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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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
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Ny State Psychiatric Institute
Columbia University
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    • 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
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    • 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
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    • C07—ORGANIC CHEMISTRY
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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
    • C—CHEMISTRY; METALLURGY
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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
    • 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
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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
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    • C07D239/93—Sulfur atoms
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    • 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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    • 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
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    • 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
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    • 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.

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US15/765,801 2015-10-05 2016-10-05 Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies Abandoned US20190112317A1 (en)

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Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190112317A1 (en) * 2015-10-05 2019-04-18 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies
WO2020109039A1 (en) 2018-11-28 2020-06-04 Basf Se Pesticidal compounds
CA3119426A1 (en) * 2018-11-30 2020-06-04 Celularity Inc. Aromatic compounds for use in activating hematopoietic stem and progenitor cells
CN116507314A (zh) 2020-09-17 2023-07-28 株式会社力森诺科 自噬激活剂
CN116600815A (zh) 2020-09-17 2023-08-15 株式会社力森诺科 自噬激活剂
WO2022059775A1 (ja) 2020-09-17 2022-03-24 昭和電工株式会社 オートファジー活性化剤
JPWO2022059763A1 (enExample) * 2020-09-17 2022-03-24
CN112209888B (zh) * 2020-10-14 2024-02-02 河南中医药大学 一种4-芳巯基喹唑啉类化合物、制备方法和医药用途
EP4426702A1 (en) * 2021-11-04 2024-09-11 Skyhawk Therapeutics, Inc. Condensed-pyrazine amine derivatives for treating sca3

Family Cites Families (157)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3272824A (en) 1962-12-06 1966-09-13 Norwich Pharma Co 4-amino-6, 7-di(lower) alkoxyquinolines
US3266990A (en) 1963-09-24 1966-08-16 Warner Lambert Pharmaceutical Derivatives of quinazoline
US3936461A (en) 1973-09-24 1976-02-03 Warner-Lambert Company Substituted 4-benzylquinolines
US4114939A (en) 1976-09-13 1978-09-19 Conco Inc. Vacuum pickup head
IL89028A0 (en) 1988-01-29 1989-08-15 Lilly Co Eli Quinoline,quinazoline and cinnoline derivatives
IL89027A (en) 1988-01-29 1993-01-31 Lilly Co Eli Quinazoline derivatives, process for their preparation and fungicidal, insecticidal and miticidal compositions containing them
IL89029A (en) 1988-01-29 1993-01-31 Lilly Co Eli Fungicidal quinoline and cinnoline derivatives, compositions containing them, and fungicidal methods of using them
WO1990005523A2 (en) 1988-11-15 1990-05-31 The Upjohn Company Phenanthrolinedicarboxylate esters, 4-aminoquinoline and isoquinoline derivatives as inhibitors of hiv reverse transcriptase
US5034393A (en) * 1989-07-27 1991-07-23 Dowelanco Fungicidal use of pyridopyrimidine, pteridine, pyrimidopyrimidine, pyrimidopyridazine, and pyrimido-1,2,4-triazine derivatives
WO1992017452A1 (en) 1991-04-03 1992-10-15 Korea Research Institute Of Chemical Technology 2-quinolinone derivatives
US5721237A (en) 1991-05-10 1998-02-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties
JPH05213884A (ja) 1991-06-14 1993-08-24 Upjohn Co:The 新規な４−アミノキノリン類およびこれを有効成分とする高血圧・鬱血性心不全の予防・治療剤
NZ243082A (en) 1991-06-28 1995-02-24 Ici Plc 4-anilino-quinazoline derivatives; pharmaceutical compositions, preparatory processes, and use thereof
PT100905A (pt) 1991-09-30 1994-02-28 Eisai Co Ltd Compostos heterociclicos azotados biciclicos contendo aneis de benzeno, ciclo-hexano ou piridina e de pirimidina, piridina ou imidazol substituidos e composicoes farmaceuticas que os contem
AU661533B2 (en) 1992-01-20 1995-07-27 Astrazeneca Ab Quinazoline derivatives
