WO2022245061A1 - 벤즈아미드 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 - Google Patents
벤즈아미드 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 Download PDFInfo
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- WO2022245061A1 WO2022245061A1 PCT/KR2022/006895 KR2022006895W WO2022245061A1 WO 2022245061 A1 WO2022245061 A1 WO 2022245061A1 KR 2022006895 W KR2022006895 W KR 2022006895W WO 2022245061 A1 WO2022245061 A1 WO 2022245061A1
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- methyl
- fluoro
- indol
- hydroxyphenyl
- substituted
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 35
- 201000011510 cancer Diseases 0.000 title claims abstract description 32
- 239000004480 active ingredient Substances 0.000 title claims abstract description 19
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- 229910052736 halogen Inorganic materials 0.000 claims description 71
- 150000001875 compounds Chemical class 0.000 claims description 69
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- 108060006698 EGF receptor Proteins 0.000 claims description 42
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D209/04—Indoles; Hydrogenated indoles
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- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
- A23V2250/30—Other Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the present invention relates to a benzamide derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
- the occurrence of cancer is related to various environmental factors including chemicals, radiation, and viruses, and changes in oncogenes, tumor suppressor genes, and genes related to apoptosis and DNA repair. Understanding the mechanism enables a new treatment, targeted chemotherapy.
- Targeted therapies are generally made to show their effects by targeting molecules that are characteristic of cancer cells. (matrix), cell cycle regulator, and apoptosis.
- matrix matrix
- cell cycle regulator cell cycle regulator
- apoptosis apoptosis inhibitors
- 'signal transduction pathway inhibitors' and 'angiogenesis inhibitors' including tyrosine kinase inhibitors, that are used as important target therapeutics in the treatment.
- Protein tyrosine kinases have been found to play an important role in many malignancies, and in particular, epidermal growth factor receptor (EGFR), a receptor tyrosine kinase of the erbB family, has been shown to play an important role in non-small cell lung cancer. It is abnormally active in many epithelial cell tumors, including NSCLC, breast cancer, glioma, squamous cell carcinoma of the head and neck, colorectal cancer, rectal carcinoma, head and neck cancer, gastric cancer and prostate cancer, and the EGFR-tyrosine kinase It has been known that activation causes sustained cell proliferation, invasion of surrounding tissues, distant metastasis, angiogenesis, and increases cell survival.
- EGFR epidermal growth factor receptor
- the EGFR is one of the ErbB tyrosine kinase receptors family (EGFR, HER-2, ErbB-3, ErbB-4), which includes an extracellular ligand-binding domain and a tyrosine kinase domain It is a transmembrane tyrosine kinase that has an intracellular domain including a tyrosine kinase domain.
- Non-Patent Document 1 Nat Rev Cancer 2007; 7:169-81. Epidermal growth factor receptor mutations in lung cancer).
- EGFR is overexpressed in more than half of non-small cell lung cancer (NSCLC), and many studies have been conducted as a target for treatment.
- EGFR TKIs tyrosine kinase inhibitors
- representative drugs include the first-generation drug gefitinib (IRESSA TM ), second-generation drug erlotinib (TARCEVA TM ), lapatinib (TYKERB TM , TYVERB TM ).
- an activating mutation of EGFR correlates with a response to gefitinib therapy in nonsmall-cell lung cancer (NSCLC). More specifically, the EGFR mutations are largely divided into sensitizing mutations and resistant mutations. The deletion of exon 19 and the L858R point mutation in exon 21 are the most important sensitizing mutations, and about 85- It accounts for 90%, and mutations in exon 19 are known to have better sensitivity to TKIs. On the other hand, the T790M point mutation in exon 20 is known to be found in more than 50% of acquired resistance patients as the most important resistance mutation.
- Somatic mutations identified to date include in-frame deletions in exon 19 or insertions in exon 20, as well as point mutations that alter a single nucleic acid residue within an expressed protein (e.g., L858R, G719S, G719C, G719A, L861Q).
- EGFR_del19 or EGFR_L858R is a major cause of non-small cell lung cancer and head and neck cancer, and their therapeutic drugs, Iressa and Tarceva, have been developed and are currently used in clinical practice.
- these drugs were used in patients, acquired resistance was observed in which EGFR secondary mutations based on the drug's structure were observed, and it was also found that this is the main cause of actual drug resistance.
- EGFR 1st generation inhibitors are used for an average of about 10 months, acquired resistance, called the T790M mutation located in the gatekeeper of EGFR kinase, occurs, so that EGFR 1st generation inhibitors do not have a drug effect. That is, EGFR_del19_T790M or EGFR_L858R_T790M double mutations occur, preventing the existing therapeutic agents from exhibiting drug efficacy.
- An object of one aspect of the present invention is to provide a benzamide derivative capable of preventing or treating cancer by inhibiting EGFR mutation.
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the benzamide derivative as an active ingredient.
- Another object of the present invention is to provide a health functional food composition for preventing or improving cancer containing the benzamide derivative as an active ingredient.
- Another object of the present invention is to provide a combination preparation for preventing or treating cancer containing the benzamide derivative as an active ingredient.
- a compound represented by Formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is provided.
- X, Y and Z are independently carbon or nitrogen atoms
- R 1 is -H, -OH, halogen, C 1-10 alkyl unsubstituted or substituted with one or more halogens, C 1-10 alkoxy unsubstituted or substituted with one or more halogens, nitro, C 1-10 alkylsulfanyl , cyano, amino, C 1-10 alkylamino, or 5-6 membered heteroaryl;
- R 2 is substituted C 6-10 aryl or substituted 5-10 membered heteroaryl
- substituted C 6-10 aryl or substituted 5-10 membered heteroaryl is, respectively, halogen, unsubstituted or substituted C 1-10 alkyl and unsubstituted or substituted 4-10 membered fully or partially saturated hetero
- At least one substituent selected from the group consisting of cycloalkyl is a substituted aryl or heteroaryl
- substituted C 1-10 alkyl is substituted with a 5-6 membered heterocycloalkyl substituted with 1 or 2 C 1-5 alkyl substituted amino;
- the substituted 4-10 membered fully or partially saturated heterocycloalkyl is -OH, halogen, unsubstituted or one or more halogen substituted C 1-5 alkyl, 5-6 membered heterocycloalkyl substituted C 1- 5 alkyl, unsubstituted or substituted with one or more halogens C 1-5 alkoxy, nitro, C 1-5 alkylsulfanyl, cyano, unsubstituted or substituted with 1 or 2 C 1-5 alkyl amino, unsubstituted or 5-6 membered heterocycloalkyl substituted with C 1-5 alkyl, C 1-5 alkoxycarbonyl, 5-6 membered heteroaryl, C 6-10 arylaminocarbonyl and C 1-5 alkoxy-C 1- is a 4-10 membered heterocycloalkyl substituted with at least one substituent selected from the group consisting of 5 alkoxy-C 6-10 aryl;
- R 3 is halogen
- R 4 is —OH, halogen, or C 1-15 alkoxy
- R 5 is -H, -OH, halogen, C 1-4 alkyl, or C 1-4 alkoxy;
- R 6 is -H, -OH, halogen, C 1-4 alkyl, or C 1-4 alkoxy.
