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WO2017018751A1 - Novel compound having blt inhibitory activity and composition, for preventing or treating inflammatory diseases, comprising same as active ingredient - Google Patents

Novel compound having blt inhibitory activity and composition, for preventing or treating inflammatory diseases, comprising same as active ingredient Download PDF

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Publication number
WO2017018751A1
WO2017018751A1 PCT/KR2016/008070 KR2016008070W WO2017018751A1 WO 2017018751 A1 WO2017018751 A1 WO 2017018751A1 KR 2016008070 W KR2016008070 W KR 2016008070W WO 2017018751 A1 WO2017018751 A1 WO 2017018751A1
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Prior art keywords
methyl
biphenyl
fluorophenyl
equiv
yloxy
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PCT/KR2016/008070
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French (fr)
Korean (ko)
Inventor
최용석
김재홍
이경
한효경
위준동
권진선
구자일
Original Assignee
동국대학교 산학협력단
고려대학교 산학협력단
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Priority claimed from KR1020160093760A external-priority patent/KR101796390B1/en
Application filed by 동국대학교 산학협력단, 고려대학교 산학협력단 filed Critical 동국대학교 산학협력단
Priority to JP2018503552A priority Critical patent/JP6814794B2/en
Priority to CN201680055552.XA priority patent/CN108349875B/en
Priority to US15/745,348 priority patent/US10494333B2/en
Priority to EP16830784.1A priority patent/EP3327001B1/en
Publication of WO2017018751A1 publication Critical patent/WO2017018751A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings

Definitions

  • the present invention relates to a novel compound and its use, and more particularly, to a novel compound exhibiting inhibitory activity of Leukotriene B4 receptor 2 (BLT2) and a pharmaceutical composition for preventing or treating inflammatory diseases comprising the same as an active ingredient.
  • BLT2 Leukotriene B4 receptor 2
  • Inflammatory reactions are one of the body's immune systems that are activated through various mechanisms of action to protect against physical or chemical agents, bacterial infections, and immunological stimuli. However, if such an inflammatory response persists, it promotes mucosal damage, thereby causing inflammatory diseases such as rheumatoid arthritis, arteriosclerosis, gastritis, and asthma due to redness, fever, swelling, pain, and dysfunction. have. These inflammatory reactions are classified into acute and chronic inflammations over time, and acute inflammations can cause symptoms such as erythema, fever, pain, and edema, while inflammatory reactions last several days to several weeks. Is a prolonged inflammatory state, sometimes over several years to decades, and is accompanied by histological changes such as invasion of monocytes, proliferation of fibroblasts and capillaries, fibrosis due to increased connective tissue, and tissue destruction. .
  • pro-inflammatory cytokines pro-inflammatory cytokines
  • interferon-gamma INF- ⁇
  • tumor necrosis factor- ⁇ TNF- ⁇
  • interleukin-1 interleukin-1, IL-1
  • interleukin during inflammatory processes in the body INF- ⁇
  • cytokines such as -6 (interleukin-6, IL-6), nitric oxide (NO) and prostaglandin E2 (PGE2)
  • cytokines such as -6 (interleukin-6, IL-6), nitric oxide (NO) and prostaglandin E2 (PGE2) are well known as major inflammatory agents.
  • leukotriene B4 is a group of inflammatory lipid mediators synthesized from arachidonic acid (AA) by the 5-lipoxygenase pathway that mediates acute and chronic inflammation.
  • LTB 4 is known to have a biological effect by binding to two types of receptors, BLT1 and BLT2.
  • Leukotriene B4 receptor 2 (BLT2) is a group of G protein-coupled receptors (GPCRs) that has low affinity for LTB 4 and is a lipid mediator of arachidonic acid (AA) induced through a 5-lipoxygenase dependent pathway. to be.
  • the present inventors while continuing to research to develop a substance that induces more effective termination of inflammation, in order to solve the conventional problems as described above, has produced a novel compound showing a BLT2 inhibitory activity, including the compound It was the first to develop an inflammatory disease treatment.
  • the present invention has been made to solve the above problems, the present inventors have confirmed the therapeutic effect of the inflammatory disease of the novel compound showing the BLT2 inhibitory activity and completed the present invention based on this.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory diseases, comprising the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a novel compound or a pharmaceutically acceptable salt thereof exhibiting BLT2 inhibitory activity.
  • the compound is N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentaneamide; N- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; N- (3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentaneamide; N- (4 '-(( N- 3-fluorophenyl) pentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; 1- (3-fluorophenyl) -1-((4'-methoxybiphenyl-4-yl) methyl) -3- (3- (
  • the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease, comprising the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the inflammatory disease may be selected from the group consisting of asthma, atherosclerosis, cancer, itching of the skin, rheumatoid arthritis and inflammatory bowel disease.
  • the composition may inhibit Leukotriene B4 receptor 2 (BLT2) activity.
  • BLT2 Leukotriene B4 receptor 2
  • It provides a method of treating an inflammatory disease comprising administering the pharmaceutical composition to a subject.
  • the present invention provides a therapeutic use of an inflammatory disease of a composition comprising the novel compound or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a novel compound that exhibits Leukotriene B4 receptor 2 (BLT2) inhibitory activity and a pharmaceutical composition for preventing or treating an inflammatory disease comprising the same.
  • BLT2 Leukotriene B4 receptor 2
  • the present inventors have identified a novel compound that exhibits BTL2 inhibitory activity in order to solve in vivo instability and difficulty in mass production, which are problems of conventional inflammatory disease treatment substances, and has excellent cancer cell death enhancement and metastasis suppression effect and chemotaxis inhibition of the compound.
  • the effects and anti-asthma effects have been confirmed experimentally, it is expected to be useful as a pharmaceutical composition for treating inflammatory diseases.
  • 1A to 1D show the results of confirming the growth inhibitory effect of the compound of the present invention in cells expressing BLT2 (CHO-BLT2).
  • Figure 2a to 2c is a result of confirming whether cancer cell death enhanced by the treatment of the compound of the present invention and the anti-cancer drug cisplatin complex in ovarian cancer cells (SKOV-3 cells) showing anticancer drug resistance.
  • 3A to 3D show results of confirming chemotaxis inhibitory effect and IC50 (50% inhibitory concentration) of cells by treatment with a compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells).
  • 4A and 4B show the results of confirming the chemotaxis inhibitory effect of cells treated with the compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells) or cells expressing BLT1 (CHO-BLT1).
  • Figure 7 is a result of confirming the effect of reducing airway hypersensitivity by the compound treatment of the present invention in mice with severe asthma induced.
  • the present inventors based on the fact that the treatment of the novel compound prepared in the example can significantly inhibit the growth of BLT2 expressing cells, enhance the cancer cell death of the compound, inhibit cancer cell metastasis, inhibit BLT2-dependent chemotaxis, and The anti-asthma effect and the like have been specifically confirmed, and the present invention has been completed based on this.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1 -C 10 alkyl, or ego,
  • R 2 is hydrogen, , , or ego,
  • R 3 is hydrogen, , , or ego,
  • R 4 is hydrogen, , , , or ego,
  • R a is hydrogen, C 1 -C 10 alkyl, C 1 -C 5 carboxyl,
  • R 5 , R 6 , and R 7 are each independently hydrogen, halogen, nitro, methyl, trifluoromethyl or methoxy,
  • R 1 is butyl and R 2 is When R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen;
  • R 1 is butyl
  • R 3 is When R 2 , R 4 , R 5 , R 6 , and R 7 are hydrogen
  • R 1 is butyl
  • R 4 is , R 2 , R 3 , R 5 , R 6 , and R 7 are hydrogen
  • R 1 is butyl
  • R 4 is , R 2 , R 3 , R 5 , R 6 , and R 7 are hydrogen
  • R 1 is butyl
  • R 4 is When R 6 is fluorine, R 2 , R 3 , R 5 , and R 7 are hydrogen;
  • R 1 is pentyl
  • R 4 is When R 6 is fluorine
  • R 2 , R 3 , R 5 , and R 7 are hydrogen
  • R 1 is pentyl
  • R 4 is , Except that R 6 is fluorine, R 2 , R 3 , R 5 , and R 7 are hydrogen.
