WO2017062500A2 - 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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Publication number
WO2017062500A2
WO2017062500A2 PCT/US2016/055561 US2016055561W WO2017062500A2 WO 2017062500 A2 WO2017062500 A2 WO 2017062500A2 US 2016055561 W US2016055561 W US 2016055561W WO 2017062500 A2 WO2017062500 A2 WO 2017062500A2
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compound
group
optionally substituted
salt
racemate
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French (fr)
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WO2017062500A3 (en
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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
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Ny State Psychiatric Institute
Columbia University
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Priority to US15/765,801 priority Critical patent/US20190112317A1/en
Priority to CA3000988A priority patent/CA3000988A1/en
Priority to CN201680062131.XA priority patent/CN108473435A/en
Priority to MX2018004109A priority patent/MX2018004109A/en
Priority to EP16854245.4A priority patent/EP3359526A4/en
Priority to KR1020187012344A priority patent/KR20180086187A/en
Application filed by Ny State Psychiatric Institute, Columbia University filed Critical Ny State Psychiatric Institute
Priority to AU2016333987A priority patent/AU2016333987A1/en
Priority to JP2018536715A priority patent/JP6740354B2/en
Priority to BR112018006873-0A priority patent/BR112018006873A2/en
Priority to US15/480,220 priority patent/US10487091B2/en
Publication of WO2017062500A2 publication Critical patent/WO2017062500A2/en
Publication of WO2017062500A3 publication Critical patent/WO2017062500A3/en
Priority to CA3037260A priority patent/CA3037260A1/en
Priority to JP2019518267A priority patent/JP2019529514A/en
Priority to KR1020197012934A priority patent/KR20190058620A/en
Priority to CN201780064731.4A priority patent/CN110023289A/en
Priority to PCT/US2017/054969 priority patent/WO2018067589A1/en
Priority to AU2017338769A priority patent/AU2017338769A1/en
Priority to EP17859036.0A priority patent/EP3523281A4/en
Priority to MX2019003805A priority patent/MX2019003805A/en
Priority to BR112019006887A priority patent/BR112019006887A2/en
Priority to IL258498A priority patent/IL258498A/en
Anticipated expiration legal-status Critical
Priority to ZA2018/02294A priority patent/ZA201802294B/en
Priority to US16/027,990 priority patent/US10865214B2/en
Priority to US16/027,951 priority patent/US11230558B2/en
Priority to US16/027,930 priority patent/US11008341B2/en
Priority to ZA2019/01694A priority patent/ZA201901694B/en
Priority to IL265750A priority patent/IL265750B/en
Priority to US16/818,388 priority patent/US11261199B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • 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
    • C07D239/88—Oxygen 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
    • C07D239/93—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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    • C07D403/02—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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    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
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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
    • 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
    • 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
  • 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.
  • 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.
  • FIG. 2 shows Western blots of LC3-II levels in primary cortical neurons following a 6 hour treatment with WHYKD 1 ( ⁇ 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 WHYKD 1 (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 ⁇ ), and their ability to convert phospholipids to phosphatidylethanols in the presence of ethanol.
  • C Control
  • 12 WHYKD12
  • 15 WHYKD
  • 19 WHYKD 19
  • 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 ⁇ ), and their ability to convert phospholipids to phosphatidylethanols in the presence of ethanol.
  • PLD phospholipase D
  • PLD1 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.
  • inhibition of PLD results in higher levels of tau and p62 aggregates in organotypic brain slices.
  • Y 1 and Y 2 are independently selected from the group consisting of CH and N;
  • X is selected from the group consisting of H, halide, and aryl
  • R 1 is selected from the group consisting of optionally substituted thioheteroaryl, hydroxyl-substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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:
  • the compound is:
  • the compound is:
  • Y 1 is CH
  • R 1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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 optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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
  • R 1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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 thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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 thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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 thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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 thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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
  • R 2 is optionally substituted (2-aminoethyl)aryl
  • the compound is selected from the group consisting of:
  • Y 3 is CH
  • R 2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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 thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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 is CH or N
  • R is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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 thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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 thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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:
  • X is H or halide
  • Z 1 is O
  • R 4 is selected from the group consisting of H, optionally substituted alkyl, Et, CF 3 , optionally substituted cycloalkyl, optionally substituted aryl, optionally
  • 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.
  • Example 1 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
  • X H, F, CI, Br, I, CH 3 , CF 3
  • R 1 H, alkyl, cycloalkyl, aryl, heteroaryl
  • Scheme 2 shows preparation of 1 -chloro-7-fluoroisoquinoline.
