WO2021034087A1 - 신규한 암전이 억제 활성을 갖는 화합물, 이의 제조방법 및 상기 화합물을 포함하는 암 전이 및 침윤 억제, 또는 대장암 치료용 약학적 조성물 - Google Patents

신규한 암전이 억제 활성을 갖는 화합물, 이의 제조방법 및 상기 화합물을 포함하는 암 전이 및 침윤 억제, 또는 대장암 치료용 약학적 조성물 Download PDF

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WO2021034087A1
WO2021034087A1 PCT/KR2020/010999 KR2020010999W WO2021034087A1 WO 2021034087 A1 WO2021034087 A1 WO 2021034087A1 KR 2020010999 W KR2020010999 W KR 2020010999W WO 2021034087 A1 WO2021034087 A1 WO 2021034087A1
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oxo
benzamide
phenylethyl
oxoethyl
methyl
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PCT/KR2020/010999
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English (en)
French (fr)
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김경근
하형호
김항건
배우균
배정아
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주식회사 셀젠텍
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Priority to EP20853761.3A priority Critical patent/EP4019495A4/en
Priority to US17/634,361 priority patent/US20230150924A1/en
Publication of WO2021034087A1 publication Critical patent/WO2021034087A1/ko

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    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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    • 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
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a novel compound having cancer metastasis inhibiting activity, and a pharmaceutical composition for inhibiting cancer metastasis or treating colon cancer comprising the compound.
  • the number of deaths from cancer (malignant neoplasm) in Korea was 62,887, or 25.5% (29.6% of male deaths and 20.5% of female deaths) out of the total 246,515 deaths in Korea in 2002, and deaths from cancer accounted for the number one cause of death. have.
  • cancer treatment one of the biggest causes of failure to reduce the mortality rate of cancer patients is the failure to inhibit cancer cell invasion and metastasis during malignant tumor formation.
  • Recent studies have identified genes related to cancer metastasis (eg, Twist, KAI1), and through this, the molecular mechanism of the cancer metastasis process is at the level of elucidation. Therefore, drugs or treatment methods that can effectively inhibit or prevent cancer metastasis using genes related to cancer metastasis have not been reported yet. In the US, recent statistical analysis shows that metastatic cancer has not improved survival rates over the past 20 to 30 years.
  • KAI1 (Kangai 1) was initially identified as a suppressor of a transgene in prostate carcinoma.
  • the KAI1 protein is located in the human chromosome 11p11 and belongs to the transmembrane 4 superfamily (TM4SF).
  • KAI1 can regulate signal transduction from cell to cell and from cell to extracellular matrix (ECM), and may be involved in several basic biological processes such as fusion, migration, attachment, mutation and invasion.
  • ECM extracellular matrix
  • Reduced or deleted KAI1 expression has been demonstrated to be associated with metastasis and prognosis of various carcinomas including laryngeal cancer, prostate cancer, breast cancer, lung cancer, gastric cancer, colon cancer and hepatocellular carcinoma.
  • the present inventors have made intensive research efforts to discover a novel small molecule compound capable of inhibiting metastasis of cancer, especially colon cancer.As a result, the novel compounds according to the present invention effectively increase the activity of the KAI1 promoter gene. It was confirmed that it would be able to exhibit excellent cancer metastasis activity, and the present invention was completed.
  • an embodiment of the present invention provides a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof:
  • X is C or N
  • L is a C1 to C4 alkylene or bond
  • R 1 is hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 alkoxy, di(C1-C4 alkyl)amino, mono(C1-C4 alkyl)amino, amino, unsubstituted or Is a substituted 5- to 12-membered heterocycle
  • the substituted alkyl is unsubstituted or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C9 aryl, benzyl, hydroxy-C1-C6 alkyl and C3-C8 cycloalkyl Amino substituted with one or two substituents selected from the group consisting of; Or unsubstituted or C1-C4 alkyl, C1-C4 alkoxycarbonyl, unsubstituted or C1-C4 alkyl, C1-C4 alkoxy, halogen And C6-C9 aryl substituted with one or two substituents selected from the group consisting of nitro, 5 to 10 membered heterocycle or heteroaryl substituted with one or two substituents selected from the group consisting of It may be substituted with a 5- to 12-membered heterocycle or heteroaryl);
  • R 2 is , , , or ego
  • R 3 is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted C1-C6 alkoxy, non-substituted Ring or substituted 5- to 9-membered heteroaryl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C6-C10 aryloxy, unsubstituted or substituted 5- to 9-membered heterocyclyl, unsubstituted Or substituted 5- to 9-membered heterocyclyloxy, nitro, , And -O-CH 2 -C(O)-NH-R 5 is at least one selected from the group consisting of;
  • R 4 is hydrogen; halogen; C1-C6 alkyl unsubstituted or substituted with C1-C4 alkoxy, phenoxy or phenyl (wherein phenyl may be unsubstituted or substituted with halogen); C2-C6 alkenyl; Amino; Di(C1-C4alkyl)amino; C6 unsubstituted or substituted with one or more selected from the group consisting of halogen, C1-C4 alkoxy, C1-C4 alkyl unsubstituted or substituted with one or more halogens, nitro, C1-C4 alkylcarbonyloxy and -SO 2 -C9 aryl; C3-C8 cycloalkyl; 5 to 9 membered heterocyclyl;
  • R 5 is at least one (one or two) selected from the group consisting of hydrogen, halogen, hydroxy, unsubstituted or substituted C1-C4 alkyl, nitro, and C6-C10 aryloxy;
  • n is an integer of 0 to 2, preferably an integer of 0 to 1.
  • substituted C1-C6 alkyl of R 3 substituted C2-C6 alkenyl, substituted C3-C8 cycloalkyl, substituted C1-C6 alkoxy, substituted 5-9 membered heteroaryl, substituted C6 -C10 aryl, substituted C6-C10 aryloxy, substituted 5- to 9-membered heterocyclyl, substituted 5- to 9-membered heterocyclyloxy are C1-C4 alkoxy, C6-C9 aryl and C6-C9 It may be substituted with one or more selected from the group consisting of aryloxy, more preferably one or more substituted with one or more selected from the group consisting of phenyl, methoxy and phenoxy.
  • the present invention effectively increases the activity of the KAI1 promoter gene by increasing the activity of the KAI1 promoter, thereby exhibiting excellent cancer metastasis and invasion inhibition, or therapeutic activity of colorectal cancer, so it is useful as a metastasis and invasion inhibitor and therapeutic agent of cancer.
  • halogen examples include fluoro, chloro, bromo, and iodo.
  • alkyl refers to a linear or branched aliphatic saturated hydrocarbon group, preferably alkyl having 1 to 6 carbon atoms, more preferably alkyl having 1 to 4 carbon atoms.
  • alkyls are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethyl Butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.
  • heterocycle refers to a non-aromatic ring containing a hetero atom selected from nitrogen atoms, sulfur atoms, and oxygen atoms other than carbon atoms as ring constituent atoms, and preferably 1 to 4 heteroatoms It includes a 5-membered to 12-membered non-aromatic ring containing.
  • non-aromatic ring examples include tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetra Hydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl,
  • heteroaryl refers to an aromatic ring containing a heteroatom selected from nitrogen atoms, sulfur atoms, and oxygen atoms other than carbon atoms as ring constituent atoms, and preferably 1 to 4 heteroatoms It includes 5 to 12 membered aromatic rings.
  • aromatic rings examples include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1, 2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, indenyl, triazinyl and Dihydroisoquinolinyl.
  • X is C or N
  • L is a C1 to C4 alkylene or bond
  • R 1 is hydrogen, F, Cl, Br, unsubstituted or substituted C1-C4 alkyl, methoxy, N(CH 3 ) 2 , NH(CH 3 ), amino, unsubstituted or substituted 5-12 membered Is a heterocycle
  • the substituted alkyl is unsubstituted or dimethylamino, diethylamino, dipropylamino, dibutylamino, hydroxyethyl (ethyl) amino, ethyl (butyl) amino, dipentyl amino, methyl (ethynyl) ) Amino, ethyl (phenyl) amino, diallyl amino, methyl (benzyl) amino, methyl (hydroxyethyl) amino, phenyl (methyl) amino, ethyl (phenyl) amino, butyl (hydroxyethyl) amino, butyl (methyl ) Amino, dicyclohexylamino, ethoxycarbonyl-piperazine, t-butoxycarbonyl-piperazine, fluorophenyl-piperidine, pyridinyl-piperazine, pyrimidinyl-piperazine, hydroxyethyl Piperazine, me
  • R 2 is , , , or ego
  • R 3 is hydrogen, F, Cl, Br, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C2-C4 alkenyl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted C1- C4 alkoxy, unsubstituted or substituted 5- to 9-membered heteroaryl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C6-C10 aryloxy, unsubstituted or substituted 5- to 9-membered-hetero Cyclyl, unsubstituted or substituted 5- to 9-membered heterocyclyloxy, nitro, , And -O-CH 2 -C(O)-NH-R 5 is at least one selected from the group consisting of;
  • R 4 is hydrogen; F, Cl, Br; C1-C4 alkyl unsubstituted or substituted with methoxy ethoxy, phenoxy or phenyl (wherein phenyl may be unsubstituted or substituted with halogen); C2-C4 alkenyl; Amino; Di(C1-C4alkyl)amino; C6 unsubstituted or substituted with one or more selected from the group consisting of halogen, C1-C3 alkoxy, C1-C4 alkyl unsubstituted or substituted with one or more halogens, nitro, C1-C3 alkylcarbonyloxy and -SO 2 -C9 aryl; C3-C8 cycloalkyl; 5 to 9 membered heterocyclyl;
  • R 5 is at least one (one or two) selected from the group consisting of hydrogen, halogen, hydroxy, unsubstituted or substituted C1-C4 alkyl, nitro, and C6-C10 aryloxy;
  • n is an integer of 0 to 2, preferably an integer of 0 to 1.
  • substituted C1-C4 alkyl of R 3 substituted C2-C4 alkenyl, substituted C3-C8 cycloalkyl, substituted C1-C4 alkoxy, substituted 5-9 membered heteroaryl, substituted C6 -C10 aryl, substituted C6-C10 aryloxy, substituted 5- to 9-membered heterocyclyl, substituted 5- to 9-membered heterocyclyloxy are C1-C4 alkoxy, C6-C9 aryl and C6-C9 It may be substituted with one or more selected from the group consisting of aryloxy, more preferably one or more substituted with one or more selected from the group consisting of phenyl, methoxy and phenoxy.
  • these compounds may be compounds represented by compounds 1 to 305 shown in Table 1 below.
  • the compound of the present invention may exist in the form of a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • pharmaceutically acceptable salt of the present invention is a concentration that is relatively non-toxic and harmless to patients, and the side effects caused by this salt do not degrade the beneficial efficacy of the compounds represented by Formulas 1 to 3. Means any and all organic or inorganic addition salts.
  • Acid addition salts are prepared by conventional methods, for example, dissolving a compound in an excess acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • the same molar amount of the compound and an acid or alcohol (eg glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.
  • organic acids and inorganic acids can be used as the free acid
  • hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids
  • methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid can be used as organic acids.
  • maleic acid succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.
  • maleic acid succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.
  • succinic acid succinic acid
  • oxalic acid benzoic acid
  • tartaric acid
  • a pharmaceutically acceptable metal salt can be made using a base.
  • the alkali metal salt 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.
  • the metal salt is particularly suitable for preparing sodium, potassium, or calcium salt, but is not limited thereto.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group
  • other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate , Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and the like, and preparation of salts known in the art It can be manufactured through a method.
  • the salt of the compound of formula 1 of the present invention is a pharmaceutically acceptable salt, which exhibits pharmacological activity equivalent to that of the compound of formula 1, for example, by inhibiting the migration and invasion of colon cancer cells, death due to metastasis of colon cancer cells Any salt of the compound of Formula 1 that delays or treats colon cancer can be used without limitation.
  • the compound represented by Formula 1 according to the present invention includes, without limitation, all possible stereoisomers and solvates such as possible hydrates that can be prepared from, as well as pharmaceutically acceptable salts thereof.
  • the solvate and stereoisomer of the compound represented by Formula 1 can be prepared from the compound represented by Formula 1 using a method known in the art.
  • the compound represented by Formula 1 according to the present invention may be prepared in a crystalline or amorphous form, and when prepared in a crystalline form, it may be optionally hydrated or solvated.
  • a compound containing various amounts of water as well as a stoichiometric hydrate of the compound represented by Formula 1 may be included.
  • the solvate of the compound represented by Formula 1 according to the present invention includes both a stoichiometric solvate and a non-stoichiometric solvate.
  • the compound of Formula 1 according to the present invention may be prepared by the following exemplary method, and a specific example is the same as the reaction schemes described in the Examples below.
  • the manufacturing method of the present invention may be synthesized and used by purchasing and using a commercially available compound as it is, or by performing one or more reactions known in the art as it is or appropriately changed as reactants used in the above reaction schemes. For example, it may be synthesized by performing one or more reactions in a series of sequences in consideration of the presence, type and/or position of reactive functional groups and/or hetero elements included in the skeleton structure, but is not limited thereto.
  • the present invention provides a composition for inhibiting cancer metastasis and invasion comprising the compound of the present invention as an active ingredient.
  • the present invention is for the treatment of cancer comprising the compound of the present invention and a pharmaceutically acceptable salt thereof as an active ingredient, preferably for the treatment of cancer such as colon cancer, laryngeal cancer, lung cancer, stomach cancer, hepatocellular carcinoma, prostate cancer, breast cancer, etc.
  • the composition is provided.
  • the composition may be a pharmaceutical composition.
  • a specific compound represented by Formula 1 was newly synthesized, and the effect of increasing the expression of the KAI1 promoter gene and inhibiting cancer invasion was confirmed.
  • treatment of the present invention refers to any action in which symptoms of colon cancer are improved or advantageously changed by administration of the pharmaceutical composition of the present invention.
  • a pharmaceutical composition comprising it as an active ingredient inhibits metastasis and invasion of cancer, and It can be used to treat colon cancer.
  • composition of the present invention may further include a pharmaceutically acceptable carrier, diluent or excipient, and powders, granules, tablets, capsules, suspensions, emulsions, according to a conventional method according to the purpose of each use, It can be formulated and used in various forms, such as oral formulations such as syrup and aerosol, and injections of sterile injection solutions, and can be administered orally or administered through various routes including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration. .
  • compositions of suitable carriers, excipients or diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like.
  • the composition of the present invention may further include a filler, an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, a preservative, and the like.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the composition, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. Is formulated by mixing. Further, in addition to simple excipients, lubricants such as magnesium stearate and talc may be used.
  • liquid formulations for oral use include suspensions, liquid solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents. I can.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.
  • the base for suppositories is Withepsol, Macrogol, and Tween61. Cacao butter, laurin paper, glycerogelatin, and the like may be used.
  • the injection may include conventional additives such as solubilizing agents, isotonic agents, suspending agents, emulsifying agents, stabilizing agents, and preservatives.
  • the formulation may be prepared by a conventional mixing, granulating or coating method, and the active ingredient is contained in an amount effective for medical treatment, specifically, inhibition of metastasis and invasion of cancer or treatment of colon cancer.
  • composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is the health condition of the patient, The type of disease, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used in combination or concurrently, and other factors well known in the medical field. I can.
  • the composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.
  • the dosage amount is not limited in any way to the scope of the present invention.
  • the preferred dosage of the compound of the present invention varies depending on the condition and weight of the patient, the degree of disease, the form of the drug, the route and duration of administration, but may be appropriately selected by those skilled in the art.
  • the present invention provides a method of inhibiting metastasis and invasion of cancer, or treating colon cancer, comprising administering the pharmaceutical composition of the present invention to an individual in need thereof.
  • the term “individual” of the present invention means monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, including humans with cancer metastasis and invasion potential, metastasis and infiltration, or colon cancer. , It means all animals, including mice, rats, rabbits, or guinea pigs, and by administering the pharmaceutical composition of the present invention to an individual, cancer metastasis and invasion can be suppressed or colon cancer can be effectively treated.
  • the pharmaceutical composition of the present invention inhibits cancer metastasis and invasion by increasing the expression of the KAI1 promoter gene and exhibits a therapeutic effect of colorectal cancer, it can exhibit a synergistic effect by administering it in parallel with an existing therapeutic agent.
  • administration means providing a predetermined substance to a patient by any suitable method, and the route of administration of the composition of the present invention can be administered through any general route as long as it can reach the target tissue.
  • the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to target cells.
  • Preferred modes of administration and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drop injections and the like.
  • Injectables include aqueous solvents such as physiological saline solution and ring gel solution, non-aqueous solvents such as vegetable oils, higher fatty acid esters (e.g., oleic acid ethyl, etc.), alcohols (e.g. ethanol, benzyl alcohol, propylene glycol, glycerin, etc.). It can be prepared by using, and stabilizers for preventing deterioration (e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH control, and for inhibiting the growth of microorganisms. Preservatives (eg, phenyl mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may contain pharmaceutical carriers.
  • aqueous solvents such as physiological saline solution and ring gel solution
  • Example 1-87 Compound 1-87 according to the invention ( DKC1125a01 -43 and DKC1125b01 - 44) of Produce
  • Reagents and Conditions (a) HBr, Br 2 , H 2 O, 0° C., 1 hour; (b) NaHCO 3 , H 2 O; (c) potassium phthalimide, DMF, room temperature, overnight reaction; (d) HCl, EtOH, 80° C., 2 hours; (e) RCl, NaHCO 3 , DCM, H 2 O, 1 hour
  • Reagents and conditions (a) hexamethylenetetramine, DCM, room temperature, overnight reaction; (b) HCl, EtOH, 80° C., 2 hours; (c) RCl, NaHCO 3 , DCM, H 2 O, 1 hour
  • Example 137-150 Preparation of compound 137-150 (DKC1125f01-14) according to the present invention
  • Example 151 -200 Compounds 151-200 according to the invention ( DKC1125g01 - 50) of Produce
  • Reagents and Conditions (a)NaOH, H 2 O, MeOH, 65° C., 6h; (b) 2-amino-1-phenylethan-1-one, HATU, DIEA, rt, 10 hours; (c) 10% TFA/DCM, rt, 2 hours; (d) RCl, Et 3 N, CH 2 Cl 2 , rt, 4 hours.
  • Reagents and Conditions (a) C 3 H 5 BrO 2 , K 2 CO 3 , DMF, 50° C., 1 h; (b) NaOH, EtOH, rt, 4h; (c) RNH 2 , HATU, DIEA, DMF, rt 8h.
  • Luciferase ( luciferase ) Measurement of the effect of increasing the promoter activity associated with cancer metastasis of the compound through analysis
  • the KAI1 promoter reporter vector was used.
  • the pRL-TK vector was a vector expressing renila luciferase, and was used as an internal control indicating transformation efficiency in each of the transformed wells.
  • the adherent cells were raised using trypsin, and the number of cells was counted using a hemacytometer, and then transformed Caco2 cells 5 X 10 3 and 10% FBS, 1% penicillin/streptomycin were included in each well of a 96-well plate.
  • 100 ⁇ l of DMEM medium was dispensed and incubated for 24 hours in an incubator in the presence of 37° C. and 5% CO 2.
  • 1 ⁇ M of each of the 305 compounds prepared in Examples 1-305 was added to each of 1 ⁇ M, and after 16 hours, 100 ⁇ l of an analytical solution containing a luciferase substrate was added and dissolved for 20 minutes using a stirrer.
  • the cells after lysis were measured for luciferase activity using a luciferase reporter assay system (Promega, USA).
  • the experiment was conducted using DMSO-treated group as a control group and PHA-665752, which is known to increase KAI1 promoter activity, as a positive control group.
  • significance was verified by one-way analysis of variance (One-way ANOVA, Tukey's HSD) at p ⁇ 0.05 significance level, and SPSS 17.0 (Chicago, USA) statistical program was used.
  • the results are shown in Tables 14 to 20. In Table 14-20, PHA is PHA-665752, and KIT is KITENIN.

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Abstract

본 발명은 신규한 KAI1 프로모터 활성을 증가시키는 화합물, 이의 약학적으로 허용가능한 염 및 이들을 포함하는 암 전이 및 침윤 억제용 또는 대장암 치료용 조성물을 제공한다.

Description

신규한 암전이 억제 활성을 갖는 화합물, 이의 제조방법 및 상기 화합물을 포함하는 암 전이 및 침윤 억제, 또는 대장암 치료용 약학적 조성물
본 발명은 신규한 암전이 억제 활성을 갖는 화합물, 및 상기 화합물을 포함하는 암 전이 억제 또는 대장암 치료용 약학적 조성물에 관한 것이다.
국내의 암(악성신생물) 사망자수는 2002년 우리나라 총 사망자 246,515명 가운데 25.5%(남자 사망자의 29.6%, 여자 사망자의 20.5%)인 62,887명으로 암으로 인한 사망이 사망원인의 1위를 차지하고 있다. 이는 우리나라 인구 10만 명당 약 131명이 암으로 사망한다는 것을 의미한다(2002년 통계청). 암치료의 관점에서 보면 암환자의 사망률을 감소시키지 못하는 가장 큰 원인 중의 하나는 악성종양화 과정에서 암세포의 침윤과 전이를 억제하지 못함으로 인해 발생하는 것이다. 최근의 연구들은 암전이에 관련된 유전자(예: Twist, KAI1)들이 동정되고 있고 이를 통해 암전이 과정의 분자적 기전을 규명하는 수준이다. 따라서 이러한 암전이에 관련된 유전자를 이용하여 암전이를 효율적으로 억제 또는 예방할 수 있는 약제나 치료 방법등은 아직까지 보고되지 않았다. 미국의 경우 최근의 통계분석 결과는 전이성 암의 경우 지난 20-30년간 5년간 생존률이 향상되지 않았음을 보여주고 있다.
관련하여, KAI1(Kangai 1)은 최초에 전립선 암종(prostate carcinoma)에서의 전이 유전자의 억제유전자(suppressor)로 동정되었다. KAI1 단백질은 인간 크로모좀 11p11에 위치하며, 트랜스멤브레인 4 수퍼패밀리(TM4SF)에 속한다. KAI1은 세포에서 세포로, 그리고 세포에서 세포외매트릭스(ECM)로의 시그널 트랜스덕션을 조절할 수 있고, 융합, 이동, 부착, 변이 및 침윤과 같은 몇몇 기초적인 생물학적 프로세스에 관여할 수 있다. 감소되는 또는 결실된 KAI1 발현은 후두암, 전립선암, 유방암, 폐암, 위암, 대장암 및 간세포암을 포함하는 다양한 암종의 전이 및 예후와 관련되어 있는 것이 입증되었다.
현재 암을 치료하는 방법으로는 초기에 발견되는 암일 경우 수술, 항암제, 방사선 치료 등이 이용되고 있으나 그 부작용 또한 큰 문제로 대두되고 있으며, 대부분 1차 종양이 관찰된 시점에서는 이미 암의 전이가 발견된다.　 또한, 말기 암이나 전이된 암의 경우 특별한 치료법이 없어 시한부 인생으로 삶을 마감하는 상황이다. 이에 따라, 암 치료를 위한 새로운 접근방법으로 독성이 비교적 낮은 천연물로부터 부작용이 적고 암 종의 전이를 억제하거나 감소시키는 효능이 뛰어난 발암 억제제 및 암 치료제를 개발하기 위한 연구가 진행되고 있다.
이와 같은 배경하에서, 본 발명자들은 암전이, 특히 대장암의 전이를 저해할 수 있는 신규한 소분자 화합물을 발굴하기 위하여 예의 연구 노력한 결과, 본 발명에 따른 신규 화합물들이 효율적으로 KAI1 프로모터 유전자의 활성을 증가시켜 탁월한 암전이 활성을 나타낼 수 있을 것임을 확인하고, 본 발명을 완성하였다.
상기와 같은 과제를 달성하고자, 본 발명의 일 구현예는, 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다:
Figure PCTKR2020010999-appb-img-000001
상기 식에서,
X는 C 또는 N이고;
L은 C1 내지 C4의 알킬렌 또는 결합(bond)이고;
R 1은 수소, 할로겐, 비치환되거나 치환된 C1-C4 알킬, 비치환되거나 치환된 C1-C4 알콕시, 디(C1-C4 알킬)아미노, 모노(C1-C4 알킬)아미노, 아미노, 비치환되거나 치환된 5원 내지 12원의 헤테로사이클이고
(이때, 상기 치환된 알킬은 비치환되거나, 또는 C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, C6-C9 아릴, 벤질, 하이드록시-C1-C6알킬 및 C3-C8 사이클로알킬로 이루어진 군으로부터 선택되는 1종 또는 2종의 치환기로 치환된 아미노; 또는 비치환되거나, 또는 C1-C4 알킬, C1-C4 알콕시카르보닐, 비치환되거나 C1-C4 알킬, C1-C4 알콕시, 할로겐 및 니트로로 이루어지는 군으로부터 선택되는 1종 또는 2종의 치환기로 치환된 C6-C9 아릴, 5원 내지 10원의 헤테로사이클 또는 헤테로아릴로 이루어진 군으로부터 선택되는 1종 또는 2종의 치환기로 치환된 5원 내지 12원의 헤테로사이클 또는 헤테로아릴로 치환될 수 있다);
R 2는
Figure PCTKR2020010999-appb-img-000002
,
Figure PCTKR2020010999-appb-img-000003
,
Figure PCTKR2020010999-appb-img-000004
, 또는
Figure PCTKR2020010999-appb-img-000005
이고;
R 3는 수소, 할로겐, 비치환되거나 치환된 C1-C6 알킬, 비치환되거나 치환된 C2-C6 알케닐, 비치환되거나 치환된 C3-C8 사이클로알킬, 비치환되거나 치환된 C1-C6 알콕시, 비치환되거나 치환된 5원 내지 9원 헤테로아릴, 비치환되거나 치환된 C6-C10 아릴, 비치환되거나 치환된 C6-C10 아릴옥시, 비치환되거나 치환된 5원- 내지 9원 헤테로사이클릴, 비치환되거나 치환된 5원- 내지 9원 헤테로사이클릴옥시, 니트로,
Figure PCTKR2020010999-appb-img-000006
,
Figure PCTKR2020010999-appb-img-000007
및 -O-CH 2-C(O)-NH-R 5로 이루어진 군으로부터 선택되는 1종 이상이고;
R 4는 수소; 할로겐; 비치환되거나 C1-C4 알콕시, 페녹시 또는 페닐(이때 페닐은 비치환되거나 할로겐으로 치환될 수 있음)로 치환된 C1-C6 알킬; C2-C6 알케닐; 아미노; 디(C1-C4알킬)아미노; 비치환되거나 할로겐, C1-C4 알콕시, 비치환되거나 1 이상의 할로겐으로 치환된 C1-C4 알킬, 니트로, C1-C4 알킬카르보닐옥시 및 -SO 2로 이루어진 군으로부터 선택되는 1종 이상으로 치환된 C6-C9 아릴; C3-C8 사이클로알킬; 5원 내지 9원의 헤테로사이클릴이고;
R 5는 수소, 할로겐, 하이드록시, 비치환되거나 치환된 C1-C4 알킬, 니트로, C6-C10 아릴옥시로 이루어진 군으로부터 선택되는 1종 이상(1종 또는 2종)이고;
n은 0 내지 2의 정수이며, 바람직하게는 0 내지 1의 정수이다.
바람직하게, 상기 R 3의 치환된 C1-C6 알킬, 치환된 C2-C6 알케닐, 치환된 C3-C8 사이클로알킬, 치환된 C1-C6 알콕시, 치환된 5원 내지 9원 헤테로아릴, 치환된 C6-C10 아릴, 치환된 C6-C10 아릴옥시, 치환된 5원- 내지 9원 헤테로사이클릴, 치환된 5원- 내지 9원 헤테로사이클릴옥시는 C1-C4 알콕시, C6-C9 아릴 및 C6-C9 아릴옥시로 이루어진 군으로부터 선택되는 1종 이상으로 치환될 수 있고, 더욱 바람직하게는 페닐, 메톡시 및 페녹시로 이루어진 군으로부터 선택되는 1종 이상으로 치환된 것일 수 있다.
본 발명은 우수한 KAI1 프로모터 활성 증가를 통해 효율적으로 KAI1 프로모터 유전자의 활성을 증가시켜 탁월한 암전이 및 침윤 억제, 또는 대장암의 치료 활성을 나타낼 것이므로, 암의 전이 및 침윤억제제 및 치료제로서 유용하다.
이하 본 발명을 더욱 상세하게 설명한다.
본 명세서에서 사용되는 각 치환기의 정의에 대해 상세히 설명한다. 명시하지 않는 한, 각 치환기는 하기의 정의를 갖는다.
본 명세서 중, "할로겐"의 예는 플루오로, 클로로, 브로모 및 아이오도를 포함한다.
본 명세서 중, "알킬"은 직쇄 또는 분지쇄의 지방족 포화 탄화수소기를 의미하며, 바람직하게 탄소수 1 내지 6의 알킬, 더욱 바람직하게는 탄소수 1 내지 4의 알킬일 수 있다. 이러한 알킬의 예는 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, sec-부틸, 터트-부틸, 펜틸, 이소펜틸, 네오펜틸, 1-에틸프로필, 헥실, 이소헥실, 1,1-디메틸부틸, 2,2-디메틸부틸, 3,3-디메틸부틸 및 2-에틸부틸을 포함한다.
본 명세서 중, "헤테로사이클"은 고리 구성 원자로서 탄소 원자 이외의 질소 원자, 황 원자 및 산소 원자에서 선택되는 헤테로원자를 함유하는 비방향족 고리를 의미하며, 바람직하게는 1 내지 4의 상기 헤테로원자를 포함하는 5원 내지 12원의 비방향족환을 포함한다. 이러한 비방향족환의 예는 테트라히드로티에닐, 테트라히드로푸라닐, 피롤리닐, 피롤리디닐, 이미다졸리닐, 이미다졸리디닐, 옥사졸리닐, 옥사졸리디닐, 피라졸리닐, 피라졸리디닐, 티아졸리닐, 티아졸리디닐, 테트라히드로이소티아졸릴, 테트라히 드로옥사졸릴, 테트라히드로이속사졸릴, 피페리디닐, 피페라지닐, 테트라히드로피리디닐, 디히드로피리디닐, 디히드로티오피라닐, 테트라히드로피리미디닐, 테트라히드로피리다지닐, 디히드로피라닐, 테트라히드로피라닐, 테트라히드로티오피라닐, 모르폴리닐, 티오모르폴리닐, 아제파닐, 디아제파닐 및 아제피닐을 포함한다.
본 명세서 중, "헤테로아릴"은 고리 구성 원자로서 탄소 원자 이외의 질소 원자, 황 원자 및 산소 원자에서 선택되는 헤테로원자를 함유하는 방향족 고리를 의미하며, 바람직하게는 1 내지 4의 상기 헤테로원자를 포함하는 5원 내지 12원의 방향족환을 포함한다. 이러한 방향족환의 예는 티에닐, 푸릴, 피롤릴, 이미다졸릴, 피라졸릴, 티아졸릴, 이소티아졸릴, 옥사졸릴, 이속사졸릴, 피리딜, 피라지닐, 피리미디닐, 피리다지닐, 1,2,4-옥사디아졸릴, 1,3,4-옥사디아졸릴, 1,2,4-티아디아졸릴, 1,3,4-티아디아졸릴, 트리아졸릴, 테트라졸릴, 인데닐, 트리아지닐 및 디하이드로이소퀴놀리닐을 포함한다.
바람직한 양태에서, 상기 화학식 1의 화합물에서,
X는 C 또는 N이고;
L은 C1 내지 C4의 알킬렌 또는 결합(bond)이고;
R 1은 수소, F, Cl, Br, 비치환되거나 치환된 C1-C4 알킬, 메톡시, N(CH 3) 2, NH(CH 3), 아미노, 비치환되거나 치환된 5원 내지 12원의 헤테로사이클이고
(이때, 상기 치환된 알킬은 비치환되거나, 또는 디메틸아미노, 디에틸아미노, 디프로필아미노, 디부틸아미노, 하이드록시에틸(에틸)아미노, 에틸(부틸)아미노, 디펜틸아미노, 메틸(에틴일)아미노, 에틸(페닐)아미노, 디알릴아미노, 메틸(벤질)아미노, 메틸(하이드록시에틸)아미노, 페닐(메틸)아미노, 에틸(페닐)아미노, 부틸(하이드록시에틸)아미노, 부틸(메틸)아미노, 디사이클로헥실아미노, 에톡시카르보닐-피페라진, t-부톡시카르보닐-피페라진, 플루오로페닐-피페리딘, 피리딘일-피페라진, 피리미딘일-피페라진, 하이드록시에틸피페라진, 메톡시페닐-피페라진, 나이트로페닐-피페라진, 디메틸모폴린, 모폴린, 메틸피페라진, 디하이드록시이소퀴놀린, 사이클로헥실(메틸)아미노, 이소프로필(메틸)아미노, 플루오로페닐-피페라진, 피페리딘일피페리딘으로 치환될 수 있다);
R 2는
Figure PCTKR2020010999-appb-img-000008
,
Figure PCTKR2020010999-appb-img-000009
,
Figure PCTKR2020010999-appb-img-000010
, 또는
Figure PCTKR2020010999-appb-img-000011
이고;
R 3는 수소, F, Cl, Br, 비치환되거나 치환된 C1-C4 알킬, 비치환되거나 치환된 C2-C4 알케닐, 비치환되거나 치환된 C3-C8 사이클로알킬, 비치환되거나 치환된 C1-C4 알콕시, 비치환되거나 치환된 5원 내지 9원 헤테로아릴, 비치환되거나 치환된 C6-C10 아릴, 비치환되거나 치환된 C6-C10 아릴옥시, 비치환되거나 치환된 5원- 내지 9원- 헤테로사이클릴, 비치환되거나 치환된 5원- 내지 9원 헤테로사이클릴옥시, 니트로,
Figure PCTKR2020010999-appb-img-000012
,
Figure PCTKR2020010999-appb-img-000013
및 -O-CH 2-C(O)-NH-R 5로 이루어진 군으로부터 선택되는 1종 이상이고;
R 4는 수소; F, Cl, Br; 비치환되거나 메톡시 에톡시, 페녹시 또는 페닐(이때 페닐은 비치환되거나 할로겐으로 치환될 수 있음)로 치환된 C1-C4 알킬; C2-C4 알케닐; 아미노; 디(C1-C4알킬)아미노; 비치환되거나 할로겐, C1-C3 알콕시, 비치환되거나 1 이상의 할로겐으로 치환된 C1-C4 알킬, 니트로, C1-C3 알킬카르보닐옥시 및 -SO 2로 이루어진 군으로부터 선택되는 1종 이상으로 치환된 C6-C9 아릴; C3-C8 사이클로알킬; 5원 내지 9원의 헤테로사이클릴이고;
R 5는 수소, 할로겐, 하이드록시, 비치환되거나 치환된 C1-C4 알킬, 니트로, C6-C10 아릴옥시로 이루어진 군으로부터 선택되는 1종 이상(1종 또는 2종)이고;
n은 0 내지 2의 정수이며, 바람직하게는 0 내지 1의 정수이다.
