WO2023146244A1 - Benzodioxane derivative compounds and medical use thereof - Google Patents

Benzodioxane derivative compounds and medical use thereof Download PDF

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Publication number
WO2023146244A1
WO2023146244A1 PCT/KR2023/001073 KR2023001073W WO2023146244A1 WO 2023146244 A1 WO2023146244 A1 WO 2023146244A1 KR 2023001073 W KR2023001073 W KR 2023001073W WO 2023146244 A1 WO2023146244 A1 WO 2023146244A1
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WIPO (PCT)
Prior art keywords
cancer
compound
dihydrobenzo
dioxin
acetamide
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PCT/KR2023/001073
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French (fr)
Korean (ko)
Inventor
최인희
이보라
김영미
김성훈
김대규
Original Assignee
재단법인 한국파스퇴르연구소
재단법인 의약바이오컨버젼스연구단
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Publication of WO2023146244A1 publication Critical patent/WO2023146244A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring

Definitions

  • the present disclosure relates to a compound comprising a benzodioxane scaffold or a pharmaceutically acceptable salt thereof.
  • the present disclosure also relates to pharmaceutical compositions comprising such compounds or pharmaceutically acceptable salts thereof.
  • the present disclosure also relates to useful methods of treating or preventing cancer using such compounds. That is, the present disclosure relates to the pharmaceutical use of the compounds according to the present disclosure for treating or preventing cancer.
  • Cancer is a leading cause of death worldwide, and among them, lung cancer is one of the most common cancers after breast cancer.
  • Lung cancer is largely divided into small cell lung cancer and non-small cell lung cancer. It is important to differentiate between the two types of lung cancer because they have different types of growth and different degrees of spread, so treatment and prognosis are different. Lung cancer is often asymptomatic, and early diagnosis is difficult in most cases, so it is often detected late. Lung cancer is known to progress faster than other cancers and metastasize to other organs. For lung cancer, radiation therapy or drug therapy is the main treatment rather than surgical treatment.
  • AIMP2 ARS-interacting multi-functional protein 2
  • International Patent Publication WO2006-057500 A1 discloses that AIMP2 is a novel tumor suppressor and functions to enhance TGF- ⁇ signaling through direct interaction with Smad2/3.
  • International Patent Publication WO2006-057500 A1 describes that AIMP2-DX2, which is a mutant in which exon 2 of AIMP2 is missing, is specifically expressed in cancer cell lines and tissues.
  • AIMP2 levels were dramatically reduced in cells transformed with AIMP2-DX2, regardless of TGF- ⁇ , and it was confirmed that AIMP2-DX2 production resulted in loss of AIMP2 activity.
  • AIMP2-DX2 induces a decrease in AIMP2 level and is closely related to cancer formation and progression, it is possible to diagnose various cancers such as lung cancer, liver cancer, skin cancer, breast cancer, kidney cancer, and osteosarcoma through the generation of AIMP2-DX2. It has been revealed that it can.
  • AIMP2 activates p53 to promote apoptosis (Proc. Natl Acad Sci August 12, 2008 105 (32) 11206-11211; https://doi.org/10.1073/pnas.0800297105 .)
  • AIMP2-DX2 has been found to cause cancer by inhibiting the pro-apoptosis function of AIMP2 by interfering with AIMP2 and p53 binding by competing with AIMP2 (PLoS Genet 2011 Mar;7(3):e1001351. doi : 10.1371/journal.pgen.1001351.).
  • the problem to be solved by the present disclosure is to inhibit the activity of AIMP2-DX2, effectively induce the death of cancer cells, and thereby provide a compound that is effective in preventing and treating cancer, particularly lung cancer.
  • Another object of the present disclosure is to provide a pharmaceutical composition for treating or preventing cancer, particularly lung cancer, containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present disclosure is to provide a method for treating or preventing cancer, particularly lung cancer, comprising administering a compound according to the present invention to a patient in need of such treatment or prevention.
  • the present invention provides a benzodioxane derivative compound of Formula 1 or Formula 2 (preferably Formula 1) or a pharmaceutically acceptable salt thereof.
  • R 10 , R 11 , R 12 and R 13 independently of each other are hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, or hydroxy;
  • R 14 is phenyl; or wherein R 14 is optionally substituted with one or more substituents from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, phenyl, phenyl substituted with C1-C3 alkyl, and hydroxy becomes,
  • X is S, O or NH.
  • R 6 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, or hydroxy (preferably hydrogen);
  • X is -CH 2 - or -C(O)-;
  • Y is a direct connection, -CH 2 -, or -C(O)-;
  • Z is a direct link, -NH-, or -CH 2 -;
  • XYZ is -CH 2 -, -CH 2 C(O)NH-, or -C(O)CH 2 CH 2 -);
  • R 15 are independently of each other C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, or hydroxy;
  • n is an integer from 1 to 3;
  • the present inventors While studying compounds targeting AIMP2-DX2, the present inventors confirmed that compounds containing benzodioxane scaffolds are very good at inhibiting these targets, and as a result, exhibit excellent anticancer activity against cancer, especially lung cancer, and the present invention has been completed. That is, the compounds of the present invention inhibit the growth of cancer cells by inhibiting AIMP2-DX2, and can control cancer specifically without cytotoxicity.
  • substituent may be (1) unsubstituted or (2) substituted with one or more of the defined substituents. If the substitutable position is unsubstituted, the default substituent is a hydrido radical.
  • alkyl refers to a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms (unless the number of carbon atoms is specifically limited). "Lower alkyl” means a straight chain or branched alkyl having 1 to 4 carbon atoms.
  • saturated straight-chain alkyls are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n- decyl, while saturated branched alkyl is -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-
  • alkoxy means -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -O(CH 2 ) 3 CH 3 , -O(CH 2 ) 4 CH 3 , -O-(alkyl), including -O(CH 2 ) 5 CH 3 , and the like, wherein alkyl is as defined above.
  • C 1-6 alkyl means an alkyl having 1 to 6 carbon atoms.
  • haloalkyl or haloalkoxy refers to an alkyl or alkoxy group in which one or more hydrogen atoms of each of the alkyl or alkoxy groups are replaced by halogen atoms.
  • haloalkyl is -CF 3 , -CHF 2 , -CH 2 F, -CBr 3 , -CHBr 2 , -CH 2 Br, -CC1 3 , -CHC1 2 , -CH 2 CI, -CI 3 , -CHI 2 , -CH 2 I, -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CH 2 -CBr 3 , -CH 2 -CHBr 2 , -CH 2 -CH 2 Br, -CH 2 -CC1 3 , -CH 2 -CHC1 2 , -CH 2 -CH 2 CI, -CH 2 -CI 3 , -CH 2 -CHI 2 , -CH 2 -CH 2 I, and the like include that In one preferred aspect of the present invention, haloalkyl is CF 3 . wherein alkyl and halogen
  • cycloalkyl means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and not having carbon-carbon multiple bonds.
  • monocyclic rings include, but are not limited to, (C 3 -C 7 )cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl).
  • polycyclic rings examples include fused bicyclic rings such as octahydropentalene, decahydronaphthalene, and the like; spiro rings such as spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane and the like; and bridged bicyclic rings such as bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. Cycloalkyl groups may be optionally substituted. In one embodiment, a cycloalkyl group is a monocyclic ring (ring).
  • a compound that is 2-([1,1'-Biphenyl]-4-yl)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide (Compound 28); or It is a pharmaceutically acceptable salt thereof.
  • the compounds represented by Chemical Formula 1 or 2 according to the present invention the compounds exhibited superior anticancer effects compared to other compounds having similar structures.
  • a compound that is 2-([1,1'-Biphenyl]-4-yl)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide (Compound 28); or It is a pharmaceutically acceptable salt thereof.
  • the compounds represented by Chemical Formula 1 or 2 according to the present invention the compounds exhibited far superior anti-cancer effects compared to other compounds having similar structures.
  • “pharmaceutically acceptable salts” include salts of active compounds prepared with relatively non-toxic acids and bases depending on the specific substituents found in the compounds mentioned herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts.
  • acidic addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts are acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid ( fumaric), mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric acid, tartaric acid, methanesulfonic, and their analogues.
  • Hydrogen chloride hydrogen bromide, nitric acid, carbonic acid, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide or phosphorous acid ( phosphorous acid) and its analogues.
  • salts of amino acids such as alginate and analogs thereof and analogs of organic acids such as glucuronic or galactunoric acids and analogs thereof.
  • Other examples of salts are well known from the literature known in the art to which this invention pertains.
  • the term "compound of the present invention” is meant to include not only the compounds of formula 1 or 2, but also clathrates, hydrates, solvates, or polymorphs thereof.
  • the term “compound of the present invention” is meant to include pharmaceutically acceptable salts of the compounds of the present invention when pharmaceutically acceptable salts thereof are not mentioned.
  • the compounds of the present invention are stereomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, 97% ee or more, or 99% ee or more))).
  • polymorph refers to a solid crystal form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in terms of physical properties include, but are not limited to, stability (e.g. heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't. Differences in stability may be due to chemical reactivity changes (e.g. differential oxidation such as faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g.
  • kinetically Tablet fragments stored as the preferred polymorph may be thermodynamically converted to a more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity).
  • Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates, or may be more difficult to filter or wash, than another polymorph, eg, due to its shape or particle size distribution.
  • solvent compound refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and can be administered in very small amounts to humans.
  • hydrate refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate refers to a compound of the present invention in the form of a crystal lattice containing spaces (eg, channels) in which guest molecules (eg, solvent or water) are confined. or a salt thereof.
  • the term "purified" means that when isolated, the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and In other embodiments, at least 99.9% pure.
  • the invention further provides a method of treating a disease or condition in a subject having or susceptible to having one or more of the following diseases or conditions by administering to the subject a therapeutically effective amount of one or more such compounds.
  • the treatment is a preventative treatment.
  • the treatment is a palliative treatment.
  • the treatment is a restorative treatment.
  • Compounds for inhibiting AIMP2-DX2 of the present invention are useful for various therapeutic or prophylactic applications (eg, cancer). These compounds can be used to inhibit AIMP2-DX2, and can also be used for the treatment of AIMP2-DX2 related diseases or to prevent the worsening of these diseases.
  • the method of the present invention comprises administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound according to the present invention.
  • the present invention provides a method of treating an AIMP2-DX2 related disease comprising administering to a subject a therapeutically effective amount of a compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof.
  • Such methods include administering to a subject in need of treatment a compound of the present invention in an amount sufficient to inhibit AIMP2-DX2, ie, a therapeutically effective amount.
  • a compound of the present invention can be administered to the subject in the form of a pharmaceutical composition described herein.
  • the AIMP2-DX2 related disease is, but is not limited to, cancer.
  • the cancer is lung cancer, breast cancer, colon cancer, small cell lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma, uterine cancer, rectal cancer, proximal anal cancer, colon cancer, Breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, leukemia , lymphocytic lymphoma, bladder cancer, kidney cancer, ureteric cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, CNS lymphoma, spinal cord tumor, brainstem glioma, or pituitary
  • the present invention provides a pharmaceutical use for treating or preventing cancer, particularly lung cancer, of the compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof.
  • Suitable subjects to be treated according to the present invention include mammalian subjects.
  • Mammals according to the present invention include, but are not limited to, humans, canines, felines, bovines, caprines, equines, ovines, and pigs. (porcine), rodents (rodents), lagomorphs (lagomorphs), primates (primates) and the like, including mammals in utero ( in utero ).
  • a suitable subject to be treated according to the present invention is a human.
  • a compound of the present invention is generally administered in a therapeutically effective amount.
  • Effective amount refers to slowing down or minimizing the progression of an AIMP2-DX2 related disease, particularly cancer (preferably lung cancer), or treating or managing an AIMP2-DX2 related disease, particularly cancer (preferably lung cancer). refers to the amount of a compound of the present invention sufficient to provide a therapeutic benefit in "Effective amount” also refers to an amount sufficient to inhibit or reduce AIMP2-DX2 activity either in vitro or in vivo .
  • the compounds of the present invention can be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in a dosage effective for the intended treatment.
  • An effective dosage is generally from about 0.001 to about 100 mg/kg of body weight/day, preferably from about 0.01 to about 50 mg/kg/day, in single or divided administration. Dosage levels below the lower end of this range may be suitable depending on the age, species, and disease or condition being treated. In other cases, still larger doses can be used without detrimental side effects. Larger doses may be divided into several smaller doses for administration throughout the day.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.
  • the use of the pharmaceutical composition is for the treatment or prevention of AIMP2-DX2 related diseases, preferably cancer, more preferably lung cancer, which will be described later.
  • pharmaceutically acceptable means suitable for use as a pharmaceutical preparation, generally considered safe for such use, and officially approved for such use by a national regulatory agency or approved by the Korean Pharmacopoeia or the United States Means in the pharmacopeia list.