DE4208254A1 (de) 1992-03-14 1993-09-16 Hoechst Ag Substituierte pyrimidine, verfahren zu ihrer herstellung und ihre verwendung als schaedlingsbekaempfungsmittel und fungizid
US5326766A (en) * 1992-08-19 1994-07-05 Dreikorn Barry A 4-(2-(4-(2-pyridinyloxy)phenyl)ethoxy)quinazoline and analogues thereof
WO1994004527A1 (en) 1992-08-19 1994-03-03 Dowelanco Pyridylethoxy-, pyridylethylamino-, and pyridylpropyl-derivatives of quinoline and quinazoline as insecticides and fungicides
GB9314893D0 (en) 1993-07-19 1993-09-01 Zeneca Ltd Quinazoline derivatives
GB9314884D0 (en) 1993-07-19 1993-09-01 Zeneca Ltd Tricyclic derivatives
IL112249A (en) 1994-01-25 2001-11-25 Warner Lambert Co Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds
GB9510757D0 (en) 1994-09-19 1995-07-19 Wellcome Found Therapeuticaly active compounds
US5650415A (en) 1995-06-07 1997-07-22 Sugen, Inc. Quinoline compounds
JPH11507052A (ja) 1995-06-07 1999-06-22 スージェン・インコーポレーテッド キナゾリンおよび医薬組成物
GB9514265D0 (en) 1995-07-13 1995-09-13 Wellcome Found Hetrocyclic compounds
DE69622183D1 (de) 1995-11-07 2002-08-08 Kirin Brewery Chinolinderivate und chinazolinderivate welche die autophosphorylierung des von blutplättchen abstammenden wachstumsfaktorrezeptors inhibiren und sie enthaltende pharmazeutische zusammensetzungen
CA2242425C (en) 1996-02-13 2006-07-18 Zeneca Limited Quinazoline derivatives as vegf inhibitors
US6391874B1 (en) 1996-07-13 2002-05-21 Smithkline Beecham Corporation Fused heterocyclic compounds as protein tyrosine kinase inhibitors
CN1252054C (zh) 1996-09-25 2006-04-19 曾尼卡有限公司 抑制生长因子的作用的喹啉衍生物
US6002008A (en) 1997-04-03 1999-12-14 American Cyanamid Company Substituted 3-cyano quinolines
UA73073C2 (uk) 1997-04-03 2005-06-15 Уайт Холдінгз Корпорейшн Заміщені 3-ціанохіноліни, спосіб їх одержання та фармацевтична композиція
US6251912B1 (en) 1997-08-01 2001-06-26 American Cyanamid Company Substituted quinazoline derivatives
AU1631699A (en) 1997-12-18 1999-07-05 E.I. Du Pont De Nemours And Company Cyclohexylamine arthropodicides and fungicides
ES2219033T3 (es) * 1998-07-22 2004-11-16 Daiichi Suntory Pharma Co., Ltd. Inhibidores de nf-kappa b que contienen derivados de indano como ingrediente activo.
US6297258B1 (en) 1998-09-29 2001-10-02 American Cyanamid Company Substituted 3-cyanoquinolines
ES2241324T3 (es) 1998-10-08 2005-10-16 Astrazeneca Ab Derivados de quinazolina.
IL144461A0 (en) 1999-01-22 2002-05-23 Kirin Brewery Quinoline and quinazoline derivatives and pharmaceutical compositions containing them
EE05345B1 (et) 1999-02-10 2010-10-15 Astrazeneca Ab Kinasoliini derivaadid angiogeneesi inhibiitoritena
GB9904103D0 (en) 1999-02-24 1999-04-14 Zeneca Ltd Quinoline derivatives
GB9910579D0 (en) 1999-05-08 1999-07-07 Zeneca Ltd Chemical compounds
GB9910577D0 (en) 1999-05-08 1999-07-07 Zeneca Ltd Chemical compounds
GB9910580D0 (en) 1999-05-08 1999-07-07 Zeneca Ltd Chemical compounds
HK1046688A1 (zh) 1999-09-21 2003-01-24 Astrazeneca Ab 喹唑啉化合物和含有喹唑啉化合物的藥物組合物
EE200200119A (et) 1999-09-21 2003-04-15 Astrazeneca Ab Kinasoliini derivaadid ja nende kasutamine ravimitena
GB9930061D0 (en) 1999-12-20 2000-02-09 Glaxo Group Ltd Quinolone compounds for use in treating viral infections
EP1243582A4 (en) 1999-12-24 2003-06-04 Kirin Brewery CHINOLINE AND CHINAZOLINE DERIVATIVES AND MEDICATIONS CONTAINING THEM
US6906063B2 (en) 2000-02-04 2005-06-14 Portola Pharmaceuticals, Inc. Platelet ADP receptor inhibitors
IL151626A0 (en) 2000-04-07 2003-04-10 Astrazeneca Ab Quinazoline compounds
BR0111754A (pt) 2000-06-28 2003-04-29 Astrazeneca Ab Uso de um composto, método para inibir aurora 2 quinase em um animal de sangue quente, composto, e, composição farmacêutica
DE10042064A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Chinazoline, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US6576644B2 (en) 2000-09-06 2003-06-10 Bristol-Myers Squibb Co. Quinoline inhibitors of cGMP phosphodiesterase
US7067532B2 (en) 2000-11-02 2006-06-27 Astrazeneca Substituted quinolines as antitumor agents
ATE409185T1 (de) 2001-04-19 2008-10-15 Astrazeneca Ab Chinazolin derivate
EP1382604B1 (en) 2001-04-27 2005-12-28 Kirin Beer Kabushiki Kaisha Quinoline derivative having azolyl group and quinazoline derivative
PE20030008A1 (es) 2001-06-19 2003-01-22 Bristol Myers Squibb Co Inhibidores duales de pde 7 y pde 4
CA2454538A1 (en) 2001-06-22 2003-01-03 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives capable of inhibiting autophosphorylation of hepatocyte growth factor receptors, and pharmaceutical composition comprising the same
ES2272737T3 (es) 2001-07-16 2007-05-01 Astrazeneca Ab Derivados de quinolina y su uso como inhibidores de tirosina quinasas.
