US20190112317A1 - Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies - Google Patents

Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies Download PDF

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US20190112317A1
US20190112317A1 US15/765,801 US201615765801A US2019112317A1 US 20190112317 A1 US20190112317 A1 US 20190112317A1 US 201615765801 A US201615765801 A US 201615765801A US 2019112317 A1 US2019112317 A1 US 2019112317A1
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compound
group
optionally substituted
salt
racemate
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Kirsten Alison Rinderspacher
Wai YU
Karen Duff
Donald Landry
Shi-Xian Deng
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Ny State Psychiatric Institute
Columbia University of New York
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Ny State Psychiatric Institute
Columbia University of New York
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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    • C07—ORGANIC CHEMISTRY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/93—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to compounds which are activators of autophagic flux and pharmaceutical compositions comprising said compounds. It further relates to use of said compounds in the treatment of neurodegenerative diseases, particularly Alzheimer's disease.
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • a ⁇ amyloid beta
  • tau proteinopathies
  • AD accounts for most of the dementias afflicting individuals over 65 and is estimated to cost $226 billion in healthcare, long-term care, and hospice for people with AD and other dementias annually. This extensive economic and societal burden does not account for lost income of many at-home primary caregivers including spouses and other family members.
  • Autophagic flux (including the fusion of autophagosomes to lysosomes) is a novel regulator of autophagy as it leads to the clearance of protein aggregates and reversal of pathophysiological decline. Therefore, there exists an ongoing need for promoters of autophagic flux and the clearance of autophagosomes bearing proteinopathies.
  • a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof.
  • methods of making the compounds and pharmaceutical compositions are also provided in, e.g., the Examples provided below.
  • a method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein is provided.
  • a method of enhancing autophagic flux comprises providing to a cell or a protein aggregate an effective amount of a compound or pharmaceutical composition disclosed herein.
  • FIG. 1 is a graph showing a photodiode array (PDA) spectrum of WHYKD8 in mouse brain.
  • PDA photodiode array
  • FIG. 2 shows Western blots of LC3-II levels in primary cortical neurons following a 6 hour treatment with WHYKD1 ( ⁇ BafA1) or WHYKD5.
  • FIG. 3 shows Western blots of LC3-II, tau, and p62 levels in organotypic slice cultures following a 6 hour treatment with WHYKD1 (top) or WHYKD3, WHYKD5, WHYKD8, WHYKD9, or WHYKD12 (bottom).
  • FIG. 4 is a bar graph showing the activation of phospholipase D (PLD) by the WHYKD series compounds (10 ⁇ M), and their ability to convert phospholipids to phosphatidylethanols in the presence of ethanol.
  • FIG. 5 is a bar graph showing the activation of phospholipase D (PLD) by the WHYKD series compounds (1 ⁇ M), and their ability to convert phospholipids to phosphatidylethanols in the presence of ethanol.
  • PLD phospholipase D
  • a compound having the formula (II):
  • Y 1 and Y 2 are independently selected from the group consisting of CH and wherein X is selected from the group consisting of H, halide, and aryl; wherein R 1 is selected from the group consisting of optionally substituted thioheteroaryl, hydroxyl-substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • a compound having the formula (III):
  • Y 1 is CH; wherein Y 2 is N; wherein X is halide; wherein R 1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • a compound having the formula (IV):
  • X is halide; wherein R 1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • a compound having the formula (V):
  • R 1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • a compound having the formula (VI):
  • R 1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • a compound having the formula (VII):
  • R 1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • R 1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • Y 3 is CH or N; wherein R 2 is optionally substituted (2-aminoethyl)aryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • Y 3 is CH; wherein R 2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • a compound having the formula (XI):
  • R 2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • a compound having the formula (XII):
  • Y 4 is CH or N; wherein R 3 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • R 2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • R 2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • the compound is selected from the group consisting of:
  • a compound having the formula (XV):
  • X is H or halide; wherein Z 1 is O; wherein R 4 is selected from the group consisting of H, optionally substituted alkyl, Et, CF 3 , optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and
  • the compound is selected from the group consisting of:
  • a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof.
  • a method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein is provided.
  • the neurodegenerative disease is a proteinopathy.
  • Proteinopathies include, but are not limited to, Parkinson's disease, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Paget's disease of bone (PDB), cerebral ⁇ -amyloid angiopathy, prion diseases, familial dementia, CADASIL, amyloidosis, Alexander disease, seipinopathies, type II diabetes, pulmonary alveolar proteinosis, cataracts, cystic fibrosis and sickle cell disease.
  • Parkinson's disease Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), inclusion body myopathy (IBM
  • the proteinopathy is a tauopathy.