  • Preferred examples of the compound represented by Formula 1 according to the present invention are as follows:
  • the term "pharmaceutically acceptable” is suitable for use in contact with the tissue of a subject (eg, a human being) because the benefit / risk ratio is reasonable without excessive toxicity, irritation, allergic reactions or other problems or complications.
  • a compound or composition is within the scope of sound medical judgment.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
  • the acid addition salts according to the present invention can be dissolved in conventional methods, for example, by dissolving a compound represented by the formula (1) in an excess of an aqueous solution of an acid, which salt is a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation using. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
  • a novel compound exhibiting BLT2 inhibitory activity was prepared a novel compound exhibiting BLT2 inhibitory activity (see Examples 1 to 57), and confirmed the growth inhibition of BLT2 expressing cells by the novel compound treatment (see Experimental Example 2).
  • cancer cell death may be enhanced by complex treatment with cisplatin, an anticancer agent, and that chemotaxis of BLT2 expressing cells may be inhibited (see Experimental Examples 3 to 4), and LTB4 and BLT2 binding inhibition using the compound of the present invention.
  • the effect was confirmed (see Experimental Example 5), and in asthma-induced mice, the effect of reducing airway hypersensitivity and the inhibition of IL-4 production was specifically identified (see Experimental Example 6). Confirmed that it can.
  • the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • prevention means any action that inhibits or delays the development of an inflammatory disease by administration of a pharmaceutical composition according to the present invention.
  • treatment means any action that improves or advantageously alters the symptoms of an inflammatory disease by administration of a pharmaceutical composition according to the present invention.
  • the inflammatory disease is due to overexpression of Leukotriene B4 receptor 2 (BLT2), and may be at least one selected from asthma, atherosclerosis, cancer, skin itch, rheumatoid arthritis and inflammatory bowel disease, but is limited thereto. It is not.
  • BLT2 Leukotriene B4 receptor 2
  • all BLT2-associated inflammatory diseases known in the art are considered to be included in inflammatory diseases that can be prevented or treated with a compound having the structure of Formula 1 of the present invention.
  • the cancer may be any cancer caused by overexpression of BLT2 or the oncogene Ras.
  • the cancer may be selected from the group consisting of bladder cancer, prostate cancer, pancreatic cancer, breast cancer, brain tumor, skin cancer, and liver cancer, but is not limited thereto.
  • BLT2 Leukotriene B4 receptor 2 is one of the group of G protein-coupled receptors (GPCR), which has a low affinity for LTB 4 ( Leukotriene B4; LTB 4 ), and the composition of the present invention is a cell growth by By inhibiting the inflammatory disease can be prevented or treated. More specifically, the inhibition of the production of ROS induced by BLT2 activity may inhibit LTB 4 -induced chemotaxis.
  • GPCR G protein-coupled receptors
  • the term “inhibition” means inhibiting any step of transcription, mRNA processing, translation, translocation, and maturation of a gene, or inhibition of protein-to-protein binding, activation of a protein, or signaling through it. .
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient.
  • the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
  • it may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
  • compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level refers to the type of disease, the severity, the activity of the drug, It may be determined according to the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently and other factors well known in the medical field.
  • the pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general 0.001 to 150 mg, preferably 0.01 to 100 mg, per kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day.
  • the dose may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention by any method.
  • the present invention also provides a method of treating an inflammatory disease comprising administering the pharmaceutical composition to a subject.
  • subject means a subject in need of treatment for a disease, and more specifically, a mammal, such as a primate, mouse, dog, cat, horse and cow, which is human or non-human. .
  • reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain 3'-nitrobiphenyl.
  • EA ethyl acetate
  • MgSO 4 Medium Pressure Liquid Chromatography
  • Step 2 N -((3'- Nitrobiphenyl -4- days) methyl Aniline ( N -((3'- nitrobiphenyl -4- yl Manufacture of methyl) aniline)
  • 3'-nitrobiphenyl-4-carbaldehyde (1.0 equiv) and aniline (Aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
  • Step 3 N -((3'- Nitrobiphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((3'- nitrobiphenyl -4-yl) methyl)- N -phenylpentanamide)
  • N -((3'-nitrobiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then on ice Cooled. Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • DCM dichloromethane
  • TAA triethanolamine
  • Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium s
  • Step 4 N -((3'- Aminobiphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((3'- aminobiphenyl -4-yl) methyl)- N -phenylpentanamide)
  • N -((3'-nitrobiphenyl-4-yl) methyl) -N-phenylpentanamide (1.0 equiv) obtained in step 3 above was mixed well with RBF, and methanol was added thereto. After cooling the RBF, 10% Pd / C (20 wt%) was added and the mixed solution was stirred overnight at room temperature, H 2 feed conditions. After the reaction was completed, the resultant was filtered through a pad of silica, and then concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((3'-aminobiphenyl-4-yl) methyl) -N-phenylpentaneamide (N-((3'-aminobiphenyl-4-yl) methyl) -N-phenylpentanamide) was obtained (92% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • Step 5 N -((3 '-(4- Methylphenylsulfonamido ) Biphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl)- N -phenylpentanamide)
  • N -((3'-aminobiphenyl-4-yl) methyl) -N -phenylpentaneamide (1.0 equiv) and Triethylamine (2.0 equiv) obtained in step 4 were added to a dichloromethane (DCM) solution. After thawing, it was cooled on ice. Thereafter, 4-methoxybenzene sulfonyl chloride (1.5 equiv) was added, followed by stirring overnight at room temperature. After the reaction was completed, DCM was concentrated by evaporation.
  • DCM dichloromethane
  • the concentrate was purified by column chromatography to give the final product, N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentanamide ( N -((3'- (4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N- phenylpentanamide) was obtained (25% yield).
  • Step 1 (3- Fluoro -((3'- Nitrobiphenyl -4- days) methyl Aniline (3- fluoro - N -((3'- nitrobiphenyl Preparation of -4-yl) methyl) aniline)
  • Step 2 ( N -(3- Fluorophenyl )- N -((3'- Nitrobiphenyl -4- days) methyl ) Pentaneamide ( N -(3-fluorophenyl)- N Preparation of-((3'-nitrobiphenyl-4-yl) methyl) pentanamide)
  • step 1 (3-fluoro-((3'-nitrobiphenyl-4-yl) methyl) aniline obtained in step 1 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. After the reaction was completed, valeroyl chloride (3.0 equiv) was added, followed by stirring at room temperature for 4 hours, after completion of the reaction, RBF was added thereto, and the organic solvent layer was added thereto. After washing with brine and separating, the organic solvent layers were combined, the water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered and evaporated to concentrate the concentrated solution by Medium Pressure Liquid Chromatography (MPLC).
  • MgSO 4 anhydrous magnesium sulfate
  • Step 3 N -((3'- Aminobiphenyl -4- days) methyl )- N -(3- Fluorophenyl ) Pentaneamide ( N -((3'-aminobiphenyl-4-yl) methyl)- N Preparation of-(3-fluorophenyl) pentanamide)
  • N- (3-fluorophenyl) -N -((3'-nitrobiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in step 2 was mixed well with RBF, and methanol After cooling the RBF, 10% Pd / C (20wt%) was added and the mixed solution was stirred overnight at room temperature, H 2 feed conditions, after completion of the reaction, filtered through a pad of silica ., and then concentrated by evaporation the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) N - ((3'- amino-biphenyl-4-yl) methyl) - N - pentane amide (3-fluorophenyl) (N - ((3'-aminobiphenyl-4 -yl) methyl) - N - (3-fluorophenyl) pentanamide a) was obtained (89% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • Step 4 N -(3- Fluorophenyl )- N -((3 '-(4- Methylphenylsulfonamido ) Biphenyl -4- days) methyl ) Pentaneamide ( N -(3-fluorophenyl)- N Preparation of-((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentanamide)
  • the concentrate was purified by column chromatography to obtain the final product, N- (3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentaneamide ( N -(3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentanamide) was obtained (25% yield).