바람직하게, 상기 R 3의 치환된 C1-C4 알킬, 치환된 C2-C4 알케닐, 치환된 C3-C8 사이클로알킬, 치환된 C1-C4 알콕시, 치환된 5원 내지 9원 헤테로아릴, 치환된 C6-C10 아릴, 치환된 C6-C10 아릴옥시, 치환된 5원- 내지 9원 헤테로사이클릴, 치환된 5원- 내지 9원 헤테로사이클릴옥시는 C1-C4 알콕시, C6-C9 아릴 및 C6-C9 아릴옥시로 이루어진 군으로부터 선택되는 1종 이상으로 치환될 수 있고, 더욱 바람직하게는 페닐, 메톡시 및 페녹시로 이루어진 군으로부터 선택되는 1종 이상으로 치환된 것일 수 있다.
구체적인 양태에서, 이들 화합물은 하기 표 1에 나타난 화합물 1 내지 305로 표시되는 화합물일 수 있다.
Figure PCTKR2020010999-appb-img-000014
Figure PCTKR2020010999-appb-img-000015
Figure PCTKR2020010999-appb-img-000016
Figure PCTKR2020010999-appb-img-000017
Figure PCTKR2020010999-appb-img-000018
Figure PCTKR2020010999-appb-img-000019
Figure PCTKR2020010999-appb-img-000020
Figure PCTKR2020010999-appb-img-000021
Figure PCTKR2020010999-appb-img-000022
Figure PCTKR2020010999-appb-img-000023
Figure PCTKR2020010999-appb-img-000024
Figure PCTKR2020010999-appb-img-000025
Figure PCTKR2020010999-appb-img-000026
Figure PCTKR2020010999-appb-img-000027
Figure PCTKR2020010999-appb-img-000028
Figure PCTKR2020010999-appb-img-000029
Figure PCTKR2020010999-appb-img-000030
Figure PCTKR2020010999-appb-img-000031
Figure PCTKR2020010999-appb-img-000032
Figure PCTKR2020010999-appb-img-000033
Figure PCTKR2020010999-appb-img-000034
Figure PCTKR2020010999-appb-img-000035
Figure PCTKR2020010999-appb-img-000036
Figure PCTKR2020010999-appb-img-000037
Figure PCTKR2020010999-appb-img-000038
Figure PCTKR2020010999-appb-img-000039
Figure PCTKR2020010999-appb-img-000040
Figure PCTKR2020010999-appb-img-000041
Figure PCTKR2020010999-appb-img-000042
Figure PCTKR2020010999-appb-img-000043
Figure PCTKR2020010999-appb-img-000044
Figure PCTKR2020010999-appb-img-000045
Figure PCTKR2020010999-appb-img-000046
Figure PCTKR2020010999-appb-img-000047
Figure PCTKR2020010999-appb-img-000048
Figure PCTKR2020010999-appb-img-000049
Figure PCTKR2020010999-appb-img-000050
Figure PCTKR2020010999-appb-img-000051
Figure PCTKR2020010999-appb-img-000052
Figure PCTKR2020010999-appb-img-000053
Figure PCTKR2020010999-appb-img-000054
Figure PCTKR2020010999-appb-img-000055
Figure PCTKR2020010999-appb-img-000056
Figure PCTKR2020010999-appb-img-000057
Figure PCTKR2020010999-appb-img-000058
한편, 본 발명의 화합물은 약학적으로 허용 가능한 염의 형태로 존재할 수 있다. 상기 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1 내지 3으로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기 또는 무기 부가염을 의미한다.
산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올(예, 글리콜 모노메틸에테르)을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.
이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 요오드화수소산(hydroiodic acid) 등을 사용할 수 있으며, 이들에 제한되지 않는다.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.
본 발명의 화합물의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용가능한 염으로는 히드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄술포네이트(메실레이트) 및 p-톨루엔술포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.
본 발명의 화학식 1의 화합물의 염으로는 약학적으로 허용가능한 염으로서, 화학식 1의 화합물과 동등한 약리활성을 나타내는, 예컨대, 대장암 세포의 이동 및 침윤을 억제시켜 대장암 세포의 전이에 의한 사망을 지연시키거나 대장암을 치료하는 화학식 1의 화합물의 염이면 제한없이 모두 사용 가능하다.
또한, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은, 이의 약학적으로 허용 가능한 염뿐만 아니라 이로부터 제조될 수 있는 가능한 수화물 등의 용매화물 및 가능한 모든 입체 이성질체를 제한없이 포함한다. 상기 화학식 1로 표시되는 화합물의 용매화물 및 입체이성질체는 당업계에 공지된 방법을 사용하여 화학식 1로 표시되는 화합물로부터 제조할 수 있다.
나아가, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 결정 형태 또는 비결정 형태로 제조될 수 있으며, 결정 형태로 제조될 경우 임의로 수화되거나 용매화될 수 있다. 본 발명에서는 상기 화학식 1로 표시되는 화합물의 화학양론적 수화물뿐만 아니라 다양한 양의 물을 함유하는 화합물이 포함될 수 있다. 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 용매화물은 화학양론적 용매화물 및 비화학양론적 용매화물 모두를 포함한다.
본 발명에 따른 화학식 1의 화합물은 하기 예시적인 방법으로 제조될 수 있으며, 구체적인 일 예는 이하 실시예에 기재된 반응식들과 같다.
본 발명의 제조방법은, 상기 반응식들에 사용되는 반응물들로서, 시판되는 화합물을 구입하여 그대로 사용하거나, 당업계에 공지된 하나 이상의 반응을 그대로 또는 적절히 변경하여 수행함으로써 합성하여 사용할 수 있다. 예컨대, 골격 구조에 포함된 반응성 작용기 및/또는 헤테로원소의 존재, 종류 및/또는 위치를 고려하여 하나 이상의 반응을 일련의 순서로 수행하여 합성할 수 있으나, 이에 제한되지 않는다.
또 다른 양태로서, 본 발명의 화합물을 유효성분으로 포함하는 암전이 및 침윤 억제용 조성물을 제공한다. 또한 본 발명은 본 발명의 화합물, 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 암 치료용, 바람직하게는 대장암, 후두암, 폐암, 위암, 간세포암, 전립선암, 유방암 등의 암 치료용 조성물을 제공한다. 바람직하게, 상기 조성물은 약학적 조성물일 수 있다.
본 발명의 구체적인 실시예에서는, 화학식 1로 표시되는 구체적인 화합물을 새롭게 합성하고, 이들의 KAI1 프로모터 유전자 발현 증가 및 암의 침윤 억제 효과를 확인하였다.
본 발명의 용어 "치료"란 본 발명의 약학적 조성물의 투여로 대장암 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.
전술한 바와 같이, 본 발명의 화합물은 KAI1 프로모터 유전자의 발현을 증가시킬 뿐 아니라, 암의 전이 및 침윤 억제 효과를 나타내므로, 이를 유효성분으로 포함하는 약학적 조성물은 암의 전이 및 침윤 억제, 그리고 대장암 치료에 사용될 수 있다.
예컨대, 본 발명의 조성물은 약학적으로 허용가능한 담체, 희석제 또는 부형제를 추가로 포함할 수 있으며, 각각의 사용 목적에 맞게 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁제, 에멀젼, 시럽, 에어로졸 등의 경구 제형, 멸균 주사 용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여하거나 정맥내, 복강내, 피하, 직장, 국소 투여 등을 포함한 다양한 경로를 통해 투여될 수 있다. 이러한 조성물에 포함될 수 있는 적합한 담체, 부형제 또는 희석제의 예로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸셀룰로즈, 미정질셀룰로스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수 있다. 또한, 본 발명의 조성물은 충전제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.
경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로스, 락토즈, 젤라틴 등을 혼합하여 제형화한다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크와 같은 윤활제가 사용될 수 있다.
경구용 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 예시될 수 있으며, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.
비경구 투여를 위한 제제에는 멸균된 수용액제, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈61. 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 한편, 주사제에는 용해제, 등장화제, 현탁화제, 유화제, 안정화제, 방부제 등과 같은 종래의 첨가제가 포함될 수 있다.
상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있으며 활성 성분을 의학적 치료, 구체적으로 암의 전이 및 침윤의 억제나 대장암의 치료에 유효한 양으로 포함한다.
이때, 본 발명의 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명의 용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.
예컨대, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.
본 발명의 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물의 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.
또 다른 양태로서 본 발명은, 상기 본 발명의 약학적 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는 암의 전이 및 침윤 억제, 또는 대장암을 치료하는 방법을 제공한다.
본 발명의 용어 "개체"란, 암이 전이 및 침윤 가능성이 있거나, 혹은 전이 및 침윤되거나 대장암이 발병한 인간을 포함한 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미하고, 본 발명의 약학적 조성물을 개체에게 투여함으로써 암의 전이 및 침윤을 억제하거나 대장암을 효과적으로 치료할 수 있다. 또한, 본 발명의 약학적 조성물은 KAI1 프로모터 유전자의 발현을 증가시킴으로써 암 전이 및 침윤을 억제하고 대장암의 치료 효과를 나타내는 것이므로, 기존의 치료제와 병행하여 투여함으로써 시너지적인 효과를 나타낼 수 있다.
본 발명의 용어 "투여"란, 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내투여, 직장내 투여될 수 있으나, 이에 제한되지는 않는다. 또한, 본 발명의 약학적 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥 주사제, 피하 주사제, 피내 주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성 용제, 식물유, 고급 지방산 에스테르(예, 올레인산에칠 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물 발육을 저지하기 위한 보존제(예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레졸, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 한정되는 것은 아니다.
실시예 1-87. 본 발명에 따른 화합물 1-87( DKC1125a01 -43 및 DKC1125b01 - 44)의 제조
본 발명의 화합물 1 내지 87(DKC1125a01-43 및 DKC1125b01-44)를 다음 반응식 1에 따라 합성하였다.
[반응식 1]
Figure PCTKR2020010999-appb-img-000059
시약 및 조건: (a) RCl, NaHCO 3, DCM, H 2O, 1시간
화합물 1-43( DKC1125a01 -43) 및 화합물 44-87( DKC1125b01 - 44)의 일반적인 제조방법:
CH 2Cl 2(1mL) 및 sat. NaHCO 3(2 mL)를 격렬히 교반하고 얼음 욕(ice bath)에서 냉각시켰다. 하기 표 2 및 3에 기재된 산 염화물(0.29 mmol)을 각각 첨가한 다음, 즉시 아미노아세토페논 하이드로클로라이드 (50 mg, 0.29 mmol)를 첨가하였다. 1 시간에 걸쳐 실온으로 가온하면서 교반을 계속하였다. 이어서, 유기층을 분리하고, Na 2SO 4로 건조시키고, 용매를 증발시켰다 (수율: 80 내지 90 %).
Figure PCTKR2020010999-appb-img-000060
Figure PCTKR2020010999-appb-img-000061
화합물 1-87(DKC1125a01-43 및 DKC1125b01-44)의 제조확인
4- 클로로 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a01 ) 1H-NMR (400 MHz, CDCl 3) δ 8.01 (dd, J = 8.5, 1.1 Hz, 2H), 7.87-7.92 (m, 2H), 7.62-7.66 (m, 1H), 7.50-7.53 (m, 2H), 7.34 (s, 1H), 7.10-7.18 (m, 2H), 4.94 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 275 (M+1).
* N-(2-옥소-2- 페닐에틸 )-2- 페녹시프로판아마이드 ( DKC1125a02 ) 1H-NMR (400 MHz, CDCl 3) δ 7.95-7.97 (m, 2H), 7.62 (tt, J = 7.5, 1.4 Hz, 1H), 7.55 (s, 1H), 7.47-7.51 (m, 2H), 7.29-7.33 (m, 2H), 6.97-7.03 (m, 3H), 4.67-4.87 (m, 2H), 1.63 (d, J = 6.9 Hz, 3H). MS(ESI): m/z 284 (M+1).
2- 플루오로 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a03 ) 1H-NMR (400 MHz, CDCl 3) δ 8.13 (td, J = 7.7, 1.9 Hz, 1H), 8.04 (dd, J = 8.5, 1.1 Hz, 2H), 7.90 (d, J = 11.4 Hz, 1H), 7.63-7.66 (m, 1H), 7.48-7.55 (m, 3H), 7.26-7.30 (m, 1H), 7.15-7.21 (m, 1H), 5.01 (dd, J = 4.1, 0.9 Hz, 2H). MS(ESI): m/z 258 (M+1).
4- 플루오로 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a04 ) 1H-NMR (400 MHz, CDCl 3) δ 8.02-8.04 (m, 2H), 7.88-7.93 (m, 2H), 7.63-7.67 (m, 1H), 7.53 (t, J = 7.8 Hz, 2H), 7.29 (s, 1H), 7.11-7.17 (m, 2H), 4.95 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 258 (M+1).
N-(2-옥소-2- 페닐에틸 ) 퓨란 -2- 카복사마이드 ( DKC1125a05 ) 1H-NMR (400 MHz, CDCl 3) δ 7.98-8.00 (m, 2H), 7.58-7.62 (m, 1H), 7.47-7.50 (m, 3H), 7.45-7.31 (1H), 7.13-7.13 (m, 1H), 6.49 (q, J = 1.8 Hz, 1H), 4.90 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 230 (M+1).
2- 클로로 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a06 ) 1H-NMR (400 MHz, CDCl 3) δ 8.01 (dt, J = 8.2, 1.6 Hz, 2H), 7.72 (dd, J = 7.3, 1.8 Hz, 1H), 7.63 (tt, J = 7.4, 1.4 Hz, 1H), 7.48-7.53 (m, 3H), 7.30-7.43 (m, 3H), 4.98 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 275 (M+1).
3- 클로로 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a07 ) 1H-NMR (400 MHz, CDCl 3) δ 8.00-8.03 (m, 2H), 7.88 (t, J = 1.8 Hz, 1H), 7.75 (dd, J = 7.8, 0.9 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.48-7.54 (m, 3H), 7.39 (t, J = 8.0 Hz, 2H), 4.94 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 275 (M+1).
(E)-N-(2-옥소-2- 페닐에틸 ) 부트 -2- 엔아마이드 ( DKC1125a08 ) 1H-NMR (400 MHz, CDCl 3) δ 8.00 (dt, J = 8.4, 1.5 Hz, 2H), 7.63 (tt, J = 7.5, 1.4 Hz, 1H), 7.49-7.52 (m, 2H), 6.92 (td, J = 7.5, 6.4 Hz, 1H), 6.64 (s, 1H), 5.98 (dt, J = 15.2, 1.7 Hz, 1H), 4.84 (d, J = 4.6 Hz, 2H), 1.89 (dd, J = 6.9, 1.8 Hz, 3H). MS(ESI): m/z 204 (M+1).
N-(2-옥소-2- 페닐에틸 )-3- 페닐프로판아마이드 ( DKC1125a09 ) 1H-NMR (400 MHz, CDCl 3) δ 7.95 (dt, J = 8.4, 1.5 Hz, 2H), 7.58-7.62 (m, 1H), 7.45-7.49 (m, 2H), 7.16-7.29 (m, 5H), 6.69 (s, 1H), 4.74 (d, J = 4.1 Hz, 2H), 3.00 (t, J = 7.8 Hz, 2H), 2.62 (dd, J = 8.7, 6.9 Hz, 2H). MS(ESI): m/z 268 (M+1).
N-(2-옥소-2- 페닐에틸 ) 아크릴아마이드 ( DKC1125a10 ) 1H-NMR (400 MHz, CDCl 3) δ 7.99-8.01 (m, 2H), 7.63 (tt, J = 7.5, 1.4 Hz, 1H), 7.49-7.53 (m, 2H), 6.88 (s, 1H), 6.25-6.39 (m, 2H), 5.71 (dd, J = 9.6, 1.8 Hz, 1H), 4.87 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 190 (M+1).
2- 메틸 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a11 ) 1H-NMR (400 MHz, CDCl 3) δ 8.00 (dt, J = 8.2, 1.6 Hz, 2H), 7.62 (tt, J = 7.4, 1.4 Hz, 1H), 7.47-7.52 (m, 3H), 7.32 (td, J = 7.4, 1.7 Hz, 1H), 7.21 (t, J = 7.5 Hz, 2H), 6.97 (s, 1H), 4.92 (d, J = 4.6 Hz, 2H), 2.48 (s, 3H). MS(ESI): m/z 254 (M+1).
4- 메톡시 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a12 ) 1H-NMR (400 MHz, CDCl 3) δ 7.99-8.01 (m, 2H), 7.62 (tt, J = 7.4, 1.4 Hz, 1H), 7.48-7.51 (m, 3H), 7.39-7.45 (m, 3H), 7.34 (t, J = 7.8 Hz, 1H), 7.04 (dq, J = 8.2, 1.2 Hz, 1H), 4.92 (d, J = 4.1 Hz, 2H), 3.84 (t, J = 4.6 Hz, 3H). MS(ESI): m/z 270 (M+1).
3- 메틸 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a13 ) 1H-NMR (400 MHz, CDCl 3) δ 8.01-8.04 (m, 2H), 7.70 (s, 1H), 7.67 (td, J = 4.0, 2.1 Hz, 1H), 7.63 (tt, J = 7.4, 1.4 Hz, 1H), 7.49-7.53 (m, 2H), 7.32-7.36 (m, 3H), 4.94 (d, J = 4.6 Hz, 2H), 2.38 (d, J = 14.2 Hz, 3H). MS(ESI): m/z 254 (M+1).
N-(2-옥소-2- 페닐에틸 ) 프로피온아마이드 ( DKC1125a14 ) 1H-NMR (400 MHz, CDCl 3) δ 7.99 (dt, J = 8.2, 1.6 Hz, 2H), 7.63 (tt, J = 7.4, 1.4 Hz, 1H), 7.49-7.53 (m, 2H), 6.63 (s, 1H), 4.78 (d, J = 4.1 Hz, 2H), 2.36 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H). MS(ESI): m/z 192 (M+1).
N-(2-옥소-2- 페닐에틸 ) 사이클로헥산카복사마이드 ( DKC1125a15 ) 1H-NMR (400 MHz, CDCl 3) δ 7.97-8.01 (m, 2H), 7.59-7.64 (m, 1H), 7.47-7.51 (m, 2H), 6.68 (s, 1H), 4.58-4.78 (m, 2H), 2.21-2.29 (m, 1H), 1.95 (dd, J = 22.2, 12.1 Hz, 2H), 1.76-1.84 (m, 2H), 1.49 (q, J = 11.9 Hz, 2H), 1.19-1.35 (m, 4H). MS(ESI): m/z 246 (M+1).
N-(2-옥소-2- 페닐에틸 ) 사이클로프로판카복사마이드 ( DKC1125a16 ) 1H-NMR (400 MHz, CDCl 3) δ 7.99 (dt, J = 8.2, 1.6 Hz, 2H), 7.63 (tt, J = 7.4, 1.4 Hz, 1H), 7.48-7.53 (m, 2H), 6.82 (s, 1H), 4.80 (d, J = 4.1 Hz, 2H), 1.57 (tt, J = 8.4, 3.8 Hz, 1H), 0.99-1.03 (m, 2H), 0.80 (td, J = 7.4, 4.3 Hz, 2H). MS(ESI): m/z 204 (M+1).
N-(2-옥소-2- 페닐에틸 ) 사이클로부탄카복사마이드 ( DKC1125a17 ) 1H-NMR (400 MHz, CDCl 3) δ 7.98 (dt, J = 8.4, 1.5 Hz, 2H), 7.62 (tt, J = 7.3, 1.5 Hz, 1H), 7.48-7.51 (m, 2H), 6.59 (s, 1H), 4.77 (d, J = 4.3 Hz, 2H), 3.12-3.21 (m, 1H), 2.29-2.39 (m, 2H), 2.16-2.24 (m, 2H), 1.84-2.05 (m, 2H). MS(ESI): m/z 218 (M+1).
N-(2-옥소-2- 페닐에틸 ) 싸이오펜 -2- 카복사마이드 ( DKC1125a18 ) 1H-NMR (400 MHz, CDCl 3) δ 8.01-8.04 (m, 2H), 7.62-7.67 (m, 2H), 7.50-7.54 (m, 3H), 7.19 (s, 1H), 7.11 (dd, J = 4.8, 3.9 Hz, 1H), 4.95 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 246 (M+1).
3, 3i메틸 -N-(2-옥소-2- 페닐에틸 ) 부탄아마이드 ( DKC1125a19 ) 1H-NMR (400 MHz, CDCl 3) δ 7.97-8.00 (m, 2H), 7.60-7.64 (m, 1H), 7.47-7.52 (m, 2H), 6.62 (d, J = 13.7 Hz, 1H), 4.79 (dd, J = 4.3, 1.1 Hz, 2H), 2.21 (S, 2H), 1.07 (d, J = 1.4 Hz, 9H). MS(ESI): m/z 234 (M+1).
N-(2-옥소-2- 페닐에틸 ) 펜탄아마이드 ( DKC1125a20 ) 1H-NMR (400 MHz, CDCl 3) δ 7.99 (dt, J = 8.4, 1.5 Hz, 2H), 7.60-7.64 (m, 1H), 7.48-7.52 (m, 2H), 6.68 (s, 1H), 4.78 (d, J = 4.1 Hz, 2H), 2.32 (t, J = 7.5 Hz, 2H), 1.64-1.71 (m, 2H), 1.34-1.41 (m, 2H), 0.93 (td, J = 7.3, 2.3 Hz, 3H). MS(ESI): m/z 220 (M+1).
3-니트로-N-(2-옥소-2- 페닐에틸 ) 벤젠설폰아마이드 ( DKC1125a21 ) 1H-NMR (400 MHz, CDCl 3) δ 8.76 (t, J = 2.1 Hz, 1H), 8.40-8.43 (m, 1H), 8.23-8.25 (m, 1H), 7.85-7.87 (m, 2H), 7.74 (t, J = 8.2 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 5.94 (s, 1H), 4.57 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 321 (M+1).
2,4- 디플루오로 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a22 ) 1H-NMR (400 MHz, CDCl 3) δ 8.15 (td, J = 8.8, 6.6 Hz, 1H), 8.03 (dd, J = 8.5, 1.1 Hz, 2H), 7.83 (d, J = 10.5 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 6.89-7.03 (m, 2H), 4.99 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 276 (M+1).
2- 메톡시 -N-(2-옥소-2- 페닐에틸 ) 아세트아마이드 ( DKC1125a23 ) 1H-NMR (400 MHz, CDCl 3) δ 7.97-8.00 (m, 2H), 7.60-7.64 (m, 1H), 7.48-7.55 (m, 3H), 4.80 (d, J = 5.0 Hz, 2H), 3.99 (s, 2H), 3.48 (s, 3H). MS(ESI): m/z 208 (M+1).
N-(2-옥소-2- 페닐에틸 ) 피발아마이드 ( DKC1125a24 ) 1H-NMR (400 MHz, CDCl 3) δ 7.97-8.07 (m, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 6.85 (s, 1H), 4.74 (d, J = 4.1 Hz, 2H), 1.12-1.34 (m, 9H). MS(ESI): m/z 220 (M+1).
N-(2-옥소-2- 페닐에틸 ) 메탄설폰아마이드 ( DKC1125a25 ) 1H-NMR (400 MHz, CDCl 3) δ 7.94-7.97 (m, 2H), 7.64 (tt, J = 7.4, 1.4 Hz, 1H), 7.49-7.53 (m, 2H), 5.60 (t, J = 4.6 Hz, 1H), 4.69 (d, J = 5.0 Hz, 2H), 3.03 (s, 3H). MS(ESI): m/z 214 (M+1).
4- 플루오로 -N-(2-옥소-2- 페닐에틸 ) 벤젠설폰아마이드 ( DKC1125a26 ) 1H-NMR (400 MHz, CDCl 3) δ 7.93 (tt, J = 7.2, 2.4 Hz, 2H), 7.84-7.87 (m, 2H), 7.60-7.64 (m, 1H), 7.46-7.50 (m, 2H), 7.14-7.20 (m, 2H), 5.80 (t, J = 4.6 Hz, 1H), 4.49 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 294 (M+1).
4- 메틸 -N-(2-옥소-2- 페닐에틸 ) 벤젠설폰아마이드 ( DKC1125a27 ) 1H-NMR (400 MHz, CDCl 3) δ 7.85 (dd, J = 8.5, 1.1 Hz, 2H), 7.79 (d, J = 8.7 Hz, 2H), 7.58-7.62 (m, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 5.74 (t, J = 4.3 Hz, 1H), 4.47 (d, J = 4.6 Hz, 2H), 2.39 (s, 3H). MS(ESI): m/z 290 (M+1).
N-(2-옥소-2- 페닐에틸 )-1- 페닐메탄설폰아마이드 ( DKC1125a28 ) 1H-NMR (400 MHz, CDCl 3) δ 7.78 (d, J = 7.3 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.42-7.47 (m, 4H), 7.29-7.34 (m, 3H), 5.55 (t, J = 4.3 Hz, 1H), 4.35 (s, 2H), 4.31 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 290 (M+1).
N-(2-옥소-2- 페닐에틸 )-3,5- 비스(트리플루오로메틸)벤즈아마이드 (DKC1125a29) 1H-NMR (400 MHz, CDCl 3) δ 8.34 (s, 2H), 8.03-8.06 (m, 3H), 7.66-7.70 (m, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.49 (s, 1H), 5.00 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 376 (M+1).
N-(2-옥소-2- 페닐에틸 )-2-( 트리플루오로메틸 ) 벤즈아마이드 ( DKC1125a30 ) 1H-NMR (400 MHz, CDCl 3) δ 7.97-7.99 (m, 2H), 7.48-7.71 (m, 7H), 7.07 (s, 1H), 4.95 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 308 (M+1).
N-(2-옥소-2- 페닐에틸 )-3-( 트리플루오로메틸 ) 벤즈아마이드 ( DKC1125a31 ) 1H-NMR (400 MHz, CDCl 3) δ 8.17 (s, 1H), 8.02-8.07 (m, 3H), 7.79 (d, J = 8.2 Hz, 1H), 7.58-7.68 (m, 2H), 7.51-7.55 (m, 2H), 7.43 (s, 1H), 4.98 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 308 (M+1).
N-(2-옥소-2- 페닐에틸 )-4-( 트리플루오로메틸 ) 벤즈아마이드 ( DKC1125a32 ) 1H-NMR (400 MHz, CDCl 3) δ 8.00-8.06 (m, 4H), 7.75 (d, J = 8.2 Hz, 2H), 7.65-7.69 (m, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.37 (s, 1H), 4.98 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 308 (M+1).
2- 클로로 -4- 플루오로 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a33 ) 1H-NMR (400 MHz, CDCl 3) δ 7.99-8.01 (m, 2H), 7.77 (dd, J = 8.7, 5.9 Hz, 1H), 7.62-7.66 (m, 1H), 7.49-7.55 (m, 3H), 7.15 (dd, J = 8.5, 2.5 Hz, 1H), 7.04 (td, J = 8.2, 2.7 Hz, 1H), 4.97 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 293 (M+1).
3-니트로-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a34 ) 1H-NMR (400 MHz, CDCl 3) δ 8.73 (t, J = 2.1 Hz, 1H), 8.37 (dd, J = 7.8, 1.8 Hz, 1H), 8.23 (dt, J = 7.9, 1.4 Hz, 1H), 8.02-8.04 (m, 2H), 7.64-7.69 (m, 2H), 7.51-7.55 (m, 3H), 5.00 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 285 (M+1).
3,4- 디플루오로 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a35 ) 1H-NMR (400 MHz, CDCl 3) δ 8.02-8.04 (m, 2H), 7.73-7.78 (m, 1H), 7.62-7.68 (m, 2H), 7.52-7.56 (m, 2H), 7.23-7.29 (m, 2H), 4.94-4.95 (m, 2H). MS(ESI): m/z 276 (M+1).
3,5- 디클로로 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a36) 1H-NMR (400 MHz, CDCl 3) δ 8.01-8.03 (m, 2H), 7.75 (d, J = 1.8 Hz, 2H), 7.66 (tt, J = 7.4, 1.4 Hz, 1H), 7.50-7.55 (m, 3H), 7.33 (s, 1H), 4.94 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 309 (M+1).
2,3- 디클로로 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a37 ) 1H-NMR (400 MHz, CDCl 3) δ 7.99-8.01 (m, 2H), 7.63-7.67 (m, 1H), 7.51-7.55 (m, 4H), 7.27 (t, J = 8.0 Hz, 2H), 4.98 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 309 (M+1).
N-(2-옥소-2- 페닐에틸 )-4-( 트리플루오로메톡시 ) 벤즈아마이드 ( DKC1125a38 ) 1H-NMR (400 MHz, CDCl 3) δ 8.01-8.03 (m, 2H), 7.93 (dt, J = 9.3, 2.3 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.39 (s, 1H), 7.28 (d, J = 8.2 Hz, 2H), 4.95 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 324 (M+1).
N-(2-옥소-2- 페닐에틸 )-3-( 트리플루오로메톡시 ) 벤즈아마이드 ( DKC1125a39 ) 1H-NMR (400 MHz, CDCl 3) δ 8.01 (dd, J = 8.5, 1.1 Hz, 2H), 7.77-7.81 (m, 2H), 7.61-7.66 (m, 1H), 7.46-7.53 (m, 4H), 7.37 (dt, J = 8.4, 1.1 Hz, 1H), 4.95 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 324 (M+1).
3,5-디메틸-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a40 ) 1H-NMR (400 MHz, CDCl 3) δ 8.00-8.02 (m, 2H), 7.60-7.64 (m, 1H), 7.50 (t, J = 7.5 Hz, 4H), 7.34 (s, 1H), 7.13 (s, 1H), 4.93 (d, J = 4.1 Hz, 2H), 2.31-2.36 (m, 6H). MS(ESI): m/z 268 (M+1).
N-(2-옥소-2- 페닐에틸 )-2-( 트리플루오로메톡시 ) 벤즈아마이드 ( DKC1125a41 ) 1H-NMR (400 MHz, CDCl 3) δ 8.03 (tt, J = 5.3, 1.9 Hz, 3H), 7.80 (s, 1H), 7.63 (tt, J = 7.4, 1.4 Hz, 1H), 7.49-7.55 (m, 3H), 7.40 (td, J = 7.5, 1.1 Hz, 1H), 7.34 (dt, J = 8.2, 1.4 Hz, 1H), 4.99 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 324 (M+1).
3,5- 디메톡시 -N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125a42) 1H-NMR (400 MHz, CDCl 3) δ 7.99-8.02 (m, 2H), 7.63 (tt, J = 7.4, 1.4 Hz, 1H), 7.48-7.52 (m, 2H), 7.36 (d, J = 3.7 Hz, 1H), 7.00 (d, J = 2.3 Hz, 2H), 6.59 (t, J = 2.3 Hz, 1H), 4.92 (d, J = 4.1 Hz, 2H), 3.80 (d, J = 10.1 Hz, 6H). MS(ESI): m/z 300 (M+1).
N-(2-옥소-2- 페닐에틸 )-[1,1'- bi페닐 ]-4- 카복사마이드 ( DKC1125a43 ) 1H-NMR (400 MHz, CDCl 3) δ 8.04-8.06 (m, 2H), 7.97 (dt, J = 8.4, 1.9 Hz, 2H), 7.61-7.71 (m, 5H), 7.53 (t, J = 7.8 Hz, 2H), 7.45-7.49 (m, 2H), 7.37-7.41 (m, 2H), 4.99 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 316 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-2- 플루오로벤즈아마이드 ( DKC1125b01) 1H-NMR (400 MHz, CDCl 3) δ 8.11 (tt, J = 7.9, 2.4 Hz, 1H), 7.97 (dt, J = 9.0, 2.1 Hz, 2H), 7.84-7.87 (m, 1H), 7.47-7.53 (m, 3H), 7.25-7.29 (m, 1H), 7.10-7.19 (m, 1H), 4.97 (dd, J = 4.3, 1.1 Hz, 2H). MS(ESI): m/z 293 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-4- 플루오로벤즈아마이드 ( DKC1125b02 ) 1H-NMR (400 MHz, CDCl 3) δ 7.88-7.97 (m, 4H), 7.50 (dd, J = 8.0, 1.6 Hz, 2H), 7.26 (s, 1H), 7.12-7.16 (m, 2H), 4.91 (d, J = 2.7 Hz, 2H). MS(ESI): m/z 293 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 퓨란 -2- 카복사마이드 ( DKC1125b03 ) 1H-NMR (400 MHz, CDCl 3) δ 7.96-7.98 (m, 2H), 7.48-7.51 (m, 2H), 7.28-7.39 (m, 1H), 7.16 (d, J = 1.8 Hz, 1H), 6.52 (s, 1H), 4.90 (t, J = 2.1 Hz, 2H). MS(ESI): m/z 265 (M+1).
