WO2010140835A2 - Novel pyridone compounds or pharmaceutically acceptable salts thereof, method for producing the same, and pharmaceutical composition containing the same for treating cancer - Google Patents

Novel pyridone compounds or pharmaceutically acceptable salts thereof, method for producing the same, and pharmaceutical composition containing the same for treating cancer Download PDF

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WO2010140835A2
WO2010140835A2 PCT/KR2010/003539 KR2010003539W WO2010140835A2 WO 2010140835 A2 WO2010140835 A2 WO 2010140835A2 KR 2010003539 W KR2010003539 W KR 2010003539W WO 2010140835 A2 WO2010140835 A2 WO 2010140835A2
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oxo
dihydropyridin
hydroxy
acrylamide
hydroxyacrylamide
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PCT/KR2010/003539
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Korean (ko)
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WO2010140835A3 (en
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한균희
최은현
이철호
박정은
조미선
서정제
김환묵
박성규
이기호
이창우
이기훈
김현정
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연세대학교 산학협력단
한국생명공학연구원
주식회사바이오러넥스
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Publication of WO2010140835A2 publication Critical patent/WO2010140835A2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel pyridone compound or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
  • Cancer is characterized by "uncontrolled cell growth,” which results in the formation of cell masses called tumors that infiltrate surrounding tissues and, in severe cases, metastasize to other organs of the body. Academia is also called neoplasia.
  • Cancer is an intractable chronic disease that, even if treated with surgery, radiation, and chemotherapy, in many cases does not heal fundamentally, suffers the patient, and ultimately leads to death. More than 20 million people worldwide suffer from cancer, and more than 6 million people die of cancer each year, and 11 million people are expected to die by 2020, so cancer is an urgent need to find a cure. Disease. Cancer varies from country to country, but in developed countries and Korea accounts for more than 20% of all deaths. However, despite many efforts, the exact cause or mechanism of cancer development is still unknown. There are many factors that cause cancer, but they can be divided into internal and external factors. It is not known exactly how normal cells are transformed into cancer cells, but at least 80-90% is known to be influenced by external factors such as environmental factors. Internal factors include genetic factors, immunological factors, and external factors include chemicals, radiation, and viruses. Genes involved in the development of cancer include oncogenes and tumor suppressor genes, which occur when the balance between them is broken down by internal or external factors described above.
  • Cancer is classified into blood cancer and solid cancer, and it occurs in almost every part of the body such as lung cancer, stomach cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer, and skin cancer.
  • chemotherapy agents except surgery or radiation therapy, are collectively called anticancer agents, and most of them show anticancer activity by inhibiting the synthesis of hexane.
  • Chemotherapeutic agents are broadly classified into antimetabolites, alkylating agents, antimitotic drugs, and hormones.
  • Metabolism inhibitors inhibit the metabolic processes required for cancer cell proliferation, including folic acid derivatives such as methotrexate, purine derivatives such as 6-mercaptopurine and 6-thioguanine, and 5 Pyrimidine derivatives such as 5-fluorouracil and cytarabine.
  • Alkylating agent is an anti-cancer effect by modifying the structure of the DNA and cutting the chain by introducing an alkyl group to the guanine of DNA, such as chlorambucil (cycloambucil) and cyclophosphamide (cyclophosphamide), nitrogen mustard compounds, thio Ethyleneimine compounds such as thiotepa, alkylsulfonate compounds such as busulfan, nitrosourea compounds such as carmustine, and triazene compounds such as dacarbazine. have.
  • chlorambucil cycloambucil
  • cyclophosphamide cyclophosphamide
  • nitrogen mustard compounds such as thio Ethyleneimine compounds such as thiotepa
  • alkylsulfonate compounds such as busulfan
  • nitrosourea compounds such as carmustine
  • triazene compounds such as dacarbazine.
  • Mitosis inhibitors are mitotic phase specific drugs that inhibit mitosis and inhibit cell division, including anticancer drugs such as actinomycin D, doxorubicin, bleomycin, and mitomycin; Plant alkaloids such as vincristine and vinblastine; Taxoids, such as mitosis inhibitors including taxane rings, are included.
  • anticancer drugs such as actinomycin D, doxorubicin, bleomycin, and mitomycin
  • Plant alkaloids such as vincristine and vinblastine
  • Taxoids such as mitosis inhibitors including taxane rings
  • hormones such as corticosteroids and progesterone and platinum-containing compounds such as cisplatin are used as anticancer agents.
  • RUNX is a Runt-related transcription factor (RUNX) and is a new tumor suppressor that has recently been identified for cancer suppression activity.
  • RUNX has a runt domain called PEBP2 / CBF (polyoma virul enhancer binding protein 2 / core binding factor), which is a signaling target for the TGF- ⁇ superfamily and plays an important role in the development of mammals. Do it.
  • the rungs family consists of RUNX1 (PEBP2aB / CBFA2 / AML1), RUNX2 (PEBP2aB / CBFA1 / AML3) and RUNX3 (PEB2aC / CBFA3 / AML2). These three Rungs families play important roles in normal development and differentiation and oncogenesis.
  • RUNX1 which plays an important role in the hematopoietic process, is the most frequent part of chromosomal translocation in leukemia and accounts for about 30% of the causes of acute leukemia.
  • RUNX2 is essential for bone development and is associated with cleido-cranial dysplasia, an autosomal dominant bone disease.
  • RUNX3 is a cancer suppressor. Deletion of the Runx3 gene in mice causes gastric cancer, and since its function was first reported, it has been reported that RUNX3 is inactivated in several solid cancers. In gastric cancer, RUNX3 has been reported to have hemizygous defects on the chromosome or inactivated by methylation of the RUNX3 promoter region.
  • RUNX3 is known to function as a cancer suppressor by inducing apoptosis or inhibiting the cell cycle similarly to a p53 cancer suppressor.
  • RUNX3 induces apoptosis-inducing gene, Bim, which plays a key role in apoptosis induced by TGFbeta, and induces p21, which plays an important role in cell cycle arrest. It has been reported to inhibit cell growth.
  • histone deacetylase (HDAC) inhibitors can be used to restore transcriptional blockade by DNA methylation on the RUNX3 promoter, leading to expression of RUNX3, and to deacetylation of RUNX3 by HDAC at the PTM stage.
  • HDAC histone deacetylase
  • Inhibition of RUNX3 protein can regulate stabilization and transcriptional activity, so it is possible to control chemotherapy by regulating PTM level as well as epigenetics.
  • Histones are basic proteins that bind to the nucleus DNA of eukaryotic cells and undergo reversible acetylation of the amino groups of lysine residues at specific positions in each molecule of histones.
  • the acetylation of histones is involved in the regulation of the expression of genetic information, which is related to the formation of higher levels of chromatin and the cell division cycle, and histone acetyltransferases (HATs) and histone deacetylases. Stable (HDACs).
  • HDAC is an enzyme that deacetylates the positive charge of the lysine residue present in the amino terminus of histones to recharge, thereby inhibiting transcription, and is highly expressed under poor environmental conditions such as hypoxia, low glucose, and cell cancer, thereby inhibiting cell proliferation.
  • hypoxia low glucose
  • cell cancer thereby inhibiting cell proliferation.
  • the role of promoting cell proliferation by inhibiting the expression of the factor is recognized as an important factor in regulating the cancerous and differentiation of cells.
  • HDAC histone deacetylation
  • the first compound used as an HDAC inhibitor is n-butyrate, which is not only applied to the treatment of colorectal cancer, but also used in biochemistry and molecular biology experiments as an HDAC enzyme inhibitor.
  • the effective concentration of n-butyrate is in the level of milimolar (mM), which is not suitable for the analysis of HDAC functions such as affecting other enzymes, cytoskeleton, and cell membranes in the cell.
  • mM milimolar
  • the present inventors have effectively studied the new mechanism of anticancer agent that effectively inhibits the enzymatic activity of histone deacetylase and increases the expression and activity of RUNX to selectively induce terminal differentiation of tumor cells, inhibit tumor growth and induce apoptosis.
  • a novel pyridone compound was synthesized, and it was confirmed that this compound exhibited tumor cell growth inhibitory effect by inducing the increase of RUNX3 activity through excellent HDAC inhibitory activity, and completed the present invention.
  • the present invention is to provide a novel pyridone compound or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1-4 alkyl; C 2-4 alkenyl; Unsubstituted phenyl or phenyl substituted with 1 to 3 R 3 ; Pyridinyl; Thienyl; Unsubstituted naphthalenyl or naphthalenyl substituted with halogen; Quinolinyl; Indanyl; Benzothiophenyl; Furanyl or benzofuranyl,
  • R 2 is hydroxy; C 1-3 alcohol; Or NHR 4 ,
  • R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; C 1-4 haloalkoxy; C 2-4 alkenyl; Nitro; Phenyl; Unsubstituted phenoxy or phenoxy substituted with C 1-4 alkoxy or halogen; Or benzyloxy,
  • R 4 is hydroxy; Or aminophenyl,
  • L is a bond; C 1-4 alkylene; Or C 2-4 alkylene, and
  • R 1 is methyl; 2-propenyl; Unsubstituted phenyl or phenyl substituted with 1 to 3 R 3 ; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-thienyl; 1-naphthalenyl; 2-naphthalenyl; 1-bromo-2-naphthalenyl; 6-bromo-2-naphthalenyl; 1-quinolinyl; 2-indanyl; Benzothiophen-2-yl; 2-furanyl or benzofuran-2-yl.
  • R 2 is hydroxy; Methoxy; Or NHR 4 .
  • R 3 is F; Cl; Br; methyl; ethyl; Isopropyl; Tet-butyl; Methoxy; Ethoxy; Propoxy; CF 3 ; OCF 3 ; Ethenyl; Nitro; Phenyl; Unsubstituted phenoxy or phenoxy substituted with methoxy or F; Or benzyloxy.
  • R 4 is hydroxy or 2-aminophenyl.
  • L is a bond; Ethylene; Trimethylene; Or propenylene ( )to be.
  • R 1 is phenyl substituted with one R 3 .
  • R 1 is phenyl substituted with two R 3 , wherein R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; Or nitro.
  • R 3 is F; Cl; methyl; Methoxy; CF 3 ; Or nitro.
  • R 1 is phenyl substituted with three R 3 , wherein R 3 is halogen; Or C 1-4 alkoxy.
  • R 3 is F; Or methoxy.
  • R 1 is 3-methoxyphenyl; 3-trifluoromethoxyphenyl; 3-chlorophenyl; 3-bromophenyl; 1-naphthalenyl; 2-naphthalenyl; 6-bromo-2-naphthalenyl; 1-quinolinyl; 4-isopropylphenyl; 4-nitrophenyl; 2-bromophenyl; 2-methoxyphenyl; Or 2,5-ditrifluoromethylphenyl.
  • R 1 is phenyl substituted with R 3 at position 2 of phenyl, and R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; Or C 1-4 haloalkoxy,
  • R 1 is phenyl substituted with R 3 at position 3 of phenyl, and R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; C 1-4 haloalkoxy; C 2-4 alkenyl; Nitro; Phenoxy; Or benzyloxy, or
  • R 1 is phenyl substituted with R 3 at position 4 of phenyl, and R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; C 1-4 haloalkoxy; Nitro; Phenyl; Phenoxy unsubstituted or substituted with C 1-4 alkoxy or halogen; Or benzyloxy.
  • R 1 is C 1-4 alkyl; C 2-4 alkenyl; Indanyl; Or furanyl, and L is a bond,
  • R 1 is unsubstituted phenyl or phenyl substituted with 1 to 3 R 3 ; Pyridinyl; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Quinolinyl; Benzothiophenyl; Or benzofuranyl, wherein L is methylene,
  • R 1 is phenyl substituted with 1 to 3 R 3 ; Thienyl; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Or quinolinyl, wherein L is ethylene, or
  • R 1 is phenyl substituted with 1 to 3 R 3 ; Pyridinyl; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Or quinolinyl, wherein L is trimethylene, or
  • R 1 is phenyl substituted with 1 to 3 R 3 ; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Or quinolinyl, wherein L is propylene ( )to be.
  • R 1 is methyl; Ethenyl; 2-indanyl; Or 2-furanyl, wherein L is a bond,
  • R 1 is phenyl substituted with 1 to 3 R 3 ; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 1-naphthalenyl; 2-naphthalenyl; 1-quinolinyl; Benzothiophen-2-yl; Or benzofuran-2-yl, wherein L is methylene,
  • R 1 is phenyl substituted with 1 to 3 R 3 ; 2-thienyl; 1-naphthalenyl; 2-naphthalenyl; 6-bromo-2-naphthalenyl; Or 1-quinolinyl, wherein L is ethylene,
  • R 1 is phenyl substituted with 1 to 3 R 3 ; 3-pyridinyl; 1-naphthalenyl; 1-naphthalenyl; 6-bromo-2-naphthalenyl; or 1-quinolinyl, wherein L is trimethylene, or
  • R 1 is phenyl substituted with 1 to 3 R 3 ; 1-naphthalenyl; 2-naphthalenyl; 6-bromo-2-naphthalenyl; Or 1-quinolinyl, wherein L is propenylene ( )to be.
  • Preferred compounds among the pyridone compounds of formula 1 of the present invention are specifically as follows:
  • the compounds of the present invention can be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.
  • Acid addition salts formed by free acid are useful.
  • Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • organic acids and inorganic acids may be used as the free acid
  • hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid
  • methanesulfonic acid, p -toluenesulfonic acid, acetic acid, and trifluoro may be used as the organic acid.
  • Acetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, Galacturonic acid, glutamic acid, glutaric acid (glutaric acid), glucuronic acid (glucuronic acid), aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid and the like can be used.
  • Bases may also be used to prepare pharmaceutically acceptable metal salts.
  • An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable to prepare sodium, potassium or calcium salt, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
  • Pharmaceutically acceptable salts of the compound represented by Formula 1 include salts of acidic or basic groups which may be present in the compound of Formula 1, unless otherwise indicated.
  • pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group
  • other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts. It can be prepared through.
  • the present invention provides a process for preparing the compound of formula 1.
  • the compound of Formula 1 may be prepared as in Scheme 1 below.
  • step 6) by reacting the compound of formula 8 prepared in step 5) Is a double bond).
  • R 1 , R 2 , L are as defined in the formula (1), X is a halogen atom.
  • An example of a method for preparing a pyridone compound of Formula 1 of the present invention is as follows.
  • step 2 injecting pyridinium dichloromate and celite in an methylene chloride 0.1M solution of the compound of formula 5 prepared in step 2) under anhydrous and agitation, stirring at room temperature for 12 hours, and then generating The mixture was filtered through methylene chloride and concentrated under reduced pressure, and the obtained primary compound was purified by silica gel column chromatography to obtain a compound of formula 6.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the cancer may include lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, anal muscle cancer, colon cancer, breast cancer, fallopian tube carcinoma, Endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, Chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary central nervous system lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, etc.
  • CNS central nervous system
  • the compound according to the present invention is excellent in tumor cell growth inhibitory effect, it can be usefully used for the treatment of cancer diseases.
  • compositions comprising a compound of formula 1 according to the invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.
  • Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • compositions according to the invention can be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, external preparations, suppositories or sterile injectable solutions according to conventional methods.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin and the like. Can be prepared by mixing. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used.
  • Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • utopsol macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • Preferred dosages of the compounds according to the invention depend on the condition and body weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably in an amount of 0.001 to 100 mg / kg once to several times daily.
  • compositions according to the invention can also be used in the form of their pharmaceutically acceptable salts, and can also be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.
  • the pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • the present invention provides a method for treating cancer comprising administering to a patient an effective amount of a pyridone compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the cancer may include lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, anal muscle cancer, colon cancer, breast cancer, fallopian tube carcinoma, Endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, Chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary central nervous system lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, etc.
  • CNS central nervous system
  • the optimal amount and dosage interval of the individual doses of the compounds of the present invention will be determined by the nature and extent of the disease being treated, the dosage form, the route and site, and the age and health of the particular patient being treated, and ultimately the physician It will be appreciated by those skilled in the art that the appropriate dosage will be determined. Such dosing can be repeated as often as appropriate. If side effects occur, the dosage and frequency can be altered or reduced in accordance with normal clinical practice.
  • the compound according to the present invention is excellent in RUNX3 activity inducing effect, HDAC inhibitory activity and tumor cell growth inhibitory effect, it can be usefully used for the prevention or treatment of cancer.
  • FIG. 1 shows that 4 ⁇ 10 7 cells / ml of the human-derived gastric cancer cell line MKN28 was transplanted into a female SPF BALB / c nude mouse (6 weeks old), and then the compound prepared in Examples 42, 44, 55, and 69 was intravenously. A total of 10 mg / kg doses per day was then used to show changes in body weight of the animals during the administration period.
  • FIG. 2 shows that 4 ⁇ 10 7 cells / ml of the human-derived gastric cancer cell line MKN28 was transplanted into a female SPF BALB / c nude mouse (6 weeks old), and then the compounds prepared in Examples 42, 44, 55, and 69 were intravenously. A total of 10 mg / kg 20 mg / kg daily showed tumor size change during the administration period.
  • FIG. 3 shows that 4 ⁇ 10 7 cells / ml of the human-derived gastric cancer cell line MKN28 was transplanted into a female SPF BALB / c nude mouse (6 weeks old), and then the compounds prepared in Examples 42, 44, 55, and 69 were intravenously injected. Tumor weight was measured on the last day (10th day) after total administration of 20mg / kg 10 times a day.
  • the target compound was obtained as follows.
  • oxalyl chloride (2M methylene chloride, 3 equiv) and dimethyl sulfoxide (5 equiv) in 0.1M solution of methylene chloride was anhydrous, injected at -78 °C and the compound obtained in step 1-2 under 10 minutes stirring Injected and stirred at the same temperature for 15 minutes.
  • triethylamide (10 equiv) was injected at the same temperature and stirred at -78 ° C to room temperature for 1 hour. Water was stopped to stop the reaction and extracted with methylene chloride. The organic layer was washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered with methylene chloride and concentrated under reduced pressure.
  • Example 2 In a preparation similar to the preparation described in Example 1, the compounds of Examples 2 to 183 were prepared. Chemical structures and physical properties of the prepared compounds are shown in Table 1 below.
  • Runx activity was used for screening by constructing a cell line that constantly expressed a reporter vector with a fragment that repeatedly linked the Runx binding site.
  • Cell lines were cultured in a 37 ° C., 5% CO 2 concentration incubator in DMEM medium containing 10% FBS. Seed to 1x10 4 cells / well in a 96 well plate. After 24 hours of incubation, the compounds were treated at a concentration of 1 ⁇ M with replacement of medium containing 10% FBS and the medium was added at 100 ⁇ l / well. After 24 hours of incubation, Luciferase activity was measured.
  • Luciferase activity assay was performed using Promega's Bright-Glo Luciferase Assay System (E2620).
  • the process of preparing the reaction solution is as follows. Take out and dissolve one bottle of Bright-Glo buffer (100ml) and one bottle of Bright-Glo Substrate (powder) stored at -20 °C, and mix 100ml of Bright-Glo buffer in Bright-Glo Substrate until the substrate is completely dissolved. gave.
  • Assay process is as follows. Plates containing cultured cells were removed from the incubator, and the same volume of Luciferase Reagent (100 ⁇ l) as the culture medium was added to each well using a multi-pipette. After complete cell lysis (Cell lysis) was allowed to stand for 2 minutes at room temperature luc activity was measured on a Luminometer. The Luminometer used Promega's GloMax-MultiDetection System (E7031).
  • RUNX activity analysis degree of the compounds prepared in the above Example is shown in Table 2 below.
  • HDAC activity analysis was performed based on the biomolar (ACOMOL) HDAC Fluorimetirc Assay / Drug Discovery Kit (AK-500) analysis system.
  • the analysis consists of two steps.
  • the first step is an enzyme reaction step in which the HDAC reacts with the substrate.
  • an HDAC inhibitor was added to measure the degree of inhibition of HDAC enzyme activity.
  • the compounds of the above examples as HDAC enzyme activity inhibitors were prepared in 96-well plates at concentrations of 0.03, 0.1, 0.3, 1, 3 and 10 ⁇ M, respectively, in a reaction buffer (50 mM Tris / Cl, pH 8.0).
  • HeLa nuclear extract was used as the HDAC enzyme source, and the reaction buffer (50 mM Tris / Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 ) was used to obtain a final concentration of 0.5ul. Diluted to add 15 ⁇ l.
  • the 50 mM Fluor de Lys TM substrate was added to the reaction buffer (50 mM Tris / Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 ) so that the final concentration was 100 ⁇ M. 25 ⁇ l was added by dilution and enzymatic reaction was performed at 37 ° C. for 30 minutes.
  • the second step was a detection step, in which a fluorescent label lysine developer of 20X concentration (Flour de Lys TM developer) was diluted with reaction buffer to a 1X concentration, 50 ⁇ l was added and reacted for 15 minutes at room temperature.
  • HDAC inhibitory activity (IC 50 ) degree of the representative compounds prepared in the above Examples are shown in Tables 3 and 4.
  • Example HDACIC 50 ( ⁇ M)
  • Example HDACIC 50 ( ⁇ M)
  • Example HDACIC 50 ( ⁇ M)
  • Example HDACIC 50 ( ⁇ M) Example HDACIC 50 ( ⁇ M)
  • Example HDACIC 50 ( ⁇ M) 91 0.06 122 > 10 153 0.42 92 0.24 123 > 10 154 4.47 93 0.75 124 0.09 155 0.63 94 0.67 125 0.08 156 > 10 95 0.11 126 0.07 157 0.03 96 0.18 127 0.07 158 0.02 97 0.47 128 0.05 159 0.02 98 0.07 129 0.47 160 0.04 99 0.76 130 0.30 161 100 0.15 131 0.05 162 > 10 101 0.61 132 0.27 163 > 10 102 0.06 133 > 10 164 > 10 103 0.08 134 > 10 165 > 10 104 0.11 135 > 10 166 105 0.16 136 0.36 167 1.06 106 0.08 137 0.02 168 > 10 107 0.38 138 0.04 169 > 10 108 0.11 139 0.03 170 > 10 109 0.37 140 0.001 171 > 10 110 0.13 141 > 10
  • Human tumor cell lines PC-3 prostate cancer, ATCC, USA
  • MDA-MB-231 breast cancer, ATCC, USA
  • ACHN renal cancer, ATCC, USA
  • HCT-15 colon cancer, ATCC, USA
  • NCI -H23 Lung Cancer, ATCC, USA
  • NUGC-3 Semach Cancer, ATCC, USA
  • FBS Fetal Bovine Serum
  • an appropriate concentration (approximately 5 x 10 4 cells / ml) of cells in RPMI 1640 medium containing 5% fetal bovine serum was dispensed into a 96 well plate and then treated at 5% CO 2 , 37 ° C. Incubated. After dispensing the cells, fix the cells by adding 50 ⁇ l of 50% trichloroacetic acid per well in a time zero (T 0 ) plate to determine the cell concentration after one day and immediately before processing the compounds. It was set as. In the case of cells treated with the compound, 50 ⁇ l of 50% trichloroacetic acid was added to the wells after 48 hours to fix the cells.
  • the compound according to the present invention can be seen that the tumor cell growth inhibition effect is excellent.
  • the compound prepared in Examples 42, 44, 55, and 69 was intravenously injected 20 mg per day. A total of 10 mg / kg were administered, and 10 mg of suberoylanilide hydroxamic acid (SAHA) was administered intravenously once daily for 10 days.
  • SAHA suberoylanilide hydroxamic acid
  • the weight change of the animals is shown in FIG. 1, the change in tumor size is shown in FIG. 2, and the tumor weight at the last day (day 10) is shown in FIG. 3.
  • mice administered intravenously with the compounds according to the invention did not show any unusual general symptoms during the test period.
  • results of the last day (10 days) of the change in the body weight of the mouse compared to the solvent control compound sample of the present invention 20mg / kg administration group there was no weight loss.
  • the results of the last day (day 10) showed 25.6% and 28.3% in the compound sample of the present invention (Examples 42, 44, 55, 69) compared to the solvent control group (20 mg / kg), respectively. , 40.6% (p ⁇ 0.05), 27.6% of tumor growth inhibitory effect was observed.
  • Positive control (SAHA / 20 mg / kg / Q1D: 10 times) group showed 44.6% of tumor growth inhibitory effect.
  • the tumors were sacrificed at the end of the experiment (day 10), and the weights of the tumors were measured.
  • the compound samples of the present invention were compared with the solvent control (Examples 42, 44, 55, and 69).
  • Tumor weight reductions of 27.9%, 32.4%, 42.6% (p ⁇ 0.01) and 26.0% were observed in the administration group (20 mg / kg), respectively.
  • a positive control (SAHA / 20 mg / kg / Q1D: 10) group showed a 45.6% reduction in tumor weight.
  • Human gastric cancer cell line MKN28 was cultured in an incubator at 37 ° C., 5% CO 2 with RPMI 1640 medium containing 10% Fetal bovine serum (FBS).
  • FBS Fetal bovine serum
  • Compounds according to the invention were treated at a concentration of 1 ⁇ M. Cells were harvested after an additional 24 hours of incubation. Total RNA was extracted from the cells using an Easy blue Total RNA extract kit (Intron / Cat. No. 17061) and isolated according to the manufacturer's protocol.
  • cDNA synthesis was synthesized using ImProm-II TM Reverse Transcriptase (Promega / Cat. No. A3802) as olig (dT) primer with 2 ⁇ g total RNA as a template.
  • dT olig
  • primer sets of RUNX3 forward primer: 5'-GCA GGC AAT GAC GAG AAC TA-3 'and RUNX3 reverse primer: 5'-GTC TGG TCC TCC AGC TTC TG-3' were used.
  • I-star Max TM II DNA polymerase Intron / Cat.No. 25173
  • Taq polymerase was used for the PCR reaction.
  • the PCR conditions are shown in Table 6 (PCR reaction solution) and Table 7 (PCR condition (2-step PCR)). It was performed as follows.