  • N obtained in Step 3 in Example 3 - ((3'-amino-biphenyl-4-yl) methyl) - N - pentane amide, methyl -p- toluic acid trifluoroacetate (3-fluorophenyl) ( Trifluromethyl-p-toluic acid (1.2 equiv), EDC (1.2 equiv), HOBt (1.2 equiv), and N , N -diisopropylethylamine (DIPEA) (1.2 equiv) in dichloromethane, DCM After dissolving in solution, it was stirred overnight at room temperature. After the reaction was completed, water was added.
  • DIPEA N -diisopropylethylamine
  • step 2 3 - Fluoro - N -((4'- Methoxybiphenyl -4- days) methyl Aniline (3- fluoro - N -((4'- methoxybiphenyl Preparation of -4-yl) methyl) aniline)
  • step 1 4-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and 3-fluoroaniline (3-fluroaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. . The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
  • TLC thin layer chromatography
  • step 3 1 -(3- Fluorophenyl ) -1-((4'- Methoxybiphenyl -4- days) methyl ) -3- (3- ( Trifluoromethyl ) Phenyl) Urea (1- (3- fluorophenyl ) -1-((4'- methoxybiphenyl -4- yl ) methyl) -3- (3- ( trifluoromethyl Preparation of) phenyl) urea)
  • 3-fluoro- N -((4-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in tetrahydrofuran (THF) solution, and then trifluoromethylphenyl isocyanate (trifluromethylphenyl isocyanate) (1.0 equiv) was added, the mixed solution was stirred overnight, and after completion of the reaction, silica was added to adsorb RBF and the crude product, which was purified by Medium Pressure Liquid Chromatography (MPLC).
  • MPLC Medium Pressure Liquid Chromatography
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final product N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4- Methoxyphenylsulfonyl) methaneamide ( N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methanamide) was obtained (61% yield). .
  • MPLC Medium Pressure Liquid Chromatography
  • Example 7 1- (3- Fluorophenyl ) -1-((4'- Hydroxybiphenyl -4- days) methyl ) -3- (3- ( Trifluoromethyl ) Phenyl) urea (1- (3- fluorophenyl ) -1-((4'- hydroxybiphenyl -4- yl Preparation of) methyl) -3- (3- (trifluoromethyl) phenyl) urea) (AC-1318)
  • Step 1 ethyl-2- (4 '-((1- (3- Fluorophenyl ) -3- (3- ( Trifluoromethyl ) Phenyl) Eureido ) methyl ) Biphenyl 4-yloxy) acetate (Ethyl-2- (4 '-((1- (3- fluorophenyl ) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetate)
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl-2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl ) Biphenyl-4-yloxy) acetate (Ethyl-2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetate ) (96% yield).
  • step 2 2 -(4 '-((1- (3- Fluorophenyl ) -3- (3- ( Trifluoromethyl ) Phenyl) Eureido ) methyl ) Biphenyl -4- Iloxy Acetic acid (2- (4 '-((1- (3- fluorophenyl ) -3- (3- ( trifluoromethyl ) phenyl) ureido ) methyl) biphenyl-4-yloxy) acetic acid)
  • Step 1 N -(3- Fluorophenyl )- N -((4'- Methoxybiphenyl -4- days) methyl ) Pentaneamide ( N -(3-fluorophenyl)- N Preparation of-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide ( N- (3-fluorophenyl ) -N -((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (100% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • Step 2 N -(3- Fluorophenyl )- N -((4'- Hydroxybiphenyl -4- days) methyl ) Pentaneamide ( N -(3-fluorophenyl)- N Preparation of-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide)
  • N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in step 1 was diluted with dichloromethane (DCM). After melting in, cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
  • DCM dichloromethane
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide ( N- (3-fluorophenyl ) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) was obtained (85% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • Step 3 ethyl 4- (4 '-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy ) Butanoate (Ethyl 4- (4 '-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoate)
  • N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in step 2 were prepared. It was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. Ethyl 4-chlorobutanoate (3.0 equiv) was added and the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoate (Ethyl 4- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoate) was obtained (92% yield).
  • step 4 4 -(4'-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Butanoic acid (4- (4 '-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoic acid)
  • Ethyl 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoate obtained in step 3 (Ethyl 4- (4'-( ( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoate) was mixed well with tetrahydrofuran (THF) solution, LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • THF tetrahydrofuran
  • step 3 of Example 9 using ethyl 2-chloro-2-methylpropanoate (3.0 equiv) instead of ethyl 4-chlorobutanoate (Ethyl 4-chlorobutanoate) Ethyl 4- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoate (Ethyl 4- (4'-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl -4-yloxy) butanoate) was obtained (yield 92%), and the final product 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) in the same manner as in step 4 of Example 9 Methyl) biphenyl-4-yloxy) -2-methylpropanoic acid 2- (4 '-(( N- (3-fluorophenyl) pentanamido)
  • step 3 of Example 9 using methyl (2E) -3-chloroacrylate (3.0 equiv) instead of ethyl 4-chlorobutanoate (E) -methyl 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylate ((E) -methyl 3- (4'- (( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acrylate) was prepared (yield 100%), and the final product (E) -3- ( 4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylic acid ((E) -3- (4'-(( N- (3-fluorophenyl) pentanamido ) methyl) biphenyl-4-yloxy) acrylic acid) was obtained (29% yield).
  • step 3 of Example 9 using methyl 3-chloroacetate (3.0 equiv) instead of ethyl 4-chlorobutanoate, methyl 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) propanoate (Methyl 3- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4 -yloxy) propanoate) (yield 26.2%), and the final product 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) in the same manner as in step 4 of Example 9
  • Biphenyl-4-yloxy) propanoic acid (3- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) propanoic acid) was obtained (45% yield).
  • Step 1 methyl 2- (4 '-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Acetate (Methyl 2- (4 '-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
  • N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide and K 2 CO 3 (3.0 equiv) obtained in step 2 of Example 9 were prepared. It was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. Methyl bromoacetate (3.0 equiv) was added and the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to prepare methyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (Methyl 2- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained.
  • step 2 2 -(4'-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Acetic acid (2- (4 '-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
  • Methyl 2- (4 ′-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate obtained in step 1 above was added to a tetrahydrofuran (THF) solution. After mixing well, LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • THF tetrahydrofuran
  • Step 3 N -(3- Fluorophenyl ) -N -((4 '-(2- (4- Methylpiperazine -1-yl) -2- Oxoethoxy ) Biphenyl -4- days) methyl Pentaneamide ( N -(3- fluorophenyl )- N -((4 '-(2- (4- methylpiperazin -One- yl )-2- oxoethoxy ) biphenyl-4-yl) methyl) pentanamide)
  • N- (3-fluorophenyl)- The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield N- (3-fluorophenyl)-, the final product.
  • MPLC Medium Pressure Liquid Chromatography
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final product, Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4- Iloxy) acetate (Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (61.3% yield).
  • N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide and K 2 CO 3 (3.0 equiv) obtained in step 2 of Example 9 were prepared. It was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. After adding methyl propiolate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N -((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl as the final product.