  • Tauopothies include but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), Lytico-Bodig disease, subacute sclerosing panencephalitis, ganglioglioma, gangliocytoma, and argyrophilic grain disease.
  • the neurodegenerative disease is Alzheimer's disease.
  • a method of enhancing autophagic flux comprises providing to a cell or a protein aggregate an effective amount of a compound or pharmaceutical composition disclosed herein.
  • Scheme 2 shows preparation of 1-chloro-7-fluoroisoquinoline.
  • the WHYKD series of compounds were synthesized for optimal brain penetrance based on the molecular weight (MW) and partition coefficient (log P), according to Lipinski's Rule for CNS penetrance: MW ⁇ 400, log P ⁇ 5.
  • a photodiode array was used to detect WHYKD8 in mouse brain ( FIG. 1 ). The sample was readily detected with a discrete peak based on time (left) and with a measurable area under the curve (AUC) (inset).
  • LC3-II levels were measured in primary cortical neurons following 6 hours of treatment with WHYKD1, WHYKD5, or WHYKD1+BafA1 ( FIG. 2 ). The presence of LC3-II is an indication of autophagy.
  • LC3-II levels were then measured in organotypic slice cultures following 6 hours of treatment with WHYKD1 ( FIG. 3 , top panel). Other compounds in the WHYKD series produced similar results ( FIG. 3 , bottom panel).
  • RFP is a tag on the tau protein and also can be probed.
  • PLD activation converts phospholipids to phosphatidylethanols in the presence of ethanol. This conversion was measured to show that the WHYKD series of compounds activate PLD at 10 ⁇ M concentration ( FIG. 4 ) and at 1 ⁇ M ( FIG. 5 ).
  • FIPI is a non-competitive inhibitor of PLD activity and was used as a negative control.

Abstract

The present application discloses compounds which are activators of autophagic flux and pharmaceutical compositions comprising said activators. It further discloses use of said compounds and pharmaceutical compositions in the treatment of neurodegenerative diseases, particularly proteinopathies and tauopathies such as Alzheimer's disease. It further discloses methods of enhancing autophagic flux.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • The present application claims benefit to U.S. Provisional Application Ser. No. 62/237,342, filed Oct. 5, 2015. The entire contents of the above application are incorporated by reference as if recited in full herein.
    • FIELD OF THE DISCLOSURE
  • The present disclosure relates to compounds which are activators of autophagic flux and pharmaceutical compositions comprising said compounds. It further relates to use of said compounds in the treatment of neurodegenerative diseases, particularly Alzheimer's disease.
    • BACKGROUND OF THE INVENTION
  • Alzheimer's disease (AD) affects approximately five million Americans and this number is predicted to triple by 2050. At present, there are no therapies to treat Alzheimer's or other related tauopathies. While clinical trials using immunotherapy targeting amyloid beta (Aβ) have had limited success, this in only subset of those afflicted with AD or other neurodegenerative diseases. Moreover, there are no therapies targeting other proteinopathies, including tau, the other major neuropathological component of AD. AD accounts for most of the dementias afflicting individuals over 65 and is estimated to cost $226 billion in healthcare, long-term care, and hospice for people with AD and other dementias annually. This extensive economic and societal burden does not account for lost income of many at-home primary caregivers including spouses and other family members.
  • Enhancing autophagy has been shown to have therapeutic potential in the treatment of Alzheimer's disease. Autophagic flux (including the fusion of autophagosomes to lysosomes) is a novel regulator of autophagy as it leads to the clearance of protein aggregates and reversal of pathophysiological decline. Therefore, there exists an ongoing need for promoters of autophagic flux and the clearance of autophagosomes bearing proteinopathies.
    • SUMMARY OF THE INVENTION
  • In some embodiments, compounds including pharmaceutically acceptable salts thereof, which are disclosed herein, are provided.
  • In some embodiments a pharmaceutical composition is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof. In other embodiments, methods of making the compounds and pharmaceutical compositions are also provided in, e.g., the Examples provided below.
  • In some embodiments a method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein is provided.
  • In some embodiments a method of enhancing autophagic flux is provided. This method comprises providing to a cell or a protein aggregate an effective amount of a compound or pharmaceutical composition disclosed herein.
  • These and other aspects of the invention are further disclosed in the detailed description and examples which follow.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
  • FIG. 1 is a graph showing a photodiode array (PDA) spectrum of WHYKD8 in mouse brain.
  • FIG. 2 shows Western blots of LC3-II levels in primary cortical neurons following a 6 hour treatment with WHYKD1 (±BafA1) or WHYKD5.