3- 클로로 -N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125b04 ) 1H-NMR (400 MHz, CDCl 3) δ 7.94-7.96 (m, 2H), 7.86 (t, J = 1.6 Hz, 1H), 7.73 (dd, J = 7.8, 0.9 Hz, 1H), 7.47-7.50 (m, 3H), 7.35-7.41 (m, 2H), 4.91 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 309 (M+1).
(E)-N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 부트 -2- 엔아마이드 ( DKC1125b05 ) 1H-NMR (400 MHz, CDCl 3) δ 7.93-7.96 (m, 2H), 7.47-7.50 (m, 2H), 6.92 (q, J = 7.3 Hz, 1H), 6.59 (s, 1H), 5.97 (dd, J = 15.1, 1.8 Hz, 1H), 4.81 (d, J = 4.6 Hz, 2H), 1.89 (dd, J = 6.9, 1.8 Hz, 3H). MS(ESI): m/z 239 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-3- 페닐프로판아마이드 ( DKC1125b06 ) 1H-NMR (400 MHz, CDCl 3) δ 7.89 (dt, J = 9.0, 2.3 Hz, 2H), 7.45 (dt, J = 8.8, 2.3 Hz, 2H), 7.25-7.30 (m, 2H), 7.17-7.22 (m, 3H), 6.62 (s, 1H), 4.70 (d, J = 4.1 Hz, 2H), 3.00 (t, J = 7.9 Hz, 2H), 2.62 (dd, J = 8.7, 6.9 Hz, 2H). MS(ESI): m/z 303 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 아크릴아마이드 ( DKC1125b07 ) 1H-NMR (400 MHz, CDCl 3) δ 7.93-7.96 (m, 2H), 7.48-7.51 (m, 2H), 6.78 (s, 1H), 6.23-6.39 (m, 2H), 5.73 (dd, J = 10.1, 1.8 Hz, 1H), 4.83 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 225 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-2- 메틸벤즈아마이드 ( DKC1125b08 ) 1H-NMR (400 MHz, CDCl 3) δ 7.95 (dt, J = 9.0, 2.1 Hz, 2H), 7.46-7.51 (m, 3H), 7.32-7.36 (m, 1H), 7.21-7.27 (m, 2H), 6.90 (s, 1H), 4.90 (d, J = 4.6 Hz, 2H), 2.47 (d, J = 4.6 Hz, 3H). MS(ESI): m/z 289 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-4- 메톡시벤즈아마이드 ( DKC1125b09 ) 1H-NMR (400 MHz, CDCl 3) δ 7.94 (dt, J = 9.0, 2.1 Hz, 2H), 7.48 (dt, J = 8.7, 1.9 Hz, 2H), 7.40-7.43 (m, 2H), 7.31-7.37 (m, 2H), 7.04-7.07 (m, 1H), 4.90 (d, J = 4.1 Hz, 2H), 3.84 (s, 3H). MS(ESI): m/z 305 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-3- 메틸벤즈아마이드 ( DKC1125b10 ) 1H-NMR (400 MHz, CDCl 3) δ 7.96 (dt, J = 9.0, 2.1 Hz, 2H), 7.64-7.69 (m, 2H), 7.48 (dt, J = 9.0, 2.1 Hz, 2H), 7.30-7.34 (m, 3H), 4.91 (d, J = 4.3 Hz, 2H), 2.39 (d, J = 10.1 Hz, 3H). MS(ESI): m/z 289 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 프로피온아마이드 ( DKC1125b11 ) 1H-NMR (400 MHz, CDCl 3) δ 7.92-7.95 (m, 2H), 7.47-7.50 (m, 2H), 6.60 (s, 1H), 4.75 (d, J = 4.6 Hz, 2H), 2.35 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H). MS(ESI): m/z 227 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 사이클로헥산카복사마이드 ( DKC1125b12 ) 1H-NMR (400 MHz, CDCl 3) δ 7.92 (dt, J = 8.8, 2.2 Hz, 2H), 7.48 (dt, J = 9.0, 2.1 Hz, 2H), 6.62 (s, 1H), 4.73 (d, J = 4.6 Hz, 2H), 2.24 (tt, J = 11.7, 3.6 Hz, 1H), 1.92 (dd, J = 13.5, 2.1 Hz, 2H), 1.80-1.84 (m, 2H), 1.67-1.71 (m, 1H), 1.49 (qd, J = 12.2, 2.9 Hz, 2H), 1.21-1.36 (m, 3H). MS(ESI): m/z 281 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 사이클로프로판카복사마이드 ( DKC1125b13 ) 1H-NMR (400 MHz, CDCl 3) δ 7.92-7.95 (m, 2H), 7.48-7.50 (m, 2H), 6.70 (s, 1H), 4.76 (d, J = 4.6 Hz, 2H), 1.51-1.56 (m, 1H), 1.01 (dt, J = 8.2, 3.5 Hz, 2H), 0.81 (td, J = 7.4, 4.3 Hz, 2H). MS(ESI): m/z 239 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 사이클로부탄카복사마이드 ( DKC1125b14 ) 1H-NMR (400 MHz, CDCl 3) δ 7.91-7.94 (m, 2H), 7.46-7.49 (m, 2H), 6.50 (s, 1H), 4.74 (d, J = 4.1 Hz, 2H), 3.11-3.20 (m, 1H), 1.85-2.38 (m, 6H). MS(ESI): m/z 253 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 싸이오펜 -2- 카복사마이드 ( DKC1125b15 ) 1H-NMR (400 MHz, CDCl 3) δ 7.94-7.97 (m, 2H), 7.64 (dd, J = 3.7, 0.9 Hz, 1H), 7.47-7.52 (m, 3H), 7.09-7.19 (m, 2H), 4.90 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 281 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-2-( 메톡시메틸 ) 벤즈아마이드 ( DKC1125b16 ) 1H-NMR (400 MHz, CDCl 3) δ 9.19 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 7.97 (dt, J = 9.0, 2.1 Hz, 2H), 7.42-7.49 (m, 3H), 6.98-7.08 (m, 2H), 4.97 (d, J = 4.1 Hz, 2H), 4.25 (q, J = 7.0 Hz, 2H), 1.70 (t, J = 7.1 Hz, 3H). MS(ESI): m/z 319 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-3, 3i메틸부탄아마이드 ( DKC1125b17 ) 1H-NMR (400 MHz, CDCl 3) δ 7.93 (dt, J = 9.0, 2.1 Hz, 2H), 7.48 (dt, J = 9.0, 2.3 Hz, 2H), 6.52 (s, 1H), 4.75 (d, J = 4.6 Hz, 2H), 2.20 (s, 2H), 1.07 (d, J = 2.3 Hz, 9H). MS(ESI): m/z 269 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 펜탄아마이드 ( DKC1125b18 ) 1H-NMR (400 MHz, CDCl 3) δ 7.93 (dt, J = 9.0, 2.3 Hz, 2H), 7.47-7.50 (m, 2H), 6.63 (s, 1H), 4.75 (d, J = 4.6 Hz, 2H), 2.32 (t, J = 7.5 Hz, 2H), 1.62-1.71 (m, 2H), 1.33-1.43 (m, 2H), 0.93 (td, J = 7.2, 4.3 Hz, 3H). MS(ESI): m/z 255 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-4- 메톡시벤즈아마이드 ( DKC1125b19 ) 1H-NMR (400 MHz, CDCl 3) δ 7.96-7.99 (m, 2H), 7.84-7.87 (m, 2H), 7.49-7.51 (m, 2H), 7.19 (s, 1H), 6.94-6.97 (m, 2H), 4.92 (d, J = 4.1 Hz, 2H), 3.86 (d, J = 4.1 Hz, 3H). MS(ESI): m/z 305 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-3- 니트로벤젠설폰아마이드 ( DKC1125b20 ) 1H-NMR (400 MHz, CDCl 3) δ 8.75 (t, J = 1.8 Hz, 1H), 8.42-8.44 (m, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.75 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 8.7 Hz, 2H), 5.81 (s, 1H), 4.53 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 356 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-2,4- 디플루오로벤즈아마이드 ( DKC1125b21 ) 1H-NMR (400 MHz, CDCl 3) δ 8.11-8.18 (m, 1H), 7.97 (dt, J = 9.0, 2.3 Hz, 2H), 7.77-7.80 (m, 1H), 7.50 (dt, J = 9.0, 2.3 Hz, 2H), 6.98-7.03 (m, 1H), 6.88-6.95 (m, 1H), 4.96 (dd, J = 4.1, 0.9 Hz, 2H). MS(ESI): m/z 311 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-2- 메톡시아세트아마이드 ( DKC1125b22 ) 1H-NMR (400 MHz, CDCl 3) δ 7.93 (dt, J = 8.8, 2.2 Hz, 2H), 7.49 (dt, J = 9.0, 2.1 Hz, 3H), 4.77 (d, J = 4.6 Hz, 2H), 3.99 (s, 2H), 3.49 (s, 3H). MS(ESI): m/z 243 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 피발아마이드 ( DKC1125b23 ) 1H-NMR (400 MHz, CDCl 3) δ 7.92-7.95 (m, 2H), 7.47-7.50 (m, 2H), 6.79 (s, 1H), 4.71 (d, J = 4.1 Hz, 2H), 1.27 (d, J = 5.5 Hz, 9H). MS(ESI): m/z 255 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-4- 플루오로벤젠설폰아마이드 ( DKC1125b24 ) 1H-NMR (400 MHz, CDCl 3) δ 7.92 (tt, J = 7.3, 2.3 Hz, 2H), 7.80 (dt, J = 9.0, 2.1 Hz, 2H), 7.45 (dt, J = 8.8, 2.3 Hz, 2H), 7.18 (tt, J = 8.8, 2.7 Hz, 2H), 5.73 (t, J = 4.3 Hz, 1H), 4.46 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 329 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-4- 메틸벤젠설폰아마이드 ( DKC1125b25 ) 1H-NMR (400 MHz, CDCl 3) δ 7.77-7.81 (m, 4H), 7.44 (dd, J = 6.6, 1.6 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 5.66 (s, 1H), 4.43 (d, J = 4.6 Hz, 2H), 2.40 (s, 3H). MS(ESI): m/z 325 (M+1).
4- 클로로 -N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 벤젠설폰아마이드 ( DKC1125b26 ) 1H-NMR (400 MHz, CDCl 3) δ 7.99 (dt, J = 9.3, 2.3 Hz, 1H), 7.78-7.85 (m, 3H), 7.61 (dt, J = 9.0, 2.3 Hz, 1H), 7.44-7.49 (m, 3H), 5.71 (t, J = 4.3 Hz, 1H), 4.45 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 345 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-1- 페닐메탄설폰아마이드 ( DKC1125b27 ) 1H-NMR (400 MHz, CDCl 3) δ 7.72 (dt, J = 9.0, 2.1 Hz, 2H), 7.41-7.46 (m, 4H), 7.32-7.36 (m, 3H), 5.36 (t, J = 4.3 Hz, 1H), 4.35 (s, 2H), 4.24 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 325 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-4- 메톡시벤젠설폰아마이드 ( DKC1125b28 ) 1H-NMR (400 MHz, CDCl 3) δ 7.78-7.84 (m, 4H), 7.45 (dt, J = 9.0, 2.3 Hz, 2H), 6.96 (dt, J = 9.6, 2.5 Hz, 2H), 4.42 (d, J = 4.6 Hz, 2H), 3.84 (s, 3H). MS(ESI): m/z 341 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-3,5- 비스(트리플루오로메틸)벤즈아마이드 (DKC1125b29) 1H-NMR (400 MHz, CDCl 3) δ 8.33 (s, 2H), 8.04 (s, 1H), 7.98 (dd, J = 6.9, 1.8 Hz, 2H), 7.53 (dd, J = 6.9, 1.8 Hz, 2H), 7.46 (s, 1H), 4.97 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 411 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-2-( 트리플루오로메틸 ) 벤즈아마이드 (DKC1125b30) 1H-NMR (400 MHz, CDCl 3) δ 7.94 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 7.3 Hz, 1H), 7.54-7.63 (m, 3H), 7.50 (d, J = 8.7 Hz, 2H), 6.98 (s, 1H), 4.93 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 343 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-3-( 트리플루오로메틸 ) 벤즈아마이드 (DKC1125b31) 1H-NMR (400 MHz, CDCl 3) δ 8.15 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.96 (dt, J = 9.0, 2.1 Hz, 2H), 7.76-7.79 (m, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.48-7.51 (m, 2H), 4.94 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 343 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-4-( 트리플루오로메틸 ) 벤즈아마이드 (DKC1125b32) 1H-NMR (400 MHz, CDCl 3) δ 7.96-8.00 (m, 4H), 7.74 (d, J = 8.2 Hz, 2H), 7.52 (dt, J = 8.8, 2.2 Hz, 2H), 7.36 (s, 1H), 4.94 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 343 (M+1).
2- 클로로 -N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-4- 플루오로벤즈아마이드 (DKC1125b33) 1H-NMR (400 MHz, CDCl 3) δ 7.96 (dt, J = 9.0, 2.1 Hz, 2H), 7.80 (dd, J = 8.7, 5.9 Hz, 1H), 7.51 (dt, J = 9.0, 2.3 Hz, 2H), 7.46 (s, 1H), 7.19 (dd, J = 8.5, 2.5 Hz, 1H), 7.05-7.10 (m, 1H), 4.95 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 327 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-3- 니트로벤즈아마이드 ( DKC1125b34 ) 1H-NMR (400 MHz, CDCl 3) δ 8.74 (t, J = 1.8 Hz, 1H), 8.41 (dq, J = 8.2, 1.1 Hz, 1H), 8.23 (dd, J = 7.8, 0.9 Hz, 1H), 7.98-8.01 (m, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.52-7.55 (m, 2H), 7.38 (s, 1H), 4.97 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 320 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-3,4- 디플루오로벤즈아마이드 ( DKC1125b35 ) 1H-NMR (400 MHz, CDCl 3) δ 7.97 (dt, J = 9.0, 2.3 Hz, 2H), 7.75 (ddd, J = 10.6, 7.4, 2.2 Hz, 1H), 7.61-7.65 (m, 1H), 7.51 (dt, J = 9.0, 2.1 Hz, 2H), 7.23-7.29 (m, 2H), 4.91 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 311 (M+1).
3,5- 디클로로 -N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125b36 ) 1H-NMR (400 MHz, CDCl 3) δ 7.98 (dt, J = 9.0, 2.3 Hz, 2H), 7.74 (d, J = 1.8 Hz, 2H), 7.53 (td, J = 4.5, 2.1 Hz, 3H), 7.21 (s, 1H), 4.91 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 344 (M+1).
2,3- 디클로로 -N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125b37 ) 1H-NMR (400 MHz, CDCl 3) δ 7.95 (d, J = 7.8 Hz, 2H), 7.49-7.55 (m, 4H), 7.28 (t, J = 7.5 Hz, 2H), 4.94 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 344 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-4-( 트리플루오로메톡시 ) 벤즈아마이드 (DKC1125b38) 1H-NMR (400 MHz, CDCl 3) δ 7.97 (dt, J = 9.0, 2.1 Hz, 2H), 7.93 (dt, J = 9.1, 2.4 Hz, 2H), 7.50 (dt, J = 9.1, 2.0 Hz, 2H), 7.26-7.32 (m, 3H), 4.92 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 359 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-3-( 트리플루오로메톡시 ) 벤즈아마이드 (DKC1125b39) 1H-NMR (400 MHz, CDCl 3) δ 7.96 (dt, J = 8.8, 2.2 Hz, 2H), 7.77-7.79 (m, 1H), 7.75 (s, 1H), 7.48-7.52 (m, 3H), 7.36-7.40 (m, 2H), 4.92 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 359 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-3,5- 디메틸벤즈아마이드 ( DKC1125b40 ) 1H-NMR (400 MHz, CDCl 3) δ 7.98 (dt, J = 9.0, 2.1 Hz, 2H), 7.50 (dt, J = 9.0, 2.1 Hz, 2H), 7.47 (s, 2H), 7.23 (s, 1H), 7.16 (s, 1H), 4.92 (d, J = 4.1 Hz, 2H), 2.37 (s, 6H). MS(ESI): m/z 303 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-2-( 트리플루오로메톡시 ) 벤즈아마이드 (DKC1125b41) 1H-NMR (400 MHz, CDCl 3) δ 8.04 (dd, J = 7.8, 1.4 Hz, 1H), 7.97 (dt, J = 9.1, 2.1 Hz, 2H), 7.76 (s, 1H), 7.48-7.56 (m, 3H), 7.41 (td, J = 7.5, 1.2 Hz, 1H), 7.35 (dd, J = 8.2, 1.4 Hz, 1H), 4.96 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 359 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-3,5- 디메톡시벤즈아마이드 ( DKC1125b42 ) 1H-NMR (400 MHz, CDCl 3) δ 7.95 (dt, J = 9.0, 2.1 Hz, 2H), 7.48 (dt, J = 9.0, 2.3 Hz, 2H), 7.31 (t, J = 3.9 Hz, 1H), 6.99 (d, J = 2.3 Hz, 2H), 6.59 (t, J = 2.3 Hz, 1H), 4.89 (d, J = 4.6 Hz, 2H), 3.82 (s, 6H). MS(ESI): m/z 335 (M+1).
N-(2-(4- 클로로페닐 )-2- 옥소에틸 )-[1,1'- bi페닐 ]-4- 카복사마이드 (DKC1125b43) 1H-NMR (400 MHz, CDCl 3) δ 7.95-8.01 (m, 4H), 7.70 (d, J = 8.2 Hz, 2H), 7.62-7.65 (m, 2H), 7.46-7.54 (m, 4H), 7.40-7.42 (m, 1H), 7.31 (s, 1H), 4.96 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 351 (M+1).
4- 클로로 -N-(2-(4- 클로로페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125b44 ) 1H-NMR (400 MHz, CDCl 3) δ 7.90 (dd, J = 6.6, 2.1 Hz, 2H), 7.75 (dd, J = 8.7, 2.3 Hz, 2H), 7.36-7.45 (m, 4H), 7.23 (s, 1H), 4.85 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 309 (M+1).
실시예 88-121. 본 발명에 따른 화합물 88-122(DKC1125c01-34)의 제조
본 발명의 화합물 88 내지 122(DKC1125c01-34)를 다음 반응식 2에 따라 합성하였다.
[반응식 2]
Figure PCTKR2020010999-appb-img-000062
시약 및 조건: (a) HBr, Br 2, H 2O, 0℃, 1시간; (b) NaHCO 3, H 2O; (c) 포타슘 프탈이미드, DMF, 상온, 밤새 반응시킴; (d) HCl, EtOH, 80℃, 2시간; (e) RCl, NaHCO 3, DCM, H 2O, 1시간
2- 브로모 -1-(4-(디메틸아미노)페닐)에탄-1-온 ( 1)의 합성 :
0℃에서 HBr (100 mL) 중 1-(4-(디메틸아미노)페닐)에탄-1-온(5g, 30.63 mmol)의 용액에 Br 2(4.9 g, 30.63 mmol)를 1시간 동안 적가하였다. 반응이 완료된 후, 생성물을 CH 2Cl 2로 2회 추출하고 포화 NaHCO 3로 세척하였다. 유기층을 MgSO 4로 건조시키고, 용매를 증발시켰다. 생성된 조(crude) 생성물을 컬럼 크로마토 그래피로 정제하여서 반응식 2의 화합물 (1)(7.09g, 95 %)을 수득하였다.
1H NMR (400 MHz, CDCl 3) δ 7.89 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 4.36(s, 2H), 3.08 (s, 6H).
2-아미노-1-(4-(디메틸아미노)페닐)에탄-1-온 하이드로클로라이드 ( 2)의 합성
2-브로모-1-(4-(디메틸아미노)페닐)에탄-1-온(1.6 g, 24.78 mmol)을 20 mL의 건조한 칼륨 프탈이미드(5.05 g, 27.26 mmol) 용액에 용해시키고, 75℃에서 18 시간 동안 유지하였다. 제조된 현탁액을 교반하면서 90 mL의 물에서 퀀칭시키고 이를 40 분 동안 유지시키고, 생성물을 수집하여, 50 mL의 물로 세척하고, 50 mL의 아세토니트릴로 0℃에서 밤새 재결정시켰다(4.58 g, 60 %). 얻어진 고체를 1:2의 농축 HCl 및 EtOH의 용액 (90 mL)에 용해시켰다. 반응물을 환류하에 2시간 동안 끓였다. 침전을 여과하고 물, 이어서 EtOH (2.61 g, 70 %)로 세척하였다.
1H NMR (400 MHz, (CD 3) 2SO) δ 7.91 (d, J = 9.5 Hz, 2H) 6.66 (d, J = 9.5 Hz, 2H), 5.06 (s, 2H), 1.22 (s, 6H).
화합물 88-121( DKC1125c01 - 34)의 일반적인 제조방법
CH 2Cl 2 (1 mL) 및 sat. NaHCO 3 (2 mL)를 격렬히 교반하고 얼음 욕에서 냉각시켰다. 하기 표 4에 기재된 산 염화물 (0.29 mmol)을 각각 첨가한 다음, 즉시 2-아미노-1-(4-(디메틸아미노)페닐)에탄-1-온 디하이드로클로라이드 ( 2, 50 mg, 0.29 mmol)를 첨가하였다. 1 시간에 걸쳐 실온으로 가온하면서 교반을 계속하였다. 이어서, 유기층을 분리하고, Na 2SO 4로 건조시키고, 용매를 증발시켰다. 잔사를 컬럼 크로마토그래피로 정제하였다(수율: 70~80%).
Figure PCTKR2020010999-appb-img-000063
화합물 88-121(DKC1125c01-34)의 제조확인
4- 클로로 -N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 벤즈아마이드 (DKC1125c01) 1H-NMR (400 MHz, CDCl 3) δ 7.90-7.92 (m, 2H), 7.83 (dd, J = 6.4, 1.8 Hz, 2H), 7.42-7.44 (m, 3H), 6.68 (d, J = 9.1 Hz, 2H), 4.83 (d, J = 4.1 Hz, 2H), 3.09 (s, 6H). MS(ESI): m/z 318 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-2- 페녹시프로판아마이드 (DKC1125c02) 1H-NMR (400 MHz, CDCl 3) δ 7.85 (dt, J = 9.8, 2.5 Hz, 2H), 7.68 (s, 1H), 7.27-7.33 (m, 2H), 6.97-7.01 (m, 3H), 6.64 (dt, J = 9.8, 2.5 Hz, 2H), 4.56-4.80 (m, 2H), 3.06 (d, J = 7.3 Hz, 6H), 1.62 (d, J = 6.4 Hz, 3H). MS(ESI): m/z 327 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-2- 플루오로벤즈아마이드 (DKC1125c03) 1H-NMR (400 MHz, CDCl 3) δ 8.12 (td, J = 7.8, 1.8 Hz, 1H), 8.01-8.04 (m, 1H), 7.93 (dt, J = 9.6, 2.5 Hz, 2H), 7.46-7.52 (m, 1H), 7.25-7.29 (m, 1H), 7.14-7.19 (m, 1H), 6.66-6.70 (m, 2H), 4.89-4.90 (m, 2H), 3.08 (s, 6H). MS(ESI): m/z 301 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-4- 플루오로벤즈아마이드 (DKC1125c04) 1H-NMR (400 MHz, CDCl 3) δ 7.87-7.94 (m, 4H), 7.42 (d, J = 11.0 Hz, 1H), 7.11-7.16 (m, 2H), 6.68 (dd, J = 12.1, 3.0 Hz, 2H), 4.84 (d, J = 4.1 Hz, 2H), 3.11 (d, J = 15.1 Hz, 6H). MS(ESI): m/z 301 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 퓨란 -2- 카복사마이드 ( DKC1125c05 ) 1H-NMR (400 MHz, CDCl 3) δ 7.90-7.93 (m, 2H), 7.56 (s, 1H), 7.50 (t, J = 0.9 Hz, 1H), 7.15 (d, J = 3.7 Hz, 1H), 6.67-6.70 (m, 2H), 6.51 (q, J = 1.7 Hz, 1H), 4.82 (d, J = 4.1 Hz, 2H), 3.09 (s, 6H). MS(ESI): m/z 273 (M+1).
2- 클로로 -N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 벤즈아마이드 (DKC1125c06) 1H-NMR (400 MHz, CDCl 3) δ 7.90-7.93 (m, 2H), 7.72 (dd, J = 7.5, 2.1 Hz, 1H), 7.54 (s, 1H), 7.31-7.45 (m, 3H), 6.67-6.70 (m, 2H), 4.88 (d, J = 4.1 Hz, 2H), 3.09 (s, 6H). MS(ESI): m/z 318 (M+1).
3- 클로로 -N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 벤즈아마이드 (DKC1125c07) 1H-NMR (400 MHz, CDCl 3) δ 7.88-7.94 (m, 3H), 7.75 (dt, J = 7.8, 1.4 Hz, 1H), 7.50 (dq, J = 8.1, 1.0 Hz, 1H), 7.38-7.44 (m, 2H), 6.68-6.70 (m, 2H), 4.84 (d, J = 4.1 Hz, 2H), 3.10 (s, 6H). MS(ESI): m/z 318 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 아크릴아마이드 ( DKC1125c08 ) 1H-NMR (400 MHz, CDCl 3) δ 7.86-7.91 (m, 2H), 6.86 (s, 1H), 6.67 (dt, J = 9.8, 2.5 Hz, 2H), 6.35 (dd, J = 16.9, 1.8 Hz, 1H), 6.25 (dd, J = 17.2, 9.8 Hz, 1H), 5.70 (dd, J = 10.1, 1.8 Hz, 1H), 4.74 (d, J = 4.1 Hz, 2H), 3.09 (s, 6H). MS(ESI): m/z 233 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-2- 메틸벤즈아마이드 ( DKC1125c09 ) 1H-NMR (400 MHz, CDCl 3) δ 7.91 (dt, J = 9.8, 2.5 Hz, 2H), 7.49 (d, J = 7.3 Hz, 1H), 7.33 (td, J = 7.5, 1.5 Hz, 1H), 7.23-7.26 (m, 2H), 7.04 (s, 1H), 6.66-6.70 (m, 2H), 4.86 (d, J = 4.1 Hz, 2H), 3.09 (s, 6H), 2.50 (s, 3H). MS(ESI): m/z 297 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-4- 메톡시벤즈아마이드 (DKC1125c10) 1H-NMR (400 MHz, CDCl 3) δ 7.93 (dt, J = 9.6, 2.5 Hz, 2H), 7.42-7.46 (m, 3H), 7.37 (t, J = 8.0 Hz, 1H), 7.05-7.08 (m, 1H), 6.69 (dt, J = 9.8, 2.3 Hz, 2H), 4.85 (d, J = 3.7 Hz, 2H), 3.87 (s, 3H), 3.10 (s, 6H). MS(ESI): m/z 313 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-3- 메틸벤즈아마이드 ( DKC1125c11 ) 1H-NMR (400 MHz, CDCl 3) δ 7.91-7.94 (m, 2H), 7.69 (dd, J = 8.2, 6.4 Hz, 2H), 7.44 (s, 1H), 7.32-7.37 (m, 2H), 6.69 (d, J = 9.1 Hz, 2H), 4.85 (d, J = 3.7 Hz, 2H), 3.11 (d, J = 14.6 Hz, 6H), 2.40 (d, J = 14.2 Hz, 3H). MS(ESI): m/z 297 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 프로피온아마이드 ( DKC1125c12 ) 1H-NMR (400 MHz, CDCl 3) δ 7.86-7.92 (m, 2H), 6.65-6.71 (m, 3H), 4.66 (d, J = 4.1 Hz, 2H), 3.08 (t, J = 15.3 Hz, 6H), 2.34 (q, J = 7.6 Hz, 2H), 1.18-1.25 (m, 3H). MS(ESI): m/z 235 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 사이클로프로판카복사마이드 (DKC1125c13) 1H-NMR (400 MHz, CDCl 3) δ 7.86-7.91 (m, 2H), 6.86 (s, 1H), 6.67 (dt, J = 9.8, 2.5 Hz, 2H), 4.68 (d, J = 4.3 Hz, 2H), 3.08 (s, 6H), 1.54 (tt, J = 8.4, 3.8 Hz, 1H), 1.00 (dt, J = 8.1, 3.3 Hz, 2H), 0.78 (dt, J = 11.6, 3.4 Hz, 2H). MS(ESI): m/z 247 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 싸이오펜 -2- 카복사마이드 (DKC1125c14) 1H-NMR (400 MHz, CDCl 3) δ 7.92 (dt, J = 9.6, 2.4 Hz, 2H), 7.63 (dd, J = 3.9, 1.1 Hz, 1H), 7.50 (dd, J = 5.0, 0.9 Hz, 1H), 7.29 (s, 1H), 7.11 (dd, J = 5.0, 3.7 Hz, 1H), 6.68 (dt, J = 9.8, 2.3 Hz, 2H), 4.83 (d, J = 4.1 Hz, 2H), 3.09 (s, 6H). MS(ESI): m/z 289 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-3, 3i메틸부탄아마이드 (DKC1125c15) 1H-NMR (400 MHz, CDCl 3) δ 7.87 (dt, J = 9.6, 2.5 Hz, 2H), 6.66 (dt, J = 9.8, 2.5 Hz, 2H), 6.61 (s, 1H), 4.67 (d, J = 4.1 Hz, 2H), 3.07 (d, J = 8.7 Hz, 6H), 2.19 (s, 2H), 1.07 (s, 9H). MS(ESI): m/z 277 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 펜탄아마이드 ( DKC1125c16 ) 1H-NMR (400 MHz, CDCl 3) δ 7.87-7.90 (m, 2H), 6.65-6.68 (m, 3H), 4.66 (d, J = 4.1 Hz, 2H), 3.08 (s, 6H), 2.30 (t, J = 7.5 Hz, 2H), 1.63-1.71 (m, 2H), 1.34-1.41 (m, 3H), 0.93 (t, J = 7.3 Hz, 3H). MS(ESI): m/z 263 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-4- 메톡시벤즈아마이드 (DKC1125c17) 1H-NMR (400 MHz, CDCl 3) δ 7.93 (dt, J = 9.8, 2.5 Hz, 2H), 7.86 (dt, J = 9.5, 2.5 Hz, 2H), 7.36 (s, 1H), 6.93-6.97 (m, 2H), 6.68-6.71 (m, 2H), 4.84 (d, J = 4.1 Hz, 2H), 3.87 (d, J = 4.1 Hz, 3H), 3.09 (s, 6H). MS(ESI): m/z 313 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-2,4- 디플루오로벤즈아마이드 (DKC1125c18) 1H-NMR (400 MHz, CDCl 3) δ 8.15 (td, J = 8.9, 6.7 Hz, 1H), 7.91-7.97 (m, 3H), 6.98-7.02 (m, 1H), 6.89-6.95 (m, 1H), 6.69 (dt, J = 9.8, 2.3 Hz, 2H), 4.88-4.89 (m, 2H), 3.10 (s, 6H). MS(ESI): m/z 319 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-2- 메톡시아세트아마이드 (DKC1125c19) 1H-NMR (400 MHz, CDCl 3) δ 7.88 (dt, J = 9.8, 2.5 Hz, 2H), 7.64 (s, 1H), 6.67 (dt, J = 9.6, 2.4 Hz, 2H), 4.70 (d, J = 4.6 Hz, 2H), 3.98 (s, 2H), 3.48 (s, 3H), 3.08 (s, 6H). MS(ESI): m/z 251 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-4- 플루오로벤젠설폰아마이드 (DKC1125c20) 1H-NMR (400 MHz, CDCl 3) δ 7.88-7.94 (m, 2H), 7.73 (dt, J = 9.8, 2.5 Hz, 2H), 7.13-7.18 (m, 2H), 6.60-6.63 (m, 2H), 5.83 (t, J = 4.1 Hz, 1H), 4.35 (d, J = 4.1 Hz, 2H), 3.02-3.09 (m, 6H). MS(ESI): m/z 337 (M+1).