  • MPLC Medium Pressure Liquid Chromatography
  • Step 1 methyl 4 '-((2- Fluorophenylamino ) methyl ) Biphenyl -2- Carboxylate Preparation of (Methyl 4 '-((2-fluorophenylamino) methyl) biphenyl-2-carboxylate)
  • Methyl 4'-formylbiphenyl-4-carboxylate (1.0 equiv) and 2-fluoroaniline (3.0 equiv) were dissolved in methanol, and then at room temperature. Stirred for 4 h. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
  • Step 2 methyl 4'-(( N -(2- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Carboxylate (Methyl 4 '-(( N -(1-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate)
  • Methyl 4 '-((2-fluorophenylamino) methyl) biphenyl-4-carboxylate obtained in step 1 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. , Cooled on ice. Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • DCM dichloromethane
  • TAA triethanolamine
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4 '-(( N- (2-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylate (Methyl 4'-(( N- (1-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate) was obtained (95% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • step 3 4 '-(( N -(2- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Carboxylic acid (4'-(( N Preparation of-(2-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid)
  • step 2 4 '-(( N- (2-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylate (1.0 equiv) obtained in step 2 was mixed well with tetrahydrofuran (THF) , LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • THF tetrahydrofuran
  • EA ethyl acetate
  • Methyl 4'-formylbiphenyl-3-carboxylate instead of methyl 4'-formylbiphenyl-4-carboxylate, 2-methoxyaniline instead of 2-fluoroaniline (2 4 '-((2-methoxyphenylamino) methyl) biphenyl-3-carboxylate (Methyl 4'-((2-Methoxyphenylamino) methyl) in the same manner as in Step 1 of Example 16 using -Methoxyaniline ) biphenyl-3-carboxylate) and methyl 4 '-(( N- (2-methoxyphenyl) pentaneamido) methyl) biphenyl-3- in the same manner as in steps 2 and 3 of Example 16 Carboxylate (Methyl 4 '-(( N- (2-Methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylate) was prepared, resulting in 4'-(( N- (2-
  • Methyl 4'-formylbiphenyl-3-carboxylate instead of methyl 4'-formylbiphenyl-4-carboxylate, 3-methoxyaniline instead of 2-fluoroaniline (3 4 '-((3-methoxyphenylamino) methyl) biphenyl-3-carboxylate (Methyl 4'-((3-Methoxyphenylamino) methyl) in the same manner as in Step 1 of Example 16 using -Methoxyaniline ) biphenyl-3-carboxylate) and methyl 4 '-(( N- (3-methoxyphenyl) pentaneamido) methyl) biphenyl-3- in the same manner as in steps 2 and 3 of Example 16.
  • Carboxylate (Methyl 4 '-(( N- (3-Methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylate) was prepared, resulting in 4'-(( N- (3-methoxyphenyl) pentaneamido) Methyl) biphenyl-3-carboxylic acid (4 '-(( N- (3-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) was obtained (92% yield).
  • Example 20 4 '-(( N -(4- Methoxyphenyl ) Pentanamido ) methyl ) Biphenyl -3- Carboxylic acid (4'-(( N Preparation of-(4-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) (AC-1078)
  • Methyl 4'-formylbiphenyl-3-carboxylate instead of methyl 4'-formylbiphenyl-4-carboxylate, 4-methoxyaniline instead of 2-fluoroaniline (4 4 '-((4-methoxyphenylamino) methyl) biphenyl-3-carboxylate (Methyl 4'-((4-Methoxyphenylamino) methyl) in the same manner as in Step 1 of Example 16 using -Methoxyaniline ) biphenyl-3-carboxylate) and methyl 4 '-(( N- (4-methoxyphenyl) pentaneamido) methyl) biphenyl-3- in the same manner as in Step 2 and Step 3 of Example 16 A carboxylate (Methyl 4 '-(( N- (4-Methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylate) was prepared, resulting in 4'-(( N
  • Methyl 3-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane).
  • H 2 O (5: 1) was dissolved in a mixed solution.
  • Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
  • Step 2 methyl 4'-(( Phenylamino ) methyl ) Biphenyl -3- Carboxylate (methyl 4 '-( Preparation of (phenylamino) methyl) biphenyl-2-carboxylate)
  • Methyl 4′-formylbiphenyl-3-carboxylate (1.0 equiv) and aniline (aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
  • Step 3 methyl 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -3- Carboxylate Preparation of (methyl 4 '-((N-phenylpentanamido) methyl) biphenyl-3-carboxylate)
  • step 2 4 '-((phenylamino) methyl) biphenyl-3-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • DCM dichloromethane
  • TAA triethanolamine
  • Valeroyl chloride 2.0 equiv
  • step 4 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -3- Carboxylic acid Preparation of (4 '-((N-phenylpentanamido) methyl) biphenyl-3-carboxylic acid)
  • Methyl 4 ′-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF), and then LiOH solution was added thereto. , Was stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • Step 5 N-((3 '-(4-methoxypiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide (N-((3'-(4-methylpiperazine -1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide)
  • the concentrate was purified by column chromatography to obtain N-((3 '-(4-methoxypiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide (N- ((3 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide) was obtained (93% yield).
  • Example 23 4 '-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -2- Carboxylic acid (4'-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylic acid) (AC-891)
  • Methyl 3-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane).
  • H 2 O (5: 1) was dissolved in a mixed solution.
  • Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
  • step 2 4 '-((3- Fluorophenylamino ) methyl ) Biphenyl -2- Carboxylate (4 '-( Preparation of (3-fluorophenylamino) methyl) biphenyl-2-carboxylate)
  • Methyl 4'-formylbiphenyl-2-carboxylate (1.0 equiv) and 3-fluoroaniline (3-fluoroaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
  • Step 3 Methyl 4 '- (( N- (3- fluorophenyl) pentane amido) methyl) biphenyl-2-carboxylate (Methyl 4' - ((N- (3-fluorophenyl) pentanamido) methyl) biphenyl -2-carboxylate)
  • step 2 4 '-((3-fluorophenylamino) methyl) biphenyl-2-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then ice Cooled in. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • DCM dichloromethane
  • TAA triethanolamine
  • Valeroyl chloride 2.0 equiv
  • the concentrate was purified by column chromatography to prepare methyl 4 '-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-2-carboxylate (Methyl 4'-((N- (3- fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylate) was obtained (92% yield).
  • step 4 4 '-((N- (3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -2- Carboxylic acid Preparation of (4 '-((N- (3-fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylic acid)
  • Methyl 4 ′-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-2-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF). Then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • Example 24 4 '-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Carboxylic acid (4'-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) (AC-893)
  • Methyl 3-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane).
  • H 2 O (5: 1) was dissolved in a mixed solution.
  • Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
  • Step 2 methyl 4 '-((3- Fluoroamino ) methyl ) Biphenyl -4- Carboxylate (Methyl 4 '-( Preparation of (3-fluorophenylamino) methyl) biphenyl-4-carboxylate)
  • Methyl 4'-formylbiphenyl-4-carboxylate (1.0 equiv) and 3-fluoroaniline (3-fluoroaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
  • Step 3 methyl 4 '-((N- (3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Carbosylate Preparation of (Methyl 4 '-((N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate)
  • Methyl 4 '-((3-fluoroamino) methyl) biphenyl-4-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then ice Cooled at. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • DCM dichloromethane
  • TAA triethanolamine
  • Valeroyl chloride 2.0 equiv
  • step 4 4 '-((N- (3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Carboxylic acid Preparation of (4 '-((N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid)
  • Methyl 4 ′-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-carbosylate (1.0 equiv) obtained in step 3 above was added to tetrahydrofuran (THF). After mixing, LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • Example 25 N -(3- Fluorophenyl )- N -((4'-( Morpholine -4- Carbonyl )-[1,1'- Biphenyl -4- days) methyl ) Pentaneamide ( N- (3-fluorophenyl)- N Preparation of-((4 '-(morpholine-4-carbonyl)-[1,1'-biphenyl] -4-yl) methyl) pentanamide) (AC-950)
  • the concentrate was purified by column chromatography to give the final product N- (3-fluorophenyl) -N-((4 '-(morpholine-4-carbonyl)-[1,1'-biphenyl-4- Il) methyl) pentaneamide (N- (3-fluorophenyl) -N-((4 '-(morpholine-4-carbonyl)-[1,1'-biphenyl] -4-yl) methyl) pentanamide) was obtained. (93% yield).