  • the compound described herein, or a pharmaceutically acceptable salt thereof can be administered as follows.
  • the compound of the present invention can be administered orally, and oral is a concept including swallowing.
  • Oral administration allows the compounds of the present invention to enter the gastrointestinal tract or be directly absorbed from the mouth into the bloodstream, eg, by buccal or sublingual administration.
  • compositions suitable for oral administration may be in solid, liquid, gel, or powder form, and may have formulations such as tablets, lozenges, capsules, granules, powders, and the like. .
  • compositions for oral administration may optionally be enteric coated and exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.
  • Liquid formulations may include solutions, syrups and suspensions, and such liquid compositions may be contained in soft or hard capsules.
  • Such formulations may include a pharmaceutically acceptable carrier such as water, ethanol, polyethylene glycol, cellulose, or oil.
  • the formulation may also contain one or more emulsifying and/or suspending agents.
  • the amount of active ingredient drug may be present from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the total weight of the tablet.
  • Tablets may also contain a disintegrant comprising from about 0.5% to about 35% by weight, more usually from about 2% to about 25% by weight of the dosage form.
  • disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.
  • Suitable glidants included for making into tablets may be present in amounts from about 0.1% to about 5% by weight, and include talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like. It can be used as a lubricant, but the present invention is not limited to these types of additives.
  • Gelatin polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. may be used as a binder for preparing tablets.
  • Mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. may be used as suitable diluents for preparing tablets, but the present invention is not limited to these types of additives. .
  • the solubilizing agent that may be included in the tablet may be used in an amount of about 0.1% to about 3% by weight based on the total weight of the tablet, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, Diethylene glycol monoethyl ether, dimethylisosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR TM (Nikkol), oleyl ester, Gelucire TM , caprylic/caprylic mono/ Diglyceride, sorbitan fatty acid ester, Solutol HS TM and the like can be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to the specific types of these solubilizing agents.
  • Compounds of the present invention may be administered directly into the bloodstream, muscle, or intestine.
  • Suitable methods for parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, and the like.
  • Suitable devices for parenteral administration include injectors (including needle and needleless syringes) and infusion methods.
  • compositions for parenteral administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
  • parenteral formulations are liquid compositions, and these liquid compositions are aqueous solutions containing the active ingredient, salt, buffer, tonicity agent and the like according to the present invention.
  • Parenteral formulations may also be prepared in dried form (eg lyophilized) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle such as sterile water. Solubility-enhancing agents may also be used in the preparation of parenteral solutions.
  • the compound of Formula 1 or 2 (preferably Formula 1) or a pharmaceutically acceptable salt thereof of the present invention inhibits the activity of AIMP2-DX2, which is an anticancer drug target, and effectively induces the death of cancer cells, thereby cancer, It is particularly effective in preventing and treating lung cancer.
  • lung cancer cell line H549 was transfected with pGL2-DX2 and cultured for 24 hours, followed by treatment with the test compound. After further incubation for 4 hours, luciferase activity was measured using a luminometer with a luciferase assay kit according to the manufacturer's protocol (Promega, USA).
  • the compound 1 was synthesized as follows.
  • 105 compounds having a structure similar to Compound 1 were evaluated.
  • H549 a lung cancer cell line, was transfected with pGL2-DX2 and incubated for 24 hours, and then treated with the 105 compounds. After further culturing for 24 hours, the luciferase activity was measured using a luminometer with a luciferase assay kit according to the manufacturer's protocol (Promega, USA).
  • the prepared compounds are collectively shown in Table 2 below.
  • the anticancer activity of the compounds in Table 2 was evaluated (the anticancer activity of Table 1 was also evaluated in the same manner).
  • A549 cells were seeded in a 100x15 mm cell culture dish and 24 hours later, cells were transfected with pGL2-AIMP2-DX2.
  • a 1.5 mL Eppendorf tube was prepared and 10 ⁇ g of each pGL2-AIMP2-DX2 was added thereto.
  • the mixture was mixed by vortexing for 5 seconds.
  • 20 ⁇ L of Turbofect was added to the tube, mixed by vortexing for 5 seconds, and left for 15 minutes. While the reaction tube was left standing, the medium was removed from the culture dish, and then 6 mL of new cell culture medium was added.
  • the reaction mixture was added to the cell culture dish, mixed gently, and incubated in a CO 2 incubator for 4 hours. After 4 hours, the medium was exchanged with fresh cell culture medium. After 24 hours, the cells were removed from the culture dish and suspended in 10 mL of RPMI growth medium. After adding 10 ⁇ L of trypan blue dye 0.4% to 10 ⁇ L of the cell suspension, the number of cells was measured using a Countess II FL Automated Cell Counter. Based on the measured cell number, 25,000 transfected cells were seeded in a white flat bottom 96-well plate.
  • the cell culture medium was removed, and 100 ⁇ L of serum-free RPMI medium supplemented with three-fold serially diluted compounds (0.003-10, 50 ⁇ M) was added to the cell plate, followed by culturing for 24 hours. After 24 hours, after removing the cell culture medium contained in the wells of the plate, 10 ⁇ L of Luciferase Cell Culture Lysis buffer was added to each well of the plate, and incubated for 30 minutes to lyse the cells. A predetermined amount of reconstituted Luciferase reagent was prepared by combining Luciferase substrate and Luciferase dilution buffer and mixing well by vortexing.
  • the compounds according to the present invention showed excellent effects, and among them, the effects of compounds 17, 23, 24 and 28 were very excellent.
  • Each 2x10 6 A549, H460, and WI-26 cells were seeded in a 100x15 mm cell culture dish and cultured in a CO2 incubator for 48 hours. After 48 hours, the cells were removed from the culture dish and suspended in 10 mL of RPMI or DMEM growth medium. After adding 10 ⁇ L of trypan blue dye 0.4% to 10 ⁇ L of the cell suspension, the number of cells was measured using a Countess II FL Automated Cell Counter. Based on the measured cell number, 25,000 cells were seeded in a 96-well plate.
  • the cell culture medium was removed, and 100 ⁇ L of serum-free RPMI or DMEM medium supplemented with three-fold serially diluted compounds (0.003-10, 50 ⁇ M) was added to the cell plate, followed by culturing for 96 hours.
  • MTT solution MTT powder was dissolved in PBS to a concentration of 5 mg/mL. Since the activity of the MTT solution may decrease when exposed to light, it was stored in the dark after preparing the solution. After 96 hours, 20 uL MTT solution was added to the plate wells, followed by incubation in a CO 2 incubator for 30 minutes.
  • the specific compounds of the present invention inhibited AIMP2-DX2 compared to Compound 1, and it was confirmed that the cancer inhibitory effect was excellent. In particular, it can be confirmed that it is effective in A549 and H460 cells, which are lung cancer cells.

Abstract

The present disclosure provides a benzodioxane scaffold compound having AIMP2-DX2 inhibitory activity or a pharmaceutically acceptable salt thereof. The present disclosure also provides a composition comprising such a compound or a pharmaceutically acceptable salt thereof. The present disclosure also provides medical uses of the compound, salt thereof, and composition comprising same for the treatment or prevention of cancer according to the present disclosure. The present disclosure also provides a method for treating or preventing cancer, the method comprising administering an effective amount of the compound, salt thereof, or composition containing same according to the present disclosure to a subject in need of treatment.

Description

벤조다이옥세인 유도체 화합물 및 이의 의약 용도Benzodioxane derivative compounds and their medicinal uses
본 출원은 2022년 1월 25일에 출원된 한국특허출원 제10-2022-0011057호에 기초한 우선권을 주장하며, 해당 출원의 명세서 및 도면에 개시된 모든 내용은 본 출원에 원용된다.This application claims priority based on Korean Patent Application No. 10-2022-0011057 filed on January 25, 2022, and all contents disclosed in the specification and drawings of the application are incorporated into this application.
본 개시는 벤조다이옥세인 스캐폴드를 포함하는 화합물 또는 이의 약학적으로 허용 가능한 염에 관한 것이다. 본 개시는 또한 이러한 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 약학 조성물에 관한 것이다. 본 개시는 또한 이러한 화합물을 이용하여, 암을 치료 또는 예방하는 유용한 방법에 관한 것이다. 즉, 본 개시는 본 개시에 따른 화합물들의 암을 치료 또는 예방하기 위한 의약 용도에 관한 것이다.The present disclosure relates to a compound comprising a benzodioxane scaffold or a pharmaceutically acceptable salt thereof. The present disclosure also relates to pharmaceutical compositions comprising such compounds or pharmaceutically acceptable salts thereof. The present disclosure also relates to useful methods of treating or preventing cancer using such compounds. That is, the present disclosure relates to the pharmaceutical use of the compounds according to the present disclosure for treating or preventing cancer.
암은 전 세계적 주요 사망 원인이며, 그중에서도 폐암은 유방암 다음으로 가장 흔하게 발병하는 암 중 하나이다. Cancer is a leading cause of death worldwide, and among them, lung cancer is one of the most common cancers after breast cancer.
폐암은 소세포 폐암(small cell lung cancer)과 비소세포 폐암(non-small cell lung cancer)으로 크게 나뉜다. 폐암의 2 종류 암은 자라는 형식과 퍼지는 정도가 달라 치료법과 예후가 다르기 때문에 두 종류를 구분하는 것이 중요하다. 폐암의 경우 무증상이 많아 대부분 조기 진단이 어려워 늦게 발견되는 경우가 많다. 폐암은 다른 암들에 비해 진행속도가 빠르고 다른 장기로 전이 된다고 알려져 있다. 폐암은 외과적 치료보다는 방사선 치료나 약물 치료가 주된 치료법이다. Lung cancer is largely divided into small cell lung cancer and non-small cell lung cancer. It is important to differentiate between the two types of lung cancer because they have different types of growth and different degrees of spread, so treatment and prognosis are different. Lung cancer is often asymptomatic, and early diagnosis is difficult in most cases, so it is often detected late. Lung cancer is known to progress faster than other cancers and metastasize to other organs. For lung cancer, radiation therapy or drug therapy is the main treatment rather than surgical treatment.
조기검진과 의약기술의 발달로 전반적인 생존율은 높아지고 있으나, 다양한 형태의 암과 지속적인 내성의 발생으로 인하여 새로운 폐암 항암제 수요는 지속되고 있다.Although the overall survival rate is increasing due to early screening and development of medical technology, demand for new lung cancer anticancer drugs continues due to the occurrence of various types of cancer and persistent resistance.
한편, AIMP2(ARS-interacting multi-functional protein 2)의 유전적 붕괴가 c-myc의 과발현을 유도하고 이로 인해 폐의 치조 상피세포(alveolar epithelial cell)가 과증식되면서 신생쥐의 치사(neonatal lethality)가 유도되며, AIMP2가 TGF-β에 의해 유도되고 핵으로 이동하여 c-myc의 발현을 억제한다는 것이 분자 및 세포학적 분석으로 밝혀진 바 있다(Nat Genet. 2003 Jul;34(3):330-6. doi: 10.1038/ng1182.)On the other hand, genetic disruption of AIMP2 (ARS-interacting multi-functional protein 2) induces overexpression of c-myc, which leads to overproliferation of alveolar epithelial cells in the lungs, leading to neonatal lethality in mice. Molecular and cytological analyzes have shown that AIMP2 is induced by TGF-β, translocates to the nucleus, and inhibits the expression of c-myc (Nat Genet. 2003 Jul;34(3):330-6. doi: 10.1038/ng1182.)
국제특허공개 WO2006-057500 A1는 AIMP2가 신규한 암 억제자(tumor suppressor)이며, Smad2/3와 직접적 상호작용을 통하여 TGF-β의 신호전달을 강화시키는 기능을 한다고 개시하고 있다. 또, 국제특허공개 WO2006-057500 A1는 암 세포주 및 조직에서 AIMP2의 엑손 2가 결손된 형태의 변이체인 AIMP2-DX2가 특이적으로 발현된다고 기술하고 있다. 또한, AIMP2-DX2로 형질전환된 세포에서는 TGF-β와 상관없이 AIMP2 수준이 극적으로 감소되는 것으로서 AIMP2-DX2 생성이 AIMP2 활성의 상실을 초래한다는 것이 확인되었다. AIMP2-DX2가 AIMP2 수준의 감소를 유발하고, 이로 인한 암 형성과 진행에 밀접하게 연관되어 있으므로 AIMP2-DX2의 생성을 통해 폐암, 간암, 피부암, 유방암, 신장암, 골육종 등의 다양한 암을 진단할 수 있음이 밝혀진 바 있다. International Patent Publication WO2006-057500 A1 discloses that AIMP2 is a novel tumor suppressor and functions to enhance TGF-β signaling through direct interaction with Smad2/3. In addition, International Patent Publication WO2006-057500 A1 describes that AIMP2-DX2, which is a mutant in which exon 2 of AIMP2 is missing, is specifically expressed in cancer cell lines and tissues. In addition, AIMP2 levels were dramatically reduced in cells transformed with AIMP2-DX2, regardless of TGF-β, and it was confirmed that AIMP2-DX2 production resulted in loss of AIMP2 activity. Since AIMP2-DX2 induces a decrease in AIMP2 level and is closely related to cancer formation and progression, it is possible to diagnose various cancers such as lung cancer, liver cancer, skin cancer, breast cancer, kidney cancer, and osteosarcoma through the generation of AIMP2-DX2. It has been revealed that it can.
