Classifications

• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • 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
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • 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
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • 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
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • 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 invention relates to a novel structural 1,3,4-oxadiazole derivative compound having a histone deacetylase 6 (HDAC 6) inhibitory activity, a method for preparing the same, and uses thereof.
• HDAC 6 histone deacetylase 6
• HDACs In humans, 18 HDACs are known, and are classified into four classes depending on homology with yeast HDACs.
• the 11 HDACs using zinc as a cofactor may be divided into 3 groups of Class I (HDAC1, 2, 3 and 8), Class II (IIa: HDAC4, 5, 7 and 9; IIb: HDAC6 and 10) and Class IV (HDAC 11).
• HDACs using zinc as a cofactor may be divided into 3 groups of Class I (HDAC1, 2, 3 and 8), Class II (IIa: HDAC4, 5, 7 and 9; IIb: HDAC6 and 10) and Class IV (HDAC 11).
• 7 HDACs of Class III (SIRT 1-7) use NAD+ as a cofactor instead of zinc (Bolden et al., Nat. Rev. Drug Discov. 2006, 5(9), 769-784).
• HDAC inhibitors are in the preclinical or clinical development stage, up to date, only non-selective HDAC inhibitors are known as anticancer agents, wherein vorinostat (SAHA) and romidepsin (FK228) have been approved for the treatment of cutaneous T-cell lymphoma, and panobinostat (LBH-589) has been approved for the treatment of multiple myeloma.
• SAHA vorinostat
• FK2228 romidepsin
• LH-589 panobinostat
• non-selective HDACs inhibitors are generally known to cause side effects such as fatigue, nausea, and the like, at high doses (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767).
• HDAC6 one of the class IIb HDACs, is known to be mainly present in cytoplasma and be involved in the deacetylation of a number of non-histone substrates (HSP90, coractin, etc.) including a tubulin protein (Yao et al., Mol. Cell 2005, 18, 601-607). HDAC6 may have two catalytic domains, and a zinc finger domain of C-terminal may bind to ubiquitinated proteins.
• HDAC6 is known to play an important role in various diseases such as cancer, inflammatory diseases, autoimmune diseases, neurological diseases, and neurodegenerative disorders, and the like, since it has a number of non-histone proteins as substrates (Santo et al., Blood 2012 119, 2579-2589; Vishwakarma et al., International Immunopharmacology 2013, 16, 72-78; Hu et al., J. Neurol. Sci. 2011, 304, 1-8).
• the zinc-binding groups are hydroxamic acid or benzamide, wherein the hydroxamic acid derivative show strong HDAC inhibitory effects, but have problems such as low bioavailability and serious off-target activity.
• the benzamide contains aniline, and thus also has a problem of generating toxic metabolites in vivo (Woster et al., Med. Chem. Commun. 2015, online publication).
• the compound represented by Chemical Formula I may be in the following ranges:
• n 0 or 1.
• alkyl as used herein may refer to a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon in which the carbon atoms are connected, unless otherwise specified.
• C 1-4 alkyl may mean an alkyl containing 1 to 4 carbon atoms.
• the acyclic alkyl may include, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, sec-butyl, isobutyl, tert-butyl, and the like, but is not limited to thereto.
• alkoxy may refer to -(O-alkyl) as an alkyl ether group, wherein the alkyl is the same as defined above.
• C 1-4 alkoxy may mean an alkoxy containing C 1-4 alkyl, i.e. -(O-C 1-4 alkyl); and examples of the alkoxy may include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butyoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
• halo may be F, Cl, Br or I.
• haloalkyl may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with at least one halo as defined herein.
• haloalkyl include, but are no limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with at least one halogen such as F, Cl, Br, or I.
• aminoalkyl may refer to a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with amino-(NR'R'').
• R' and R'' may each independently be selected from the group consisting of hydrogen and C 1-4 alkyl, and the selected R' and R'' may each independently be substituted or unsubstituted.
• Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess aqueous acid solution and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. An equimolar amounts of the compound and an acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.
• a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
• the present invention provides a method for preparing a 1,3,4-oxadiazole derivative compound represented by the following Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
• hydrazine is added to Compound 1-1 to prepare Compound 1-2, followed by reaction with trifluoroacetic anhydride or difluoroacetic anhydride to prepare Compound 1-3, and then a bromination reaction is performed to synthesize Compound 1-4.