  • Example 26 N -(3- Fluorophenyl )- N -((4 '-(4- Methylpiperazine -One- Carbonyl ) Biphenyl -4- days) methyl ) Pentaneamide ( N -(3- fluorophenyl )- N -((4 '-(4- methylpiperazine -1-carbonyl) biphenyl-4- yl methyl) pentanamide Preparation of (AC-951)
  • step 1 4 '-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Carboxylic acid (4'-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid)
  • Phenyl) pentaneamido) methyl) biphenyl-4-carboxylate (Methyl 4 '-(( N- (3-Methoxyphenyl) pentanamido) methyl) biphenyl-4-carboxylate) was prepared and 4'-(( N- ( 3-methoxyphenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid (4 '-(( N- (3-methoxyphenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) was obtained (94% yield). .
  • Step 2 N -(3- Fluorophenyl )- N -((4 '-(4- Methylpiperazine -One- Carbonyl ) Biphenyl -4- days) methyl ) Pentaneamide ( N -(3-fluorophenyl)- N Preparation of-((4 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide)
  • the concentrate was purified by column chromatography to give the final product N- (3-fluorophenyl) -N -((4 '-(4-methylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) Pentaneamide (N- (3-fluorophenyl) -N -((4 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) was obtained (93% yield).
  • Example 27 N -((2 '-(1H- Tetrazole -5 days) Biphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl)- N -phenylpentanamide) (AC-952)
  • step 1 4 '-(( Phenylamino ) methyl ) Biphenyl -2- Carbon Nitrile (4'-(( phenylamino ) methyl) biphenyl-2-carbonitrile)
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give 4 '-((phenylamino) methyl) biphenyl-2-carbonitrile (4'-((phenylamino) methyl) biphenyl-2-carbonitrile) ( 86% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • Step 2 N -((2'- Cyanophenyl -4- days) methyl )- N - Phenylpentaneamide (N-((2'- cyanobiphenyl -4- yl Preparation of Methyl) -N-phenylpentanamide)
  • step 1 4 '-((phenylamino) methyl) biphenyl-2-carbonitrile obtained in step 1 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then cooled on ice. .
  • Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • MgSO 4 anhydrous magnesium sulfate
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N -((2'-cyanophenyl-4-yl) methyl) -N -phenylpentanamide (N-((2'-cyanobiphenyl-4-yl) methyl) -N-phenylpentanamide) was obtained (92%).
  • MPLC Medium Pressure Liquid Chromatography
  • Step 3 N -((2 '-(1H- Tetrazole -5 days) Biphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl)- N -phenylpentanamide)
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N -phenylpentanamide ( N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N- phenylpentanamide) was obtained (92% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • Step 2 N -((4'- Methoxybiphenyl -4- days) methyl Aniline ( N -((4'- methoxybiphenyl -4- yl Manufacture of methyl) aniline)
  • Step 3 N -((4'- Methoxybiphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((4'- methoxybiphenyl -4-yl) methyl)- N -phenylpentanamide)
  • N -((4'-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then on ice Cooled. Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • DCM dichloromethane
  • TAA triethanolamine
  • Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final product, N -((4'-methoxybiphenyl-4-yl) methyl) -N -phenylpentaneamide ( N -((4'-methoxybiphenyl- 4-yl) methyl) -N- phenylpentanamide) was obtained (100% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • N -((4'-methoxybiphenyl-4-yl) methyl) -N -phenylpentaneamide (1.0 equiv) obtained in Example 28 was dissolved in a dichloromethane (DCM) solution, and then iced. Cooled at. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
  • DCM dichloromethane
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N -((4'-hydroxybiphenyl-4-yl) methyl) -N -phenylpentanamide ( N -((4'-hydroxybiphenyl-) as a final product. 4-yl) methyl) -N- phenylpentanamide) was obtained (80% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • Step 1 ethyl (2- (4 '-(( N - Phenylpentaneamido ) methyl ) Biphenyl -4- Iloxy Acetate (Ethyl (2- (4 '-(( N -phenylpentanamido) methyl) biphenyl-4-yloxy) acetate)
  • N -((4'-hydroxybiphenyl-4-yl) methyl) -N -phenylpentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 29 were replaced with N , N -di Dissolved in methylformamide (DMF) solution and cooled on ice.
  • Ethylbromoacetate (3.0 equiv) was added and the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl (2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetate (Ethyl (2- (4'- (( N- phenylpentanamido) methyl) biphenyl-4-yloxy) acetate was obtained.
  • MPLC Medium Pressure Liquid Chromatography
  • step 2 2 -(4'-(( N - Phenylpentaneamido ) methyl ) Biphenyl -4- Iloxy Acetic acid (2- (4 '-(( N -phenylpentanamido) methyl) biphenyl-4-yloxy) acetic acid)
  • Ethyl (2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was mixed well with tetrahydrofuran (THF). Then, LiOH solution was added and stirred for 4 hours After completion of the reaction, the mixed solution was concentrated and 2N HCl was added until acidic and extracted with ethyl acetate (EA) in vacuo.
  • EA ethyl acetate
  • Example 32 N -(3- Fluorophenyl )- N -((4'- Hydroxybiphenyl -4- days) methyl ) Pentaneamide ( N -(3-fluorophenyl)- N Preparation of-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) (AC-1070)
  • N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in Example 31 was converted to dichloromethane (DCM). After dissolving in solution, it was cooled in ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
  • DCM dichloromethane
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide ( N- ( 3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) was obtained (85% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
  • Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
  • step 2 3 - Chloro -N- ((4'-methoxyphenyl-4-yl) methyl) aniline (3- chloro -N-((4'- methoxybiphenyl Preparation of -4-yl) methyl) aniline)
  • Step 3 N- (3- Chlorophenyl ) -N- ((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3- chlorophenyl ) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final compound, N- (3-chlorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3 -chlorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (85% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • N- (3-chlorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in Example 34 was diluted with dichloromethane (DCM). After melting in, cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
  • DCM dichloromethane
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-chlorophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (N- (3) as a final product.
  • MPLC Medium Pressure Liquid Chromatography
  • Step 1 ethyl 2- (4 ′-((N- (3- Chlorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N- (3-chlorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
  • N- (3-chlorophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 35 were prepared. It was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain ethyl 2- (4 '-((N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- ( 4 '-((N- (3-chlorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (75% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • step 2 2 -(4 '-((N- (3- Chlorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of acetic acid (2- (4 '-((N- (3-chlorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
  • Ethyl 2- (4 '-((N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was added with tetrahydrofuran (THF). After mixing well), LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
  • Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
  • step 2 3 - Bromo -N- ((4'-methoxyphenyl-4-yl) methyl) aniline (3- chloro -N-((4'- methoxybiphenyl Preparation of -4-yl) methyl) aniline)
  • Step 3 N- (3- Bromophenyl ) -N- ((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3- bromophenyl ) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
  • step 2 3-bromo-N-((4'-methoxyphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. Then cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • DCM dichloromethane
  • TAA triethanolamine
  • the concentrated solution was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain a final compound, N- (3-bromophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- ( 3-bromophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (73% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • N- (3-bromophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in Example 37 was converted to dichloromethane (DCM). After dissolving in solution, it was cooled in ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
  • DCM dichloromethane
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield N- (3-bromophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (N- ( 3-bromophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) was obtained (89% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • Step 1 ethyl 2- (4 ′-((N- (3- Bromophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N- (3-bromophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 2- (4 '-((N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4 '-((N- (3-bromophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (85% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • step 2 2 -(4 '-((N- (3- Bromophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of acetic acid (2- (4 '-((N- (3-bromophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
  • Ethyl 2- (4 '-((N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was converted to tetrahydrofuran, THF) was mixed well, then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • Example 40 N -((4'- Methoxybiphenyl -4- days) methyl )- N - (3- ( Trifluoromethyl ) Phenyl) Pentaneamide ( N -((4'-methoxybiphenyl-4-yl) methyl)- N Preparation of-(3- (trifluoromethyl) phenyl) pentanamide) (AC-1634)
  • 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
  • Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
  • Step 2 N-((4'- Methoxybiphenyl -4- days) methyl ) -3- (Trifluoromethyl) aniline (N- ( Preparation of (4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline)
  • Step 3 N-((4'- Methoxybiphenyl -4- days) methyl ) -N- (3- ( Trifluoromethyl ) Phenyl) Pentaneamide
  • N-((4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine , TEA) was added and then cooled on ice.
