Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
  • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
  • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • A61K31/4245—Oxadiazoles
• • 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
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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

Definitions

• Also provided is a method for treating a condition or disorder mediated by at least one histone deacetylase in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein.
• haloalkyl denotes an C 1-6 alkyl group wherein the alkyl is substituted with one halogen up to fully substituted and a fully substituted C 1-6 haloalkyl can be represented by the formula C n L2 n+ i wherein L is a halogen and "n" is 1, 2, 3 or 4; when more than one halogen is present then they may be the same or different and selected from the group consisting of F, CI, Br and I, such as F.
• heterobicyclyl ring systems including a spirocycle include: l-oxa-5- azaspiro[3.3]heptan-5-yl, l-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-l-azaspiro[3.3]heptan- l- yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, l,5-diazaspiro[3.3]heptan-l-yl, 1,6- diazaspiro[3.3]heptan-6-yl, l,6-diazaspiro[3.3]heptan- l-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 1- oxa-5-azaspiro[3.4]octan-5-yl, l-oxa-6-azaspiro[3.4]octan-6-yl, 2-oxa
• histone deacetylase and "HDAC” are intended to refer to any one of a family of enzymes that remove N e -acetyl groups from the ⁇ -amino groups of lysine residues of a protein (for example, a histone, or tubulin). Unless otherwise indicated by context, the term “histone” is meant to refer to any histone protein, including HI, H2A, H2B, H3, H4, and H5, from any species. In some embodiments, the histone deacetylase is a human HDAC, including, but not limited to, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-9, and HDAC- 10.
• R 3 and R 4 together with the nitrogen atom to which they are attached, form a 4 or 7-membered heteromonocyclic group optionally substituted with one to five substituents each independently selected from: C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 haloalkyl, 3 or 4-membered cycloalkoxy, 3 or 4-membered cycloalkyl, 3 or 4-membered heterocycloalkyl, aryl, and heteroaryl, wherein aryl and heteroaryl are optionally further substituted with one to five substituents each independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and halo.
• R 3 and R 4 are as described herein. Also provided is a compound selected from:
• a method of treating a hematological disorder mediated by HDAC in a subject in need of such a treatment comprising administering to the subject a therapeutically effective amount of at least one compound, or pharmaceutically acceptable salt thereof, described herein.
• packaged pharmaceutical compositions are also provided. Such packaged pharmaceutical compositions. Such packaged pharmaceutical compositions.
• Step 4 (R)-N-( l-Cyclopropyl-2-(pyrrolidin-l-yl)ethyl)-4-(5-(trifluoromethyl)- 1,2,4- oxadiazol-3 -yl)benzamide
• Step 4 ( ?)-N-(l-(3,4-Dihydroisoquinolin-2(lH)-yl)propan-2-yl)-4-(5-(trifluoromethyl)-l,2,4- oxadiazol-3 -yl)benzamide
• Step 2 ( ?)-l-(Azepan-l-yl)propan-2-amine
• Step 2 ( ?)-l-((1 ?,5S)-3-Azabicyclo[3.2.1]octan-3-yl)propan-2-amine
• Step 5 tert-ButyX ((2 ?)-l-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)propan-2- yl)carbamate
• the plate is incubated for 15 minutes at 37 °C.
• the reaction is then stopped by adding 25 ⁇ ⁇ of 3x (30 ⁇ ) developer/stop solution to the assay plates using either the Bravo, Janus or a 16-channel Matrix multi-channel pipette.
• the assay plate is then shaken for 2 minutes on an orbital shaker at 900 rpm.
• the assay plate is incubated at 37 °C for 1 hour in a tissue culture incubator followed by shaking for 1 minute at maximum rpm on an orbital shaker.
• the fluorescence is measured (Excitation: 355 nm, Emission: 460 nm) using PerkinElmer EnVision in top read mode.
• Assay 5 ⁇ ⁇ of each solution of 1 :20 diluted compound from above was transferred to the Greiner microtitre assay plates with 75,000 cells/well using the Bravo. Cells were then incubated for 2 hours at 37 °C and 5% C0 2 . The assay was then started by adding 10 ⁇ ⁇ of 5x (500 ⁇ ) substrate to the assay plate using either the Bravo or 16-channel Matrix multichannel pipette. The cells were then incubated for 3 hours at 37°C and 5% C0 2 . Next, 25 ⁇ ⁇ of 3x lysis buffer was added to each well using either the 125 ⁇ ⁇ 16 channel pipette or the Bravo.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Neurosurgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Biomedical Technology (AREA)
• General Chemical & Material Sciences (AREA)
• Neurology (AREA)
• Epidemiology (AREA)
• Psychology (AREA)
• Psychiatry (AREA)
• Hospice & Palliative Care (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Enzymes And Modification Thereof (AREA)
• Immobilizing And Processing Of Enzymes And Microorganisms (AREA)

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• 2016
  • 2016-05-06 CA CA2984618A patent/CA2984618C/en active Active
  • 2016-05-06 WO PCT/US2016/031335 patent/WO2016179554A1/en not_active Ceased
  • 2016-05-06 CN CN201680040061.8A patent/CN107735088B/zh active Active
  • 2016-05-06 KR KR1020177034461A patent/KR20180002729A/ko not_active Withdrawn
  • 2016-05-06 AU AU2016258188A patent/AU2016258188B2/en active Active
  • 2016-05-06 JP JP2017557324A patent/JP6805172B2/ja active Active
  • 2016-05-06 EA EA201792247A patent/EA036965B1/ru not_active IP Right Cessation
  • 2016-05-06 US US15/148,907 patent/US10053434B2/en active Active
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  • 2016-05-06 EP EP16790203.0A patent/EP3291810B1/en active Active
• 2017
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• 2018
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