  • FIG. 3 shows Western blots of LC3-II, tau, and p62 levels in organotypic slice cultures following a 6 hour treatment with WHYKD1 (top) or WHYKD3, WHYKD5, WHYKD8, WHYKD9, or WHYKD12 (bottom).
  • FIG. 4 is a bar graph showing the activation of phospholipase D (PLD) by the WHYKD series compounds (10 μM), and their ability to convert phospholipids to phosphatidylethanols in the presence of ethanol. C=Control, 12=WHYKD12, 15=WHYKD15, 19=WHYKD19, 5=WHYKD5, 8=WHYKD8, Fipi=a noncompetitive inhibitor of PLD activity.
  • FIG. 5 is a bar graph showing the activation of phospholipase D (PLD) by the WHYKD series compounds (1 μM), and their ability to convert phospholipids to phosphatidylethanols in the presence of ethanol.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • Although macroautophagy is known to be an essential degradative process whereby autophagosomes mediate the engulfment and delivery of cytoplasmic components into lysosomes, the lipid changes underlying autophagosomal membrane dynamics are undetermined. The inventors have previously shown that PLD1, which is primarily associated with the endosomal system, partially relocalizes to the outer membrane of autophagosome-like structures upon nutrient starvation (Dall'Armi, 2010). The localization of PLD1, as well as the starvation-induced increase in PLD activity, are altered by wortmannin, a phosphatidylinositol 3-kinase inhibitor, suggesting PLD1 may act downstream of Vps34. Pharmacological inhibition of PLD and genetic ablation of PLD1 in mouse cells decreased the starvation-induced expansion of LC3-positive compartments, consistent with a role of PLD1 in the regulation of autophagy. Furthermore, inhibition of PLD results in higher levels of tau and p62 aggregates in organotypic brain slices. These in vitro and in vivo findings establish a role for PLD1 in autophagy.
  • In some embodiments, a compound is provided having the formula (II):
  • Figure US20190112317A1-20190418-C00001
  • wherein Y1 and Y2 are independently selected from the group consisting of CH and
    wherein X is selected from the group consisting of H, halide, and aryl;
    wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, hydroxyl-substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
    or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00002
    Figure US20190112317A1-20190418-C00003
    Figure US20190112317A1-20190418-C00004
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In one embodiment the compound is:
  • Figure US20190112317A1-20190418-C00005
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In another embodiment the compound is:
  • Figure US20190112317A1-20190418-C00006
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (III):
  • Figure US20190112317A1-20190418-C00007
  • wherein Y1 is CH;
    wherein Y2 is N;
    wherein X is halide;
    wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
    or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00008
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (IV):
  • Figure US20190112317A1-20190418-C00009
  • wherein X is halide;
    wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00010
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (V):
  • Figure US20190112317A1-20190418-C00011
  • wherein X is H;
    wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
    or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00012
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (VI):
  • Figure US20190112317A1-20190418-C00013
  • wherein X is H;
    wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
    or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00014
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (VII):
  • Figure US20190112317A1-20190418-C00015
  • wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
    or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00016
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (VIII):
  • Figure US20190112317A1-20190418-C00017
  • wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
    or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00018
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (IX):
  • Figure US20190112317A1-20190418-C00019
  • wherein Y3 is CH or N;
    wherein R2 is optionally substituted (2-aminoethyl)aryl,
    or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00020
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (X):
  • Figure US20190112317A1-20190418-C00021
  • wherein Y3 is CH;
    wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
    or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00022
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (XI):
  • Figure US20190112317A1-20190418-C00023
  • wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
    or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00024
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (XII):
  • Figure US20190112317A1-20190418-C00025
  • wherein Y4 is CH or N;
    wherein R3 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
    or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00026
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (XIII):
  • Figure US20190112317A1-20190418-C00027
  • wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
    or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00028
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (XIV):
  • Figure US20190112317A1-20190418-C00029
  • wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
    or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00030
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments, a compound is provided having the formula (XV):
  • Figure US20190112317A1-20190418-C00031
  • wherein X is H or halide;
    wherein Z1 is O;
    wherein R4 is selected from the group consisting of H, optionally substituted alkyl, Et, CF3, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and
  • Figure US20190112317A1-20190418-C00032
  • In some embodiments, the compound is selected from the group consisting of:
  • Figure US20190112317A1-20190418-C00033
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In one embodiment the compound is
  • Figure US20190112317A1-20190418-C00034
  • or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
  • In some embodiments a pharmaceutical composition is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof.