또한 DNA가 damage가 되었을 때 AIMP2는 p53을 activation 시켜 apoptosis를 촉진한다(Proc. Natl Acad Sci August 12, 2008 105 (32) 11206-11211; https://doi.org/10.1073/pnas.0800297105.) AIMP2-DX2는 이와 같은 AIMP2와 경쟁적으로 작용하여 AIMP2와 p53의 결합을 방해하여 AIMP2의 pro-apoptosis 기능을 저해하여 암을 유발하는 것으로 규명되었다(PLoS Genet 2011 Mar;7(3):e1001351. doi: 10.1371/journal.pgen.1001351.). Also, when DNA is damaged, AIMP2 activates p53 to promote apoptosis (Proc. Natl Acad Sci August 12, 2008 105 (32) 11206-11211; https://doi.org/10.1073/pnas.0800297105 .) AIMP2-DX2 has been found to cause cancer by inhibiting the pro-apoptosis function of AIMP2 by interfering with AIMP2 and p53 binding by competing with AIMP2 (PLoS Genet 2011 Mar;7(3):e1001351. doi : 10.1371/journal.pgen.1001351.).
따라서 본 개시가 해결하고자 하는 과제는 AIMP2-DX2의 활성을 저해하여, 암세포의 사멸을 효과적으로 유도하며, 이를 통해 암, 특히 폐암의 예방 및 치료에 효과를 나타내는 화합물을 제공하는 것이다. Therefore, the problem to be solved by the present disclosure is to inhibit the activity of AIMP2-DX2, effectively induce the death of cancer cells, and thereby provide a compound that is effective in preventing and treating cancer, particularly lung cancer.
본 개시의 다른 목적은 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암, 특히 폐암의 치료 또는 예방용 약학 조성물을 제공하는 것이다.Another object of the present disclosure is to provide a pharmaceutical composition for treating or preventing cancer, particularly lung cancer, containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 개시의 또 다른 목적은 본 발명에 따른 화합물을 암의 치료 또는 예방이 필요한 환자에게 투여하는 것을 특징으로 하는 암, 특히 폐암의 치료 또는 예방 방법을 제공하는 것이다.Another object of the present disclosure is to provide a method for treating or preventing cancer, particularly lung cancer, comprising administering a compound according to the present invention to a patient in need of such treatment or prevention.
본 발명 화합물Compound of the present invention
상기 해결하고자 하는 과제를 달성하기 위하여, 일 태양에서, 본 발명은 하기 화학식 1 또는 화학식 2 (바람직하게는 화학식 1)의 벤조다이옥세인 유도체 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.In order to achieve the above object to be solved, in one aspect, the present invention provides a benzodioxane derivative compound of Formula 1 or Formula 2 (preferably Formula 1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2023001073-appb-img-000001
Figure PCTKR2023001073-appb-img-000001
상기 화학식 1에서, In Formula 1,
R10, R11, R12 및 R13은 서로 독립적으로 수소, C1-C4 알킬, C3-C6 사이클로알킬, C1-C4 알콕시, 또는 하이드록시이고, R 10 , R 11 , R 12 and R 13 independently of each other are hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, or hydroxy;
R14는 페닐,
Figure PCTKR2023001073-appb-img-000002
또는
Figure PCTKR2023001073-appb-img-000003
이고, 여기에서 R14는 선택적으로 C1-C3 알킬, C1-C3 알콕시, C1-C3 할로알콕시, 할로겐, 페닐, C1-C3 알킬로 치환된 페닐, 및 하이드록시로 이루어진 군으로부터 하나 이상의 치환기로 치환되며, R 14 is phenyl;
Figure PCTKR2023001073-appb-img-000002
or
Figure PCTKR2023001073-appb-img-000003
wherein R 14 is optionally substituted with one or more substituents from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, phenyl, phenyl substituted with C1-C3 alkyl, and hydroxy becomes,
X는 S, O 또는 NH임. X is S, O or NH.
[화학식 2][Formula 2]
Figure PCTKR2023001073-appb-img-000004
Figure PCTKR2023001073-appb-img-000004
상기 화학식 2에 있어서, In Formula 2,
R6은 수소, C1-C4 알킬, C3-C6 사이클로알킬, C1-C4 알콕시, 또는 하이드록시이고 (바람직하게는 수소), R 6 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, or hydroxy (preferably hydrogen);
X는 -CH2- 또는 -C(O)-이고, X is -CH 2 - or -C(O)-;
Y는 직접 연결, -CH2-, 또는 -C(O)-이고,Y is a direct connection, -CH 2 -, or -C(O)-;
Z은 직접 연결, -NH-, 또는 -CH2-이고,Z is a direct link, -NH-, or -CH 2 -;
(바람직하게는, X-Y-Z은 -CH2-, -CH2C(O)NH-, 또는 -C(O)CH2CH2-임),(preferably, XYZ is -CH 2 -, -CH 2 C(O)NH-, or -C(O)CH 2 CH 2 -);
R15는 서로 독립적으로 C1-C3 알킬, C1-C3 알콕시, C1-C3 할로알콕시, 할로겐, 또는 하이드록시이며, R 15 are independently of each other C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, or hydroxy;
n은 1 내지 3의 정수임.n is an integer from 1 to 3;
본 발명자들은 AIMP2-DX2를 타깃하는 화합물을 연구하던 중, benzodioxane 스캐폴드를 포함하는 화합물이 이러한 타깃의 억제에 매우 우수하며, 결과적으로 암, 특히 폐암에 대한 우수한 항암 활성을 나타내는 것을 확인하고 본 발명을 완성하였다. 즉, 본 발명의 화합물들은 AIMP2-DX2를 억제함으로써 암세포의 성장을 억제하고, 세포 독성 없이 암 특이적으로 암을 제어할 수 있다.While studying compounds targeting AIMP2-DX2, the present inventors confirmed that compounds containing benzodioxane scaffolds are very good at inhibiting these targets, and as a result, exhibit excellent anticancer activity against cancer, especially lung cancer, and the present invention has been completed. That is, the compounds of the present invention inhibit the growth of cancer cells by inhibiting AIMP2-DX2, and can control cancer specifically without cytotoxicity.
본 명세서에서 용어 "치환기(substituent)", "라디칼(radical)", "기(group)", "모이어티(moiety)", 및 "절편(fragment)"은 서로 바꾸어 사용할 수 있다.In this specification, the terms “substituent”, “radical”, “group”, “moiety”, and “fragment” are used interchangeably.
만약 치환기가 "임의로 치환된" 또는 “선택적으로 치환된”으로 설명된다면, 상기 치환기는 (1) 치환되지 않거나 (2) 또는 정의된 치환기들 중 하나 이상으로 치환될 수 있다. 만약 치환 가능한 위치가 치환되지 않은 경우 기본(default) 치환기는 하이드리도 라디칼이다.If a substituent is described as "optionally substituted" or "optionally substituted", the substituent may be (1) unsubstituted or (2) substituted with one or more of the defined substituents. If the substitutable position is unsubstituted, the default substituent is a hydrido radical.
본 명세서에서 사용된 용어 "알킬"은 (탄소수가 특별히 한정되지 않은 경우) 탄소수 1 내지 10을 가진 포화된 직쇄상 또는 분지상의 비-고리(cyclic) 탄화수소를 의미한다. "저급 알킬"은 탄소수가 1 내지 4인 직쇄상 또는 분지상 알킬을 의미한다. 대표적인 포화 직쇄상 알킬은 -메틸, -에틸, -n-프로필, -n-부틸, -n-펜틸, -n-헥실, -n-헵틸, -n-옥틸, -n-노닐 과 -n-데실을 포함하고, 반면에 포화 분지상 알킬은 -이소프로필, -sec-부틸, -이소부틸, -tert-부틸, 이소펜틸, 2-메틸헥실, 3-메틸부틸, 2-메틸펜틸, 3-메틸펜틸, 4-메틸펜틸, 2-메틸헥실, 3-메틸헥실, 2-메틸펜틸, 3-메틸펜틸, 4-메틸펜틸, 2-메틸헥실, 3-메틸헥실, 4-메틸헥실, 5- 메틸헥실, 2,3-디메틸부틸, 2,3-디메틸펜틸, 2,4-디메틸펜틸, 2,3-디메틸헥실, 2,4-디메틸헥실, 2,5-디메틸헥실, 2,2-디메틸펜틸, 2,2-디메틸헥실, 3,3-디메틸펜틸, 3,3-디메틸헥실, 4,4-디메틸헥실, 2-에틸펜틸, 3-에틸펜틸, 2-데틸헥실, 3-에틸헥실, 4-에틸헥실, 2-메틸-2-에틸펜틸, 2-메틸-3-에틸펜틸, 2-메틸-4-에틸펜틸, 2-메틸-2-에틸헥실, 2-메틸-3-에틸헥실, 2-메틸-4-에틸헥실, 2,2-디에틸펜틸, 3,3-디에틸헥실, 2,2-디에틸헥실, 및 3,3-디에틸헥실을 포함한다. As used herein, the term "alkyl" refers to a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms (unless the number of carbon atoms is specifically limited). "Lower alkyl" means a straight chain or branched alkyl having 1 to 4 carbon atoms. Representative saturated straight-chain alkyls are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n- decyl, while saturated branched alkyl is -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- Methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethyl Pentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-decylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl.
본 명세서에서 사용된 용어 "알콕시"는 -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, 및 이와 유사한 것을 포함하는 -O-(알킬)을 의미하며, 여기에서 알킬은 위에서 정의된 것과 같다. As used herein, the term "alkoxy" means -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -O(CH 2 ) 3 CH 3 , -O(CH 2 ) 4 CH 3 , -O-(alkyl), including -O(CH 2 ) 5 CH 3 , and the like, wherein alkyl is as defined above.
본 명세서에서 “C1-6”, "C1-6", 또는 "C1-C6"와 같이 기재될 경우 이는 탄소수가 1 내지 6개임을 의미한다. 예를 들어, C1-6알킬은 탄소수가 1 내지 6인 알킬을 의미한다.In the present specification, when described as “C 1-6 ”, “C1-6”, or “C1-C6”, it means that the number of carbon atoms is 1 to 6. For example, C 1-6 alkyl means an alkyl having 1 to 6 carbon atoms.
본 명세서에서 사용된 용어 "할로겐" 및 "할로"는 플루오린, 클로린, 브로민 또는 아이오딘을 의미한다. 본 발명의 바람직한 일 태양에 있어, 할로겐은 클로린 또는 플루오린이다.As used herein, the terms "halogen" and "halo" mean fluorine, chlorine, bromine or iodine. In a preferred aspect of the present invention, halogen is chlorine or fluorine.
본 명세서에서 사용된 용어 "할로알킬", 또는 “할로알콕시”은 알킬 또는 알콕시의 각각 하나 이상의 수소 원자가 할로겐 원자로 치환된 알킬, 또는 알콕시 그룹을 의미한다. 예를 들어, 할로알킬은 -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CC13, -CHC12, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CC13, -CH2-CHC12, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, 및 이와 유사한 것을 포함한다. 본 발명의 바람직한 일 태양에서, 할로알킬은 CF3이다. 여기에서 알킬 및 할로겐은 위에서 정의된 것과 같다.As used herein, the term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group in which one or more hydrogen atoms of each of the alkyl or alkoxy groups are replaced by halogen atoms. For example, haloalkyl is -CF 3 , -CHF 2 , -CH 2 F, -CBr 3 , -CHBr 2 , -CH 2 Br, -CC1 3 , -CHC1 2 , -CH 2 CI, -CI 3 , -CHI 2 , -CH 2 I, -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CH 2 -CBr 3 , -CH 2 -CHBr 2 , -CH 2 -CH 2 Br, -CH 2 -CC1 3 , -CH 2 -CHC1 2 , -CH 2 -CH 2 CI, -CH 2 -CI 3 , -CH 2 -CHI 2 , -CH 2 -CH 2 I, and the like include that In one preferred aspect of the present invention, haloalkyl is CF 3 . wherein alkyl and halogen are as defined above.