• Compound 1-4 is Zn-Binder moiety of HDAC 6 inhibitor and is used as an intermediate in the synthesis of all compounds.
• Reaction Scheme 3 Compound 3-1 having an aldehyde structure is subjected to reductive amination to prepare Compound 3-2, then Compound 3-3 is prepared using hydrazine, and then 1,3,4-oxadiazol-2(3H)-one Compound 3-4 is prepared using CDI. Then, Compound 3-5 may be prepared through a substitution reaction with Compound 1-4. Examples of Compound 3-5 to be prepared by Reaction Scheme 3 above may include Compound Nos. 2 and 4, and the like.
• dioxolane compound 3-1-1 protecting the aldehyde structure is prepared using ethylene glycol from Compound 3-1, and then Compound 3-1-2 is prepared using hydrazine. Then, 1,3,4-oxadiazol-2(3H)-thione Compound 3-1-3 is prepared by employing CDI and using 1,3,4-oxadiazol-2(3H)-one and potassium ethylxanthate. Then, Compound 3-1-4 is prepared through a substitution reaction with Compound 1-4, and Compound 3-1-5 is prepared by removing dioxolane, an aldehyde protecting group, using iron (III) chloride hexahydrate. Then, Compound 3-5 may be prepared through reductive amination.
• Reaction Scheme 3-2 Compound 3-1 having an aldehyde structure is subjected to reductive amination to prepare Compound 3-2-1, then Compound 3-2-2 is prepared using hydrazine, and then 1,3,4-oxadiazol-2(3H)-thione Compound 3-2-4 is prepared by employing CDI and using 1,3,4-oxadiazol-2(3H)-one and potassium ethylxanthate.
• Compound 3-2-3 is prepared by adding Lawesson's reagent to Compound 3-2-2, and then 1,3,4-thiadiazol-2(3H)-one Compound 3-2-4 is prepared by using CDI.
• ester compound 4-1 having a halogen element is subjected to C-C coupling (Suzuki-coupling) reaction to prepare Compound 4-2, followed by a reduction reaction to prepare Compound 4-3.
• Compound 4-3 is prepared through C-N coupling (Buchwald-raction) and substitution reaction from Compound 4-1.
• Compound 4-4 is prepared using hydrazine, and then 1,3,4-oxadiazol-2(3H)-thione
• Compound 4-6 is prepared by employing CDI and using 1,3,4-oxadiazol-2(3H)-one and potassium ethylxanthate.
• Compound 4-5 is prepared by adding Lawesson's reagent to Compound 4-4, and then 1,3,4-thiadiazol-2(3H)-one Compound 4-6 is prepared by using CDI.
• Compound 4-7 is prepared through a substitution reaction with Compound 1-4, and then Compound 4-8 is prepared by removing an amine protecting group.
• Examples of Compound 4-8 may include Compound Nos. 20, 23, and 36, and the like.
• Compound 4-9 may be prepared through reductive amination. Examples of Compound 4-9 to be prepared by Reaction Scheme 4 above may include Compound Nos.
• Compound 5-6 may be prepared by removing the amine protecting group of Compound 5-5 prepared according to Reaction Scheme 5, and examples of Compound 5-6 may include Compound Nos. 3, 11, 33, 34, 35, and the like.
• Compound 5-7 is prepared through reductive amination.
• Examples of Compound 5-7 to be prepared by Reaction Scheme 5 above may include Compound Nos. 12, 13, 14, 135, 136, 137, 138, 139, 140, 141, and the like.
• acetate compound 6-2 is prepared through a substitution reaction from bromo compound 6-1, followed by a substitution reaction to prepare hydrazine carboxylate compound 6-3, and then 1,3,4-oxadiazin-2-one Compound 6-4 is prepared by using sodium ethylate. Then, Compound 6-5 is prepared through a substitution reaction with Compound 1-4. Examples of Compound 6-5 to be prepared by Reaction Scheme 6 above may include Compound Nos. 69, 70, 71, 72, 73, 74, and the like.