- Another aspect of the present invention is a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- Another aspect of the present invention is a health function for preventing or improving cancer containing the compound represented by Formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- a food composition is provided.
- Another aspect of the present invention is a combination preparation for preventing or treating cancer containing the compound represented by Formula 1, its optical isomer, its solvate, its hydrate, or its pharmaceutically acceptable salt as an active ingredient. to provide.
- the benzamide derivatives provided in one aspect of the present invention can be used for the prevention or treatment of cancer by suppressing EGFR mutation, and when administered in combination with EGFR antagonists such as Cetuximab, a significant increase in anticancer activity (synergy) ) and can be usefully used as an anticancer agent.
- EGFR antagonists such as Cetuximab
- alkylene alkenyl or “alkyl”, unless otherwise specified, include straight or branched chain saturated hydrocarbon moieties.
- C1-6 alkyl means an alkyl having a backbone of 1 to 6 carbons. Specifically, C1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl and the like.
- cycloalkyl includes carbocyclic groups containing carbon atoms, unless otherwise specified.
- C3-C8 cycloalkyl means a cycloalkyl with a backbone of 3 to 8 carbons.
- C3-C8 cycloalkyl may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- heterocycloalkyl includes monovalent saturated moieties consisting of 1 to 3 rings containing 1, 2, 3 or 4 heteroatoms selected from N, O or S.
- the two or three rings may include bridged, fused or spiro heterocycloalkyls.
- heteroaryl refers to a single ring or two or three fused rings having one or more aromatic rings containing 1, 2, 3 or 4 ring heteroatoms selected from N, O or S. It may contain an aromatic radical of
- a compound represented by Formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is provided.
- X, Y and Z are independently carbon or nitrogen atoms
- R 1 is -H, -OH, halogen, C 1-10 alkyl unsubstituted or substituted with one or more halogens, C 1-10 alkoxy unsubstituted or substituted with one or more halogens, nitro, C 1-10 alkylsulfanyl , cyano, amino, C 1-10 alkylamino, or 5-6 membered heteroaryl;
- R 2 is substituted C 6-10 aryl or substituted 5-10 membered heteroaryl
- substituted C 6-10 aryl or substituted 5-10 membered heteroaryl is, respectively, halogen, unsubstituted or substituted C 1-10 alkyl and unsubstituted or substituted 4-10 membered fully or partially saturated hetero
- At least one substituent selected from the group consisting of cycloalkyl is a substituted aryl or heteroaryl
- substituted C 1-10 alkyl is substituted with a 5-6 membered heterocycloalkyl substituted with 1 or 2 C 1-5 alkyl substituted amino;
- the substituted 4-10 membered fully or partially saturated heterocycloalkyl is -OH, halogen, unsubstituted or one or more halogen substituted C 1-5 alkyl, 5-6 membered heterocycloalkyl substituted C 1- 5 alkyl, unsubstituted or substituted with one or more halogens C 1-5 alkoxy, nitro, C 1-5 alkylsulfanyl, cyano, unsubstituted or substituted with 1 or 2 C 1-5 alkyl amino, unsubstituted or 5-6 membered heterocycloalkyl substituted with C 1-5 alkyl, C 1-5 alkoxycarbonyl, 5-6 membered heteroaryl, C 6-10 arylaminocarbonyl and C 1-5 alkoxy-C 1- is a 4-10 membered heterocycloalkyl substituted with at least one substituent selected from the group consisting of 5 alkoxy-C 6-10 aryl;
- R 3 is halogen
- R 4 is —OH, halogen, or C 1-15 alkoxy
- R 5 is -H, -OH, halogen, C 1-4 alkyl, or C 1-4 alkoxy;
- R 6 is -H, -OH, halogen, C 1-4 alkyl, or C 1-4 alkoxy.
- X, Y and Z are independently carbon or nitrogen atoms
- R 1 is -H, -OH, halogen, C 1-5 alkyl unsubstituted or substituted with one or more halogens, C 1-5 alkoxy unsubstituted or substituted with one or more halogens, nitro, C 1-5 alkylsulfanyl , cyano, amino, C 1-5 alkylamino, or 5-6 membered heteroaryl;
- R 2 is substituted C 6-10 aryl or substituted 5-6 membered heteroaryl
- substituted C 6-10 aryl or substituted 5-6 membered heteroaryl is, respectively, a halogen, an unsubstituted or substituted C 1-5 alkyl, and an unsubstituted or substituted 4-8 membered 4-8 membered group containing at least one N.
- At least one substituent selected from the group consisting of fully or partially saturated heterocycloalkyl is a substituted aryl or heteroaryl,
- substituted C 1-5 alkyl is substituted with a 6-membered heterocycloalkyl in which two C 1-5 alkyl are substituted with substituted amino;
- the substituted 4-8 membered fully or partially saturated heterocycloalkyl is -OH, halogen, unsubstituted or one or more halogen substituted C 1-5 alkyl, or 5-6 membered heterocycloalkyl substituted C 1 -5 alkyl, unsubstituted or substituted with one or more halogens C 1-5 alkoxy, nitro, C 1-5 alkylsulfanyl, cyano, unsubstituted or substituted with 1 or 2 C 1-5 alkyl amino, non-substituted 5-6 membered heterocycloalkyl substituted by ring or C 1-5 alkyl, C 1-5 alkoxycarbonyl, 5-6 membered heteroaryl, C 6-10 arylaminocarbonyl and C 1-5 alkoxy-C 1 -5 alkoxy- C 6-10 4-8 membered heterocycloalkyl substituted with at least one substituent selected from the group consisting of aryl;
- R 3 is halogen
- R 4 is —OH, halogen, or C 1-10 alkoxy
- R 5 is -H, -OH, or halogen
- R 6 can be -H, halogen, C 1-4 alkyl, or C 1-4 alkoxy.
