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000115_0001
Figure imgf000116_0001
115
Figure imgf000117_0001
Figure imgf000118_0001
in free or pharmaceutically acceptable salt form.
The method of any one of claims 1-5, wherein the benzo[c]-chromen-6-one derivative is
Figure imgf000119_0001
in free form.
7. The method of claim 1 or 2, wherein the benzo[c]-chromen-6-one derivative is selected from the compounds of Table I, in free or pharmaceutically acceptable salt form.
8. The method of claim 1, 2, or 7, wherein the benzo[c]-chromen-6-one derivative is selected from the compounds of Table I, in free form.
9. The method of any one of the preceding claims, wherein the benzo[c]-chromen-6-one derivative is an allosteric, dissociative inhibitor of mTORC-1 and mTORC-2.
10. The method of any one of the preceding claims, wherein the disease is Hutchinson- Gilford Progeria Syndrome (HGPS).
11. The method of any one of claims 1-9, wherein the disease is Parkinson's disease.
12. The method of any one of claims 1-9, wherein the disease is Huntington's disease.
13. The method of any one of the preceding claims comprising administering the benzo[c]- chromen-6-one derivative in an amount effective to increase autophagy.
14. The method of any one of the preceding claims comprising administering the benzo[c]- chromen-6-one derivative in an amount effective to decrease mRNA translation.
15. The method of any one of the preceding claims comprising administering the benzo[c]- chromen-6-one derivative in an amount effective to decrease cellular progerin levels.
16. The method of any one of the preceding claims, wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1).
17. The method of claim 16, wherein the inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) is rapamycin or a rapamycin analog (rapalog).
18. The method of any one of the preceding claims, wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with an inhibitor of mammalian target of rapamycin complex 1 (mTORC-1) and mammalian target of rapamycin complex 2 (mTORC-2).
19. The method of any one of the preceding claims, wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of a stimulator of autophagy.
20. The method of any one of claims 1-10 or 13-19, wherein the benzo[c]-chromen-6-one derivative is administered concurrently or sequentially, in any order, with one or more of a farnesyl transferase inhibitor, HMG-CoA reductase inhibitor, farnesyl pyrophosphate synthetase inhibitor, progerin expression inhibitor, an antisense oligonucleotide that targets mutated LMNA mRNA or pre-mRNA transcripts, a statin, and a bisphosphonate.
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