• Reaction Scheme 7 Compound 7-2 protected by an amine protecting group of Compound 7-1 is prepared, then a triple bond compound 7-4 is prepared through a substitution reaction with Compound 7-3, and then oxazol-2(3H)-one compound 7-5 is prepared using silver bis(trifluoromethanesulfonyl)imide.
• Compound 7-6 may be prepared using hydrazine, followed by reaction with trifluoroacetic anhydride or difluoroacetic anhydride, to prepare Compound 7-7.
• Examples of compound to be prepared by Reaction Scheme 7 may include Compound Nos. 142, 143, and the like.
• Compound 8-2 may be prepared through a substitution reaction with Compound 1-4 from imidazol-2-one compound 8-1.
• Examples of compound to be prepared by Reaction Scheme 8 may include Compound Nos. 144, and the like.
• the Chemical Formula I is as defined above.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising the compound represented by Chemical Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
• the infectious disease may be prion disease.
• the neoplasm may be a benign tumor (for example, myelodysplasia syndrome) or a malignant tumor (for example, multiple myeloma, lymphoma, leukemia, lung cancer, colorectal cancer, colon cancer, prostate cancer, urothelial cell carcinoma, breast cancer, melanoma, skin cancer, liver cancer, brain cancer, stomach cancer, ovarian cancer, pancreatic cancer, head and neck cancer, oral cancer, or glioma).
• the endocrine, nutritional and metabolic disease may be Wilson's disease, amyloidosis or diabetes.
• the mental and behavioral disorder may be depression or Rett syndrome.
• the neurological diseases may include central nervous system atrophy (for example, Huntington's disease, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA)), neurodegenerative disease (for example, Alzheimer's disease), movement disorder (for example, Parkinson's disease), neuropathy (for example, hereditary neuropathy (Charcot-Marie-Tooth disease), sporadic neuropathy, inflammatory neuropathy, drug-induced neuropathy), motor neuron disease (for example, amyotrophic lateral sclerosis (ALS)), or central nervous system demyelinating disease (for example, multiple sclerosis (MS)).
• the eye and ocular adnexal disease may be uveitis.
• the circulatory disease may be atrial fibrillation or stroke.
• stereoisomer and pharmaceutically acceptable salt are as described above in the stereoisomer and pharmaceutically acceptable salt of the compound represented by Chemical Formula I of the present invention.
• the pharmaceutical composition of the present invention may further comprise at least one or more pharmaceutically acceptable carrier in addition to the compound represented by Chemical Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof.
• the pharmaceutically acceptable carrier may be saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more of these ingredients, and, if necessary, may contain other conventional additives such as antioxidants, buffers, bacteriostatic agents, and the like.
• composition of the present invention may be administered orally or parenterally (for example, intravenous, subcutaneous, intraperitoneal or topical application) according to the desired method, and the dosage varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease.
• the daily dosage of the compound represented by Chemical Formula I of the present invention is about 1 to 1000 mg/kg, preferably 5 to 100 mg/kg, and may be divided and administered once or several times a day.
• the pharmaceutical composition of the present invention may further comprise at least one active ingredient exhibiting the same or similar efficacy in addition to the compound represented by Chemical Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof.
• the present invention provides a method for preventing or treating histone deacetylase 6 activity-related diseases, comprising: administering a therapeutically effective amount of the compound represented by Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
• the subject may be a mammal including a human.
• the method for preventing or treating histone deacetylase 6 activity-related diseases comprises not only dealing with the disease itself prior to the onset of symptoms, but also inhibiting or avoiding symptoms thereof by administering the compound represented by Chemical Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof.
• the method for preventing or treating histone deacetylase 6 activity-related diseases of the present invention may further administering a therapeutically effective amount of an additional active agent that is helpful in treating the diseases together with the compound represented by Chemical Formula I, wherein the additional active agent may exhibit synergistic or adjuvant effects together with the compound represented by Chemical Formula I above.
• the present invention provides a method for selectively inhibiting histone deacetylase 6 (HDAC6) by administering the compound represented by Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to mammals, including humans.
• HDAC6 histone deacetylase 6
• the present invention provides uses of a compound represented by Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of histone deacetylase 6 activity-related diseases.