- X, Y and Z are independently carbon or nitrogen atoms
- R 1 is -H, -OH, halogen, C 1-5 alkyl unsubstituted or substituted with one or more halogens, C 1-5 alkoxy unsubstituted or substituted with one or more halogens, nitro, C 1-5 alkylsulfanyl , cyano, amino, C 1-5 alkylamino, or 5-membered heteroaryl containing at least one N;
- R 2 is substituted phenyl or substituted 6-membered heteroaryl containing at least one N;
- substituted phenyl or substituted 6-membered heteroaryl is an unsubstituted or substituted 4 to 8-membered fully or partially saturated hetero group containing at least one halogen, unsubstituted or substituted C 1-3 alkyl, and N, respectively.
- At least one substituent selected from the group consisting of cycloalkyl is substituted phenyl or heteroaryl,
- substituted C 1-3 alkyl is substituted with a 6-membered heterocycloalkyl in which two C 1-3 alkyl are substituted with substituted amino;
- the substituted 4-8 membered heterocycloalkyl is -OH, unsubstituted or 5-6 membered heterocycloalkyl substituted C 1-3 alkyl, unsubstituted or 1 or 2 C 1-3 alkyl substituted amino , 5-6 membered heterocycloalkyl unsubstituted or substituted with C 1-3 alkyl, C 1-4 alkoxycarbonyl, 5-membered heteroaryl containing at least one N, phenylaminocarbonyl and C 1-3 alkoxy- C 1-3 is a 4-8 membered heterocycloalkyl substituted with at least one substituent selected from the group consisting of alkoxy-phenyl;
- R 3 is halogen
- R 4 is —OH, halogen, or C 1-5 alkoxy
- R 5 is -H, -OH, or halogen
- R 6 can be -H, halogen, C 1-4 alkyl, or C 1-4 alkoxy.
- X, Y and Z are independently carbon or nitrogen atoms
- R 1 is -H, -F, -Cl, -OH, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , iso-propyl, tert-butyl, -SCH 3 , -NO 2 , -CN, or imidazole;
- R 3 is -F, or -Cl
- R 4 is -OH, or -OCH 3 ;
- R 5 is -H, -OH, -F, -Cl, C 1-4 straight or branched chain alkyl, or C 1-4 straight or branched chain alkoxy;
- R 6 can be -H, -OH, -F, -Cl, C 1-4 straight-chain or branched-chain alkyl, or C 1-4 straight-chain or branched-chain alkoxy.
- X is a carbon or nitrogen atom
- Y and Z are carbon atoms
- R 1 is -H, -F, -Cl, -OH, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , iso-propyl, tert-butyl, -SCH 3 , -NO 2 , -CN, or imidazole;
- R 3 is -F
- R 4 is -OH, or -OCH 3 ;
- R 5 is -H
- R 6 can be -H, -F, or -Cl.
- the compound represented by Formula 1 may be a compound represented by Formula 2 below.
- X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently as defined in Formula 1 above.
- X is a carbon or nitrogen atom
- Y and Z are carbon atoms
- R 1 is -H, -F, -Cl, -OH, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , iso-propyl, tert-butyl, -SCH 3 , -NO 2 , -CN, or imidazole;
- R 3 is -F
- R 4 is -OH or -OCH 3 ;
- R 5 is -H
- R 6 can be -H, -F or -Cl.
- the compound represented by Formula 1 may be any one compound selected from the following compound groups.
- the compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
- Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
- Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, etc., organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get from Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulphate, sulphite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i.
- the acid addition salt according to the present invention can be prepared by a conventional method.
- a precipitate formed by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid thereto It may be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.
- a pharmaceutically acceptable metal salt may be prepared using a base.
- An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt.
- the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).
- the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like prepared therefrom.
- hydrate refers to a compound of the present invention that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or a salt thereof.
- the hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
- the hydrate may contain 1 equivalent or more, preferably 1 to 5 equivalents of water.
- Such a hydrate may be prepared by crystallizing the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof of the present invention from water or a water-containing solvent.
- solvate refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
- Preferred solvents in this regard are those that are volatile, non-toxic, and/or suitable for administration to humans.
- isomers refers to compounds of the present invention or salts thereof that have the same chemical formula or molecular formula but differ structurally or sterically. These isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers (enantiomers). All these isomers and mixtures thereof are also included within the scope of the present invention.
- the compound represented by Formula 1 may be prepared through the general formula described below, and representative formulas 1 to 2 corresponding to the preparation process of the compound of Example 1 are shown below.
- Another aspect of the present invention is,
- a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- the compound may prevent or treat cancer by inhibiting EGFR (epidermal growth factor receptor) mutations
- EGFR epidermal growth factor receptor
- the EGFR (epidermal growth factor receptor) mutations are from the group consisting of EGFR L858R/T790M and EGFR L858R/T790M/C797S. There may be one or more selected.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms during clinical administration. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient, for example, starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
- Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc.
- various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included.
- Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, and emulsions.
- Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
- a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration is performed by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. depending on how
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed in water together with a stabilizer or buffer to prepare a solution or suspension, which is prepared in an ampoule or vial unit dosage form can be manufactured with
- the composition may be sterilized and/or contain preservatives, stabilizers, hydration agents or emulsification accelerators, salts and/or buffers for osmotic pressure control, and other therapeutically useful substances, and may contain conventional methods such as mixing and granulation. It can be formulated according to the coating or coating method.
- Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally boric acid such as starch, agar, alginic acid or its sodium salt. release or effervescent mixtures and/or absorbents, colorants, flavors, and sweeteners.
- binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally
- the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
- pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment or improvement, and the effective dose level is dependent on the type and severity of the subject, age, sex, and activity of the drug. , sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field. For example, effective amounts of 0.001 mg/kg to 100 mg/kg, 0.01 mg/kg to 10 mg/kg or 0.1 mg/kg to 1 mg/kg are included.
- the upper limit of the amount of the pharmaceutical composition of the present invention can be selected and implemented by those skilled in the art within an appropriate range.
- Another aspect of the present invention is,
- a health functional food composition for preventing or improving cancer containing the compound represented by Formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is provided.
- the compound represented by Formula 1 according to the present invention may be added to food as it is or used together with other foods or food ingredients, and may be appropriately used according to conventional methods.
- the mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement).
- the amount of the compound in the health food may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food.
- the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
- the health functional beverage composition of the present invention is not particularly limited in other components except for containing the compound as an essential component in the indicated ratio, and may contain various flavoring agents or natural carbohydrates as additional components like conventional beverages.
- natural carbohydrates include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrins, cyclodextrins, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol.
- natural flavoring agents thaumatin, stevia extract (eg rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can advantageously be used.
- the proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.
- the compound represented by Formula 1 according to the present invention is various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pect acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like.