  • In some embodiments a method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein is provided. In some embodiments the neurodegenerative disease is a proteinopathy. Proteinopathies include, but are not limited to, Parkinson's disease, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Paget's disease of bone (PDB), cerebral β-amyloid angiopathy, prion diseases, familial dementia, CADASIL, amyloidosis, Alexander disease, seipinopathies, type II diabetes, pulmonary alveolar proteinosis, cataracts, cystic fibrosis and sickle cell disease. In some aspects of this embodiment, the proteinopathy is a tauopathy. Tauopothies include but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), Lytico-Bodig disease, subacute sclerosing panencephalitis, ganglioglioma, gangliocytoma, and argyrophilic grain disease. In a preferred embodiment, the neurodegenerative disease is Alzheimer's disease.
  • In some embodiments a method of enhancing autophagic flux is provided. This method comprises providing to a cell or a protein aggregate an effective amount of a compound or pharmaceutical composition disclosed herein.
  • The embodiments described in this disclosure can be combined in various ways. Any aspect or feature that is described for one embodiment can be incorporated into any other embodiment mentioned in this disclosure. While various novel features of the inventive principles have been shown, described and pointed out as applied to particular embodiments thereof, it should be understood that various omissions and substitutions and changes may be made by those skilled in the art without departing from the spirit of this disclosure. Those skilled in the art will appreciate that the inventive principles can be practiced in other than the described embodiments, which are presented for purposes of illustration and not limitation.
    • EXAMPLES
  • The following examples are provided to further illustrate certain aspects of the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way.
    • Example 1 Example Synthetic Schemes
  • Scheme 1 shows the synthesis of compounds of the formula:
  • Figure US20190112317A1-20190418-C00035
  • e.g., compounds of formula (II) and formula (III).
  • Figure US20190112317A1-20190418-C00036
  • Scheme 2 shows preparation of 1-chloro-7-fluoroisoquinoline.
  • Figure US20190112317A1-20190418-C00037
  • Scheme 3 shows the synthesis of compounds of the formula:
  • Figure US20190112317A1-20190418-C00038
  • e.g., compounds of formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII).
  • Figure US20190112317A1-20190418-C00039
  • Scheme 4 shows the synthesis of compounds of the formula:
  • Figure US20190112317A1-20190418-C00040
  • e.g., compounds of formula (XII), and formula (XIII).
  • Figure US20190112317A1-20190418-C00041
  • Scheme 5 shows the synthesis of compounds of the formula:
  • Figure US20190112317A1-20190418-C00042
  • e.g., compounds of formula (IX), formula (X), and formula (XI).
  • Figure US20190112317A1-20190418-C00043
  • Scheme 6 shows the synthesis of compounds of the formula:
  • Figure US20190112317A1-20190418-C00044
  • e.g., compounds of formula (XIV).
  • Figure US20190112317A1-20190418-C00045
    • Example 2 Activators of Autophagic Flux and Phospholipase D
  • The WHYKD series of compounds were synthesized for optimal brain penetrance based on the molecular weight (MW) and partition coefficient (log P), according to Lipinski's Rule for CNS penetrance: MW≤400, log P≤5.
  • Activators according to the formula:
  • Figure US20190112317A1-20190418-C00046
  • were synthesized according to the schemes above. Molecular weights and log P were calculated. Results are shown in Table 1 below.
  • TABLE 1
    PROJECT
    STRUCTURE ID M.W. log P X Y1 Y2 R1
    Figure US20190112317A1-20190418-C00047
         		WHYKD3  323.17 3.85 Br N N thioheteroaryl
    Figure US20190112317A1-20190418-C00048
         		WHYKD4  369.44 5.69 aryl N N Thioheteroaryl
    Figure US20190112317A1-20190418-C00049
         		WHYKD5  262.27 3.18 F N N Thioheteroaryl
    Figure US20190112317A1-20190418-C00050
         		WHYKD6  244.48 3.02 H N N thioheteroaryl
    Figure US20190112317A1-20190418-C00051
         		WHYKD7  278.72 3.58 Cl N N thioheteroaryl
    Figure US20190112317A1-20190418-C00052
         		WHYKD8  299.76 3.91 Cl N N (2- aminoethyl)aryl
    Figure US20190112317A1-20190418-C00053
         		WHYKD9  182.58 2.58 F N N Cl
    Figure US20190112317A1-20190418-C00054
         		WHYKD10 243.29 2.9  H N CH thioheteroaryl
    Figure US20190112317A1-20190418-C00055
         		WHYKD11 261.28 3.06 F N CH thioheteroaryl
    Figure US20190112317A1-20190418-C00056
         		WHYKD12 262.35 4.35 F N N thiocycloalkyl
    Figure US20190112317A1-20190418-C00057
         		WHYKD13 316.44 5.21 F N N thiocycloalkyl
    Figure US20190112317A1-20190418-C00058
         		WHYKD14 314.42 4.66 F N N thiocycloalkyl
    Figure US20190112317A1-20190418-C00059
         		WHYKD15 248.32 3.96 F N N thiocycloalkyl
    Figure US20190112317A1-20190418-C00060
         		WHYKD16 274.36 4.19 F N N thiocycloalkyl
    Figure US20190112317A1-20190418-C00061
         		WHYKD17 357.49 4.09 F N N thiocycloalkyl
    Figure US20190112317A1-20190418-C00062
         		WHYKD18 386.48 4.41 F N N thiocycloalkyl
    Figure US20190112317A1-20190418-C00063
         		WHYKD19 264.32 2.63 F N N thiocycloalkyl
    Figure US20190112317A1-20190418-C00064
         		WHYKD20 296.36 4.8  F N N thioaryl
  • Activators according to the formula:
  • Figure US20190112317A1-20190418-C00065
  • were synthesized according to the schemes above. Molecular weights and log P were calculated. Results are shown in Table 2 below.