본 명세서에서 사용된 용어 "사이클로알킬(cycloalkyl)"은 탄소 및 수소 원자를 가지며 탄소-탄소 다중 결합을 가지지 않는 모노사이클릭 또는 폴리사이클릭 포화 고리(ring)를 의미한다. 모노사이클릭 고리의 예는 (C3-C7)사이클로알킬 (예를 들어, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실 및 사이클로헵틸)을 포함하나 이에 한정되는 것은 아니다. 폴리사이클릭 고리의 예는 octahydropentalene, decahydronaphthalene 등과 같은 융합된(fused) 바이사이클릭(bicyclic) 고리; spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane 등과 같은 스피로 고리; 및 bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane 등과 같은 가교된(bridged) 바이사이클릭 고리를 포함하나 이에 한정되는 것은 아니다. 사이클로알킬 그룹은 선택적으로 치환될 수 있다. 일 실시예에서, 사이클로알킬 그룹은 모노사이클릭 링(고리)이다. As used herein, the term "cycloalkyl" means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and not having carbon-carbon multiple bonds. Examples of monocyclic rings include, but are not limited to, (C 3 -C 7 )cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl). Examples of polycyclic rings include fused bicyclic rings such as octahydropentalene, decahydronaphthalene, and the like; spiro rings such as spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane and the like; and bridged bicyclic rings such as bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. Cycloalkyl groups may be optionally substituted. In one embodiment, a cycloalkyl group is a monocyclic ring (ring).
본 명세서에 있어, * 또는
Figure PCTKR2023001073-appb-img-000005
은 다른 moiety와 연결되어 있는 것을 의미한다.In this specification, * or
Figure PCTKR2023001073-appb-img-000005
means that it is connected to another moiety.
바람직하게, 본 개시에 따른 화합물은 Preferably, the compound according to the present disclosure
(4-(5-bromo-2-ethoxybenzyl)piperazin-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone (화합물 7), (4-(5-bromo-2-ethoxybenzyl)piperazin-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone (Compound 7),
N-(2-chlorophenyl)-2-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)acetamide (화합물 8),N-(2-chlorophenyl)-2-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)acetamide (Compound 8),
(4-(3-chlorobenzyl)piperazin-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone (화합물 9),(4-(3-chlorobenzyl)piperazin-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone (Compound 9),
3-(3-chloro-4-methylphenyl)-1-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)propan-1-one (화합물 10),3-(3-chloro-4-methylphenyl)-1-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)propan-1-one (compound 10),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-methylbenzofuran-3-yl)acetamide (화합물 12),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-methylbenzofuran-3-yl)acetamide (Compound 12),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-ethylbenzofuran-3-yl)acetamide (화합물 13),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-ethylbenzofuran-3-yl)acetamide (Compound 13),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(naphthalen-2-yl)acetamide (화합물 14),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(naphthalen-2-yl)acetamide (Compound 14),
N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-methoxybenzofuran-3-yl)acetamide (화합물 15),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-methoxybenzofuran-3-yl)acetamide (Compound 15),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6,7-dimethylbenzofuran-3-yl)acetamide (화합물 16),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6,7-dimethylbenzofuran-3-yl)acetamide (Compound 16),
N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(5,6-dimethylbenzofuran-3-yl)acetamide (화합물 17),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(5,6-dimethylbenzofuran-3-yl)acetamide (Compound 17),
N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(1H-indol-3-yl)acetamide (화합물 18),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(1H-indol-3-yl)acetamide (Compound 18),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(1H-indol-5-yl)acetamide (화합물 19),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(1H-indol-5-yl)acetamide (Compound 19),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(quinolin-6-yl)acetamide (화합물 20),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(quinolin-6-yl)acetamide (Compound 20),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(quinolin-8-yl)acetamide (화합물 21),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(quinolin-8-yl)acetamide (Compound 21),
N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(2-(m-tolyl)thiazol-4-yl)acetamide (화합물 22),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(2-(m-tolyl)thiazol-4-yl)acetamide (Compound 22),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-ethylphenyl)acetamide (화합물 23),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-ethylphenyl)acetamide (Compound 23),
N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-hydroxy-2-methylphenyl)acetamide (화합물 24),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-hydroxy-2-methylphenyl)acetamide (Compound 24),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-fluorophenyl)acetamide (화합물 25),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-fluorophenyl)acetamide (Compound 25),
N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-(trifluoromethoxy)phenyl)acetamide (화합물 26),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-(trifluoromethoxy)phenyl)acetamide (Compound 26),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(3,4-dimethylphenyl)acetamide (화합물 27), 또는 N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(3,4-dimethylphenyl)acetamide (Compound 27), or
2-([1,1'-Biphenyl]-4-yl)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide (화합물 28)인 화합물 또는 이의 약학적으로 허용 가능한 염이다. 본 발명에 따른 화학식 1 또는 2의 화합물들 중 상기 화합물들은 항암 효과 측면에서 구조가 유사한 다른 화합물들 대비 뛰어난 효과를 나타내었다.A compound that is 2-([1,1'-Biphenyl]-4-yl)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide (Compound 28); or It is a pharmaceutically acceptable salt thereof. Among the compounds represented by Chemical Formula 1 or 2 according to the present invention, the compounds exhibited superior anticancer effects compared to other compounds having similar structures.
더욱 바람직하게, 본 개시에 따른 화합물은 More preferably, the compound according to the present disclosure
3-(3-chloro-4-methylphenyl)-1-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)propan-1-one (화합물 10), 3-(3-chloro-4-methylphenyl)-1-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)propan-1-one (compound 10),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-methylbenzofuran-3-yl)acetamide (화합물 12),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-methylbenzofuran-3-yl)acetamide (Compound 12),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-ethylbenzofuran-3-yl)acetamide (화합물 13),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-ethylbenzofuran-3-yl)acetamide (Compound 13),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(naphthalen-2-yl)acetamide (화합물 14),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(naphthalen-2-yl)acetamide (Compound 14),
N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(5,6-dimethylbenzofuran-3-yl)acetamide (화합물 17),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(5,6-dimethylbenzofuran-3-yl)acetamide (Compound 17),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(1H-indol-5-yl)acetamide (화합물 19),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(1H-indol-5-yl)acetamide (Compound 19),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(quinolin-6-yl)acetamide (화합물 20),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(quinolin-6-yl)acetamide (Compound 20),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-ethylphenyl)acetamide (화합물 23),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-ethylphenyl)acetamide (Compound 23),
N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-hydroxy-2-methylphenyl)acetamide (화합물 24),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-hydroxy-2-methylphenyl)acetamide (Compound 24),
N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-fluorophenyl)acetamide (화합물 25), 또는N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-fluorophenyl)acetamide (Compound 25), or
2-([1,1'-Biphenyl]-4-yl)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide (화합물 28)인 화합물 또는 이의 약학적으로 허용 가능한 염이다. 본 발명에 따른 화학식 1 또는 2의 화합물들 중 상기 화합물들은 항암 효과 측면에서 구조가 유사한 다른 화합물들 대비 훨씬 더 월등히 뛰어난 효과를 나타내었다.A compound that is 2-([1,1'-Biphenyl]-4-yl)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide (Compound 28); or It is a pharmaceutically acceptable salt thereof. Among the compounds represented by Chemical Formula 1 or 2 according to the present invention, the compounds exhibited far superior anti-cancer effects compared to other compounds having similar structures.
본 발명에 있어 "약학적으로 허용 가능한 염"은 여기서 언급한 화합물들에서 발견되는 특정 치환체에 의존하는 비교적 비독성 산 및 염기로 제조된 활성 화합물의 염들을 포함한다. 본 발명의 화합물들은 상대적으로 산성 기능성을 포함할 때, 염기(base) 부가 염들은 충분한 양의 원하는 염기, 순수한 또는 적당한 비활성(inert) 용매로 그러한 화합물들의 중성 형태를 접촉하여 얻을 수 있다. 약학적으로 허용 가능한 염기 부가 염의 예들은 나트륨, 칼륨, 칼슘, 암모늄, 유기 아미노 또는 마그네슘 염 또는 유사한 염을 포함한다. 본 발명의 화합물들은 상대적으로 염기성 기능성을 포함할 때, 산성 부가 염들은 충분한 양의 원하는 산, 순수한 또는 적당한 비활성(inert) 용매로 그러한 화합물들의 중성 형태를 접촉하여 얻을 수 있다. 약학적으로 허용 가능한 산성 부가 염의 예들은 초산, 프로피온산, 이소부틸산, 옥살릭산(oxalic), 마레익(maleic), 말로닉(malonic), 안식향성, 숙신산, 수버릭(suberic), 푸마릭(fumaric), 만데릭(mandelic), 프탈릭(phthalic), 벤젠설포닉(benzenesulfonic), p-토릴설포닉(tolylsulfonic), 구연산, 주석산, 메탄솔포닉(methanesulfonic), 및 그 유사체를 포함하는 상대적으로 비독성 유기산에서 유래한 염들 뿐만 아니라, 염화수소, 브롬화 수소, 질산, 탄산, 일수소탄산(monohydrogencarbonic), 인산(phosphoric), 일수소인산, 이수소인산, 황산, 일수소황산, 요오드화수소 또는 아인산(phosphorous acid) 및 그 유사체를 포함한다. 또한 알긴네이트(arginate)와 그 유사체와 같은 아미노산의 염 및 글루쿠로닉(glucuronic) 또는 갈락투노릭(galactunoric) 산들과 그 유사체와 같은 유기산의 유사체를 포함한다. 염들의 다른 예들은 본 발명이 속한 분야에서 공지된 문헌들을 통해 잘 알려져 있다. In the present invention, "pharmaceutically acceptable salts" include salts of active compounds prepared with relatively non-toxic acids and bases depending on the specific substituents found in the compounds mentioned herein. When compounds of the present invention contain relatively acidic functionality, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functionality, acidic addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts are acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid ( fumaric), mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric acid, tartaric acid, methanesulfonic, and their analogues. Hydrogen chloride, hydrogen bromide, nitric acid, carbonic acid, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide or phosphorous acid ( phosphorous acid) and its analogues. Also included are salts of amino acids such as alginate and analogs thereof and analogs of organic acids such as glucuronic or galactunoric acids and analogs thereof. Other examples of salts are well known from the literature known in the art to which this invention pertains.
본 명세서에서 사용된 용어인 "본 발명의 화합물"은 화학식 1 또는 2 각각의 화합물들뿐만 아니라, 이들의 클라드레이트(clathrates), 수화물, 용매화물, 또는 다형체를 포함하는 의미이다. 또한 용어 “본 발명의 화합물”은 이의 약학적으로 허용 가능한 염이 언급되지 않을 경우 본 발명 화합물의 약학적으로 허용 가능한 염도 포함하는 의미이다. 일 실시예에 본 발명의 화합물은 입체이성질체적으로 순수한 화합물들(예를 들어, 다른 입체이성질체가 실질적으로 없는(예를 들어, 85% ee 이상, 90% ee 이상, 95% ee 이상, 97% ee 이상, 또는 99% ee 이상))로 존재할 수 있다. 즉, 본 발명에 따른 화학식 1 또는 2의 화합물 또는 그의 염이 호변이성적(tautomeric) 이성질체 및/또는 입체이성질체(예를 들어, 기하이성질체(geometrical isomer) 및 배좌 이성질체(conformational isomers))일 경우 그들의 분리된 이성질체 및 혼합물 각각 또한 본 발명의 화합물의 범주에 포함된다. 본 발명의 화합물 또는 그의 염이 구조 내에 비대칭 탄소(asymmetric carbon)를 가지고 있는 경우에, 그들의 광학 활성 화합물 및 라세믹 혼합물들 또한 본 발명의 화합물의 범위에 포함된다. As used herein, the term "compound of the present invention" is meant to include not only the compounds of formula 1 or 2, but also clathrates, hydrates, solvates, or polymorphs thereof. In addition, the term "compound of the present invention" is meant to include pharmaceutically acceptable salts of the compounds of the present invention when pharmaceutically acceptable salts thereof are not mentioned. In one embodiment, the compounds of the present invention are stereomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, 97% ee or more, or 99% ee or more))). That is, when the compound of Formula 1 or 2 or a salt thereof according to the present invention is a tautomeric isomer and/or a stereoisomer (eg, geometrical isomer and conformational isomer), their separation Each of the isomers and mixtures thereof are also included within the scope of the compounds of the present invention. In case the compounds of the present invention or their salts have an asymmetric carbon in their structure, their optically active compounds and racemic mixtures are also included in the scope of the compounds of the present invention.