  • R 1 ⁇ , alkyl, cycloalkyi, aryl, heteroaryl
  • R 1 H, alkyl, cycloalkyi, aryl, heteroaryl
  • R 1 H, alkyl, cycloalkyi, aryl, heteroaryl
  • R 1 H, alkyl, cycloalkyl, aryl, heteroaryl
  • 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.
  • Table 7 Modifications to the core and side chain (Series 3)
  • Table 8 Modifications to the core and side chain (Series 4)
  • Table 9 Modifications to the core and side chain (Series 5)
  • Table 10 Modifications to the core and side chain (Series 6)
  • Table 1 1 Modifications to the core and side chain (Series 7)
  • Table 12 Modifications to the core and side chain (Series 8)
  • 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 ⁇ concentration (FIG. 4) and at 1 ⁇ (FIG. 5).
  • FIPI is a non-competitive inhibitor of PLD activity and was used as a negative control.

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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

ACTIVATORS OF AUTOPHAGIC FLUX AND PHOSPHOLIPASE D AND
CLEARANCE OF PROTEIN AGGREGATES INCLUDING TAU AND TREATMENT
OF PROTEINOPATHIES
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims benefit to U.S. Provisional Application Serial No. 62/237,342, filed October 5, 2015. The entire contents of the above application are incorporated by reference as if recited in full herein.
FIELD OF THE DISCLOSURE
[0002] 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
[0003] 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 (Αβ) 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.
[0004] 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
[0005] In some embodiments, compounds including pharmaceutically acceptable salts thereof, which are disclosed herein, are provided.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] These and other aspects of the invention are further disclosed in the detailed description and examples which follow. BRIEF DESCRIPTION OF THE DRAWINGS
[0010] 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.
[0011] FIG. 1 is a graph showing a photodiode array (PDA) spectrum of WHYKD8 in mouse brain.
[0012] FIG. 2 shows Western blots of LC3-II levels in primary cortical neurons following a 6 hour treatment with WHYKD 1 (± BafA1 ) or WHYKD5.
[0013] FIG. 3 shows Western blots of LC3-II, tau, and p62 levels in organotypic slice cultures following a 6 hour treatment with WHYKD 1 (top) or WHYKD3, WHYKD5, WHYKD8, WHYKD9, or WHYKD12 (bottom).
[0014] FIG. 4 is a bar graph showing the activation of phospholipase D (PLD) by the WHYKD series compounds (10μΜ), and their ability to convert phospholipids to phosphatidylethanols in the presence of ethanol. C = Control, 12 = WHYKD12, 15 = WHYKD 15, 19 = WHYKD 19, 5 = WHYKD5, 8 = WHYKD8, Fipi = a noncompetitive inhibitor of PLD activity.
[0015] FIG. 5 is a bar graph showing the activation of phospholipase D (PLD) by the WHYKD series compounds (1 μΜ), and their ability to convert phospholipids to phosphatidylethanols in the presence of ethanol.
DETAILED DESCRIPTION OF THE INVENTION
[0016] 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 (DaH'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.
[0017] In some embodiments, a compound is provided having the formula (II):
Figure imgf000005_0001
wherein Y1 and Y2 are independently selected from the group consisting of CH and N;
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 thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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. [0018] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000006_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0019] In one embodiment the compound is:
Figure imgf000007_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0020] In another embodiment the compound is:
Figure imgf000007_0002
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0021] In some embodiments, a compound is provided having the formula (III):
wherein Y1 is CH;
Figure imgf000007_0003
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 thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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. some embodiments, the compound is selected from the group
Figure imgf000008_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0023] In some embodiments, a compound is provided having the formula
(IV):
Figure imgf000008_0002
wherein X is halide;
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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.
[0024] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000009_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0025] In some embodiments, a compound is provided having the formula (V):
Figure imgf000009_0002
wherein X is H;
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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.
[0026] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000010_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0027] In some embodiments, a compound is provided having the formula
(VI):
wherein X is H;
Figure imgf000010_0002
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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.
[0028] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000011_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0029] In some embodiments, a compound is provided having the formula (VII):
Figure imgf000011_0002
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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.
[0030] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000012_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0031] In some embodiments, a compound is provided having the formula
(VIII):
Figure imgf000012_0002
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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.
[0032] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000013_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0033] In some embodiments, a compound is provided having the formula (IX):
Figure imgf000013_0002
wherein Y3 is CH or N;
wherein R2 is optionally substituted (2-aminoethyl)aryl,
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0034] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000014_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0035] In some embodiments, a compound is provided having the formula (X):
Figure imgf000014_0002
wherein Y3 is CH;
wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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.