  • TABLE 2
    PROJECT
    STRUCTURE ID M.W. log P Y3 R2
    Figure US20190112317A1-20190418-C00066
         		WHYKD21 272.33 3.36 N (2- aminoethyl)aryl
    Figure US20190112317A1-20190418-C00067
         		WHYKD23 271.34 3.66 CH (2- aminoethyl)aryl

    Activators according to the formula:
  • Figure US20190112317A1-20190418-C00068
  • were synthesized according to the schemes above. Molecular weights and log P were calculated. Results are shown in Table 3 below.
  • TABLE 3
    PROJECT
    STRUCTURE ID M.W. log P Y4 R3
    Figure US20190112317A1-20190418-C00069
         		WHYKD1 251.29 2.56 N thioheteroaryl
    Figure US20190112317A1-20190418-C00070
         		WHYKD2 272.33 2.89 N (2- aminoethyl)aryl
    Figure US20190112317A1-20190418-C00071
         		WHYKD22 271.34 3.34 CH (2- aminoethyl)aryl
  • Activators according to the formula:
  • Figure US20190112317A1-20190418-C00072
  • were synthesized according to the schemes above. Molecular weights and log P were calculated. Results are shown in Table 4 below.
  • TABLE 4
    PROJECT log
    STRUCTURE ID M.W. P X Y1 Y2 R4 Z1
    Figure US20190112317A1-20190418-C00073
         		WHYKD24 164.14 1.02 F N N H O
    • Example 3 Design of Derivatives
  • Several series of derivatives were synthesized based on the following lead compounds:
  • Figure US20190112317A1-20190418-C00074
  • In addition to log P, the topological polar surface area (tPSA), C Log P (log P calculated by group contribution method), and Log S (solubility) were calculated. Results are shown in the Tables below.
  • TABLE 5
    Modifications to the core and side chain (Series 1)
    STRUCTURE log P tPSA CLogP LogS
    Figure US20190112317A1-20190418-C00075
         		3.35 52.68 2.65154 −3.235
    Figure US20190112317A1-20190418-C00076
         		3.12 61.47 2.34241 −3.295
    Figure US20190112317A1-20190418-C00077
         		2.94 40.32 1.83259 −4.663
    Figure US20190112317A1-20190418-C00078
         		3.19 27.96 3.25375 −3.864
    Figure US20190112317A1-20190418-C00079
         		4.14 12.36 4.64041 −4.354
    Figure US20190112317A1-20190418-C00080
         		2.71 49.11 2.01759 −4.354
    Figure US20190112317A1-20190418-C00081
         		2.95 36.75 3.23654 −3.554
    Figure US20190112317A1-20190418-C00082
         		2.8  21.59 2.80041 −3.813
    Figure US20190112317A1-20190418-C00083
         		4.56 12.36 5.19941 −4.832
  • TABLE 6
    Modifications to the core and side chain (Series 2)
    STRUCTURE log P tPSA CLogP LogS
    Figure US20190112317A1-20190418-C00084
         		2.31 77.4 0.803829 −1.704
    Figure US20190112317A1-20190418-C00085
         		2.07 86.19 0.539011 −1.765
    Figure US20190112317A1-20190418-C00086
         		1.9 65.04 −0.0366305 −3.133
    Figure US20190112317A1-20190418-C00087
         		1.66 73.83 0.148224 −2.824
    Figure US20190112317A1-20190418-C00088
         		2.14 52.68 1.40054 −2.334
    Figure US20190112317A1-20190418-C00089
         		1.91 61.47 1.38428 −2.024
    Figure US20190112317A1-20190418-C00090
         		3.09 37.08 2.83701 −2.823
    Figure US20190112317A1-20190418-C00091
         		3.51 37.08 3.39601 −3.301
    Figure US20190112317A1-20190418-C00092
         		1.76 46.31 0.997011 −2.283
  • TABLE 7
    Modifications to the core and side chain (Series 3)
    STRUCTURE log P tPSA CLogP LogS
    Figure US20190112317A1-20190418-C00093
         		2.89 77.4 0.647513 −1.626
    Figure US20190112317A1-20190418-C00094
         		2.65 86.19 0.382662 −1.686
    Figure US20190112317A1-20190418-C00095