  • 293 cell lines derived from human embryonic kidney were cultured in DMEM medium containing 10% FBS and seeded in 60 mm dish with 1x10 6 cells.
  • myc tagged RUNX3 expression vector (10 ⁇ g) was introduced into 293 cells using WelFect-Ex plus (WelGene, Korea) transfection reagent according to the manufacturer's protocol.
  • the compounds according to the invention were treated at a concentration of 1 ⁇ M while replacing with medium containing 10% FBS. After 24 hours of incubation, the cells were recovered and proteins were separated from the cells using RIPA lysis buffer.
  • an anti-myc monoclonal antibody (9E10, SantaCruz) was added to 600 ⁇ g of cell lysate, and the reaction was stirred at 4 ° C. for 16-24 hours to stir well.
  • 40 ⁇ l of agarose-G beads (Millipore) was added to each reaction solution, followed by stirring at 4 ° C. for 4 hours, followed by centrifugation at 12,000 rpm to precipitate the RUNX3-antibody-beads complex, followed by removal of the supernatant. It was. 800 ⁇ l RIPA lysis buffer was added to the precipitate, washed with a stirrer at 4 ° C.
  • the stability of RUNX3 was compared with the amount of RUNX3 expression in 40 ⁇ g of cell lysate after SDS-PAGE and the protein transferred by anti-myc-antibody in western blot.
  • the expression level of tubulin was used as a loading control.
  • Injection solution containing 10 mg of the active ingredient was prepared by the following method.
  • the components of the injection solution are as follows.
  • Syrup containing the compound of Formula 1 as an active ingredient 2% was prepared by the following method.
  • the components of the syrup are as follows.
  • a tablet containing 15 mg of the active ingredient was prepared by the following method.
  • the components of the tablet are as follows.

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Abstract

The present invention relates to novel pyridone compounds or pharmaceutically acceptable salts thereof, a method for producing the same and a pharmaceutical composition containing the same for treating cancer. The compounds according to the present invention utilize the superior effects of the RUNX activity found in the HDAC inhibitor for inhibiting tumor cell growth, and are thus useful for treating cancer.

Description

신규한 피리돈 화합물 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 포함하는 암 치료용 약학 조성물Novel pyridone compounds or pharmaceutically acceptable salts thereof, methods for preparing the same, and pharmaceutical compositions for treating cancer comprising the same
본 발명은 신규한 피리돈 화합물 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a novel pyridone compound or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
암이란 "제어되지 않는 세포성장"으로 특징지어지며, 이러한 비정상적인 세포성장에 의해 종양(tumor)이라고 불리는 세포 덩어리가 형성되어 주위의 조직으로 침투하고 심한 경우에는 신체의 다른 기관으로 전이되기도 한다. 학문적으로는 신생물(neoplasia)이라고도 불린다.Cancer is characterized by "uncontrolled cell growth," which results in the formation of cell masses called tumors that infiltrate surrounding tissues and, in severe cases, metastasize to other organs of the body. Academia is also called neoplasia.
암은 수술, 방사선 및 화학요법으로 치료를 하더라도 많은 경우에 근본적인 치유가 되지 못하고 환자에게 고통을 주며 궁극적으로는 죽음에 이르게 하는 난치성 만성질환이다. 전 세계적으로 암으로 고통받는 환자는 2000만 명이 넘으며, 매년 600만 명 이상이 암으로 사망하고 있고, 2020년경에는 1,100만 명이 암으로 사망할 것으로 예측되므로 암은 시급히 그 치료법을 찾아내어야 할 중요 질환이다. 암은 나라마다 차이는 있지만 선진국이나 우리나라의 경우 전체 사망원인의 20% 이상을 차지한다. 하지만 많은 노력에도 불구하고 아직까지 암 발생의 정확한 원인이나 기전은 밝혀져 있지 않은 상태이다. 암의 발생요인으로는 여러 가지가 있으나, 내적 요인과 외적 요인으로 구분하기도 한다. 정상세포가 어떠한 기전을 거쳐 암세포로 형질전환이 되는지에 대해서는 정확하게 규명되지는 않았으나, 적어도 80-90%가 환경요인 등 외적인자에 의해 영향을 받아 발생하는 것으로 알려져 있다. 내적 요인으로는 유전 인자, 면역학적 요인 등이 있으며, 외적 요인으로는 화학물질, 방사선, 바이러스 등이 있다. 암의 발생에 관련되는 유전자에는 종양형성유전자 (oncogenes)와 종양억제유전자(tumor suppressor genes)가 있는데, 이들 사이의 균형이 위에서 설명한 내적 혹은 외적 요인들에 의해 무너질 때 암이 발생하게 된다.Cancer is an intractable chronic disease that, even if treated with surgery, radiation, and chemotherapy, in many cases does not heal fundamentally, suffers the patient, and ultimately leads to death. More than 20 million people worldwide suffer from cancer, and more than 6 million people die of cancer each year, and 11 million people are expected to die by 2020, so cancer is an urgent need to find a cure. Disease. Cancer varies from country to country, but in developed countries and Korea accounts for more than 20% of all deaths. However, despite many efforts, the exact cause or mechanism of cancer development is still unknown. There are many factors that cause cancer, but they can be divided into internal and external factors. It is not known exactly how normal cells are transformed into cancer cells, but at least 80-90% is known to be influenced by external factors such as environmental factors. Internal factors include genetic factors, immunological factors, and external factors include chemicals, radiation, and viruses. Genes involved in the development of cancer include oncogenes and tumor suppressor genes, which occur when the balance between them is broken down by internal or external factors described above.
암은 혈액암과 고형암으로 크게 분류되며, 폐암, 위암, 유방암, 구강암, 간암, 자궁암, 식도암, 피부암 등 신체의 거의 모든 부위에서 발생한다. 이들 악성종양을 치료하기 위해 사용하는 방법들 중 수술이나 방사선 요법을 제외한 화학요법제를 총칭하여 항암제라고 하며, 주로 헥산의 합성을 저해하여 항암활성을 나타내는 물질이 대부분이다.Cancer is classified into blood cancer and solid cancer, and it occurs in almost every part of the body such as lung cancer, stomach cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer, and skin cancer. Among the methods used to treat these malignancies, chemotherapy agents, except surgery or radiation therapy, are collectively called anticancer agents, and most of them show anticancer activity by inhibiting the synthesis of hexane.
화학요법제는 크게 대사길항제(antimetabolites), 알킬화제(alkylating agents), 유사분열 억제제(antimitotic drugs), 호르몬제(hormones) 등으로 분류된다. 대사길항제는 암세포의 증식에 필요한 대사과정을 저해하는 것으로, 메토트렉세이트(methotrexate)와 같은 엽산 유도체, 6-머캅토퓨린(6-mercaptopurine) 및 6-티오구아닌(6-thioguanine)과 같은 퓨린 유도체, 5-플루오로우라실(5-fluorouracil) 및 시타라빈(cytarabine)과 같은 피리미딘 유도체 등이 있다. 알킬화제는 DNA의 구아닌 등에 알킬기를 도입하여 DNA의 구조를 변형시키고 사슬을 절단시켜 항암효과를 발휘하는 것으로, 클로람부실(chlorambucil) 및 시클로포스파미드(cyclophosphamide)와 같은 니트로겐 머스타드계 화합물, 티오테파(thiotepa)와 같은 에틸렌이민계 화합물, 부설판(busulfan)과 같은 알킬설포네이트계 화합물, 카르무스틴(carmustine)과 같은 니트로소우레아계 화합물, 다카바진(dacarbazine)과 같은 트리아젠계 화합물이 있다. 유사분열 억제제는 분열시기 특이성 약물로서 유사분열을 차단하여 세포분열을 억제하는 것으로, 악티노마이신 D(actinomycin D), 독소루비신, 블레오마이신, 미토마이신과 같은 항암성 항암제; 빈크리스틴, 빈블라스틴과 같은 식물 알칼로이드; 탁산환을 포함하는 유사분열 저해제인 탁소이드 등이 포함된다. 이외에 부신피질호르몬이나 프로게스테론과 같은 호르몬제와 시스플라틴 같은 백금함유 화합물이 항암제로서 사용되고 있다.Chemotherapeutic agents are broadly classified into antimetabolites, alkylating agents, antimitotic drugs, and hormones. Metabolism inhibitors inhibit the metabolic processes required for cancer cell proliferation, including folic acid derivatives such as methotrexate, purine derivatives such as 6-mercaptopurine and 6-thioguanine, and 5 Pyrimidine derivatives such as 5-fluorouracil and cytarabine. Alkylating agent is an anti-cancer effect by modifying the structure of the DNA and cutting the chain by introducing an alkyl group to the guanine of DNA, such as chlorambucil (cycloambucil) and cyclophosphamide (cyclophosphamide), nitrogen mustard compounds, thio Ethyleneimine compounds such as thiotepa, alkylsulfonate compounds such as busulfan, nitrosourea compounds such as carmustine, and triazene compounds such as dacarbazine. have. Mitosis inhibitors are mitotic phase specific drugs that inhibit mitosis and inhibit cell division, including anticancer drugs such as actinomycin D, doxorubicin, bleomycin, and mitomycin; Plant alkaloids such as vincristine and vinblastine; Taxoids, such as mitosis inhibitors including taxane rings, are included. In addition, hormones such as corticosteroids and progesterone and platinum-containing compounds such as cisplatin are used as anticancer agents.
화학요법제의 가장 큰 문제는 약제 내성으로써, 항암제에 의한 초기의 성공적인 반응에도 불구하고 결국에는 치료가 실패하게 되는 주요 요인이다. 약제 내성의 원인을 규명하는 연구와 동시에 기존의 약제에 내성을 지닌 암을 치료하기 위해서는 새로운 기전을 가진 항암제의 개발이 지속적으로 필요하다. The biggest problem with chemotherapeutic agents is drug resistance, which, despite the initial successful response by anticancer agents, is a major factor that eventually causes treatment to fail. In addition to researching the cause of drug resistance, the development of anti-cancer drugs with new mechanisms is needed to treat cancers resistant to existing drugs.
렁스(RUNX)는 런트 관련 전사인자(Runt-related transcription factor, RUNX)이며 최근 암억제활성이 규명된 새로운 암억제 인자(tumor suppressor)로서 여러 암을 대상으로 많은 연구들이 진행되고 있다. RUNX는 PEBP2/CBF(polyoma virul enhancer binding protein 2/core binding factor)라고 불리는 런트(Runt) 도메인을 가지고 있고 이 런트 도메인 전사인자는 TGF-β 슈퍼패밀리의 신호전달 목표가 되고 포유류의 발생 과정에 중요한 역할을 한다. RUNX is a Runt-related transcription factor (RUNX) and is a new tumor suppressor that has recently been identified for cancer suppression activity. RUNX has a runt domain called PEBP2 / CBF (polyoma virul enhancer binding protein 2 / core binding factor), which is a signaling target for the TGF-β superfamily and plays an important role in the development of mammals. Do it.
렁스 패밀리는 RUNX1(PEBP2aB/CBFA2/AML1), RUNX2(PEBP2aB/CBFA1/AML3) 및 RUNX3(PEB2aC/CBFA3/AML2)로 이루어져 있다. 이 3가지의 렁스 패밀리는 정상적인 발생 및 분화 과정과 종양화 과정에서 중요한 역할을 한다. The rungs family consists of RUNX1 (PEBP2aB / CBFA2 / AML1), RUNX2 (PEBP2aB / CBFA1 / AML3) and RUNX3 (PEB2aC / CBFA3 / AML2). These three Rungs families play important roles in normal development and differentiation and oncogenesis.
조혈과정에서 중요한 역할을 하는 RUNX1은 백혈병에서 염색체 전좌가 가장 빈번하게 일어나는 부분이고, 급성 백혈병의 원인 중 약 30%를 차지한다. RUNX2는 골 발생에 필수적이고 상염색체 우성 골질환인 빗장뼈머리뼈 형성이상(cleido-cranial dysplasia)과 연관이 있다. RUNX3는 암억제자로서 마우스에서 Runx3 유전자의 결손은 위암을 일으키는 것으로 그 기능이 처음 보고된 이래로 여러 고형암에서 RUNX3가 불활성화 되어 있음이 보고되었다. 위암에서 RUNX3는 염색체상에서 hemizygous 결손을 보이거나 RUNX3 프로모터 부위의 메틸레이션에 의해서 불활성화 되어있음이 보고되고 있다. RUNX3는 p53 암억제자와 유사하게 세포사멸을 유도하거나 세포주기를 억제함으로써 암억제자로서의 기능을 하는 것으로 알려져 있다. 위암세포에서 RUNX3는 세포사멸사 유도 유전자인 Bim을 유도하여 TGFbeta에 의해 유도되는 세포사멸의 핵심적인 역할을 담당할 뿐 아니라, 세포주기억제 (Cell cycle arrest)에 중요한 역할을 담당하는 p21을 유도하여 세포성장을 억제하는 것으로 보고가 되었다. RUNX1, which plays an important role in the hematopoietic process, is the most frequent part of chromosomal translocation in leukemia and accounts for about 30% of the causes of acute leukemia. RUNX2 is essential for bone development and is associated with cleido-cranial dysplasia, an autosomal dominant bone disease. RUNX3 is a cancer suppressor. Deletion of the Runx3 gene in mice causes gastric cancer, and since its function was first reported, it has been reported that RUNX3 is inactivated in several solid cancers. In gastric cancer, RUNX3 has been reported to have hemizygous defects on the chromosome or inactivated by methylation of the RUNX3 promoter region. RUNX3 is known to function as a cancer suppressor by inducing apoptosis or inhibiting the cell cycle similarly to a p53 cancer suppressor. In gastric cancer cells, RUNX3 induces apoptosis-inducing gene, Bim, which plays a key role in apoptosis induced by TGFbeta, and induces p21, which plays an important role in cell cycle arrest. It has been reported to inhibit cell growth.
또한 RUNX3의 활성을 조절하는 중요한 기전으로 최근 번역 후 수식 (post-translational modification, PTM) 수준에서 RUNX3 단백의 아세틸화를 통해서 RUNX3의 활성을 증가시킬 수 있음이 보고되었다. 이는 아세틸전이효소 (Acetyl transferase)인 p300을 통한 RUNX3의 아세틸화는 RUNX3의 유비퀴틴화에 의한 RUNX3 단백의 파괴를 방해함으로서 RUNX3 단백을 안정화시켜 지속적으로 활성을 유지하는데 중요한 역할을 한다.In addition, as an important mechanism regulating the activity of RUNX3, it has recently been reported that the activity of RUNX3 can be increased through the acetylation of RUNX3 protein at the post-translational modification (PTM) level. This acetylation of RUNX3 through p300, an acetyl transferase (Acetyl transferase) plays an important role in stabilizing RUNX3 protein by maintaining the activity by preventing the destruction of RUNX3 protein by ubiquitination of RUNX3.
따라서 히스톤 탈아세틸화 효소 (Histon deacetylase, HDAC) 저해제를 이용하여 RUNX3 프로모터상의 DNA 메틸화에 의한 전사 차단을 회복하여 RUNX3의 발현을 유도할 수 있을 뿐 아니라, PTM 단계에서 HDAC에 의한 RUNX3의 탈아세틸화를 억제함으로 RUNX3 단백의 안정화와 전사 활성을 조절할 수 있으므로 후성학적으로 조절뿐 아니라 PTM 수준에서의 조절을 통해 항암치료가 가능할 것으로 판단된다.Thus, histone deacetylase (HDAC) inhibitors can be used to restore transcriptional blockade by DNA methylation on the RUNX3 promoter, leading to expression of RUNX3, and to deacetylation of RUNX3 by HDAC at the PTM stage. Inhibition of RUNX3 protein can regulate stabilization and transcriptional activity, so it is possible to control chemotherapy by regulating PTM level as well as epigenetics.
히스톤은 진핵세포의 핵내 DNA와 결합하고 있는 염기성 단백질로서 히스톤의 각 분자 중 특정 위치의 라이신 잔기의 아미노기에 가역적인 아세틸화가 일어난다. 이러한 히스톤의 아세틸화 반응은 염색질(chromatin)의 고차구조 형성이나 세포분열주기 등과 관계가 있어서 유전자 정보의 발현조절에 관여하며, 히스톤 아세틸전이효소(acetyltransferases) (HATs) 및 히스톤 디아세틸라제(histone deacetylase)(HDACs)에 의해 안정하게 조절된다. Histones are basic proteins that bind to the nucleus DNA of eukaryotic cells and undergo reversible acetylation of the amino groups of lysine residues at specific positions in each molecule of histones. The acetylation of histones is involved in the regulation of the expression of genetic information, which is related to the formation of higher levels of chromatin and the cell division cycle, and histone acetyltransferases (HATs) and histone deacetylases. Stable (HDACs).
한편, HDAC는 히스톤의 아미노 말단에 존재하는 라이신 잔기의 양전하를 탈아세틸화시켜 다시 전하를 부여하여 전사를 억제하는 효소로서, 저산소증, 저포도당, 세포 암화 등 열악한 환경조건에서 고 발현되어 세포증식 억제인자의 발현을 저해함으로써 세포증식을 촉진시키는 역할을 하는 것이 최근 밝혀지면서 세포의 암화 및 분화를 조절하는데 있어 중요한 인자로 인식되고 있다. On the other hand, HDAC is an enzyme that deacetylates the positive charge of the lysine residue present in the amino terminus of histones to recharge, thereby inhibiting transcription, and is highly expressed under poor environmental conditions such as hypoxia, low glucose, and cell cancer, thereby inhibiting cell proliferation. Recently, it is recognized that the role of promoting cell proliferation by inhibiting the expression of the factor is recognized as an important factor in regulating the cancerous and differentiation of cells.
또한, 비정상적인 히스톤 탈아세틸화의 조절이 급성 백혈병이 생기게 하는 중요한 원인 중의 하나라고 알려지면서 HDAC 활성의 비정상적인 조절에 의하여 일어나는 종양단백질(oncoprotein)의 부적절한 전사 억제와 염색질 구조에서의 이상이 정상적인 세포 분화에 영향을 미쳐 암 형성을 유도한다는 것이 알려지게 되었다. 따라서, HDAC는 유전자 발현의 억제인자로서 뿐만 아니라 새로운 항암제 개발의 표적분자로서 매우 중요한 연구대상이 되고 있다.In addition, abnormal control of histone deacetylation is known to be one of the important causes of acute leukemia, and improper transcription inhibition and abnormal chromatin structure of oncoproteins caused by abnormal control of HDAC activity may contribute to normal cell differentiation. It has been known to affect and induce cancer formation. Therefore, HDAC has become a very important research subject not only as an inhibitor of gene expression but also as a target molecule for the development of new anticancer drugs.
이러한 HDAC 저해제로 최초 사용된 화합물은 n-뷰티레이트(n-butyrate)로, 이 물질은 현재도 대장암의 치료에 적용되고 있을 뿐만 아니라 HDAC 효소 저해제로 생화학과 분자생물학 실험에 사용되고 있다. 그러나, n-뷰티레이트는 그 유효농도가 밀리몰(milimolar, mM) 수준으로 높아 세포내 다른 효소나 세포골격, 세포막 등에 영향을 미치는 등 HDAC 기능 해석에 적합하지 않은 성질을 가지고 있어 보다 선택적이고 약효가 우수한 HDAC 저해제의 개발이 요구되고 있다. The first compound used as an HDAC inhibitor is n-butyrate, which is not only applied to the treatment of colorectal cancer, but also used in biochemistry and molecular biology experiments as an HDAC enzyme inhibitor. However, the effective concentration of n-butyrate is in the level of milimolar (mM), which is not suitable for the analysis of HDAC functions such as affecting other enzymes, cytoskeleton, and cell membranes in the cell. There is a need for development of good HDAC inhibitors.
이에 본 발명자들은 히스톤 디아세틸라제의 효소활성을 효과적으로 저해하여 RUNX의 발현 및 활성을 증가시켜 종양세포의 말기 분화를 선택적으로 유도하고 종양성장을 억제하며 아폽토시스를 유발하는 새로운 기전의 항암제에 대해 연구하던 중, 신규한 피리돈 화합물을 합성하였으며, 이 화합물이 우수한 HDAC 저해활성을 통한 RUNX3의 활성 증가 유도로 종양세포 성장 억제 효과를 나타냄을 확인하고 본 발명을 완성하였다.Therefore, the present inventors have effectively studied the new mechanism of anticancer agent that effectively inhibits the enzymatic activity of histone deacetylase and increases the expression and activity of RUNX to selectively induce terminal differentiation of tumor cells, inhibit tumor growth and induce apoptosis. Among them, a novel pyridone compound was synthesized, and it was confirmed that this compound exhibited tumor cell growth inhibitory effect by inducing the increase of RUNX3 activity through excellent HDAC inhibitory activity, and completed the present invention.
본 발명은 신규한 피리돈 화합물 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물을 제공하고자 한다.The present invention is to provide a novel pyridone compound or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
상기의 과제를 해결하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.In order to solve the above problems, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2010003539-appb-I000001
Figure PCTKR2010003539-appb-I000001
상기 식에서, Where
R1은 C1-4 알킬; C2-4 알케닐; 비치환 페닐 또는 1 내지 3개의 R3로 치환된 페닐; 피리디닐; 티에닐; 비치환 나프탈레닐 또는 할로겐으로 치환된 나프탈레닐; 퀴놀리닐; 인다닐; 벤조티오페닐; 퓨라닐 또는 벤조퓨라닐이고,R 1 is C 1-4 alkyl; C 2-4 alkenyl; Unsubstituted phenyl or phenyl substituted with 1 to 3 R 3 ; Pyridinyl; Thienyl; Unsubstituted naphthalenyl or naphthalenyl substituted with halogen; Quinolinyl; Indanyl; Benzothiophenyl; Furanyl or benzofuranyl,
R2는 하이드록시; C1-3 알콜시; 또는 NHR4이고, R 2 is hydroxy; C 1-3 alcohol; Or NHR 4 ,
R3는 할로겐; C1-4 알킬; C1-4 알콕시; C1-4 할로알킬; C1-4 할로알콕시; C2-4 알케닐; 니트로; 페닐; 비치환 펜옥시 또는 C1-4 알콕시 또는 할로겐으로 치환된 펜옥시; 또는 벤질옥시이고,R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; C 1-4 haloalkoxy; C 2-4 alkenyl; Nitro; Phenyl; Unsubstituted phenoxy or phenoxy substituted with C 1-4 alkoxy or halogen; Or benzyloxy,
R4는 하이드록시; 또는 아미노페닐이고, R 4 is hydroxy; Or aminophenyl,
L은 결합; C1-4 알킬렌; 또는 C2-4 알킬렌이고, 및L is a bond; C 1-4 alkylene; Or C 2-4 alkylene, and
Figure PCTKR2010003539-appb-I000002
은 단일결합 또는 이중결합을 나타낸다.
Figure PCTKR2010003539-appb-I000002
Represents a single bond or a double bond.
바람직하게는, 상기 R1은 메틸; 2-프로페닐; 비치환 페닐 또는 1 내지 3개의 R3로 치환된 페닐; 2-피리디닐; 3-피리디닐; 4-피리디닐; 2-티에닐; 1-나프탈레닐; 2-나프탈레닐; 1-브로모-2-나프탈레닐; 6-브로모-2-나프탈레닐; 1-퀴놀리닐; 2-인다닐; 벤조티오펜-2-일; 2-퓨라닐 또는 벤조퓨란-2-일이다. Preferably, R 1 is methyl; 2-propenyl; Unsubstituted phenyl or phenyl substituted with 1 to 3 R 3 ; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-thienyl; 1-naphthalenyl; 2-naphthalenyl; 1-bromo-2-naphthalenyl; 6-bromo-2-naphthalenyl; 1-quinolinyl; 2-indanyl; Benzothiophen-2-yl; 2-furanyl or benzofuran-2-yl.
바람직하게는, 상기 R2는 하이드록시; 메톡시; 또는 NHR4이다.Preferably, R 2 is hydroxy; Methoxy; Or NHR 4 .
바람직하게는, 상기 R3은 F; Cl; Br; 메틸; 에틸; 이소프로필; 테트-부틸; 메톡시; 에톡시; 프로폭시; CF3; OCF3; 에테닐; 니트로; 페닐; 비치환 펜옥시 또는 메톡시 또는 F로 치환된 펜옥시; 또는 벤질옥시이다. Preferably, R 3 is F; Cl; Br; methyl; ethyl; Isopropyl; Tet-butyl; Methoxy; Ethoxy; Propoxy; CF 3 ; OCF 3 ; Ethenyl; Nitro; Phenyl; Unsubstituted phenoxy or phenoxy substituted with methoxy or F; Or benzyloxy.
바람직하게는, 상기 R4는 하이드록시 또는 2-아미노페닐이다. Preferably, R 4 is hydroxy or 2-aminophenyl.
바람직하게는, 상기 L은 결합; 에틸렌; 트리메틸렌; 또는 프로페닐렌(
Figure PCTKR2010003539-appb-I000003
)이다. Preferably, L is a bond; Ethylene; Trimethylene; Or propenylene (
Figure PCTKR2010003539-appb-I000003
)to be.
바람직하게는, 상기 R1은 하나의 R3로 치환된 페닐이다. Preferably, R 1 is phenyl substituted with one R 3 .
바람직하게는, 상기 R1은 두 개의 R3로 치환된 페닐이고, 상기 R3는 할로겐; C1-4 알킬; C1-4 알콕시; C1-4 할로알킬; 또는 니트로이다. Preferably, R 1 is phenyl substituted with two R 3 , wherein R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; Or nitro.
보다 바람직하게는, 상기 R3는 F; Cl; 메틸; 메톡시; CF3; 또는 니트로이다. More preferably, R 3 is F; Cl; methyl; Methoxy; CF 3 ; Or nitro.