4- 클로로 -N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 벤젠설폰아마이드 (DKC1125c21) 1H-NMR (400 MHz, CDCl 3) δ 7.83 (dt, J = 9.0, 2.3 Hz, 2H), 7.72 (dt, J = 9.8, 2.5 Hz, 2H), 7.45 (dt, J = 9.0, 2.3 Hz, 2H), 6.61 (dt, J = 9.7, 2.5 Hz, 2H), 5.85 (t, J = 4.1 Hz, 1H), 4.35 (d, J = 4.1 Hz, 2H), 3.02-3.09 (m, 6H). MS(ESI): m/z 354 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 벤젠설폰아마이드 ( DKC1125c22 ) 1H-NMR (400 MHz, CDCl 3) δ 7.88-7.93 (m, 2H), 7.73 (dt, J = 9.6, 2.4 Hz, 2H), 7.46-7.57 (m, 3H), 6.59-6.63 (m, 2H), 5.82 (t, J = 3.9 Hz, 1H), 4.35 (d, J = 4.6 Hz, 2H), 3.02-3.07 (m, 6H). MS(ESI): m/z 319 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-1- 페닐메탄설폰아마이드 (DKC1125c23) 1H-NMR (400 MHz, CDCl 3) δ 7.67-7.71 (m, 2H), 7.39-7.43 (m, 2H), 7.32-7.34 (m, 3H), 6.60-6.64 (m, 2H), 5.46 (t, J = 4.1 Hz, 1H), 4.33 (d, J = 8.7 Hz, 2H), 4.23 (d, J = 4.1 Hz, 2H), 3.08 (s, 6H). MS(ESI): m/z 333 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-4- 메톡시벤젠설폰아마이드 (DKC1125c24) 1H-NMR (400 MHz, CDCl 3) δ 7.80 (dt, J = 9.5, 2.5 Hz, 2H), 7.71 (dt, J = 9.9, 2.4 Hz, 2H), 6.92 (dt, J = 9.5, 2.5 Hz, 2H), 6.58-6.61 (m, 2H), 5.73 (t, J = 4.3 Hz, 1H), 4.31 (d, J = 4.6 Hz, 2H), 3.81 (s, 3H), 3.02 (d, J = 17.4 Hz, 6H). MS(ESI): m/z 349 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-2-( 트리플루오로메틸 ) 벤즈아마이드 ( DKC1125c25 ) 1H-NMR (400 MHz, CDCl 3) δ 7.91 (dt, J = 9.6, 2.4 Hz, 2H), 7.72-7.75 (m, 1H), 7.61-7.65 (m, 2H), 7.55-7.60 (m, 1H), 7.11 (s, 1H), 6.69 (dt, J = 9.8, 2.5 Hz, 2H), 4.87 (d, J = 4.1 Hz, 2H), 3.10 (d, J = 6.4 Hz, 6H). MS(ESI): m/z 351 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-3-( 트리플루오로메틸 ) 벤즈아마이드 ( DKC1125c26 ) 1H-NMR (400 MHz, CDCl 3) δ 8.18 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.94 (dt, J = 9.8, 2.3 Hz, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.51 (s, 1H), 6.71 (dt, J = 9.8, 2.5 Hz, 2H), 4.87 (d, J = 4.1 Hz, 2H), 3.11 (s, 6H). MS(ESI): m/z 351 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-4-( 트리플루오로메틸 ) 벤즈아마이드 ( DKC1125c27 ) 1H-NMR (400 MHz, CDCl 3) δ 8.00 (d, J = 8.2 Hz, 2H), 7.92 (dd, J = 7.1, 2.1 Hz, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.52 (s, 1H), 6.68-6.70 (m, 2H), 4.86 (d, J = 4.1 Hz, 2H), 3.10 (s, 6H). MS(ESI): m/z 351 (M+1).
2- 클로로 -N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-4- 플루오로벤즈아마이드 (DKC1125c28) 1H-NMR (400 MHz, CDCl 3) δ 7.90-7.93 (m, 2H), 7.79 (dd, J = 8.5, 6.2 Hz, 1H), 7.58 (s, 1H), 7.19 (dd, J = 8.5, 2.5 Hz, 1H), 7.05-7.10 (m, 1H), 6.69 (dd, J = 9.4, 2.5 Hz, 2H), 4.88 (d, J = 4.1 Hz, 2H), 3.10 (d, J = 3.7 Hz, 6H). MS(ESI): m/z 336 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-3,4- 디플루오로벤즈아마이드 (DKC1125c29) 1H-NMR (400 MHz, CDCl 3) δ 7.90-7.93 (m, 2H), 7.74-7.79 (m, 1H), 7.64 (tt, J = 6.1, 2.0 Hz, 1H), 7.42 (s, 1H), 7.22-7.29 (m, 1H), 6.68-6.71 (m, 2H), 4.83-4.89 (m, 2H), 3.13 (d, J = 15.1 Hz, 5H). MS(ESI): m/z 319 (M+1).
3,5- 디클로로 -N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 벤즈아마이드 (DKC1125c30) 1H-NMR (400 MHz, CDCl 3) δ 7.93 (dt, J = 9.8, 2.5 Hz, 2H), 7.75-7.77 (m, 2H), 7.52 (q, J = 2.3 Hz, 1H), 7.42 (s, 1H), 6.68-6.72 (m, 2H), 4.83 (d, J = 3.7 Hz, 2H), 3.10-3.15 (m, 6H). MS(ESI): m/z 352 (M+1).
2,3- 디클로로 -N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 ) 벤즈아마이드 (DKC1125c31) 1H-NMR (400 MHz, CDCl 3) δ 7.91 (dt, J = 9.8, 2.5 Hz, 2H), 7.54 (ddd, J = 10.6, 7.9, 1.5 Hz, 2H), 7.33 (s, 1H), 7.27-7.31 (m, 1H), 6.69 (dt, J = 9.6, 2.5 Hz, 2H), 4.88 (d, J = 4.1 Hz, 2H), 3.11 (s, 6H). MS(ESI): m/z 352 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-4-( 트리플루오로메톡시 ) 벤즈아마이드 ( DKC1125c32 ) 1H-NMR (400 MHz, CDCl 3) δ 7.91-7.97 (m, 4H), 7.45 (s, 1H), 7.30-7.32 (m, 2H), 6.70 (dt, J = 9.8, 2.5 Hz, 2H), 4.85 (d, J = 4.1 Hz, 2H), 3.11 (s, 6H). MS(ESI): m/z 367 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-3,5- 디메틸벤즈아마이드 (DKC1125c33) 1H-NMR (400 MHz, CDCl 3) δ 7.91-7.95 (m, 2H), 7.49 (s, 2H), 7.42 (d, J = 3.7 Hz, 1H), 7.15 (s, 1H), 6.69 (dd, J = 11.9, 2.7 Hz, 2H), 4.84 (d, J = 4.1 Hz, 2H), 3.11 (d, J = 15.1 Hz, 6H), 2.34-2.37 (m, 6H). MS(ESI): m/z 311 (M+1).
N-(2-(4-(디메틸아미노)페닐)-2- 옥소에틸 )-3,5- 디메톡시벤즈아마이드 (DKC1125c34) 1H-NMR (400 MHz, CDCl 3) δ 7.93 (dd, J = 11.9, 2.7 Hz, 2H), 7.39 (s, 1H), 7.01 (d, J = 2.3 Hz, 2H), 6.69 (dd, J = 11.9, 2.7 Hz, 2H), 6.60 (t, J = 2.3 Hz, 1H), 4.84 (d, J = 4.1 Hz, 2H), 3.83-3.89 (m, 6H), 3.10 (s, 6H). MS(ESI): m/z 343 (M+1).
실시예 122 -129. 본 발명에 따른 화합물 122-129(DKC1125d01-08)의 제조
본 발명의 화합물 122 내지 129(DKC1125d01-08)를 다음 반응식 3에 따라 합성하였다.
[반응식 3]
Figure PCTKR2020010999-appb-img-000064
시약 및 조건: (a) 헥사메틸렌테트라민, DCM, 상온, 밤새 반응; (b) HCl, EtOH, 80℃, 2시간; (c) RCl, NaHCO 3, DCM, H 2O, 1시간
2-아미노-1-(3-메톡시페닐)에탄-1-온 하이드로클로라이드 (3)의 합성
2-브로모-1-(3-메톡시페닐)에탄-1-온 (5 g, 21.83 mmol)을 25 mL CH 2Cl 2에 용해시키고 헥사메틸렌테트라민(3.06 g, 21.83 mmol)을 처리하였다. 상온에서 밤새 반응시킨 후에, 반응물을 얼음조에서 냉각시키고 형성된 침전물을 CH 2Cl 2 및 EtOH로 세척하여 헥사메틸렌테트라민염을 수득하였다. 농축 HCl 및 EtOH (1 : 2)의 용액 (90 mL)으로 염을 처리하여 원하는 아민을 수득하였다. 생성된 침전물은 여과하고 물, 이후 에탄올(2.95g, 65%)로 세척하였다.
1H NMR (400 MHz, (CD 3) 2SO) δ 8.50(s, 3H), 7.61(dd, J = 0.9, 7.8 Hz, 1H), 7.50-7.53(m, 2H), 7.31(m, 1H), 4.58(d, J = 4.4 Hz, 2H), 3.85(s, 3H).
화학식 122-129(DKC1125d01-08)의 일반적인 제조방법
CH 2Cl 2(1mL) 및 sat. NaHCO 3(2 mL)를 격렬히 교반하고 얼음 욕(ice bath)에서 냉각시켰다. 하기 표 5에 기재된 산 염화물(0.29 mmol)을 각각 첨가한 다음, 즉시 2-아미노-1-(3-메톡시페닐)에탄-1-온 하이드로클로라이드 ( 3, 50 mg, 0.29 mmol)를 첨가하였다. 1 시간에 걸쳐 실온으로 가온하면서 교반을 계속하였다. 이어서, 유기층을 분리하고, Na 2SO 4로 건조시키고, 용매를 증발시켰다 (수율: 80 내지 90 %).
Figure PCTKR2020010999-appb-img-000065
화합물 122-129(DKC1125d01-08)의 제조확인
4- 클로로 -N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125d01 ) 1H-NMR (400 MHz, CDCl 3) δ 7.83 (dd, J = 8.7, 2.3 Hz, 2H), 7.61 (dd, J = 7.7, 0.8 Hz, 1H), 7.52-7.54 (m, 2H), 7.44 (dd, J = 8.2, 1.8 Hz, 3H), 7.29 (s, 1H), 7.19 (dd, J = 8.2, 2.7 Hz, 1H), 4.94 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 305 (M+1).
(E)-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 부트 -2- 엔아마이드 ( DKC1125d02 ) 1H-NMR (400 MHz, CDCl 3) δ 7.58 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 2.1 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.17 (dd, J = 8.0, 2.5 Hz, 1H), 6.92 (q, J = 7.3 Hz, 1H), 5.98 (dd, J = 15.3, 1.6 Hz, 1H), 4.83 (d, J = 4.1 Hz, 2H), 3.87 (s, 3H), 1.89 (dd, J = 6.9, 1.4 Hz, 3H), 1.61 (d, J = 6.4 Hz, 1H). MS(ESI): m/z 234 (M+1).
N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 프로피온아마이드 ( DKC1125d03 ) 1H-NMR (400 MHz, CDCl 3) δ 7.64-7.50 (1H), 7.50-7.43 (1H), 7.43-7.33 (1H), 7.20-7.07 (1H), 6.72-6.46 (1H), 4.77-4.68 (2H), 3.87-3.77 (3H), 2.38-2.25 (2H), 1.25-1.08 (3H). MS(ESI): m/z 222 (M+1).
N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 사이클로프로판카복사마이드 ( DKC1125d04 ) 1H-NMR (400 MHz, CDCl 3) δ 7.56 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 2.1 Hz, 1H), 7.41 (q, J = 7.8 Hz, 1H), 7.16 (dd, J = 8.2, 2.3 Hz, 1H), 6.79 (s, 1H), 4.78 (d, J = 4.1 Hz, 2H), 3.86 (s, 3H), 1.53-1.59 (m, 1H), 0.99-1.04 (m, 2H), 0.78-0.84 (m, 2H). MS(ESI): m/z 234 (M+1).
N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 사이클로부탄카복사마이드 ( DKC1125d05 ) 1H-NMR (400 MHz, CDCl 3) δ 7.56 (dd, J = 7.8, 1.4 Hz, 1H), 7.49 (q, J = 1.4 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.16 (dt, J = 8.2, 1.4 Hz, 1H), 6.51 (s, 1H), 4.75 (d, J = 4.1 Hz, 2H), 3.86 (s, 3H), 3.11-3.20 (m, 1H), 2.29-2.39 (m, 2H), 2.17-2.25 (m, 2H), 1.85-2.05 (m, 2H). MS(ESI): m/z 248 (M+1).
N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 싸이오펜 -2- 카복사마이드 ( DKC1125d06 ) 1H-NMR (400 MHz, CDCl 3) δ 7.62 (d, J = 3.7 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.49-7.51 (m, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.17 (dd, J = 8.2, 2.7 Hz, 1H), 7.13 (s, 1H), 7.10 (t, J = 4.3 Hz, 1H), 4.91 (d, J = 4.1 Hz, 2H). MS(ESI): m/z 276 (M+1).
N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 펜탄아마이드 ( DKC1125d07 ) 1H-NMR (400 MHz, CDCl 3) δ 7.56 (dd, J = 6.4, 1.4 Hz, 1H), 7.49 (q, J = 1.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.16 (dq, J = 8.2, 1.2 Hz, 1H), 6.64 (s, 1H), 4.76 (d, J = 4.6 Hz, 2H), 3.86 (s, 3H), 2.32 (t, J = 7.8 Hz, 2H), 1.64-1.71 (m, 2H), 1.34-1.41 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). MS(ESI): m/z 250 (M+1).
N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 벤젠설폰아마이드 ( DKC1125d08 ) 1H-NMR (400 MHz, CDCl 3) δ 7.89-7.92 (m, 2H), 7.48-7.58 (m, 3H), 7.34-7.42 (m, 3H), 7.14 (dq, J = 8.0, 1.2 Hz, 1H), 5.77 (t, J = 4.3 Hz, 1H), 4.47 (d, J = 4.6 Hz, 2H), 3.83 (s, 3H). MS(ESI): m/z 306 (M+1).
실시예 130 -136. 본 발명에 따른 화합물 130-129(DKC1125e01-07)의 제조
화합물 130-136(DKC1125e01-07)의 합성
본 발명의 화합물 130 내지 136(DKC1125e01-07)을 다음 반응식 4에 따라 합성하였다.
[반응식 4]
Figure PCTKR2020010999-appb-img-000066
시약 및 조건: (a) 헥사메틸렌테트라민, DCM, 밤새 반응시킴; (b) HCl, EtOH, 80℃, 2시간; (c) RCl, NaHCO 3, DCM, H 2O, 1시간
2-아미노-1-(피리딘-3-일)에탄-1-온 하이드로클로라이드 (4)의 합성
2-브로모-1-(피리딘-3-일)에탄-1-온 (5g, 25.00mmol)을 25 mL의 CH 2Cl 2에 용해시키고, 25 mL CH 2Cl 2. 중의 헥사메틸렌테트라민 (3.50g, 25.00mmol)용액으로 처리하였다. 상온에서 밤새 반응시킨 후, 반응물을 얼음조로 냉각시키고 형성된 침전물을 CH 2Cl 2 및 EtOH로 세척하였고, 헥사메틸렌테트라민 염을 얻었다. 원하는 아민을 제조하기 위하여 농축 염산 및 에탄올 (1:2) 용액(90mL)을 사용하여 상기 염을 처리하였다. 얻어진 침전물을 여과하고 물 및 이어 에탄올로 세척하여 표제 화합물을 얻었다(1.30g, 30%).
1H-NMR (400 MHz, (CD 3) 2SO) δ 9.24 (t, J = 1.1 Hz, 1H), 8.93 (q, J = 2.3 Hz, 1H), 8.57 (s, 2H), 8.49 (dt, J = 8.1, 1.9 Hz, 1H), 7.73-7.76 (m, 1H), 4.67 (d, J = 5.5 Hz, 2H).
화합물 130-136(DKC1125e01-07)의 일반적인 제조방법
CH 2Cl 2 (1 mL) 및 sat. NaHCO 3 (2 mL)를 격렬히 교반하고 얼음 조에서 냉각시켜다. 하기 표 6의 산 염화물(0.29 mmol)을 첨가한 후, 즉시 2-아미노-1-(피리딘-3-일)에탄-1-온 하이드로클로라이드( 4, 50 mg, 0.29 mmol)를 첨가하였다. 1 시간에 걸쳐 실온으로 가온하면서 교반을 계속 하였다. 이어서, 유기층을 분리하고, Na 2SO 4로 건조시키고, 용매를 증발시켰다. 잔사를 컬럼크로마토그래피 로 정제하였다(수율: 30 ~ 40 %).
Figure PCTKR2020010999-appb-img-000067
화합물 130-136(DKC1125e01-07)의 제조확인
4- 클로로 -N-(2-옥소-2-(피리딘-3-일)에틸) 벤즈아마이드 ( DKC1125e01 ) 1H-NMR (400 MHz, CDCl 3) δ 9.23 (s, 1H), 8.84 (d, J = 3.7 Hz, 1H), 8.27 (dt, J = 7.9, 1.9 Hz, 1H), 7.80 (dt, J = 9.0, 2.1 Hz, 2H), 7.47 (dd, J = 8.0, 4.8 Hz, 1H), 7.42 (dt, J = 9.0, 2.1 Hz, 2H), 7.25 (s, 1H), 4.95 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 276 (M+1).
N-(2-옥소-2-(피리딘-3-일)에틸)-2- 페녹시프로판아마이드 ( DKC1125e02 ) 1H-NMR (400 MHz, CDCl 3) δ 9.18 (d, J = 1.8 Hz, 1H), 8.83 (dd, J = 4.8, 1.6 Hz, 1H), 8.24 (dt, J = 7.8, 1.8 Hz, 1H), 7.45-7.51 (m, 2H), 7.31 (t, J = 8.0 Hz, 2H), 6.96-7.04 (m, 3H), 4.68-4.87 (m, 3H), 1.63 (d, J = 6.9 Hz, 3H). MS(ESI): m/z 285 (M+1).
2- 플루오로 -N-(2-옥소-2-(피리딘-3-일)에틸) 벤즈아마이드 ( DKC1125e03 ) 1H-NMR (400 MHz, CDCl 3) δ 9.27 (s, 1H), 8.87 (d, J = 3.7 Hz, 1H), 8.32 (dt, J = 8.2, 1.8 Hz, 1H), 8.11 (td, J = 8.0, 1.8 Hz, 1H), 7.84 (d, J = 11.9 Hz, 1H), 7.49-7.54 (m, 2H), 7.26-7.30 (m, 1H), 7.18 (ddd, J = 11.9, 8.2, 0.9 Hz, 1H), 5.02-5.03 (m, 2H). MS(ESI): m/z 259 (M+1).
4- 플루오로 -N-(2-옥소-2-(피리딘-3-일)에틸) 벤즈아마이드 ( DKC1125e04 ) 1H-NMR (400 MHz, CDCl 3) δ 9.22 (s, 1H), 8.83 (d, J = 3.7 Hz, 1H), 8.27 (dt, J = 8.2, 1.8 Hz, 1H), 7.85-7.88 (m, 2H), 7.46 (q, J = 4.1 Hz, 1H), 7.24 (d, J = 4.1 Hz, 1H), 7.09-7.13 (m, 2H), 4.94 (d, J = 4.6 Hz, 2H). MS(ESI): m/z 259 (M+1).
(E)-N-(2-옥소-2-(피리딘-3-일)에틸) 부트 -2- 엔아마이드 ( DKC1125e05 ) 1H-NMR (400 MHz, CDCl 3) δ 9.32-9.09 (1H), 8.92-8.71 (1H), 8.35-8.16 (1H), 7.60-7.35 (1H), 6.96-6.84 (1H), 6.00-5.89 (1H), 4.88-4.81 (2H), 1.92-1.75 (3H). MS(ESI): m/z 205 (M+1).
2- 메틸 -N-(2-옥소-2-(피리딘-3-일)에틸) 벤즈아마이드 ( DKC1125e06 ) 1H-NMR (400 MHz, CDCl 3) δ 9.24 (d, J = 1.8 Hz, 1H), 8.86 (dd, J = 4.8, 1.1 Hz, 1H), 8.30 (dt, J = 7.9, 1.9 Hz, 1H), 7.50 (q, J = 4.1 Hz, 2H), 7.34-7.38 (m, 1H), 7.23-7.27 (m, 2H), 6.88 (s, 1H), 4.98 (d, J = 4.6 Hz, 2H), 2.50 (s, 3H). MS(ESI): m/z 255 (M+1).
N-(2-옥소-2-(피리딘-3-일)에틸) 프로피온아마이드 ( DKC1125e07 ) 1H-NMR (400 MHz, CDCl 3) δ 9.21 (d, J = 2.3 Hz, 1H), 8.85 (dd, J = 4.8, 1.6 Hz, 1H), 8.27 (dt, J = 8.1, 1.9 Hz, 1H), 7.46-7.50 (m, 1H), 6.57 (s, 1H), 4.80 (d, J = 4.1 Hz, 2H), 2.37 (q, J = 7.6 Hz, 2H), 1.20-1.26 (m, 3H). MS(ESI): m/z 193 (M+1).
실시예 137 -150. 본 발명에 따른 화합물 137-150(DKC1125f01-14)의 제조
화합물 137-150(DKC1125f01-14)의 합성
본 발명의 화합물 137 내지 140(DKC1125f01-14)을 다음 반응식 5에 따라 합성하였다.
[반응식 5]
Figure PCTKR2020010999-appb-img-000068
시약 및 조건: (a) HBr, Br2, (b) NaHCO 3, H 2O, (c) 포타슘프탈이미드, DMF, (d) HCl, MeOH, 140℃, 2시간; (e) RCl, NaHCO 3, DCM, H 2O, 1시간
2-브로모-1-(4-모폴리노페닐)에탄-1-온 (5)의 합성
0℃에서 HBr (100 mL) 중 1-(4-모폴리노페닐)에탄-1-온(5 g, 24.36 mmol)의 용액에 Br 2(3.89 g, 24.36 mmol)를 1시간 동안 적가하였다. 반응이 완료된 후, 생성물을 CH 2Cl 2로 2회 추출하고 포화 NaHCO 3로 세척하였다. 유기층을 MgSO 4로 건조시키고, 용매를 증발시켰다. 생성된 조(crude) 생성물을 컬럼 크로마토 그래피로 정제하여서 반응식 5의 화합물 (1) (6.23 g, 90%)을 수득하였다.
1H NMR (400 MHz, CDCl 3) δ 7.95 (d, J = 4.0 Hz, 2H), 7.04 (d, J = 4.0 Hz, 2H), 4.60 (s, 2H), 3.83 (m, 4H), 3.65 (m, 4H).
2-아미노-1-[4-( 모폴린 -4-일)페닐]에탄-1-온 디하이드로클로라이드 ( 6)의 합성
2-브로모-1-(4-모폴리노페닐)에탄-1-온( 5, 6g, 21.11 mmol)을 20 mL의 건조한 포타슘 프탈이미드(4.30 g, 23.22 mmol) 용액에 용해시키고, 75℃에서 18 시간 동안 유지하였다. 제조된 현탁액을 교반하면서 90 mL의 물에서 퀀칭시키고 이를 40 분 동안 유지시키고, 생성물을 수집하였다. 이를 50 mL의 물로 세척하고, 50 mL의 아세토니트릴로 0℃에서 밤새 재결정시켰다(4.58 g, 60 %). 얻어진 고체를 1:2의 농축 HCl 및 EtOH의 용액 (90 mL)에 용해시켰다. 반응물을 환류하에 2시간 동안 끓였다. 침전을 여과하고 물, 이어서 EtOH (3.79 g, 70 %)로 세척하였다.
1H-NMR (400 MHz, (CD 3) 2SO) δ 1.87(d, J = 9.0 Hz, 2H), 7.03(d, J = 9.0 Hz, 2H), 4.45(d, J = 4.5 Hz, 2H), 3.73(dd, J = 4.0, 5.0 Hz, 4H), 3.35(dd, J = 4.0, 5.0 Hz, 4H).
화합물 137-150(DKC1125f01-14)의 일반적인 제조방법
CH 2Cl 2 (1 mL) 및 sat. NaHCO 3 (2 mL)를 격렬히 교반하고 얼음 조에서 냉각시켜다. 하기 표 7의 산 염화물(0.29 mmol)을 첨가한 후, 즉시 2-아미노-1-(4-모폴리노페닐)에탄-1-온 디하이드로클로라이드 ( 6, 50mg, 0.29mmol)를 첨가하였다. 1 시간에 걸쳐 실온으로 가온하면서 교반을 계속 하였다. 이어서, 유기층을 분리하고, Na 2SO 4로 건조시키고, 용매를 증발시켰다. 잔사를 컬럼크로마토그래피 로 정제하였다(수율: 65~80%).
Figure PCTKR2020010999-appb-img-000069
화합물 137-150(DKC1125f01-14)의 제조확인
2- 플루오로 -N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125f01 ) 1H-NMR (400 MHz, CDCl 3) δ 8.13 (td, J = 7.8, 1.8 Hz, 1H), 7.95-7.99 (m, 3H), 7.48-7.53 (m, 1H), 7.26-7.30 (m, 1H), 7.16-7.21 (m, 1H), 6.91 (dt, J = 9.6, 2.4 Hz, 2H), 4.92 (dd, J = 4.1, 0.9 Hz, 2H), 3.88 (t, J = 5.0 Hz, 4H), 3.36 (t, J = 4.8 Hz, 4H). MS(ESI): m/z 343 (M+1).
2- 클로로 -N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125f02 ) 1H-NMR (400 MHz, CDCl 3) δ 7.94 (dt, J = 9.6, 2.4 Hz, 2H), 7.73 (dd, J = 7.8, 1.8 Hz, 1H), 7.49 (s, 1H), 7.32-7.45 (m, 3H), 6.90 (dd, J = 11.9, 2.7 Hz, 2H), 4.90 (d, J = 4.6 Hz, 2H), 3.86 (t, J = 5.0 Hz, 4H), 3.36 (t, J = 5.0 Hz, 4H). MS(ESI): m/z 360 (M+1).
(E)-N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 부트 -2- 엔아마이드 ( DKC1125f03 ) 1H-NMR (400 MHz, CDCl 3) δ 7.92 (d, J = 8.7 Hz, 2H), 6.87-6.95 (m, 3H), 6.65 (s, 1H), 5.96 (dd, J = 15.3, 1.6 Hz, 1H), 4.75 (d, J = 4.1 Hz, 2H), 3.86 (t, J = 4.8 Hz, 4H), 3.35 (t, J = 4.8 Hz, 4H), 1.89 (d, J = 6.9 Hz, 3H). MS(ESI): m/z 289 (M+1).
4- 메톡시 -N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125f04 ) 1H-NMR (400 MHz, CDCl 3) δ 7.96 (d, J = 9.1 Hz, 2H), 7.33-7.45 (m, 4H), 7.06-7.08 (m, 1H), 6.91 (d, J = 8.7 Hz, 2H), 4.87 (d, J = 4.1 Hz, 2H), 3.86-3.88 (m, 8H), 3.36 (t, J = 5.0 Hz, 3H). MS(ESI): m/z 355 (M+1).
3- 메틸 -N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125f05 ) 1H-NMR (400 MHz, CDCl 3) δ 7.97 (d, J = 9.1 Hz, 2H), 7.69 (dd, J = 8.9, 6.6 Hz, 2H), 7.35-7.38 (m, 3H), 6.92 (d, J = 8.7 Hz, 2H), 4.88 (d, J = 4.1 Hz, 2H), 3.88 (t, J = 4.8 Hz, 4H), 3.37 (t, J = 4.8 Hz, 4H), 2.43 (s, 3H). MS(ESI): m/z 339 (M+1).
N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 프로피온아마이드 ( DKC1125f06 ) 1H-NMR (400 MHz, CDCl 3) δ 7.89-7.93 (m, 2H), 6.89 (dt, J = 11.9, 2.3 Hz, 2H), 6.65 (s, 1H), 4.69 (d, J = 4.1 Hz, 2H), 3.87 (t, J = 5.0 Hz, 4H), 3.35 (t, J = 5.0 Hz, 4H), 2.35 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.5 Hz, 4H). MS(ESI): m/z 377 (M+1).
N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 사이클로프로판카복사마이드 (DKC1125f07) 1H-NMR (400 MHz, CDCl 3) δ 7.92 (d, J = 9.1 Hz, 2H), 6.89 (d, J = 9.1 Hz, 2H), 6.81 (s, 1H), 4.71 (d, J = 4.1 Hz, 2H), 3.87 (t, J = 5.0 Hz, 4H), 3.35 (t, J = 5.0 Hz, 4H), 1.52-1.58 (m, 1H), 0.99-1.03 (m, 2H), 0.80 (dt, J = 11.6, 3.4 Hz, 2H). MS(ESI): m/z 289 (M+1).
N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 사이클로부탄카복사마이드 ( DKC1125f08 ) 1H-NMR (400 MHz, CDCl 3) δ 7.90-7.93 (m, 2H), 6.89 (dd, J = 11.9, 2.7 Hz, 2H), 6.56 (s, 1H), 4.68 (d, J = 4.1 Hz, 2H), 3.87 (t, J = 5.0 Hz, 4H), 3.35 (t, J = 5.0 Hz, 4H), 3.11-3.19 (m, 1H), 2.29-2.39 (m, 2H), 2.17-2.25 (m, 2H), 1.88-2.06 (m, 2H). MS(ESI): m/z 303 (M+1).
N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 펜탄아마이드 ( DKC1125f09 ) 1H-NMR (400 MHz, CDCl 3) δ 7.91 (d, J = 9.1 Hz, 2H), 6.89 (d, J = 9.1 Hz, 2H), 6.64 (s, 1H), 4.69 (d, J = 4.1 Hz, 2H), 3.87 (t, J = 4.8 Hz, 4H), 3.35 (t, J = 5.0 Hz, 4H), 2.32 (t, J = 7.5 Hz, 2H), 1.64-1.72 (m, 2H), 1.36-1.44 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). MS(ESI): m/z 305 (M+1).
4- 플루오로 -N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 벤젠설폰아마이드 (DKC1125f10) 1H-NMR (400 MHz, CDCl 3) δ 7.92 (qd, J = 4.8, 2.5 Hz, 2H), 7.76-7.79 (m, 2H), 7.15-7.20 (m, 2H), 6.83-6.86 (m, 2H), 4.38 (d, J = 4.1 Hz, 2H), 3.86 (t, J = 4.8 Hz, 4H), 3.34 (t, J = 5.0 Hz, 4H). MS(ESI): m/z 379 (M+1).
4- 클로로 -N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 벤젠설폰아마이드 ( DKC1125f11 ) 1H-NMR (400 MHz, CDCl 3) δ 7.82-7.92 (m, 2H), 7.75-7.78 (m, 2H), 7.47 (dt, J = 9.1, 2.3 Hz, 2H), 6.82-6.85 (m, 2H), 5.78 (t, J = 4.3 Hz, 1H), 4.38 (d, J = 4.6 Hz, 2H), 3.84-3.89 (m, 4H), 3.34 (t, J = 5.0 Hz, 4H). MS(ESI): m/z 396 (M+1).
N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 벤젠설폰아마이드 ( DKC1125f12 ) 1H-NMR (400 MHz, CDCl 3) δ 7.89-7.94 (m, 2H), 7.77 (dd, J = 7.1, 2.1 Hz, 2H), 7.48-7.57 (m, 4H), 6.84 (d, J = 9.1 Hz, 2H), 4.39 (d, J = 4.6 Hz, 2H), 3.84-3.88 (m, 5H), 3.33 (t, J = 5.0 Hz, 4H). MS(ESI): m/z 361 (M+1).
N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 )-1- 페닐메탄설폰아마이드 ( DKC1125f13 ) 1H-NMR (400 MHz, CDCl 3) δ 7.72 (dt, J = 9.6, 2.4 Hz, 2H), 7.40-7.45 (m, 2H), 7.33-7.37 (m, 3H), 6.83-6.86 (m, 2H), 4.33 (s, 2H), 4.25 (d, J = 4.6 Hz, 2H), 3.87 (t, J = 4.8 Hz, 4H), 3.35 (t, J = 5.0 Hz, 4H). MS(ESI): m/z 375 (M+1).
4- 메톡시 -N-(2-(4- 모폴리노페닐 )-2- 옥소에틸 ) 벤젠설폰아마이드 ( DKC1125f14 ) 1H-NMR (400 MHz, CDCl 3) δ 7.82 (dt, J = 9.5, 2.4 Hz, 2H), 7.76 (d, J = 9.1 Hz, 2H), 6.94 (dt, J = 9.6, 2.5 Hz, 2H), 6.83 (d, J = 9.1 Hz, 2H), 5.72 (t, J = 4.1 Hz, 1H), 4.35 (d, J = 4.6 Hz, 2H), 3.85 (dd, J = 8.9, 3.9 Hz, 7H), 3.32 (t, J = 5.0 Hz, 4H). MS(ESI): m/z 391 (M+1).
실시예 151 -200. 본 발명에 따른 화합물 151-200( DKC1125g01 - 50)의 제조
화합물 151-200( DKC1125g01 - 50)의 합성
본 발명의 화합물 151 내지 200(DKC1125g01-50)을 다음 반응식 6에 따라 합성하였다.
[반응식 6]
Figure PCTKR2020010999-appb-img-000070
시약 및 조건: (a)NaOH, H 2O, MeOH, 65℃, 6h; (b)2-아미노-1-페닐에탄-1-온, HATU, DIEA, rt, 10 시간; (c)10 % TFA/DCM, rt, 2 시간; (d)RCl, Et 3N, CH 2Cl 2, rt, 4 시간.
2-((1-( 터트 - 부톡시카르보닐 )) 피페리딘-4-일) 옥시 ) 벤조산 ( 1)의 합성
메탄올(20 mL) 중의 터트-부틸 4-(2-(메톡시카르보닐)페녹시)피페리딘-1-카르복실레이트 (2.0 g, 5.69 mol)용액에 4N NaOH (6 mL)를 부가하였다. 제조된 용액을 65℃에서 6시간 동안 교반하였다. 반응을 TLC로 체크하면서 모니터링 하였다. 반응이 완결된 후, 제조된 혼합물에 물 및 HCl을 가하여 산성 pH를 유지하고 EA로 추출하였다. 유기층을 분리하고 이를 브라인으로 세척하였다(3 x 100mL). 세척된 용액을 무수 Na 2SO 4, 로 건조하고 진공에서 용매를 증발시켰다. 잔사를 컬럼 크로마토그래피(EtOAc:Hexane 1:1) 로 정제하여 (1)의 화합물을 백색 분말형태로 수득하였다 (1.8 g, 90%).