JP4383870B2 (ja) 2001-10-17 2009-12-16 協和発酵キリン株式会社 線維芽細胞増殖因子受容体自己リン酸化を阻害するキノリン誘導体およびキナゾリン誘導体並びにそれらを含有する医薬組成物
EP1451156A4 (en) 2001-11-27 2005-05-25 Merck & Co Inc 4-AMINOCHINOLINVERBINDUNGEN
AU2002347359A1 (en) 2001-12-05 2003-06-17 Astrazeneca Ab Quinoline derivatives
AU2002347336A1 (en) 2001-12-05 2003-06-17 Astrazeneca Ab Quinoline derivatives
GB0129099D0 (en) 2001-12-05 2002-01-23 Astrazeneca Ab Chemical compounds
WO2003047583A1 (en) 2001-12-05 2003-06-12 Astrazeneca Ab Pharmaceutical compositions comprising benzofuranyl substituted 3-cyanoquinoline derivatives and their use for the treatment of solid tumours
AU2002347360A1 (en) 2001-12-05 2003-06-17 Astrazeneca Ab Pharmaceutical compositions comprising benzofuranyl substituted 3-cyanoquinoline derivatives and their use for the treatment of solid tumours
AU2002365664A1 (en) 2001-12-05 2003-06-17 Astrazeneca Ab Quinoline derivatives as antitumour agents
WO2003055866A1 (en) 2001-12-21 2003-07-10 Bayer Pharmaceuticals Corporation Quinazoline and quinoline derivative compounds as inhibitors of prolylpeptidase, inducers of apoptosis and cancer treatment agents
EP2292615A1 (en) 2002-02-01 2011-03-09 AstraZeneca AB Quinazoline compounds
JPWO2003093238A1 (ja) 2002-05-01 2005-09-08 麒麟麦酒株式会社 マクロファージコロニー刺激因子受容体自己リン酸化を阻害するキノリン誘導体およびキナゾリン誘導体
DE10221018A1 (de) 2002-05-11 2003-11-27 Boehringer Ingelheim Pharma Verwendung von Hemmern der EGFR-vermittelten Signaltransduktion zur Behandlung von gutartiger Prostatahyperplasie (BPH)/Prostatahypertrophie
MY140680A (en) 2002-05-20 2010-01-15 Bristol Myers Squibb Co Hepatitis c virus inhibitors
GB0215823D0 (en) 2002-07-09 2002-08-14 Astrazeneca Ab Quinazoline derivatives
EP1528925B1 (en) 2002-07-09 2009-04-22 Astrazeneca AB Quinazoline derivatives for use in the treatment of cancer
EP1521747B1 (en) 2002-07-15 2018-09-05 Symphony Evolution, Inc. Receptor-type kinase modulators and methods of use
AU2003257666A1 (en) 2002-08-23 2004-03-11 Kirin Beer Kabushiki Kaisha COMPOUND HAVING TGFss INHIBITORY ACTIVITY AND MEDICINAL COMPOSITION CONTAINING THE SAME
WO2004039782A1 (ja) 2002-10-29 2004-05-13 Kirin Beer Kabushiki Kaisha Ｆｌｔ３自己リン酸化を阻害するキノリン誘導体およびキナゾリン誘導体並びにそれらを含有する医薬組成物
GB0225579D0 (en) 2002-11-02 2002-12-11 Astrazeneca Ab Chemical compounds
RU2350618C2 (ru) 2002-11-04 2009-03-27 Астразенека Аб ПРОИЗВОДНЫЕ ХИНАЗОЛИНА В КАЧЕСТВЕ ИНГИБИТОРОВ Src ТИРОЗИНКИНАЗЫ
JO2785B1 (en) 2003-05-27 2014-03-15 شركة جانسين فارماسوتيكا ان. في Quinazoline derivatives
ATE440825T1 (de) * 2003-06-06 2009-09-15 Vertex Pharma Pyrimidin-derivate zur verwendung als modulatoren von atp-bindende kassette transportern
CN1838950A (zh) * 2003-06-23 2006-09-27 神经化学（国际）有限公司 治疗蛋白质聚集疾病的方法
US20050026805A1 (en) 2003-07-14 2005-02-03 Ici Americas, Inc. Solvated nonionic surfactants and fatty acids
GB0318422D0 (en) 2003-08-06 2003-09-10 Astrazeneca Ab Chemical compounds
GB0322722D0 (en) 2003-09-27 2003-10-29 Glaxo Group Ltd Compounds
AU2004298448B2 (en) 2003-12-18 2010-09-09 Janssen Pharmaceutica N.V. Pyrido- and pyrimidopyrimidine derivatives as anti- proliferative agents