본 명세서에서 사용될 경우, 용어 "결정다형(polymorph)"은 본 발명의 화합물의 고체 결정 형태 또는 그것의 복합체를 의미한다. 같은 화합물의 다른 결정다형은 다른 물리적, 화학적 그리고/또는 스펙트럼적 특성을 보인다. 물리적 특성 측면의 차이점으로는 안정성(예를 들어, 열 또는 빛 안정성), 압축성과 밀도(제제화 및 생산물 제조에 중요함), 그리고 용해율(생물학적 이용률에 영향을 줄 수 있음)을 포함하나, 이에 한정되지 아니한다. 안정성에서 차이는 화학반응성 변화들(예를 들어, 또 다른 다형으로 구성되었을 때보다 하나의 다형으로 구성되었을 때 더 빠르게 변색이 되는 것 같은 차별적 산화) 또는 기계적인 특징들(예를 들어 동역학적으로 선호된 다형체로서 저장된 정제 파편들이 열역학 적으로 더 안정된 다형으로 변환) 또는 둘 다(하나의 다형의 정제는 높은 습도에서 더 분해에 예민)를 야기한다. 결정다형의 다른 물리적 성질들은 그들의 가공에 영향을 줄 수 있다. 예를 들어, 한 결정다형은 또 다른 결정다형에 비하여, 예를 들어, 그것의 형태 또는 입자의 크기 분포에 기인하여 용매화합물을 형성할 가능성이 많을 수 있거나, 여과 또는 세척이 더 어려울 수 있다.As used herein, the term "polymorph" refers to a solid crystal form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in terms of physical properties include, but are not limited to, stability (e.g. heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't. Differences in stability may be due to chemical reactivity changes (e.g. differential oxidation such as faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g. kinetically Tablet fragments stored as the preferred polymorph may be thermodynamically converted to a more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity). Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates, or may be more difficult to filter or wash, than another polymorph, eg, due to its shape or particle size distribution.
본 명세서에서 사용된 용어 "용매 화합물"은 비공유 분자간의 힘에 의해 결합된 화학량론적 또는 비-화학량론적인 양의 용매를 포함하는 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 의미한다. 바람직한 용매들은 휘발성이고, 비독성이며, 인간에게 극소량 투여될 수 있다.As used herein, the term “solvent compound” refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and can be administered in very small amounts to humans.
본 명세서에서 사용된 용어 "수화물(hydrate)"은 비공유 분자간의 힘에 의해 결합된 화학량론적 또는 비-화학량론적인 양의 물을 포함하는 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 의미한다. As used herein, the term "hydrate" refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. .
본 명세서에서 사용된 용어 "클라드레이트(clathrate)"은 게스트 분자(예를 들어, 용매 또는 물)를 가두어 놓은 공간(예를 들어, 채널(channel))을 포함한 결정 격자의 형태의 본 발명의 화합물 또는 그것의 염을 의미한다. As used herein, the term "clathrate" refers to a compound of the present invention in the form of a crystal lattice containing spaces (eg, channels) in which guest molecules (eg, solvent or water) are confined. or a salt thereof.
본 명세서에서 사용된 용어 "정제된(purified)"은 분리될 때, 분리체는 90% 이상 순수한 것을 의미하며, 일 실시예에서는 95% 이상 순수하고, 다른 실시 예에서는 99% 이상 순수하고, 또 다른 실시예에서는 99.9% 이상 순수한 것을 의미한다.As used herein, the term "purified" means that when isolated, the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and In other embodiments, at least 99.9% pure.
본 발명 화합물의 의약 용도 및 치료 방법Medical Uses and Treatment Methods of the Compounds of the Invention
본 발명은 하나 이상의 상기와 같은 화합물의 치료적으로 유효한 양을 개체에게 투여함으로써 하기 질병 또는 상태(condition)를 갖거나 갖기 쉬운 개체에서 하기 질병 또는 상태(condition)를 치료하는 방법을 더 제공한다. 일 태양에서, 상기 치료는 예방 치료(preventative treatment)이다. 또 다른 태양에서, 상기 치료는 완화 치료(palliative treatment)이다. 또 다른 태양에서, 상기 치료는 회복 치료(restorative treatment)이다.The invention further provides a method of treating a disease or condition in a subject having or susceptible to having one or more of the following diseases or conditions by administering to the subject a therapeutically effective amount of one or more such compounds. In one aspect, the treatment is a preventative treatment. In another aspect, the treatment is a palliative treatment. In another aspect, the treatment is a restorative treatment.
1. 질병 또는 상태(Condition)1. Disease or Condition
본 발명의 AIMP2-DX2 억제용 화합물들은 다양한 치료학적 또는 예방학적 용도(예를 들어, 암)에 유용하다. 이러한 화합물들은 AIMP2-DX2을 억제하기 위해 사용될 수 있으며, 또 AIMP2-DX2 관련 질환의 치료를 위해서 또는 이러한 질병의 악화를 방지하기 위하여 사용될 수 있다. 본 발명의 방법은 치료 또는 예방이 필요한 개체에게 치료적으로 또는 예방학적으로 유효한 양의 본 발명에 따른 화합물을 포함하는 약학 조성물을 투여하는 것을 포함한다. Compounds for inhibiting AIMP2-DX2 of the present invention are useful for various therapeutic or prophylactic applications (eg, cancer). These compounds can be used to inhibit AIMP2-DX2, and can also be used for the treatment of AIMP2-DX2 related diseases or to prevent the worsening of these diseases. The method of the present invention comprises administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound according to the present invention.
다른 태양에서, 본 발명은 화학식 1 또는 2의 화합물 또는 이의 약학적으로 허용 가능한 염의 치료적으로 유효한 양을 개체에게 투여하는 단계를 포함하는 AIMP2-DX2 관련 질환을 치료하는 방법을 제공한다. 이러한 방법은 AIMP2-DX2을 억제하기 위해 충분한 양, 즉, 치료학적으로 유효한 양의 본 발명 화합물을 치료가 필요한 개체에게 투여하는 단계를 포함한다. 이러한 방법에 있어, 본 발명의 화합물은 본 명세서에서 설명되는 약학 조성물의 형태로 상기 개체에 투여될 수 있다. In another aspect, the present invention provides a method of treating an AIMP2-DX2 related disease comprising administering to a subject a therapeutically effective amount of a compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof. Such methods include administering to a subject in need of treatment a compound of the present invention in an amount sufficient to inhibit AIMP2-DX2, ie, a therapeutically effective amount. In this method, a compound of the present invention can be administered to the subject in the form of a pharmaceutical composition described herein.
본 발명에 있어, AIMP2-DX2 관련 질환은, 이에 한정되는 것은 아니지만, 암이다. 본 발명의 바람직한 일 태양에서, 상기 암은 폐암, 유방암, 대장암, 소세포폐암, 위암, 간암, 혈액암, 골암, 췌장암, 피부암, 두경부암, 흑색종, 자궁암, 직장암, 항문부근암, 결장암, 유방암, 나팔관암종, 자궁내막암종, 자궁경부암, 질암, 음문암종, 호지킨병, 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 백혈병, 림프구림프종, 방광암, 신장암, 수뇨관암, 신장세포 암종, 신장골반 암종, CNS 종양, CNS 림프종, 척수 종양, 뇌간신경교종 또는 뇌하수체 선종이다. 본 발명의 더욱 바람직한 일 태양에서, 상기 암은 폐암이다. In the present invention, the AIMP2-DX2 related disease is, but is not limited to, cancer. In a preferred embodiment of the present invention, the cancer is lung cancer, breast cancer, colon cancer, small cell lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma, uterine cancer, rectal cancer, proximal anal cancer, colon cancer, Breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, leukemia , lymphocytic lymphoma, bladder cancer, kidney cancer, ureteric cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, CNS lymphoma, spinal cord tumor, brainstem glioma, or pituitary adenoma. In a more preferred aspect of the present invention, the cancer is lung cancer.
즉, 본 발명은 화학식 1 또는 2의 화합물 또는 이의 약학적으로 허용 가능한 염의 암, 특히, 폐암을 치료 또는 예방하기 위한 의약 용도를 제공한다. That is, the present invention provides a pharmaceutical use for treating or preventing cancer, particularly lung cancer, of the compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof.
2. 개체 (Subjects)2. Subjects
본 발명에 따라 치료될 적합한 개체는 포유동물 개체를 포함한다. 본 발명에 따른 포유동물은, 이에 한정되는 것은 아니지만, 인간, 개(canine), 고양잇과동물(feline), 소(bovine), 염소(caprine), 말(equine), 양(ovine), 돼지(porcine), 설치류(rodents), 토끼목(lagomorphs), 영장류(primates) 등을 포함하고, 자궁 내의(in utero) 포유동물을 포함한다. Suitable subjects to be treated according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, humans, canines, felines, bovines, caprines, equines, ovines, and pigs. (porcine), rodents (rodents), lagomorphs (lagomorphs), primates (primates) and the like, including mammals in utero ( in utero ).
일 태양에서, 본 발명에 따른 치료될 적합한 개체는 인간이다.In one aspect, a suitable subject to be treated according to the present invention is a human.
3. 투여 및 투여량 (Administration and Dosing)3. Administration and Dosing
본 발명의 화합물은 일반적으로 치료적으로 유효한 양이 투여된다. A compound of the present invention is generally administered in a therapeutically effective amount.
본 명세서에서 사용된 "유효량"은 AIMP2-DX2 관련 질환, 특히 암 (바람직하게는 폐암)의 진행을 늦추거나 또는 최소화하거나, AIMP2-DX2 관련 질환, 특히 암 (바람직하게는 폐암)의 치료 또는 관리에서 치료상 이점을 제공하기에 충분한 본 발명의 화합물의 양을 말한다. "유효량"은 또한 생체외(in vitro) 또는 생체내(in vivo) 어떤 쪽이든 AIMP2-DX2 활성을 억제 또는 줄이기에 충분한 양을 말한다. "Effective amount" as used herein refers to slowing down or minimizing the progression of an AIMP2-DX2 related disease, particularly cancer (preferably lung cancer), or treating or managing an AIMP2-DX2 related disease, particularly cancer (preferably lung cancer). refers to the amount of a compound of the present invention sufficient to provide a therapeutic benefit in "Effective amount" also refers to an amount sufficient to inhibit or reduce AIMP2-DX2 activity either in vitro or in vivo .
본 발명의 화합물은 임의의 적합한 경로에 의하여 이러한 경로에 적당한 약학 조성물의 형태, 그리고 의도된 치료를 위하여 효과적인 투여량으로 투여될 수 있다. 효과적인 투여량은 단일 또는 분할 투여로 일반적으로 약 0.001 내지 약 100 mg/체중kg/일이고, 바람직하게는 약 0.01 내지 약 50 mg/kg/일이다. 나이, 종, 및 치료될 질병 또는 상태(condition)에 따라 이 범위의 하한 미만의 투여량 수준이 적합할 수 있다. 다른 경우에는, 여전히 더 큰 투여량이 해로운 부작용없이 사용될 수 있다. 더 큰 투여량은 하루 동안 투여를 위하여, 여러 작은 투여량으로 분할될 수 있다. The compounds of the present invention can be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in a dosage effective for the intended treatment. An effective dosage is generally from about 0.001 to about 100 mg/kg of body weight/day, preferably from about 0.01 to about 50 mg/kg/day, in single or divided administration. Dosage levels below the lower end of this range may be suitable depending on the age, species, and disease or condition being treated. In other cases, still larger doses can be used without detrimental side effects. Larger doses may be divided into several smaller doses for administration throughout the day.
본 발명 화합물의 약학 조성물Pharmaceutical composition of the compound of the present invention
다른 태양에서, 본 발명은 화학식 1 또는 2의 화합물 또는 이의 약학적으로 허용 가능한 염, 및 약학적으로 허용 가능한 담체 또는 첨가제를 포함하는 약학 조성물이 제공한다. 본 발명의 일 태양에 있어, 상기 약학 조성물의 용도는 후술하는 AIMP2-DX2 관련 질환, 바람직하게는 암, 더욱 바람직하게는 폐암의 치료 또는 예방 용도이다.In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive. In one aspect of the present invention, the use of the pharmaceutical composition is for the treatment or prevention of AIMP2-DX2 related diseases, preferably cancer, more preferably lung cancer, which will be described later.
용어 "약학적으로 허용 가능한"은 약학적 제제로 사용하기에 적합한 것을 의미하며, 일반적으로 이러한 사용을 위하여 안전한 것으로 간주되며, 이러한 사용을 위하여 국가의 관리 기관에 의하여 공식적으로 승인되거나 한국 약전 또는 미국 약전의 명단에 있는 것을 의미한다. The term "pharmaceutically acceptable" means suitable for use as a pharmaceutical preparation, generally considered safe for such use, and officially approved for such use by a national regulatory agency or approved by the Korean Pharmacopoeia or the United States Means in the pharmacopeia list.
약학 조성물, 제형 및 투여 경로Pharmaceutical Compositions, Formulations and Routes of Administration
상기 설명된 질병 또는 상태(condition)의 치료를 위하여, 본 명세서에서 설명된 상기 화합물 또는 이의 약학적으로 허용 가능한 염은 다음과 같이 투여될 수 있다.For the treatment of a disease or condition described above, the compound described herein, or a pharmaceutically acceptable salt thereof, can be administered as follows.