1H-NMR (400 MHz, CDCl 3) δ 8.20 (dd, J = 7.8, 1.8 Hz, 1H), 7.52-7.57 (m, 1H), 7.12-7.17 (m, 1H), 7.06 (d, J = 8.2 Hz, 1H), 4.73-4.79 (m, 1H), 4.09-4.14 (m, 1H), 3.83 (q, J = 4.4 Hz, 2H), 3.29 (tt, J = 13.3, 4.4 Hz, 2H), 2.04 (d, J = 3.7 Hz, 8H), 1.84 (tt, J = 13.0, 4.3 Hz, 2H), 1.47 (s, 9H). MS (ESI): m/z 322 (M +1).
터트 -부틸 4-(2-((2-옥소-2- 페닐에틸 )카르보닐) 페녹시 )피페리딘-1- 카르복실레이트 ( 2)의 합성
DMF(10 mL) 중의 2-((1-(터트-부톡시카르보닐))피페리딘-4-일)옥시)벤조산 ( 1, 1.0 g, 3.11 mol) 및 2-아미노-1-페닐에탄-1-온 (534 mg, 3.11 mol) 용액에 DIEA(1.3 mL, 7.78 mol)를 교반하며서 가하고 이후 HATU (1.1 g, 3.11 mmol)를 가하였다. 제조된 용액을 실온에서 10 시간 교반하였다. 반응을 TLC로 체크하면서 모니터링 하였다. 반응이 완결된 후, 제조된 혼합물에 물을 가하고 EA로 추출하였다. 유기층을 분리하고 이를 브라인으로 세척하였다(3 x 100mL). 세척된 용액을 무수 Na 2SO 4, 로 건조하고 진공에서 용매를 증발시켰다. 잔사를 컬럼 크로마토그래피(EtOAc:Hexane 2:3) 로 정제하여 (2)의 화합물을 백색 분말형태로 수득하였다 (1.3 g, 76%).
1H-NMR (400 MHz, CDCl 3) δ 9.00 (s, 1H), 8.24 (dd, J = 8.0, 2.1 Hz, 1H), 7.63 (tt, J = 7.4, 1.4 Hz, 2H), 7.50-7.54 (m, 2H), 7.44 (dd, J = 8.7, 1.4 Hz, 2H), 7.02-7.10 (m, 2H), 5.01 (d, J = 3.7 Hz, 2H), 4.66-4.71 (m, 1H), 3.95 (s, 2H), 3.17-3.23 (m, 2H), 2.96 (d, J = 5.5 Hz, 4H), 1.47 (s, 9H). MS (ESI): m/z 439 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-(피페리딘-4- 일옥시 ) 벤즈아민 ( 3)의 합성
질소 가스 하에서, 무수 디클로로메탄(20 mL) 중의 터트-부틸 4-(2-((2-옥소-2-페닐에틸) 카르보닐) 페닐)피페리딘-1-카르복실레이트 (2, 1.0 g, 3.11 mol)의 용액에 트리플루오로아세트산 (1.3 mL, 7.78 mol)을 가하였다. 반응 용액을 실온에서 2 시간 동안 교반하였다. 반응이 완결된 후 혼합물에서 용매를 증발시키고 컬럼 크로마토그래피로 정제하여 (3)의 화합물을 황색 고체로 수득하였다 (0.9 g, 90%).
1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.44 (dd, J = 8.7, 1.4 Hz, 1H), 7.03-7.09 (m, 2H), 5.30 (s, 1H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 339 (M +1).
화합물 150-200( DKC1125g01 - 50)의 일반적인 제조방법
디클로로메탄 중의 N-(2-옥소-2-페닐에틸)-2-(피페리딘-4-일옥시)벤즈아민 ( 3, 10 mg, 0.029 mmol) 및 하기 표 8의 산 염화물(10 μL, 0.07 mmol)에 트리에틸아민을 부가하였다(3.7μL, 0.029 mmol). 이 반응 혼합물을 상온에서 1시간 동안 교반하였다. 반응이 완결된 후, 상기 혼합물을 증발시켜 컬럼 크로마토그래피(EtOAc: Hexane 1:2)로 정제하여 표제 화합물을 고체로 수득하였다(12 mg, 83%).
Figure PCTKR2020010999-appb-img-000071
화합물 150-200( DKC1125g01 - 50)의 제조확인
2-((1-(4- 클로로벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g01 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.28-7.32 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 477 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-((1-(2- 페녹시프로파노일 )피페리딘-4-일) 옥시 ) 벤즈아마이드 ( DKC1125g02 ) 1H-NMR (400 MHz, CDCl 3) δ 8.96 (s, 1H), 8.20 (dd, J = 7.8, 1.8 Hz, 1H), 7.80-8.91 (m, 2H), 7.64-7.68 (m, 2H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.28-7.34 (m, 2H), 7.03-7.12 (m, 2H), 5.01 (d, J = 4.1 Hz, 2H), 4.7-4.9 (m, 1H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.87 (s, 3H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 487 (M +1).
2-((1-(2- 플루오로벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g03 ) 1H-NMR (400 MHz, CDCl 3) δ 8.99 (s, 1H), 8.28 (dd, J = 7.8, 1.8 Hz, 1H), 8.30-8.08 (m, 2H), 7.68-7.69 (m, 2H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.28-7.34 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 461 (M +1).
2-((1-(4- 플루오로벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g04 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 2H), 7.54-7.58 (m, 2H), 7.36-7.43 (m, 2H), 7.28-7.34 (m, 2H), 7.06-7.14 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 461 (M +1).
2-((1-( 퓨란 -2-카르보닐)피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g05 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.10-8.18 (m, 2H), 7.63-7.67 (m, 2H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.28-7.32 (m, 2H), 7.03-7.12 (m, 1H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 433 (M +1).
2-((1-(2- 클로로벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g06 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.61-7.65 (m, 2H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.28-7.32 (m, 2H), 7.06-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 477 (M +1).
2-((1-(3- 클로로벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g07 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.20-7.30 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 477 (M +1).
(E)-2-((1-( 부트 -2- enoyl )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g08 ) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.20 (dd, J = 7.8, 1.8 Hz, 1H), 8.08-8.12 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.44 (dd, J = 8.7, 1.4 Hz, 1H), 7.03-7.09 (m, 2H), 5.30 (s, 1H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.88 (s, 1H), 2.78-2.84 (m, 1H), 2.6 (s, 3H), 2.17-2.25 (m, 4H), 2.16 (s, 1 H), 1.94-2.03 (m, 2H). MS (ESI): m/z 407 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-((1-(3- 페닐프로파노일 )피페리딘-4-일) 옥시 ) 벤즈아마이드 ( DKC1125g09 ) 1H-NMR (400 MHz, CDCl 3) δ 8.95 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.02-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 2H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.22-7.32 (m, 2H), 7.03-7.12 (m, 2H), 5.01 (d, J = 4.1 Hz, 2H), 4.60-4.64 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.58-2.70 (m, 2H), 2.54 (d, J = 2.4 Hz, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 471 (M +1).
2-((1- 아크릴로일피페리딘 -4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125g10) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.42 (dd, J = 8.6, 1.3 Hz, 1H), 7.03-7.09 (m, 2H), 6.20 (s, 2H), 5.02 (s, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.6 (s, 2H), 2.17-2.25 (m, 4H), 1.94-2.03 (m, 3H). MS (ESI): m/z 393 (M +1).
2-((1-(2- 메틸벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g11 ) 1H-NMR (400 MHz, CDCl 3) δ 8.93 (s, 1H), 8.20 (dd, J = 7.4, 1.8 Hz, 1H), 8.02-8.06 (m, 2H), 7.62-7.64 (m, 1H), 7.60-7.63 (m,, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.20-7.30 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.9 (s, 3H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 457 (M+1).
2-((1-(2- 메톡시벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g12 ) 1H-NMR (400 MHz, CDCl 3) δ 8.90 (s, 1H), 8.24 (dd, J = 7.8, 1.8 Hz, 1H), 8.01-8.07 (m, 2H), 7.64-7.69 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.20-7.30 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.9 (s, 3H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 473 (M +1).
2-((1-(3- 메틸벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g13 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.12-8.18 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.22-7.32 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.9 (s, 3H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 457 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-((1- 프로피오닐피페리딘 -4-일) 옥시 ) 벤즈아마이드 (DKC1125g14) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.42 (dd, J = 8.6, 1.3 Hz, 1H), 7.03-7.09 (m, 2H), 5.30 (s, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.79 (m, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H), 1.94-2.03 (m, 3H). MS (ESI): m/z 395 (M+1).
2-((1-( 사이클로헥산카르보닐 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g15 ) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.44 (dd, J = 8.7, 1.4 Hz, 1H), 7.03-7.09 (m, 2H), 5.30 (s, 1H), 4.61-4.68 (m, 1H), 4.20-4.40 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.88 (s, 2H), 2.78-2.84 (m, 2H), 2.50-2.68 (m, 4H), 2.22-2.46 (m, 2H), 2.17-2.25 (m, 4H), 2.06 -2.14 (m, 2 H). MS (ESI): m/z 449 (M +1).
2-((1-( 사이클로프로판카르보닐 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 )벤즈아마이드 ( DKC1125g16 ) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.42 (dd, J = 8.7, 1.4 Hz, 1H), 7.03-7.09 (m, 2H), 5.30 (s, 2H), 4.61-4.68 (m, 1H), 4.26-4.44 (m, 1H), 3.26-4.10 (m, 2H), 2.78-2.84 (m, 2H), 2.54-2.62 (m, 4H), 2.16-2.24 (m, 4H). MS (ESI): m/z 407 (M +1).
2-((1-( 사이클로부탄카르보닐 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g17 ) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.47 (dd, J = 8.7, 1.4 Hz, 1H), 7.03-7.09 (m, 2H), 5.30 (s, 2H), 5.02 (d, J = 4.1 Hz, 1H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.40-2.64 (m, 4H), 2.30-2.34 (m, 2H), 2.06 -2.14 (m, 4H), MS (ESI): m/z 421 (M+1).
N-(2-옥소-2- 페닐에틸 )-2-((1-( 싸이오펜 -2-카르보닐)피페리딘-4-일) 옥시 ) 벤즈아마이드 ( DKC1125g18 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.12-8.16 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.22-7.30 (m, 2H), 7.03-7.12 (m, 1H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 449 (M +1).
2-((1-(2-( 메톡시메틸 ) 벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g19 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.12-8.18 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.20-7.29 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.92 (s, 3H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.96 (s, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 487 (M +1).
2-((1-(3,3- di메틸butanoyl )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g20 ) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.10-8.16 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.46 (dd, J = 8.7, 1.4 Hz 1H), 7.03-7.09 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.9 (m, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). 1.97 (s, 9H). MS (ESI): m/z 437 (M +1).
2-((1-( 모폴린 -4-카르보닐)피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g21 ) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.44 (dd, J = 8.7, 1.4 Hz, 1H), 7.03-7.09 (m, 2H), 5.30 (s, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.8 (m, 2H), 2.78-2.84 (m, 2H), 2.20-2.27 (m, 4H), 2.14-2.18 (m, 2H), 2.10-2.14 (m, 4H). MS (ESI): m/z 452 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-((1- 펜타노일피페리딘 -4-일) 옥시 ) 벤즈아마이드 (DKC1125g22) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.48 (dd, J = 8.7, 1.4 Hz, 1H), 7.03-7.09 (m, 2H), 5.30 (s, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.89 (s, 2 H), 2.78-2.84 (m, 2H), 2.24-2.29 (m, 2H), 2.17-2.25 (m, 4H), 2.16 (s, 2H), 1.79 (s, 3H). MS (ESI): m/z 523 (M +1).
2-((1-(4- 메톡시벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g23 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.22-7.28 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.23 (s, 3H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 573 (M +1).
2-((1-(4- 시아노벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g24 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.22-7.28 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 471 (M +1).
2-((1-((3-( 디옥소 -l5- sulfanyl )페닐) 설포닐 )피페리딘-4-일) 옥시 )-N-(2-옥소-2-페닐에틸)벤즈아마이드 ( DKC1125g25 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.24-7.32 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 542 (M +1).
2-(4-(2-((2-옥소-2- 페닐에틸 ) 카바모일 ) 페녹시 ) piperidine -1-카르보닐) 페닐acetate ( DKC1125g26 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.10-7.34 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 4.21-4.30 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 520 (M +1).
2-((1-(2,4- 디플루오로벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g27 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.20-7.36 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 479 (M +1).
2-((1-(2- 메톡시아세틸 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g28 ) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.44 (ddd, J = 8.7, 6.9, 1.4 Hz, 1H), 7.03-7.09 (m, 2H), 5.30 (m, 1H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 2H), 3.97 (s, 3H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 411 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-((1- pivaloyl피페리딘 -4-일) 옥시 ) 벤즈아마이드 (DKC1125g29) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.44 (dd, J = 8.7, 1.4 Hz, 1H), 7.03-7.09 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). 1.92 (s, 9H). MS (ESI): m/z 423 (M +1).
N,N - di메틸 -4-(2-((2-옥소-2- 페닐에틸 ) 카바모일 ) 페녹시 ) piperidine -1- 카복사마이드 ( DKC1125g30 ) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.44 (dd, J = 8.7, 1.4 Hz, 1H), 7.03-7.09 (m, 2H), 5.30 (s, 2H), 4.61-4.68 (m, 1H), 4.62-4.66 (m, 6H), 3.28 (s, 2H), 2.79 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 410 (M +1).
2-((1-(4- 브로모벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g31 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.24-7.34 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 521 (M +1).
2-((1- 아세틸피페리딘 -4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125g32) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.44 (dd, J = 8.7, 1.4 Hz, 1H), 7.03-7.09 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.9 (s, 3H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 381 (M +1).
2-((1-( 메틸설포닐 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125g33) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 7.44 (dd, J = 8.7, 1.4 Hz, 1H), 7.03-7.09 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.8 (s, 3H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 417 (M +1).
2-((1-((4- 플루오로페닐 ) 설포닐 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 )벤즈아마이드 ( DKC1125g34 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.24-7.34 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 497 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-((1- 토실피페리딘 -4-일) 옥시 ) 벤즈아마이드 (DKC1125g35) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 2H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.24-7.34 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.96 (s, 3H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 493 (M +1).
2-((1-((4- 클로로페닐 ) 설포닐 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g36 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 2H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.24-7.34 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 513 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-((1-( 페닐설포닐 )피페리딘-4-일) 옥시 ) 벤즈아마이드 (DKC1125g37) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 2H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.24-7.34 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 479 (M +1).
2-((1-( 벤질설포닐 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125g38) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 2H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.2-7.3 (m, 2H), 7.03-7.12 (m, 2H), 5.04 (s, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 457 (456.18 +1). MS (ESI): m/z 493 (M +1).
2-((1-((4- 메톡시페닐 ) 설포닐 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g39 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.28-7.30 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.91 (s, 3H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 409 (M +1).
2-((1-(3,5- 비스(트리플루오로메틸)벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2-페닐에틸)벤즈아마이드 ( DKC1125g40 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.28-7.30 (m, 2H), 7.03-7.12 (m, 1H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 579 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-((1-(2-( 트리플루오로메틸 ) 벤조일 )피페리딘-4-일)옥시)벤즈아마이드 ( DKC1125g41 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.28-7.30 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 511 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-((1-(3-( 트리플루오로메틸 ) 벤조일 )피페리딘-4-일)옥시)벤즈아마이드 ( DKC1125g42 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.28-7.30 (m, 2H), 7.03-7.12 (m, 2H), 5.40 (d, J = 4.2 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 511 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-((1-(4-( 트리플루오로메틸 ) 벤조일 )피페리딘-4-일)옥시)벤즈아마이드 ( DKC1125g43 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.22-7.30 (m, 2H), 7.08-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 511 (M +1).
2-((1-(2- 클로로 -4- 플루오로벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 )벤즈아마이드 ( DKC1125g44 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.25-7.32 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 495 (M +1).
2-((1-(3- 니트로벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g45 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.62-7.66 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.28-7.30 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 488 (M +1).
2-((1-(3,4- 디플루오로벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g46 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.00-8.08 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.38-7.48 (m, 2H), 7.23-7.34 (m, 2H), 7.03-7.12 (m, 1H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 479 (M +1).
2-((1-(3,5- 디클로로벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g47 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.10-8.18 (m, 2H), 7.64-7.68 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.25-7.32 (m, 1H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 511 (M +1).
2-((1-(2,3- 디클로로벤조일 )피페리딘-4-일) 옥시 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125g48 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.22-8.26 (m, 1H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.25-7.32 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 511 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-((1-(4-( 트리플루오로메톡시 ) 벤조일 )피페리딘-4-일)옥시)벤즈아마이드 ( DKC1125g49 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.10-8.16 (m, 2H), 7.62-7.64 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.21-7.30 (m, 1H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 527 (M +1).
N-(2-옥소-2- 페닐에틸 )-2-((1-(3-( 트리플루오로메톡시 ) 벤조일 )피페리딘-4-일)옥시)벤즈아마이드 ( DKC1125g50 ) 1H-NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 8.10-8.18 (m, 2H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.53-7.57 (m, 2H), 7.36-7.43 (m, 2H), 7.21-7.30 (m, 2H), 7.03-7.12 (m, 2H), 5.02 (d, J = 4.1 Hz, 2H), 4.61-4.68 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.78-2.84 (m, 2H), 2.17-2.25 (m, 4H). MS (ESI): m/z 527 (M +1).
실시예 201-230. 본 발명에 따른 화합물 201-230(DKC1125h01-30)의 제조
화합물 201-230(DKC1125h01-30)의 합성
본 발명의 화합물 201 내지 230(DKC1125h01-30)을 다음 반응식 7에 따라 합성하였다.
[반응식 7]
화합물 201 내지 230(DKC1125h01-30)의 합성
Figure PCTKR2020010999-appb-img-000072
시약 및 조건: (a) C 3H 5BrO 2 , K 2CO 3 , DMF, 50℃, 1h; (b)NaOH , EtOH, rt , 4h; (c)RNH 2, HATU, DIEA, DMF, rt 8h.
메틸 2-(2((-옥소-2-페닐에틸)카바밀)페녹시)아세테이트 (1)의 합성
DMF에 용해시킨 2-하이드록시-N-(2-옥소-2-페닐에틸)벤즈아마이드 (500 mg, 1.97 mmol) 및 메틸 2-브로모아세테이트(240 μL, 2.97mol)의 용액을 칼슘 카보네이트(677 mg, 4.97 mol)에 부가하였다. 제조된 용액을 50℃에서 9시간 동안 교반하였다. 반응을 TLC로 체크하여 모니터링하였다. 반응이 완결된 후 혼합물에 물 및 HCl을 가하여 산성 pH를 유지하고 EtOAc로 추출하고, 유기층을 분리하고, 브라인으로 세척한 후(3 x 100mL), 도출되는 용액을 Na 2SO 4로 건조하여 용매를 증발시켰다. 잔사를 컬럼 크로마토그래피로 정제하여 화합물 (1)을 백색 분말로 수득하였다 (0.6 g, 84%).
1H-NMR (400 MHz, CDCl 3) δ 9.89 (d, J = 10.5 Hz, 1H), 8.14-8.20 (m, 1H), 7.74-7.80 (m, 1H), 7.51-7.58 (m, 1H), 7.38-7.49 (m, 2H), 6.96-6.99 (m, 2H), 6.83 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 4.74 (d, J = 5.9 Hz, 2H), 4.51 (s, 2H), 3.88 (q, J = 7.2 Hz, 3H). MS (ESI): m/z 328 (M +1).
2-(2((-옥소-2-페닐에틸)카바밀)페녹시)아세트산 (2)의 합성
에탄올(10 mL) 중의 메틸 2-(2((-옥소-2-페닐에틸)카바밀)페녹시)아세테이트 ( 1, 0.6g, 1.77 mol) 용액에 4N NaOH (6mL)를 교반하며서 가하고 이후 2N HCl (1mL)를 가하였다. 제조된 용액을 실온에서 4 시간 교반하였다. 반응을 TLC로 체크하면서 모니터링 하였다. 반응이 완결된 후, 제조된 혼합물에 물 및 HCl을 가하여 산성 pH를 유지하고 EA로 추출하였다. 유기층을 분리하고 이를 브라인으로 세척하였다(3 x 100mL). 세척된 용액을 무수 Na 2SO 4로 건조하고 진공에서 용매를 증발시켰다. 잔사를 컬럼 크로마토그래피(EtOAc:Hexane 2:3) 로 정제하여 (2)의 화합물을 백색 분말형태로 수득하였다 (567mg, 83 %).
1H-NMR (400 MHz, CDCl 3) δ 9.01 (t, J = 5.3 Hz, 1H), 8.03-8.06 (m, 2H), 7.93 (dd, J = 7.3, 1.8 Hz, 1H), 7.67-7.71 (m, 2H), 7.55-7.59 (m, 1H), 7.49-7.53 (m, 1H), 7.09-7.14 (m, 2H), 4.93 (s, 2H), 4.87 (d, J = 5.5 Hz, 2H). MS (ESI): m/z 314 (M +1).
화합물 201-230(DKC1125h01-30)의 일반적인 제조방법
DMF 중의 2-(2((-옥소-2-페닐에틸)카바밀)페녹시)아세트산 ( 2, 20 mg ,0.069 mmol) 및 하기 표 9의 아민(10μL, 0.069 mmol) 용액에 HATU (18 mg, 0.069 mmol)를 가하였다. 최종적으로 DIEA (24 μL, 0.143 mmol)를 부가하여 반응 혼합물을 1시간 동안 교반하였다. 반응이 완결된 후 반응 혼합물을 로타 베이퍼(Rota vapor)로 증발시키고, 컬럼 크로마토그래피로 정제하여 고체형태의 목적 화합물을 수득하였다(12 mg, 80-90%).
Figure PCTKR2020010999-appb-img-000073
화합물 201-230(DKC1125h01-30)의 제조확인
2-(2-옥소-2-( 페닐아미노 ) 에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125h01) 1H-NMR (400 MHz, CDCl 3) δ 9.76 (s, 1H), 8.48 (s, 1H), 8.01-8.03 (m, 1H), 7.81-7.84 (m, 1H), 7.74-7.77 (m, 2H), 7.49-7.56 (m, 3H), 7.29 (dd, J = 7.2, 1.8 Hz, 3H), 7.10-7.15 (m, 2H), 7.05-7.08 (m, 1H), 5.03 (t, J = 3.9 Hz, 2H), 4.83 (s, 2H). MS (ESI): m/z 389 (M +1).
2-(2-옥소-2-(o- toyl아미노 ) 에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125h02) 1H-NMR (400 MHz, CDCl 3) δ 9.74 (s, 1H), 8.38 (s, 1H), 8.01-8.03 (m, 2H), 7.81-7.84 (m, 1H), 7.74-7.77 (m, 1H), 7.49-7.56 (m, 3H), 7.29 (dd, J = 7.2, 1.8 Hz, 3H), 7.10-7.15 (m, 2H), 7.05-7.08 (m, 1H), 5.03 (t, J = 3.9 Hz, 2H), 4.83 (s, 2H), 2.9 (s, 3H). MS (ESI): m/z 403 (M +1).
2-(2-( 알릴아미노 )-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125h03) 1H-NMR (400 MHz, CDCl 3) δ 9.70 (s, 1H), 8.64 (s, 1H), 8.02 (d, J = 7.3 Hz, 1H), 7.79 (dd, J = 7.8, 1.4 Hz, 1H), 7.71 (d, J = 3.2 Hz, 3H), 7.52-7.56 (m, 3H), 6.89-6.94 (m, 1H), 5.03 (t, J = 3.9 Hz, 2H), 4.83 (s, 2H), 4.66 (s, 1H), 4.04-4.10 (m, 2H), 3.95 (t, J = 5.7 Hz, 2H) . MS (ESI): m/z 353(M +1).
2-(2-( 벤질아미노 )-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125h04) 1H-NMR (400 MHz, CDCl 3) δ 9.76 (s, 1H), 8.01-8.03 (m, 2H), 7.81-7.84 (m, 1H), 7.74-7.77 (m, 2H), 7.49-7.56 (m, 3H), 7.18 (dd, J = 7.2, 1.8 Hz, 3H), 7.10-7.15 (m, 2H), 7.05-7.08 (m, 1H), 5.24 (s, 2H), 5.01 (t, J = 3.9 Hz, 2H), 4.67 (s, 2H). MS (ESI): m/z 403(M +1).
2-(2-(( 플루오로벤질 )아미노)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h05 ) 1H-NMR (400 MHz, CDCl 3) δ 9.76 (s, 1H), 8.71 (s, 1H), 8.01-8.03 (m, 2H), 7.81-7.84 (m, 1H), 7.74-7.77 (m, 1H), 7.49-7.56 (m, 3H), 7.30 (dd, J =7.4, 1.8 Hz, 3H), 7.10-7.15 (m, 2H), 7.05-7.08 (m, 1H), 5.03 (t, J = 3.9 Hz, 2H), 4.83 (s, 2H). MS (ESI): m/z 421(M +1).
2-(2-((2- 메톡시 -4- 메틸페닐 )아미노)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 )벤즈아마이드 ( DKC1125h06) 1H-NMR (400 MHz, CDCl 3) δ 8.81 (s, 2H), 8.17 (q, J = 2.3 Hz, 1H), 8.14 (dd, J = 7.8, 1.8 Hz, 1H), 7.90-7.92 (m, 2H), 7.60-7.64 (m, 1H), 7.46-7.53 (m, 3H), 7.15-7.19 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 1H), 5.42 (d, J = 4.1 Hz, 2H), 4.79 (s, 2H). 3.96 (s, 3H), 3.12 (s, 1H). MS (ESI): m/z 433 (M +1).
2-(2-((3- 플루오로 -4- 메톡시페닐 )아미노)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 )벤즈아마이드 ( DKC1125h07 ) 1H-NMR (400 MHz, CDCl 3) δ 8.78 (s, 2H), 8.17 (q, J = 2.3 Hz, 2H), 8.15 (dd, J = 7.8, 1.8 Hz, 2H), 7.90-7.92 (m, 2H), 7.62-7.64 (m, 2H), 7.03 (d, J = 8.2 Hz, 2H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 1H), 5.03 (d, J = 4.1 Hz, 2H), 4.89 (s, 2H), 3.68 (d, J = 3.2 Hz, 3H). MS (ESI): m/z 437 (M +1).
2-(2-옥소-2-(피리딘-3- 일아미노 ) 에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h08 ) 1H-NMR (400 MHz, CDCl 3) δ 9.76 (s, 1H), 8.84 (s, 1H), 8.01-8.03 (m, 2H), 7.81-7.84 (m, 1H), 7.74-7.77 (m, 1H), 7.89-7.59 (m, 3H), 7.48-7.42 (dd, J = 7.4, 1.8 Hz, 3H), 7.20-7.25 (m, 2H), 7.05-7.08 (m, 1H), 5.47(t, J = 3.9 Hz, 2H), 4.87 (s, 2H). MS (ESI): m/z 390 (M +1).
2-(2-((3- 메톡시페닐 )아미노)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h09 ) 1H-NMR (400 MHz, CDCl 3) δ 8.62 (s, 1H), 8.17 (q, J = 2.3 Hz, 1H), 8.14 (dd, J = 7.8, 1.8 Hz, 2H), 7.90-7.92 (m, 2H), 7.60-7.64 (m, 1H), 7.46-7.53 (m, 3H), 7.15-7.19 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 1H), 5.03 (d, J = 4.1 Hz, 2H), 4.89 (s, 2H), 3.61 (d, J = 3.2 Hz, 3H). MS (ESI): m/z 419 (M +1).
2-(2-옥소-2-((2- 프로필페닐 )아미노) 에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h10 ) 1H-NMR (400 MHz, CDCl 3) δ 8.91 (s, 1H), 8.60 (s, 1H), 8.17 (q, J = 2.3 Hz, 1H), 8.15 (dd, J = 7.8, 1.8 Hz, 2H), 7.90-7.92 (m, 2H), 7.60-7.64 (m, 1H), 7.15-7.19 (m, 1H), 7.03 (d, J = 8.2 Hz, 2H), 6.82 (dd, J = 8.2, 1.4 Hz, 2H), 6.57-6.61 (m, 2H), 5.03 (d, J = 4.1 Hz, 2H), 4.89 (s, 2H), 3.61 (d, J = 3.2 Hz, 3H), 2.66-2.72 (m, 2H), 2.42-2.50 (m, 2H). MS (ESI): m/z 431 (M +1).
2-(2-((1- 플루오로 -3- 니트로페닐 )아미노)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸벤즈아마이드 ( DKC1125h11 ) 1H-NMR (400 MHz, CDCl 3) δ 8.80 (s, 1H), 8.68 (s, 1H), 8.17 (q, J = 2.3 Hz, 2H), 8.14 (dd, J = 7.8, 1.8 Hz, 2H), 7.90-7.92 (m, 2H), 7.60-7.64 (m, 1H), 7.05-7.16 (m, 1H), 7.03 (d, J = 8.2 Hz, 2H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 1H), 5.52 (d, J = 4.1 Hz, 2H), 4.90 (s, 2H). MS (ESI): m/z 452 (M +1).
2-(2-(( 벤조 [1, 3] 다이옥솔 -5- 일메틸 )아미노)-2- 옥소에톡시 )- N -(2-옥소-2-페닐에틸벤즈아마이드 ( DKC1125h12 ) 1H-NMR (400 MHz, CDCl 3) δ 8.90 (s, 1H), 8.71 (s, 1H),8.17 (q, J = 2.3 Hz, 1H), 8.14 (dd, J = 7.8, 1.8 Hz, 1H), 7.90-7.92 (m, 2H), 7.60-7.64 (m, 1H), 7.46-7.53 (m, 3H), 7.15-7.19 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 1H), 6.0 (s, 2H), 5.01 (d, J = 4.1 Hz, 2H), 4.68 (s, 2H). MS (ESI): m/z 447 (M +1).
2-(2-옥소-2-((4- 프로필페닐 )아미노) 에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h13 ) 1H-NMR (400 MHz, CDCl 3) δ 9.02 (s, 1H), 8.71 (s, 1H), 8.17 (q, J = 2.3 Hz, 1H), 8.03 (dd, J = 7.8, 1.8 Hz, 2H), 7.91-7.92 (m, 2H), 7.62-7.64 (m, 1H), 7.44-7.50 (m, 2H), 7.16-7.19 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 2H), 5.20 (d, J = 4.1 Hz, 2H), 4.54 (s, 2H), 3.61 (d, J = 3.2 Hz, 3H). 2.66 -2.8(m, 2H), 2.42-2.48 (m, 2H). MS (ESI): m/z 431 (M +1).
2-(2-옥소-2-((3- 페녹시페닐 )아미노) 에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h14 ) 1H-NMR (400 MHz, CDCl 3) δ 8.71 (s, 1H), 8.17 (q, J = 2.3 Hz, 1H), 8.14 (dd, J = 7.8, 1.8 Hz, 1H), 7.90-7.92 (m, 2H), 7.70-7.80 (m, 2H), 7.61-7.64 (m, 2H), 7.50-7.60 (m, 2H), 7.46-7.53 (m, 3H), 7.15-7.19 (m, 2H), 7.03 (d, J = 8.2 Hz, 2H), 6.57-6.61 (m, 1H), 5.02 (d, J = 4.1 Hz, 2H), 4.67 (s, 2H). MS (ESI): m/z 481 (M +1).
2-(2-((3,4- 디메톡시벤질 )아미노)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h15 ) 1H-NMR (400 MHz, CDCl 3) δ 8.22 (s, 2H), 8.18 (q, J = 2.3 Hz, 2H), 8.12 (dd, J = 7.8, 1.8 Hz, 2H), 7.90-7.91 (m, 2H), 7.60-7.64 (m, 1H), 7.15-7.19 (m, 1H), 7.03 (d, J = 8.2 Hz, 2H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 1H), 5.10 (d, J = 4.1 Hz, 2H), 4.02 (s, 2H), 3.61 (d, J = 3.2 Hz, 3H), 2.31 (d, J = 2.3 Hz, 3H). MS (ESI): m/z 463 (M +1).
2-(2-((3,4- 디메톡시페닐 )아미노)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h16 ) 1H-NMR (400 MHz, CDCl 3) δ 8.20 (s, 2H), 8.17 (q, J = 2.3 Hz, 2H), 8.14 (dd, J = 7.8, 1.8 Hz, 2H), 7.90-7.92 (m, 2H), 7.60-7.64 (m, 1H), 7.15-7.19 (m, 1H), 7.03 (d, J = 8.2 Hz, 2H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 1H), 5.34 (d, J = 4.1 Hz, 2H), 4.33 (s, 2H), 3.61 (d, J = 3.2 Hz, 3H), 2.31 (d, J = 2.3 Hz, 3H). MS (ESI): m/z 449 (M +1).
2-(2-( 벤조[ d ][1,3]다이옥솔 -5- 일아미노 )-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 )벤즈아마이드 ( DKC1125h17 ) 1H-NMR (400 MHz, CDCl 3) δ 8.90 (s, 1H), 8.71 (s, 1H), 8.17 (q, J = 2.3 Hz, 1H), 8.14 (dd, J = 7.8, 1.8 Hz, 1H), 7.90-7.92 (m, 2H), 7.60-7.64 (m, 1H), 7.46-7.53 (m, 3H), 7.15-7.19 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 1H), 6.0 (s, 2H), 5.01 (d, J = 4.1 Hz, 2H), 4.68 (s, 2H). MS (ESI): m/z 433 (M +1).