바람직하게는, 상기 R1은 세 개의 R3로 치환된 페닐이고, 상기 R3는 할로겐; 또는 C1-4 알콕시이다. Preferably, R 1 is phenyl substituted with three R 3 , wherein R 3 is halogen; Or C 1-4 alkoxy.
바람직하게는, 상기 R3는 F; 또는 메톡시이다. Preferably, R 3 is F; Or methoxy.
바람직하게는, 상기 R1은 3-메톡시페닐; 3-트리플루오로메톡시페닐; 3-클로로페닐; 3-브로모페닐; 1-나프탈레닐; 2-나프탈레닐; 6-브로모-2-나프탈레닐; 1-퀴놀리닐; 4-이소프로필페닐; 4-니트로페닐; 2-브로모페닐; 2-메톡시페닐; 또는 2,5-디트리플루오로메틸페닐이다. Preferably, R 1 is 3-methoxyphenyl; 3-trifluoromethoxyphenyl; 3-chlorophenyl; 3-bromophenyl; 1-naphthalenyl; 2-naphthalenyl; 6-bromo-2-naphthalenyl; 1-quinolinyl; 4-isopropylphenyl; 4-nitrophenyl; 2-bromophenyl; 2-methoxyphenyl; Or 2,5-ditrifluoromethylphenyl.
바람직하게는, 상기 R1은 페닐의 2번 위치에 R3으로 치환된 페닐이고, 상기 R3는 할로겐; C1-4 알킬; C1-4 알콕시; C1-4 할로알킬; 또는 C1-4 할로알콕시이거나, Preferably, R 1 is phenyl substituted with R 3 at position 2 of phenyl, and R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; Or C 1-4 haloalkoxy,
상기 R1은 페닐의 3번 위치에 R3로 치환된 페닐이고, 상기 R3는 할로겐; C1-4 알킬; C1-4 알콕시; C1-4 할로알킬; C1-4 할로알콕시; C2-4 알케닐; 니트로; 펜옥시; 또는 벤질옥시이거나, 또는 R 1 is phenyl substituted with R 3 at position 3 of phenyl, and R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; C 1-4 haloalkoxy; C 2-4 alkenyl; Nitro; Phenoxy; Or benzyloxy, or
상기 R1은 페닐의 4번 위치에 R3로 치환된 페닐이고, 상기 R3는 할로겐; C1-4 알킬; C1-4 알콕시; C1-4 할로알킬; C1-4 할로알콕시; 니트로; 페닐; 비치환된 펜옥시 또는 C1-4 알콕시 또는 할로겐으로 치환된 펜옥시; 또는 벤질옥시이다. R 1 is phenyl substituted with R 3 at position 4 of phenyl, and R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; C 1-4 haloalkoxy; Nitro; Phenyl; Phenoxy unsubstituted or substituted with C 1-4 alkoxy or halogen; Or benzyloxy.
바람직하게는, 상기 R1은 C1-4 알킬; C2-4 알케닐; 인다닐; 또는 퓨라닐이고, 상기 L은 결합이거나, Preferably, R 1 is C 1-4 alkyl; C 2-4 alkenyl; Indanyl; Or furanyl, and L is a bond,
상기 R1은 비치환된 페닐 또는 1 내지 3개의 R3으로 치환된 페닐; 피리디닐; 비치환된 나프탈레닐 또는 할로겐으로 치환된 나프탈레닐; 퀴놀리닐; 벤조티오페닐; 또는 벤조퓨라닐이고, 상기 L은 메틸렌이거나, R 1 is unsubstituted phenyl or phenyl substituted with 1 to 3 R 3 ; Pyridinyl; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Quinolinyl; Benzothiophenyl; Or benzofuranyl, wherein L is methylene,
상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 티에닐; 비치환된 나프탈레닐 또는 할로겐으로 치환된 나프탈레닐; 또는 퀴놀리닐이고, 상기 L은 에틸렌이거나, R 1 is phenyl substituted with 1 to 3 R 3 ; Thienyl; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Or quinolinyl, wherein L is ethylene, or
상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 피리디닐; 비치환된 나프탈레닐 또는 할로겐으로 치환된 나프탈레닐; 또는 퀴놀리닐이고, 상기 L은 트리메틸렌이거나, 또는 R 1 is phenyl substituted with 1 to 3 R 3 ; Pyridinyl; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Or quinolinyl, wherein L is trimethylene, or
상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 비치환된 나프탈레닐 또는 할로겐으로 치환된 나프탈레닐; 또는 퀴놀리닐이고, 상기 L은 프로필렌(
Figure PCTKR2010003539-appb-I000004
)이다. R 1 is phenyl substituted with 1 to 3 R 3 ; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Or quinolinyl, wherein L is propylene (
Figure PCTKR2010003539-appb-I000004
)to be.
바람직하게는, 상기 R1은 메틸; 에테닐; 2-인다닐; 또는 2-퓨라닐이고, 상기 L은 결합이거나, Preferably, R 1 is methyl; Ethenyl; 2-indanyl; Or 2-furanyl, wherein L is a bond,
상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 2-피리디닐; 3-피리디닐; 4-피리디닐; 1-나프탈레닐; 2-나프탈레닐; 1-퀴놀리닐; 벤조티오펜-2-일; 또는 벤조퓨란-2-일이고, 상기 L은 메틸렌이거나, R 1 is phenyl substituted with 1 to 3 R 3 ; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 1-naphthalenyl; 2-naphthalenyl; 1-quinolinyl; Benzothiophen-2-yl; Or benzofuran-2-yl, wherein L is methylene,
상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 2-티에닐; 1-나프탈레닐; 2-나프탈레닐; 6-브로모-2-나프탈레닐; 또는 1-퀴놀리닐이고, 상기 L은 에틸렌이거나,R 1 is phenyl substituted with 1 to 3 R 3 ; 2-thienyl; 1-naphthalenyl; 2-naphthalenyl; 6-bromo-2-naphthalenyl; Or 1-quinolinyl, wherein L is ethylene,
상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 3-피리디닐; 1-나프탈레닐; 1-나프탈레닐; 6-브로모-2-나프탈레닐; or 1-퀴놀리닐이고, 상기 L은 트리메틸렌이거나, 또는 R 1 is phenyl substituted with 1 to 3 R 3 ; 3-pyridinyl; 1-naphthalenyl; 1-naphthalenyl; 6-bromo-2-naphthalenyl; or 1-quinolinyl, wherein L is trimethylene, or
상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 1-나프탈레닐; 2-나프탈레닐; 6-브로모-2-나프탈레닐; 또는 1-퀴놀리닐이고, 상기 L은 프로페닐렌(
Figure PCTKR2010003539-appb-I000005
)이다. R 1 is phenyl substituted with 1 to 3 R 3 ; 1-naphthalenyl; 2-naphthalenyl; 6-bromo-2-naphthalenyl; Or 1-quinolinyl, wherein L is propenylene (
Figure PCTKR2010003539-appb-I000005
)to be.
본 발명의 화학식 1의 피리돈 화합물 중 바람직한 화합물은 구체적으로 하기와 같다:Preferred compounds among the pyridone compounds of formula 1 of the present invention are specifically as follows:
1) (E)-3-(1-(4-브로모벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,1) (E) -3- (1- (4-bromobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
2) (E)-3-(1-(3-플루오로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,2) (E) -3- (1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
3) (E)-3-(1-(2-플루오로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,3) (E) -3- (1- (2-fluorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
4) (E)-3-(1-(2,5-비스(트리플루오로메틸)벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,4) (E) -3- (1- (2,5-bis (trifluoromethyl) benzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
5) (E)-3-(1-(3,4-디플루오로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,5) (E) -3- (1- (3,4-difluorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
6) (E)-N-하이드록시-3-(1-(4-니트로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,6) (E) -N-hydroxy-3- (1- (4-nitrobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
7) (E)-N-하이드록시-3-(2-옥소-1-(3,4,5-트리플루오로벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,7) (E) -N-hydroxy-3- (2-oxo-1- (3,4,5-trifluorobenzyl) -1,2-dihydropyridin-3-yl) acrylamide,
8) (E)-3-(1-(4-테트-부틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,8) (E) -3- (1- (4-tet-butylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
9) (E)-N-하이드록시-3-(1-메틸-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,9) (E) -N-hydroxy-3- (1-methyl-2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
10) (E)-3-(1-알릴-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,10) (E) -3- (1-allyl-2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
11) (E)-N-하이드록시-3-(1-(4-이소프로필벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,11) (E) -N-hydroxy-3- (1- (4-isopropylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
12) (E)-N-하이드록시-3-(2-옥소-1-(3-페닐프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,12) (E) -N-hydroxy-3- (2-oxo-1- (3-phenylpropyl) -1,2-dihydropyridin-3-yl) acrylamide,
13) (E)-3-(1-(3-(4-플루오로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,13) (E) -3- (1- (3- (4-fluorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
14) (E)-3-(1-(3-(3-플루오로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,14) (E) -3- (1- (3- (3-fluorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
15) (E)-3-(1-(3-(2-플루오로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,15) (E) -3- (1- (3- (2-fluorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
16) (E)-3-(1-(3-(4-클로로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,16) (E) -3- (1- (3- (4-chlorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
17) (E)-3-(1-(3-(3-클로로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,17) (E) -3- (1- (3- (3-chlorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
18) (E)-3-(1-(3-(2-클로로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,18) (E) -3- (1- (3- (2-chlorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
19) (E)-N-하이드록시-3-(1-(3-(4-이소프로필페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,19) (E) -N-hydroxy-3- (1- (3- (4-isopropylphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
20) (E)-N-하이드록시-3-(2-옥소-1-(3-(3,4,5-트리플루오로페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,20) (E) -N-hydroxy-3- (2-oxo-1- (3- (3,4,5-trifluorophenyl) propyl) -1,2-dihydropyridin-3-yl) Acrylamide,
21) (E)-3-(1-(3-(비페닐-4-일)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,21) (E) -3- (1- (3- (biphenyl-4-yl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
22) (E)-N-하이드록시-3-(2-옥소-1-(3-(4-(트리플루오로메톡시)페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,22) (E) -N-hydroxy-3- (2-oxo-1- (3- (4- (trifluoromethoxy) phenyl) propyl) -1,2-dihydropyridin-3-yl) acrylic amides,
23) (E)-N-하이드록시-3-(2-옥소-1-(3-(3-(트리플루오로메톡시)페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,23) (E) -N-hydroxy-3- (2-oxo-1- (3- (3- (trifluoromethoxy) phenyl) propyl) -1,2-dihydropyridin-3-yl) acrylic amides,
24) (E)-N-하이드록시-3-(2-옥소-1-(3-(2-(트리플루오로메톡시)페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,24) (E) -N-hydroxy-3- (2-oxo-1- (3- (2- (trifluoromethoxy) phenyl) propyl) -1,2-dihydropyridin-3-yl) acrylic amides,
25) (E)-N-하이드록시-3-(2-옥소-1-(3-(4-펜옥시페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,25) (E) -N-hydroxy-3- (2-oxo-1- (3- (4-phenoxyphenyl) propyl) -1,2-dihydropyridin-3-yl) acrylamide,
26) (E)-3-(1-(3-(3,4-디플루오로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,26) (E) -3- (1- (3- (3,4-difluorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide ,
27) (E)-N-하이드록시-3-(1-(4-메틸펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,27) (E) -N-hydroxy-3- (1- (4-methylphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
28) (E)-N-하이드록시-3-(1-(3-메틸펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,28) (E) -N-hydroxy-3- (1- (3-methylphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
29) (E)-N-하이드록시-3-(1-(2-메틸펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,29) (E) -N-hydroxy-3- (1- (2-methylphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
30) (E)-N-하이드록시-3-(2-옥소-1-(2-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,30) (E) -N-hydroxy-3- (2-oxo-1- (2- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) acrylamide,
31) (E)-3-(1-(2-브로모벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,31) (E) -3- (1- (2-bromobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
32) (E)-N-하이드록시-3-(1-(2-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,32) (E) -N-hydroxy-3- (1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
33) (E)-3-(1-(4-에틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,33) (E) -3- (1- (4-ethylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
34) (E)-3-(1-(2-에틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,34) (E) -3- (1- (2-ethylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
35) (E)-3-(1-(4-(4-플루오로펜옥시)펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,35) (E) -3- (1- (4- (4-fluorophenoxy) phenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
36) (E)-N-하이드록시-3-(1-(4-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,36) (E) -N-hydroxy-3- (1- (4-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
37) (E)-N-하이드록시-3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,37) (E) -N-hydroxy-3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
38) (E)-3-(1-(3-브로모벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,38) (E) -3- (1- (3-bromobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
39) (E)-3-(1-(4-플루오로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,39) (E) -3- (1- (4-fluorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
40) (E)-N-하이드록시-3-(2-옥소-1-(3-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,40) (E) -N-hydroxy-3- (2-oxo-1- (3- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) acrylamide,
41) (E)-N-하이드록시-3-(1-(3-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,41) (E) -N-hydroxy-3- (1- (3-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
42) (E)-N-하이드록시-3-(2-옥소-1-(3-펜옥시벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,42) (E) -N-hydroxy-3- (2-oxo-1- (3-phenoxybenzyl) -1,2-dihydropyridin-3-yl) acrylamide,
43) (E)-N-하이드록시-3-(2-옥소-1-(4-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,43) (E) -N-hydroxy-3- (2-oxo-1- (4- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) acrylamide,
44) (E)-N-하이드록시-3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,44) (E) -N-hydroxy-3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
45) (E)-N-하이드록시-3-(1-(나프탈렌-1-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,45) (E) -N-hydroxy-3- (1- (naphthalen-1-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
46) (E)-3-(1-(3-(2-브로모페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,46) (E) -3- (1- (3- (2-bromophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
47) (E)-3-(1-(3-(4-브로모페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,47) (E) -3- (1- (3- (4-bromophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
48) (E)-N-하이드록시-3-(1-(3-(3-메톡시페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,48) (E) -N-hydroxy-3- (1- (3- (3-methoxyphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
49) (E)-N-하이드록시-3-(1-(3-(4-메톡시페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,49) (E) -N-hydroxy-3- (1- (3- (4-methoxyphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
50) (E)-N-하이드록시-3-(1-(3-(2-메톡시페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,50) (E) -N-hydroxy-3- (1- (3- (2-methoxyphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
51) (E)-N-하이드록시-3-(1-(3-(나프탈렌-1-일)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,51) (E) -N-hydroxy-3- (1- (3- (naphthalen-1-yl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
52) (E)-N-하이드록시-3-(1-(3-(나프탈렌-2-일)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,52) (E) -N-hydroxy-3- (1- (3- (naphthalen-2-yl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
53) (E)-3-(1-(3-(3-브로모페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,53) (E) -3- (1- (3- (3-bromophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
54) (E)-3-(1-벤질-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,54) (E) -3- (1-benzyl-2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
55) (E)-N-하이드록시-3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,55) (E) -N-hydroxy-3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) acrylamide,
56) (E)-N-하이드록시-3-(1-(4-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,56) (E) -N-hydroxy-3- (1- (4-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
57) (E)-3-(1-(3,5-비스(트리플루오로메틸)벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,57) (E) -3- (1- (3,5-bis (trifluoromethyl) benzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
58) (E)-N-하이드록시-3-(1-(4-메틸-3-니트로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,58) (E) -N-hydroxy-3- (1- (4-methyl-3-nitrobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
59) (E)-3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,59) (E) -3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
60) (E)-N-하이드록시-3-(2-옥소-1-펜에틸-1,2-디하이드로피리딘-3-일)아크릴아미드,60) (E) -N-hydroxy-3- (2-oxo-1-phenethyl-1,2-dihydropyridin-3-yl) acrylamide,
61) (E)-N-하이드록시-3-(1-(2-메틸-3-니트로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,61) (E) -N-hydroxy-3- (1- (2-methyl-3-nitrobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
62) (E)-3-(1-(4-브로모펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,62) (E) -3- (1- (4-bromophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
63) (E)-N-하이드록시-3-(1-(3-메톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,63) (E) -N-hydroxy-3- (1- (3-methoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
64) (E)-3-(1-(4-클로로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,64) (E) -3- (1- (4-chlorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
65) (E)-3-(1-(2-클로로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,65) (E) -3- (1- (2-chlorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
66) (E)-3-(1-(3-클로로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,66) (E) -3- (1- (3-chlorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
67) (E)-N-하이드록시-3-(1-(2-(나프탈렌-1-일)에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,67) (E) -N-hydroxy-3- (1- (2- (naphthalen-1-yl) ethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
68) (E)-N-하이드록시-3-(1-(2-메톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,68) (E) -N-hydroxy-3- (1- (2-methoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
69) (E)-N-하이드록시-3-(1-(2-(나프탈렌-2-일)에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,69) (E) -N-hydroxy-3- (1- (2- (naphthalen-2-yl) ethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
70) (E)-3-(1-(2-브로모펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,70) (E) -3- (1- (2-bromophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
71) (E)-3-(1-(3-브로모펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,71) (E) -3- (1- (3-bromophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
72) (E)-N-하이드록시-3-(2-옥소-1-(3-펜옥시펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,72) (E) -N-hydroxy-3- (2-oxo-1- (3-phenoxyphenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
73) (E)-3-(1-(2-(비페닐-4일)에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,73) (E) -3- (1- (2- (biphenyl-4yl) ethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
74) (E)-3-(1-(4-플루오로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,74) (E) -3- (1- (4-fluorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
75) (E)-3-(1-(2-플루오로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,75) (E) -3- (1- (2-fluorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
76) (E)-3-(1-(4-테트-부틸펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,76) (E) -3- (1- (4-tet-butylphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
77) (E)-3-(1-(3-플루오로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,77) (E) -3- (1- (3-fluorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
78) (E)-3-(1-(3-에톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,78) (E) -3- (1- (3-ethoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
79) (E)-N-하이드록시-3-(1-(4-이소프로필펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,79) (E) -N-hydroxy-3- (1- (4-isopropylphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
80) (E)-N-하이드록시-3-(1-(4-메톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,80) (E) -N-hydroxy-3- (1- (4-methoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
81) (E)-N-하이드록시-3-(1-(4-(4-메톡시펜옥시)펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,81) (E) -N-hydroxy-3- (1- (4- (4-methoxyphenoxy) phenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
82) (E)-3-(1-(4-(벤질옥시)펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,82) (E) -3- (1- (4- (benzyloxy) phenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
83) (E)-N-하이드록시-3-(2-옥소-1-(4-(트리플루오로메틸)펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,83) (E) -N-hydroxy-3- (2-oxo-1- (4- (trifluoromethyl) phenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
84) (E)-3-(1-(2-에톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,84) (E) -3- (1- (2-ethoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
85) (E)-N-하이드록시-3-(2-옥소-1-(3-비닐펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,85) (E) -N-hydroxy-3- (2-oxo-1- (3-vinylphenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
86) (E)-N-하이드록시-3-(2-옥소-1-(4-(트리플루오로메톡시)펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,86) (E) -N-hydroxy-3- (2-oxo-1- (4- (trifluoromethoxy) phenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
87) (E)-3-(1-(4-에톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,87) (E) -3- (1- (4-ethoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
88) (E)-N-하이드록시-3-(2-옥소-1-(2-(트리플루오로메틸)펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,88) (E) -N-hydroxy-3- (2-oxo-1- (2- (trifluoromethyl) phenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
89) (E)-N-하이드록시-3-(2-옥소-1-(3-(트리플루오로메틸)펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,89) (E) -N-hydroxy-3- (2-oxo-1- (3- (trifluoromethyl) phenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
90) (E)-N-하이드록시-3-(2-옥소-1-(4-프로폭시펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,90) (E) -N-hydroxy-3- (2-oxo-1- (4-propoxyphenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
91) (E)-N-하이드록시-3-(2-옥소-1-(4-펜옥시펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,91) (E) -N-hydroxy-3- (2-oxo-1- (4-phenoxyphenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
92) (E)-3-(1-(3-(벤질옥시)펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,92) (E) -3- (1- (3- (benzyloxy) phenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
93) (E)-3-(1-(2-(벤질옥시)펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,93) (E) -3- (1- (2- (benzyloxy) phenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
94) (E)-N-하이드록시-3-(1-(4-니트로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,94) (E) -N-hydroxy-3- (1- (4-nitrophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
95) (E)-3-(1-(3,4-디클로로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,95) (E) -3- (1- (3,4-dichlorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
96) (E)-N-하이드록시-3-(1-(3-(4-메톡시펜옥시)펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,96) (E) -N-hydroxy-3- (1- (3- (4-methoxyphenoxy) phenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
97) (E)-3-(1-(3,4-디플루오로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,97) (E) -3- (1- (3,4-difluorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
98) (E)-3-(1-(4-에틸펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,98) (E) -3- (1- (4-ethylphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
99) (E)-N-하이드록시-3-(2-옥소-1-(3,4,5-트리메톡시펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,99) (E) -N-hydroxy-3- (2-oxo-1- (3,4,5-trimethoxyphenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
100) (E)-3-(1-(2,4-디클로로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,100) (E) -3- (1- (2,4-dichlorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
101) (E)-3-(1-(2,3-디하이드로-1H-인덴-2-일)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,101) (E) -3- (1- (2,3-dihydro-1H-inden-2-yl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
102) (E)-N-하이드록시-3-(2-옥소-1-(3-m-톨릴프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,102) (E) -N-hydroxy-3- (2-oxo-1- (3-m-tolylpropyl) -1,2-dihydropyridin-3-yl) acrylamide,
103) (E)-N-하이드록시-3-(2-옥소-1-(3-o-톨릴프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,103) (E) -N-hydroxy-3- (2-oxo-1- (3-o-tolylpropyl) -1,2-dihydropyridin-3-yl) acrylamide,
104) (E)-N-하이드록시-3-(2-옥소-1-(3-p-톨릴프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,104) (E) -N-hydroxy-3- (2-oxo-1- (3-p-tolylpropyl) -1,2-dihydropyridin-3-yl) acrylamide,
105) (E)-3-(1-(2-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,105) (E) -3- (1- (2-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
106) (E)-3-(1-(4-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,106) (E) -3- (1- (4-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
107) (E)-3-(1-(3-(4-테트-부틸페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,107) (E) -3- (1- (3- (4-tet-butylphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
108) (E)-N-하이드록시-3-(2-옥소-1-(3-(2-(트리플루오로메틸)페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,108) (E) -N-hydroxy-3- (2-oxo-1- (3- (2- (trifluoromethyl) phenyl) propyl) -1,2-dihydropyridin-3-yl) acrylic amides,
109) (E)-N-하이드록시-3-(2-옥소-1-(3-(4-(트리플루오로메틸)페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,109) (E) -N-hydroxy-3- (2-oxo-1- (3- (4- (trifluoromethyl) phenyl) propyl) -1,2-dihydropyridin-3-yl) acrylic amides,
110) (E)-N-하이드록시-3-(2-옥소-1-(3-(3-(트리플루오로메틸)페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,110) (E) -N-hydroxy-3- (2-oxo-1- (3- (3- (trifluoromethyl) phenyl) propyl) -1,2-dihydropyridin-3-yl) acrylic amides,
111) (E)-3-(1-(3-(4-에틸페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,111) (E) -3- (1- (3- (4-ethylphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
112) (E)-3-(1-(비페닐-4-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,112) (E) -3- (1- (biphenyl-4-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
113) (E)-3-(1-(2-(6-브로모나프탈렌-2-일)에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,113) (E) -3- (1- (2- (6-bromonaphthalen-2-yl) ethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
114) (E)-3-(1-(2,4-디메톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,114) (E) -3- (1- (2,4-dimethoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
115) (E)-메틸 3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴레이트,115) (E) -methyl 3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylate,
116) (E)-3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴릭 애시드,116) (E) -3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic acid,
117) 3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노익 애시드,117) 3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoic acid,
118) N-하이드록시-3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)프로판아미드,118) N-hydroxy-3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) propanamide,
119) 메틸 3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)프로파노에이트,119) methyl 3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) propanoate,