  • Valeroyl chloride 2.0 equiv was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide as a final compound.
  • MPLC Medium Pressure Liquid Chromatography
  • N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide (1.0 equiv) obtained in Example 40 was converted to dichloromethane ( dichloromethane, DCM) solution, and then cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
  • dichloromethane dichloromethane, DCM
  • TLC thin layer chromatography
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide as a final product.
  • MPLC Medium Pressure Liquid Chromatography
  • Step 1 ethyl 2- (4 ′-((N- (3- ( Trifluoro ) Phenyl) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N- (3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
  • EA ethyl acetate
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give 2- (4 '-((N- (3- (trifluoro) phenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4 '-((N- (3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (100% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • step 2 2 -(4 '-((N- (3- ( Trifluoromethyl ) Phenyl) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of acetic acid (2- (4 '-((N- (3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
  • 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
  • Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
  • Step 2 N-((4'- Methoxybiphenyl -4- days) methyl ) -3- (Trifluoromethyl) aniline (N- ( Preparation of (4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline)
  • Step 3 N-((4'- Methoxybiphenyl -4- days) methyl ) -N-m- Tolylpentaneamide (N-((4'- methoxybiphenyl Preparation of -4-yl) methyl) -N-m-tolylpentanamide)
  • N-((4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine , TEA) was added and then cooled on ice.
  • Valeroyl chloride 2.0 equiv was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain the final compound, N-((4'-methoxybiphenyl-4-yl) methyl) -Nm-tolylpentaneamide (N-((4'-methoxybiphenyl- 4-yl) methyl) -Nm-tolylpentanamide) was obtained (90% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • N-((4'-methoxybiphenyl-4-yl) methyl) -Nm-tolylpentanamide (1.0 equiv) obtained in Example 43 was dissolved in a dichloromethane (DCM) solution, and then iced. Cooled at. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
  • DCM dichloromethane
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-hydroxyphenyl-4-yl) methyl) -Nm-tolylpentaneamide (N-((4'-hydroxybiphenyl-4) as a final product.
  • MPLC Medium Pressure Liquid Chromatography
  • Step 1 ethyl 2- (4 '-((N-m- Tolylpentaneamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N-m-tolylpentanamido) methyl) biphenyl-4-yloxy) acetate)
  • N-((4'-hydroxyphenyl-4-yl) methyl) -Nm-tolylpentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 44 were replaced with N , N -dimethyl. It was dissolved in formamide (DMF) solution and then cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain ethyl 2- (4 '-((Nm-tolylpentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4'-(( Nm-tolylpentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (100% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • step 2 2 -(4 '-((N-m- Tolylpentaneamido ) methyl ) Biphenyl -4- Iloxy Preparation of acetic acid (2- (4 '-((N-m-tolylpentanamido) methyl) biphenyl-4-yloxy) acetic acid)
  • Ethyl 2- (4 '-((Nm-tolylpentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was mixed well with tetrahydrofuran (THF). , LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
  • Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
  • Step 2 N-((4'- Methoxybiphenyl -4- days) methyl ) -3- Nitroaniline (N- ( (4'- methoxybiphenyl Preparation of -4-yl) methyl) -3-nitroaniline)
  • Step 3 N-((4'- Methoxybiphenyl -4- days) methyl ) -N- (3-nitrophenyl) pentaneamide
  • Step 3 N-((4'- Methoxybiphenyl -4- days) methyl ) -N- (3-nitrophenyl) pentaneamide
  • N-((4'-methoxybiphenyl-4-yl) methyl) -3-nitroaniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. Then cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • DCM dichloromethane
  • TAA triethanolamine
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentaneamide (N-((4 '). -methoxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide) was obtained (91% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • Step 4 N-((4'- Hydroxyphenyl -4- days) methyl ) -N- (3- Nitrophenyl ) Pentaneamide Preparation of (N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide)
  • N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentaneamide (1.0 equiv) obtained in step 3 was added to a dichloromethane (DCM) solution. After thawing, it was cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
  • DCM dichloromethane
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield N-((4'-hydroxyphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentaneamide (N-((4 '-hydroxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide) was obtained (30% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • Step 1 ethyl 2- (4 ′-((N- (3- Nitrophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N- (3-nitrophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
  • N-((4'-hydroxyphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 46 were added to N. , Dissolved in N -dimethylformamide (DMF) solution and cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 2- (4 '-((N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- ( 4 '-((N- (3-nitrophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (91% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • step 2 2 -(4 '-((N- (3- Nitrophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of acetic acid (2- (4 '-((N- (3-nitrophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
  • Ethyl 2- (4 ′-((N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was added to tetrahydrofuran (THF). After mixing well), LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • Example 48 N -(3- Iodophenyl )- N -((4'- Methoxybiphenyl -4- days) methyl ) Pentaneamide ( N -(3-iodophenyl)- N Preparation of-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1643)
  • 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
  • Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
  • step 2 3 - Iodo -N-((4'- Methoxybiphenyl -4- days) methyl Aniline (3- iodo -N-((4'- methoxybiphenyl Preparation of -4-yl) methyl) aniline)
  • step 1 4'-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and 3-iodoaniline (2.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
  • TLC thin layer chromatography
  • Step 3 N- (3- Iodophenyl ) -N-((4'- Methoxybiphenyl -4- days) methyl ) Pentaneamide (N- (3- iodophenyl ) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
  • step 2 3-iodo-N-((4'-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) After addition, it was cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • DCM dichloromethane
  • TOA triethanolamine
  • the concentrated solution was purified by Medium Pressure Liquid Chromatography (MPLC), and the final compound, N- (3-iodophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3-iodophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (80% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • N- (3-iodophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in Example 48 was converted to dichloromethane (DCM). After dissolving in solution, it was cooled in ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
  • DCM dichloromethane
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3-iodophenyl) pentaneamide (N- ( (4'-hydroxybiphenyl-4-yl) methyl) -N- (3-iodophenyl) pentanamide) was obtained (90% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • Example 50 2- (4 '-(( N -(3- Iodophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Acetic acid (2- (4 '-(( N Preparation of-(3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1645)
  • Step 1 ethyl 2- (4 ′-((N- (3- Iodophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N- (3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 2- (4 '-((N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4 '-((N- (3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (89% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • step 2 2 -(4 '-((N- (3- Iodophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of acetic acid (2- (4 '-((N- (3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
  • Ethyl 2- (4 '-((N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was converted to tetrahydrofuran, THF) was mixed well, then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
  • Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
  • step 2 3 - Fluoro -N-((4'- Methoxybiphenyl -4- days) methyl Aniline (3- fluoro -N-((4'- methoxybiphenyl Preparation of -4-yl) methyl) aniline)
  • Step 3 N- (3- Fluorophenyl ) -N-((4'- Methoxybiphenyl -4- days) methyl ) Pentaneamide Preparation of (N- (3-fluorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
  • step 2 3-fluoro-N-((4'-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) After addition, it was cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • DCM dichloromethane
  • TOA triethanolamine
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain N- (3-fluorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3-fluorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (81% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3-iodophenyl) pentaneamide (1.0 equiv) obtained in Example 51 was converted to dichloromethane (DCM). After dissolving in solution, it was cooled in ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
  • DCM dichloromethane
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N-((4'-hydroxy- [1,1'-biphenyl] -4-yl) as a final product.