EA200601176A1 (ru) 2003-12-18 2006-10-27 Янссен Фармацевтика Н.В. 3-цианохинолиновые производные с антипролиферативной активностью
AP2006003619A0 (en) 2003-12-23 2006-06-30 Pfizer Novel quinoline derivatives
CN1930128A (zh) 2004-01-16 2007-03-14 惠氏公司 受体酪氨酸激酶抑制剂的喹啉中间体及其合成
AU2006216266C1 (en) 2005-02-23 2010-08-26 Shionogi & Co., Ltd. Quinazoline derivative having tyrosine kinase inhibitory activity
CN101115736A (zh) * 2005-03-14 2008-01-30 神经研究公司 钾通道调节剂和它们的医药用途
NZ556248A (en) * 2005-03-14 2010-06-25 Neurosearch As Pyrazolyl-quinazoline potassium channel modulating agents and their medical use
WO2006108059A1 (en) 2005-04-06 2006-10-12 Exelixis, Inc. C-met modulators and methods of use
GB0509227D0 (en) 2005-05-05 2005-06-15 Chroma Therapeutics Ltd Intracellular enzyme inhibitors
US20090221624A1 (en) 2005-05-06 2009-09-03 Olivo Paul D 4-aminoquinoline compounds for treating virus-related conditions
KR101353763B1 (ko) 2005-11-07 2014-01-21 에자이 알앤드디 매니지먼트 가부시키가이샤 혈관 신생 저해 물질과 ｃ―ｋｉｔ 키나아제 저해 물질의병용
WO2007055513A1 (en) 2005-11-08 2007-05-18 Hanmi Pharm. Co., Ltd. Quinazoline derivatives as a signal transduction inhibitor and method for the preparation thereof
CA2833706C (en) 2005-11-11 2014-10-21 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
WO2007076035A2 (en) 2005-12-21 2007-07-05 Abbott Laboratories Anti-viral compounds
PL1981863T3 (pl) 2006-01-26 2013-03-29 Boehringer Ingelheim Int Sposób wytwarzania pochodnych chinazoliny podstawionych przez ugrupowanie aminokrotonyloaminowe
US7601716B2 (en) 2006-05-01 2009-10-13 Cephalon, Inc. Pyridopyrazines and derivatives thereof as ALK and c-Met inhibitors
US8080563B2 (en) 2006-07-07 2011-12-20 Kalypsys Bicyclic heteroaryl inhibitors of PDE4
US8673929B2 (en) 2006-07-20 2014-03-18 Gilead Sciences, Inc. 4,6-di- and 2,4,6-trisubstituted quinazoline derivatives and pharmaceutical compositions useful for treating viral infections
JP2010501570A (ja) 2006-08-23 2010-01-21 エックスティーエル バイオファーマシューティカルズ リミテッド ４−チオ置換キノリンおよびナフチリジン化合物
CN101553490A (zh) * 2006-10-23 2009-10-07 Sgx药品公司 用作蛋白激酶调节剂的二环三唑类化合物
CA2676173A1 (en) 2007-02-16 2008-08-28 Amgen Inc. Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors
US8148532B2 (en) 2007-03-14 2012-04-03 Guoqing Paul Chen Spiro substituted compounds as angiogenesis inhibitors
US8163923B2 (en) 2007-03-14 2012-04-24 Advenchen Laboratories, Llc Spiro substituted compounds as angiogenesis inhibitors
DE102007032739A1 (de) 2007-07-13 2009-01-15 Merck Patent Gmbh Chinazolinamidderivate
US8143276B2 (en) 2007-08-22 2012-03-27 Xtl Biopharmaceuticals Ltd. 4-thio substituted quinoline and naphthyridine compounds
CN101784533B (zh) 2007-08-22 2013-08-21 艾博特股份有限两合公司 4-苄基氨基喹啉、含有它们的药物组合物和它们在治疗中的用途
HRP20161522T1 (hr) 2008-01-18 2017-02-10 Natco Pharma Limited Derivati 6.7-dialkoksi kinazolina korisni za liječenje poremećaja povezanih s rakom
WO2009148659A2 (en) 2008-03-05 2009-12-10 Georgetown University Antimalarial quinolines and methods of use thereof