120) (E)-메틸 3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)아크릴레이트,120) (E) -methyl 3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) acrylate,
121) (E)-N-(2-아미노페닐)-3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,121) (E) -N- (2-aminophenyl) -3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) acrylamide ,
122) (E)-N-(2-아미노페닐)-3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,122) (E) -N- (2-aminophenyl) -3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
123) 메틸 3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노에이트,123) methyl 3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoate,
124) (E)-3-(1-신나밀-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,124) (E) -3- (1-cinnamil-2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
125) (E)-3-(1-((E)-3-(4-브로모페닐)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,125) (E) -3- (1-((E) -3- (4-bromophenyl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
126) (E)-3-(1-((E)-3-(3-브로모페닐)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,126) (E) -3- (1-((E) -3- (3-bromophenyl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
127) (E)-3-(1-((E)-3-(2-브로모페닐)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,127) (E) -3- (1-((E) -3- (2-bromophenyl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
128) (E)-3-(1-(3-(2-에톡시페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,128) (E) -3- (1- (3- (2-ethoxyphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
129) (E)-N-하이드록시-3-(2-옥소-1-(피리딘-2-일메틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,129) (E) -N-hydroxy-3- (2-oxo-1- (pyridin-2-ylmethyl) -1,2-dihydropyridin-3-yl) acrylamide,
130) (E)-N-하이드록시-3-(2-옥소-1-(피리딘-3-일메틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,130) (E) -N-hydroxy-3- (2-oxo-1- (pyridin-3-ylmethyl) -1,2-dihydropyridin-3-yl) acrylamide,
131) (E)-3-(1-(3-(1-브로모나프탈렌-2-일)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,131) (E) -3- (1- (3- (1-bromonaphthalen-2-yl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
132) N-하이드록시-3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)프로판아미드,132) N-hydroxy-3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) propanamide,
133) 3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)프로파노익 애시드,133) 3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) propanoic acid,
134) N-(2-아미노페닐)-3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)프로판아미드,134) N- (2-aminophenyl) -3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) propanamide,
135) N-(2-아미노페닐)-3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)프로판아미드,135) N- (2-aminophenyl) -3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) propanamide,
136) (E)-N-하이드록시-3-(2-옥소-1-(2-(티오펜-2-일)에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,136) (E) -N-hydroxy-3- (2-oxo-1- (2- (thiophen-2-yl) ethyl) -1,2-dihydropyridin-3-yl) acrylamide,
137) (E)-N-하이드록시-3-(1-((E)-3-(나프탈렌-2-일)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,137) (E) -N-hydroxy-3- (1-((E) -3- (naphthalen-2-yl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic amides,
138) (E)-N-하이드록시-3-(2-옥소-1-((E)-3-(3-(트리플루오로메톡시)페닐)알릴)-1,2-디하이드로피리딘-3-일)아크릴아미드,138) (E) -N-hydroxy-3- (2-oxo-1-((E) -3- (3- (trifluoromethoxy) phenyl) allyl) -1,2-dihydropyridine-3 -Yl) acrylamide,
139) (E)-N-하이드록시-3-(1-((E)-3-(3-메톡시페닐)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,139) (E) -N-hydroxy-3- (1-((E) -3- (3-methoxyphenyl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic amides,
140) (E)-N-하이드록시-3-(1-((E)-3-(나프탈렌-1-일)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,140) (E) -N-hydroxy-3- (1-((E) -3- (naphthalen-1-yl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic amides,
141) (E)-메틸 3-(2-옥소-1-(3-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)아크릴레이트,141) (E) -methyl 3- (2-oxo-1- (3- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) acrylate,
142) (E)-N-(2-아미노페닐)-3-(2-옥소-1-(3-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,142) (E) -N- (2-aminophenyl) -3- (2-oxo-1- (3- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) acrylamide ,
143) N-(2-아미노페닐)-3-(2-옥소-1-(3-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)프로판아미드,143) N- (2-aminophenyl) -3- (2-oxo-1- (3- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) propanamide,
144) (E)-메틸 3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴레이트,144) (E) -methyl 3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylate,
145) (E)-3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴릭 애시드,145) (E) -3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic acid,
146) 3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시프로판아미드,146) 3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxypropanamide,
147) (E)-N-(2-아미노페닐)-3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,147) (E) -N- (2-aminophenyl) -3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
148) (E)-메틸 3-(1-(4-니트로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴레이트,148) (E) -methyl 3- (1- (4-nitrobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylate,
149) (E)-N-(2-아미노페닐)-3-(1-(4-니트로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,149) (E) -N- (2-aminophenyl) -3- (1- (4-nitrobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
150) (E)-3-(1-(4-니트로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴릭 애시드,150) (E) -3- (1- (4-nitrobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic acid,
151) (E)-3-(1-(3-(6-브로모나프탈렌-2-일)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,151) (E) -3- (1- (3- (6-bromonaphthalen-2-yl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
152) (E)-N-하이드록시-3-(2-옥소-1-(퀴놀린-2-일메틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,152) (E) -N-hydroxy-3- (2-oxo-1- (quinolin-2-ylmethyl) -1,2-dihydropyridin-3-yl) acrylamide,
153) (E)-N-하이드록시-3-(2-옥소-1-(피리딘-4-일메틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,153) (E) -N-hydroxy-3- (2-oxo-1- (pyridin-4-ylmethyl) -1,2-dihydropyridin-3-yl) acrylamide,
154) (E)-N-하이드록시-3-(2-옥소-1-(2-(피리딘-2-일)에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,154) (E) -N-hydroxy-3- (2-oxo-1- (2- (pyridin-2-yl) ethyl) -1,2-dihydropyridin-3-yl) acrylamide,
155) (E)-N-하이드록시-3-(2-옥소-1-(3-(피리딘-3-일)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,155) (E) -N-hydroxy-3- (2-oxo-1- (3- (pyridin-3-yl) propyl) -1,2-dihydropyridin-3-yl) acrylamide,
156) (E)-N-하이드록시-3-(2-옥소-1-(2-(피리딘-4-일)에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,156) (E) -N-hydroxy-3- (2-oxo-1- (2- (pyridin-4-yl) ethyl) -1,2-dihydropyridin-3-yl) acrylamide,
157) (E)-N-하이드록시-3-(2-옥소-1-((E)-3-(3-(트리플루오로메틸)페닐)알릴)-1,2-디하이드로피리딘-3-일)아크릴아미드,157) (E) -N-hydroxy-3- (2-oxo-1-((E) -3- (3- (trifluoromethyl) phenyl) allyl) -1,2-dihydropyridine-3 -Yl) acrylamide,
158) (E)-3-(1-((E)-3-(3-클로로페닐)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,158) (E) -3- (1-((E) -3- (3-chlorophenyl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide ,
159) (E)-N-하이드록시-3-(1-((E)-3-(2-메톡시페닐)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,159) (E) -N-hydroxy-3- (1-((E) -3- (2-methoxyphenyl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic amides,
160) (E)-N-하이드록시-3-(2-옥소-1-((E)-3-(퀴놀린-2-일)알릴)-1,2-디하이드로피리딘-3-일)아크릴아미드,160) (E) -N-hydroxy-3- (2-oxo-1-((E) -3- (quinolin-2-yl) allyl) -1,2-dihydropyridin-3-yl) acrylic amides,
161) 3-(1-(2-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노익 애시드,161) 3- (1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoic acid,
162) 메틸 3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노에이트,162) methyl 3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoate,
163) 3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노익 애시드,163) 3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoic acid,
164) (E)-3-(2-옥소-1-(3-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)아크릴릭 애시드,164) (E) -3- (2-oxo-1- (3- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) acrylic acid,
165) 메틸 3-(2-옥소-1-(3-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)프로파노에이트,165) methyl 3- (2-oxo-1- (3- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) propanoate,
166) (E)-N-(2-아미노페닐)-3-(1-(2-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,166) (E) -N- (2-aminophenyl) -3- (1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
167) N-하이드록시-3-(1-(2-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로판아미드,167) N-hydroxy-3- (1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanamide,
168) (E)-메틸 3-(2-옥소-1-(퀴놀린-2-일메틸)-1,2-디하이드로피리딘-3-일)아크릴레이트,168) (E) -methyl 3- (2-oxo-1- (quinolin-2-ylmethyl) -1,2-dihydropyridin-3-yl) acrylate,
169) (E)-3-(2-옥소-1-(퀴놀린-2-일메틸)-1,2-디하이드로피리딘-3-일)아크릴릭 애시드,169) (E) -3- (2-oxo-1- (quinolin-2-ylmethyl) -1,2-dihydropyridin-3-yl) acrylic acid,
170) (E)-N-(2-아미노페닐)-3-(2-옥소-1-(퀴놀린-2-일메틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,170) (E) -N- (2-aminophenyl) -3- (2-oxo-1- (quinolin-2-ylmethyl) -1,2-dihydropyridin-3-yl) acrylamide,
171) N-(2-아미노페닐)-3-(2-옥소-1-(퀴놀린-2-일메틸)-1,2-디하이드로피리딘-3-일)프로판아미드,171) N- (2-aminophenyl) -3- (2-oxo-1- (quinolin-2-ylmethyl) -1,2-dihydropyridin-3-yl) propanamide,
172) (E)-메틸 3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴레이트,172) (E) -methyl 3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylate,
173) (E)-3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴릭 애시드,173) (E) -3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic acid,
174) (E)-N-(2-아미노페닐)-3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,174) (E) -N- (2-aminophenyl) -3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
175) 메틸 3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노에이트,175) methyl 3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoate,
176) 3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노익 애시드,176) 3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoic acid,
177) N-(2-아미노페닐)-3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로판아미드,177) N- (2-aminophenyl) -3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanamide,
178) N-하이드록시-3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로판아미드,178) N-hydroxy-3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanamide,
179) (E)-3-(1-(벤조[b]티오펜-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,179) (E) -3- (1- (benzo [b] thiophen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
180) (E)-3-(1-(벤조퓨란-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,180) (E) -3- (1- (benzofuran-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
181) (E)-3-(1-(퓨란-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,181) (E) -3- (1- (furan-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
182) (E)-메틸 3-(1-(2-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴레이트, 또는182) (E) -methyl 3- (1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylate, or
183) (E)-3-(1-(2-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴릭 애시드.183) (E) -3- (1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic acid.
본 발명의 화합물들은 당해 기술분야에서 통상적인 방법에 따라 약학적으로 허용가능한 염 및 용매화물로 제조될 수 있다.The compounds of the present invention can be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.
약학적으로 허용가능한 염으로는 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 산부가염은 통상의 방법, 예를 들면 화합물을 과량의 산 수용액에 용해시키고, 이 염을 메탄올, 에탄올, 아세톤 또는 아세토니트릴과 같은 수혼화성 유기 용매를 사용하여 침전시켜서 제조한다. As the pharmaceutically acceptable salt, acid addition salts formed by free acid are useful. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고, 유기산으로는 메탄설폰산, p-톨루엔설폰산, 아세트산, 트리플루오로아세트산, 시트르산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산 (propionic acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산 (gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산 (glucuronic acid), 아스파르트산, 아스코르빈산, 카본산, 바닐릭산, 히드로 아이오딕산 등을 사용할 수 있다.In this case, organic acids and inorganic acids may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, and trifluoro may be used as the organic acid. Acetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, Galacturonic acid, glutamic acid, glutaric acid (glutaric acid), glucuronic acid (glucuronic acid), aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid and the like can be used.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 제조할 수 있다. 알칼리 금속 또는 알칼리 토금속염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리토 금속 수산화물 용액 중에 용해하고, 비용해 화합물염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하며, 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리토 금속염을 적당한 은염(예, 질산은)과 반응시켜 얻는다.Bases may also be used to prepare pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salt, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
상기 화학식 1로 표시되는 화합물의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들면, 약학적으로 허용가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨 염이 포함되며, 아미노기의 기타 약학적으로 허용가능한 염으로는 히드로브로마이드, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄설포네이트(메실레이트) 및 p-톨루엔설포네이트(토실레이트) 염이 있으며, 당업계에서 알려진 염의 제조방법이나 제조과정을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the compound represented by Formula 1 include salts of acidic or basic groups which may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts. It can be prepared through.
다른 하나의 양태로서, 본 발명은 화학식 1의 화합물의 제조방법을 제공한다.In another aspect, the present invention provides a process for preparing the compound of formula 1.
본 발명의 바람직한 일 양태로서, 상기 화학식 1의 화합물은 하기 반응식 1과 같이 제조될 수 있다.In a preferred embodiment of the present invention, the compound of Formula 1 may be prepared as in Scheme 1 below.
즉, 하기 1) 내지 5)의 단계들을 포함하여 하기 반응식 1에서와 같이 제조될 수 있다:That is, it may be prepared as in Scheme 1 including the steps of 1) to 5) below:
1) 화학식 2의 화합물을 아세톤 중에서 화학식 3의 화합물 및 탄산칼륨과 반응시켜 화학식 4의 화합물을 제조하는 단계;1) preparing a compound of formula 4 by reacting a compound of formula 2 with a compound of formula 3 and potassium carbonate in acetone;
2) 상기 1)단계에서 제조된 화학식 4의 화합물을 테트라하이드로퓨란 중에서 다이아이소뷰틸 알루미늄 하이드라이드(DIBAL-H)와 반응시켜 화학식 5의 화합물을 제조하는 단계,2) preparing a compound of formula 5 by reacting the compound of formula 4 prepared in step 1) with diisobutyl aluminum hydride (DIBAL-H) in tetrahydrofuran,
3) 옥살릴 클로라이드의 메틸렌클로라이드 용액에 디메틸설폭사이드(DMSO), 상기 2)단계에서 제조된 화학식 5의 화합물 및 트리에틸아미드를 일정 시간 간격으로 첨가하여 반응시키거나, 또는 상기 2)단계에서 제조된 화학식 5의 화합물의 메틸렌클로라이드 용액에 피리디니움 디클로메이트와 셀라이트를 첨가하여 반응시켜 화학식 6의 화합물을 제조하는 단계,3) To the methylene chloride solution of oxalyl chloride, dimethyl sulfoxide (DMSO), the compound of formula 5 prepared in step 2) and triethylamide are added at regular time intervals or reacted, or prepared in step 2). Preparing a compound of Chemical Formula 6 by adding pyridinium dichloromate and celite to a methylene chloride solution of the compound of Chemical Formula 5;
4) 상기 3)단계에서 제조된 화학식 6의 화합물을 메틸렌클로라이드 중에서 메틸-(트리페닐포스포라닐리딘)아세테이트와 반응시켜 화학식 7의 화합물을 제조하는 단계,4) preparing a compound of formula 7 by reacting the compound of formula 6 prepared in step 3) with methyl- (triphenylphosphoranylidine) acetate in methylene chloride,
5) 상기 4)단계에서 제조된 화학식 7의 화합물을 메탄올 중에서 포타슘 하이드록시아미드와 반응시켜 화학식 8의 화합물을 제조하는 단계, 및5) preparing a compound of formula 8 by reacting the compound of formula 7 prepared in step 4) with potassium hydroxyamide in methanol, and
6) 상기 5)단계에서 제조된 화학식 8의 화합물을 반응시켜 화학식 9(화학식 1에서
Figure PCTKR2010003539-appb-I000006
가 이중결합인 화합물)를 제조하는 단계.6) by reacting the compound of formula 8 prepared in step 5)
Figure PCTKR2010003539-appb-I000006
Is a double bond).
또는, 7) 상기 4)단계에서 제조된 화학식 7의 화합물을 메탄올 중에서 H2/Pd-C와 반응시켜 화학식 10의 화합물을 제조하는 단계, Or 7) preparing a compound of formula 10 by reacting the compound of formula 7 prepared in step 4) with H 2 / Pd-C in methanol;
8) 상기 7)단계에서 제조된 화학식 10의 화합물을 메탄올 중에서 포타슘 하이드록시아미드와 반응시켜 화학식 11의 화합물을 제조하는 단계, 및8) preparing a compound of formula 11 by reacting the compound of formula 10 prepared in step 7) with potassium hydroxyamide in methanol, and
6) 상기 8)단계에서 제조된 화학식 11의 화합물을 반응시켜 화학식 12(화학식 1에서
Figure PCTKR2010003539-appb-I000007
가 단일결합인 화합물)를 제조하는 단계.6) by reacting the compound of formula 11 prepared in step 8)
Figure PCTKR2010003539-appb-I000007
Is a single bond).
[반응식 1]Scheme 1
Figure PCTKR2010003539-appb-I000008
Figure PCTKR2010003539-appb-I000008
상기에서, R1, R2, L은 상기 화학식 1에서 정의한 바와 같으며, X는 할로겐 원자이다. In the above, R 1 , R 2 , L are as defined in the formula (1), X is a halogen atom.
본 발명의 화학식 1의 피리돈 화합물의 제조방법의 일례를 설명하면 다음과 같다.An example of a method for preparing a pyridone compound of Formula 1 of the present invention is as follows.
1) 화학식 3의 화합물의 아세톤 0.5M 용액에 화학식 2의 화합물과 탄산 칼륨을 교반상태에서 주입한 후 12시간 가열하였다. 생성 혼합물을 아세톤으로 여과한 다음 감압 농축하였다. 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법으로 정제하여 화학식 4의 화합물을 얻었다.1) The compound of formula 2 and potassium carbonate were injected into acetone 0.5M solution of the compound of formula 3 under stirring, followed by heating for 12 hours. The resulting mixture was filtered through acetone and then concentrated under reduced pressure. The obtained primary compound was purified by silica gel column chromatography to obtain a compound of formula 4.
2) 상기 1)단계에서 제조된 화학식 4의 화합물의 테트라하이드로퓨란 0.5M 용액에 다이아이소뷰틸 알루미늄 하이드라이드(1M 테트라하이드로퓨란)를 -78℃, 교반상태에서 주입한 후 실온에서 12시간 교반하였다. 생성 혼합물에 (±)-포타슘 소디움 타르트레이트 테트라하이드라이드 수용액을 1시간 교반하여 반응을 중지시켰다. 얻어진 혼합물에 에틸아세테이트를 넣어 추출해 주었다. 유기층을 포화 소금물 용액으로 세척한 뒤 황산 나트륨으로 건조하고 에틸아세테이트로 여과한 다음 감압 농축하였다. 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법으로 정제하여 화학식 5의 화합물을 얻었다.2) Diisobutyl aluminum hydride (1M tetrahydrofuran) was injected into the tetrahydrofuran 0.5M solution of the compound of formula 4 prepared in step 1) at -78 ° C and stirred, followed by stirring at room temperature for 12 hours. . The reaction was stopped by stirring (±) -potassium sodium tartrate tetrahydride aqueous solution in the resulting mixture for 1 hour. Ethyl acetate was added to the mixture and extracted. The organic layer was washed with saturated brine solution, dried over sodium sulfate, filtered with ethyl acetate and concentrated under reduced pressure. The obtained primary compound was purified by silica gel column chromatography to obtain a compound of formula 5.
3) 옥살릴 클로라이드(2M 메틸렌클로라이드)의 메틸렌클로라이드 0.1M 용액에 디메틸설폭사이드(DMSO)를 무수, -78℃에서 주입한 후 10분 교반 상태에서 상기 2)단계에서 제조된 화학식 5의 화합물의를 주입하여 같은 온도에서 15분 교반하였다. 15분 후 트리에틸아미드를 같은 온도에서 주입하여주고 -78℃에서 상온까지 1시간 교반하였다. 물을 주입하여 반응을 중지하고 메틸렌클로라이드로 추출하였다. 유기층을 포화 소금물 용액으로 세척한 뒤 무수 황산 나트륨으로 건조하고 메틸렌클로라이드로 여과한 다음 감압 농축하였다. 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법으로 정제하여 화학식 6의 화합물을 얻었다. 3) Injecting dimethylsulfoxide (DMSO) in 0.1M solution of methylene chloride of oxalyl chloride (2M methylene chloride) anhydrous, -78 ℃ and then stirred for 10 minutes to the compound of formula 5 prepared in step 2) It was injected and stirred for 15 minutes at the same temperature. After 15 minutes, triethylamide was injected at the same temperature and stirred at -78 ° C to room temperature for 1 hour. Water was stopped to stop the reaction and extracted with methylene chloride. The organic layer was washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered with methylene chloride and concentrated under reduced pressure. The obtained primary compound was purified by silica gel column chromatography to obtain a compound of formula 6.
또는, 상기 방법 외에 상기 2)단계에서 제조된 화학식 5의 화합물의 메틸렌클로라이드 0.1M 용액에 피리디니움 디클로메이트와 셀라이트를 무수, 교반 상태에서 주입한 후 상온에서 12시간 교반한 다음, 생성 혼합물을 메틸렌클로라이드로 여과하여 감압 농축하고, 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법으로 정제하여 화학식 6의 화합물을 얻었다.Alternatively, in addition to the above method, injecting pyridinium dichloromate and celite in an methylene chloride 0.1M solution of the compound of formula 5 prepared in step 2) under anhydrous and agitation, stirring at room temperature for 12 hours, and then generating The mixture was filtered through methylene chloride and concentrated under reduced pressure, and the obtained primary compound was purified by silica gel column chromatography to obtain a compound of formula 6.
4) 상기 3)단계에서 제조된 화학식 6의 화합물의 메틸렌클로라이드 0.1M 용액에 메틸-(트리페닐포스포라닐리딘)아세테이트를 교반 상태에서 주입한 후 12시간 가열하여 교반하였다. 생성 혼합물을 감압 농축하고 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법으로 정제하여 화학식 7의 화합물을 얻었다.4) Methyl- (triphenylphosphoranilidine) acetate was injected into the methylene chloride 0.1M solution of the compound of formula 6 prepared in step 3) under stirring, followed by heating and stirring for 12 hours. The resulting mixture was concentrated under reduced pressure and the resulting primary compound was purified by silica gel column chromatography to obtain a compound of formula 7.
5) 상기 4)단계에서 제조된 화학식 7의 화합물에 메틸린클로라이드 0.05M 용액에 1,2-페닐린다이아민, 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 (EDC), 4-디메틸아미노피리딘 (DMAP)을 무수에서 순차적으로 주입하여 상온에서 12시간 교반하였다. 생성 혼합물을 감압 농축하였다. 얻어진 일차 화합물을 대용량 박층 크로마토그래피 방법으로 정제하여 화학식 8의 화합물을 얻었다.5) 1,2-phenylindalimeamine, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), 4, in 0.05M solution of methyl chloride in the compound of formula 7 prepared in step 4) -Dimethylaminopyridine (DMAP) was injected sequentially in anhydrous and stirred for 12 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The obtained primary compound was purified by a large-capacity thin layer chromatography method to obtain a compound of formula 8.
6) 상기 5)단계에서 제조된 화학식 8의 화합물에 메탄올, 테트라하이드로퓨란 0.3M 혼합용액(1:1)에 수산화리튬(1M 수용액)을 0℃에서 주입한 후 같은 온도에서 4시간 교반하였다. 생성 혼합물을 감압 농축하였다. 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법으로 정제하여 화학식 9의 화합물을 얻었다.6) Lithium hydroxide (1M aqueous solution) was added to the compound of Chemical Formula 8 prepared in step 5) in a mixed solution of methanol and tetrahydrofuran 0.3M (1: 1) at 0 ° C., followed by stirring at the same temperature for 4 hours. The resulting mixture was concentrated under reduced pressure. The obtained primary compound was purified by silica gel column chromatography to obtain a compound of formula 9.
또는, 7) 상기 4)단계에서 제조된 화학식 7의 화합물에 메탄올 0.1M 용액에 팔라듐차콜을 무수에서 주입한 후 수소가스를 주입하여 상온에서 12시간 교반하였다. 생성 혼합물을 여과종이로 거른 뒤 여과액을 감압농축하였다. 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법으로 정제하여 화학식 10의 화합물을 얻었다. Or, 7) Palladium charcoal to the compound of formula 7 prepared in step 4) in methanol 0.1M solution in anhydrous and then hydrogen gas was injected and stirred at room temperature for 12 hours. The resulting mixture was filtered through filter paper and the filtrate was concentrated under reduced pressure. The obtained primary compound was purified by silica gel column chromatography to obtain a compound of formula 10.
8) 상기 7)단계 제조된 화학식 10의 화합물에 메틸린클로라이드 0.05M 용액에 1,2-페닐린다이아민, 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 (EDC), 4-디메틸아미노피리딘 (DMAP)을 무수에서 순차적으로 주입하여 상온에서 12시간 교반하였다. 생성 혼합물을 감압 농축하였다. 얻어진 일차 화합물을 대용량 박층 크로마토그래피 방법으로 정제하여 화학식 11의 화합물을 얻었다.8) 1,2-phenylindalimeamine, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), 4- Dimethylaminopyridine (DMAP) was sequentially injected in anhydrous and stirred at room temperature for 12 hours. The resulting mixture was concentrated under reduced pressure. The obtained primary compound was purified by a large-capacity thin layer chromatography method to obtain a compound of formula (11).
9) 상기 8)단계에서 제조된 화학식 11의 화합물에 메탄올, 테트라하이드로퓨란 0.3M 혼합용액(1:1)에 수산화리튬(1M 수용액)을 0℃에서 주입한 후 같은 온도에서 4시간 교반하였다. 생성 혼합물을 감압 농축하였다. 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법으로 정제하여 화학식 12의 화합물을 얻었다. 9) Lithium hydroxide (1M aqueous solution) was added to the compound of Formula 11 prepared in step 8) in methanol, tetrahydrofuran 0.3M mixed solution (1: 1) at 0 ° C., and stirred at the same temperature for 4 hours. The resulting mixture was concentrated under reduced pressure. The obtained primary compound was purified by silica gel column chromatography to obtain a compound of formula 12.
본 발명에서, 상기 반응식 1에서 사용하는 화학식 3의 화합물의 제조방법은 하기 반응식 2와 같이 수행될 수 있다.In the present invention, the method of preparing a compound of Formula 3 used in Scheme 1 may be performed as in Scheme 2 below.
[반응식 2] Scheme 2
Figure PCTKR2010003539-appb-I000009
Figure PCTKR2010003539-appb-I000009
본 발명의 화학식 3의 화합물의 제조방법에 대해 구체적으로 설명하면 다음과 같다.Hereinafter, a method for preparing the compound of Formula 3 of the present invention will be described in detail.
2-하이드록시니코티닉 에시드 (2g, 14.38mmol)의 메탄올 0.2M 용액에 (±)-캄포-10-설포닉 에시드(2.67g, 11.50mmol)를 교반상태에서 주입한 후 12시간 가열하였다. 생성혼합물에 탄산수소나트륨을 교반 상태에서 주입하여 반응을 종료시킨 다음 감압 농축하였다. 얻어진 혼합물을 물로 희석하여 주고 메틸렌클로라이드로 추출하여 주었다. 유기층을 포화 소금물 용액으로 세척한 뒤 황산 마그네슘으로 건조하고 에틸 아세테이트로 여과한 다음 감압증류 하여, 화합물 3을 80%의 수율(1.77g)로 얻었다.(±) -camphor-10-sulfonic acid (2.67 g, 11.50 mmol) was injected into a 0.2 M solution of methanol of 2-hydroxynicotinic acid (2 g, 14.38 mmol), followed by heating for 12 hours. Sodium hydrogen carbonate was injected into the resulting mixture under stirring to terminate the reaction, followed by concentration under reduced pressure. The obtained mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with a saturated brine solution, dried over magnesium sulfate, filtered with ethyl acetate, and distilled under reduced pressure to obtain compound 3 in a yield of 80% (1.77 g).