- the compound represented by Formula 1 of the present invention may contain fruit flesh for preparing natural fruit juice, fruit juice beverages, and vegetable beverages.
- Another aspect of the present invention is,
- a combination preparation for preventing or treating cancer containing the compound represented by Formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is provided.
- the combination preparation may be a combination administration of one or more selected from the components described below together with the compound represented by Formula 1.
- the anti-cancer treatment described above herein may be applied as a monotherapy, or may include conventional surgery or radiotherapy or chemotherapy or immunotherapy in addition to the compound of the present invention.
- Such chemotherapy can be administered concurrently, sequentially or separately with treatment with a compound of the present invention, which can include one or more of the following categories of anti-cancer agents.
- antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (e.g., cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard , melphalan, chlorambucil, busulfan, temozolamide and nitrosourea); antimetabolites (eg gemcitabine and antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (eg anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, dactinomycin and mithramycin); mitotic inhibitors (eg, vinca alkaloids such as vincribid
- cytostatic agents such as antiestrogens (eg tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodooxifene), antiandrogens (eg bicalutamide, flo tamid, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (eg goserelin, leuprorelin and buserelin), progesterones (eg megestrol acetate), aroma enzyme inhibitors (eg, anastrozole, letrozole, vorazole and eximestane) and inhibitors of 5 ⁇ -reductase such as finasteride;
- antiestrogens eg tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodooxifene
- antiandrogens eg
- invasion inhibitors eg c-Src kinase class inhibitors such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazine-1 -yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline [AZD0530 (Saracatinib); WO 01/94341], N-(2-chloro-6-methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl amino ⁇ thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med.
- c-Src kinase class inhibitors such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazine-1 -yl)ethoxy]-5-tetrahydropyran-4-yloxyquin
- growth factor action inhibitors include growth factor antibodies and growth factor receptor antibodies (eg, anti-erbB2 antibody trastuzumab [HerceptinTM], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuk) Simab [Erbitux, C225] and any growth factor or growth factor receptor antibody disclosed in Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
- tyrosine kinase inhibitor for example an epidermal growth factor class inhibitor (eg an EGFR class tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3 -Morpholinopropoxy)-quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4- Amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine ( CI 1033), N-(2-[2-Dimethylaminoethyl-methylamino]-5- ⁇ [4-(1H-indol-3-yl)pyrimidin-2-yl]amino
- angiogenesis inhibitors such as those that inhibit the effect of vascular endothelial growth factor [eg, the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM), and, for example, VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindole- 5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 of WO 00/47212), such as WO 97/22596, WO 97/ 30035, compounds such as those disclosed in WO 97/32856 and WO 98/13354, and compounds that act by other mechanisms (eg, linom
- vascular damaging agents such as Combretastatin A4 and the compounds disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
- antisense therapies eg, those against the targets listed above, such as ISIS 2503, anti-ras antisense;
- gene therapy approaches e.g., approaches to replace aberrant genes, such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches, such as cytosine approaches using aminase, thymidine kinase or bacterial nitroreductase enzymes, and approaches that increase patient resistance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy); and
- Immunotherapy approaches eg, ex vivo and in vivo approaches that increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor
- Approaches using, approaches that reduce T cell anergy, approaches using transfected immune cells, such as dendritic cells transfected with cytokines, approaches using tumor cell lines transfected with cytokines, anti-idiotypic antibodies approaches that reduce the action of immune suppressor cells such as regulatory T cells, myeloid derived suppressor cells or IDO (indole amine 2,3-deoxygenase) expressing dendritic cells, and tumor associated antigens such as NY- approaches using cancer vaccines consisting of proteins or peptides derived from ESO-1, MAGE-3, WT1 or Her2/neu).
- a pharmaceutical product for the combination treatment of cancer comprising a compound of formula (I) as defined above and a further anti-tumor agent as defined above.
- a pharmaceutical composition for the combined treatment of cancer comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and a further antitumor agent as defined above product is provided.
- combination treatment when used in reference to combination treatment, it should be understood that it may refer to simultaneous, separate or sequential administration.
- concomitant administration should be interpreted similarly.
- “combination therapy” refers to simultaneous administration.
- “combination treatment” refers to separate administration.
- “combination treatment” refers to sequential administration. If the administration is sequential or separate, a delay in administration of the second component should be such that the benefits of the effect resulting from the use of the combination are not lost. Therefore, in one embodiment, sequential treatment comprises administering each component of the combination within a period of 11 days. In another embodiment, the period is 10 days.
- the period is 9 days. In another embodiment, the period is 8 days. In another embodiment, the period is 7 days. In another embodiment, the period is no more than 6 days. In another embodiment, the period is no more than 5 days. In another embodiment, the period is no more than 4 days. In another embodiment, the period is no more than 3 days. In another embodiment, the period is no more than 2 days. In another embodiment, the period of time is less than 24 hours. In another embodiment, the period is no more than 12 hours.
- Another aspect of the present invention is,
- a method for treating cancer comprising administering to a subject is provided.
- Another aspect of the present invention is,
- a compound represented by Formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in preventing or treating cancer is provided.
- Another aspect of the present invention is,
- the benzamide derivatives provided in one aspect of the present invention can be used for the prevention or treatment of cancer by suppressing EGFR mutation, and when administered in combination with EGFR antagonists such as Cetuximab, a significant increase in anticancer activity (synergy) ) effect can be usefully used as an anticancer agent, which is supported by examples and experimental examples described later.
- EGFR antagonists such as Cetuximab
- the reaction was quenched by adding a saturated aqueous solution of NH 4 Cl to the mixture, and extracted with ethyl acetate. The ethyl acetate layer was collected, dried over anhydrous magnesium sulfate and filtered. The solvent was removed via evaporation under reduced pressure.
- Methyl 4'-hydroxy-5-methyl-[1,1'-biphenyl]-3-carboxylate 100 mg, 0.41 mmol
- trifluoromethanesulfonic anhydride dissolved in anhydrous dichloromethane at room temperature (128 mg, 0.45 mmol)
- pyridine 0.052 ml, 0.64 mmol
- the mixture was stirred for 3 h.
- the residue was extracted with water, sodium bicarbonate and washed with brine.
- the organic layer was dried over magnesium sulfate, filtered and concentrated.
- Example compounds prepared in Examples 1 to 62 are summarized and shown in Table 1 below.
- Example rescue Example rescue One 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62
- the cell growth inhibition ability of the compound of the present invention on Ba/F3 cell lines in which EGFR WT and mutations were overexpressed was evaluated using the CellTiter 96 AQueous Non-Radioactive Cell Proliferation Assay system sold by Promega, as follows. experimented. AQueous Non-Radioactive Cell Proliferation Assay shows that MTS (3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2- (4-sulfophenyl)-2H-tetrazolium) is reduced with Formazan and the degree of color development is measured to confirm the cell growth inhibition ability.