  • MPLC Medium Pressure Liquid Chromatography
  • Example 53 2-((4 '-(( N -(3- Fluorophenyl ) Acetamido ) methyl )-[1,1'- Biphenyl ] -4-day) Oxy Acetic acid (2-((4 '-(( N -(3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid) (AC- 1648 of Produce
  • Step 1 ethyl 2- (4 ′-((N- (3- Fluorophenyl ) Acetoamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N- (3-fluorophenyl) acetamido) methyl) biphenyl-4-yloxy) acetate)
  • EA ethyl acetate
  • the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 2- (4 '-((N- (3-fluorophenyl) acetoamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4 '-((N- (3-fluorophenyl) acetamido) methyl) biphenyl-4-yloxy) acetate) was obtained (91% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • step 2 2 -((4 '-((N- (3- Fluorophenyl ) Acetamido ) methyl )-[1,1'- Biphenyl ] -4-day) Oxy Preparation of acetic acid (2-((4 '-((N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid)
  • Ethyl 2- (4 '-((N- (3-fluorophenyl) acetoamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was converted to tetrahydrofuran, THF) was mixed well, then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • Example 54 N -((4 '-(4- Isopropyl piperazine -One- Carbonyl ) Biphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((4 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl)- N -phenylpentanamide) (AC-1649)
  • reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4'-formylbiphenyl.
  • EA ethyl acetate
  • MgSO 4 Medium Pressure Liquid Chromatography
  • Step 2 methyl 4'-(( Phenylamino ) methyl ) Biphenyl -4- Carboxylate Preparation of (methyl 4 '-((phenylamino) methyl) biphenyl-4-carboxylate)
  • Methyl 4′-formylbiphenyl-4-carboxylate (1.0 equiv) and aniline (aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
  • Step 3 methyl 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -4- Carboxylate (methyl 4 '-( Preparation of (N-phenylpentanamido) methyl) biphenyl-4-carboxylate)
  • Methyl 4 '-((phenylamino) methyl) biphenyl-4-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then cooled on ice. .
  • Valeroyl chloride 2.0 equiv was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • the concentrated solution was purified by Medium Pressure Liquid Chromatography (MPLC), and methyl 4 '-((N-phenylpentaneamido) methyl) biphenyl-4-carboxylate (methyl 4'-((N-phenylpentanamido) methyl) biphenyl -4-carboxylate) was obtained (57% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • step 4 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -4- Carboxylic acid Preparation of (4 '-((N-phenylpentanamido) methyl) biphenyl-4-carboxylic acid)
  • Methyl 4 ′-((N-phenylpentaneamido) methyl) biphenyl-4-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF), and then LiOH solution was added thereto. , Was stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • step 5 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -4- Carboxylic acid Preparation of (4 '-((N-phenylpentanamido) methyl) biphenyl-4-carboxylic acid)
  • the concentrate was purified by column chromatography to obtain 4 '-((N-phenylpentaneamido) methyl) biphenyl-4-carboxylic acid (4'-((N-phenylpentanamido) methyl) biphenyl-4-carboxylic acid ) was obtained (50% yield).
  • Example 55 N -(4-fluorophenyl)- N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide ( N -(4-fluorophenyl)- N Preparation of-((4 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) (AC-1650)
  • Step 1 methyl 4'- Formylbiphenyl -4- Carboxylate (methyl 4'- formylbiphenyl -4- carboxylate Manufacture of
  • reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4'-formylbiphenyl.
  • EA ethyl acetate
  • MgSO 4 Medium Pressure Liquid Chromatography
  • Step 2 methyl 4 '-((4- Fluorophenylamino ) methyl ) Biphenyl -4- Carboxylate Preparation of (methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-4-carboxylate)
  • Step 3 methyl 4 '-((N- (4- Fluorophenyl Pentaamido) methyl ) Biphenyl -4- Carboxylate (methyl 4 '-((N- Preparation of (4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate)
  • step 2 4 '-((4-fluorophenylamino) methyl) biphenyl-4-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then ice Cooled in. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 12 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • DCM dichloromethane
  • TAA triethanolamine
  • Valeroyl chloride 2.0 equiv
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give methyl 4 '-((N- (4-fluorophenyl) pentamido) methyl) biphenyl-4-carboxylate (methyl 4'-((N- (4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate) was obtained (85% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • step 4 4 '-((N- (4- Fluorophenyl Pentaamido) methyl ) Biphenyl -4- Carboxylic acid Preparation of (4 '-((N- (4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid)
  • Methyl 4 ′-((N- (4-fluorophenyl) pentamido) methyl) biphenyl-4-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF). Then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • Step 5 N -(4-fluorofluorophenyl) -N-((4 '-(4-isopropylliprazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide ( N Preparation of-(4-fluorophenyl) -N-((4 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide)
  • Example 56 N -((3 '-(4- Isopropyl piperazine -One- Carbonyl ) Biphenyl -4- days) methyl )- N - Phenylpentaneamide ( N- ((3 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl)- N Preparation of -phenylpentanamide) (AC-1651)
  • Methyl 2-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane).
  • H 2 O (10: 1) was dissolved in a mixed solution.
  • Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
  • reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4'-formylbiphenyl.
  • EA ethyl acetate
  • MgSO 4 Medium Pressure Liquid Chromatography
  • Step 2 methyl 4'-(( Phenylamino ) methyl ) Biphenyl -3- Carboxylate Preparation of (methyl 4 '-((phenylamino) methyl) biphenyl-4-carboxylate)
  • Methyl 4′-formylbiphenyl-3-carboxylate (1.0 equiv) and aniline (aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
  • Step 3 methyl 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -3- Carboxylate Preparation of (methyl 4 '-((N-phenylpentanamido) methyl) biphenyl-3-carboxylate)
  • Methyl 4 '-((phenylamino) methyl) biphenyl-3-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then cooled on ice. .
  • Valeroyl chloride 2.0 equiv was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • MgSO 4 anhydrous magnesium sulfate
  • the concentrated solution was purified by Medium Pressure Liquid Chromatography (MPLC), and methyl 4 '-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylate (methyl 4'-((N-phenylpentanamido) methyl) biphenyl -3-carboxylate) was obtained (96% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • step 4 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -3- Carboxylic acid Preparation of (4 '-((N-phenylpentanamido) methyl) biphenyl-3-carboxylic acid)
  • Methyl 4 ′-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF), and then LiOH solution was added thereto. , Was stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • Step 5 N-((3 '-(4- Isopropyl piperazine -One- Carbonyl ) Biphenyl -4- days) methyl ) -N- Phenylpentaneamide
  • the concentrate was purified by column chromatography to obtain N-((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentaneamide (N- ((3 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide) was obtained (70% yield).
  • Methyl 2-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane).
  • H 2 O (10: 1) was dissolved in a mixed solution.
  • Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
  • reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4'-formylbiphenyl.
  • EA ethyl acetate
  • MgSO 4 Medium Pressure Liquid Chromatography
  • Step 2 methyl 4 '-((4- Fluorophenylamino ) methyl ) Biphenyl -3- Carboxylate Preparation of (methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-3-carboxylate)
  • Methyl 4'-formylbiphenyl-3-carboxylate (1.0 equiv) and 4-fluoroaniline (4-fluoroaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
  • Step 3 methyl 4 '-((N- (4- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -3- Carboxylate (methyl 4 '-((N- Preparation of (4-fluorophenyl) pentanamido) methyl) biphenyl-3-carboxylate)
  • Methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-3-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. Cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
  • DCM dichloromethane
  • TAA triethanolamine
  • the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give methyl 4 '-((N- (4-fluorophenyl) pentaneamido) methyl) biphenyl-3-carboxylate (methyl 4'-((N -(4-fluorophenyl) pentanamido) methyl) biphenyl-3-carboxylate) was obtained (96% yield).