1H-NMR 500MHz, DMSO-d6, δ 8.04 (dd, 1H, JA=5.0Hz, JB=7.5Hz), 7.65 (dd, 1H, JA=4.0Hz, JB=6.0Hz), 6.26 (t, 1H, J=5.0Hz), 3.72 (s, 3H) 1 H-NMR 500 MHz, DMSO-d6, δ 8.04 (dd, 1H, JA = 5.0 Hz, JB = 7.5 Hz), 7.65 (dd, 1H, JA = 4.0 Hz, JB = 6.0 Hz), 6.26 (t, 1H , J = 5.0 Hz), 3.72 (s, 3H)
또 다른 하나의 양태로서, 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물을 제공한다.As another aspect, the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 암은 폐암, 비소세포성 폐암, 결장암, 골암, 췌장암, 피부암, 두부 또는 경부 암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 위암, 항문부근암, 결장암, 유방암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신장세포 암종, 신장골반 암종, 중추신경계(CNS; central nervous system) 종양, 1차 중추신경계 림프종, 척수 종양, 뇌간 신경교종, 뇌하수체 선종 등이 있다.The cancer may include lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, anal muscle cancer, colon cancer, breast cancer, fallopian tube carcinoma, Endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, Chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary central nervous system lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, etc. There is this.
본 발명에 따른 화합물은 종양세포 성장 억제 효과가 우수하므로, 암 질환 치료에 유용하게 이용될 수 있다.Since the compound according to the present invention is excellent in tumor cell growth inhibitory effect, it can be usefully used for the treatment of cancer diseases.
본 발명에 따른 화학식 1의 화합물을 포함하는 약학 조성물은 통상의 방법에 따른 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다. 본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.Pharmaceutical compositions comprising a compound of formula 1 according to the invention may further comprise a suitable carrier, excipient or diluent according to conventional methods. Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명에 따른 조성물은 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The compositions according to the invention can be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, external preparations, suppositories or sterile injectable solutions according to conventional methods.
상세하게는, 제형화할 경우 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로오스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 오일, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.Specifically, when formulated, it may be formulated using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like that are commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin and the like. Can be prepared by mixing. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used. Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. As the base of the suppository, utopsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명에 따른 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서 본 발명의 화합물은 0.0001 내지 100 mg/kg으로, 바람직하게는 0.001 내지 100 mg/kg의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다.Preferred dosages of the compounds according to the invention depend on the condition and body weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably in an amount of 0.001 to 100 mg / kg once to several times daily.
본 발명에 따른 화합물의 약학적 투여 형태는 이들의 약학적으로 허용가능한 염의 형태로도 사용될 수 있고, 또한 단독으로 또는 기타 약학적 활성 화합물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다.Pharmaceutical dosage forms of the compounds according to the invention can also be used in the form of their pharmaceutically acceptable salts, and can also be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.
본 발명의 약학 조성물은 랫트, 마우스, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 (intracerebroventricular) 주사에 의해 투여될 수 있다.The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
또 다른 하나의 양태로서, 본 발명은 화학식 1로 표시되는 피리돈 화합물 또는 이의 약학적으로 허용가능한 염의 유효량을 환자에게 투여하는 것을 포함하는 암 치료 방법을 제공한다.As another aspect, the present invention provides a method for treating cancer comprising administering to a patient an effective amount of a pyridone compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
상기 암은 폐암, 비소세포성 폐암, 결장암, 골암, 췌장암, 피부암, 두부 또는 경부 암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 위암, 항문부근암, 결장암, 유방암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신장세포 암종, 신장골반 암종, 중추신경계(CNS; central nervous system) 종양, 1차 중추신경계 림프종, 척수 종양, 뇌간 신경교종, 뇌하수체 선종 등이 있다.The cancer may include lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, anal muscle cancer, colon cancer, breast cancer, fallopian tube carcinoma, Endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, Chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary central nervous system lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, etc. There is this.
본 발명 화합물의 개별적인 투약의 최적량 및 투약 간격은 치료되고 있는 병의 성질 및 정도, 투여 제형, 경로 및 부위, 그리고 치료되고 있는 특정 환자의 나이와 건강상태에 의해 결정될 것이고, 의사가 궁극적으로 사용될 적절한 투약을 결정할 것이라는 것은 당해 분야의 당업자가 알 수 있을 것이다. 이러한 투약은 적절할 정도로 자주 반복될 수 있다. 부작용이 생긴다면, 보통의 임상 진료에 따라서 투여량 및 빈도를 변경하거나 또는 감소시킬 수 있다.The optimal amount and dosage interval of the individual doses of the compounds of the present invention will be determined by the nature and extent of the disease being treated, the dosage form, the route and site, and the age and health of the particular patient being treated, and ultimately the physician It will be appreciated by those skilled in the art that the appropriate dosage will be determined. Such dosing can be repeated as often as appropriate. If side effects occur, the dosage and frequency can be altered or reduced in accordance with normal clinical practice.
본 발명에 따른 화합물은 RUNX3 활성 유도 효과와 HDAC 저해활성 및 종양세포 성장 억제 효과가 우수하므로, 암의 예방 또는 치료에 유용하게 이용될 수 있다.The compound according to the present invention is excellent in RUNX3 activity inducing effect, HDAC inhibitory activity and tumor cell growth inhibitory effect, it can be usefully used for the prevention or treatment of cancer.
도 1은 인체 유래 위암 세포주 MKN28의 4×107 cells/㎖를 암컷 S.P.F BALB/c 누드 마우스(6주령)에 이식한 후, 상기 실시예 42, 44, 55, 69에서 제조한 화합물을 정맥으로 하루 20 mg/kg씩 총 10회 투여한 후 투여 기간 동안 동물의 체중 변화를 나타낸 것이다.FIG. 1 shows that 4 × 10 7 cells / ml of the human-derived gastric cancer cell line MKN28 was transplanted into a female SPF BALB / c nude mouse (6 weeks old), and then the compound prepared in Examples 42, 44, 55, and 69 was intravenously. A total of 10 mg / kg doses per day was then used to show changes in body weight of the animals during the administration period.
도 2는 인체 유래 위암 세포주 MKN28의 4×107 cells/㎖를 암컷 S.P.F BALB/c 누드 마우스(6주령)에 이식한 후, 상기 실시예 42, 44, 55, 69에서 제조한 화합물을 정맥으로 하루 20 mg/kg씩 총 10회 투여한 후 투여 기간 동안 종양크기의 변화를 나타낸 것이다.FIG. 2 shows that 4 × 10 7 cells / ml of the human-derived gastric cancer cell line MKN28 was transplanted into a female SPF BALB / c nude mouse (6 weeks old), and then the compounds prepared in Examples 42, 44, 55, and 69 were intravenously. A total of 10 mg / kg 20 mg / kg daily showed tumor size change during the administration period.
도 3은 인체 유래 위암 세포주 MKN28의 4×107 cells/㎖를 암컷 S.P.F BALB/c 누드 마우스(6주령)에 이식한 후, 상기 실시예 42, 44, 55, 69에서 제조한 화합물을 정맥으로 하루 20mg/kg씩 총 10회 투여한 후 최종일(10일째)에 종양무게를 측정한 결과를 나타낸 것이다.FIG. 3 shows that 4 × 10 7 cells / ml of the human-derived gastric cancer cell line MKN28 was transplanted into a female SPF BALB / c nude mouse (6 weeks old), and then the compounds prepared in Examples 42, 44, 55, and 69 were intravenously injected. Tumor weight was measured on the last day (10th day) after total administration of 20mg / kg 10 times a day.
이하, 본 발명을 하기 실시예에 의거하여 좀 더 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들 만으로 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.
실시예 1 : (E)-3-(1-(4-브로모벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드((E)-3-(1-(4-bromobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-N-hydroxyacrylamide)의 제조Example 1 (E) -3- (1- (4-bromobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide ((E) -3 Preparation of-(1- (4-bromobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide)
1-1. 1-(4-브로모-벤질)-2-옥소-1,2-디하이드로-피리딘-3-카르복실릭 엑시드 메틸 에스터의 제조1-1. Preparation of 1- (4-bromo-benzyl) -2-oxo-1,2-dihydro-pyridine-3-carboxylic acid methyl ester
Figure PCTKR2010003539-appb-I000010
Figure PCTKR2010003539-appb-I000010
화학식 3의 화합물(1g, 6.53mmol)의 아세톤 0.5M 용액에 4-브로모벤질 브로마이드(1.96g, 7.84mmol)와 탄산 칼륨(1.81g, 13.06mmol)를 교반상태에서 주입한 후 12시간 가열하였다. 생성 혼합물을 아세톤으로 여과한 다음 감압 농축하였다. 얻어진 일차 화합물을 실리카겔 컬럼크러마토그래피 방법(용출제: 3% 메탄올/클로로로포름)으로 정제하여 목적 화합물을 41%의 수율(0.86g)로 얻었다. 4-bromobenzyl bromide (1.96g, 7.84mmol) and potassium carbonate (1.81g, 13.06mmol) were injected into a 0.5% acetone 0.5M solution of the compound of formula 3 (1g, 6.53mmol) and heated for 12 hours. . The resulting mixture was filtered through acetone and then concentrated under reduced pressure. The obtained primary compound was purified by silica gel column chromatography (eluent: 3% methanol / chloroform) to obtain the target compound in 41% yield (0.86 g).
1H-NMR (500MHz, DMSO-d6) δ 7.94 (d, 1H, J=7.0Hz), 7.72 (d, 1H, J=5.0Hz), 7.55-7.53 (m, 3H), 7.28-7.26 (m, 3H), 7.10 (d, 1H, J=15.5Hz), 6.37 (t, 1H, J=7.0Hz), 5.13 (s, 2H), 1.23 (s, 1H) 1 H-NMR (500 MHz, DMSO-d6) δ 7.94 (d, 1H, J = 7.0 Hz), 7.72 (d, 1H, J = 5.0 Hz), 7.55-7.53 (m, 3H), 7.28-7.26 (m , 3H), 7.10 (d, 1H, J = 15.5 Hz), 6.37 (t, 1H, J = 7.0 Hz), 5.13 (s, 2H), 1.23 (s, 1H)
1-2. 1-(4-브로모-벤질)-3-디하이드록시메틸-1H-피리딘-2-온의 제조1-2. Preparation of 1- (4-bromo-benzyl) -3-dihydroxymethyl-1H-pyridin-2-one
Figure PCTKR2010003539-appb-I000011
Figure PCTKR2010003539-appb-I000011
상기 1-1 단계에서 얻은 화합물(0.8g, 2.48mmol)의 테트라하이드로퓨란 0.5M용액에 다이아이소뷰틸 알루미늄 하이드라이드(6.20ml(1M 테트라하이드로퓨란), 6.20mmol)를 -78℃, 교반상태에서 주입한 후 실온에서 12시간 교반하였다. 생성 혼합물에 (±)-포타슘 소디움 타르트레이트 테트라하이드라이드 수용액을 1시간 교반하여 반응을 중지시켰다. 얻어진 혼합물에 에틸아세테이트를 넣어 추출해 주었다. 유기층을 포화 소금물 용액으로 세척한 뒤 황산 나트륨으로 건조하고 에틸아세테이트로 여과한 다음 감압 농축하였다. 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법(용출제: 5% 메탄올/클로로포름)으로 정제하여 목적 화합물를 52%의 수율(0.23g)로 얻었다. Diisobutyl aluminum hydride (6.20ml (1M tetrahydrofuran), 6.20mmol) in 0.5M tetrahydrofuran 0.5M solution of the compound (0.8g, 2.48mmol) obtained in step 1-1 was stirred at -78 ° C. After the injection, the mixture was stirred at room temperature for 12 hours. The reaction was stopped by stirring (±) -potassium sodium tartrate tetrahydride aqueous solution in the resulting mixture for 1 hour. Ethyl acetate was added to the mixture and extracted. The organic layer was washed with saturated brine solution, dried over sodium sulfate, filtered with ethyl acetate and concentrated under reduced pressure. The obtained primary compound was purified by silica gel column chromatography method (eluant: 5% methanol / chloroform) to obtain the target compound in 52% yield (0.23 g).
1H-NMR 500MHz, DMSO-d6, δ 8.17-8.16(m, 1H), 8.05-8.04(m, 1H), 7.53(d, 2H, J=8.5Hz), 7.24(d, 2H, J=8.5Hz), 6.29(t, 1H, J=6.5Hz), 5.07(s, 2H), 2.30(d, 2H, J=5.0Hz) 1 H-NMR 500 MHz, DMSO-d6, δ 8.17-8.16 (m, 1H), 8.05-8.04 (m, 1H), 7.53 (d, 2H, J = 8.5 Hz), 7.24 (d, 2H, J = 8.5 Hz), 6.29 (t, 1H, J = 6.5 Hz), 5.07 (s, 2H), 2.30 (d, 2H, J = 5.0 Hz)
ESI (m/z) 294.00 (M)ESI (m / z) 294.00 (M)
1-3. 1-(4-브로모-벤질)-2-옥소-1,2-디하이드로-피리딘-3-카르바알데하이드의 제조1-3. Preparation of 1- (4-bromo-benzyl) -2-oxo-1,2-dihydro-pyridine-3-carbaaldehyde
Figure PCTKR2010003539-appb-I000012
Figure PCTKR2010003539-appb-I000012
상기 1-2 단계에서 얻은 화합물(0.23g, 0.78mmol)의 메틸렌클로라이드 0.1M용액에 피리디니움 디클로메이트(0.59g, 1.56mmol)와 셀라이트(0.59g)를 무수, 교반 상태에서 주입한 후 상온에서 12시간 교반하였다. 생성 혼합물을 메틸렌클로라이드로 여과하여 감압 농축하였다. 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법(용출제: 에틸아세테이트:헥산=2:1)으로 정제하여 목적 화합물을 13%의 수율(0.03g)로 얻었다.Pyridinium dichloromate (0.59 g, 1.56 mmol) and celite (0.59 g) were injected into a 0.1 M solution of the compound (0.23 g, 0.78 mmol) obtained in the above step 1-2 under anhydrous and stirred conditions. After stirring at room temperature for 12 hours. The resulting mixture was filtered through methylene chloride and concentrated under reduced pressure. The obtained primary compound was purified by silica gel column chromatography method (eluent: ethyl acetate: hexane = 2: 1) to obtain the target compound in 13% yield (0.03 g).
상기 방법 외에 하기와 같이 목적 화합물을 얻을 수 있었다. In addition to the above method, the target compound was obtained as follows.
즉, 메틸렌클로라이드 0.1M 용액에 옥살릴 클로라이드(2M 메틸렌클로라이드, 3 equiv)와 디메틸설폭사이드(5 equiv)를 무수, -78℃에서 주입한 후 10분 교반 상태에서 상기 1-2 단계에서 얻은 화합물를 주입하여 같은 온도에서 15분 교반하였다. 15분 후 트리에틸아미드(10 equiv)를 같은 온도에서 주입하여 주고 -78℃에서 상온까지 1시간 교반하였다. 물을 주입하여 반응을 중지하고 메틸렌클로라이드로 추출하였다. 유기층을 포화 소금물 용액으로 세척한 뒤 무수 황산 나트륨으로 건조하고 메틸렌클로라이드로 여과한 다음 감압 농축하였다. 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법(용출제: 에틸아세테이트:헥산=2:1)으로 정제하여 목적 화합물을 얻었다. In other words, oxalyl chloride (2M methylene chloride, 3 equiv) and dimethyl sulfoxide (5 equiv) in 0.1M solution of methylene chloride was anhydrous, injected at -78 ℃ and the compound obtained in step 1-2 under 10 minutes stirring Injected and stirred at the same temperature for 15 minutes. After 15 minutes, triethylamide (10 equiv) was injected at the same temperature and stirred at -78 ° C to room temperature for 1 hour. Water was stopped to stop the reaction and extracted with methylene chloride. The organic layer was washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered with methylene chloride and concentrated under reduced pressure. The obtained primary compound was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 2: 1) to obtain the target compound.
1H-NMR 500MHz, DMSO-d6, δ 10.1(s, 1H), 8.31(d, 1H, J=6.5Hz), 7.99(d, 1H, J=6.5Hz), 7.56(d, 2H, J=2.5Hz), 7.31(d, 2H, J=7.5Hz), 6.49(t, 1H, J=6.5Hz), 5.17(s, 2H) 1 H-NMR 500 MHz, DMSO-d6, δ 10.1 (s, 1H), 8.31 (d, 1H, J = 6.5 Hz), 7.99 (d, 1H, J = 6.5 Hz), 7.56 (d, 2H, J = 2.5 Hz), 7.31 (d, 2H, J = 7.5 Hz), 6.49 (t, 1H, J = 6.5 Hz), 5.17 (s, 2H)
1-4. (E)-3-[1-(4-브로모-벤질)-2-옥소-1,2-디하이드로-피리딘-3-릴]-아크릴릭 엑시드 메틸 에스터의 제조1-4. Preparation of (E) -3- [1- (4-bromo-benzyl) -2-oxo-1,2-dihydro-pyridin-3-yl] -acrylic acid methyl ester
Figure PCTKR2010003539-appb-I000013
Figure PCTKR2010003539-appb-I000013
상기 1-3 단계에서 얻은 화합물(0.03g, 0.10mmol)의 메틸렌클로라이드 0.1M용액에 메틸-(트리페닐포스포라닐리딘)아세테이트(0.16g, 0.50mmol)를 교반 상태에서 주입한 후 12시간 가열하여 교반하였다. 생성 혼합물을 감압 농축하고 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법(용출제: 에틸아세테이트:헥산=1:3)으로 정제하여 목적 화합물을 90%의 수율(0.03g)로 얻었다.Methyl- (triphenylphosphoranilidine) acetate (0.16 g, 0.50 mmol) was injected into a 0.1 M solution of the compound (0.03 g, 0.10 mmol) obtained in the above step 1-3, followed by heating for 12 hours. And stirred. The resulting mixture was concentrated under reduced pressure and the resulting primary compound was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1: 3) to obtain the target compound in 90% yield (0.03 g).
1H-NMR 500MHz, CDCl3, δ 8.01 (dd, 1H, JA=5.0Hz, JB=7.0Hz), 7.55 (t, 3H, J=5.0Hz), 7.27 (dd, 3H, JA=6.0Hz, JB=8.0Hz), 7.05 (d, 1H, J=15.5Hz), 6.41 (t, 1H, J=6.5Hz), 5.15 (s, 2H), 3.69 (s, 3H) 1 H-NMR 500 MHz, CDCl 3 , δ 8.01 (dd, 1H, JA = 5.0 Hz, JB = 7.0 Hz), 7.55 (t, 3H, J = 5.0 Hz), 7.27 (dd, 3H, JA = 6.0 Hz, JB = 8.0Hz), 7.05 (d, 1H, J = 15.5Hz), 6.41 (t, 1H, J = 6.5Hz), 5.15 (s, 2H), 3.69 (s, 3H)
ESI (m/z) 348.00 (M)ESI (m / z) 348.00 (M)
1-5. (E)-3-[1-(4-브로모-벤질)-2-옥소-1,2-디하이드로-피리딘-3-릴]-N-하이드록시-아크릴아미드의 제조1-5. Preparation of (E) -3- [1- (4-bromo-benzyl) -2-oxo-1,2-dihydro-pyridine-3-yl] -N-hydroxy-acrylamide
Figure PCTKR2010003539-appb-I000014
Figure PCTKR2010003539-appb-I000014
상기 1-4 단계에서 얻은 화합물(0.03g, 0.09mmol)의 메탄올 0.2M 용액에 포타슘 하이드록시아미드(0.26ml(1.7M 메탄올, 0.50mmol), 0.45mmol)을 0℃, 무수, 교반 상태에서 주입한 후 12시간 온도를 유지하여 교반하였다. 생성 혼합물을 감압 농축하고 얻어진 일차 화합물을 실리카겔 컬럼크로마토그래피 방법(용출제: 5% 메탄올/클로로포름)으로 정제하여 목적 화합물을 25%의 수율(0.008g)로 얻었다.Potassium hydroxyamide (0.26 ml (1.7 M methanol, 0.50 mmol), 0.45 mmol) was injected into a 0.2 M methanol solution of the compound (0.03 g, 0.09 mmol) obtained in the step 1-4 at 0 ° C., anhydrous, and stirred. After stirring, the temperature was maintained for 12 hours. The resulting mixture was concentrated under reduced pressure and the resulting primary compound was purified by silica gel column chromatography (eluent: 5% methanol / chloroform) to give the title compound in 25% yield (0.008 g).
1H-NMR 500MHz, DMSO-d6, δ 7.94 (d, 1H, J=7.0Hz), 7.72 (d, 1H, J=5.0Hz), 7.55-7.53 (m, 3H), 7.28-7.26 (m, 3H), 7.10 (d, 1H, J=15.5Hz), 6.37 (t, 1H, J=7.0Hz), 5.13 (s, 2H), 1.23 (s, 1H) 1 H-NMR 500 MHz, DMSO-d6, δ 7.94 (d, 1H, J = 7.0 Hz), 7.72 (d, 1H, J = 5.0 Hz), 7.55-7.53 (m, 3H), 7.28-7.26 (m, 3H), 7.10 (d, 1H, J = 15.5 Hz), 6.37 (t, 1H, J = 7.0 Hz), 5.13 (s, 2H), 1.23 (s, 1H)
ESI (m/z) 349.00 (M)ESI (m / z) 349.00 (M)
실시예 2~114Examples 2 to 114
상기 실시예 1에 기재된 제조방법과 유사한 제조방법으로, 실시예 2~183의 화합물을 제조하였다. 제조된 화합물들의 화학구조 및 물성치는 하기 표 1에 나타내었다.In a preparation similar to the preparation described in Example 1, the compounds of Examples 2 to 183 were prepared. Chemical structures and physical properties of the prepared compounds are shown in Table 1 below.
표 1
Figure PCTKR2010003539-appb-T000001
 Table 1
Figure PCTKR2010003539-appb-T000001
Figure PCTKR2010003539-appb-I000015
Figure PCTKR2010003539-appb-I000015
Figure PCTKR2010003539-appb-I000016
Figure PCTKR2010003539-appb-I000016
Figure PCTKR2010003539-appb-I000017
Figure PCTKR2010003539-appb-I000017
Figure PCTKR2010003539-appb-I000018
Figure PCTKR2010003539-appb-I000018
Figure PCTKR2010003539-appb-I000019
Figure PCTKR2010003539-appb-I000019
Figure PCTKR2010003539-appb-I000020
Figure PCTKR2010003539-appb-I000020
Figure PCTKR2010003539-appb-I000021
Figure PCTKR2010003539-appb-I000021
Figure PCTKR2010003539-appb-I000022
Figure PCTKR2010003539-appb-I000022
Figure PCTKR2010003539-appb-I000023
Figure PCTKR2010003539-appb-I000023
Figure PCTKR2010003539-appb-I000024
Figure PCTKR2010003539-appb-I000024
Figure PCTKR2010003539-appb-I000025
Figure PCTKR2010003539-appb-I000025
Figure PCTKR2010003539-appb-I000026
Figure PCTKR2010003539-appb-I000026
Figure PCTKR2010003539-appb-I000027
Figure PCTKR2010003539-appb-I000027
Figure PCTKR2010003539-appb-I000028
Figure PCTKR2010003539-appb-I000028
Figure PCTKR2010003539-appb-I000029
Figure PCTKR2010003539-appb-I000029
Figure PCTKR2010003539-appb-I000030
Figure PCTKR2010003539-appb-I000030
Figure PCTKR2010003539-appb-I000031
Figure PCTKR2010003539-appb-I000031
Figure PCTKR2010003539-appb-I000032
Figure PCTKR2010003539-appb-I000032
실험예 1 : RUNX 활성분석Experimental Example 1 RUNX Activity Analysis
Runx binding site를 반복적으로 연결시킨 단편(fragment)을 가진 reporter vector를 항시적으로 발현하는 세포주를 구축하여 Runx 활성을 검색에 사용하였다.Runx activity was used for screening by constructing a cell line that constantly expressed a reporter vector with a fragment that repeatedly linked the Runx binding site.
세포주는 10%의 FBS를 포함하는 DMEM 배지로 37℃, 5% CO2 농도의 배양기에서 배양하였다. 96 well plate에 1x104 cells/well로 seeding하였다. 24시간 배양 후 10% FBS를 포함하는 배지로 교체하면서 상기 화합물들을 1 μM의 농도로 처리하며 배지는 100 ㎕/well로 첨가하였다. 추가적으로 24 시간 배양 후 Luciferase 활성을 측정하였다. Cell lines were cultured in a 37 ° C., 5% CO 2 concentration incubator in DMEM medium containing 10% FBS. Seed to 1x10 4 cells / well in a 96 well plate. After 24 hours of incubation, the compounds were treated at a concentration of 1 μM with replacement of medium containing 10% FBS and the medium was added at 100 μl / well. After 24 hours of incubation, Luciferase activity was measured.
Luciferase 활성 분석은 프로메가사(Promega)의 Bright-Glo Luciferase Assay System(E2620)을 사용하여 수행하였다. Luciferase activity assay was performed using Promega's Bright-Glo Luciferase Assay System (E2620).
반응액을 준비하는 과정은 다음과 같다. -20℃에 보관된 Bright-Glo buffer 1병(100ml)과 Bright-Glo Substrate 1병(powder)을 꺼내서 녹인 후, Bright-Glo buffer 100ml을 Bright-Glo Substrate에 넣어 substrate가 완전히 녹을 때 까지 잘 섞어주었다. The process of preparing the reaction solution is as follows. Take out and dissolve one bottle of Bright-Glo buffer (100ml) and one bottle of Bright-Glo Substrate (powder) stored at -20 ℃, and mix 100ml of Bright-Glo buffer in Bright-Glo Substrate until the substrate is completely dissolved. gave.
Assay 과정은 다음과 같다. 배양기로부터 배양된 세포가 있는 plate를 꺼내어 각각의 well에 배양 배지와 동일 부피의 Luciferase Reagent(100 ㎕)를 multi-pipette을 이용하여 첨가하였다. 완전한 세포 용해(Cell lysis)를 위하여 2분 동안 실온에 방치한 후 Luminometer에서 luc 활성을 측정하였다. 이때 Luminometer는 프로메가사(Promega)의 GloMax-MultiDetection System (E7031)을 이용하였다. Assay process is as follows. Plates containing cultured cells were removed from the incubator, and the same volume of Luciferase Reagent (100 μl) as the culture medium was added to each well using a multi-pipette. After complete cell lysis (Cell lysis) was allowed to stand for 2 minutes at room temperature luc activity was measured on a Luminometer. The Luminometer used Promega's GloMax-MultiDetection System (E7031).