AU2009226136B2 (en) 2008-03-17 2013-08-15 Ambit Biosciences Corporation Quinazoline derivatives as RAF kinase modulators and methods of use thereof
US7829574B2 (en) 2008-05-09 2010-11-09 Hutchison Medipharma Enterprises Limited Substituted quinazoline compounds and their use in treating angiogenesis-related diseases
CA2727103A1 (en) 2008-07-03 2010-01-07 Merck Patent Gmbh Naphthyridinones as aurora kinase inhibitors
WO2010018555A2 (en) 2008-08-14 2010-02-18 University Of Cape Town Quinoline compounds containing a dibemethin group
US8268843B2 (en) 2008-08-29 2012-09-18 Dow Agrosciences, Llc. 5,8-difluoro-4-(2-(4-(heteroaryloxy)-phenyl)ethylamino)quinazolines and their use as agrochemicals
IT1393351B1 (it) 2009-03-16 2012-04-20 Eos Ethical Oncology Science Spa In Forma Abbreviata Eos Spa Procedimento per la preparazione della 6-(7-((1-amminociclopropil)metossi)-6-metossichinolin-4-ilossi)-n-metil-1-naftammide e suoi intermedi di sintesi
JP2012520891A (ja) 2009-03-19 2012-09-10 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング スルホニルキノリンの製造方法
EP2408300B1 (en) 2009-03-21 2016-05-11 Sunshine Lake Pharma Co., Ltd. Amino ester derivatives, salts thereof and methods of use
ES2353093B1 (es) * 2009-05-20 2012-01-03 Consejo Superior De Investigaciones Científicas (Csic) Uso de derivados de quinazolinas y sus composiciones farmacéuticas en enfermedades neurodegenerativas.
CN102625799A (zh) 2009-06-25 2012-08-01 安姆根有限公司 杂环化合物及其用途
PH12012500097A1 (en) * 2009-07-21 2011-01-27 Shanghai Inst Organic Chem Potent small molecule inhibitors of autophagy, and methods of use thereof
WO2011014039A1 (en) * 2009-07-31 2011-02-03 Rohm And Haas Electronic Materials Korea Ltd. Novel organic electroluminescent compounds and organic electroluminescent device using the same
CU24144B1 (es) 2010-01-04 2016-01-29 Nippon Soda Co Compuesto heterocíclico conteniendo nitrógeno y fungicida para el uso en agricultura y jardinería
US8575203B2 (en) 2010-04-21 2013-11-05 Boehringer Ingelheim International Gmbh Chemical compounds
WO2011143444A2 (en) * 2010-05-14 2011-11-17 President And Fellows Of Harvard College Diphenylbutypiperidine autophagy inducers
AU2011271462A1 (en) 2010-06-30 2013-01-10 Amgen Inc. Nitrogen containing heterocyclic compounds as PIK3 -delta inhibitors
WO2012012320A1 (en) * 2010-07-19 2012-01-26 Millenium Pharmaceuticals, Inc. Substituted hydroxamic acids and uses thereof
UY33549A (es) 2010-08-10 2012-01-31 Glaxo Group Ltd Quinolil aminas como agentes inhibidores de las quinasas
WO2012044993A1 (en) * 2010-09-30 2012-04-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Compounds, pharmaceutical compositions, and methods of treating or preventing neurodegenerative diseases or disorders
EP2651405A2 (en) 2010-12-14 2013-10-23 Electrophoretics Limited Casein kinase 1 (ck1 ) inhibitors
WO2012090179A2 (en) * 2010-12-30 2012-07-05 Lupin Limited Isoquinoline derivatives as cannabinoid receptor modulators
