# US 10,865,214 B2 · Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,865,214 B2 - Document ID: US10865214B2 - Status: Granted - Kind: B2 - Application number: 16/027,990 - Filed: 2018-07-05 - Published: 2018-11-01 - Granted: 2020-12-15 - Earliest claimed: 2015-10-05 - Assignees: The Trustees of Columbia University in they City of New York; NY State Psychiatric Institute - Applicants: The Trustees of Columbia University In the City of New York; Ny State Psychiatric Institute - Inventors: Kirsten Alison Rinderspacher; Wai Yu; Karen Duff; Donald Landry; Shi-Xian Deng - Web page: https://patentgrep.com/patent/US10865214B2 ## CPC - C07D 513/04: Ortho-condensed systems - A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine - A61P 25/28: 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 - C07D 217/22: 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 - C07D 239/86: with hetero atoms directly attached in position 4 - C07D 239/88: Oxygen atoms - C07D 239/93: Sulfur atoms - C07D 239/94: Nitrogen atoms - C07D 401/12: linked by a chain containing hetero atoms as chain links - C07D 403/12: linked by a chain containing hetero atoms as chain links - C07D 405/12: linked by a chain containing hetero atoms as chain links - C07D 471/04: Ortho-condensed systems - C07D 491/04: Ortho-condensed systems - C07D 491/048: the oxygen-containing ring being five-membered - C07D 495/04: Ortho-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## 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. ## Claims ### Claim 1 A compound having the formula (IV): wherein X is halide; wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof. ### Claim 2 (depends on 1) The compound of claim 1, wherein the compound is selected from the group consisting of: or a salt thereof. ### Claim 3 A compound having the formula (V): wherein X is H; wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, 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. ### Claim 4 (depends on 3) The compound of claim 3, wherein the compound is selected from the group consisting of: or a salt thereof. ### Claim 5 A compound having the formula (VI): wherein X is H; wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, 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. ### Claim 6 (depends on 5) The compound of claim 5, wherein the compound is selected from the group consisting of: or a salt thereof. ### Claim 7 (depends on 1, 3, 5) A pharmaceutical composition comprising a compound of any one of claims 1, 3 or 5 or a pharmaceutically acceptable salt thereof. ### Claim 8 (depends on 1, 3, 5) 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, 3 or 5, wherein the neurodegenerative disease is a proteinopathy. ### Claim 9 (depends on 8) The method of claim 8, wherein the proteinopathy is a tauopathy. ### Claim 10 (depends on 1, 5, 6) 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, 6 or 5, wherein the neurodegenerative disease is Alzheimer's disease. ### Claim 11 (depends on 1, 3, 5) 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, 3 or 5. ### Claim 12 (depends on 1, 3, 5) A method of treating a proteinopathy comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1, 3 or 5. ### Claim 13 (depends on 1, 3, 5) A method of treating a tauopathy comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1, 3 or 5. ### Claim 14 (depends on 7) A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 7, wherein the neurodegenerative disease is a proteinopathy. ### Claim 15 (depends on 14) The method of claim 14, wherein the proteinopathy is a tauopathy. ### Claim 16 (depends on 7) A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 7, wherein the neurodegenerative disease is Alzheimer's disease. ### Claim 17 (depends on 7) A method of enhancing autophagic flux comprising providing to a cell or a protein aggregate an effective amount of the pharmaceutical composition of claim 7. ### Claim 18 A method of treating a proteinopathy comrising administering to a subject in need thereof an effective amount of the pharmaceutical composition of cliam 7. ### Claim 19 (depends on 7) A method of treating a tauopathy comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 7.