[0036] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000015_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0037] In some embodiments, a compound is provided having the formula (XI):
Figure imgf000015_0002
wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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.
[0038] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000016_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0039] In some embodiments, a compound is provided having the formula (XII):
Figure imgf000016_0002
wherein Y is CH or N;
wherein R is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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.
[0040] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000017_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0041] In some embodiments, a compound is provided having the formula
(XIII):
Figure imgf000017_0002
wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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.
[0042] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000018_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0043] In some embodiments, a compound is provided having the formula
(XIV):
Figure imgf000018_0002
wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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.
[0044] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000019_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0045] In some embodiments, a compound is provided having the formula
(XV):
Figure imgf000019_0002
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 imgf000019_0003
[0046] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000020_0001
Figure imgf000020_0002
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
[0048] In some embodiments a pharmaceutical composition is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof.
[0049] 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.
[0050] 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.
[0051] 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
[0052] 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
[0053] Scheme 1 shows the synthesis of compounds of the formula:
Figure imgf000022_0001
e.g., compounds of formula (II) and formula
Scheme 1
Figure imgf000022_0002
X = H, F, CI, Br, I, CH3, CF3
Y= S, NH, N
Y1= CH, N
Y2 = CH, N
Y3 = CH, N
R1 = H, alkyl, cycloalkyl, aryl, heteroaryl
n = 0, 1
[0054] Scheme 2 shows preparation of 1 -chloro-7-fluoroisoquinoline.
Scheme 2
Figure imgf000023_0001
[0055] Scheme 3 shows the synthesis of compounds of the formula:
Figure imgf000023_0002
e.g., compounds of formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII).
Scheme 3
Figure imgf000024_0001
Υ= CH, Ν
Υ1= CH, Ν
Υ2 = CH, Ν
Y3 = CH, Ν
Y4 = CH, Ν
Y5 = CH, Ν
Ζ = S, Ν, ΝΗ
R1 = Η, alkyl, cycloalkyi, aryl, heteroaryl
n = 0, 1
[0056] Scheme 4 shows the synthesis of compounds of the formula:
Figure imgf000024_0002
e.g., compounds of formula (XII), and formula (XIII).
Scheme 4
Figure imgf000025_0001
Y= CH, N
Y1= CH, N
Z = S, N, NH
R1 = H, alkyl, cycloalkyi, aryl, heteroaryl
n = 0, 1
[0057] Scheme 5 shows the synthesis of compounds of the formula:
Figure imgf000025_0002
e.g., compounds of formula (IX), formula (X), and formula (XI).
Scheme 5
Figure imgf000025_0003
x = o, S
Y= CH, N
Y1= CH, N
Z = S, N, NH
R1 = H, alkyl, cycloalkyi, aryl, heteroaryl
n = 0, 1 [0058] Scheme 6 shows the synthesis of compounds of the formula:
Figure imgf000026_0001
e.g., compounds of formula (XIV).
Scheme 6
Figure imgf000026_0002
Y= CH, N
Y1= CH, N
Z = S, N, NH
R1 = H, alkyl, cycloalkyl, aryl, heteroaryl
n = 0, 1
Example 2
Activators of autophagic flux and phospholipase D
[0059] 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.
[0060] Activators according to the formula:
Figure imgf000027_0001
were synthesized according to the schemes above. Molecular weights and log P were calculated. Results are shown in Table 1 below.
Table 1
Figure imgf000027_0002
Figure imgf000028_0001
Figure imgf000029_0002
1] Activators according to the formula:
Figure imgf000029_0001
were synthesized according to the schemes above. Molecular weights and log P were calculated. Results are shown in Table 2 below.
Table 2
Figure imgf000030_0002
[0062] Activators according to the formula:
Figure imgf000030_0001
were synthesized according to the schemes above. Molecular weights and log P were calculated. Results are shown in Table 3 below. Table 3
Figure imgf000031_0002
[0063] Activators according to the formula:
Figure imgf000031_0001
were synthesized according to the schemes above. Molecular weights and log P were calculated. Results are shown in Table 4 below. Table 4
Figure imgf000032_0002
Example 3
Design of derivatives
[0064] Several series of derivatives were synthesized based on the following lead compounds:
Figure imgf000032_0001
[0065] In addition to log P, the topological polar surface area (tPSA), CLogP (log P calculated by group contribution method), and LogS (solubility) were calculated. Results are shown in the Tables below.