구강 투여(Oral administration)Oral administration
본 발명의 화합물은 구강으로 투여될 수 있으며, 구강은 연하(swallowing)를 포함하는 개념이다. 구강 투여에 의하여 본 발명의 화합물이 위장관(gastrointestinal tract)에 들어가거나, 예를 들어, 구강(buccal) 또는 설하(sublingual) 투여와 같이, 입으로부터 혈류로 직접적으로 흡수될 수 있다. The compound of the present invention can be administered orally, and oral is a concept including swallowing. Oral administration allows the compounds of the present invention to enter the gastrointestinal tract or be directly absorbed from the mouth into the bloodstream, eg, by buccal or sublingual administration.
구강 투여를 위한 적합한 조성물은 고형상, 액상, 겔(gel), 또는 파우더 형상일 수 있으며, 정제(tablet), 로젠지(lozenge), 캡슐(capsule), 과립제, 산제 등의 제형을 가질 수 있다. Compositions suitable for oral administration may be in solid, liquid, gel, or powder form, and may have formulations such as tablets, lozenges, capsules, granules, powders, and the like. .
구강 투여를 위한 조성물은 선택적으로 장용 코팅(enteric coating)될 수 있으며, 장용 코팅을 통하여 지연된(delayed) 또는 지속된(sustained) 방출을 나타낼 수 있다. 즉, 본 발명에 따른 구강 투여를 위한 조성물은 즉시 또는 변형된(modified) 방출 패턴을 가진 제형일 수 있다. Compositions for oral administration may optionally be enteric coated and exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.
액체 제형은 용액, 시럽 및 현탁액을 포함할 수 있으며, 이러한 액상 조성물은 연질 또는 경질 캡슐 내에 함유된 형태일 수 있다. 이러한 제형은 약학적으로 허용 가능한 담체, 예를 들어, 물, 에탄올, 폴리에틸렌글리콜, 셀룰로오스, 또는 오일(oil)을 포함할 수 있다. 상기 제형은 또한 하나 이상의 유화제 및/또는 현탁제를 포함할 수 있다.Liquid formulations may include solutions, syrups and suspensions, and such liquid compositions may be contained in soft or hard capsules. Such formulations may include a pharmaceutically acceptable carrier such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulation may also contain one or more emulsifying and/or suspending agents.
정제(tablet) 제형에서, 활성 성분인 약물의 양은 정제 총 중량 대비 약 0.05 중량% 내지 약 95 중량%, 더욱 일반적으로 제형의 약 2 중량% 내지 약 50 중량%로 존재할 수 있다. 또한, 정제는 약 0.5 중량% 내지 약 35 중량%, 더욱 일반적으로 제형의 약 2 중량% 내지 약 25 중량%를 포함하는 붕해제를 함유할 수 있다. 붕해제의 예로는 유당, 전분, 소디움스타치글리콜레이트, 크로스포비돈, 크로스카멜로스소디움(croscarmellose sodium), 말토덱스트린 또는 이들의 혼합물이 사용될 수 있으나 이에 한정되는 것은 아니다.In tablet formulations, the amount of active ingredient drug may be present from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the total weight of the tablet. Tablets may also contain a disintegrant comprising from about 0.5% to about 35% by weight, more usually from about 2% to about 25% by weight of the dosage form. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.
정제로 제조하기 위해 포함되는 적합한 활택제는 약 0.1 중량% 내지 약 5 중량% 양으로 존재할 수 있고, 탈크(talc), 이산화규소, 스테아린산, 칼슘, 아연 또는 마그네슘 스테아레이트, 소듐 스테아릴 푸마레이트 등이 활택제로 사용될 수 있으나, 본 발명은 이러한 첨가제들의 종류에 한정되는 것은 아니다. Suitable glidants included for making into tablets may be present in amounts from about 0.1% to about 5% by weight, and include talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like. It can be used as a lubricant, but the present invention is not limited to these types of additives.
정제로 제조하기 위한 결합제(binder)로는 젤라틴, 폴리에틸렌글리콜, 당(sugar), 검(gum), 녹말(starch), 폴리비닐피롤리돈, 하이드록시프로필셀룰로오스, 하이드록시프로필메틸셀룰로오스 등이 사용될 수 있으며, 정제로 제조하기 위한 적합한 희석제로는 만니톨, 자일리톨, 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 녹말(starch), 미결정셀룰로오스 등이 사용될 수 있으나, 본 발명은 이러한 첨가제들의 종류에 한정되는 것은 아니다. Gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. may be used as a binder for preparing tablets. Mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. may be used as suitable diluents for preparing tablets, but the present invention is not limited to these types of additives. .
선택적으로 정제에 포함될 수 있는 가용화제는 정제 총 중량 대비 약 0.1 중량% 내지 약 3 중량% 양이 사용될 수 있고, 예를 들어, 폴리소르베이트, 소디움 라우릴설페이트, 소디움 도데실설페이트, 프로필렌 카보네이트, 디에틸렌글리콜모노에틸에테르, 디메틸이소소르비드, 폴리옥시에틸렌글리콜화된 천연 또는 수소화 피마자유, HCORTM(Nikkol), 올레일에스테르, 젤루시어(GelucireTM), 카프릴릭/카프릴산 모노/디글리세리드, 소르비탄지방산에스테르, 솔루톨HSTM 등이 본 발명에 따른 약학 조성물에 사용될 수 있으나, 본 발명은 이러한 가용화제의 구체적 종류에 한정되는 것은 아니다.Optionally, the solubilizing agent that may be included in the tablet may be used in an amount of about 0.1% to about 3% by weight based on the total weight of the tablet, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, Diethylene glycol monoethyl ether, dimethylisosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR ™ (Nikkol), oleyl ester, Gelucire ™ , caprylic/caprylic mono/ Diglyceride, sorbitan fatty acid ester, Solutol HS TM and the like can be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to the specific types of these solubilizing agents.
비경구 투여(Parenteral Administration)Parenteral Administration
본 발명의 화합물은 혈류, 근육, 또는 내장 내로 직접 투여될 수 있다. 비경구 투여를 위한 적합한 방법은 정맥내(intravenous), 근육내(intra-muscular), 피하 동맥내(subcutaneous intraarterial), 복강내(intraperitoneal), 척추강내(intrathecal), 두개내(intracranial) 주사 등을 포함한다. 비경구 투여를 위한 적합한 장치는 (바늘 및 바늘 없는 주사기를 포함하는) 주사기(injector) 및 주입 방법(infusion method)을 포함한다.Compounds of the present invention may be administered directly into the bloodstream, muscle, or intestine. Suitable methods for parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, and the like. include Suitable devices for parenteral administration include injectors (including needle and needleless syringes) and infusion methods.
비경구 투여를 위한 조성물은 즉시 또는 변형된 방출 패턴을 가진 제형일 수 있으며, 변형된 방출 패턴은 지연된(delayed) 또는 지속된(sustained) 방출 패턴일 수 있다. Compositions for parenteral administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
대부분의 비경구 제형은 액상 조성물이며, 이러한 액상 조성물은 본 발명에 따른 약효 성분, 염, 완충제, 등장화제 등을 포함하는 수용액이다.Most parenteral formulations are liquid compositions, and these liquid compositions are aqueous solutions containing the active ingredient, salt, buffer, tonicity agent and the like according to the present invention.
비경구 제형은 또한 건조된 형태(예를 들어, 동결 건조) 또는 멸균 비-수용액으로서 제조될 수 있다. 이들 제형은 멸균수(sterile water)와 같은 적합한 비히클(vehicle)과 함께 사용될 수 있다. 용해도 증강제(solubility-enhancing agents) 또한 비경구 용액의 제조에 사용될 수 있다.Parenteral formulations may also be prepared in dried form (eg lyophilized) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle such as sterile water. Solubility-enhancing agents may also be used in the preparation of parenteral solutions.
본 발명의 상기 화학식 1 또는 2 (바람직하게는 화학식 1)의 화합물 또는 이의 약학적으로 허용 가능한 염은 항암제 타겟인 AIMP2-DX2의 활성을 저해하여, 암세포의 사멸을 효과적으로 유도하며, 이를 통해 암, 특히 폐암의 예방 및 치료에 효과적이다. The compound of Formula 1 or 2 (preferably Formula 1) or a pharmaceutically acceptable salt thereof of the present invention inhibits the activity of AIMP2-DX2, which is an anticancer drug target, and effectively induces the death of cancer cells, thereby cancer, It is particularly effective in preventing and treating lung cancer.
이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 그러나, 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 하기 실시예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예들은 본 발명이 속한 분야에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples and the like will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
[실시예 1] 예비 실험[Example 1] Preliminary experiment
AIMP2-DX2의 활성을 특이적으로 억제하는 화합물을 탐색하고자 폐암 세포주인 H549에 pGL2-DX2를 transfection 하고 24시간 배양 후 시험 화합물을 처리하였다. 이후 4시간을 추가 배양한 후, 제조사 프로토콜 (Promega, 미국)에 따른 루시퍼라제 분석 키트로 루미노미터를 이용하여 루시퍼라제 활성을 측정하였다.In order to search for compounds that specifically inhibit the activity of AIMP2-DX2, lung cancer cell line H549 was transfected with pGL2-DX2 and cultured for 24 hours, followed by treatment with the test compound. After further incubation for 4 hours, luciferase activity was measured using a luminometer with a luciferase assay kit according to the manufacturer's protocol (Promega, USA).
그 결과, 22개의 화합물이 1차적으로 탐색되었고, 22개의 화합물을 정상 세포인 WI-26세포에 처리하여 48시간 후에 MTT에세이를 하여, 세포독성이 없는 것을 최종적으로 선택하였다. 그 결과 하기 (E)-3-(5-((2-(2,3-다이하이드로벤조[b][1,4]다이옥신-2-카보닐)하이드라지닐리딘)메틸)퓨란-2-닐)벤조산 (화합물 1)이 1차적으로 선택되었다.As a result, 22 compounds were initially screened, and WI-26 cells, which are normal cells, were treated with 22 compounds, and after 48 hours, MTT assay was performed, and those without cytotoxicity were finally selected. As a result, the following ( E )-3-(5-((2-(2,3-dihydrobenzo[ b ][1,4]dioxine-2-carbonyl)hydrazinylidine)methyl)furan-2- Nyl)benzoic acid (Compound 1) was the first choice.
[화합물 1][Compound 1]
Figure PCTKR2023001073-appb-img-000006
Figure PCTKR2023001073-appb-img-000006
[실시예 2] 화합물 1의 합성[Example 2] Synthesis of Compound 1
상기 화합물 1은 다음과 같이 합성하였다.The compound 1 was synthesized as follows.
Figure PCTKR2023001073-appb-img-000007
Figure PCTKR2023001073-appb-img-000007
A1 합성A1 synthesis
EtOH (10 mL)에 용해된 2,3-다이하이드로 벤조[b][1,4]다이옥신-2-카복실산 (300 mg, 1.66 mmol) 용액에 SOCl2 (990 mg, 8.32 mmol)를 첨가하였다. 상기 혼합물을 80 ℃에 1시간 가열하였다. 그 뒤, 상기 반응 혼합물을 상온으로 식힌 후 농축하였다. 물로 희석한 후 EtOAC로 추출하고(3회) 유기 상을 Na2SO4로 진공에서 증발시켰다. 이것을 추가 정제 하지 않고 다음 반응에 사용하였다.To a solution of 2,3-dihydrobenzo[b][1,4]dioxin-2-carboxylic acid (300 mg, 1.66 mmol) in EtOH (10 mL) was added SOCl 2 (990 mg, 8.32 mmol). The mixture was heated at 80 °C for 1 hour. Then, the reaction mixture was cooled to room temperature and then concentrated. After dilution with water, it was extracted with EtOAC (3 times) and the organic phase was evaporated over Na 2 SO 4 in vacuo. This was used in the next reaction without further purification.
A2 합성A2 synthesis
EtOH (10 mL)에 용해된 하이드라진 모노하이드레이트 (554 mg, 17.3 mmol) 와 A1 (360 mg, 1.73 mmol) 을 21시간 동안 환류시켰다. 상기 반응물을 진공에서(in vacuo) 증발 시키고, 추가 정제 하지 않고 A2를 얻었다.Hydrazine monohydrate (554 mg, 17.3 mmol) and A1 (360 mg, 1.73 mmol) dissolved in EtOH (10 mL) were refluxed for 21 hours. The reactants were evaporated in vacuo and A2 was obtained without further purification.