상기 실시예에서 제조된 화합물들의 RUNX 활성분석 정도를 하기 표 2에 나타내었다.RUNX activity analysis degree of the compounds prepared in the above Example is shown in Table 2 below.
표 2
Figure PCTKR2010003539-appb-T000002
 TABLE 2
Figure PCTKR2010003539-appb-T000002
Figure PCTKR2010003539-appb-I000033
Figure PCTKR2010003539-appb-I000033
실험예 2 : HDAC 활성분석Experimental Example 2 HDAC Activity Analysis
HDAC 활성분석은 바이오몰사(BIOMOL)의 HDAC Fluorimetirc Assay/Drug Discovery Kit(AK-500) 분석 시스템에 기초하여 수행하였다. 분석은 두 단계로 이루어지는데, 제1 단계는 HDAC와 기질이 반응하는 효소반응 단계로서, 이 단계에서 HDAC 저해제를 넣어 HDAC 효소활성 저해정도를 측정하였다. 먼저, 반응 혼합물을 제조하기 위하여 96-well plate에 HDAC 효소활성 저해제로서 상기 실시예의 화합물들을 각각 0.03, 0.1, 0.3, 1, 3 및 10 μM 농도로 반응 완충용액(50 mM Tris/Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2)에 희석하여 10 ㎕씩 첨가하였다. HDAC 효소원으로는 HeLa 세포핵 추출물(nuclear extract)을 사용하였는데, 최종 농도가 0.5ul이 되도록 반응 완충용액(50 mM Tris/Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2)에 희석하여 15 ㎕를 첨가하였다. 이 때, 50 mM 형광표지 라이신(Fluor de LysTM) 기질은 최종 농도가 100 μM이 되도록 반응 완충용액(50 mM Tris/Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2)에 희석하여 25 ㎕를 첨가하였고 37℃에서 30분 동안 효소반응을 수행하였다. 이어지는 제2 단계는 검출단계로서, 20X 농도의 형광표지 라이신 디벨로퍼(Flour de LysTM developer)를 1X 농도가 되도록 반응 완충용액으로 희석하여 50 ㎕를 넣고 실온에서 15분간 반응시켰다. 상기 형광물질로부터 355 ㎚에서 여기(excitation)되고 460 ㎚에서 방출되어 나오는 광을 형광측정용 기판 판독기(fluorometric plate reader)로 검출하였다. 이 때, 효소활성이 높을수록 460 ㎚에서 방출되어 나오는 형광도가 낮아지게 되고, HDAC 저해제가 포함되지 않은 경우와 포함된 경우에서 검출된 형광도를 비교하여 HDAC 저해효과를 측정하였다. 이 때, 대조군으로는 기존에 HDAC 저해제로 알려진 SAHA를 동일한 농도로 사용하였다. 460 ㎚에서 측정된 흡광도를 대조군에 대한 백분율로 환산한 후, HDAC 활성을 50% 저해하는 화합물의 농도(IC50(μM))를 산출하였다.HDAC activity analysis was performed based on the biomolar (ACOMOL) HDAC Fluorimetirc Assay / Drug Discovery Kit (AK-500) analysis system. The analysis consists of two steps. The first step is an enzyme reaction step in which the HDAC reacts with the substrate. In this step, an HDAC inhibitor was added to measure the degree of inhibition of HDAC enzyme activity. First, in order to prepare a reaction mixture, the compounds of the above examples as HDAC enzyme activity inhibitors were prepared in 96-well plates at concentrations of 0.03, 0.1, 0.3, 1, 3 and 10 μM, respectively, in a reaction buffer (50 mM Tris / Cl, pH 8.0). , 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 ) and added to 10 μl. HeLa nuclear extract was used as the HDAC enzyme source, and the reaction buffer (50 mM Tris / Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 ) was used to obtain a final concentration of 0.5ul. Diluted to add 15 μl. At this time, the 50 mM Fluor de Lys TM substrate was added to the reaction buffer (50 mM Tris / Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 ) so that the final concentration was 100 μM. 25 μl was added by dilution and enzymatic reaction was performed at 37 ° C. for 30 minutes. The second step was a detection step, in which a fluorescent label lysine developer of 20X concentration (Flour de Lys TM developer) was diluted with reaction buffer to a 1X concentration, 50 μl was added and reacted for 15 minutes at room temperature. Light excited from the fluorescent material at 355 nm and emitted at 460 nm was detected by a fluorometric plate reader. In this case, the higher the enzyme activity, the lower the fluorescence emitted at 460 nm, and the HDAC inhibitory effect was measured by comparing the fluorescence detected in the case with and without the HDAC inhibitor. At this time, SAHA, known as an HDAC inhibitor, was used as a control at the same concentration. After absorbance measured at 460 nm was converted into a percentage relative to the control, the concentration of compound (IC 50 (μM)) that inhibited HDAC activity by 50% was calculated.
상기 실시예에서 제조된 대표적 화합물들의 HDAC 저해활성(IC50) 정도를 하기 표 3 및 4에 나타내었다.HDAC inhibitory activity (IC 50 ) degree of the representative compounds prepared in the above Examples are shown in Tables 3 and 4.
표 3
실시예 HDACIC50(μM) 실시예 HDACIC50(μM) 실시예 HDACIC50(μM)
1 0.11 31 0.21 61 0.18
2 0.43 32 0.07 62 0.52
3 0.63 33 0.11 63 0.37
4 0.23 34 0.16 64 0.30
5 0.57 35 >10 65 0.18
6 0.21 36 0.50 66 0.14
7 1.05 37 0.23 67 0.42
8 0.23 38 0.56 68 1.00
9 2.49 39 >10 69 0.09
10 1.52 40 0.23 70 1.15
11 0.10 41 5.45 71 0.14
12 0.34 42 0.13 72 0.09
13 0.61 43 0.40 73 0.27
14 0.55 44 0.04 74 0.36
15 0.19 45 0.56 75 0.43
16 0.14 46 0.74 76 0.11
17 0.07 47 0.25 77 0.46
18 0.08 48 0.04 78 0.12
19 0.18 49 0.11 79 0.05
20 0.54 50 0.08 80 0.06
21 0.22 51 0.03 81 0.33
22 0.28 52 0.07 82 0.20
23 0.12 53 0.11 83 0.15
24 0.09 54 2.05 84 0.24
25 0.37 55 0.05 85 0.10
26 0.24 56 0.66 86 0.08
27 0.12 57 0.05 87 0.08
28 0.38 58 2.34 88 0.37
29 0.33 59 0.06 89 0.22
30 0.51 60 0.99 90 0.07
TABLE 3
Example HDACIC 50 (μM) Example HDACIC 50 (μM) Example HDACIC 50 (μM)
One 0.11 31 0.21 61 0.18
2 0.43 32 0.07 62 0.52
3 0.63 33 0.11 63 0.37
4 0.23 34 0.16 64 0.30
5 0.57 35 > 10 65 0.18
6 0.21 36 0.50 66 0.14
7 1.05 37 0.23 67 0.42
8 0.23 38 0.56 68 1.00
9 2.49 39 > 10 69 0.09
10 1.52 40 0.23 70 1.15
11 0.10 41 5.45 71 0.14
12 0.34 42 0.13 72 0.09
13 0.61 43 0.40 73 0.27
14 0.55 44 0.04 74 0.36
15 0.19 45 0.56 75 0.43
16 0.14 46 0.74 76 0.11
17 0.07 47 0.25 77 0.46
18 0.08 48 0.04 78 0.12
19 0.18 49 0.11 79 0.05
20 0.54 50 0.08 80 0.06
21 0.22 51 0.03 81 0.33
22 0.28 52 0.07 82 0.20
23 0.12 53 0.11 83 0.15
24 0.09 54 2.05 84 0.24
25 0.37 55 0.05 85 0.10
26 0.24 56 0.66 86 0.08
27 0.12 57 0.05 87 0.08
28 0.38 58 2.34 88 0.37
29 0.33 59 0.06 89 0.22
30 0.51 60 0.99 90 0.07
표 4
실시예 HDACIC50(μM) 실시예 HDACIC50(μM) 실시예 HDACIC50(μM)
91 0.06 122 >10 153 0.42
92 0.24 123 >10 154 4.47
93 0.75 124 0.09 155 0.63
94 0.67 125 0.08 156 >10
95 0.11 126 0.07 157 0.03
96 0.18 127 0.07 158 0.02
97 0.47 128 0.05 159 0.02
98 0.07 129 0.47 160 0.04
99 0.76 130 0.30 161
100 0.15 131 0.05 162 >10
101 0.61 132 0.27 163 >10
102 0.06 133 >10 164 >10
103 0.08 134 >10 165 >10
104 0.11 135 >10 166
105 0.16 136 0.36 167 1.06
106 0.08 137 0.02 168 >10
107 0.38 138 0.04 169 >10
108 0.11 139 0.03 170 >10
109 0.37 140 0.001 171 >10
110 0.13 141 >10 172 >10
111 0.31 142 >10 173 >10
112 0.37 143 >10 174 >10
113 0.34 144 >10 175 >10
114 0.23 145 >10 176 >10
115 >10 146 0.22 177 >10
116 >10 147 >10 178 0.30
117 >10 148 >10 179 0.03
118 0.06 149 >10 180 0.03
119 >10 150 >10 181 0.30
120 >10 151 0.01 182 >10
121 >10 152 0.03 183 >10
Table 4
Example HDACIC 50 (μM) Example HDACIC 50 (μM) Example HDACIC 50 (μM)
91 0.06 122 > 10 153 0.42
92 0.24 123 > 10 154 4.47
93 0.75 124 0.09 155 0.63
94 0.67 125 0.08 156 > 10
95 0.11 126 0.07 157 0.03
96 0.18 127 0.07 158 0.02
97 0.47 128 0.05 159 0.02
98 0.07 129 0.47 160 0.04
99 0.76 130 0.30 161
100 0.15 131 0.05 162 > 10
101 0.61 132 0.27 163 > 10
102 0.06 133 > 10 164 > 10
103 0.08 134 > 10 165 > 10
104 0.11 135 > 10 166
105 0.16 136 0.36 167 1.06
106 0.08 137 0.02 168 > 10
107 0.38 138 0.04 169 > 10
108 0.11 139 0.03 170 > 10
109 0.37 140 0.001 171 > 10
110 0.13 141 > 10 172 > 10
111 0.31 142 > 10 173 > 10
112 0.37 143 > 10 174 > 10
113 0.34 144 > 10 175 > 10
114 0.23 145 > 10 176 > 10
115 > 10 146 0.22 177 > 10
116 > 10 147 > 10 178 0.30
117 > 10 148 > 10 179 0.03
118 0.06 149 > 10 180 0.03
119 > 10 150 > 10 181 0.30
120 > 10 151 0.01 182 > 10
121 > 10 152 0.03 183 > 10
실험예 3 : 종양세포의 성장억제실험Experimental Example 3 Growth Inhibition Test of Tumor Cells
본 발명에 따른 화합물들의 약효를 검색하기 위하여, 하기와 같은 실험을 수행하였다.In order to search for the efficacy of the compounds according to the present invention, the following experiment was performed.
인간 종양세포주 PC-3(전립선암, ATCC, 미국), MDA-MB-231(유방암, ATCC, 미국), ACHN(신장암, ATCC, 미국), HCT-15(결장암, ATCC, 미국), NCI-H23(폐암, ATCC, 미국) 및 NUGC-3(위암, ATCC, 미국)를 10% 소태아혈청(Fetal Bovine Serum; FBS)이 포함된 RPMI 1640 배지를 사용하여 배양하였다.Human tumor cell lines PC-3 (prostate cancer, ATCC, USA), MDA-MB-231 (breast cancer, ATCC, USA), ACHN (renal cancer, ATCC, USA), HCT-15 (colon cancer, ATCC, USA), NCI -H23 (Lung Cancer, ATCC, USA) and NUGC-3 (Stomach Cancer, ATCC, USA) were cultured using RPMI 1640 medium containing 10% Fetal Bovine Serum (FBS).
항암활성을 측정하고자 할 때는, 5% 소태아혈청을 포함하는 RPMI 1640 배지에 적절한 농도(약 5 x 104 cells/㎖)의 세포를 96 well plate에 분주한 후 5% CO2, 37℃에서 배양하였다. 세포를 분주한 후, 하루가 경과한 다음 화합물들을 처리하기 직전의 세포 농도를 결정하기 위하여 제로시간(Time zero, T0) 플레이트에 50% 트리클로로아세트산을 웰당 50㎕씩 넣어 세포들을 고정하고 영점으로 정하였다. 화합물을 처리한 세포들의 경우에는 48시간 이후에 50% 트리클로로아세트산을 웰당 50㎕씩 넣어 세포들을 고정하였다. 세포에 가해지는 화합물들의 최종 농도는 0.1, 0.3, 1, 3, 10 μM이 되도록 하였다. 고정한 플레이트는 수돗물로 세척하고 건조시킨 후, 0.1% 아세트산에 용해된 설포로다민 B(sulphorhodamine B; SRB)의 0.4% 용액을 웰당 100㎕를 가하여 세포를 염색하였다. 30 분간 방치한 후, 0.1% 아세트산으로 세척하고 다시 상온에서 건조시킨 후 10 mM 트리스 베이스(pH 10.5)를 가하여 염색시약을 용해시켰다. 540 ㎚에서 측정된 흡광도를 대조군에 대한 백분율로 환산한 후, 암세포의 성장을 50% 억제하는 화합물의 농도(GI50(μM))를 산출하였다.In order to measure anticancer activity, an appropriate concentration (approximately 5 x 10 4 cells / ml) of cells in RPMI 1640 medium containing 5% fetal bovine serum was dispensed into a 96 well plate and then treated at 5% CO 2 , 37 ° C. Incubated. After dispensing the cells, fix the cells by adding 50 μl of 50% trichloroacetic acid per well in a time zero (T 0 ) plate to determine the cell concentration after one day and immediately before processing the compounds. It was set as. In the case of cells treated with the compound, 50 μl of 50% trichloroacetic acid was added to the wells after 48 hours to fix the cells. Final concentrations of compounds added to the cells were 0.1, 0.3, 1, 3, 10 μM. The fixed plate was washed with tap water and dried, and then stained with 100 μl / well of 0.4% solution of sulforhodamine B (SRB) dissolved in 0.1% acetic acid. After leaving for 30 minutes, the resultant was washed with 0.1% acetic acid and dried at room temperature again, and then 10 mM tris base (pH 10.5) was added to dissolve the dyeing reagent. After absorbance measured at 540 nm was converted into a percentage of the control group, the concentration of the compound (GI 50 (μM)) that inhibits the growth of cancer cells by 50% was calculated.
결과는 표 5에 나타내었다.The results are shown in Table 5.
표 5
Figure PCTKR2010003539-appb-T000003
 Table 5
Figure PCTKR2010003539-appb-T000003
Figure PCTKR2010003539-appb-I000034
Figure PCTKR2010003539-appb-I000034
Figure PCTKR2010003539-appb-I000035
Figure PCTKR2010003539-appb-I000035
Figure PCTKR2010003539-appb-I000036
Figure PCTKR2010003539-appb-I000036
Figure PCTKR2010003539-appb-I000037
Figure PCTKR2010003539-appb-I000037
Figure PCTKR2010003539-appb-I000038
Figure PCTKR2010003539-appb-I000038
상기 표 5에 나타난 바와 같이, 본 발명에 따른 화합물은 종양세포 성장 억제 효과가 우수함을 알 수 있다.As shown in Table 5, the compound according to the present invention can be seen that the tumor cell growth inhibition effect is excellent.
실험예 4 : 동물실험계의 종양성장억제실험Experimental Example 4: Tumor Growth Inhibition Test of Animal Experimental System
인체 유래 위암 세포주 MKN28의 4×107 cells/㎖를 암컷 S.P.F BALB/c 누드 마우스(6주령)에 이식한 후, 상기 실시예 42, 44, 55, 69에서 제조한 화합물을 정맥으로 하루 20 mg/kg씩 총 10회 투여하고, 양성대조군으로는 suberoylanilide hydroxamic acid(SAHA) 20 mg/kg를 매일 한 번씩 정맥 투여하여 10회를 투여하였다.After transplanting 4 × 10 7 cells / ml of the human-derived gastric cancer cell line MKN28 into female SPF BALB / c nude mice (6 weeks old), the compound prepared in Examples 42, 44, 55, and 69 was intravenously injected 20 mg per day. A total of 10 mg / kg were administered, and 10 mg of suberoylanilide hydroxamic acid (SAHA) was administered intravenously once daily for 10 days.
독성정도를 알아보기 위하여, 투여 기간 동안 동물의 체중 변화, 사망동물, 종양크기 및 종양무게를 관찰하였다.To determine the degree of toxicity, the change in body weight, dead animals, tumor size and tumor weight were observed during the administration period.
동물의 체중 변화는 도 1에 나타내었고, 종양크기의 변화는 도2에 나타내었으며, 최종일(10일째)에서의 종양무게는 도 3에 나타내었다.The weight change of the animals is shown in FIG. 1, the change in tumor size is shown in FIG. 2, and the tumor weight at the last day (day 10) is shown in FIG. 3.
도 1에 나타난 바와 같이, 본 발명에 따른 화합물 (실시예 42, 44, 55, 69)을 정맥 투여한 마우스는 시험기간 동안 특이한 일반증상이 관찰되지 않았다. 또한, 마우스 체중변화의 최종일(10일째) 결과를 보면 용매 대조군과 비교하여 본 발명의 화합물 시료 (실시예 42, 44, 55, 69) 20mg/kg 투여군에서는 체중 감소가 없었다. 양성대조물질(SAHA/ 20 mg/kg / Q1D: 10회) 투여군에서도 체중 감소가 나타나지 않았다.As shown in Figure 1, mice administered intravenously with the compounds according to the invention (Examples 42, 44, 55, 69) did not show any unusual general symptoms during the test period. In addition, the results of the last day (10 days) of the change in the body weight of the mouse compared to the solvent control compound sample of the present invention (Examples 42, 44, 55, 69) 20mg / kg administration group there was no weight loss. No weight loss was seen in the positive control (SAHA / 20 mg / kg / Q1D: 10 times) groups.
도 2에 나타난 바와 같이, 최종일(10일째) 결과를 보면 용매 대조군과 비교하여 본 발명의 화합물 시료 (실시예 42, 44, 55, 69) 투여군(20 mg/kg)에서 각각 25.6%, 28.3%, 40.6%(p<0.05), 27.6%의 종양성장 억제효과가 관찰되었다. 양성대조물질(SAHA/ 20 mg/kg / Q1D: 10회) 투여군에서는 44.6%의 종양성장 억제효과가 나타났다.As shown in FIG. 2, the results of the last day (day 10) showed 25.6% and 28.3% in the compound sample of the present invention (Examples 42, 44, 55, 69) compared to the solvent control group (20 mg / kg), respectively. , 40.6% (p <0.05), 27.6% of tumor growth inhibitory effect was observed. Positive control (SAHA / 20 mg / kg / Q1D: 10 times) group showed 44.6% of tumor growth inhibitory effect.
도 3에 나타난 바와 같이, 실험 최종일(10일째)에 마우스를 희생시켜 종양을 절제한 후 그 무게를 측정한 결과, 용매 대조군과 비교하여 본 발명의 화합물 시료 (실시예 42, 44, 55, 69) 투여군(20 mg/kg)에서 각각 27.9%, 32.4%, 42.6%(p<0.01), 26.0%의 종양무게 감소가 관찰되었다. 양성대조물질(SAHA/ 20 mg/kg / Q1D: 10회) 투여군에서는 45.6%의 종양무게 감소가 나타났다.As shown in FIG. 3, the tumors were sacrificed at the end of the experiment (day 10), and the weights of the tumors were measured. The compound samples of the present invention were compared with the solvent control (Examples 42, 44, 55, and 69). ) Tumor weight reductions of 27.9%, 32.4%, 42.6% (p <0.01) and 26.0% were observed in the administration group (20 mg / kg), respectively. A positive control (SAHA / 20 mg / kg / Q1D: 10) group showed a 45.6% reduction in tumor weight.
실험예 5 : RUNX3 mRNA 발현 유도Experimental Example 5 Induction of RUNX3 mRNA Expression
본 발명에 따른 화합물들의 RUNX3 전사에 미치는 영향을 확인하기 위하여, 하기와 같은 실험을 수행하였다.In order to confirm the effect on the RUNX3 transcription of the compounds according to the invention, the following experiment was performed.
인간 위암 세포주 MKN28을 10% 소태아혈청(Fetal bovine serum; FBS)이 포함된 RPMI 1640 배지로 37℃, 5% CO2 농도의 배양기에서 배양하였다. RUNX3 mRNA 발현 유도에 미치는 영향을 확인하기 위하여, MKN28 세포주를 1x106 cells를 60 mm dish에 seeding하여 10% FBS를 포함하는 RPMI1640 배지에서 24 시간 배양 후, 10% FBS를 포함하는 배지로 교체하면서 본 발명에 따른 화합물들을 1μM의 농도로 처리하였다. 추가적으로 24 시간 배양 후 세포를 회수하였다. 세포로부터 total RNA를 Easy blue Total RNA extract kit(Intron/ Cat. No. 17061)을 사용하였으며 제조사의 프로토콜에 따라 분리하였다. cDNA 합성은 2 μg의 total RNA를 주형으로 하여 olig(dT) primer로 ImProm-Ⅱ™Reverse Transcriptase(Promega /Cat. No. A3802)을 사용하여 합성 하였다. RUNX3 mRNA발현을 확인하기 위하여 RUNX3 forward primer: 5'-GCA GGC AAT GAC GAG AAC TA-3', RUNX3 reverse primer : 5'-GTC TGG TCC TCC AGC TTC TG-3'의 primer set를 사용하였다. PCR반응을 위해 I-star Max™Ⅱ DNA polymerase(Intron/ Cat .No. 25173) Taq polymerase를 사용하였으며 PCR 조건은 하기 표 6(PCR 반응액) 및 표 7(PCR 조건(2-step PCR))과 같이 수행하였다.Human gastric cancer cell line MKN28 was cultured in an incubator at 37 ° C., 5% CO 2 with RPMI 1640 medium containing 10% Fetal bovine serum (FBS). In order to confirm the effect on RUNX3 mRNA expression induction, seeded MKN28 cell line 1x10 6 cells in 60 mm dish and incubated in RPMI1640 medium containing 10% FBS for 24 hours, and then replaced with medium containing 10% FBS. Compounds according to the invention were treated at a concentration of 1 μM. Cells were harvested after an additional 24 hours of incubation. Total RNA was extracted from the cells using an Easy blue Total RNA extract kit (Intron / Cat. No. 17061) and isolated according to the manufacturer's protocol. cDNA synthesis was synthesized using ImProm-II ™ Reverse Transcriptase (Promega / Cat. No. A3802) as olig (dT) primer with 2 μg total RNA as a template. To confirm RUNX3 mRNA expression, primer sets of RUNX3 forward primer: 5'-GCA GGC AAT GAC GAG AAC TA-3 'and RUNX3 reverse primer: 5'-GTC TGG TCC TCC AGC TTC TG-3' were used. I-star Max ™ II DNA polymerase (Intron / Cat.No. 25173) Taq polymerase was used for the PCR reaction. The PCR conditions are shown in Table 6 (PCR reaction solution) and Table 7 (PCR condition (2-step PCR)). It was performed as follows.
표 6
Runx3 GAPDH
Template 2㎕ 1㎕
Primer-F (10uM) 0.4㎕ (4pmole) 0.4㎕ (4pmole)
Primer-R (10 uM) 0.4㎕ (4pmole) 0.4㎕ (4pmole)
i-star Max™Ⅱ DNA polymerase(5u/㎕) 0.2㎕ (1U) 0.2㎕ (1U)
10× PCR buffer 2㎕ 2㎕
dNTP mixture(2.5 mM) 1㎕ 1㎕
Sterilized distilled water 14㎕ 15㎕
Total volume 20㎕ 20㎕
Table 6
Runx3 GAPDH
Template
2 μl 1 μl
Primer-F (10uM) 0.4 μl (4 pmole) 0.4 μl (4 pmole)
Primer-R (10 uM) 0.4 μl (4 pmole) 0.4 μl (4 pmole)
i-star Max ™ Ⅱ DNA polymerase (5u / μl) 0.2 μl (1U) 0.2 μl (1U)
10 × PCR buffer 2 μl 2 μl
dNTP mixture (2.5 mM) 1 μl 1 μl
Sterilized distilled water 14 μl 15 μl
Total volume 20 μl 20 μl
표 7
Stage 1 initial denaturation 1 cycle 94℃ 10sec
Stage 2 PCR RUNX3 : 35cycleGAPDH : 25cycle 94℃ 5sec
60℃ 30sec
Stage 3 1 cycle 60℃ 30sec
4℃ ∞
TABLE 7
Stage 1 initial denaturation 1 cycle 94 ℃ 10sec
Stage
2 PCR RUNX3: 35cycleGAPDH: 25cycle 94 ℃ 5sec
60 ℃ 30sec
Stage 3 1 cycle 60 ℃ 30sec
4 ℃ ∞
본 발명에 따른 화합물들의 RUNX3 mRNA 발현 유도 결과를 도 4에 나타내었다.4 shows the results of inducing RUNX3 mRNA expression of the compounds according to the present invention.
실시예 6: RUNX3 아세틸화 및 안정화에 미치는 영향 확인 실험Example 6: Experiment to confirm the effect on RUNX3 acetylation and stabilization
본 발명에 따른 화합물들에 대하여 RUNX3의 아세틸화와 단백의 안정화에 미치는 영향을 확인하기 위하여 하기와 같은 실험을 실시하였다.In order to confirm the effects on the acetylation of RUNX3 and the stabilization of proteins with respect to the compounds according to the present invention, the following experiment was performed.