         		2.48 65.04 −0.192932 −3.117
    Figure US20190112317A1-20190418-C00096
         		2.25 73.83 −0.00808129 −2.806
    Figure US20190112317A1-20190418-C00097
         		2.73 52.68 1.24423 −2.303
    Figure US20190112317A1-20190418-C00098
         		2.49 61.47 1.22796 −1.992
    Figure US20190112317A1-20190418-C00099
         		3.68 37.08 2.68066 −2.893
    Figure US20190112317A1-20190418-C00100
         		4.09 37.08 3.23966 −3.372
    Figure US20190112317A1-20190418-C00101
         		2.34 46.31 0.840662 −2.256
  • TABLE 8
    Modifications to the core and side chain (Series 4)
    STRUCTURE log P tPSA CLogP LogS
    Figure US20190112317A1-20190418-C00102
         		1.68 77.4 0.647513 −1.441
    Figure US20190112317A1-20190418-C00103
         		1.45 86.19 0.382662 −1.501
    Figure US20190112317A1-20190418-C00104
         		1.28 65.04 −0.192932 −2.932
    Figure US20190112317A1-20190418-C00105
         		1.04 73.83 −0.00808129 −2.621
    Figure US20190112317A1-20190418-C00106
         		1.52 52.68 1.24423 −2.119
    Figure US20190112317A1-20190418-C00107
         		1.28 61.47 1.22796 −1.808
    Figure US20190112317A1-20190418-C00108
         		2.47 37.08 2.68066 −2.704
    Figure US20190112317A1-20190418-C00109
         		2.89 37.08 3.23966 −3.183
    Figure US20190112317A1-20190418-C00110
         		1.13 46.31 0.840662 −2.071
  • TABLE 9
    Modifications to the core and side chain (Series 5)
    STRUCTURE log P tPSA CLogP LogS
    Figure US20190112317A1-20190418-C00111
         		1.68 77.4 0.647513 −1.466
    Figure US20190112317A1-20190418-C00112
         		1.45 86.19 0.382662 −1.526
    Figure US20190112317A1-20190418-C00113
         		1.28 65.04 −0.192932 −2.957
    Figure US20190112317A1-20190418-C00114
         		1.04 73.83 −0.00808129 −2.646
    Figure US20190112317A1-20190418-C00115
         		1.52 52.68 1.24423 −2.144
    Figure US20190112317A1-20190418-C00116
         		1.28 61.47 1.22796 −1.832
    Figure US20190112317A1-20190418-C00117
         		2.47 37.08 2.68066 −2.733
    Figure US20190112317A1-20190418-C00118
         		2.89 37.08 3.23966 −3.212
    Figure US20190112317A1-20190418-C00119
         		1.13 46.31 0.840662 −2.096
  • TABLE 10
    Modifications to the core and side chain (Series 6)
    STRUCTURE log P tPSA CLogP LogS
    Figure US20190112317A1-20190418-C00120
         		2.11 77.4 0.857513 −1.525
    Figure US20190112317A1-20190418-C00121
         		1.87 86.19 0.592663 −1.585
    Figure US20190112317A1-20190418-C00122
         		1.7 65.04 0.0170677 −3.017
    Figure US20190112317A1-20190418-C00123
         		1.46 73.83 0.201919 −2.705
    Figure US20190112317A1-20190418-C00124
         		1.94 52.68 1.45423 −2.203
    Figure US20190112317A1-20190418-C00125
         		1.71 61.47 1.43796 −1.892
    Figure US20190112317A1-20190418-C00126
         		2.89 37.08 2.89066 −2.787
    Figure US20190112317A1-20190418-C00127
         		3.31 37.08 3.44966 −3.266
    Figure US20190112317A1-20190418-C00128
         		1.55 46.31 1.05066 −2.155
  • TABLE 11
    Modifications to the core and side chain (Series 7)
    STRUCTURE log P tPSA CLogP LogS
    Figure US20190112317A1-20190418-C00129
         		1.63 74.27 1.1096 −1.275
    Figure US20190112317A1-20190418-C00130
         		1.4 83.06 0.834 −1.333
    Figure US20190112317A1-20190418-C00131
         		1.23 61.91 0.272969 −2.704
    Figure US20190112317A1-20190418-C00132
         		0.99 70.7 0.457768 −2.391
    Figure US20190112317A1-20190418-C00133
         		1.47 49.55 1.70682 −1.904