- MTS 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2- (4-sulfophenyl)-2H-tetrazolium
- the /C797S (LTC) mutation cell line was purchased and used as a cell line provided by Professor Cho Byeong-cheol's laboratory at Yonsei University. All cell lines were cultured in RPMI containing 10% FBS and 1% penicillin-streptomycin with 1 ⁇ g/ml of puromycine added to them in a 37°C 5% CO 2 incubator.
- the cell survival inhibitory effect of the compound according to each EGFR mutation was analyzed according to the following analysis reaction method.
- the relative value (% Control) compared to 0 nM was obtained to confirm the cell growth inhibitory ability of the compound.
- the measured values were analyzed using the Prism program (version 8.0, Graphpad Software, Inc.), and the IC 50 value (Inhibition concentration50), which is an indicator of the compound's cell growth inhibitory ability, was calculated.
- the compounds of the present invention exhibit very good activity against EGFR L858R/T790M and L858R/T790M/C797S mutations.
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Abstract
Description
실시예 | 구조 | 실시예 | 구조 |
1 | 2 | ||
3 | 4 | ||
5 | 6 | ||
7 | 8 | ||
9 | 10 | ||
11 | 12 | ||
13 | 14 | ||
15 | 16 | ||
17 | 18 | ||
19 | 20 | ||
21 | 22 | ||
23 | 24 | ||
25 | 26 | ||
27 | 28 | ||
29 | 30 | ||
31 | 32 | ||
33 | 34 | ||
35 | 36 | ||
37 | 38 | ||
39 | 40 | ||
41 | 42 | ||
43 | 44 | ||
45 | 46 | ||
47 | 48 | ||
49 | 50 | ||
51 | 52 | ||
53 | 54 | ||
55 | 56 | ||
57 | 58 | ||
59 | 60 | ||
61 | 62 |
실시예 | Ba/F3 EGFR double mutant L858R/T790M, IC50 (nM) |
Ba/F3 EGFR triple mutant L858R/T790M/C797S, IC50 (nM) |
1 | +++ | +++ |
2 | + | + |
3 | + | + |
4 | + | + |
5 | +++ | + |
6 | + | + |
7 | + | + |
8 | + | + |
9 | + | + |
10 | +++ | ++ |
11 | + | + |
12 | ++ | + |
13 | + | + |
14 | ++ | + |
15 | + | + |
16 | +++ | ++ |
17 | +++ | +++ |
18 | +++ | +++ |
19 | +++ | +++ |
20 | ++ | + |
21 | +++ | +++ |
22 | +++ | +++ |
23 | +++ | +++ |
24 | +++ | +++ |
25 | +++ | +++ |
26 | +++ | ++ |
27 | ++ | + |
28 | + | + |
29 | +++ | ++ |
30 | + | + |
31 | + | + |
32 | +++ | +++ |
33 | +++ | +++ |
34 | +++ | ++ |
35 | + | +++ |
36 | +++ | +++ |
37 | ++ | +++ |
38 | + | + |
39 | +++ | +++ |
40 | +++ | ++ |
41 | +++ | +++ |
42 | +++ | ++ |
43 | +++ | ++ |
44 | +++ | +++ |
45 | +++ | +++ |
46 | - | +++ |
47 | - | + |
48 | - | ++ |
49 | - | +++ |
50 | - | +++ |
51 | - | + |
52 | - | + |
53 | - | +++ |
54 | - | +++ |
55 | - | + |
56 | - | + |
+++: < 30 nM, ++: 30-200 nM, +:>200 nM |
Claims (15)
- 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 이의 용매화물, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염:[화학식 1]상기 화학식 1에서,X, Y 및 Z는 독립적으로 탄소 또는 질소 원자이고;R1은 -H, -OH, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 C1-10알킬, 비치환 또는 하나 이상의 할로겐이 치환된 C1-10알콕시, 니트로, C1-10알킬설파닐, 시아노, 아미노, C1-10알킬아미노, 또는 5-6원자헤테로아릴이고;R2는 치환된 C6-10아릴, 또는 치환된 5-10원자헤테로아릴이고,여기서 상기 치환된 C6-10아릴 또는 치환된 5-10원자헤테로아릴은 각각, 할로겐, 비치환 또는 치환된 C1-10알킬 및 비치환 또는 치환된 4-10원자의 완전 또는 부분 포화된 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 하나 이상의 치환체가 치환된 아릴 또는 헤테로아릴이고,여기서 상기 치환된 C1-10알킬은 1 또는 2개의 C1-5알킬이 치환된 아미노로 치환된 5-6원자헤테로사이클로알킬로 치환되고,상기 치환된 4-10원자의 완전 또는 부분 포화된헤테로사이클로알킬은 -OH, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 C1-5알킬, 5-6원자헤테로사이클로알킬이 치환된 C1-5알킬, 비치환 또는 하나 이상의 할로겐이 치환된 C1-5알콕시, 니트로, C1-5알킬설파닐, 시아노, 비치환 또는 1 또는 2개의 C1-5알킬이 치환된 아미노, 비치환 또는 C1-5알킬로 치환된 5-6원자헤테로사이클로알킬, C1-5알콕시카보닐, 5-6원자헤테로아릴, C6-10아릴아미노카보닐 및 C1-5알콕시-C1-5알콕시- C6-10아릴로 이루어지는 군으로부터 선택되는 하나 이상의 치환체가 치환된 4-10원자헤테로사이클로알킬이고;R3은 할로겐이고;R4는 -OH, 할로겐, 또는 C1-15알콕시이고;R5는 -H, -OH, 할로겐, C1-4알킬, 또는 C1-4알콕시이고; 및R6은 -H, -OH, 할로겐, C1-4알킬, 또는 C1-4알콕시이다.