인간 태아 신장(human embryonic kidney) 유래의 293 세포주를 10% FBS를 포함한 DMEM배지에서 배양하였으며 1x106 cells로 60 mm dish에 seeding하였다. 다음날, myc tagging된 RUNX3 expression vector(10μg)를 WelFect-Ex plus(WelGene, Korea) transfection reagent를 이용하여 제조사의 프로토콜에 따라 293 세포에 도입시켰다. 다음날, 10% FBS를 포함한 배지로 교체하면서 본 발명에 따른 화합물들을 1μM의 농도로 처리하였다. 추가적으로 24시간 배양한 후 세포를 회수하여 RIPA lysis buffer를 이용하여 세포로부터 단백을 분리하였다. RUNX3를 침전시키기 위해 600μg의 세포용해액에 anti-myc monoclonal antibody(9E10, SantaCruz사)를 첨가한 후 4℃에서 16-24 시간 동안 반응액이 잘 섞이도록 교반하면서 반응을 시켰다. 각 반응액에 40μl의 agarose-G beads(Millipore사)를 첨가한 후 4℃에서 4시간동안 교반하면서 반응시킨 후 RUNX3-antibody-beads 복합체를 침전시키기 위해 12,000rpm 으로 원심분리한 후 상층액을 제거하였다. 침전물에 800 ㎕ RIPA lysis buffer를 첨가하여 4℃에서 20분간 교반기에서 수세 후 12,000 rpm에서 30초동안 원심분리한 후 pellet을 남기고 상층액을 제거하였다. 수세단계는 4번 반복하였다. 마지막으로 남은 pellet에 동일 부피의 40μl 2 x SDS-PAGE loading dye를 첨가한 후 100℃에서 10분간 끓여 단백질을 denaturation 시킨 후 상층액 40μl를 8% SDS-PAGE gel에 loading하였다. gel상에 분리된 단백을 PVDF membrane으로 electrotransfer 한 후, membrane을 anti-Acetyl-lysine antibody로 western blot을 수행하여 RUNX3의 아세틸화를 확인하였다. RUNX3의 안정성은 40 μg의 세포용해액을 SDS-PAGE 후 이동된 단백을 anti-myc-antibody로 western blot으로 RUNX3 발현량을 비교하였다. Tubulin의 발현 정도를 Loading control로 사용하였다. 293 cell lines derived from human embryonic kidney were cultured in DMEM medium containing 10% FBS and seeded in 60 mm dish with 1x10 6 cells. The following day, myc tagged RUNX3 expression vector (10μg) was introduced into 293 cells using WelFect-Ex plus (WelGene, Korea) transfection reagent according to the manufacturer's protocol. The next day, the compounds according to the invention were treated at a concentration of 1 μM while replacing with medium containing 10% FBS. After 24 hours of incubation, the cells were recovered and proteins were separated from the cells using RIPA lysis buffer. To precipitate RUNX3, an anti-myc monoclonal antibody (9E10, SantaCruz) was added to 600 μg of cell lysate, and the reaction was stirred at 4 ° C. for 16-24 hours to stir well. 40 μl of agarose-G beads (Millipore) was added to each reaction solution, followed by stirring at 4 ° C. for 4 hours, followed by centrifugation at 12,000 rpm to precipitate the RUNX3-antibody-beads complex, followed by removal of the supernatant. It was. 800 μl RIPA lysis buffer was added to the precipitate, washed with a stirrer at 4 ° C. for 20 minutes, centrifuged at 12,000 rpm for 30 seconds, and the pellet was removed to remove the supernatant. The washing step was repeated four times. Finally, 40μl 2 x SDS-PAGE loading dye was added to the remaining pellets, boiled at 100 ° C for 10 minutes to denature the protein, and 40μl of the supernatant was loaded on 8% SDS-PAGE gel. After the protein isolated on the gel electrotransfer to PVDF membrane, the acetylation of RUNX3 was confirmed by western blot of the membrane with anti-Acetyl-lysine antibody. The stability of RUNX3 was compared with the amount of RUNX3 expression in 40 μg of cell lysate after SDS-PAGE and the protein transferred by anti-myc-antibody in western blot. The expression level of tubulin was used as a loading control.
본 발명에 따른 화합물들의 RUNX3 아세틸화와 안정화에 대한 결과를 도 5에 나타내었다.Results of RUNX3 acetylation and stabilization of the compounds according to the invention are shown in FIG. 5.
하기에 본 발명의 조성물을 위한 제제예를 예시한다.Examples of preparations for the compositions of the present invention are illustrated below.
제제예 1 : 주사액제의 제조Formulation Example 1 Preparation of Injection Solution
유효성분 10㎎을 함유하는 주사액제는 다음과 같은 방법으로 제조하였다.Injection solution containing 10 mg of the active ingredient was prepared by the following method.
화학식 1의 화합물 1g, 염화나트륨 0.6g 및 아스코르브산 0.1g을 증류수에 용해시켜서 100㎖를 만들었다. 이 용액을 병에 넣고 20℃에서 30분간 가열하여 멸균시켰다.1 g of Compound 1, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. The solution was bottled and sterilized by heating at 20 ° C for 30 minutes.
상기 주사액제의 구성성분은 다음과 같다.The components of the injection solution are as follows.
화학식 1의 화합물 1 g1 g of compound of Formula 1
염화나트륨 0.6 g0.6 g sodium chloride
아스코르브산 0.1 g0.1 g of ascorbic acid
증류수 정량Distilled Water Determination
제제예 2 : 시럽제의 제조Formulation Example 2 Preparation of Syrup
화학식 1의 화합물을 유효성분 2%(중량/부피)로 함유하는 시럽은 다음과 같은 방법으로 제조하였다.Syrup containing the compound of Formula 1 as an active ingredient 2% (weight / volume) was prepared by the following method.
화학식 1의 화합물, 사카린, 당을 온수 80g에 용해시켰다. 이 용액을 냉각시킨 후, 여기에 글리세린, 사카린, 향미료, 에탄올, 소르브산 및 증류수로 이루어진 용액을 제조하여 혼합하였다. 이 혼합물에 물을 첨가하여 100㎖가 되게 하였다.Compound 1, saccharin and sugars were dissolved in 80 g of warm water. After the solution was cooled, a solution consisting of glycerin, saccharin, spices, ethanol, sorbic acid and distilled water was prepared and mixed thereto. Water was added to this mixture to 100 ml.
상기 시럽제의 구성성분은 다음과 같다.The components of the syrup are as follows.
화학식 1의 화합물 2 g2 g of a compound of formula 1
사카린 0.8 gSaccharin 0.8 g
당 25.4 g25.4 g per
글리세린 8.0 gGlycerin 8.0 g
향미료 0.04 g0.04 g of spices
에탄올 4.0 gEthanol 4.0 g
소르브산 0.4 g0.4 g of sorbic acid
증류수 정량Distilled Water Determination
제제예 3 : 정제의 제조Formulation Example 3 Preparation of Tablet
유효성분 15㎎이 함유된 정제는 다음과 같은 방법으로 제조하였다.A tablet containing 15 mg of the active ingredient was prepared by the following method.
화학식 1의 화합물 250g을 락토오스 175.9g, 감자전분 180g 및 콜로이드성 규산 32g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄해서 14 메쉬체를 통과시켰다. 이것을 건조시키고 여기에 감자전분 160g, 활석 50g 및 스테아린산 마그네슘 5g을 첨가해서 얻은 혼합물을 정제로 만들었다.250 g of compound 1 was mixed with 175.9 g lactose, 180 g potato starch, and 32 g colloidal silicic acid. 10% gelatin solution was added to the mixture, which was then ground and passed through a 14 mesh sieve. It was dried and the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into a tablet.
상기 정제의 구성성분은 다음과 같다.The components of the tablet are as follows.
화학식 1의 화합물 250 g250 g of compound of Formula 1
락토오스 175.9 gLactose 175.9 g
감자전분 180 g180 g potato starch
콜로이드성 규산 32 g32 g of colloidal silicic acid
10% 젤라틴 용액10% gelatin solution
감자전분 160 gPotato Starch 160 g
활석 50 g50 g of talc
스테아린산 마그네슘 5 g5 g of magnesium stearate

Claims (18)

  1. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염:A compound represented by formula (1) or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2010003539-appb-I000039
    Figure PCTKR2010003539-appb-I000039
    상기 식에서, Where
    R1은 C1-4 알킬; C2-4 알케닐; 비치환 페닐 또는 1 내지 3개의 R3로 치환된 페닐; 피리디닐; 티에닐; 비치환 나프탈레닐 또는 할로겐으로 치환된 나프탈레닐; 퀴놀리닐; 인다닐; 벤조티오페닐; 퓨라닐 또는 벤조퓨라닐이고,R 1 is C 1-4 alkyl; C 2-4 alkenyl; Unsubstituted phenyl or phenyl substituted with 1 to 3 R 3 ; Pyridinyl; Thienyl; Unsubstituted naphthalenyl or naphthalenyl substituted with halogen; Quinolinyl; Indanyl; Benzothiophenyl; Furanyl or benzofuranyl,
    R2는 하이드록시; C1-3 알콜시; 또는 NHR4이고, R 2 is hydroxy; C 1-3 alcohol; Or NHR 4 ,
    R3는 할로겐; C1-4 알킬; C1-4 알콕시; C1-4 할로알킬; C1-4 할로알콕시; C2-4 알케닐; 니트로; 페닐; 비치환 펜옥시 또는 C1-4 알콕시 또는 할로겐으로 치환된 펜옥시; 또는 벤질옥시이고,R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; C 1-4 haloalkoxy; C 2-4 alkenyl; Nitro; Phenyl; Unsubstituted phenoxy or phenoxy substituted with C 1-4 alkoxy or halogen; Or benzyloxy,
    R4는 하이드록시; 또는 아미노페닐이고, R 4 is hydroxy; Or aminophenyl,
    L은 결합; C1-4 알킬렌; 또는 C2-4 알킬렌이고, 및L is a bond; C 1-4 alkylene; Or C 2-4 alkylene, and
    Figure PCTKR2010003539-appb-I000040
    은 단일결합 또는 이중결합을 나타낸다.
    Figure PCTKR2010003539-appb-I000040
    Represents a single bond or a double bond.
  2. 제1항에 있어서, The method of claim 1,
    상기 R1은 메틸; 2-프로페닐; 비치환 페닐 또는 1 내지 3개의 R3로 치환된 페닐; 2-피리디닐; 3-피리디닐; 4-피리디닐; 2-티에닐; 1-나프탈레닐; 2-나프탈레닐; 1-브로모-2-나프탈레닐; 6-브로모-2-나프탈레닐; 1-퀴놀리닐; 2-인다닐; 벤조티오펜-2-일; 2-퓨라닐 또는 벤조퓨란-2-일인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.R 1 is methyl; 2-propenyl; Unsubstituted phenyl or phenyl substituted with 1 to 3 R 3 ; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-thienyl; 1-naphthalenyl; 2-naphthalenyl; 1-bromo-2-naphthalenyl; 6-bromo-2-naphthalenyl; 1-quinolinyl; 2-indanyl; Benzothiophen-2-yl; A compound, or a pharmaceutically acceptable salt thereof, characterized in that it is 2-furanyl or benzofuran-2-yl.
  3. 제1항에 있어서, The method of claim 1,
    상기 R2는 하이드록시; 메톡시; 또는 NHR4인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.R 2 is hydroxy; Methoxy; Or NHR 4 , or a pharmaceutically acceptable salt thereof.
  4. 제1항에 있어서, The method of claim 1,
    상기 R3은 F; Cl; Br; 메틸; 에틸; 이소프로필; 테트-부틸; 메톡시; 에톡시; 프로폭시; CF3; OCF3; 에테닐; 니트로; 페닐; 비치환 펜옥시 또는 메톡시 또는 F로 치환된 펜옥시; 또는 벤질옥시인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.R 3 is F; Cl; Br; methyl; ethyl; Isopropyl; Tet-butyl; Methoxy; Ethoxy; Propoxy; CF 3 ; OCF 3 ; Ethenyl; Nitro; Phenyl; Unsubstituted phenoxy or phenoxy substituted with methoxy or F; Or benzyloxy or a pharmaceutically acceptable salt thereof.
  5. 제1항에 있어서, The method of claim 1,
    상기 R4는 하이드록시 또는 2-아미노페닐인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.R 4 is hydroxy or 2-aminophenyl, or a pharmaceutically acceptable salt thereof.
  6. 제1항에 있어서, The method of claim 1,
    상기 L은 결합; 에틸렌; 트리메틸렌; 또는 프로페닐렌(
    Figure PCTKR2010003539-appb-I000041
    )인것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.    L is a bond; Ethylene; Trimethylene; Or propenylene (
    Figure PCTKR2010003539-appb-I000041
    Or a pharmaceutically acceptable salt thereof.
  7. 제1항에 있어서, The method of claim 1,
    상기 R1은 하나의 R3로 치환된 페닐인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.R 1 is phenyl substituted with one R 3 , or a pharmaceutically acceptable salt thereof.
  8. 제1항에 있어서, The method of claim 1,
    상기 R1은 두 개의 R3로 치환된 페닐이고, R 1 is phenyl substituted with two R 3 ,
    상기 R3는 할로겐; C1-4 알킬; C1-4 알콕시; C1-4 할로알킬; 또는 니트로인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; Or nitro or a pharmaceutically acceptable salt thereof.
  9. 제8항에 있어서, The method of claim 8,
    상기 R3는 F; Cl; 메틸; 메톡시; CF3; 또는 니트로인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.R 3 is F; Cl; methyl; Methoxy; CF 3 ; Or nitro or a pharmaceutically acceptable salt thereof.
  10. 제1항에 있어서, The method of claim 1,
    상기 R1은 세 개의 R3로 치환된 페닐이고, R 1 is phenyl substituted with three R 3 ,
    상기 R3는 할로겐; 또는 C1-4 알콕시인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.R 3 is halogen; Or C 1-4 alkoxy, or a pharmaceutically acceptable salt thereof.
  11. 제10항에 있어서, The method of claim 10,
    상기 R3는 F; 또는 메톡시인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.R 3 is F; Or methoxy, or a pharmaceutically acceptable salt thereof.
  12. 제1항에 있어서, The method of claim 1,
    상기 R1은 3-메톡시페닐; 3-트리플루오로메톡시페닐; 3-클로로페닐; 3-브로모페닐; 1-나프탈레닐; 2-나프탈레닐; 6-브로모-2-나프탈레닐; 1-퀴놀리닐; 4-이소프로필페닐; 4-니트로페닐; 2-브로모페닐; 2-메톡시페닐; 또는 2,5-디트리플루오로메틸페닐인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.R 1 is 3-methoxyphenyl; 3-trifluoromethoxyphenyl; 3-chlorophenyl; 3-bromophenyl; 1-naphthalenyl; 2-naphthalenyl; 6-bromo-2-naphthalenyl; 1-quinolinyl; 4-isopropylphenyl; 4-nitrophenyl; 2-bromophenyl; 2-methoxyphenyl; Or 2,5-ditrifluoromethylphenyl or a pharmaceutically acceptable salt thereof.
  13. 제1항에 있어서, The method of claim 1,
    상기 R1은 페닐의 2번 위치에 R3으로 치환된 페닐이고, 상기 R3는 할로겐; C1-4 알킬; C1-4 알콕시; C1-4 할로알킬; 또는 C1-4 할로알콕시이거나, R 1 is phenyl substituted with R 3 at position 2 of phenyl, and R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; Or C 1-4 haloalkoxy,
    상기 R1은 페닐의 3번 위치에 R3로 치환된 페닐이고, 상기 R3는 할로겐; C1-4 알킬; C1-4 알콕시; C1-4 할로알킬; C1-4 할로알콕시; C2-4 알케닐; 니트로; 펜옥시; 또는 벤질옥시이거나, 또는 R 1 is phenyl substituted with R 3 at position 3 of phenyl, and R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; C 1-4 haloalkoxy; C 2-4 alkenyl; Nitro; Phenoxy; Or benzyloxy, or
    상기 R1은 페닐의 4번 위치에 R3로 치환된 페닐이고, 상기 R3는 할로겐; C1-4 알킬; C1-4 알콕시; C1-4 할로알킬; C1-4 할로알콕시; 니트로; 페닐; 비치환된 펜옥시 또는 C1-4 알콕시 또는 할로겐으로 치환된 펜옥시; 또는 벤질옥시인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.R 1 is phenyl substituted with R 3 at position 4 of phenyl, and R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; C 1-4 haloalkoxy; Nitro; Phenyl; Phenoxy unsubstituted or substituted with C 1-4 alkoxy or halogen; Or benzyloxy or a pharmaceutically acceptable salt thereof.
  14. 제1항에 있어서, The method of claim 1,
    상기 R1은 C1-4 알킬; C2-4 알케닐; 인다닐; 또는 퓨라닐이고, 상기 L은 결합이거나, R 1 is C 1-4 alkyl; C 2-4 alkenyl; Indanyl; Or furanyl, and L is a bond,
    상기 R1은 비치환된 페닐 또는 1 내지 3개의 R3으로 치환된 페닐; 피리디닐; 비치환된 나프탈레닐 또는 할로겐으로 치환된 나프탈레닐; 퀴놀리닐; 벤조티오페닐; 또는 벤조퓨라닐이고, 상기 L은 메틸렌이거나, R 1 is unsubstituted phenyl or phenyl substituted with 1 to 3 R 3 ; Pyridinyl; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Quinolinyl; Benzothiophenyl; Or benzofuranyl, wherein L is methylene,
    상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 티에닐; 비치환된 나프탈레닐 또는 할로겐으로 치환된 나프탈레닐; 또는 퀴놀리닐이고, 상기 L은 에틸렌이거나, R 1 is phenyl substituted with 1 to 3 R 3 ; Thienyl; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Or quinolinyl, wherein L is ethylene, or
    상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 피리디닐; 비치환된 나프탈레닐 또는 할로겐으로 치환된 나프탈레닐; 또는 퀴놀리닐이고, 상기 L은 트리메틸렌이거나, 또는 R 1 is phenyl substituted with 1 to 3 R 3 ; Pyridinyl; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Or quinolinyl, wherein L is trimethylene, or
    상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 비치환된 나프탈레닐 또는 할로겐으로 치환된 나프탈레닐; 또는 퀴놀리닐이고, 상기 L은 프로필렌(
    Figure PCTKR2010003539-appb-I000042
    )인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.    R 1 is phenyl substituted with 1 to 3 R 3 ; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Or quinolinyl, wherein L is propylene (
    Figure PCTKR2010003539-appb-I000042
    Or a pharmaceutically acceptable salt thereof.
  15. 제1항에 있어서, The method of claim 1,
    상기 R1은 메틸; 에테닐; 2-인다닐; 또는 2-퓨라닐이고, 상기 L은 결합이거나, R 1 is methyl; Ethenyl; 2-indanyl; Or 2-furanyl, wherein L is a bond,
    상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 2-피리디닐; 3-피리디닐; 4-피리디닐; 1-나프탈레닐; 2-나프탈레닐; 1-퀴놀리닐; 벤조티오펜-2-일; 또는 벤조퓨란-2-일이고, 상기 L은 메틸렌이거나, R 1 is phenyl substituted with 1 to 3 R 3 ; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 1-naphthalenyl; 2-naphthalenyl; 1-quinolinyl; Benzothiophen-2-yl; Or benzofuran-2-yl, wherein L is methylene,
    상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 2-티에닐; 1-나프탈레닐; 2-나프탈레닐; 6-브로모-2-나프탈레닐; 또는 1-퀴놀리닐이고, 상기 L은 에틸렌이거나,R 1 is phenyl substituted with 1 to 3 R 3 ; 2-thienyl; 1-naphthalenyl; 2-naphthalenyl; 6-bromo-2-naphthalenyl; Or 1-quinolinyl, wherein L is ethylene,
    상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 3-피리디닐; 1-나프탈레닐; 1-나프탈레닐; 6-브로모-2-나프탈레닐; or 1-퀴놀리닐이고, 상기 L은 트리메틸렌이거나, 또는 R 1 is phenyl substituted with 1 to 3 R 3 ; 3-pyridinyl; 1-naphthalenyl; 1-naphthalenyl; 6-bromo-2-naphthalenyl; or 1-quinolinyl, wherein L is trimethylene, or
    상기 R1은 1 내지 3개의 R3으로 치환된 페닐; 1-나프탈레닐; 2-나프탈레닐; 6-브로모-2-나프탈레닐; 또는 1-퀴놀리닐이고, 상기 L은 프로페닐렌(
    Figure PCTKR2010003539-appb-I000043
    )인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.    R 1 is phenyl substituted with 1 to 3 R 3 ; 1-naphthalenyl; 2-naphthalenyl; 6-bromo-2-naphthalenyl; Or 1-quinolinyl, wherein L is propenylene (
    Figure PCTKR2010003539-appb-I000043
    Or a pharmaceutically acceptable salt thereof.