JP6026441B2 (ja) 2011-03-04 2016-11-16 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ キナーゼ阻害剤としてのアミノキノリン
US8664230B2 (en) 2011-03-17 2014-03-04 The Asan Foundation Pyridopyrimidine derivatives and use thereof
ITMI20110480A1 (it) 2011-03-25 2012-09-26 F I S Fabbrica Italiana Sint P A Procedimento per la preparazione di lapatinib e suoi sali
EP2734520B1 (en) * 2011-07-19 2016-09-14 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
EA023521B1 (ru) 2011-11-14 2016-06-30 Сефалон, Инк. ПРОИЗВОДНЫЕ УРАЦИЛА В КАЧЕСТВЕ ИНГИБИТОРОВ AXL И c-MET КИНАЗЫ
CN102643268B (zh) 2011-12-30 2014-05-21 沈阳药科大学 喹啉类及噌啉类化合物及其应用
ES2872348T3 (es) 2012-03-19 2021-11-02 Imperial College Innovations Ltd Compuestos de quinazolina y su uso en terapia
EP2752413B1 (en) 2012-03-26 2016-03-23 Fujian Institute Of Research On The Structure Of Matter, Chinese Academy Of Sciences Quinazoline derivative and application thereof
AR092530A1 (es) 2012-09-13 2015-04-22 Glaxosmithkline Llc Compuesto de amino-quinolina, composicion farmaceutica que lo comprende y uso de dicho compuesto para la preparacion de un medicamento
US9024023B2 (en) 2013-01-14 2015-05-05 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Efficient process for the preparation of lapatinib and salts thereof by means of new intermediates
US9353122B2 (en) 2013-02-15 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
MX2015012600A (es) 2013-03-15 2016-07-18 Rexahn Pharmaceuticals Inc Compuestos de tetrahidroisoquinolina-2-il-(quinazolina-4-il) metanona como inhibidores del crecimiento de células cancerígenas.
CN103232401B (zh) * 2013-04-12 2015-11-04 浙江工业大学 一种4-芳硫基喹唑啉类化合物的合成方法
WO2014182643A2 (en) 2013-05-07 2014-11-13 Inhibikase Therapeutics, Inc. Methods for treating hcv infection
MX362747B (es) 2013-05-13 2019-02-05 Shanghai hengrui pharmaceutical co ltd Derivado de ácido cicloalquilo, método de preparación del mismo, y aplicación farmacéutica del mismo.
AU2014353006B2 (en) 2013-11-20 2019-04-04 Signalchem Life Sciences Corp. Quinazoline derivatives as TAM family kinase inhibitors
GB201321146D0 (en) 2013-11-29 2014-01-15 Cancer Rec Tech Ltd Quinazoline compounds
GB201321126D0 (en) * 2013-11-29 2014-01-15 Velgene Biotechnology Autophagy stimulants
JP6510539B2 (ja) * 2014-01-09 2019-05-08 ザ ジェイ． デヴィッド グラッドストーン インスティテューツ， ア テスタメンタリー トラスト エスタブリッシュド アンダー ザ ウィル オブ ジェイ． デヴィッド グラッドストーン 置換ベンゾオキサジン及び関連化合物
JP6377245B2 (ja) 2014-03-24 2018-08-22 グアンドン ジョンシェン ファーマシューティカル カンパニー リミテッド Ｓｍｏ阻害剤としてのキノリン誘導体
FR3019819B1 (fr) 2014-04-09 2018-03-23 Centre National De La Recherche Scientifique (Cnrs) Composes cytotoxiques inhibiteurs de la polymerisation de la tubuline
JP2017513954A (ja) 2014-04-22 2017-06-01 ニンバス アイリス， インコーポレイテッド Ｉｒａｋ阻害剤およびその使用
CN104193728A (zh) * 2014-08-26 2014-12-10 北京大学深圳研究生院 流感病毒抑制剂及其应用
US20190112317A1 (en) * 2015-10-05 2019-04-18 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies
US9853396B1 (en) 2016-12-05 2017-12-26 Delphi Technologies, Inc. Electrical plug having a flexible terminal retention feature

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