A3 합성A3 synthesis
5-브로모퓨란-2-카르발데히드 (500 mg, 2.85 mmol), 3-보로노벤조산(711 mg, 4.29 mmol), 및 Na2CO3 (605 mg, 5.71 mmol)를 DME:H2O (v/v 3:1, 8 mL)에 용해 시켰다. PdCl2(dppf) (418 mg, 5.71 mmol)를 반응 혼합물에 첨가하고 100 ℃에서 20 시간 동안 교반하였다. 반응이 완료된 후 HCl을 이용하여 혼합물의 pH를 2로 낮추었다. 혼합물을 물로 희석시킨 후, EtOAc로 추출 (3회) 하였다. 유기층을 Na2SO4로 건조시키고 진공에서(in vacuo) 증발시켰다. 결과적으로 형성된 조 잔여물 (crude residue)를 플래쉬 컬럼 크로마토그래피 (Dichloromethane:Methanol) 97:3 ratio)로 정제하여 연한 핑크색의 A3를 얻었다.5-Bromofuran-2-carbaldehyde (500 mg, 2.85 mmol), 3-boronobenzoic acid (711 mg, 4.29 mmol), and Na 2 CO 3 (605 mg, 5.71 mmol) were added in DME:H 2 O (v/v 3:1, 8 mL). PdCl 2 (dppf) (418 mg, 5.71 mmol) was added to the reaction mixture and stirred at 100 °C for 20 h. After the reaction was completed, the pH of the mixture was lowered to 2 using HCl. The mixture was diluted with water and then extracted with EtOAc (3 times). The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The crude residue formed as a result was purified by flash column chromatography (Dichloromethane:Methanol, 97:3 ratio) to obtain pale pink A3.
화합물 1의 합성Synthesis of Compound 1
EtOH (5 mL)에 A2 (100 mg, 0.51 mmol)와 A3 (111 mg, 0.51 mmol) 용해시킨 후 혼합물을 90 ℃에서 밤새 가열하였다. 상기 반응물을 상온으로 식힌 뒤 진공에서(in vacuo) 증발시켰다. 결과적으로 형성된 조 잔여물(crude residue)을 플래쉬 컬럼 크로마토그래피 (Dichloromethane:Methanol) 99:1 ratio)로 정제 하였고, 붉은색 고체의 화합물 1을 제조하였다.A2 (100 mg, 0.51 mmol) and A3 (111 mg, 0.51 mmol) were dissolved in EtOH (5 mL) and the mixture was heated at 90 °C overnight. After cooling the reactant to room temperature, it was evaporated in vacuo. The crude residue formed as a result was purified by flash column chromatography (Dichloromethane:Methanol 99:1 ratio), and Compound 1 as a red solid was prepared.
[실시예 3][Example 3]
AIMP2-DX2의 활성을 특이적으로 억제하는 화합물을 탐색하고자 화합물 1과 구조가 유사한 105개 화합물들을 평가하였다. 폐암 세포주인 H549에 pGL2-DX2를 transfection 하고 24시간 배양 후 상기 105개의 화합물을 처리하였다. 이후 24시간을 추가 배양한 후, 제조사 프로토콜 (Promega, 미국)에 따른 루시퍼라제 분석 키트로 루미노미터를 이용하여 루시퍼라제 활성을 측정하였다. In order to search for compounds that specifically inhibit the activity of AIMP2-DX2, 105 compounds having a structure similar to Compound 1 were evaluated. H549, a lung cancer cell line, was transfected with pGL2-DX2 and incubated for 24 hours, and then treated with the 105 compounds. After further culturing for 24 hours, the luciferase activity was measured using a luminometer with a luciferase assay kit according to the manufacturer's protocol (Promega, USA).
그 결과 표 1 에 나타낸 화합물들이 AIMP2-DX2의 활성을 60% 초과하는 정도로 특이적으로 억제하는 것을 확인하였다. 표 1에 나타낸 화합물들은 화합물 1과 비슷하거나 좋은 효과를 보이는 것을 확인하였으며, 이를 통해 본 발명 화합물들의 기본 구조인 벤조다이옥신 스캐폴드를 선정하였다.As a result, it was confirmed that the compounds shown in Table 1 specifically inhibited the activity of AIMP2-DX2 by more than 60%. It was confirmed that the compounds shown in Table 1 showed similar or good effects to Compound 1, and through this, the benzodioxin scaffold, which is the basic structure of the compounds of the present invention, was selected.
Figure PCTKR2023001073-appb-img-000008
Figure PCTKR2023001073-appb-img-000008
(N.D.: not determined)(N.D.: not determined)
[실시예 4][Example 4]
하기 반응식을 이용하여 본 발명의 화학식 1로 표시되는 화합물들을 제조하였다. Compounds represented by Formula 1 of the present invention were prepared using the following reaction scheme.
Figure PCTKR2023001073-appb-img-000009
Figure PCTKR2023001073-appb-img-000009
(2,3-다이하이드로벤조[b][1,4]다이옥신-2-일)메테나민 (100 mg, 0.61 mmol), 2-([1,1'-바이피닐]-4-닐)아세트산 (141 mg, 0.67 mmol), 및 HATU (253 mg, 0.67 mmol)를 DMF (1 mL)에 용해시켰다. DIPEA (0.115 mL, 0.067 mmol)을 반응 혼합물에 첨가 하고 상온에서 20 시간 동안 교반하였다. 반응이 완료된 후 혼합물을 물로 희석시켰다. 그 후, EtOAc로 추출 (3회)하였다. 유기층을 Na2SO4로 건조시키고 진공에서(in vacuo) 증발시켰다. 결과적으로 형성된 조 잔여물(crude residue)을 플래쉬 컬럼 크로마토그래피 (Dichloromethane:Methanol) 97:3 ratio) 로 정제하여 하얀색의 A5를 얻었다.(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methenamine (100 mg, 0.61 mmol), 2-([1,1'-bipinyl]-4-yl)acetic acid (141 mg, 0.67 mmol), and HATU (253 mg, 0.67 mmol) were dissolved in DMF (1 mL). DIPEA (0.115 mL, 0.067 mmol) was added to the reaction mixture and stirred at room temperature for 20 hours. After the reaction was complete, the mixture was diluted with water. It was then extracted with EtOAc (three times). The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The resulting crude residue was purified by flash column chromatography (Dichloromethane:Methanol 97:3 ratio) to obtain white A5.
제조된 화합물들을 하기 표 2에 종합하여 나타내었다. The prepared compounds are collectively shown in Table 2 below.
Figure PCTKR2023001073-appb-img-000010
Figure PCTKR2023001073-appb-img-000010
Figure PCTKR2023001073-appb-img-000011
Figure PCTKR2023001073-appb-img-000011
Figure PCTKR2023001073-appb-img-000012
Figure PCTKR2023001073-appb-img-000012
[실시예 5] 본 발명에 따른 화합물들의 항암 활성 평가[Example 5] Evaluation of anticancer activity of compounds according to the present invention
상기 표 2의 화합물들의 항암 활성을 평가하였다 (앞서 표 1의 항암 활성 또한 동일한 방법으로 평가된 결과임).The anticancer activity of the compounds in Table 2 was evaluated (the anticancer activity of Table 1 was also evaluated in the same manner).
2x106 개의 A549 세포를 100x15 mm 세포 배양 접시에 시딩하고 24시간 후에 pGL2-AIMP2-DX2를 세포에 형질주입시켰다. 1.5 mL 에펜도르프(Eppendorf) 튜브를 준비하여 pGL2-AIMP2-DX2를 각각 10μg 첨가하였다. 플라스미드가 포함된 튜브에 예열해둔 무혈청 RPMI 배지 600μL를 첨가한 후 5초간 볼텍싱하여 혼합하였다. 그 다음 20μL의 Turbofect를 튜브에 첨가하고 5초간 볼텍싱하여 혼합한 후 15분 동안 방치하였다. 반응 튜브를 방치하는 동안 배양 접시에서 배지를 제거한 후 6mL의 새로운 세포 배양배지를 첨가하였다. 15분 후, 반응 혼합물을 세포 배양 접시에 첨가하고 부드럽게 혼합한 후 CO2 배양기에서 4시간 동안 배양하였다. 4시간 후에 배지를 새로운 세포 배양배지와 교환하였다. 24시간 후 세포를 배양 접시에서 분리하여 10mL의 RPMI 성장 배지에 현탁시켰다. 세포 현탁액 10μL에 10μL의 트리판 블루 염색약 0.4%를 첨가한 후 Countess II FL Automated Cell Counter를 사용하여 세포수를 측정하였다. 측정된 세포수를 기반으로 25,000개의 형질주입된 세포를 바닥이 평평한 흰색 96-웰 플레이트에 시딩하였다. 24시간 후 세포 배양배지를 제거하고 3배로 연속 희석된 화합물(0.003-10, 50μM)이 첨가된 무혈청 RPMI 배지 100μL를 세포 플레이트에 첨가한 후 24시간 동안 배양하였다. 24시간 후에, 플레이트 웰에 들어있던 세포 배양배지를 제거한 후, Luciferase Cell Culture Lysis buffer 10μL를 플레이트의 각 웰에 넣고, 30분간 인큐베이션하여 세포를 융해한다. Luciferase 기질과 Luciferase 희석 완충액을 조합하고 볼텍싱에 의해 잘 혼합하여 소정량의 재구성된 Luciferase 시약을 제조하였다. (장기간 보관하거나 빛에 노출되면 시약 활성에 손실이 발생할 수 있으므로, 각 실험마다 새로운 시약을 준비하였으며 시약 제조 절차는 어두운 조건에서 수행하였다.) 30분 후, 모든 웰에 제조된 Luciferse 시약을 100μL씩 첨가한 후 상온에서 10분 인큐베이션 한 후 Glomax Discover Microplate Reader를 사용하여 0.4초/웰의 통합시간(integration time)으로 루시퍼라제(Luciferase) 활성을 측정하였다.2x10 6 A549 cells were seeded in a 100x15 mm cell culture dish and 24 hours later, cells were transfected with pGL2-AIMP2-DX2. A 1.5 mL Eppendorf tube was prepared and 10 μg of each pGL2-AIMP2-DX2 was added thereto. After adding 600 μL of preheated serum-free RPMI medium to the tube containing the plasmid, the mixture was mixed by vortexing for 5 seconds. Then, 20 μL of Turbofect was added to the tube, mixed by vortexing for 5 seconds, and left for 15 minutes. While the reaction tube was left standing, the medium was removed from the culture dish, and then 6 mL of new cell culture medium was added. After 15 minutes, the reaction mixture was added to the cell culture dish, mixed gently, and incubated in a CO 2 incubator for 4 hours. After 4 hours, the medium was exchanged with fresh cell culture medium. After 24 hours, the cells were removed from the culture dish and suspended in 10 mL of RPMI growth medium. After adding 10 μL of trypan blue dye 0.4% to 10 μL of the cell suspension, the number of cells was measured using a Countess II FL Automated Cell Counter. Based on the measured cell number, 25,000 transfected cells were seeded in a white flat bottom 96-well plate. After 24 hours, the cell culture medium was removed, and 100 µL of serum-free RPMI medium supplemented with three-fold serially diluted compounds (0.003-10, 50 µM) was added to the cell plate, followed by culturing for 24 hours. After 24 hours, after removing the cell culture medium contained in the wells of the plate, 10 μL of Luciferase Cell Culture Lysis buffer was added to each well of the plate, and incubated for 30 minutes to lyse the cells. A predetermined amount of reconstituted Luciferase reagent was prepared by combining Luciferase substrate and Luciferase dilution buffer and mixing well by vortexing. (Because long-term storage or exposure to light may cause loss of reagent activity, new reagents were prepared for each experiment and the reagent preparation procedure was performed in the dark.) After 30 minutes, 100 μL of the prepared Luciferse reagent was added to all wells. After addition, after incubation at room temperature for 10 minutes, luciferase activity was measured at an integration time of 0.4 seconds/well using a Glomax Discover Microplate Reader.
그 결과를 표 3에 나타내었다. The results are shown in Table 3.
Figure PCTKR2023001073-appb-img-000013
Figure PCTKR2023001073-appb-img-000013
상기 표 3에 나타나는 바와 같이, 본 발명에 따른 화합물들은 뛰어난 효과를 나타내었으며, 그 중에서도 화합물 17, 23, 24 및 28의 효과는 매우 뛰어났다.As shown in Table 3, the compounds according to the present invention showed excellent effects, and among them, the effects of compounds 17, 23, 24 and 28 were very excellent.