2-(2-((2, 3- 다이벤조 [ b ] [1, 4]다이옥신 -6-일) 아미노)-2- 옥소에톡시 )- N -(2-옥소-2-페닐에틸)벤즈아마이드 ( DKC1125h18 ) 1H-NMR (400 MHz, CDCl 3) δ 9.01 (s, 1H), 8.71 (s, 1H), 8.17 (q, J = 2.3 Hz, 1H), 8.14 (dd J = 7.8, 1.8 Hz, 1H), 7.90-7.92 (m, 2H), 7.60-7.64 (m, 1H), 7.46-7.53 (m, 3H), 7.15-7.19 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 1H), 6.34-6.45 (m, 2H), 6.12- 6.23 (m, 2H), 5.43 (d, J = 4.1 Hz, 2H), 4.90 (s, 2H). MS (ESI): m/z 447 (M +1).
2-(2-((2,3- 디하이드로 -1 H - 인덴 -5-일)아미노)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 )벤즈아마이드 ( DKC1125h19) 1H-NMR (400 MHz, CDCl 3) δ 8.71 (s, 2H), 8.17 (q, J = 2.3 Hz, 1H), 8.14 (dd, J = 7.8, 1.8 Hz, 1H), 7.90-7.92 (m, 2H), 7.60-7.64 (m, 1H), 7.46-7.53 (m, 3H), 7.15-7.19 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 1H), 5.15 (d, J = 4.1 Hz, 2H), 4.78 (s, 2H), 3.60-3.62 (d, J = 3.1 Hz, 2H), 3.64-3.66 (d, J = 3.4 Hz, 2H), 2.31-2.34 (d, J = 2.32 Hz, 2H). MS (ESI): m/z 429 (M +1).
2-(2-((3- 이소프로폭시페닐 ) 아미노)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h20 ) 1H-NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.43(s, 1H), 8.01-8.03 (m, 2H), 7.81-7.84 (m, 1H), 7.74-7.77 (m, 1H), 7.49-7.56 (m, 3H), 7.20 (dd, J = 7.4, 1.8 Hz, 3H), 7.10-7.15 (m, 2H), 7.05-7.08 (m, 2H), 5.03 (t, J = 3.9 Hz, 2H), 4.83 (s, 2H), 4.76-4.80 (m, 3H), 4.32-4.40 (m, 3H). MS (ESI): m/z 447 (M +1).
2-(2-옥소-2-((4- 페녹시페닐 )아미노) 에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h21 ) 1H-NMR (400 MHz, CDCl 3) δ 8.31 (s, 1H), 8.17 (q, J = 2.3 Hz, 1H), 8.14 (dd, J = 7.8, 1.8 Hz, 2H), 7.90-7.92 (m, 2H), 7.80 (dd, J = 8.0, 1.8 Hz, 2H), 7.61-7.64 (m, 2H), 7.56 (s, 2H), 7.46-7.53 (m, 3H), 7.32 (d, J = 8.2 Hz, 1H), 7.24 (dd, J = 6.7, 1.4 Hz, 1H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 1H), 5.03 (d, J = 4.1 Hz, 2H), 4.89 (s, 2H). MS (ESI): m/z 481 (M +1).
2-(2-((2- 플루오로 -5-( 트리플루오로메틸 ) 페닐)아미노)-2- 옥소에톡시 )- N -(2-옥소-2-페닐에틸)벤즈아마이드 ( DKC1125h22 ) 1H-NMR (400 MHz, CDCl 3) δ 8.71 (s, 2H), 8.37 (q, J = 2.3 Hz, 2H), 8.12-8.18 (dd, J = 7.8, 1H), 7.90-7.92 (m, 2H), 7.46-7.53 (m, 3H), 7.15-7.19 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.2, 1.4 Hz, 1H), 6.57-6.61 (m, 1H), 5.13 (d, J = 4.1 Hz, 2H), 4.89 (s, 2H). MS (ESI): m/z 475 (M +1).
2-(2-((3- 하이드록시페닐 ) 아미노)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h23 ) 1H-NMR (400 MHz, CDCl 3) δ 9.56 (s, 1H), 8.43 (s, 1H), 8.01-8.03 (dd, J = 8.0, 1.4 Hz, 2H), 7.81-7.84 (m, 1H), 7.74-7.77 (m, 1H), 7.49-7.56 (m, 3H), 7.20-7.24 (m, 3H), 7.10-7.15 (m, 2H), 7.05-7.08 (m, 1H), 5.40 (m, 1H), 5.03 (t, J = 3.9 Hz, 2H), 4.83 (s, 2H). MS (ESI): m/z 405 (M +1).
2-(2-((2- 클로로페닐 ) 아미노)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h24 ) 1H-NMR (400 MHz, CDCl 3) δ 9.66 (s, 1H), 8.20(s, 1H), 8.11-8.13 (m, 2H), 7.81-7.84 (m, 1H), 7.74-7.77 (m, 1H), 7.49-7.56 (m, 3H), 7.29 (dd, J = 6.7, 1.8 Hz, 3H), 7.10-7.15 (m, 2H), 7.05-7.08 (m, 1H), 5.24 (t, J = 3.9 Hz, 2H), 4.40 (s, 2H). MS (ESI): m/z 423 (M +1).
2-(2-((3- 브로모페닐 ) 아미노)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h25 ) 1H-NMR (400 MHz, CDCl 3) δ 9.76 (s, 1H), 8.39(s, 1H), 8.01-8.03 (m, 2H), 7.81-7.84 (m, 1H), 7.74-7.77 (m, 2H), 7.49-7.56 (m, 3H), 7.24 (dd, J = 6.7, 1.4 Hz, 2H), 7.10-7.15 (m, 2H), 7.05-7.08 (m, 1H), 5.12 (t, J = 3.9 Hz, 2H), 4.90 (s, 2H). MS (ESI): m/z 467 (M +1).
2-(2-( 이소프로필아미노 )-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h26 ) 1H-NMR (400 MHz, CDCl 3) δ 9.76 (s, 1H), 8.01-8.03 (s, 1H), 7.81-7.84 (m, 1H), 7.74-7.77 (m, 2H), 7.30-7.34 (m, 2H), 7.10-7.15 (m, 2H), 7.05-7.08 (m, 1H), 6.01-6.1 (m, 1H), 5.03 (t, J = 3.9 Hz, 2H), 4.83 (s, 2H), 4.9 (s, 3H), 4.3 (s, 3H). MS (ESI): m/z 355 (M +1).
2-(2-(3,4- 디하이드로이소퀴놀린 -2(1 H )-일)-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 )벤즈아마이드 ( DKC1125h27) 1H-NMR (400 MHz, CDCl 3) δ 8.71 (s, 1H), 8.17 (d, J = 2.3 Hz, 1H), 8.14 (dd, J = 7.8, 1.8 Hz, 1H), 7.90-7.92 (m, 2H), 7.60-7.64 (m, 1H), 7.46-7.53 (m, 3H), 7.15-7.19 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.2, 1.4 Hz, 2H), 6.57-6.61 (m, 1H), 5.03 (d, J = 4.1 Hz, 2H), 4.89 (s, 2H), 3.60-3.62 (d, J = 3.1 Hz, 2H), 3.64-3.66 (d, J = 3.4 Hz, 2H), 2.31-2.34 (d, J = 2.3 Hz, 2H). MS (ESI): m/z 429 (M +1).
2-(2-옥소-2- 프로필아미노 ) 에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125h28) 1H-NMR (400 MHz, CDCl 3) δ 8.39(s, 1H), 8.02 (d, J = 7.3 Hz, 1H), 7.80 (dd, J = 7.8, 1.4 Hz, 2H), 7.62 (d, J = 3.2 Hz, 3H), 7.56-7.58 (m, 3H), 6.89-6.96 (m, 1H), 5.03 (t, J = 3.9 Hz, 2H), 4.83 (s, 2H), 4.04-4.10 (m, 2H), 3.95 (t, J = 5.7 Hz, 2H), 3.7 (s, 3H). MS (ESI): m/z 355 (M +1).
2-(2-( 이소펜틸아미노 )-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125h29) 1H-NMR (400 MHz, CDCl 3) δ 8.96 (s, 1H) 8.02 (d, J = 7.3 Hz, 1H), 7.72 (dd, J = 7.8, 1.4 Hz, 2H), 7.71 (d, J = 3.2 Hz, 3H), 7.52-7.56 (m, 3H), 6.89-6.94 (m, 1H), 5.03 (t, J = 3.9 Hz, 2H), 4.83 (s, 2H), 4.66 (s, 1H), 4.04-4.10 (m, 2H), 3.95 (t, J = 5.7 Hz, 2H), 3.8 (s, 3H), 3.3 (s, 3H). MS (ESI): m/z 383(M +1).
2-(2-( 시클로헥실아미노 )-2- 옥소에톡시 )- N -(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125h30 ) 1H-NMR (400 MHz, CDCl 3) δ 8.02 (d, J = 7.3 Hz, 1H), 7.79 (dd, J = 7.8, 1.4 Hz, 1H), 7.71 (d, J = 3.2 Hz, 3H), 7.52-7.56 (m, 3H), 6.89-6.94 (m, 1H), 5.03 (t, J = 3.9 Hz, 2H), 4.83 (s, 2H), 4.42-4.48 (m, 1H), 3.26 (td, J = 8.7, 4.3 Hz, 2H), 2.4 (m, 2H), 2.17-2.25 (m, 4H), 2.06 -2.14 (m, 2H). MS (ESI): m/z 395 (M +1).
실시예 231-305. 본 발명에 따른 화합물 231-305(DKC1125i01-75)의 제조
화합물 231-305(DKC1125i01-75)의 합성
본 발명의 화합물 231 내지 305(DKC1125i01-75)을 다음 반응식 8에 따라 합성하였다.
[반응식 8]
Figure PCTKR2020010999-appb-img-000074
브로모메틸벤조일 클로라이드(1)의 제조방법
무수 분위기(anhydrous atmosphere) 하에서 브로모메틸벤조산(1g, 4.651mmol)에 SOCl 2 (2 mL, 27.91 mmol)를 상온에서 적가하였다. 반응 혼합물은 4.5 시간동안 환류교반하였다. 반응이 완료된 후 과량의 SOCl 2를 증발시켜 제거하여 브로모메틸벤조일 클로라이드 (1)를 수득한 후(1.62 g, 6.95 mmol, 73%) 별도 정제없이 다음 단계를 진행하였다.
3-( 브로모메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (R₁= CH₂Br , R₂=H) ( 3)의 제조방법
DCM((100 mL) 중의 3-(브로모메틸)벤조일 클로라이드 (1) (1g, 4.29 mmol)에 2-아미노-1-페닐에탄-1-온 (2) (737 mg, 4.29 mmol) 및 NaHCO 3 (50 mL)를 가하였다. 반응 혼합물은 1시간 동안 실온에서 교반하였다. 이후, 이를 DCM으로 추출하고 브라인(brine)으로 세척하고, 무수 Na 2SO 4로 건조하였다. EA/HEX 시스템 컬럼을 사용하여 정제하여, 3-(브로모메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (R 1=CH 2Br, R 2=H) (3) (883 mg, 62%)를 수득하였다.
1H-NMR (400 MHz, CDCl 3) δ 8.03-8.05 (m, 2H), 7.86-7.88 (m, 2H), 7.65 (d, J = 7.3 Hz, 1H), 7.49-7.56 (m, 4H), 7.30 (s, 1H), 4.97 (d, J = 4.1 Hz, 2H), 4.52 (s, 2H).
4-( 브로모메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (R₁= CH₂Br , R₂=H) ( 3)의 제조방법
DCM(100 mL) 중의 4-(브로모메틸)벤조일 클로라이드(1) (1 g, 4.29 mmol)에 2-아미노-1-페닐에탄-1-온 (2) (736mg, 4.29mmol) 및 NaHCO 3 (50 mL)를 가하였다. 반응 혼합물은 1시간 동안 실온에서 교반하였다. 이후, 이를 DCM으로 추출하고 브라인(brine)으로 세척하고, 무수 Na 2SO 4로 건조하였다. EA/HEX 시스템 컬럼을 사용하여 정제하여, 4-(브로모메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (R 1=CH 2Br, R 2=H) (3) (1.18 g, 3.56 mmol, 83%)를 수득하였다.
1H-NMR (400 MHz, CDCl 3) δ 8.05 (dd, J = 8.5, 1.1 Hz, 2H), 7.91-7.92 (m, 1H), 7.81 (dd, J = 6.2, 1.6 Hz, 1H), 7.64-7.68 (m, 1H), 7.52-7.59 (m, 3H), 7.47 (t, J = 7.8 Hz, 1H), 7.31 (s, 1H), 4.98 (d, J = 4.1 Hz, 2H), 4.55 (s, 2H).
3-( 브로모메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 벤즈아마이드 (R₁= CH₂Br , R₂=OCH₃) (3)의 제조방법
DCM(100 mL) 중의 3-(브로모메틸)벤조일 클로라이드(1) (1 g, 4.29 mmol)에 1-아미노-3-(3-메톡시페닐)프로판-2-온 (2) (736mg, 4.29mmol) 및 NaHCO 3 (50 mL)를 가하였다. 반응 혼합물은 1시간 동안 실온에서 교반하였다. 이후, 이를 DCM으로 추출하고 브라인(brine)으로 세척하고, 무수 Na 2SO 4로 건조하였다. EA/HEX 시스템 컬럼을 사용하여 정제하여, 3-(브로모메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (R 1=CH 2Br, R 2=OCH 3) (3) (1.01g, 65%)를 수득하였다.
1H-NMR (400 MHz, CDCl 3) δ 7.91-7.92 (m, 1H), 7.81 (dt, J = 7.8, 1.4 Hz, 1H), 7.61-7.64 (m, 1H), 7.54-7.59 (m, 2H), 7.46 (q, J = 8.1 Hz, 2H), 7.18-7.21 (m, 1H), 4.96 (d, J = 4.1 Hz, 2H), 4.55 (s, 2H), 3.89 (s, 3H).
2-( 브로모메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (R₁= CH₂Br , R₂=H) ( 3)의 제조방법
DCM(100 mL) 중의 2-(브로모메틸)벤조일 클로라이드 (1) (1g, 4.29 mmol) 에 2-아미노-1-페닐에탄-1-온 (2) (736 mg, 4.29 mmol) 및 NaHCO 3 (50 mL)를 부가하였다. 반응 혼합물은 1시간 동안 실온에서 교반하였다. 이후, 이를 DCM으로 추출하고 브라인(brine)으로 세척하고, 무수 Na 2SO 4로 건조하였다. 제조된 조(crude) 생산물을 컬럼 크로마토그래피로 정제하여 (3) (955mg, 67%)의 화합물을 수득하였다.
1H-NMR (400 MHz, CDCl 3) δ 8.02-8.05 (m, 2H), 7.66 (tt, J = 7.5, 1.4 Hz, 1H), 7.37-7.59 (m, 6H), 7.10 (s, 1H), 4.99 (d, J = 4.6 Hz, 2H), 4.84 (s, 2H).
화합물 231-253(DKC1125i01-23)의 일반적인 제조방법
상기 표제 화합물을 제조하였다. 구체적으로, DCM(1 mL) 중의 3-(브로모메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (R 1=CH 2Br, R 2=H) (3) (50 mg, 0.15 mmol)에 하기 표 10에 기재된 2차 아민을 부가하였다. 이후 DIEA (39 mg, 0.30 mmol)를 가하였다. 반응 혼합물을 35℃에서 3 시간 교반하였다. EA/HEX 시스템 컬럼을 사용하여 정제하여 최종 화합물을 수득하였다(수율: 50~60%).
Figure PCTKR2020010999-appb-img-000075
화합물 254-278(DKC1125i24-48)의 일반적인 제조방법:
DCM(1 mL) 중의 4-(브로모메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (R 1=CH 2Br, R 2=H) (3) (50 mg, 0.15 mmol)를 하기 표 11의 이차 아민에 부가하였다. 이에, DIEA(39 mg, 0.30 mmol)를 부가한 후, DIEA(39 mg, 0.30 mmol). 반응 혼합물을 3 시간 동안 35 oC에서 교반하였다. 반응이 완료된 후 반응 혼합물을 EA/HEX system column을 사용하여 정제하여 최종 화합물을 수득하였다(수율: 50~60%).
Figure PCTKR2020010999-appb-img-000076
화합물 279-295(DKC1125i49-65)의 일반적인 제조방법
DCM(1 mL) 중의 3-(브로모메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (R 1=CH 2Br, R 2=OCH 3) (3) (50 mg, 0.15 mmol) 을 하기 표 12의 이차 아민에 부가하였다. 이에, DIEA(39 mg, 0.30 mmol)를 부가한 후, DIEA(39 mg, 0.30 mmol). 반응 혼합물을 3 시간 동안 35 oC에서 교반하였다. 반응이 완료된 후 반응 혼합물을 EA/HEX system column을 사용하여 정제하여 최종 화합물을 수득하였다(수율: 50~60%).
Figure PCTKR2020010999-appb-img-000077
화합물 296-305(DKC1125i66-75)의 일반적인 제조방법:
DCM(1 mL) 중의 2-(브로모메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (R 1=CH 2Br, R 2=H) (3) (50 mg, 0.15 mmol)을 하기 표 13의 이차 아민에 부가하였다. 이에, DIEA(39 mg, 0.30 mmol)를 부가한 후, 반응 혼합물을 3 시간 동안 35 oC에서 교반하였다. 반응이 완료된 후 반응 혼합물을 EA/HEX system column을 사용하여 정제하여 최종 화합물을 수득하였다(수율: 50~60%).
Figure PCTKR2020010999-appb-img-000078
화합물 231-305(DKC1125i01-75)의 제조확인
3-((디메틸아미노) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i01 ) 1H-NMR (400 MHz, CDCl 3) δ 8.02-7.29 (m, 10H), 4.94 (d, J = 4.0 Hz, 2H), 3.62 (s, 2H), 2.34 (s, 6H). MS(ESI): m/z 297 (M+1).
3-((3,4- 디하이드로이소퀴놀린 -2(1H)-일) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i02 ) 1H-NMR (400 MHz, CDCl 3) δ 8.01-7.44 (m, 10H), 7.10 (s, 3H), 6.97 (d, 8.0Hz, 1H), 4.96 (d, J = 4 Hz 2H), 3.75 (s, 2H), 3.65 (s, 2H), 2.79 (t, J = 6.0 Hz, 2H), 1.26 (t, J = 6.8 Hz, 2H). MS(ESI): m/z 385 (M+1).
3-(( 이소프로필(메틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i03) 1H-NMR (400 MHz, CDCl 3) δ 8.03-7.40 (m, 10H), 4.95 (d, J = 4.0 Hz, 2H), 3.69 (s, 2H), 3.05 (q, J = 6.4 Hz, 1H), 2.24 (s, 3H), 1.16 (d, J = 6.4 Hz, 6H). MS(ESI): m/z 325 (M+1).
3-((4-(2- 플루오로페닐 )피페라진-1-일) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i04 ) 1H-NMR (400 MHz, CDCl 3) δ 8.04-8.06 (m, 2H), 7.89 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.52-7.56 (m, 3H), 7.44 (t, J = 7.8 Hz, 1H), 7.33 (s, 1H), 6.90-7.07 (m, 4H), 4.98 (d, J = 4.6 Hz, 2H), 3.65 (s, 2H), 3.13 (t, J = 4.6 Hz, 4H), 2.67 (t, J = 4.3 Hz, 4H). MS(ESI): m/z 432 (M+1).
N-(2-옥소-2- 페닐에틸 )-3-((4-(피리미딘-2-일)피페라진-1-일) 메틸 ) 벤즈아마이드 ( DKC1125i05 ) 1H-NMR (400 MHz, CDCl 3) δ 8.27 (d, J = 4.8 Hz, 2H), 8.02-7.39 (m, 10H), 6.45 (t, J = 4.8 Hz, 1H), 4.95 (d, J = 4.4 Hz, 2H), 3.83 (t, J = 4.8 Hz, 4H), 3.60 (s, 2H), 2.52 (t, J = 4.8 Hz, 4H). MS(ESI): m/z 417 (M+1).
3-((4-(2- 메톡시페닐 )피페라진-1-일) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i06 ) 1H-NMR (400 MHz, CDCl 3) δ 8.09-7.33 (m, 10H), 7.01-6.84 (m, 4H), 4.98 (d, J = 4.0 Hz, 2H), 3.85 (s, 3H), 3.65 (s, 2H), 3.10(s, 4H), 2.68 (s, 4H). MS(ESI): m/z 445 (M+1).
3-([1,4'- 바이피페리딘 ]-1'- 일메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i07) 1H-NMR (400 MHz, CDCl 3) δ 8.01 (d, J = 8.7 Hz, 2H), 7.80 (s, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.63 (dd, J = 8.0, 6.6 Hz, 1H), 7.49-7.53 (m, 2H), 7.34-7.45 (m, 3H), 4.94 (d, J = 4.1 Hz, 2H), 3.52 (s, 2H), 2.95-3.10 (m, 6H), 2.01-2.13 (m, 5H), 1.75-1.84 (m, 2H), 1.44-1.58 (m, 4H), 1.16-1.30 (m, 2H). MS(ESI): m/z 421 (M+1).
3-((4-(4- 니트로페닐 )피페라진-1-일) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i08 ) 1H-NMR (400 MHz, CDCl 3) δ 8.02-8.14 (m, 4H), 7.88 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.63-7.67 (m, 1H), 7.51-7.54 (m, 3H), 7.41-7.46 (m, 1H), 7.34 (s, 1H), 6.79 (d, J = 9.6 Hz, 2H), 4.97 (d, J = 4.1 Hz, 2H), 3.62 (s, 2H), 3.42 (t, J = 5.0 Hz, 4H), 2.60 (t, J = 5.0 Hz, 4H). MS(ESI): m/z 460 (M+1).
3-(( 에틸(페닐)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i09) 1H-NMR (400 MHz, CDCl 3) δ 8.01-8.04 (m, 5H), 7.50-7.81 (m, 7H), 6.69 (s, 3H), 4.94 (d, J = 4.1 Hz, 2H), 4.53 (s, 2H), 3.49 (brs, 2H), 1.67 (brs, 3H). MS(ESI): m/z 373 (M+1).
N-(2-옥소-2- 페닐에틸 )-3-((4-(피리딘-2-일)피페라진-1-일) 메틸 ) 벤즈아마이드 ( DKC1125i10 ) 1H-NMR (400 MHz, CDCl 3) δ 7.98-8.17 (m, 4H), 7.82 (d, J = 7.8 Hz, 1H), 7.43-7.65 (m, 7H), 6.61-6.67 (m, 2H), 4.95 (d, J = 4.4 Hz, 2H), 3.75 (s, 2H), 3.67 (t, J = 4.8 Hz, 4H), 2.70 (brs, 4H). MS(ESI): m/z 416 (M+1).
3-(( 디알릴아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i11 ) 1H-NMR (400 MHz, CDCl 3) δ 8.03-8.06 (m, 2H), 7.30-7.84 (m, 8H), 5.85-5.95 (m, 2H), 5.15-5.24 (m, 4H), 4.97 (d, J = 4.1 Hz, 2H), 3.64 (s, 2H), 3.10 (d, J = 6.4 Hz, 4H). MS(ESI): m/z 349 (M+1).
3-(( 벤질(메틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i12) 1H-NMR (400 MHz, CDCl 3) δ 8.04-8.07 (m, 2H), 7.88 (s, 1H), 7.27-7.78 (m, 12H), 4.98 (d, J = 4.1 Hz, 2H), 3.59 (s, 2H), 3.55 (s, 2H), 2.20 (s, 3H). MS(ESI): m/z 373 (M+1).
3-(((2-하이드록시에틸)( 메틸 )아미노) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i13 ) 1H-NMR (400 MHz, CDCl 3) δ 8.03 (dd, J = 8.5, 1.1 Hz, 2H), 7.92 (s, 1H), 7.79-7.82 (m, 1H), 7.62-7.64 (m, 1H), 7.42-7.54 (m, 5H), 4.95 (d, J = 4.1 Hz, 2H), 3.76 (s, 2H), 3.71 (t, J = 5.2 Hz, 2H), 3.13 (q, J = 7.3 Hz, 1H), 2.72 (t, J = 5.3 Hz, 2H), 2.35 (s, 3H). MS(ESI): m/z 327 (M+1).
3-(( 부틸(2-하이드록시에틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i14 ) 1H-NMR (400 MHz, CDCl 3) δ 8.16 (s, 1H), 8.00-8.02 (m, 2H), 7.88 (d, J = 7.8 Hz, 1H), 7.61-7.69 (m, 3H), 7.45-7.53 (m, 3H), 4.94 (d, J = 4.6 Hz, 2H), 4.11 (s, 2H), 3.83 (t, J = 5.0 Hz, 2H), 3.13 (q, J = 7.5 Hz, 2H), 3.00 (t, J = 4.8 Hz, 2H), 2.86 (t, J = 7.8 Hz, 2H), 1.58 (t, J = 7.3 Hz, 2H), 0.90 (t, J = 7.5 Hz, 3H). MS(ESI): m/z 369 (M+1).
터트 -부틸 4-(3-((2-옥소-2- 페닐에틸 ) 카바모일 ) 벤질 )피페라진-1- 카르복실레이트 ( DKC1125i15 ) 1H-NMR (400 MHz, CDCl 3) δ 8.02-8.04 (m, 2H), 7.84 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.40-7.55 (m, 4H), 7.32 (s, 1H), 4.97 (d, J = 4.1 Hz, 2H), 3.56 (s, 2H), 3.43 (t, J = 4.8 Hz, 4H), 2.40 (brt, 4H), 1.45 (s, 9H). MS(ESI): m/z 439 (M+1).
3-(( 부틸(메틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i16) 1H-NMR (400 MHz, CDCl 3) δ 8.17 (s, 1H), 7.99-8.04 (m, 3H), 7.90 (d, J = 7.8 Hz, 1H), 7.60-7.69 (m, 2H), 7.47-7.52 (m, 3H), 4.92 (d, J = 5.0 Hz, 2H), 4.03 (s, 2H), 2.81 (t, J = 8.0 Hz, 2H), 2.54 (s, 3H), 1.73-1.77 (m, 2H), 1.48-1.58 (m, 2H), 1.32-1.40 (m, 3H). MS(ESI): m/z 339 (M+1).
3-(( 디에틸아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i17 ) 1H-NMR (400 MHz, CDCl 3) δ 8.32 (s, 1H), 7.98-8.00 (m, 2H), 7.92 (d, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.59-7.63 (m, 1H), 7.46-7.51 (m, 3H), 4.91 (d, J = 4.6 Hz, 2H), 4.12 (s, 2H), 3.02 (q, J = 7.3 Hz, 4H), 1.35 (t, J = 7.1 Hz, 6H). MS(ESI): m/z 325 (M+1).
3-(( 디프로필아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i18 ) 1H-NMR (400 MHz, CDCl 3) δ 8.04 (d, J = 7.3 Hz, 2H), 7.84 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.33-7.54 (m, 5H), 4.96 (d, J = 4.6 Hz, 2H), 3.62 (s, 2H), 2.35-2.41 (m, 4H), 1.45-1.54 (m, 4H), 0.87 (t, J = 7.3 Hz, 6H). MS(ESI): m/z 353 (M+1).
3-(( 부틸(에틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i19) 1H-NMR (400 MHz, CDCl 3) δ 7.37-8.18 (m, 10H), 4.94 (d, J = 4.1 Hz, 2H), 3.96 (s, 2H), 2.75-3.05 (m, 4H), 1.25-1.84 (m, 10H). MS(ESI): m/z 353 (M+1).
3-(( 디펜틸아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i20 ) 1H-NMR (400 MHz, CDCl 3) δ 7.31-8.05 (m, 10H), 4.97 (d, J = 4.1 Hz, 2H), 3.50-3.63 (m, 2H), 2.09-2.40 (m, 8H), 1.01-1.57 (m, 14H). MS(ESI): m/z 410 (M+1).
3-(( 에티닐(메틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i21) 1H-NMR (400 MHz, CDCl 3) δ 8.04 (d, J = 7.3 Hz, 2H), 7.79-7.85 (m, 2H), 7.63-7.67 (m, 1H), 7.32-7.55 (m, 5H), 4.97 (d, J = 4.1 Hz, 2H), 3.64 (s, 2H), 3.33 (d, J = 2.3 Hz, 1H), 2.35 (s, 3H). MS(ESI): m/z 307 (M+1).
3-( 모폴리노메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i22 ) 1H-NMR (400 MHz, CDCl 3) δ 8.04 (d, J = 7.3 Hz, 2H), 7.85 (s, 1H), 7.77 (d, J = 7.3 Hz, 1H), 7.62-7.67 (m, 1H), 7.33-7.55 (m, 5H), 4.96 (d, J = 4.6 Hz, 2H), 3.71 (t, J = 4.6 Hz, 4H), 3.56 (s, 2H), 2.46 (t, J = 4.3 Hz, 4H). MS(ESI): m/z 339 (M+1).
3-((4- 메틸피페라진 -1-일) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i23) 1H-NMR (400 MHz, CDCl 3) δ 7.34-8.04 (m, 10H), 4.96 (d, J = 4.1 Hz, 2H), 3.56 (s, 2H), 2.52 (s, 11H). MS(ESI): m/z 352 (M+1).
4-((3,4- 디하이드로이소퀴놀린 -2(1H)-일) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i24 ) 1H-NMR (400 MHz, CDCl 3) δ 8.03-8.08 (m, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.63-7.67 (m, 1H), 7.50-7.55 (m, 4H), 7.31 (brs, 1H), 7.08-7.13 (m, 3H), 6.98-7.00 (m, 1H), 4.97 (d, J = 4.1 Hz, 2H), 3.75 (s, 2H), 3.65 (s, 2H), 2.92 (t, J = 5.7 Hz, 2H), 2.76 (t, J = 5.9 Hz, 2H). MS(ESI): m/z 385 (M+1).
4-(( 시클로헥실(메틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i25) 1H-NMR (400 MHz, CDCl 3) δ 8.08 (d, J = 7.3 Hz, 2H), 7.92 (d, J = 7.8 Hz, 2H), 7.55-7.71 (m, 5H), 7.38 (s, 1H), 5.01 (d, J = 4.6 Hz, 2H), 3.91 (s, 2H), 3.72-3.79 (m, 1H), 2.43 (s, 3H), 2.09 (d, J = 11.4 Hz, 2H), 1.89 (d, J = 12.8 Hz, 2H), 1.61-1.72 (m, 2H), 1.43 (dd, J = 12.1, 2.5 Hz, 2H), 1.21-1.33 (m, 2H). MS(ESI): m/z 365 (M+1).
4-(( 이소프로필(메틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i26) 1H-NMR (400 MHz, CDCl 3) δ 8.02-8.04 (m, 2H), 7.85-7.87 (m, 2H), 7.63-7.66 (m, 1H), 7.48-7.54 (m, 4H), 7.29 (s, 1H), 4.95 (d, J = 4.1 Hz, 2H), 4.50 (s, 2H), 1.60 (s, 3H), 1.24 (s, 6H), 0.81-0.88 (m, 1H). MS(ESI): m/z 325 (M+1).
4-((4-(2- 플루오로페닐 )피페라진-1-일) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i27 ) 1H-NMR (400 MHz, CDCl 3) δ 8.03-8.06 (m, 2H), 7.85-7.87 (m, 2H), 7.63-7.68 (m, 1H), 7.47-7.56 (m, 4H), 7.30 (t, J = 4.1 Hz, 1H), 6.91-7.08 (m, 4H), 4.98 (d, J = 4.6 Hz, 2H), 3.64 (s, 2H), 3.12 (t, J = 4.8 Hz, 4H), 2.65 (t, J = 4.8 Hz, 4H). MS(ESI): m/z 433 (M+1).
N-(2-옥소-2- 페닐에틸 )-4-((4-(피리미딘-2-일)피페라진-1-일) 메틸 ) 벤즈아마이드 ( DKC1125i28 ) 1H-NMR (400 MHz, CDCl 3) δ 8.30 (d, J = 4.6 Hz, 2H), 8.03-8.05 (m, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.65 (tt, J = 7.4, 1.4 Hz, 1H), 7.46-7.55 (m, 4H), 7.30 (t, J = 3.9 Hz, 1H), 6.47 (t, J = 4.6 Hz, 1H), 4.97 (d, J = 4.6 Hz, 2H), 3.84 (t, J = 5.0 Hz, 4H), 3.60 (s, 2H), 2.51 (t, J = 5.0 Hz, 4H). MS(ESI): m/z 417 (M+1).
4-((4-(2- 메톡시페닐 )피페라진-1-일) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i29 ) 1H-NMR (400 MHz, CDCl 3) δ 8.03-8.05 (m, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.63-7.67 (m, 1H), 7.47-7.55 (m, 4H), 7.30 (t, J = 4.1 Hz, 1H), 6.84-7.02 (m, 4H), 4.97 (d = 4.1 Hz, 2H), 3.86 (s, 3H), 3.64 (s, 2H), 3.10 (brs, 4H), 2.67 (brs, 4H). MS(ESI): m/z 445 (M+1).