- 제1항에 있어서,X, Y 및 Z는 독립적으로 탄소 또는 질소 원자이고;R1은 -H, -OH, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 C1-5알킬, 비치환 또는 하나 이상의 할로겐이 치환된 C1-5알콕시, 니트로, C1-5알킬설파닐, 시아노, 아미노, C1-5알킬아미노, 또는 5-6원자헤테로아릴이고;R2는 치환된 C6-10아릴, 또는 치환된 5-6원자헤테로아릴이고,여기서 상기 치환된 C6-10아릴 또는 치환된 5-6원자헤테로아릴은 각각, 할로겐, 비치환 또는 치환된 C1-5알킬 및 N을 하나 이상 포함하는 비치환 또는 치환된 4-8원자의 완전 또는 부분포화된 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 하나 이상의 치환체가 치환된 아릴 또는 헤테로아릴이고,여기서 상기 치환된 C1-5알킬은 2개의 C1-5알킬이 치환된 아미노로 치환된 6원자헤테로사이클로알킬로 치환되고,상기 치환된 4-8원자의 완전 또는 부분 포화된 헤테로사이클로알킬은 -OH, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 C1-5알킬, 또는 5-6원자헤테로사이클로알킬이 치환된 C1-5알킬, 비치환 또는 하나 이상의 할로겐이 치환된 C1-5알콕시, 니트로, C1-5알킬설파닐, 시아노, 비치환 또는 1 또는 2개의 C1-5알킬이 치환된 아미노, 비치환 또는 C1-5알킬로 치환된 5-6원자헤테로사이클로알킬, C1-5알콕시카보닐, 5-6원자헤테로아릴, C6-10아릴아미노카보닐 및 C1-5알콕시-C1-5알콕시- C6-10아릴로 이루어지는 군으로부터 선택되는 하나 이상의 치환체가 치환된 4-8원자헤테로사이클로알킬이고;R3은 할로겐이고;R4는 -OH, 할로겐, 또는 C1-10알콕시이고;R5는 -H, -OH, 또는 할로겐이고; 및R6은 -H, 할로겐, C1-4알킬, 또는 C1-4알콕시인 것을 특징으로 하는,화합물, 이의 광학 이성질체, 이의 용매화물, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염.
- 제1항에 있어서,X, Y 및 Z는 독립적으로 탄소 또는 질소 원자이고;R1은 -H, -OH, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 C1-5알킬, 비치환 또는 하나 이상의 할로겐이 치환된 C1-5알콕시, 니트로, C1-5알킬설파닐, 시아노, 아미노, C1-5알킬아미노, 또는 N을 하나 이상 포함하는 5원자헤테로아릴이고;R2는 치환된 페닐, 또는 N을 하나 이상 포함하는 치환된 6원자헤테로아릴이고,여기서 상기 치환된 페닐 또는 치환된 6원자헤테로아릴은 각각, 할로겐, 비치환 또는 치환된 C1-3알킬 및 N을 하나 이상 포함하는 비치환 또는 치환된 4 내지 8원자의 완전 또는 부분포화된 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 하나 이상의 치환체가 치환된 페닐 또는 헤테로아릴이고,여기서 상기 치환된 C1-3의 알킬은 2개의 C1-3알킬이 치환된 아미노로 치환된 6원자헤테로사이클로알킬로 치환되고,상기 치환된 4-8원자의 헤테로사이클로알킬은 -OH, 비치환 또는 5-6원자헤테로사이클로알킬이 치환된 C1-3알킬, 비치환 또는 1 또는 2개의 C1-3알킬이 치환된 아미노, 비치환 또는 C1-3알킬로 치환된 5-6원자헤테로사이클로알킬, C1-4알콕시카보닐, N을 하나이상 포함하는 5원자헤테로아릴, 페닐아미노카보닐 및 C1-3알콕시-C1-3알콕시-페닐로 이루어지는 군으로부터 선택되는 하나 이상의 치환체가 치환된 4-8원자헤테로사이클로알킬이고;R3은 할로겐이고;R4는 -OH, 할로겐, 또는 C1-5알콕시이고;R5는 -H, -OH, 또는 할로겐이고; 및R6은 -H, 할로겐, C1-4알킬, 또는 C1-4알콕시인 것을 특징으로 하는,화합물, 이의 광학 이성질체, 이의 용매화물, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염.
- 제1항에 있어서,X, Y 및 Z는 독립적으로 탄소 또는 질소 원자이고;R1은 -H, -F, -Cl, -OH, -CH3, -CF3, -OCH3, -OCF3, iso-프로필, tert-부틸, -SCH3, -NO2, -CN, 또는 이미다졸이고,R3은 -F, 또는 -Cl이고;R4는 -OH, 또는 -OCH3이고;R5는 -H, -OH, -F, -Cl, C1-4알킬, 또는 C1-4알콕시이고; 및R6은 -H, -OH, -F, -Cl, C1-4알킬, 또는 C1-4알콕시인 것을 특징으로 하는,화합물, 이의 광학 이성질체, 이의 용매화물, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염.
- 제1항에 있어서,상기 화학식 1로 표시되는 화합물은, 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물, 이의 광학 이성질체, 이의 용매화물, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염:(1) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸-[1,1'-비페닐]-3-카르복스아미드;(2) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-이소프로필-[1,1'-비페닐]-3-카르복스아미드;(3) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메톡시-[1,1' -비페닐]-3-카르복스아미드;(4) (R)-4'-(4-아미노피페리딘-1-일)-5-(tert-부틸)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-[1,1'-비페닐]-3-카르복스아미드;(5) (R)-4'-(4-아미노피페리딘-1-일)-5-플루오로-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-[1,1'-비페닐]-3-카르복스아미드;(6) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-(트리플루오로메틸)-[1,1'-비페닐]-3-카르복사미드;(7) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-니트로-[1,1'-비페닐]-3-카르복사미드;(8) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-(메틸티오)-[1,1'-비페닐]-3-카르복사미드;(9) (R)-4'-(4-아미노피페리딘-1-일)-5-시아노-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-[1,1'-비페닐]-3-카르복사미드;(10) (R)-4'-(4-아미노피페리딘-1-일)-5-클로로-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-[1,1'-비페닐]-3-카르복스아미드;(11) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-(트리플루오로메톡시)-[1,1'-비페닐]-3-카르복스아미드;(12) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-메톡시페닐)(1H-인돌-2-일)메틸)-5-(트리플루오로메톡시)-[1,1'-비페닐]-3-카르복스아미드;(13) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-(1H-이미다졸-1-일)-[1,1'-비페닐]-3-카르복스아미드;(14) (R)-2-(4-(4-아미노피페리딘-1-일)페닐)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)이소니코틴아미드;(15) (R)-2-(4-(4-아미노피페리딘-1-일)페닐)-N-((5-플루오로-2-메톡시페닐)(1H-인돌-2-일)메틸)이소니코틴아미드;(16) (R)-3-(2-(4-아미노피페리딘-1-일)피리미딘-5-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드;(17) (R)-3-(5-(4-아미노피페리딘-1-일)피리딘-2-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드;(18) (R)-3-(5-(4-아미노피페리딘-1-일)피라진-2-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드;(19) (R)-3-(6-(4-아미노피페리딘-1-일)피리딘-3-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