[실시예 6] 세포 생존력 측정 (Cell viability test)[Example 6] Measurement of cell viability (Cell viability test)
각각 2x106 개의 A549, H460, 및 WI-26 세포를 100x15 mm 세포 배양 접시에 시딩하고 CO2 배양기에서 48시간 동안 배양하였다. 48시간 후 세포를 배양 접시에서 분리하여 10mL의 RPMI 또는 DMEM 성장 배지에 현탁시켰다. 세포 현탁액 10μL에 10μL의 트리판 블루 염색약 0.4%를 첨가한 후 Countess II FL Automated Cell Counter를 사용하여 세포수를 측정하였다. 측정된 세포수를 기반으로 25,000개의 세포를 96-웰 플레이트에 시딩하였다. 24시간 후 세포 배양배지를 제거하고 3배로 연속 희석된 화합물(0.003-10, 50μM)이 첨가된 무혈청 RPMI 또는 DMEM 배지 100μL를 세포 플레이트에 첨가한 후 96시간 동안 배양하였다. MTT 용액 조제를 위해 MTT 가루를 PBS에 5 mg/mL 농도가 되게 녹여주었다. MTT 용액은 빛에 노출되면 시약의 활성이 감소할 수 있으므로 용액 제조 후 어두운 조건에서 보관하였다. 96시간 후에, 플레이트 웰에 20 uL MTT 용액을 넣어준 후 CO2 배양기에서 30분간 인큐베이션 하였다. 30분 후 플레이트 웰에 있던 용액을 모두 제거한 후 DMSO 용액을 100 μL 넣어준 후 플레이트를 부드럽게 10회 흔들어 준 후, Microplate reader를 이용하여 420nm 파장에서 흡광도를 측정하였다. 그 결과를 표 4에 나타내었다. Each 2x10 6 A549, H460, and WI-26 cells were seeded in a 100x15 mm cell culture dish and cultured in a CO2 incubator for 48 hours. After 48 hours, the cells were removed from the culture dish and suspended in 10 mL of RPMI or DMEM growth medium. After adding 10 μL of trypan blue dye 0.4% to 10 μL of the cell suspension, the number of cells was measured using a Countess II FL Automated Cell Counter. Based on the measured cell number, 25,000 cells were seeded in a 96-well plate. After 24 hours, the cell culture medium was removed, and 100 µL of serum-free RPMI or DMEM medium supplemented with three-fold serially diluted compounds (0.003-10, 50 µM) was added to the cell plate, followed by culturing for 96 hours. To prepare the MTT solution, MTT powder was dissolved in PBS to a concentration of 5 mg/mL. Since the activity of the MTT solution may decrease when exposed to light, it was stored in the dark after preparing the solution. After 96 hours, 20 uL MTT solution was added to the plate wells, followed by incubation in a CO 2 incubator for 30 minutes. After 30 minutes, all solutions in the plate wells were removed, 100 μL of DMSO solution was added, the plate was gently shaken 10 times, and absorbance was measured at a wavelength of 420 nm using a Microplate reader. The results are shown in Table 4.
Figure PCTKR2023001073-appb-img-000014
Figure PCTKR2023001073-appb-img-000014
그 결과 표 4 에서 보는 바와 같이, 본 발명의 특정 화합물들은 화합물 1에 비하여 AIMP2-DX2를 억제시켜 암 억제 효과가 우수한 것을 확인하였다. 특히 폐암 세포인 A549와 H460 세포에서 효과적인 것을 확인할 수 있다.As a result, as shown in Table 4, the specific compounds of the present invention inhibited AIMP2-DX2 compared to Compound 1, and it was confirmed that the cancer inhibitory effect was excellent. In particular, it can be confirmed that it is effective in A549 and H460 cells, which are lung cancer cells.

Claims (9)

  1. 하기 화학식 1 또는 2로 표시되는 벤조다이옥세인 유도체 화합물 또는 이의 약학적으로 허용 가능한 염.A benzodioxane derivative compound represented by Formula 1 or 2 below or a pharmaceutically acceptable salt thereof.
    [화학식 1][Formula 1]
    Figure PCTKR2023001073-appb-img-000015
    Figure PCTKR2023001073-appb-img-000015
    상기 화학식 1에서, In Formula 1,
    R10, R11, R12 및 R13은 서로 독립적으로 수소, C1-C4 알킬, C3-C6 사이클로알킬, C1-C4 알콕시, 또는 하이드록시이고, R 10 , R 11 , R 12 and R 13 independently of each other are hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, or hydroxy;
    R14는 페닐,
    Figure PCTKR2023001073-appb-img-000016
    또는
    Figure PCTKR2023001073-appb-img-000017
    이고, 여기에서 R14는 선택적으로 C1-C3 알킬, C1-C3 알콕시, C1-C3 할로알콕시, 할로겐, 페닐, C1-C3 알킬로 치환된 페닐, 및 하이드록시로 이루어진 군으로부터 하나 이상의 치환기로 치환되며,     R 14 is phenyl;
    Figure PCTKR2023001073-appb-img-000016
    or
    Figure PCTKR2023001073-appb-img-000017
    wherein R 14 is optionally substituted with one or more substituents from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, phenyl, phenyl substituted with C1-C3 alkyl, and hydroxy becomes,
    X는 S, O 또는 NH이며,X is S, O or NH;
    [화학식 2][Formula 2]
    Figure PCTKR2023001073-appb-img-000018
    Figure PCTKR2023001073-appb-img-000018
    상기 화학식 2에 있어서, In Formula 2,
    R6은 수소, C1-C4 알킬, C3-C6 사이클로알킬, C1-C4 알콕시, 또는 하이드록시이고, R 6 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, or hydroxy;
    X는 -CH2- 또는 -C(O)-이고, Y는 직접 연결, -CH2-, 또는 -C(O)-이고, Z은 직접 연결, -NH-, 또는 -CH2-이고,X is -CH 2 - or -C(O)-, Y is a direct link, -CH 2 -, or -C(O)-, Z is a direct link, -NH-, or -CH 2 -;
    R15는 서로 독립적으로 C1-C3 알킬, C1-C3 알콕시, C1-C3 할로알콕시, 할로겐, 또는 하이드록시이며, n은 1 내지 3의 정수임. R 15 are each independently C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, or hydroxy, and n is an integer from 1 to 3;
  2. 제1항에 있어서, 상기 화합물은 The method of claim 1, wherein the compound
    (4-(5-bromo-2-ethoxybenzyl)piperazin-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone (화합물 7), (4-(5-bromo-2-ethoxybenzyl)piperazin-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone (Compound 7),
    N-(2-chlorophenyl)-2-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)acetamide (화합물 8),N-(2-chlorophenyl)-2-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)acetamide (Compound 8),
    (4-(3-chlorobenzyl)piperazin-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone (화합물 9),(4-(3-chlorobenzyl)piperazin-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone (Compound 9),
    3-(3-chloro-4-methylphenyl)-1-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)propan-1-one (화합물 10),3-(3-chloro-4-methylphenyl)-1-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)propan-1-one (compound 10),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-methylbenzofuran-3-yl)acetamide (화합물 12),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-methylbenzofuran-3-yl)acetamide (Compound 12),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-ethylbenzofuran-3-yl)acetamide (화합물 13),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-ethylbenzofuran-3-yl)acetamide (Compound 13),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(naphthalen-2-yl)acetamide (화합물 14),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(naphthalen-2-yl)acetamide (Compound 14),
    N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-methoxybenzofuran-3-yl)acetamide (화합물 15),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-methoxybenzofuran-3-yl)acetamide (Compound 15),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6,7-dimethylbenzofuran-3-yl)acetamide (화합물 16),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6,7-dimethylbenzofuran-3-yl)acetamide (Compound 16),
    N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(5,6-dimethylbenzofuran-3-yl)acetamide (화합물 17),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(5,6-dimethylbenzofuran-3-yl)acetamide (Compound 17),
    N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(1H-indol-3-yl)acetamide (화합물 18),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(1H-indol-3-yl)acetamide (Compound 18),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(1H-indol-5-yl)acetamide (화합물 19),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(1H-indol-5-yl)acetamide (Compound 19),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(quinolin-6-yl)acetamide (화합물 20),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(quinolin-6-yl)acetamide (Compound 20),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(quinolin-8-yl)acetamide (화합물 21),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(quinolin-8-yl)acetamide (Compound 21),
    N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(2-(m-tolyl)thiazol-4-yl)acetamide (화합물 22),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(2-(m-tolyl)thiazol-4-yl)acetamide (Compound 22),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-ethylphenyl)acetamide (화합물 23),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-ethylphenyl)acetamide (Compound 23),
    N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-hydroxy-2-methylphenyl)acetamide (화합물 24),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-hydroxy-2-methylphenyl)acetamide (Compound 24),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-fluorophenyl)acetamide (화합물 25),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-fluorophenyl)acetamide (Compound 25),
    N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-(trifluoromethoxy)phenyl)acetamide (화합물 26),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-(trifluoromethoxy)phenyl)acetamide (Compound 26),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(3,4-dimethylphenyl)acetamide (화합물 27), 또는 N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(3,4-dimethylphenyl)acetamide (Compound 27), or
    2-([1,1'-Biphenyl]-4-yl)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide (화합물 28)인 2-([1,1'-Biphenyl]-4-yl)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide (Compound 28)
    화합물 또는 이의 약학적으로 허용 가능한 염. A compound or a pharmaceutically acceptable salt thereof.
  3. 제2항에 있어서, 상기 화합물은The method of claim 2, wherein the compound
    3-(3-chloro-4-methylphenyl)-1-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)propan-1-one (화합물 10), 3-(3-chloro-4-methylphenyl)-1-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)propan-1-one (compound 10),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-methylbenzofuran-3-yl)acetamide (화합물 12),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-methylbenzofuran-3-yl)acetamide (Compound 12),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-ethylbenzofuran-3-yl)acetamide (화합물 13),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(6-ethylbenzofuran-3-yl)acetamide (Compound 13),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(naphthalen-2-yl)acetamide (화합물 14),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(naphthalen-2-yl)acetamide (Compound 14),
    N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(5,6-dimethylbenzofuran-3-yl)acetamide (화합물 17),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(5,6-dimethylbenzofuran-3-yl)acetamide (Compound 17),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(1H-indol-5-yl)acetamide (화합물 19),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(1H-indol-5-yl)acetamide (Compound 19),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(quinolin-6-yl)acetamide (화합물 20),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(quinolin-6-yl)acetamide (Compound 20),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-ethylphenyl)acetamide (화합물 23),N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-ethylphenyl)acetamide (Compound 23),
    N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-hydroxy-2-methylphenyl)acetamide (화합물 24),N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-hydroxy-2-methylphenyl)acetamide (Compound 24),
    N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-fluorophenyl)acetamide (화합물 25), 또는N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-2-(4-fluorophenyl)acetamide (Compound 25), or
    2-([1,1'-Biphenyl]-4-yl)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide (화합물 28)인 2-([1,1'-Biphenyl]-4-yl)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide (Compound 28)
    화합물 또는 이의 약학적으로 허용 가능한 염.A compound or a pharmaceutically acceptable salt thereof.
  4. 제1항 내지 제3항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 암의 예방 또는 치료용 약학 조성물. A pharmaceutical composition for preventing or treating cancer comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  5. 제4항에 있어서, 상기 암은 폐암, 유방암, 대장암, 소세포폐암, 위암, 간암, 혈액암, 골암, 췌장암, 피부암, 두경부암, 흑색종, 자궁암, 직장암, 항문부근암, 결장암, 유방암, 나팔관암종, 자궁내막암종, 자궁경부암, 질암, 음문암종, 호지킨병, 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 백혈병, 림프구림프종, 방광암, 신장암, 수뇨관암, 신장세포 암종, 신장골반 암종, CNS 종양, CNS 림프종, 척수 종양, 뇌간신경교종 및 뇌하수체 선종으로 이루어진 군에서 선택된 하나 이상인 암의 예방 또는 치료용 약학 조성물.The method of claim 4, wherein the cancer is lung cancer, breast cancer, colorectal cancer, small cell lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma, uterine cancer, rectal cancer, perianal cancer, colon cancer, breast cancer, Fallopian tube carcinoma, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, leukemia, lymphocyte A pharmaceutical composition for preventing or treating one or more cancers selected from the group consisting of lymphoma, bladder cancer, kidney cancer, ureteric cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma.
  6. 제5항에 있어서, 상기 암은 폐암인 암의 예방 또는 치료용 약학 조성물.The pharmaceutical composition for preventing or treating cancer according to claim 5, wherein the cancer is lung cancer.
  7. 제1항 내지 제3항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을 암의 치료 또는 예방이 필요한 개체에게 투여하는 것을 포함하는, 암의 예방 또는 치료 방법.A method for preventing or treating cancer, comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof to a subject in need of treatment or prevention of cancer.
  8. 제7항에 있어서, 상기 암은 폐암, 유방암, 대장암, 소세포폐암, 위암, 간암, 혈액암, 골암, 췌장암, 피부암, 두경부암, 흑색종, 자궁암, 직장암, 항문부근암, 결장암, 유방암, 나팔관암종, 자궁내막암종, 자궁경부암, 질암, 음문암종, 호지킨병, 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 백혈병, 림프구림프종, 방광암, 신장암, 수뇨관암, 신장세포 암종, 신장골반 암종, CNS 종양, CNS 림프종, 척수 종양, 뇌간신경교종 및 뇌하수체 선종으로 이루어진 군에서 선택된 하나 이상인, 방법. The method of claim 7, wherein the cancer is lung cancer, breast cancer, colorectal cancer, small cell lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma, uterine cancer, rectal cancer, perianal cancer, colon cancer, breast cancer, Fallopian tube carcinoma, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, leukemia, lymphocyte At least one selected from the group consisting of lymphoma, bladder cancer, kidney cancer, ureteric cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma.
  9. 제8항에 있어서, 상기 암은 폐암인, 방법.9. The method of claim 8, wherein the cancer is lung cancer.
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