4-([1,4'- 바이피페리딘 ]-1'- 일메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i30) 1H-NMR (400 MHz, CDCl 3) δ 7.99-8.02 (m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.60-7.62 (m, 1H), 7.50 (t, J = 7.8 Hz, 2H), 7.34-7.38 (m, 3H), 4.93 (d, J = 4.1 Hz, 2H), 3.65-3.72 (m, 3H), 3.54 (s, 2H), 3.11 (q, J = 7.5 Hz, 4H), 2.98 (d, J = 12.3 Hz, 2H), 2.21 (d, J = 11.9 Hz, 2H), 2.09 (t, J = 11.2 Hz, 2H), 1.86 (dd, J = 11.9, 3.7 Hz, 2H), 1.55 (t, J = 7.5 Hz, 4H). MS(ESI): m/z 421 (M+1).
4-((4-(4- 니트로페닐 )피페라진-1-일) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i31 ) 1H-NMR (400 MHz, CDCl 3) δ 8.10-8.14 (m, 2H), 8.03-8.06 (m, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.64-7.68 (m, 1H), 7.43-7.56 (m, 4H), 7.29 (t, J = 4.1 Hz, 1H), 6.80-6.84 (m, 2H), 4.98 (d, J = 4.6 Hz, 2H), 3.63 (s, 2H), 3.44 (t, J = 5.0 Hz, 4H), 2.61 (t, J = 5.3 Hz, 4H). MS(ESI): m/z 460 (M+1).
4-(( 메틸(페닐)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i32) 1H-NMR (400 MHz, CDCl 3) δ 8.04 (d, J = 7.8 Hz, 2H), 7.82-7.87 (m, 2H), 7.51-7.67 (m, 3H), 7.33-7.40 (m, 2H), 7.22-7.24 (m, 1H), 6.73-6.91 (m, 5H), 4.96 (d, J = 4.1 Hz, 2H), 4.59 (s, 2H), 3.05 (s, 3H). MS(ESI): m/z 359 (M+1).
4-(( 에틸(페닐)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i33) 1H-NMR (400 MHz, CDCl 3) δ 8.02-8.05 (m, 3H), 7.82-7.88 (m, 3H), 7.49-7.68 (m, 6H), 7.30-7.36 (m, 1H), 7.19 (dd, J = 8.9, 7.1 Hz, 1H), 6.69 (t, J = 8.0 Hz, 1H), 4.97 (d, J = 4.1 Hz, 2H), 4.52 (s, 2H), 3.50 (q, J = 7.0 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). MS(ESI): m/z 373 (M+1).
N-(2-옥소-2- 페닐에틸 )-4-((4-(피리딘-2-일)피페라진-1-일) 메틸 ) 벤즈아마이드 ( DKC1125i34 ) 1H-NMR (400 MHz, CDCl 3) δ 8.18-8.19 (m, 1H), 8.03-8.06 (m, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.63-7.68 (m, 1H), 7.45-7.56 (m, 5H), 7.29 (s, 1H), 6.60-6.65 (m, 2H), 4.98 (d, J = 4.1 Hz, 2H), 3.61 (s, 2H), 3.56 (t, J = 5.0 Hz, 4H), 2.57 (t, J = 5.0 Hz, 4H). MS(ESI): m/z 416 (M+1).
4-(( 디알릴아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i35 ) 1H-NMR (400 MHz, CDCl 3) δ 8.04 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.63-7.67 (m, 1H), 7.53 (t, J = 7.5 Hz, 2H), 7.28-7.45 (m, 3H), 5.83-5.93 (m, 2H), 5.13-5.22 (m, 4H), 4.97 (d, J = 4.1 Hz, 2H), 3.62 (s, 2H), 3.08 (d, J = 6.4 Hz, 4H). MS(ESI): m/z 349 (M+1).
4-(( 벤질(메틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i36) 1H-NMR (400 MHz, CDCl 3) δ 8.04 (d, J = 7.3 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.47-7.55 (m, 4H), 7.27-7.38 (m, 6H), 4.97 (d, J = 4.1 Hz, 2H), 3.57 (s, 2H), 3.54 (s, 2H), 2.20 (s, 3H). MS(ESI): m/z 373 (M+1).
4-(((2-하이드록시에틸)( 메틸 )아미노) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i37 ) 1H-NMR (400 MHz, CDCl 3) δ 8.02 (d, J = 7.3 Hz, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.47-7.53 (m, 4H), 7.36 (s, 1H), 4.95 (d, J = 4.6 Hz, 2H), 3.80 (s, 2H), 3.72 (t, J = 5.9 Hz, 2H), 2.75 (t, J = 5.3 Hz, 2H), 2.37 (s, 3H). MS(ESI): m/z 327 (M+1).
4-(( 부틸(2-하이드록시에틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i38 ) 1H-NMR (400 MHz, CDCl 3) δ 8.02-8.04 (m, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.46-7.54 (m, 4H), 7.34 (d, J = 3.7 Hz, 1H), 4.96 (d, J = 4.1 Hz, 2H), 3.80 (s, 2H), 3.65 (t, J = 5.0 Hz, 2H), 3.13 (q, J = 7.5 Hz, 1H), 2.75 (t, J = 5.3 Hz, 2H), 2.59 (t, J = 7.5 Hz, 2H), 1.54-1.60 (m, 2H), 1.24-1.34 (m, 2H), 0.89 (q, J = 7.3 Hz, 3H). MS(ESI): m/z 369 (M+1).
터트 -부틸 4-(4-((2-옥소-2- 페닐에틸 ) 카바모일 ) 벤질 )피페라진-1- 카르복실레이트 ( DKC1125i39 ) 1H-NMR (400 MHz, CDCl 3) δ 8.03 (d, J = 7.3 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.41-7.66 (m, 5H), 7.30 (d, J = 3.7 Hz, 1H), 4.96 (d, J = 4.1 Hz, 2H), 3.55 (s, 2H), 3.43 (t, J = 4.6 Hz, 4H), 2.38 (brs, 4H), 1.44 (s, 9H). MS(ESI): m/z 439 (M+1).
4-(( 디시클로헥실아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i40) 1H-NMR (400 MHz, CDCl 3) δ 8.03-8.05 (m, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.47-7.67 (m, 6H), 4.97 (d, J = 4.6 Hz, 2H), 3.80 (s, 2H), 2.49-2.55 (m, 2H), 1.56-1.78 (m, 10H), 1.01-1.30 (m, 10H). MS(ESI): m/z 434 (M+1).
4-(( 부틸(메틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i41) 1H-NMR (400 MHz, CDCl 3) δ 7.98-8.00 (m, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.47-7.62 (m, 5H), 7.40 (t, J = 4.1 Hz, 1H), 4.92 (d, J = 4.1 Hz, 2H), 3.80 (s, 2H), 2.58 (t, J = 8.0 Hz, 2H), 2.36 (s, 3H), 1.58-1.64 (m, 2H), 1.26-1.33 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H). MS(ESI): m/z 339 (M+1).
4-(( 디프로필아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i42 ) 1H-NMR (400 MHz, CDCl 3) δ 8.01-8.03 (m, 2H), 7.82-7.84 (m, 2H), 7.61-7.65 (m, 1H), 7.40-7.53 (m, 4H), 7.29-7.32 (m, 1H), 4.95 (d, J = 4.6 Hz, 2H), 3.66 (s, 2H), 2.42 (t, J = 7.5 Hz, 4H), 1.47-1.56 (m, 4H), 0.86 (t, J = 7.3 Hz, 6H). MS(ESI): m/z 353 (M+1).
4-(( 부틸(에틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i43) 1H-NMR (400 MHz, CDCl 3) δ 8.01-8.03 (m, 2H), 7.82-7.84 (m, 2H), 7.61-7.65 (m, 1H), 7.40-7.53 (m, 4H), 7.29-7.32 (m, 1H), 4.95 (d, J = 4.6 Hz, 2H), 3.66 (s, 2H), 2.42 (t, J = 7.5 Hz, 4H), 1.47-1.56 (m, 4H), 0.86 (t, J = 7.3 Hz, 6H). MS(ESI): m/z 353 (M+1).
4-(( 에틸(2-하이드록시에틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i44 ) 1H-NMR (400 MHz, CDCl 3) δ 8.03 (d, J = 7.3 Hz, 2H), 7.81-7.84 (m, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.28-7.54 (m, 5H), 4.96 (d, J = 4.6 Hz, 2H), 3.47-3.61 (m, 4H), 2.08-2.43 (m, 4H), 1.43-1.48 (m, 3H). MS(ESI): m/z 341 (M+1).
4-(( 에티닐(메틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i45) 1H-NMR (400 MHz, CDCl 3) δ 8.03 (d, J = 7.8 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.30-7.66 (m, 6H), 4.96 (d, J = 4.1 Hz, 2H), 3.63 (s, 2H), 3.32 (s, 1H), 2.34 (s, 3H). MS(ESI): m/z 307 (M+1).
4-( 모폴리노메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i46 ) 1H-NMR (400 MHz, CDCl 3) δ 8.04 (d, J = 7.3 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.65 (t, J = 7.3 Hz, 1H), 7.43-7.55 (m, 4H), 7.29 (s, 1H), 4.96 (d, J = 4.1 Hz, 2H), 3.72 (t, J = 4.8 Hz, 4H), 3.55 (s, 2H), 2.45 (t, J = 4.6 Hz, 4H). MS(ESI): m/z 339 (M+1).
에틸 4-(4-((2-옥소-2- 페닐에틸 ) 카바모일 ) 벤질 )피페라진-1- 카르복실레이트 (DKC1125i47) 1H-NMR (400 MHz, CDCl 3) δ 8.01 (d, J = 8.5 Hz, 2H), 7.81-7.83 (m, 2H), 7.60-7.64 (m, 1H), 7.48-7.52 (m, 2H), 7.31-7.42 (m, 3H), 4.94 (d, J = 4.1 Hz, 2H), 4.08-4.17 (m, 4H), 3.46 (t, J = 5.2 Hz, 4H), 2.38 (s, 4H), 1.23 (t, J = 6.8 Hz, 3H). MS(ESI): m/z 410 (M+1).
4-((2,6- di메틸모폴리노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i48) 1H-NMR (400 MHz, CDCl 3) δ 8.03 (d, J = 7.8 Hz, 2H), 7.84 (d, J = 7.8 Hz, 2H), 7.63-7.66 (m, 1H), 7.29-7.54 (m, 5H), 4.96 (d, J = 4.1 Hz, 2H), 3.66-3.72 (m, 2H), 3.52 (s, 2H), 2.66-2.69 (m, 2H), 1.74-1.79 (m, 2H), 1.13 (d, J = 5.9 Hz, 6H). MS(ESI): m/z 367 (M+1).
3-((3,4- 디하이드로이소퀴놀린 -2(1H)-일) 메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 )벤즈아마이드 ( DKC1125i49 ) 1H-NMR (400 MHz, CDCl 3) δ 7.79-7.90 (m, 2H), 7.53-7.63 (m, 3H), 7.32-7.46 (m, 3H), 7.17-7.20 (m, 1H), 7.09-7.12 (m, 3H), 6.98 (d, J = 7.8 Hz, 1H), 4.95 (d, J = 4.1 Hz, 2H), 3.88 (d, J = 3.2 Hz, 3H), 3.75 (s, 2H), 3.65 (s, 2H), 2.92 (t, J = 5.7 Hz, 2H), 2.77 (t, J = 5.9 Hz, 2H). MS(ESI): m/z 416 (M+1).
3-(( 시클로헥실(메틸)아미노 ) 메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125i50 ) 1H-NMR (400 MHz, CDCl 3) δ 7.97 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.37-7.59 (m, 6H), 7.13-7.16 (m, 1H), 4.91 (d, J = 4.6 Hz, 2H), 3.84 (s, 3H), 3.75 (s, 2H), 2.61 (s, 1H), 2.28 (s, 3H), 1.99 (d, J = 11.0 Hz, 2H), 1.82 (d, J = 12.8 Hz, 2H), 1.63 (d, J = 12.8 Hz, 2H), 1.19-1.36 (m, 4H). MS(ESI): m/z 396 (M+1).
3-((1-(2- 플루오로페닐 )피페리딘-4-일) 메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 )벤즈아마이드 ( DKC1125i51 ) 1H-NMR (400 MHz, CDCl 3) δ 7.77-7.88 (m, 2H), 7.33-7.63 (m, 6H), 6.91-7.19 (m, 5H), 4.95 (d, J = 4.1 Hz, 2H), 3.87 (s, 3H), 3.12 (t, J = 4.8 Hz, 4H), 2.94 (s, 1H), 2.87 (s, 1H), 2.65 (t, J = 4.8 Hz, 5H). MS(ESI): m/z 462 (M+1).
N-(2-(3- 메톡시페닐 )-2- 옥소에틸 )-3-((4-(2- 메톡시페닐 )피페라진-1-일) 메틸 )벤즈아마이드 ( DKC1125i52 ) 1H-NMR (400 MHz, CDCl 3) δ 7.88 (s, 1H), 7.77-7.80 (m, 1H), 7.61-7.63 (m, 1H), 7.54-7.56 (m, 2H), 7.41-7.45 (m, 2H), 7.33 (t, J = 3.9 Hz, 1H), 7.17-7.20 (m, 1H), 6.88-7.01 (m, 3H), 6.85 (dd, J = 8.0, 1.1 Hz, 1H), 4.95 (d, J = 4.6 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.65 (s, 2H), 3.10 (brs, 4H), 2.69 (brs, 4H). MS(ESI): m/z 475 (M+1).
3-([1,4'- 바이피페리딘 ]-1'- 일메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125i53 ) 1H-NMR (400 MHz, CDCl 3) δ 7.75-7.82 (m, 2H), 7.34-7.62 (m, 6H), 7.18 (d, J = 8.2 Hz, 1H), 4.94 (d, J = 4.1 Hz, 2H), 3.87 (s, 3H), 3.53 (s, 2H), 2.94 (d, J = 10.1 Hz, 1H), 2.61 (s, 8H), 1.99 (t, J = 11.7 Hz, 2H), 1.83 (d, J = 11.0 Hz, 2H), 1.66 (s, 4H), 1.46 (s, 2H). MS(ESI): m/z 451 (M+1).
N-(2-(3- 메톡시페닐 )-2- 옥소에틸 )-3-((4-(피리딘-2-일)피페라진-1-일) 메틸 )벤즈아마이드 ( DKC1125i54 ) 1H-NMR (400 MHz, CDCl 3) δ 8.17-8.20 (m, 1H), 7.87 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.61-7.63 (m, 1H), 7.41-7.55 (m, 5H), 7.33 (t, J = 4.3 Hz, 1H), 7.18 (dd, J = 8.0, 3.0 Hz, 1H), 6.59-6.64 (m, 2H), 4.95 (d, J = 4.1 Hz, 2H), 3.87 (s, 3H), 3.61 (s, 2H), 3.55 (t, J = 5.0 Hz, 4H), 2.57 (t, J = 5.0 Hz, 4H). MS(ESI): m/z 446 (M+1).
3-(( 디알릴아미노 ) 메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 벤즈아마이드 (DKC1125i55) 1H-NMR (400 MHz, CDCl 3) δ 7.84 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.61-7.63 (m, 1H), 7.51-7.54 (m, 2H), 7.42 (q, J = 7.9 Hz, 2H), 7.30 (d, J = 4.6 Hz, 1H), 7.18 (dd, J = 8.0, 3.0 Hz, 1H), 5.84-5.94 (m, 2H), 5.16-5.24 (m, 4H), 4.95 (d, J = 4.6 Hz, 2H), 3.88 (s, 3H), 3.64 (s, 2H), 3.10 (d, J = 6.4 Hz, 4H). MS(ESI): m/z 379 (M+1).
3-(( 벤질(메틸)아미노 ) 메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 벤즈아마이드 (DKC1125i56) 1H-NMR (400 MHz, CDCl 3) δ 7.98 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.29-7.62 (m, 11H), 7.16-7.19 (m, 1H), 4.94 (d, J = 4.6 Hz, 2H), 3.87 (s, 4H), 3.73 (s, 3H), 2.29 (s, 3H). MS(ESI): m/z 403 (M+1).
3-(( 에틸(메틸)아미노 ) 메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 벤즈아마이드 (DKC1125i57) 1H-NMR (400 MHz, CDCl 3) δ 7.30-7.91 (m, 8H), 7.18-7.21 (m, 1H), 4.96 (d, J = 4.1 Hz, 2H), 4.65 (s, 1H), 4.54 (s, 1H), 3.85-3.89 (m, 5H), 1.61 (s, 3H), 1.25 (s, 3H). MS(ESI): m/z 341 (M+1).
3-(( 부틸(2-하이드록시에틸)아미노 ) 메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 )벤즈아마이드 ( DKC1125i58 ) 1H-NMR (400 MHz, CDCl 3) δ 8.13 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.40-7.63 (m, 6H), 7.15-7.18 (m, 1H), 4.93 (d, J = 4.6 Hz, 2H), 4.06 (s, 2H), 3.87 (s, 3H), 3.80 (t, J = 5.0 Hz, 2H), 2.96 (t, J = 4.8 Hz, 2H), 2.82 (t, J = 8.0 Hz, 2H), 1.58 (t, J = 7.5 Hz, 3H), 1.30-1.35 (m, 4H). MS(ESI): m/z 400 (M+1).
터트 -부틸 4-(3-((2-(3- 메톡시페닐 )-2- 옥소에틸 ) 카바모일 ) 벤질 )피페라진-1-카르복실레이트 ( DKC1125i59 ) 1H-NMR (400 MHz, CDCl 3) δ 7.84 (s, 1H), 7.77 (dd, J = 7.8, 1.4 Hz, 1H), 7.62 (dd, J = 7.8, 0.9 Hz, 1H), 7.29-7.54 (m, 5H), 7.17-7.20 (m, 1H), 4.95 (d, J = 4.1 Hz, 2H), 3.88 (s, 3H), 3.57 (s, 2H), 3.44 (t, J = 4.6 Hz, 4H), 2.41 (brs, 4H), 1.45 (s, 9H). MS(ESI): m/z 469 (M+1).
3-(( 부틸(에틸)아미노 ) 메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 벤즈아마이드 (DKC1125i60) 1H-NMR (400 MHz, CDCl 3) δ 8.04 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.40-7.53 (m, 4H), 7.15-7.18 (m, 1H), 4.93 (d, J = 4.6 Hz, 2H), 3.87 (s, 3H), 3.82 (s, 2H), 2.72 (q, J = 7.0 Hz, 2H), 2.62 (t, J = 7.8 Hz, 2H), 1.50 (d, J = 6.9 Hz, 3H), 1.27-1.37 (m, 2H), 1.18 (t, J = 7.1 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). MS(ESI): m/z 384 (M+1).
3-(( 디펜틸아미노 ) 메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 벤즈아마이드 (DKC1125i61) 1H-NMR (400 MHz, CDCl 3) δ 7.82 (s, 1H), 7.72-7.76 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.52-7.57 (m, 2H), 7.35-7.46 (m, 2H), 7.30 (d, J = 3.2 Hz, 1H), 7.17-7.21 (m, 1H), 4.95 (d, J = 4.1 Hz, 2H), 3.88 (s, 3H), 3.55 (s, 2H), 2.02-2.43 (m, 8H), 1.39-1.58 (m, 6H), 1.22-1.32 (m, 8H). MS(ESI): m/z 371 (M+1).
3-((4-(2-하이드록시에틸)피페라진-1-일) 메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 )벤즈아마이드 ( DKC1125i62 ) 1H-NMR (400 MHz, CDCl 3) δ 7.88 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.34-7.52 (m, 4H), 7.16-7.19 (m, 1H), 4.93 (d, J = 4.6 Hz, 2H), 3.88 (s, 3H), 3.66 (s, 2H), 3.12 (t, J = 7.5 Hz, 2H), 2.95 (t, J = 4.8 Hz, 2H), 2.83 (brs, 4H), 1.50 (brs, 4H). MS(ESI): m/z 440 (M+1).
N-(2-(3- 메톡시페닐 )-2- 옥소에틸 )-3-( 모폴리노메틸 ) 벤즈아마이드 (DKC1125i63) 1H-NMR (400 MHz, CDCl 3) δ 7.91 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.49-7.59 (m, 3H), 7.37-7.42 (m, 3H), 7.13-7.16 (m, 1H), 4.91 (d, J = 4.1 Hz, 2H), 3.84 (s, 3H), 3.74 (t, J = 4.6 Hz, 4H), 3.64 (s, 2H), 3.11 (q, J = 7.3 Hz, 2H), 1.53 (q, J = 7.0 Hz, 2H). MS(ESI): m/z 369 (M+1).
3-(( 에틸(프로필)아미노 ) 메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125i64 ) 1H-NMR (400 MHz, CDCl 3) δ 8.15 (s, 1H), 7.76-7.79 (m, 1H), 7.48-7.66 (m, 3H), 7.33-7.42 (m, 3H), 7.14-7.18 (m, 1H), 4.90 (d, J = 5.0 Hz, 2H), 3.99 (s, 2H), 3.85 (s, 3H), 3.61-3.70 (m, 2H), 1.47 (d, J = 6.9 Hz, 2H), 0.94-0.99 (m, 8H). MS(ESI): m/z 369 (M+1).
3-((2,6- di메틸모폴리노 ) 메틸 )-N-(2-(3- 메톡시페닐 )-2- 옥소에틸 ) 벤즈아마이드 ( DKC1125i65 ) 1H-NMR (400 MHz, CDCl 3) δ 7.84 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.50-7.54 (m, 2H), 7.43 (td, J = 7.8, 4.1 Hz, 2H), 7.30 (d, J = 4.1 Hz, 1H), 7.17-7.20 (m, 1H), 4.95 (d, J = 4.1 Hz, 2H), 3.88 (s, 3H), 3.67-3.73 (m, 2H), 3.53 (s, 2H), 2.67 (t, J = 10.6 Hz, 2H), 1.78 (t, J = 10.7 Hz, 2H), 1.14 (d, J = 6.4 Hz, 6H). MS(ESI): m/z 397 (M+1).
2-((디메틸아미노) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i66 ) 1H-NMR (400 MHz, CDCl 3) δ 7.42-8.05 (m, 10H), 3.67 (d, J = 4.1 Hz, 2H), 3.10 (s, 2H), 1.47 (s, 6H). MS(ESI): m/z 297 (M+1).
2-((3,4- 디하이드로퀴놀린 -1(2H)-일) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i67 ) 1H-NMR (400 MHz, CDCl 3) δ 7.93-8.08 (m, 4H), 7.38-7.60 (m, 8H), 7.04-7.10 (m, 1H), 6.92 (d, J = 6.9 Hz, 1H), 4.85 (d, J = 3.7 Hz, 2H), 3.93 (s, 2H), 2.97-3.09 (m, 2H), 2.90 (t, J = 5.7 Hz, 2H), 2.83 (t, J = 5.7 Hz, 2H). MS(ESI): m/z 385 (M+1).
2-(( 시클로헥실(메틸)아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i68) 1H-NMR (400 MHz, CDCl 3) δ 7.97-8.01 (m, 3H), 7.83 (d, J = 7.3 Hz, 1H), 7.47-7.65 (m, 6H), 4.92 (s, 2H), 4.35 (s, 2H), 3.66-3.72 (m, 1H), 2.63 (s, 3H), 2.23 (d, J = 11.0 Hz, 2H), 1.89 (d, J = 13.3 Hz, 2H), 1.67 (d, J = 13.3 Hz, 2H), 1.28 (m, 4H). MS(ESI): m/z 365 (M+1).
2-((4-(2- 플루오로페닐 )피페라진-1-일) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i69 ) 1H-NMR (400 MHz, CDCl 3) δ 7.99-8.07 (m, 3H), 7.42-7.66 (m, 7H), 7.00-7.10 (m, 2H), 6.91-6.97 (m, 2H), 5.02 (d, J = 5.5 Hz, 2H), 3.81 (s, 2H), 3.12 (brs, 4H), 2.76 (brs, 4H). MS(ESI): m/z 433 (M+1).
N-(2-옥소-2- 페닐에틸 )-2-((4-(피리미딘-2-일)피페라진-1-일) 메틸 ) 벤즈아마이드 ( DKC1125i70 ) 1H-NMR (400 MHz, CDCl 3) δ 8.28 (d, J = 4.4 Hz, 2H), 7.96-8.03 (m, 3H), 7.41-7.63 (m, 6H), 7.20 (d, J = 6.8 Hz, 1H), 6.48 (t, J = 4.4 Hz, 1H), 5.02 (d, J = 5.0 Hz, 2H), 3.84 (brs, 4H), 3.74 (s, 2H), 2.60 (t, J = 5.0 Hz, 4H). MS(ESI): m/z 417 (M+1).
2-([1,4'- 바이피페리딘 ]-1'- 일메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 (DKC1125i71) 1H-NMR (400 MHz, CDCl 3) δ 7.89-7.99 (m, 3H), 7.37-7.64 (m, 5H), 7.20 (d, J = 5.9 Hz, 1H), 5.06 (d, J = 4.6 Hz, 2H), 3.66-3.73 (m, 3H), 3.06-3.15 (m, 4H), 2.02-2.25 (m, 4H), 1.49-1.58 (m, 10H). MS(ESI): m/z 421 (M+1).
N-(2-옥소-2- 페닐에틸 )-2-((4-(피리딘-2-일)피페라진-1-일) 메틸 ) 벤즈아마이드 ( DKC1125i72 ) 1H-NMR (400 MHz, CDCl 3) δ 8.16-8.17 (m, 1H), 7.97-8.03 (m, 3H), 7.59-7.63 (m, 1H), 7.39-7.54 (m, 6H), 7.22-7.24 (m, 1H), 6.60-6.67 (m, 2H), 5.00 (d, J = 5.0 Hz, 2H), 3.77 (s, 2H), 3.54 (t, J = 4.8 Hz, 4H), 2.66 (t, J = 5.0 Hz, 4H). MS(ESI): m/z 415 (M+1).
2-(( 디알릴아미노 ) 메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i73 ) 1H-NMR (400 MHz, CDCl 3) δ 8.02-8.04 (m, 2H), 7.92-7.95 (m, 1H), 7.37-7.63 (m, 7H), 5.81-5.92 (m, 2H), 5.14-5.21 (m, 4H), 4.97 (s, 2H), 3.81 (s, 2H), 3.18 (d, J = 6.9 Hz, 4H). MS(ESI): m/z 349 (M+1).
2-( 모폴리노메틸 )-N-(2-옥소-2- 페닐에틸 ) 벤즈아마이드 ( DKC1125i74 ) 1H-NMR (400 MHz, CDCl 3) δ 7.92-8.05 (m, 3H), 7.37-7.69 (m, 6H), 7.20-7.23 (m, 1H), 5.01 (d, J = 5.0 Hz, 2H), 3.67-3.73 (m, 6H), 2.55 (brs, 4H). MS(ESI): m/z 339 (M+1).
에틸 4-(2-((2-옥소-2- 페닐에틸 ) 카바모일 ) 벤질 )피페라진-1- 카르복실레이트 (DKC1125i75) 1H-NMR (400 MHz, CDCl 3) δ 8.01-8.03 (m, 2H), 7.91-7.96 (m, 1H), 7.60-7.64 (m, 1H), 7.37-7.55 (m, 6H), 7.19 (dd, J = 6.9, 1.8 Hz, 1H), 5.01 (d, J = 4.6 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.70 (s, 2H), 3.50 (t, J = 4.6 Hz, 4H), 2.50 (t, J = 5.0 Hz, 4H), 1.24 (t, J = 7.1 Hz, 3H). MS(ESI): m/z 410 (M+1).
실험예 1: 루시퍼라제 ( luciferase ) 분석을 통한 화합물의 암 전이 연관 프로모터 활성 증가 효과 측정
본 발명에 따른 화합물의 전이 연관 프로모터 활성 증가 효과를 확인하기 위하여 실험을 진행하였다.　 구체적으로, KAI1 프로모터 리포터 벡터를 사용하였다.　 이때, pRL-TK 벡터는 레닐라 루시퍼라제(renila luciferase)를 발현하는 벡터로서, 형질전환한 각각의 웰에서의 형질전환효율을 나타내는 내부 대조군으로 사용하였다.
먼저, 형질전환 24시간 전에 인간 대장암 세포주(human colon cancer cellline, Caco2) 세포 2 X 10 6 개와 10% FBS, 1% 페니실린/스트렙토 마이신이 포함된 DMEM 배지 10 ml을 직경 100 mm 플레이트에서 배양 후 트랜스펙션 시약과 KAI1 프로모터가 포함된 pRL-TK 벡터 5 μg 혼합물을 이용하여 형질전환 시킨 후, 37℃, 5% CO 2가 존재하는 배양기에서 48시간동안 배양하였다. 그 후 트립신을 이용하여 부착세포를 부양시켜 hemacytometer를 이용하여 세포수를 센 다음 96웰 플레이트의 각 웰에 형질전환된 Caco2 세포 5 X 10 3과 10% FBS, 1% 페니실린/스트렙토 마이신이 포함된 DMEM 배지 100 μl를 분주 하고 37℃, 5% CO 2가 존재하는 배양기에서 24시간 동안 배양하였다. 그 후 상기 실시예 1-305에서 제조한 305종의 화합물을 1 μM 각각 넣고 16시간 후 루시퍼레이즈 기질이 포함된 분석용 용해용액 100μl 넣고 교반기를 이용하여 20분 동안 용해하였다. 용해가 끝난 세포는 루시퍼라아제 분석 시스템(luciferase reporter assay system, Promega, USA)을 이용하여 루시퍼라아제 활성을 측정하였다. DMSO처리군을 대조군 및 KAI1 프로모터 활성을 증가시키는 것으로 알려져 있는 PHA-665752를 양성대조군으로 하여 실험을 진행하였다. 또한, 유의성 검증은 일원분산분석(One-way ANOVA, Tukey’s HSD)으로 p<0.05 유의수준에서 분석하였고, SPSS 17.0(Chicago, USA) 통계 프로그램을 사용하였다.　 그 결과를 표 14 내지 표 20에 나타내었다. 하기 표 14-20에서 PHA는 상기 PHA-665752, KIT는 KITENIN이다.
실험결과, 실시예 1-305의 화합물 1-305는 KAI1 프로모터 리포터 활성을 DMSO 대조군에 비하여 다양한 정도로 영향을 주는 것을 확인하였다.
Figure PCTKR2020010999-appb-img-000079
Figure PCTKR2020010999-appb-img-000080
Figure PCTKR2020010999-appb-img-000081
Figure PCTKR2020010999-appb-img-000082
Figure PCTKR2020010999-appb-img-000083
Figure PCTKR2020010999-appb-img-000084
Figure PCTKR2020010999-appb-img-000085
Figure PCTKR2020010999-appb-img-000086
Figure PCTKR2020010999-appb-img-000087
Figure PCTKR2020010999-appb-img-000088
Figure PCTKR2020010999-appb-img-000089

Claims (7)

  1. 하기 화학식 1로 나타내어지는 화합물, 또는 이의 약학적으로 허용가능한 염:
    [화학식 1]
    Figure PCTKR2020010999-appb-img-000090
    상기 식에서,
    X는 C 또는 N이고;
    L은 C1 내지 C4의 알킬렌 또는 결합(bond)이고;
    R 1은 수소, 할로겐, 비치환되거나 치환된 C1-C4 알킬, 비치환되거나 치환된 C1-C4 알콕시, 디(C1-C4 알킬)아미노, 모노(C1-C4 알킬)아미노, 아미노, 비치환되거나 치환된 5원 내지 12원의 헤테로사이클이고
    (이때, 상기 치환된 알킬은 비치환되거나, 또는 C1-C6알킬, C2-C6 알케닐, C2-C6 알키닐, C6-C9 아릴, 벤질, 하이드록시-C1-C6 알킬 및 C3-C8 사이클로알킬로 이루어진 군으로부터 선택되는 1종 또는 2종의 치환기로 치환된 아미노; 또는 비치환되거나, 또는 C1-C4 알킬, C1-C4 알콕시카르보닐, 비치환되거나 C1-C4 알킬, C1-C4 알콕시, 할로겐 및 니트로로 이루어지는 군으로부터 선택되는 1종 또는 2종의 치환기로 치환된 C6-C9 아릴, 5원 내지 10원의 헤테로사이클 또는 헤테로아릴로 이루어진 군으로부터 선택되는 1종 또는 2종의 치환기로 치환된 5원 내지 12원의 헤테로사이클 또는 헤테로아릴로 치환될 수 있다);
    R 2는
    Figure PCTKR2020010999-appb-img-000091
    ,
    Figure PCTKR2020010999-appb-img-000092
    ,
    Figure PCTKR2020010999-appb-img-000093
    , 또는
    Figure PCTKR2020010999-appb-img-000094
    이고;
    R 3는 수소, 할로겐, 비치환되거나 치환된 C1-C6 알킬, 비치환되거나 치환된 C2-C6 알케닐, 비치환되거나 치환된 C3-C8 사이클로알킬, 비치환되거나 치환된 C1-C6 알콕시, 비치환되거나 치환된 5원 내지 9원 헤테로아릴, 비치환되거나 치환된 C6-C10 아릴, 비치환되거나 치환된 C6-C10 아릴옥시, 비치환되거나 치환된 5원- 내지 9원 헤테로사이클릴, 비치환되거나 치환된 5원- 내지 9원 헤테로사이클릴옥시, 니트로,
    Figure PCTKR2020010999-appb-img-000095
    ,
    Figure PCTKR2020010999-appb-img-000096
    및 -O-CH 2-C(O)-NH-R 5로 이루어진 군으로부터 선택되는 1종 이상이고;
    R 4는 수소; 할로겐; 비치환되거나 C1-C4 알콕시, 페녹시 또는 페닐(이때 페닐은 비치환되거나 할로겐으로 치환될 수 있음)로 치환된 C1-C6 알킬; C2-C6 알케닐; 아미노; 디(C1-C4알킬)아미노; 비치환되거나 할로겐, C1-C4 알콕시, 비치환되거나 1 이상의 할로겐으로 치환된 C1-C4 알킬, 니트로, C1-C4 알킬카르보닐옥시 및 -SO 2로 이루어진 군으로부터 선택되는 1종 이상으로 치환된 C6-C9 아릴; C3-C8 사이클로알킬; 5원 내지 9원의 헤테로사이클릴이고;
    R 5는 수소, 할로겐, 하이드록시, 비치환되거나 치환된 C1-C4 알킬, 니트로, C6-C10 아릴옥시로 이루어진 군으로부터 선택되는 1종 이상(1종 또는 2종)이고;
    n은 0 내지 2의 정수이다.