Table 5: Modifications to the core and side chain (Series 1 )
Figure imgf000032_0003
Figure imgf000033_0001
Table 6: Modifications to the core and side chain (Series 2)
Figure imgf000034_0001
Figure imgf000035_0002
Table 7: Modifications to the core and side chain (Series 3)
Figure imgf000035_0001
Figure imgf000036_0001
Table 8: Modifications to the core and side chain (Series 4)
Figure imgf000037_0001
Figure imgf000038_0002
Table 9: Modifications to the core and side chain (Series 5)
Figure imgf000038_0001
Figure imgf000039_0001
Table 10: Modifications to the core and side chain (Series 6)
Figure imgf000040_0001
Figure imgf000041_0002
Table 1 1 : Modifications to the core and side chain (Series 7)
Figure imgf000041_0001
Figure imgf000042_0001
Table 12: Modifications to the core and side chain (Series 8)
Figure imgf000043_0001
Figure imgf000044_0001
Table 13: Modifications to the core and side chain (Series 9)
Figure imgf000044_0002
Figure imgf000045_0001
Table 14: Modifications to the core and side chain (Series 10)
Figure imgf000045_0002
Figure imgf000046_0001
Figure imgf000047_0002
Table 15: Quinazolinones (Series 1 1 )
Figure imgf000047_0001
Example 4
Detection and results of WHYKD compounds
[0066] 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). [0067] 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.
[0068] 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.
[0069] 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.
[0070] 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 10μΜ concentration (FIG. 4) and at 1 μΜ (FIG. 5). FIPI is a non-competitive inhibitor of PLD activity and was used as a negative control.
[0071] All patents, patent applications, and publications cited above are incorporated herein by reference in their entirety as if recited in full herein.
[0072] 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

What is claimed is:
1 . A compound having the formula (II):
Figure imgf000049_0001
wherein Y1 and Y2 are, independently selected from the group consisting of CH and N;
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 thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi is optionally replaced with a heteroatom selected from the group consisting of 0, 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 imgf000049_0002
Figure imgf000050_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
The compound of claim 1 , wherein the compound
Figure imgf000050_0002
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
The compound of claim 1 , wherein the compound
Figure imgf000051_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
5. A compound having the formula (III):
Figure imgf000051_0002
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 thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi is optionally replaced with a heteroatom selected from the group consisting of 0, 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 imgf000052_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
A compound having the formula (IV):
wherein X is halide;
Figure imgf000052_0002
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi is optionally replaced with a heteroatom selected from the group consisting of 0, 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 imgf000053_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
9. A compound having the formula (V):
Figure imgf000053_0002
wherein X is H;
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi is optionally replaced with a heteroatom selected from the group consisting of 0, 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 imgf000054_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
1 1 . A compound having the formula (VI):
wherein X is H;
Figure imgf000054_0002
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi 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 1 1 , wherein the compound is selected from the group consisting of:
Figure imgf000055_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
13. A compound having the formula (VII):
Figure imgf000055_0002
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi is optionally replaced with a heteroatom selected from the group consisting of 0, 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 imgf000056_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
15. A compound having the formula (VIII):
Figure imgf000056_0002
wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi is optionally replaced with a heteroatom selected from the group consisting of 0, 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 imgf000057_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
A compound having the formula (IX):
Figure imgf000057_0002
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 imgf000058_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
A compound having the formula (X):
wherein Y3 is CH;
Figure imgf000058_0002
wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi is optionally replaced with a heteroatom selected from the group consisting of 0, 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 imgf000059_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
A compound having the formula (XI):
Figure imgf000059_0002
wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi is optionally replaced with a heteroatom selected from the group consisting of 0, 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 imgf000060_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
A compound having the formula (XII):
wherein Y4 is CH or N;
Figure imgf000060_0002
wherein R3 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi is optionally replaced with a heteroatom selected from the group consisting of 0, 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 imgf000061_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
A compound having the formula (XIII):
Figure imgf000061_0002
wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi is optionally replaced with a heteroatom selected from the group consisting of 0, 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 imgf000062_0001
27. A compound having the formula (XIV):
Figure imgf000062_0002
wherein R2 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyi wherein 1 -3 carbon atoms of the cycloalkyi is optionally replaced with a heteroatom selected from the group consisting of 0, 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 imgf000063_0001
A compound having the formula (XV):
wherein X is H or halide;
Figure imgf000063_0002
wherein Z1 is 0;
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 imgf000063_0003
30. The compound of claim 29, wherein the compound is selected from the group consisting of:
Figure imgf000064_0001
or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
The compound of claim 29 wherein the compound
Figure imgf000064_0002
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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