    Figure US20190112317A1-20190418-C00134
         		1.24 58.34 1.69005 −1.592
    Figure US20190112317A1-20190418-C00135
         		2.42 33.95 3.132 −2.403
    Figure US20190112317A1-20190418-C00136
         		2.84 33.95 3.691 −2.883
    Figure US20190112317A1-20190418-C00137
         		1.08 43.18 1.292 −1.864
  • TABLE 12
    Modifications to the core and side chain (Series 8)
    STRUCTURE log P tPSA CLogP LogS
    Figure US20190112317A1-20190418-C00138
         		1.96 74.27 0.8996 −1.745
    Figure US20190112317A1-20190418-C00139
         		1.72 83.06 0.624 −1.803
    Figure US20190112317A1-20190418-C00140
         		1.55 61.91 0.0629689 −3.174
    Figure US20190112317A1-20190418-C00141
         		1.31 70.7 0.247768 −2.862
    Figure US20190112317A1-20190418-C00142
         		1.79 49.55 1.49682 −2.374
    Figure US20190112317A1-20190418-C00143
         		1.56 58.34 1.48005 −2.062
    Figure US20190112317A1-20190418-C00144
         		2.74 33.95 2.922 −2.874
    Figure US20190112317A1-20190418-C00145
         		3.16 33.95 3.481 −3.353
    Figure US20190112317A1-20190418-C00146
         		1.4 43.18 1.082 −2.335
  • TABLE 13
    Modifications to the core and side chain (Series 9)
    STRUCTURE log P tPSA CLogP LogS
    Figure US20190112317A1-20190418-C00147
         		3.0 65.04 1.74907 −2.051
    Figure US20190112317A1-20190418-C00148
         		2.76 73.83 1.47586 −2.109
    Figure US20190112317A1-20190418-C00149
         		2.59 52.68 0.911314 −3.542
    Figure US20190112317A1-20190418-C00150
         		2.36 61.47 1.09641 −3.23
    Figure US20190112317A1-20190418-C00151
         		2.84 40.32 2.34546 −2.728
    Figure US20190112317A1-20190418-C00152
         		2.6 49.11 2.32952 −2.416
    Figure US20190112317A1-20190418-C00153
         		3.79 24.72 3.77386 −3.323
    Figure US20190112317A1-20190418-C00154
         		4.2 24.72 4.33286 −3.802
    Figure US20190112317A1-20190418-C00155
         		2.45 33.95 1.93386 −2.687
  • TABLE 14
    Modifications to the core and side chain (Series 10)
    STRUCTURE log P tPSA CLogP LogS
    Figure US20190112317A1-20190418-C00156
         		2.94 65.04 1.53907 −2.188
    Figure US20190112317A1-20190418-C00157
         		2.71 73.83 1.26586 −2.247
    Figure US20190112317A1-20190418-C00158
         		2.54 52.68 0.701314 −3.68
    Figure US20190112317A1-20190418-C00159
         		2.3 61.47 0.886405 −3.367
    Figure US20190112317A1-20190418-C00160
         		2.78 40.32 2.13546 −2.866
    Figure US20190112317A1-20190418-C00161
         		2.55 49.11 2.11952 −2.554
    Figure US20190112317A1-20190418-C00162
         		3.73 24.72 3.56386 −3.468
    Figure US20190112317A1-20190418-C00163
         		4.15 24.72 4.12286 −3.947
    Figure US20190112317A1-20190418-C00164
         		2.39 33.95 1.72386 −2.824
  • TABLE 15
    Quinazolinones (Series 11)
    STRUCTURE log P tPSA CLogP LogS
    Figure US20190112317A1-20190418-C00165
         		1.02 41.46 0.506065 −1.702
    Figure US20190112317A1-20190418-C00166
         		1.42 41.46 1.07606 −2.152
    Figure US20190112317A1-20190418-C00167
         		1.69 41.46 1.22606 −2.273
    Figure US20190112317A1-20190418-C00168
         		0.86 41.46 0.305 −1.452
    Figure US20190112317A1-20190418-C00169
    Figure US20190112317A1-20190418-C00170
    • Example 4 Detection and Results of WHYKD Compounds
  • A photodiode array (PDA) was used to detect WHYKD8 in mouse brain (FIG. 1). The sample was readily detected with a discrete peak based on time (left) and with a measurable area under the curve (AUC) (inset).