  2. 제1항에 있어서, 상기 화학식 1의 화합물에서,
    X는 C 또는 N이고;
    L은 C1 내지 C4의 알킬렌 또는 결합(bond)이고;
    R 1은 수소, F, Cl, Br, 비치환되거나 치환된 C1-C4 알킬, 메톡시, N(CH 3) 2, NH(CH 3), 아미노, 비치환되거나 치환된 5원 내지 12원의 헤테로사이클이고
    (이때, 상기 치환된 알킬은 비치환되거나, 또는 디메틸아미노, 디에틸아미노, 디프로필아미노, 디부틸아미노, 하이드록시에틸(에틸)아미노, 에틸(부틸)아미노, 디펜틸아미노, 메틸(에틴일)아미노, 에틸(페닐)아미노, 디알릴아미노, 메틸(벤질)아미노, 메틸(하이드록시에틸)아미노, 페닐(메틸)아미노, 에틸(페닐)아미노, 부틸(하이드록시에틸)아미노, 부틸(메틸)아미노, 디사이클로헥실아미노, 에톡시카르보닐-피페라진, t-부톡시카르보닐-피페라진, 플루오로페닐-피페리딘, 피리딘일-피페라진, 피리미딘일-피페라진, 하이드록시에틸피페라진, 메톡시페닐-피페라진, 나이트로페닐-피페라진, 디메틸모폴린, 모폴린, 메틸피페라진, 디하이드록시이소퀴놀린, 사이클로헥실(메틸)아미노, 이소프로필(메틸)아미노, 플루오로페닐-피페라진, 피페리딘일피페리딘으로 치환될 수 있다);
    R 2는
    Figure PCTKR2020010999-appb-img-000097
    ,
    Figure PCTKR2020010999-appb-img-000098
    ,
    Figure PCTKR2020010999-appb-img-000099
    , 또는
    Figure PCTKR2020010999-appb-img-000100
    이고;
    R 3는 수소, F, Cl, Br, 비치환되거나 치환된 C1-C4 알킬, 비치환되거나 치환된 C2-C4 알케닐, 비치환되거나 치환된 C3-C8 사이클로알킬, 비치환되거나 치환된 C1-C4 알콕시, 비치환되거나 치환된 5원 내지 9원 헤테로아릴, 비치환되거나 치환된 C6-C10 아릴, 비치환되거나 치환된 C6-C10 아릴옥시, 비치환되거나 치환된 5원- 내지 9원- 헤테로사이클릴, 비치환되거나 치환된 5원- 내지 9원 헤테로사이클릴옥시, 니트로,
    Figure PCTKR2020010999-appb-img-000101
    ,
    Figure PCTKR2020010999-appb-img-000102
    및 -O-CH 2-C(O)-NH-R 5로 이루어진 군으로부터 선택되는 1종 이상이고;
    R 4는 수소; F, Cl, Br; 비치환되거나 메톡시 에톡시, 페녹시 또는 페닐(이때 페닐은 비치환되거나 할로겐으로 치환될 수 있음)로 치환된 C1-C4 알킬; C2-C4 알케닐; 아미노; 디(C1-C4알킬)아미노; 비치환되거나 할로겐, C1-C3 알콕시, 비치환되거나 1 이상의 할로겐으로 치환된 C1-C4알킬, 니트로, C1-C3알킬카르보닐옥시 및 -SO 2로 이루어진 군으로부터 선택되는 1종 이상으로 치환된 C6-C9 아릴; C3-C8 사이클로알킬; 5원 내지 9원의 헤테로사이클릴이고;
    R 5는 수소, 할로겐, 하이드록시, 비치환되거나 치환된 C1-C4 알킬, 니트로, C6-C10 아릴옥시로 이루어진 군으로부터 선택되는 1종 이상(1종 또는 2종)이고;
    상기 R 3의 치환된 C1-C4 알킬, 치환된 C2-C4 알케닐, 치환된 C3-C8 사이클로알킬, 치환된 C1-C4 알콕시, 치환된 5원 내지 9원 헤테로아릴, 치환된 C6-C10 아릴, 치환된 C6-C10 아릴옥시, 치환된 5원- 내지 9원 헤테로사이클릴, 치환된 5원- 내지 9원 헤테로사이클릴옥시는 C1-C4 알콕시, C6-C9 아릴 및 C6-C9 아릴옥시로 이루어진 군으로부터 선택되는 1종 이상으로 치환될 수 있고, 더욱 바람직하게는 페닐, 메톡시 및 페녹시로 이루어진 군으로부터 선택되는 1종 이상으로 치환된 것이고,
    n은 0 내지 2의 정수이다.
  3. 제1항에 있어서, 하기 화합물 1 내지 305로 이루어진 군으로부터 선택되는 것인, 화합물 또는 이의 약학적으로 허용가능한 염:
    4-클로로-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a01)
    N-(2-옥소-2-페닐에틸)-2-페녹시프로판아마이드 (DKC1125a02)
    2-플루오로-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a03)
    4-플루오로-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a04)
    N-(2-옥소-2-페닐에틸)퓨란-2-카복사마이드 (DKC1125a05)
    2-클로로-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a06)
    3-클로로-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a07)
    (E)-N-(2-옥소-2-페닐에틸)부트-2-엔아마이드 (DKC1125a08)
    N-(2-옥소-2-페닐에틸)-3-페닐프로판아마이드 (DKC1125a09)
    N-(2-옥소-2-페닐에틸)아크릴아마이드 (DKC1125a10)
    2-메틸-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a11)
    4-메톡시-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a12)
    3-메틸-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a13)
    N-(2-옥소-2-페닐에틸)프로피온아마이드 (DKC1125a14)
    N-(2-옥소-2-페닐에틸)사이클로헥산카복사마이드 (DKC1125a15)
    N-(2-옥소-2-페닐에틸)사이클로프로판카복사마이드 (DKC1125a16)
    N-(2-옥소-2-페닐에틸)사이클로부탄카복사마이드 (DKC1125a17)
    N-(2-옥소-2-페닐에틸)싸이오펜-2-카복사마이드 (DKC1125a18)
    3,3i메틸-N-(2-옥소-2-페닐에틸)부탄아마이드 (DKC1125a19)
    N-(2-옥소-2-페닐에틸)펜탄아마이드 (DKC1125a20)
    3-니트로-N-(2-옥소-2-페닐에틸)벤젠설폰아마이드 (DKC1125a21)
    2,4-디플루오로-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a22)
    2-메톡시-N-(2-옥소-2-페닐에틸)아세트아마이드 (DKC1125a23)
    N-(2-옥소-2-페닐에틸)피발아마이드 (DKC1125a24)
    N-(2-옥소-2-페닐에틸)메탄설폰아마이드 (DKC1125a25)
    4-플루오로-N-(2-옥소-2-페닐에틸)벤젠설폰아마이드 (DKC1125a26)
    4-메틸-N-(2-옥소-2-페닐에틸)벤젠설폰아마이드 (DKC1125a27)
    N-(2-옥소-2-페닐에틸)-1-페닐메탄설폰아마이드 (DKC1125a28)
    N-(2-옥소-2-페닐에틸)-3,5-비스(트리플루오로메틸)벤즈아마이드 (DKC1125a29)
    N-(2-옥소-2-페닐에틸)-2-(트리플루오로메틸)벤즈아마이드 (DKC1125a30)
    N-(2-옥소-2-페닐에틸)-3-(트리플루오로메틸)벤즈아마이드 (DKC1125a31)
    N-(2-옥소-2-페닐에틸)-4-(트리플루오로메틸)벤즈아마이드 (DKC1125a32)
    2-클로로-4-플루오로-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a33)
    3-니트로-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a34)
    3,4-디플루오로-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a35)
    3,5-디클로로-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a36)
    2,3-디클로로-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a37)
    N-(2-옥소-2-페닐에틸)-4-(트리플루오로메톡시)벤즈아마이드 (DKC1125a38)
    N-(2-옥소-2-페닐에틸)-3-(트리플루오로메톡시)벤즈아마이드 (DKC1125a39)
    3,5-디메틸-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a40)
    N-(2-옥소-2-페닐에틸)-2-(트리플루오로메톡시)벤즈아마이드 (DKC1125a41)
    3,5-디메톡시-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125a42)
    N-(2-옥소-2-페닐에틸)-[1,1'-bi페닐]-4-카복사마이드 (DKC1125a43)
    N-(2-(4-클로로페닐)-2-옥소에틸)-2-플루오로벤즈아마이드 (DKC1125b01)
    N-(2-(4-클로로페닐)-2-옥소에틸)-4-플루오로벤즈아마이드 (DKC1125b02)
    N-(2-(4-클로로페닐)-2-옥소에틸)퓨란-2-카복사마이드 (DKC1125b03)
    3-클로로-N-(2-(4-클로로페닐)-2-옥소에틸)벤즈아마이드 (DKC1125b04)
    (E)-N-(2-(4-클로로페닐)-2-옥소에틸)부트-2-엔아마이드 (DKC1125b05)
    N-(2-(4-클로로페닐)-2-옥소에틸)-3-페닐프로판아마이드 (DKC1125b06)
    N-(2-(4-클로로페닐)-2-옥소에틸)아크릴아마이드 (DKC1125b07)
    N-(2-(4-클로로페닐)-2-옥소에틸)-2-메틸벤즈아마이드 (DKC1125b08)
    N-(2-(4-클로로페닐)-2-옥소에틸)-4-메톡시벤즈아마이드 (DKC1125b09)
    N-(2-(4-클로로페닐)-2-옥소에틸)-3-메틸벤즈아마이드 (DKC1125b10)
    N-(2-(4-클로로페닐)-2-옥소에틸)프로피온아마이드 (DKC1125b11)
    N-(2-(4-클로로페닐)-2-옥소에틸)사이클로헥산카복사마이드 (DKC1125b12)
    N-(2-(4-클로로페닐)-2-옥소에틸)사이클로프로판카복사마이드 (DKC1125b13)
    N-(2-(4-클로로페닐)-2-옥소에틸)사이클로부탄카복사마이드 (DKC1125b14)
    N-(2-(4-클로로페닐)-2-옥소에틸)싸이오펜-2-카복사마이드 (DKC1125b15)
    N-(2-(4-클로로페닐)-2-옥소에틸)-2-(메톡시메틸)벤즈아마이드 (DKC1125b16)
    N-(2-(4-클로로페닐)-2-옥소에틸)-3,3i메틸부탄아마이드 (DKC1125b17)
    N-(2-(4-클로로페닐)-2-옥소에틸)펜탄아마이드 (DKC1125b18)
    N-(2-(4-클로로페닐)-2-옥소에틸)-4-메톡시벤즈아마이드 (DKC1125b19)
    N-(2-(4-클로로페닐)-2-옥소에틸)-3-니트로벤젠설폰아마이드 (DKC1125b20)
    N-(2-(4-클로로페닐)-2-옥소에틸)-2,4-디플루오로벤즈아마이드 (DKC1125b21)
    N-(2-(4-클로로페닐)-2-옥소에틸)-2-메톡시아세트아마이드 (DKC1125b22)
    N-(2-(4-클로로페닐)-2-옥소에틸)피발아마이드 (DKC1125b23)
    N-(2-(4-클로로페닐)-2-옥소에틸)-4-플루오로벤젠설폰아마이드 (DKC1125b24) N-(2-(4-클로로페닐)-2-옥소에틸)-4-메틸벤젠설폰아마이드 (DKC1125b25)
    4-클로로-N-(2-(4-클로로페닐)-2-옥소에틸)벤젠설폰아마이드 (DKC1125b26) N-(2-(4-클로로페닐)-2-옥소에틸)-1-페닐메탄설폰아마이드 (DKC1125b27)
    N-(2-(4-클로로페닐)-2-옥소에틸)-4-메톡시벤젠설폰아마이드 (DKC1125b28)
    N-(2-(4-클로로페닐)-2-옥소에틸)-3,5-비스(트리플루오로메틸)벤즈아마이드 (DKC1125b29)
    N-(2-(4-클로로페닐)-2-옥소에틸)-2-(트리플루오로메틸)벤즈아마이드 (DKC1125b30)
    N-(2-(4-클로로페닐)-2-옥소에틸)-3-(트리플루오로메틸)벤즈아마이드 (DKC1125b31)
    N-(2-(4-클로로페닐)-2-옥소에틸)-4-(트리플루오로메틸)벤즈아마이드 (DKC1125b32)
    2-클로로-N-(2-(4-클로로페닐)-2-옥소에틸)-4-플루오로벤즈아마이드 (DKC1125b33)
    N-(2-(4-클로로페닐)-2-옥소에틸)-3-니트로벤즈아마이드 (DKC1125b34)
    N-(2-(4-클로로페닐)-2-옥소에틸)-3,4-디플루오로벤즈아마이드 (DKC1125b35) 3,5-디클로로-N-(2-(4-클로로페닐)-2-옥소에틸)벤즈아마이드 (DKC1125b36)
    2,3-디클로로-N-(2-(4-클로로페닐)-2-옥소에틸)벤즈아마이드 (DKC1125b37)
    N-(2-(4-클로로페닐)-2-옥소에틸)-4-(트리플루오로메톡시)벤즈아마이드 (DKC1125b38)
    N-(2-(4-클로로페닐)-2-옥소에틸)-3-(트리플루오로메톡시)벤즈아마이드 (DKC1125b39)
    N-(2-(4-클로로페닐)-2-옥소에틸)-3,5-디메틸벤즈아마이드 (DKC1125b40)
    N-(2-(4-클로로페닐)-2-옥소에틸)-2-(트리플루오로메톡시)벤즈아마이드 (DKC1125b41)
    N-(2-(4-클로로페닐)-2-옥소에틸)-3,5-디메톡시벤즈아마이드 (DKC1125b42)
    N-(2-(4-클로로페닐)-2-옥소에틸)-[1,1'-bi페닐]-4-카복사마이드 (DKC1125b43)
    4-클로로-N-(2-(4-클로로페닐)-2-옥소에틸)벤즈아마이드 (DKC1125b44)
    4-클로로-N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)벤즈아마이드 (DKC1125c01)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-2-페녹시프로판아마이드 (DKC1125c02)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-2-플루오로벤즈아마이드 (DKC1125c03)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-4-플루오로벤즈아마이드 (DKC1125c04)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)퓨란-2-카복사마이드 (DKC1125c05) 2-클로로-N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)벤즈아마이드 (DKC1125c06)
    3-클로로-N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)벤즈아마이드 (DKC1125c07)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)아크릴아마이드 (DKC1125c08)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-2-메틸벤즈아마이드 (DKC1125c09)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-4-메톡시벤즈아마이드 (DKC1125c10)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-3-메틸벤즈아마이드 (DKC1125c11)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)프로피온아마이드 (DKC1125c12)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)사이클로프로판카복사마이드 (DKC1125c13)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)싸이오펜-2-카복사마이드 (DKC1125c14)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-3,3i메틸부탄아마이드 (DKC1125c15)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)펜탄아마이드 (DKC1125c16)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-4-메톡시벤즈아마이드 (DKC1125c17)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-2,4-디플루오로벤즈아마이드 (DKC1125c18)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-2-메톡시아세트아마이드 (DKC1125c19)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-4-플루오로벤젠설폰아마이드 (DKC1125c20)
    4-클로로-N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)벤젠설폰아마이드 (DKC1125c21)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)벤젠설폰아마이드 (DKC1125c22)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-1-페닐메탄설폰아마이드 (DKC1125c23)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-4-메톡시벤젠설폰아마이드 (DKC1125c24)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-2-(트리플루오로메틸)벤즈아마이드 (DKC1125c25)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-3-(트리플루오로메틸)벤즈아마이드 (DKC1125c26)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-4-(트리플루오로메틸)벤즈아마이드 (DKC1125c27)
    2-클로로-N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-4-플루오로벤즈아마이드 (DKC1125c28)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-3,4-디플루오로벤즈아마이드 (DKC1125c29)
    3,5-디클로로-N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)벤즈아마이드 (DKC1125c30)
    2,3-디클로로-N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)벤즈아마이드 (DKC1125c31)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-4-(트리플루오로메톡시)벤즈아마이드 (DKC1125c32)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-3,5-디메틸벤즈아마이드 (DKC1125c33)
    N-(2-(4-(디메틸아미노)페닐)-2-옥소에틸)-3,5-디메톡시벤즈아마이드 (DKC1125c34)
    4-클로로-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125d01)
    (E)-N-(2-(3-메톡시페닐)-2-옥소에틸)부트-2-엔아마이드 (DKC1125d02)
    N-(2-(3-메톡시페닐)-2-옥소에틸)프로피온아마이드 (DKC1125d03)
    N-(2-(3-메톡시페닐)-2-옥소에틸)사이클로프로판카복사마이드 (DKC1125d04)
    N-(2-(3-메톡시페닐)-2-옥소에틸)사이클로부탄카복사마이드 (DKC1125d05)
    N-(2-(3-메톡시페닐)-2-옥소에틸)싸이오펜-2-카복사마이드 (DKC1125d06)
    N-(2-(3-메톡시페닐)-2-옥소에틸)펜탄아마이드 (DKC1125d07)
    N-(2-(3-메톡시페닐)-2-옥소에틸)벤젠설폰아마이드 (DKC1125d08)
    4-클로로-N-(2-옥소-2-(피리딘-3-일)에틸)벤즈아마이드 (DKC1125e01)
    N-(2-옥소-2-(피리딘-3-일)에틸)-2-페녹시프로판아마이드 (DKC1125e02)
    2-플루오로-N-(2-옥소-2-(피리딘-3-일)에틸)벤즈아마이드 (DKC1125e03)
    4-플루오로-N-(2-옥소-2-(피리딘-3-일)에틸)벤즈아마이드 (DKC1125e04)
    (E)-N-(2-옥소-2-(피리딘-3-일)에틸)부트-2-엔아마이드 (DKC1125e05)
    2-메틸-N-(2-옥소-2-(피리딘-3-일)에틸)벤즈아마이드 (DKC1125e06)
    N-(2-옥소-2-(피리딘-3-일)에틸)프로피온아마이드 (DKC1125e07)
    2-플루오로-N-(2-(4-모폴리노페닐)-2-옥소에틸)벤즈아마이드 (DKC1125f01)
    2-클로로-N-(2-(4-모폴리노페닐)-2-옥소에틸)벤즈아마이드 (DKC1125f02)
    (E)-N-(2-(4-모폴리노페닐)-2-옥소에틸)부트-2-엔아마이드 (DKC1125f03)
    4-메톡시-N-(2-(4-모폴리노페닐)-2-옥소에틸)벤즈아마이드 (DKC1125f04)
    3-메틸-N-(2-(4-모폴리노페닐)-2-옥소에틸)벤즈아마이드 (DKC1125f05)
    N-(2-(4-모폴리노페닐)-2-옥소에틸)프로피온아마이드 (DKC1125f06)
    N-(2-(4-모폴리노페닐)-2-옥소에틸)사이클로프로판카복사마이드 (DKC1125f07)
    N-(2-(4-모폴리노페닐)-2-옥소에틸)사이클로부탄카복사마이드 (DKC1125f08)
    N-(2-(4-모폴리노페닐)-2-옥소에틸)펜탄아마이드 (DKC1125f09)
    4-플루오로-N-(2-(4-모폴리노페닐)-2-옥소에틸)벤젠설폰아마이드 (DKC1125f10)
    4-클로로-N-(2-(4-모폴리노페닐)-2-옥소에틸)벤젠설폰아마이드 (DKC1125f11)
    N-(2-(4-모폴리노페닐)-2-옥소에틸)벤젠설폰아마이드 (DKC1125f12)
    N-(2-(4-모폴리노페닐)-2-옥소에틸)-1-페닐메탄설폰아마이드 (DKC1125f13)
    4-메톡시-N-(2-(4-모폴리노페닐)-2-옥소에틸)벤젠설폰아마이드 (DKC1125f14)
    2-((1-(4-클로로벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g01)
    N-(2-옥소-2-페닐에틸)-2-((1-(2-페녹시프로파노일)피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g02)
    2-((1-(2-플루오로벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g03)
    2-((1-(4-플루오로벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g04)
    2-((1-(퓨란-2-카르보닐)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g05)
    2-((1-(2-클로로벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g06)
    2-((1-(3-클로로벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g07)
    (E)-2-((1-(부트-2-enoyl)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g08)
    N-(2-옥소-2-페닐에틸)-2-((1-(3-페닐프로파노일)피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g09)
    2-((1-아크릴로일피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g10)
    2-((1-(2-메틸벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g11)
    2-((1-(2-메톡시벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g12)
    2-((1-(3-메틸벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g13)
    N-(2-옥소-2-페닐에틸)-2-((1-프로피오닐피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g14)
    2-((1-(사이클로헥산카르보닐)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g15)
    2-((1-(사이클로프로판카르보닐)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g16)
    2-((1-(사이클로부탄카르보닐)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g17)
    N-(2-옥소-2-페닐에틸)-2-((1-(싸이오펜-2-카르보닐)피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g18)
    2-((1-(2-(메톡시메틸)벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g19)
    2-((1-(3,3-di메틸butanoyl)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g20)
    2-((1-(모폴린-4-카르보닐)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g21)
    N-(2-옥소-2-페닐에틸)-2-((1-펜타노일피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g22)
    2-((1-(4-메톡시벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g23)
    2-((1-(4-시아노벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g24)
    2-((1-((3-(디옥소-l5-sulfanyl)페닐)설포닐)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g25)
    2-(4-(2-((2-옥소-2-페닐에틸)카바모일)페녹시)piperidine-1-카르보닐)페닐acetate (DKC112526g)
    2-((1-(2,4-디플루오로벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g27)
    2-((1-(2-메톡시아세틸)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g28)
    N-(2-옥소-2-페닐에틸)-2-((1-pivaloyl피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g29)
    N,N-di메틸-4-(2-((2-옥소-2-페닐에틸)카바모일)페녹시)piperidine-1-카복사마이드 (DKC1125g30)
    2-((1-(4-브로모벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g31)
    2-((1-아세틸피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g32)
    2-((1-(메틸설포닐)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g33)
    2-((1-((4-플루오로페닐)설포닐)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g34)
    N-(2-옥소-2-페닐에틸)-2-((1-토실피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g35)
    2-((1-((4-클로로페닐)설포닐)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g36)
    N-(2-옥소-2-페닐에틸)-2-((1-(페닐설포닐)피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g37)
    2-((1-(벤질설포닐)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g38)
    2-((1-((4-메톡시페닐)설포닐)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g39)
    2-((1-(3,5-비스(트리플루오로메틸)벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g40)
    N-(2-옥소-2-페닐에틸)-2-((1-(2-(트리플루오로메틸)벤조일)피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g41)
    N-(2-옥소-2-페닐에틸)-2-((1-(3-(트리플루오로메틸)벤조일)피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g42)
    N-(2-옥소-2-페닐에틸)-2-((1-(4-(트리플루오로메틸)벤조일)피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g43)
    2-((1-(2-클로로-4-플루오로벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g44)
    2-((1-(3-니트로벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g45)
    2-((1-(3,4-디플루오로벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g46)
    2-((1-(3,5-디클로로벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g47)
    2-((1-(2,3-디클로로벤조일)피페리딘-4-일)옥시)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125g48)
    N-(2-옥소-2-페닐에틸)-2-((1-(4-(트리플루오로메톡시)벤조일)피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g49)
    N-(2-옥소-2-페닐에틸)-2-((1-(3-(트리플루오로메톡시)벤조일)피페리딘-4-일)옥시)벤즈아마이드 (DKC1125g50)
    2-(2-옥소-2-(페닐아미노)에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h01)
    2-(2-옥소-2-(o-toyl아미노)에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h02)
    2-(2-(알릴아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h03)
    2-(2-(벤질아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h04)
    2-(2-((플루오로벤질)아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h05)
    2-(2-((2-메톡시-4-메틸페닐)아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h06)
    2-(2-((3-플루오로-4-메톡시페닐)아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h07)
    2-(2-옥소-2-(피리딘-3-일아미노)에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h08)
    2-(2-((3-메톡시페닐)아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h09)
    2-(2-옥소-2-((2-프로필페닐)아미노)에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h10)
    2-(2-((1-플루오로-3-니트로페닐)아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸벤즈아마이드 (DKC1125h11)
    2-(2-((벤조 [1, 3] 다이옥솔-5-일메틸)아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸벤즈아마이드 (DKC1125h12)
    2-(2-옥소-2-((4-프로필페닐)아미노)에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h13)
    2-(2-옥소-2-((3-페녹시페닐)아미노)에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h14)
    2-(2-((3,4-디메톡시벤질)아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h15)
    2-(2-((3,4-di메톡시페닐)아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h16)
    2-(2-(벤조[ d][1,3]다이옥솔-5-일아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h17)
    2-(2-((2, 3-디하이드로벤조[ b] [1, 4]다이옥신-6-일) 아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h18)
    2-(2-((2,3-디하이드로-1 H-인덴-5-일)아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h19)
    2-(2-((3-이소프로폭시페닐) 아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸) 벤즈아마이드 (DKC1125h20)
    2-(2-옥소-2-((4-페녹시페닐)아미노)에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h21)
    2-(2-((2-플루오로-5-(트리플루오로메틸) 페닐)아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h22)
    2-(2-((3-하이드록시페닐) 아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸) 벤즈아마이드 (DKC1125h23)
    2-(2-((2-클로로페닐) 아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸) 벤즈아마이드 (DKC1125h24)
    2-(2-((3-브로모페닐) 아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸) 벤즈아마이드 (DKC1125h25)
    2-(2-(이소프로필아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸) 벤즈아마이드 (DKC1125h26)
    2-(2-(3,4-디하이드로이소퀴놀린-2(1 H)-일)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125h27)
    2-(2-옥소-2-프로필아미노)에톡시)- N-(2-옥소-2-페닐에틸) 벤즈아마이드 (DKC1125h28)
    2-(2-(이소펜틸아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸) 벤즈아마이드 (DKC1125h29)
    2-(2-(시클로헥실아미노)-2-옥소에톡시)- N-(2-옥소-2-페닐에틸) 벤즈아마이드 (DKC1125h30)
    3-((디메틸아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i01)
    3-((3,4-디하이드로이소퀴놀린-2(1H)-일)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i02)
    3-((이소프로필(메틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i03)
    3-((4-(2-플루오로페닐)피페라진-1-일)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i04)
    N-(2-옥소-2-페닐에틸)-3-((4-(피리미딘-2-일)피페라진-1-일)메틸)벤즈아마이드 (DKC1125i05)
    3-((4-(2-메톡시페닐)피페라진-1-일)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i06)
    3-([1,4'-바이피페리딘]-1'-일메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i07)
    3-((4-(4-니트로페닐)피페라진-1-일)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i08)
    3-((에틸(페닐)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i09)
    N-(2-옥소-2-페닐에틸)-3-((4-(피리딘-2-일)피페라진-1-일)메틸)벤즈아마이드 (DKC1125i10)
    3-((디알릴아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i11)
    3-((벤질(메틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i12)
    3-(((2-하이드록시에틸)(메틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i13)
    3-((부틸(2-하이드록시에틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i14)
    터트-부틸 4-(3-((2-옥소-2-페닐에틸)카바모일)벤질)피페라진-1-카르복실레이트 (DKC1125i15)
    3-((부틸(메틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i16)
    3-((디에틸아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i17)
    3-((디프로필아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i18)
    3-((부틸(에틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i19)
    3-((디펜틸아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i20)
    3-((에티닐(메틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i21)
    3-(모폴리노메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i22)
    3-((4-메틸피페라진-1-일)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i23)
    4-((3,4-디하이드로이소퀴놀린-2(1H)-일)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i24)
    4-((시클로헥실(메틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i25)
    4-((이소프로필(메틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i26)
    4-((4-(2-플루오로페닐)피페라진-1-일)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i27)
    N-(2-옥소-2-페닐에틸)-4-((4-(피리미딘-2-일)피페라진-1-일)메틸)벤즈아마이드 (DKC1125i28)
    4-((4-(2-메톡시페닐)피페라진-1-일)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i29)
    4-([1,4'-바이피페리딘]-1'-일메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i30)
    4-((4-(4-니트로페닐)피페라진-1-일)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i31)
    4-((메틸(페닐)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i32)
    4-((에틸(페닐)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i33)
    N-(2-옥소-2-페닐에틸)-4-((4-(피리딘-2-일)피페라진-1-일)메틸)벤즈아마이드 (DKC1125i34)
    4-((디알릴아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i35)
    4-((벤질(메틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i36)
    4-(((2-하이드록시에틸)(메틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i37)
    4-((부틸(2-하이드록시에틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i38)
    터트-부틸 4-(4-((2-옥소-2-페닐에틸)카바모일)벤질)피페라진-1-카르복실레이트 (DKC1125i39)
    4-((디시클로헥실아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i40)
    4-((부틸(메틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i41)
    4-((디프로필아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i42)
    4-((부틸(에틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i43)
    4-((에틸(2-하이드록시에틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i44)
    4-((에티닐(메틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i45)
    4-(모폴리노메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i46)
    에틸 4-(4-((2-옥소-2-페닐에틸)카바모일)벤질)피페라진-1-카르복실레이트 (DKC1125i47)
    4-((2,6-di메틸모폴리노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i48)
    3-((3,4-디하이드로이소퀴놀린-2(1H)-일)메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i49)
    3-((시클로헥실(메틸)아미노)메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i50)
    3-((1-(2-플루오로페닐)피페리딘-4-일)메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i51)
    N-(2-(3-메톡시페닐)-2-옥소에틸)-3-((4-(2-메톡시페닐)피페라진-1-일)메틸)벤즈아마이드 (DKC1125i52)
    3-([1,4'-바이피페리딘]-1'-일메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i53)
    N-(2-(3-메톡시페닐)-2-옥소에틸)-3-((4-(피리딘-2-일)피페라진-1-일)메틸)벤즈아마이드 (DKC1125i54)
    3-((디알릴아미노)메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i55)
    3-((벤질(메틸)아미노)메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i56)
    3-((에틸(메틸)아미노)메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i57)
    3-((부틸(2-하이드록시에틸)아미노)메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i58)
    터트-부틸 4-(3-((2-(3-메톡시페닐)-2-옥소에틸)카바모일)벤질)피페라진-1-카르복실레이트 (DKC1125i59)
    3-((부틸(에틸)아미노)메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i60)
    3-((디펜틸아미노)메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i61)
    3-((4-(2-하이드록시에틸)피페라진-1-일)메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i62)
    N-(2-(3-메톡시페닐)-2-옥소에틸)-3-(모폴리노메틸)벤즈아마이드 (DKC1125i63)
    3-((에틸(프로필)아미노)메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i64)
    3-((2,6-di메틸모폴리노)메틸)-N-(2-(3-메톡시페닐)-2-옥소에틸)벤즈아마이드 (DKC1125i65)
    2-((디메틸아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i66)
    2-((3,4-dihydroquinolin-1(2H)-일)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i67)
    2-((시클로헥실(메틸)아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i68)
    2-((4-(2-플루오로페닐)피페라진-1-일)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i69)
    N-(2-옥소-2-페닐에틸)-2-((4-(피리미딘-2-일)피페라진-1-일)메틸)벤즈아마이드 (DKC1125i70)
    2-([1,4'-바이피페리딘]-1'-일메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i71)
    N-(2-옥소-2-페닐에틸)-2-((4-(피리딘-2-일)피페라진-1-일)메틸)벤즈아마이드 (DKC1125i72)
    2-((디알릴아미노)메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i73) 2-(모폴리노메틸)-N-(2-옥소-2-페닐에틸)벤즈아마이드 (DKC1125i74) 및
    에틸 4-(2-((2-옥소-2-페닐에틸)카바모일)벤질)피페라진-1-카르복실레이트 (DKC1125i75).
  4. 제1항 내지 제3항 중 어느 한 항의 화합물을 포함하는, 암의 전이 및 침윤 억제용 조성물.
  5. 제4항에 있어서, 상기 암은 대장암, 후두암, 폐암, 전립선암, 유방암, 위암 및 간세포함으로 이루어진 군으로부터 선택되는 것인, 조성물.
  6. 제1항 내지 제3항 중 어느 한 항의 화합물을 포함하는 암 치료용 조성물.
  7. 제6항에 있어서, 상기 암은 대장암, 후두암, 폐암, 전립선암, 유방암, 위암 및 간세포함으로 이루어진 군으로부터 선택되는 것인, 조성물.
PCT/KR2020/010999 2019-08-19 2020-08-18 신규한 암전이 억제 활성을 갖는 화합물, 이의 제조방법 및 상기 화합물을 포함하는 암 전이 및 침윤 억제, 또는 대장암 치료용 약학적 조성물 WO2021034087A1 (ko)

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US17/634,361 US20230150924A1 (en) 2019-08-19 2020-08-18 Novel compound having cancer metastasis inhibitory activity, preparation method therefor, and pharmaceutical composition for inhibiting cancer metastasis and invasion or treating colorectal cancer, comprising compound

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