드;(20) (R)-3-(6-(4-아미노피페리딘-1-일)피리다진-3-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드;(21) (R)-3-(5-(4-아미노피페리딘-1-일)피리미딘-2-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드;(22) (R)-4'-(4-아미노피페리딘-1-일)-3'-플루오로-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸-[1,1'-비페닐]-3-카르복스아미드;(23) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-2',5-디메틸-[1,1'-비페닐]-3-카르복스아미드;(24) (R)-4'-(4-아미노피페리딘-1-일)-2'-플루오로-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸-[1,1'-비페닐]-3-카르복스아미드;(25) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-3',5-디메틸-[1,1'-비페닐]-3-카르복스아미드;(26) (R)-4'-(4-아미노피페리딘-1-일)-N-((6-플루오로-1H-인돌-2-일)(5-플루오로-2-히드록시페닐)메틸)-5-메틸-[1,1'-비페닐]-3-카르복스아미드;(27) (R)-4'-(4-아미노피페리딘-1-일)-N-((6-클로로-1H-인돌-2-일)(5-플루오로-2-히드록시페닐)메틸)-5-메틸-[1,1'-비페닐]-3-카르복스아미드;(28) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-6-메틸-[1,1'-비페닐]-3-카르복스아미드;(29) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-4-메틸-[1,1'-비페닐]-3-카르복스아미드;(30) (R)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-2-메틸-[1,1'-비페닐]-3-카르복스아미드;(31) (S)-4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸-[1,1'-비페닐]-3-카르복스아미드;(32) 4'-(4-아미노피페리딘-1-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸-[1,1'-비페닐]-3-카르복사미드;(33) (R)-3-(5-(4-아미노피페리딘-1-일)-4-메틸피리딘-2-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드;(34) (R)-3-(2-(4-아미노피페리딘-1-일)-4-메틸피리미딘-5-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드;(35) tert-부틸 (R)-4-(2-(3-(((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)카르바모일)-5-메틸페닐)피리미딘-5-일)피페라진-1-카르복실레이트;(36) (R)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-3-메틸-5-(5-(피페라진-1-일)피리미딘-2-일)벤즈아미드;(37) (R)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-3-메틸-5-(5-(4-메틸피페라진-1-일)피리미딘-2-일)벤즈아미드;(38) N-[(R)-(5-플루오로-2-히드록시-페닐)-(1H-인돌-2-일)메틸]-3-메틸-5-[5-(4-프로필-1-피페리딜)피리미딘-2-일]벤즈아미드;(39) 3-[5-[4-(디메틸아미노)-1-피페리딜]피리미딘-2-일]-N-[(R)-(5-플루오로-2-히드록시-페닐)-(1H-인돌-2-일)메틸]-5-메틸-벤즈아미드;(40) N-[(R)-(5-플루오로-2-히드록시-페닐)-(1H-인돌-2-일)메틸]-3-메틸-5-[5-(1-피페리딜)피리미딘-2-일]벤즈아미드;(41) N-[(R)-(5-플루오로-2-히드록시-페닐)-(1H-인돌-2-일)메틸]-3-메틸-5-[5-[4-(1-메틸-4-피페리딜)피페라진-1-일]피리미딘-2-일]벤즈아미드;(42) (R)-3-(5-((4-(디메틸아미노)피페리딘-1-일)메틸)피리딘-2-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일))메틸)-5-메틸벤즈아미드;(43) (R)-3-(6-((4-(디메틸아미노)피페리딘-1-일)메틸)피리딘-3-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일))메틸)-5-메틸벤즈아미드;(44) 3-[5-[(3R)-3-아미노피롤리딘-1-일]피리미딘-2-일]-N-[(R)-(5-플루오로-2-하이드록시-페닐)-(1H-인돌-2-일)메틸]-5-메틸-벤즈아미드;(45) (R)-3-(5-(4-(디에틸아미노)피페리딘-1-일)피리미딘-2-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드;(46) N-((R)-(5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-3-메틸-5-(5-(3-메틸-3,8-디아자비시클로[3.2.1]옥탄-8-일)피리미딘-2-일)벤즈아미드;(47) (R)-3-(5-(4-(1H-피롤-1-일)피페리딘-1-일)피리미딘-2-일)-N-((5-플루오로-2-하이드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드;(48) (R)-3-(5-(4-(1H-1,2,4-트리아졸-1-일)피페리딘-1-일)피리미딘-2-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드;(49) (R)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-3-(5-(4-히드록시피페리딘-1-일)피리미딘-2-일)-5-메틸벤즈아미드;(50) (R)-3-(5-([1,4'-비피페리딘]-1'-일)피리미딘-2-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드;(51) (R)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-3-메틸-5-(5-(4-(모르폴리노메틸)피페리딘-1-일)피리미딘-2-일)벤즈아미드;(52) (R)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-3-메틸-5-(5-(4-(피롤리딘-1-일메틸)피페리딘-1-일)피리미딘-2-일)벤즈아미드;(53) 3-[5-[(3R)-3-(디메틸아미노)피롤리딘-1-일]피리미딘-2-일]-N-[(R)-(5-플루오로-2-히드록시-페닐)-(1H-인돌-2-일)메틸]-5-메틸-벤즈아미드;(54) (R)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-3-메틸-5-(5-(4-(메틸아미노)피페리딘-1-일)피리미딘-2-일)벤즈아미드;(55) (R)-1-(2-(3-(((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)카르바모일)-5-메틸페닐)피리미딘-5-일)-N-페닐피페리딘-4-카르복사미드;(56) (R)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-3-(5-(4-(4-(2-메톡시에톡시)페닐)피페라진-1-일)피리미딘-2-일)-5-메틸벤즈아미드;(57) (R)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-3-메틸-5-(5-(1,2,3,6-테트라히드로피리딘-4-일)피리미딘-2-일)벤즈아미드;(58) (R)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-3-메틸-5-(5-(피페리딘-4-일)피리미딘-2-일)벤즈아미드;(59) (R)-3-(5-(3-아미노아제티딘-1-일)피리미딘-2-일)-N-((5-플루오로-2-하이드록시페닐)(1H-인돌-2-일)메틸)-5 -메틸벤즈아미드;(60) 3-(5-((S)-3-(디메틸아미노)피롤리딘-1-일)피리미딘-2-일)-N-((R)-(5-플루오로-2-히드록시페닐)(1H-인돌-2 -일)메틸)-5-메틸벤즈아미드;(61) 3-(5-((S)-3-아미노피롤리딘-1-일)피리미딘-2-일)-N-((R)-(5-플루오로-2-히드록시페닐)(1H-인돌-2-일) 메틸)-5-메틸벤즈아미드; 및(62) (R)-3-(5-(아제티딘-3-일)피리미딘-2-일)-N-((5-플루오로-2-히드록시페닐)(1H-인돌-2-일)메틸)-5-메틸벤즈아미드.