  • LC3-II levels were measured in primary cortical neurons following 6 hours of treatment with WHYKD1, WHYKD5, or WHYKD1+BafA1 (FIG. 2). The presence of LC3-II is an indication of autophagy.
  • LC3-II levels were then measured in organotypic slice cultures following 6 hours of treatment with WHYKD1 (FIG. 3, top panel). Other compounds in the WHYKD series produced similar results (FIG. 3, bottom panel). RFP is a tag on the tau protein and also can be probed.
  • These experiments show that the WHYKD series of compounds can induce autophagy and reduce the aggregated forms of tau as well as its aggresome surrogate p62.
  • PLD activation converts phospholipids to phosphatidylethanols in the presence of ethanol. This conversion was measured to show that the WHYKD series of compounds activate PLD at 10 μM concentration (FIG. 4) and at 1 μM (FIG. 5). FIPI is a non-competitive inhibitor of PLD activity and was used as a negative control.
  • All patents, patent applications, and publications cited above are incorporated herein by reference in their entirety as if recited in full herein.
  • The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims (37)

What is claimed is:
1. A compound having the formula (II):
Figure US20190112317A1-20190418-C00171
wherein Y1 and Y2 are, independently selected from the group consisting of CH and wherein X is selected from the group consisting of H, halide, and aryl;
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, hydroxyl-substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
2. The compound of claim 1, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00172
Figure US20190112317A1-20190418-C00173
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
3. The compound of claim 1, wherein the compound is:
Figure US20190112317A1-20190418-C00174
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
4. The compound of claim 1, wherein the compound is:
Figure US20190112317A1-20190418-C00175
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
5. A compound having the formula (III):
Figure US20190112317A1-20190418-C00176
wherein Y1 is CH;
wherein Y2 is N;
wherein X is halide;
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
6. The compound of claim 5, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00177
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
7. A compound having the formula (IV):
Figure US20190112317A1-20190418-C00178
wherein X is halide;
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
8. The compound of claim 7, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00179
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
9. A compound having the formula (V):
Figure US20190112317A1-20190418-C00180
wherein X is H;
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
10. The compound of claim 9, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00181
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
11. A compound having the formula (VI):
Figure US20190112317A1-20190418-C00182
wherein X is H;
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
12. The compound of claim 11, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00183
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
13. A compound having the formula (VII):
Figure US20190112317A1-20190418-C00184
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
14. The compound of claim 13, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00185
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
15. A compound having the formula (VIII):
Figure US20190112317A1-20190418-C00186
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
16. The compound of claim 15, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00187
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
17. A compound having the formula (IX):
Figure US20190112317A1-20190418-C00188
wherein Y3 is CH or N;
wherein R2 is optionally substituted (2-aminoethyl)aryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
18. The compound of claim 17, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00189
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
19. A compound having the formula (X):
Figure US20190112317A1-20190418-C00190
wherein Y3 is CH;
wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
20. The compound of claim 19, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00191
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
21. A compound having the formula (XI):
Figure US20190112317A1-20190418-C00192
wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
22. The compound of claim 21, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00193
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
23. A compound having the formula (XII):
Figure US20190112317A1-20190418-C00194
wherein Y4 is CH or N;
wherein R3 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
24. The compound of claim 23, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00195
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
25. A compound having the formula (XIII):
Figure US20190112317A1-20190418-C00196
wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
26. The compound of claim 25, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00197
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
27. A compound having the formula (XIV):
Figure US20190112317A1-20190418-C00198
wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
28. The compound of claim 27, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00199
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
29. A compound having the formula (XV):
Figure US20190112317A1-20190418-C00200
wherein X is H or halide;
wherein Z1 is O;
wherein R4 is selected from the group consisting of H, optionally substituted alkyl, Et, CF3, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and
Figure US20190112317A1-20190418-C00201
30. The compound of claim 29, wherein the compound is selected from the group consisting of:
Figure US20190112317A1-20190418-C00202
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
31. The compound of claim 29 wherein the compound is:
Figure US20190112317A1-20190418-C00203
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
32. A pharmaceutical composition comprising a compound of any one of claims 1-31 or a pharmaceutically acceptable salt thereof.
33. A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-31 or pharmaceutical composition of claim 32.
34. The method of claim 33, wherein the neurodegenerative disease is a proteinopathy.
35. The method of claim 34, wherein the proteinopathy is a tauopathy.
36. The method of claim 33, wherein the neurodegenerative disease is Alzheimer's disease.
37. A method of enhancing autophagic flux comprising providing to a cell or a protein aggregate an effective amount of a compound of any one of claims 1-31 or pharmaceutical composition of claim 32.
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