  16. 제1항에 있어서, 상기 화합물은 The compound of claim 1, wherein the compound is
    1) (E)-3-(1-(4-브로모벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,1) (E) -3- (1- (4-bromobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    2) (E)-3-(1-(3-플루오로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,2) (E) -3- (1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    3) (E)-3-(1-(2-플루오로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,3) (E) -3- (1- (2-fluorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    4) (E)-3-(1-(2,5-비스(트리플루오로메틸)벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,4) (E) -3- (1- (2,5-bis (trifluoromethyl) benzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    5) (E)-3-(1-(3,4-디플루오로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,5) (E) -3- (1- (3,4-difluorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    6) (E)-N-하이드록시-3-(1-(4-니트로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,6) (E) -N-hydroxy-3- (1- (4-nitrobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    7) (E)-N-하이드록시-3-(2-옥소-1-(3,4,5-트리플루오로벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,7) (E) -N-hydroxy-3- (2-oxo-1- (3,4,5-trifluorobenzyl) -1,2-dihydropyridin-3-yl) acrylamide,
    8) (E)-3-(1-(4-테트-부틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,8) (E) -3- (1- (4-tet-butylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    9) (E)-N-하이드록시-3-(1-메틸-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,9) (E) -N-hydroxy-3- (1-methyl-2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    10) (E)-3-(1-알릴-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,10) (E) -3- (1-allyl-2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    11) (E)-N-하이드록시-3-(1-(4-이소프로필벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,11) (E) -N-hydroxy-3- (1- (4-isopropylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    12) (E)-N-하이드록시-3-(2-옥소-1-(3-페닐프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,12) (E) -N-hydroxy-3- (2-oxo-1- (3-phenylpropyl) -1,2-dihydropyridin-3-yl) acrylamide,
    13) (E)-3-(1-(3-(4-플루오로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,13) (E) -3- (1- (3- (4-fluorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    14) (E)-3-(1-(3-(3-플루오로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,14) (E) -3- (1- (3- (3-fluorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    15) (E)-3-(1-(3-(2-플루오로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,15) (E) -3- (1- (3- (2-fluorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    16) (E)-3-(1-(3-(4-클로로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,16) (E) -3- (1- (3- (4-chlorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    17) (E)-3-(1-(3-(3-클로로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,17) (E) -3- (1- (3- (3-chlorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    18) (E)-3-(1-(3-(2-클로로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,18) (E) -3- (1- (3- (2-chlorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    19) (E)-N-하이드록시-3-(1-(3-(4-이소프로필페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,19) (E) -N-hydroxy-3- (1- (3- (4-isopropylphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    20) (E)-N-하이드록시-3-(2-옥소-1-(3-(3,4,5-트리플루오로페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,20) (E) -N-hydroxy-3- (2-oxo-1- (3- (3,4,5-trifluorophenyl) propyl) -1,2-dihydropyridin-3-yl) Acrylamide,
    21) (E)-3-(1-(3-(비페닐-4-일)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,21) (E) -3- (1- (3- (biphenyl-4-yl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    22) (E)-N-하이드록시-3-(2-옥소-1-(3-(4-(트리플루오로메톡시)페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,22) (E) -N-hydroxy-3- (2-oxo-1- (3- (4- (trifluoromethoxy) phenyl) propyl) -1,2-dihydropyridin-3-yl) acrylic amides,
    23) (E)-N-하이드록시-3-(2-옥소-1-(3-(3-(트리플루오로메톡시)페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,23) (E) -N-hydroxy-3- (2-oxo-1- (3- (3- (trifluoromethoxy) phenyl) propyl) -1,2-dihydropyridin-3-yl) acrylic amides,
    24) (E)-N-하이드록시-3-(2-옥소-1-(3-(2-(트리플루오로메톡시)페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,24) (E) -N-hydroxy-3- (2-oxo-1- (3- (2- (trifluoromethoxy) phenyl) propyl) -1,2-dihydropyridin-3-yl) acrylic amides,
    25) (E)-N-하이드록시-3-(2-옥소-1-(3-(4-펜옥시페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,25) (E) -N-hydroxy-3- (2-oxo-1- (3- (4-phenoxyphenyl) propyl) -1,2-dihydropyridin-3-yl) acrylamide,
    26) (E)-3-(1-(3-(3,4-디플루오로페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,26) (E) -3- (1- (3- (3,4-difluorophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide ,
    27) (E)-N-하이드록시-3-(1-(4-메틸펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,27) (E) -N-hydroxy-3- (1- (4-methylphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    28) (E)-N-하이드록시-3-(1-(3-메틸펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,28) (E) -N-hydroxy-3- (1- (3-methylphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    29) (E)-N-하이드록시-3-(1-(2-메틸펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,29) (E) -N-hydroxy-3- (1- (2-methylphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    30) (E)-N-하이드록시-3-(2-옥소-1-(2-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,30) (E) -N-hydroxy-3- (2-oxo-1- (2- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) acrylamide,
    31) (E)-3-(1-(2-브로모벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,31) (E) -3- (1- (2-bromobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    32) (E)-N-하이드록시-3-(1-(2-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,32) (E) -N-hydroxy-3- (1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    33) (E)-3-(1-(4-에틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,33) (E) -3- (1- (4-ethylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    34) (E)-3-(1-(2-에틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,34) (E) -3- (1- (2-ethylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    35) (E)-3-(1-(4-(4-플루오로펜옥시)펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,35) (E) -3- (1- (4- (4-fluorophenoxy) phenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    36) (E)-N-하이드록시-3-(1-(4-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,36) (E) -N-hydroxy-3- (1- (4-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    37) (E)-N-하이드록시-3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,37) (E) -N-hydroxy-3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    38) (E)-3-(1-(3-브로모벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,38) (E) -3- (1- (3-bromobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    39) (E)-3-(1-(4-플루오로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,39) (E) -3- (1- (4-fluorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    40) (E)-N-하이드록시-3-(2-옥소-1-(3-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,40) (E) -N-hydroxy-3- (2-oxo-1- (3- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) acrylamide,
    41) (E)-N-하이드록시-3-(1-(3-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,41) (E) -N-hydroxy-3- (1- (3-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    42) (E)-N-하이드록시-3-(2-옥소-1-(3-펜옥시벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,42) (E) -N-hydroxy-3- (2-oxo-1- (3-phenoxybenzyl) -1,2-dihydropyridin-3-yl) acrylamide,
    43) (E)-N-하이드록시-3-(2-옥소-1-(4-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,43) (E) -N-hydroxy-3- (2-oxo-1- (4- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) acrylamide,
    44) (E)-N-하이드록시-3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,44) (E) -N-hydroxy-3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    45) (E)-N-하이드록시-3-(1-(나프탈렌-1-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,45) (E) -N-hydroxy-3- (1- (naphthalen-1-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    46) (E)-3-(1-(3-(2-브로모페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,46) (E) -3- (1- (3- (2-bromophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    47) (E)-3-(1-(3-(4-브로모페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,47) (E) -3- (1- (3- (4-bromophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    48) (E)-N-하이드록시-3-(1-(3-(3-메톡시페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,48) (E) -N-hydroxy-3- (1- (3- (3-methoxyphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    49) (E)-N-하이드록시-3-(1-(3-(4-메톡시페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,49) (E) -N-hydroxy-3- (1- (3- (4-methoxyphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    50) (E)-N-하이드록시-3-(1-(3-(2-메톡시페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,50) (E) -N-hydroxy-3- (1- (3- (2-methoxyphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    51) (E)-N-하이드록시-3-(1-(3-(나프탈렌-1-일)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,51) (E) -N-hydroxy-3- (1- (3- (naphthalen-1-yl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    52) (E)-N-하이드록시-3-(1-(3-(나프탈렌-2-일)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,52) (E) -N-hydroxy-3- (1- (3- (naphthalen-2-yl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    53) (E)-3-(1-(3-(3-브로모페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,53) (E) -3- (1- (3- (3-bromophenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    54) (E)-3-(1-벤질-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,54) (E) -3- (1-benzyl-2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    55) (E)-N-하이드록시-3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,55) (E) -N-hydroxy-3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) acrylamide,
    56) (E)-N-하이드록시-3-(1-(4-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,56) (E) -N-hydroxy-3- (1- (4-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    57) (E)-3-(1-(3,5-비스(트리플루오로메틸)벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,57) (E) -3- (1- (3,5-bis (trifluoromethyl) benzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    58) (E)-N-하이드록시-3-(1-(4-메틸-3-니트로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,58) (E) -N-hydroxy-3- (1- (4-methyl-3-nitrobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    59) (E)-3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,59) (E) -3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    60) (E)-N-하이드록시-3-(2-옥소-1-펜에틸-1,2-디하이드로피리딘-3-일)아크릴아미드,60) (E) -N-hydroxy-3- (2-oxo-1-phenethyl-1,2-dihydropyridin-3-yl) acrylamide,
    61) (E)-N-하이드록시-3-(1-(2-메틸-3-니트로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,61) (E) -N-hydroxy-3- (1- (2-methyl-3-nitrobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    62) (E)-3-(1-(4-브로모펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,62) (E) -3- (1- (4-bromophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    63) (E)-N-하이드록시-3-(1-(3-메톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,63) (E) -N-hydroxy-3- (1- (3-methoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    64) (E)-3-(1-(4-클로로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,64) (E) -3- (1- (4-chlorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    65) (E)-3-(1-(2-클로로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,65) (E) -3- (1- (2-chlorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    66) (E)-3-(1-(3-클로로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,66) (E) -3- (1- (3-chlorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    67) (E)-N-하이드록시-3-(1-(2-(나프탈렌-1-일)에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,67) (E) -N-hydroxy-3- (1- (2- (naphthalen-1-yl) ethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    68) (E)-N-하이드록시-3-(1-(2-메톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,68) (E) -N-hydroxy-3- (1- (2-methoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    69) (E)-N-하이드록시-3-(1-(2-(나프탈렌-2-일)에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,69) (E) -N-hydroxy-3- (1- (2- (naphthalen-2-yl) ethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    70) (E)-3-(1-(2-브로모펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,70) (E) -3- (1- (2-bromophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    71) (E)-3-(1-(3-브로모펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,71) (E) -3- (1- (3-bromophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    72) (E)-N-하이드록시-3-(2-옥소-1-(3-펜옥시펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,72) (E) -N-hydroxy-3- (2-oxo-1- (3-phenoxyphenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    73) (E)-3-(1-(2-(비페닐-4일)에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,73) (E) -3- (1- (2- (biphenyl-4yl) ethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    74) (E)-3-(1-(4-플루오로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,74) (E) -3- (1- (4-fluorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    75) (E)-3-(1-(2-플루오로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,75) (E) -3- (1- (2-fluorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    76) (E)-3-(1-(4-테트-부틸펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,76) (E) -3- (1- (4-tet-butylphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    77) (E)-3-(1-(3-플루오로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,77) (E) -3- (1- (3-fluorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    78) (E)-3-(1-(3-에톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,78) (E) -3- (1- (3-ethoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    79) (E)-N-하이드록시-3-(1-(4-이소프로필펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,79) (E) -N-hydroxy-3- (1- (4-isopropylphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    80) (E)-N-하이드록시-3-(1-(4-메톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,80) (E) -N-hydroxy-3- (1- (4-methoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    81) (E)-N-하이드록시-3-(1-(4-(4-메톡시펜옥시)펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,81) (E) -N-hydroxy-3- (1- (4- (4-methoxyphenoxy) phenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    82) (E)-3-(1-(4-(벤질옥시)펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,82) (E) -3- (1- (4- (benzyloxy) phenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    83) (E)-N-하이드록시-3-(2-옥소-1-(4-(트리플루오로메틸)펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,83) (E) -N-hydroxy-3- (2-oxo-1- (4- (trifluoromethyl) phenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    84) (E)-3-(1-(2-에톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,84) (E) -3- (1- (2-ethoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    85) (E)-N-하이드록시-3-(2-옥소-1-(3-비닐펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,85) (E) -N-hydroxy-3- (2-oxo-1- (3-vinylphenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    86) (E)-N-하이드록시-3-(2-옥소-1-(4-(트리플루오로메톡시)펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,86) (E) -N-hydroxy-3- (2-oxo-1- (4- (trifluoromethoxy) phenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    87) (E)-3-(1-(4-에톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,87) (E) -3- (1- (4-ethoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    88) (E)-N-하이드록시-3-(2-옥소-1-(2-(트리플루오로메틸)펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,88) (E) -N-hydroxy-3- (2-oxo-1- (2- (trifluoromethyl) phenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    89) (E)-N-하이드록시-3-(2-옥소-1-(3-(트리플루오로메틸)펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,89) (E) -N-hydroxy-3- (2-oxo-1- (3- (trifluoromethyl) phenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    90) (E)-N-하이드록시-3-(2-옥소-1-(4-프로폭시펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,90) (E) -N-hydroxy-3- (2-oxo-1- (4-propoxyphenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    91) (E)-N-하이드록시-3-(2-옥소-1-(4-펜옥시펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,91) (E) -N-hydroxy-3- (2-oxo-1- (4-phenoxyphenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    92) (E)-3-(1-(3-(벤질옥시)펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,92) (E) -3- (1- (3- (benzyloxy) phenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    93) (E)-3-(1-(2-(벤질옥시)펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,93) (E) -3- (1- (2- (benzyloxy) phenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    94) (E)-N-하이드록시-3-(1-(4-니트로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,94) (E) -N-hydroxy-3- (1- (4-nitrophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    95) (E)-3-(1-(3,4-디클로로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,95) (E) -3- (1- (3,4-dichlorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    96) (E)-N-하이드록시-3-(1-(3-(4-메톡시펜옥시)펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,96) (E) -N-hydroxy-3- (1- (3- (4-methoxyphenoxy) phenethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    97) (E)-3-(1-(3,4-디플루오로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,97) (E) -3- (1- (3,4-difluorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    98) (E)-3-(1-(4-에틸펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,98) (E) -3- (1- (4-ethylphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    99) (E)-N-하이드록시-3-(2-옥소-1-(3,4,5-트리메톡시펜에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,99) (E) -N-hydroxy-3- (2-oxo-1- (3,4,5-trimethoxyphenethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    100) (E)-3-(1-(2,4-디클로로펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,100) (E) -3- (1- (2,4-dichlorophenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    101) (E)-3-(1-(2,3-디하이드로-1H-인덴-2-일)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,101) (E) -3- (1- (2,3-dihydro-1H-inden-2-yl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
    102) (E)-N-하이드록시-3-(2-옥소-1-(3-m-톨릴프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,102) (E) -N-hydroxy-3- (2-oxo-1- (3-m-tolylpropyl) -1,2-dihydropyridin-3-yl) acrylamide,
    103) (E)-N-하이드록시-3-(2-옥소-1-(3-o-톨릴프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,103) (E) -N-hydroxy-3- (2-oxo-1- (3-o-tolylpropyl) -1,2-dihydropyridin-3-yl) acrylamide,
    104) (E)-N-하이드록시-3-(2-옥소-1-(3-p-톨릴프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,104) (E) -N-hydroxy-3- (2-oxo-1- (3-p-tolylpropyl) -1,2-dihydropyridin-3-yl) acrylamide,
    105) (E)-3-(1-(2-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,105) (E) -3- (1- (2-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    106) (E)-3-(1-(4-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,106) (E) -3- (1- (4-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    107) (E)-3-(1-(3-(4-테트-부틸페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,107) (E) -3- (1- (3- (4-tet-butylphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    108) (E)-N-하이드록시-3-(2-옥소-1-(3-(2-(트리플루오로메틸)페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,108) (E) -N-hydroxy-3- (2-oxo-1- (3- (2- (trifluoromethyl) phenyl) propyl) -1,2-dihydropyridin-3-yl) acrylic amides,
    109) (E)-N-하이드록시-3-(2-옥소-1-(3-(4-(트리플루오로메틸)페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,109) (E) -N-hydroxy-3- (2-oxo-1- (3- (4- (trifluoromethyl) phenyl) propyl) -1,2-dihydropyridin-3-yl) acrylic amides,
    110) (E)-N-하이드록시-3-(2-옥소-1-(3-(3-(트리플루오로메틸)페닐)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,110) (E) -N-hydroxy-3- (2-oxo-1- (3- (3- (trifluoromethyl) phenyl) propyl) -1,2-dihydropyridin-3-yl) acrylic amides,
    111) (E)-3-(1-(3-(4-에틸페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,111) (E) -3- (1- (3- (4-ethylphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    112) (E)-3-(1-(비페닐-4-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,112) (E) -3- (1- (biphenyl-4-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    113) (E)-3-(1-(2-(6-브로모나프탈렌-2-일)에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,113) (E) -3- (1- (2- (6-bromonaphthalen-2-yl) ethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
    114) (E)-3-(1-(2,4-디메톡시펜에틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,114) (E) -3- (1- (2,4-dimethoxyphenethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    115) (E)-메틸 3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴레이트,115) (E) -methyl 3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylate,
    116) (E)-3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴릭 애시드,116) (E) -3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic acid,
    117) 3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노익 애시드,117) 3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoic acid,
    118) N-하이드록시-3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)프로판아미드,118) N-hydroxy-3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) propanamide,
    119) 메틸 3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)프로파노에이트,119) methyl 3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) propanoate,
    120) (E)-메틸 3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)아크릴레이트,120) (E) -methyl 3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) acrylate,
    121) (E)-N-(2-아미노페닐)-3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,121) (E) -N- (2-aminophenyl) -3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) acrylamide ,
    122) (E)-N-(2-아미노페닐)-3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,122) (E) -N- (2-aminophenyl) -3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    123) 메틸 3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노에이트,123) methyl 3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoate,
    124) (E)-3-(1-신나밀-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,124) (E) -3- (1-cinnamil-2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    125) (E)-3-(1-((E)-3-(4-브로모페닐)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,125) (E) -3- (1-((E) -3- (4-bromophenyl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
    126) (E)-3-(1-((E)-3-(3-브로모페닐)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,126) (E) -3- (1-((E) -3- (3-bromophenyl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
    127) (E)-3-(1-((E)-3-(2-브로모페닐)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,127) (E) -3- (1-((E) -3- (2-bromophenyl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
    128) (E)-3-(1-(3-(2-에톡시페닐)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,128) (E) -3- (1- (3- (2-ethoxyphenyl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    129) (E)-N-하이드록시-3-(2-옥소-1-(피리딘-2-일메틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,129) (E) -N-hydroxy-3- (2-oxo-1- (pyridin-2-ylmethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    130) (E)-N-하이드록시-3-(2-옥소-1-(피리딘-3-일메틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,130) (E) -N-hydroxy-3- (2-oxo-1- (pyridin-3-ylmethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    131) (E)-3-(1-(3-(1-브로모나프탈렌-2-일)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,131) (E) -3- (1- (3- (1-bromonaphthalen-2-yl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
    132) N-하이드록시-3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)프로판아미드,132) N-hydroxy-3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) propanamide,
    133) 3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)프로파노익 애시드,133) 3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) propanoic acid,
    134) N-(2-아미노페닐)-3-(2-옥소-1-(3-(트리플루오로메톡시)벤질)-1,2-디하이드로피리딘-3-일)프로판아미드,134) N- (2-aminophenyl) -3- (2-oxo-1- (3- (trifluoromethoxy) benzyl) -1,2-dihydropyridin-3-yl) propanamide,
    135) N-(2-아미노페닐)-3-(1-(나프탈렌-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)프로판아미드,135) N- (2-aminophenyl) -3- (1- (naphthalen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) propanamide,
    136) (E)-N-하이드록시-3-(2-옥소-1-(2-(티오펜-2-일)에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,136) (E) -N-hydroxy-3- (2-oxo-1- (2- (thiophen-2-yl) ethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    137) (E)-N-하이드록시-3-(1-((E)-3-(나프탈렌-2-일)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,137) (E) -N-hydroxy-3- (1-((E) -3- (naphthalen-2-yl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic amides,
    138) (E)-N-하이드록시-3-(2-옥소-1-((E)-3-(3-(트리플루오로메톡시)페닐)알릴)-1,2-디하이드로피리딘-3-일)아크릴아미드,138) (E) -N-hydroxy-3- (2-oxo-1-((E) -3- (3- (trifluoromethoxy) phenyl) allyl) -1,2-dihydropyridine-3 -Yl) acrylamide,
    139) (E)-N-하이드록시-3-(1-((E)-3-(3-메톡시페닐)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,139) (E) -N-hydroxy-3- (1-((E) -3- (3-methoxyphenyl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic amides,
    140) (E)-N-하이드록시-3-(1-((E)-3-(나프탈렌-1-일)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,140) (E) -N-hydroxy-3- (1-((E) -3- (naphthalen-1-yl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic amides,
    141) (E)-메틸 3-(2-옥소-1-(3-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)아크릴레이트,141) (E) -methyl 3- (2-oxo-1- (3- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) acrylate,
    142) (E)-N-(2-아미노페닐)-3-(2-옥소-1-(3-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)아크릴아미드,142) (E) -N- (2-aminophenyl) -3- (2-oxo-1- (3- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) acrylamide ,
    143) N-(2-아미노페닐)-3-(2-옥소-1-(3-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)프로판아미드,143) N- (2-aminophenyl) -3- (2-oxo-1- (3- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) propanamide,
    144) (E)-메틸 3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴레이트,144) (E) -methyl 3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylate,
    145) (E)-3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴릭 애시드,145) (E) -3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic acid,
    146) 3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시프로판아미드,146) 3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxypropanamide,
    147) (E)-N-(2-아미노페닐)-3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,147) (E) -N- (2-aminophenyl) -3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    148) (E)-메틸 3-(1-(4-니트로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴레이트,148) (E) -methyl 3- (1- (4-nitrobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylate,
    149) (E)-N-(2-아미노페닐)-3-(1-(4-니트로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,149) (E) -N- (2-aminophenyl) -3- (1- (4-nitrobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    150) (E)-3-(1-(4-니트로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴릭 애시드,150) (E) -3- (1- (4-nitrobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic acid,
    151) (E)-3-(1-(3-(6-브로모나프탈렌-2-일)프로필)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,151) (E) -3- (1- (3- (6-bromonaphthalen-2-yl) propyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylic amides,
    152) (E)-N-하이드록시-3-(2-옥소-1-(퀴놀린-2-일메틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,152) (E) -N-hydroxy-3- (2-oxo-1- (quinolin-2-ylmethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    153) (E)-N-하이드록시-3-(2-옥소-1-(피리딘-4-일메틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,153) (E) -N-hydroxy-3- (2-oxo-1- (pyridin-4-ylmethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    154) (E)-N-하이드록시-3-(2-옥소-1-(2-(피리딘-2-일)에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,154) (E) -N-hydroxy-3- (2-oxo-1- (2- (pyridin-2-yl) ethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    155) (E)-N-하이드록시-3-(2-옥소-1-(3-(피리딘-3-일)프로필)-1,2-디하이드로피리딘-3-일)아크릴아미드,155) (E) -N-hydroxy-3- (2-oxo-1- (3- (pyridin-3-yl) propyl) -1,2-dihydropyridin-3-yl) acrylamide,
    156) (E)-N-하이드록시-3-(2-옥소-1-(2-(피리딘-4-일)에틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,156) (E) -N-hydroxy-3- (2-oxo-1- (2- (pyridin-4-yl) ethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    157) (E)-N-하이드록시-3-(2-옥소-1-((E)-3-(3-(트리플루오로메틸)페닐)알릴)-1,2-디하이드로피리딘-3-일)아크릴아미드,157) (E) -N-hydroxy-3- (2-oxo-1-((E) -3- (3- (trifluoromethyl) phenyl) allyl) -1,2-dihydropyridine-3 -Yl) acrylamide,
    158) (E)-3-(1-((E)-3-(3-클로로페닐)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,158) (E) -3- (1-((E) -3- (3-chlorophenyl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide ,
    159) (E)-N-하이드록시-3-(1-((E)-3-(2-메톡시페닐)알릴)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,159) (E) -N-hydroxy-3- (1-((E) -3- (2-methoxyphenyl) allyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic amides,
    160) (E)-N-하이드록시-3-(2-옥소-1-((E)-3-(퀴놀린-2-일)알릴)-1,2-디하이드로피리딘-3-일)아크릴아미드,160) (E) -N-hydroxy-3- (2-oxo-1-((E) -3- (quinolin-2-yl) allyl) -1,2-dihydropyridin-3-yl) acrylic amides,
    161) 3-(1-(2-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노익 애시드,161) 3- (1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoic acid,
    162) 메틸 3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노에이트,162) methyl 3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoate,
    163) 3-(1-(3-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노익 애시드,163) 3- (1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoic acid,
    164) (E)-3-(2-옥소-1-(3-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)아크릴릭 애시드,164) (E) -3- (2-oxo-1- (3- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) acrylic acid,
    165) 메틸 3-(2-옥소-1-(3-(트리플루오로메틸)벤질)-1,2-디하이드로피리딘-3-일)프로파노에이트,165) methyl 3- (2-oxo-1- (3- (trifluoromethyl) benzyl) -1,2-dihydropyridin-3-yl) propanoate,
    166) (E)-N-(2-아미노페닐)-3-(1-(2-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,166) (E) -N- (2-aminophenyl) -3- (1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    167) N-하이드록시-3-(1-(2-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로판아미드,167) N-hydroxy-3- (1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanamide,
    168) (E)-메틸 3-(2-옥소-1-(퀴놀린-2-일메틸)-1,2-디하이드로피리딘-3-일)아크릴레이트,168) (E) -methyl 3- (2-oxo-1- (quinolin-2-ylmethyl) -1,2-dihydropyridin-3-yl) acrylate,
    169) (E)-3-(2-옥소-1-(퀴놀린-2-일메틸)-1,2-디하이드로피리딘-3-일)아크릴릭 애시드,169) (E) -3- (2-oxo-1- (quinolin-2-ylmethyl) -1,2-dihydropyridin-3-yl) acrylic acid,
    170) (E)-N-(2-아미노페닐)-3-(2-옥소-1-(퀴놀린-2-일메틸)-1,2-디하이드로피리딘-3-일)아크릴아미드,170) (E) -N- (2-aminophenyl) -3- (2-oxo-1- (quinolin-2-ylmethyl) -1,2-dihydropyridin-3-yl) acrylamide,
    171) N-(2-아미노페닐)-3-(2-옥소-1-(퀴놀린-2-일메틸)-1,2-디하이드로피리딘-3-일)프로판아미드,171) N- (2-aminophenyl) -3- (2-oxo-1- (quinolin-2-ylmethyl) -1,2-dihydropyridin-3-yl) propanamide,
    172) (E)-메틸 3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴레이트,172) (E) -methyl 3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylate,
    173) (E)-3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴릭 애시드,173) (E) -3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic acid,
    174) (E)-N-(2-아미노페닐)-3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴아미드,174) (E) -N- (2-aminophenyl) -3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylamide,
    175) 메틸 3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노에이트,175) methyl 3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoate,
    176) 3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로파노익 애시드,176) 3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanoic acid,
    177) N-(2-아미노페닐)-3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로판아미드,177) N- (2-aminophenyl) -3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanamide,
    178) N-하이드록시-3-(1-(3-메톡시벤질)-2-옥소-1,2-디하이드로피리딘-3-일)프로판아미드,178) N-hydroxy-3- (1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl) propanamide,
    179) (E)-3-(1-(벤조[b]티오펜-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,179) (E) -3- (1- (benzo [b] thiophen-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    180) (E)-3-(1-(벤조퓨란-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,180) (E) -3- (1- (benzofuran-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    181) (E)-3-(1-(퓨란-2-일메틸)-2-옥소-1,2-디하이드로피리딘-3-일)-N-하이드록시아크릴아미드,181) (E) -3- (1- (furan-2-ylmethyl) -2-oxo-1,2-dihydropyridin-3-yl) -N-hydroxyacrylamide,
    182) (E)-메틸 3-(1-(2-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴레이트, 및 182) (E) -methyl 3- (1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylate, and
    183) (E)-3-(1-(2-메틸벤질)-2-옥소-1,2-디하이드로피리딘-3-일)아크릴릭 애시드183) (E) -3- (1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl) acrylic acid
    로 구성되는 군으로부터 선택되는 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.Compound or pharmaceutically acceptable salt thereof, characterized in that selected from the group consisting of.
  17. 제1항 내지 제16 중 어느 한 항에 따른 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물. A pharmaceutical composition for preventing or treating cancer, comprising the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof as an active ingredient.
  18. 제17항에 있어서, 상기 암은 폐암, 비소세포성 폐암, 결장암, 골암, 췌장암, 피부암, 두부 또는 경부 암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 위암, 항문부근암, 결장암, 유방암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신장세포 암종, 신장골반 암종, 중추신경계(CNS; central nervous system) 종양, 1차 중추신경계 림프종, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종으로 이루어진 군으로부터 선택되는 1종인 것을 특징으로 하는 약학적 조성물.18. The method of claim 17, wherein the cancer is lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, anal muscle cancer, colon cancer , Breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, Penile cancer, prostate cancer, chronic or acute leukemia, lymphocyte lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary central nervous system lymphoma, spinal cord tumor, brain stem Pharmaceutical composition, characterized in that one species selected from the group consisting of glioma and pituitary adenoma.
PCT/KR2010/003539 2009-06-01 2010-06-01 Novel pyridone compounds or pharmaceutically acceptable salts thereof, method for producing the same, and pharmaceutical composition containing the same for treating cancer WO2010140835A2 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10345648A1 (en) * 2003-10-01 2005-04-21 Studiengesellschaft Kohle Mbh Production of new or known tetrahydropyranyl-pyridone compounds, for use as phosphatase inhibitors, e.g. for treating cancer, from pyridinone and pyranone compounds via several new intermediates
US20080267942A1 (en) * 2006-10-25 2008-10-30 Pfizer Limited Benzazepin-2(1h)-one derivatives
EP2065380A1 (en) * 2007-08-22 2009-06-03 F.Hoffmann-La Roche Ag Pyridoneamide derivatives as focal adhesion kinase (FAK) inhibitors and their use for the treatment of cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10345648A1 (en) * 2003-10-01 2005-04-21 Studiengesellschaft Kohle Mbh Production of new or known tetrahydropyranyl-pyridone compounds, for use as phosphatase inhibitors, e.g. for treating cancer, from pyridinone and pyranone compounds via several new intermediates
US20080267942A1 (en) * 2006-10-25 2008-10-30 Pfizer Limited Benzazepin-2(1h)-one derivatives
EP2065380A1 (en) * 2007-08-22 2009-06-03 F.Hoffmann-La Roche Ag Pyridoneamide derivatives as focal adhesion kinase (FAK) inhibitors and their use for the treatment of cancer

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