- 제1항의 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 이의 용매화물, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물.
- 제8항에 있어서,상기 화합물은 EGFR(epidermal growth factor receptor) 돌연변이를 억제하여 암을 예방 또는 치료하는 것을 특징으로 하는 약학적 조성물.
- 제9항에 있어서,상기 EGFR(epidermal growth factor receptor) 돌연변이는 EGFR L858R/T790M 및 EGFR L858R/T790M/C797S로 이루어지는 군으로부터 선택되는 하나 이상인 것을 특징으로 하는 약학적 조성물.
- 제1항의 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 이의 용매화물, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 개선용 건강기능식품 조성물.
- 제1항의 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 이의 용매화물, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 병용제제.
- 제12항에 있어서,상기 병용제제는 하기 군으로부터 선택되는 1종 이상의 성분과 함께 병용투여하는 것을 특징으로 하는 병용제제:시스플라틴, 옥살리플라틴, 카르보플라틴, 사이클로포스파미드, 질소 머스타드, 멜팔란, 클로람부실, 부술판, 테모졸아미드, 니트로소우레아, 겜시타빈, 항엽산제, 5-플루오로우라실, 테가푸르, 랄티트렉세드, 메토트렉세이트, 시토신 아라비노시드, 히드록시우레아, 아드리아마이신, 블레오마이신, 독소루비신, 다우노마이신, 에피루비신, 이다루비신, 미토마이신 C, 닥티노마이신, 미트라마이신, 빈크리스틴, 빈블라스틴, 빈데신, 비노렐빈, 탁솔, 탁소테레, 에토포시드, 테니포시드, 암사크린, 토포테칸, 캄프토테신, 타목시펜, 풀베스트란트, 토레미펜, 랄록시펜, 드롤록시펜, 요오드옥시펜, 비칼루타미드, 플로타미드, 닐루타미드, 사이프로테론 아세테이트, 고세렐린, 류프로렐린, 부세렐린, 메게스트롤 아세테이트, 아나스트로졸, 레트로졸, 보라졸, 엑시메스탄, 피나스테리드, 사라카티닙, 다사티닙, 보수티닙, 마리마스타트, 세툭시맙, 제피티닙, 에를로티닙, 패니투무맙, 오시메르티닙, 라파티닙, 이마티닙, 닐로티닙, 소라페닙, 티피파르닙, 로나파르닙, 베바시주맙, 반데타닙, 바탈라닙, 수니티닙, 악시티닙, 파조파닙, 4-(4-플루오로-2-메틸인돌-5-일옥시)-6-메톡시-7-(3-피롤리딘-1-일프로폭시)퀴나졸린, 콤브레타스타틴 A4, 지보텐탄 및 아트라센탄.
- 제1항의 화학식 1로 표시되는 화합물, 이의 광학이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 필요한 대상에게 투여하는 단계를 포함하는 암의 예방 또는 치료 방법.
- 암의 예방 또는 치료에 사용하기 위한 약제(medicament)를 제조하기 위한 제1항의 화학식 1로 표시되는 화합물, 이의 광학이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염의 용도.
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IL308518A IL308518A (en) | 2021-05-17 | 2022-05-13 | History of benzamide, a method for their preparation and a pharmaceutical preparation for use in the prevention or treatment of cancer containing them as an active ingredient |
MX2023013690A MX2023013690A (es) | 2021-05-17 | 2022-05-13 | Derivado de benzamida, metodo para preparar el mismo, y composicion farmaceutica para la prevencion o tratamiento del cancer que contiene el mismo como ingrediente activo. |
EP22804916.9A EP4342882A4 (en) | 2021-05-17 | 2022-05-13 | BENZAMIDE DERIVATIVE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION FOR THE PREVENTION OR TREATMENT OF CANCER USING IT AS ACTIVE INGREDIENT |
CN202280035706.4A CN117396463A (zh) | 2021-05-17 | 2022-05-13 | 用于预防或治疗癌症的苯甲酰胺衍生物、其制备方法和含有其作为活性成分的药物组合物 |
US18/561,855 US20240246948A1 (en) | 2021-05-17 | 2022-05-13 | Benzamide derivative, method for preparing same, and pharmaceutical composition for prevention or treatment of cancer containing same as active ingredient |
CA3220146A CA3220146A1 (en) | 2021-05-17 | 2022-05-13 | Benzamide derivatives, preparation method thereof, and pharmaceutical composition for use in preventing of treating cancer containing the same as an active ingredient |
AU2022276958A AU2022276958A1 (en) | 2021-05-17 | 2022-05-13 | Benzamide derivative, method for preparing same, and pharmaceutical composition for prevention or treatment of cancer containing same as active ingredient |
JP2023571530A JP2024519054A (ja) | 2021-05-17 | 2022-05-13 | ベンズアミド誘導体、その調製方法、およびそれを有効成分として含む、がんの予防または治療のための医薬組成物 |
BR112023024040A BR112023024040A2 (pt) | 2021-05-17 | 2022-05-13 | Composto, o isômero óptico do mesmo, o solvato do mesmo, o hidrato do mesmo ou o sal farmaceuticamente aceitável do mesmo e seu uso, composição farmacêutica que compreende o dito composto, composição de alimento funcional para a saúde e preparação combinada |
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- 2022-05-13 CA CA3220146A patent/CA3220146A1/en active Pending
- 2022-05-13 EP EP22804916.9A patent/EP4342882A4/en active Pending
- 2022-05-13 CN CN202280035706.4A patent/CN117396463A/zh active Pending
- 2022-05-13 WO PCT/KR2022/006895 patent/WO2022245061A1/ko active Application Filing
- 2022-05-13 MX MX2023013690A patent/MX2023013690A/es unknown
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- 2022-05-13 US US18/561,855 patent/US20240246948A1/en active Pending
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JP2024519054A (ja) | 2024-05-08 |
BR112023024040A2 (pt) | 2024-02-06 |
EP4342882A1 (en) | 2024-03-27 |
EP4342882A4 (en) | 2024-08-28 |
IL308518A (en) | 2024-01-01 |
CN117396463A (zh) | 2024-01-12 |
TW202306568A (zh) | 2023-02-16 |
KR20220156448A (ko) | 2022-11-25 |
MX2023013690A (es) | 2024-01-30 |
US20240246948A1 (en) | 2024-07-25 |
CA3220146A1 (en) | 2022-11-24 |
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