• the compound represented by Chemical Formula I for the manufacture of medicaments may be mixed with acceptable adjuvants, diluents, carriers, and the like, and may be prepared as a combined preparation with other active agents to have a synergistic effect of the active ingredients.
• the present invention provides uses of a compound represented by Chemical Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof for preventing or treating the histone deacetylase 6-mediated diseases.
• the compound represented by Chemical Formula I for preventing or treating the histone deacetylase 6-mediated diseases may be mixed with acceptable adjuvants, diluents, carriers, and the like, and may be prepared as a combined preparation with other active agents to have a synergistic effect of the active ingredients.
• the organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
• methylthiophene-2-carboxylate 100.00% solution, 0.163 mL, 1.410 mmol
• ethanol 10 mL
• hydrazine monohydrate 100.00% solution, 1.367 mL, 28.100 mmol
• the solvent was removed from the reaction mixture under reduced pressure to obtain a concentrate.
• a saturated aqueous solution of sodium hydrogen carbonate was poured, and the reaction mixture was extracted with dichloromethane.
• the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
• the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
• Example 45 Synthesis of Compound 45, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-phenyl-1,3,4-oxadiazol-2(3H)-thione
• Example 43 Synthesis of Compound 43, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-phenyl-1,3,4-thiadiazol-2-one
• the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
• the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
• Example 132 Synthesis of Compound 132, 5-[4-(azetidin-1-ylmethyl)phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-1,3,4-oxadiazol-2-one
• Methyl 4-formylbenzoate (100.00 %, 3,000 g, 18.275 mmol), ethylene glycol (100.00 %, 5.672 g, 91.380 mmol) and 4-methylbenzenesulfonic acid hydrate (100.00 %, 0.348 g, 1.830 mmol) were dissolved in toluene (150 mL) at room temperature, and the resulting mixture was heated to reflux overnight. The mixture was cooled to room temperature, and water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
• the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
• Example 83 Synthesis of Compound 83, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-[(4-isopropylpiperazin-1-yl)methyl]phenyl]-1,3,4-oxadiazol-2-one
• sodium triacetoxyborohydride (100.00%, 0.101 g, 0.479 mmol) was added and further stirred at the same temperature for 18 hours.
• a saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture, followed by extraction with dichloromethane.
• the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
• Example 66 Synthesis of Compound 66, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(4-isopropylpiperazin-1-yl)phenyl]-1,3,4-thiadiazol-2-one
• the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
• the organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
• Example 77 Synthesis of Compound 77, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-[(4-isopropylpiperazin-1-yl)methyl]phenyl]-1,3,4-oxadiazol-2-thione
• Example 26 Synthesis of Compound 26, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-[1-(oxetan-3-yl)-4-piperidyl]phenyl]-1,3,4-oxadiazol-2-one
• Example 27 Synthesis of Compound 27, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-[1-(1-methylazetidin-3-yl)-4-piperidyl]phenyl]-1,3,4-oxadiazol-2-one
• the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
• Example 41 Synthesis of Compound 41, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(1-methyl-4-piperidyl)phenyl]-1,3,4-thiadiazol-2-one
• Example 20 Synthesis of Compound 20, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(4-piperazin-1-ylphenyl)-1,3,4-oxadiazol-2-one
• Example 33 Synthesis of Compound 33, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(1H-indole-6-yl)-1,3,4-oxadiazol-2-one
• the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
• Example 12 Synthesis of Compound 12, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)-1,3,4-oxadiazol-2-one
• Example 135 Synthesis of Compound 135, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-5-(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)-1,3,4-oxadiazol-2-thione
• the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
• Example 144 Synthesis of Compound 144, 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-one
• HDAC enzyme activity was measured using HDAC Fluorometric Drug Discovery Kit (BML-AK511, 516) manufactured by Enzo Life Science.
• BML-AK511, 516 human recombinant HDAC1
• Fluor de Lys r -"SIRT1 BNL-KI177
• the 5-fold diluted compound was dispensed in a 96-well plate, 0.3 ⁇ g of enzyme and 10 ⁇ M substrate were added to each well and reacted at 30°C for 60 minutes, and Fluor de Lys r Developer II(BML-KI176) was added and reacted for 30 minutes to complete the reaction.

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