  • MPLC Medium Pressure Liquid Chromatography
  • step 4 4 '-((N- (4- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -3- Carboxylic acid Preparation of (4 '-((N- (4-fluorophenyl) pentanamido) methyl) biphenyl-3-carboxylic acid)
  • Methyl 4 ′-((N- (4-fluorophenyl) pentaneamido) methyl) biphenyl-3-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF). Then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
  • EA ethyl acetate
  • Step 5 N- (4- fluorophenyl ) -N-((3 '-(4- isopropylpiperazine -1-carbonyl) biphenyl-4-yl) methyl) pentanamide (N- (4- fluorophenyl ) -N-((3 '-(4- isopropylpiperazine -1-carbonyl) biphenyl-4-yl) methyl) pentanamide)
  • the concentrate was purified by column chromatography to obtain the final product, methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-3-carboxylate N- (4-fluorophenyl) -N-((3'-( 4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide (N- (4-fluorophenyl) -N-((3 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) was obtained (70% yield).
  • cells without BLT2 expression and cells with BLT2 expression were prepared in the following manner.
  • CHO cells were obtained from the Korea Cell Line Bank (KCLB, 10061), which contained 10% FBS (fetal bovine serum; Life technologies, Inc.), penicillin (50 units / mL), and antibiotic antimycotic solution (Life technologies, Inc.). It was incubated at 37 °C, 5% CO 2 conditions in RPMI 1640 medium (Invitrogen) containing the. The cells were maintained in the growth phase by splitting with Trypsin-EDTA for 3 days, respectively, in PBS (phosphate-buffered saline; 137 mM NaCl, 2.7 mM KCl, 10 mM Na 2 HPO 4 , 2mMKH 2 PO 4 ) Washed and then added to fresh medium to prepare cells free of BLT2 expression.
  • FBS fetal bovine serum
  • penicillin 50 units / mL
  • antibiotic antimycotic solution Life technologies, Inc.
  • CHO-K1 cells were transformed with pcDNA3-long form BLT2 encoding HA-tagged human BLT2, and 0.4 mg / ml of G418 (Invitrogen). , Carlsbad, CA, USA).
  • G418 Invitrogen
  • the selected clones were analyzed by RT-PCR using human-specific BLT2 primers, and representative clones were used in the experiments with cells expressing BLT2 (CHO-BLT2).
  • LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +) and ethanol treated (DMSO-) cell growth increased from 20% to 35%, and in BLT2 expressed cells (CHO-BLT2), positive control Phosphorus LY255283 pre-treated, showed about 90% cell growth compared to the control group treated with DMSO, confirming the effect of inhibiting cell growth according to the compound treatment of the Example. Specifically, the growth inhibitory effect of the compounds of the present invention AC-1632 (78.7%), AC-1635 (71.6%), AC-1646 (72.1%) and AC-1650 (82.2%) was confirmed.
  • the compounds of the present invention can inhibit the cell proliferation induced by BLT2 with very good efficiency, the compound is anti-cancer, anti-asthma Or BLT2-blocking pharmacological molecules, which can be used as therapeutic agents for the inhibition of other forms of BLT2-related inflammatory diseases.
  • the inventors have experimentally confirmed that the expression of BLT2 increases proportionally with the degree of anticancer drug resistance, and the anticancer drug resistance is significantly reduced by BLT2 inhibition. Therefore, in the ovarian cancer cells (SKOV-3 cells) exhibiting anticancer drug resistance, when the compound of the present invention in combination with the anticancer drug cisplatin, to determine whether cancer cell death is induced despite the anticancer drug resistance.
  • Cancer cell death was measured using 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) method. More specifically, 1 ⁇ 10 5 showing anticancer drug resistance Ovarian cancer cells (SKOV-3 cells) were dispensed onto a 12-well culture dish and incubated for 24 hours. 10 ⁇ M of the compound prepared in the above example, 10 ⁇ M of the control DMSO (solvent of the compound) and 10 ⁇ M of the positive control LY255283 were each pretreated in 0.5% serum RPMI medium for 30 minutes. Subsequently, cisplatin, an anticancer agent, was treated with 50 ⁇ M and then cultured for 24 hours.
  • MTT 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide
  • the compounds of the present invention can reduce the cancer drug resistance to induce cancer cell death by cisplatin, an anticancer drug with excellent efficiency, anticancer effect It can be used as a pharmaceutical ingredient for enhancement.
  • Chemotactic motility was analyzed using a Transwell chamber equipped with a 6.5-mm diameter polycarbonate filter (8- ⁇ m pore size, Corning Costar). Specifically, the bottom surface of the filter was coated with 10 ⁇ g / mL fibronectin in serum free RPMI 1640 medium at 37 ° C. for 1 hour. A dry, coated filter with RPMI 1640 medium containing varying amounts of LTB 4 is placed in the bottom well of the Transwell chamber and finally 2 ⁇ 10 4 cells of CHO cells stably expressing BLT1 and BLT2 in serum-free RPMI 1640 medium. Experiments were performed by loading into the upper wells at / 100 ⁇ L.
  • the cells were pretreated with each inhibitor for 30 minutes before dispensing. After 3 hours of incubation at 37 ° C., 5% CO 2 , the filters were fixed with methanol for 3 minutes and stained with hematoxylin and eosin for 10 minutes.
  • the cells used BLT2-expressing cells (CHO-BLT2 cells) and BLT1-expressing cells (CHO-BLT1), LY255283 and U75302 as positive controls, respectively, and LTB 4 , a ligand of BLT2 as a comparative control.
  • LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +), ethanol treated compared to (DMSO-), the cell chemotaxis was increased 2.9-fold, and 10 ⁇ M pretreatment of LY255283 used as a positive control, the ligand LTB 4 To It showed 90% chemotaxis compared to the treatment, and when the compound of the present invention (AC-1074) was pretreated with 10 ⁇ M of cells expressing BLT2, the ligand was treated with LTB 4 (DMSO +). It was confirmed that 53% inhibition of chemotaxis.
  • LTB 4 which is a ligand of BLT1 to BLT1-expressing cells (CHO-BLT1 cells)
  • 10 nM DMSO +
  • DMSO- DMSO-
  • the cell chemotaxis was increased by 2.8-fold
  • the compound (AC-1074) of the present invention was added to cells expressing BLT2 10.
  • pretreatment with M it was confirmed that there was no change in chemotaxis compared to (DMSO +) when the ligand LTB 4 was treated.
  • BLT2-expressing cells CHO-BLT2 cells
  • LPA lysophosphatidic acid
  • DMSO + ethanol treated
  • DMSO- ethanol treated
  • chemotactic activity is LTB 4 in cells stably expressing BLT2 (CHO-BLT2).
  • the compound of the present invention AC-1074
  • the compound of the present invention can significantly inhibit this chemotaxis, can be used as a pharmaceutical component for inhibiting BLT2-dependent chemotaxis induced by LTB 4 Means.
  • LTB 4 and BLT2 binding (ligand binding affinity) inhibition was analyzed by isotope tritium (H3) using the label LTB 4 ([3H] LTB 4, ARC) (specific activity 160.0 Ci / mmol).
  • Experimental method is to put 2 ⁇ 10 6 CHO-BLT2 cells in a 100 mm culture dish and incubate for 48 hours before proceeding. The harvested cells are used five times for one minute in a homogenizer to separate the proteins of the cell membrane. Thereafter, centrifugation was performed for 40 minutes at 45,000 RPM at 4 ° C to harvest only proteins of the cell membrane and quantitate them at a concentration of 40 ⁇ g / 45 ⁇ L.
  • mast cells play an important role.
  • mast cells are activated to release various cytokines (interlukin-4 and interlukin-13).
  • the cytokine causes phenomena such as influx of inflammatory cells, mucus production, and airway contraction.
  • the present inventors received female BALB / c mice that were 7 weeks old (18-20 g) from Orient (Seoungnam, Korea) and used them in the experiments to induce asthma.
  • Airway hypersensitivity was measured 24 days after initial sensitization, and mice were dissected on day 25 to observe the asthma phenotype of inflammatory cytokine IL-4 expression and the influx of inflammatory cells (neutrophils).
  • airway hypersensitivity measurement was performed after the administration of metacholine (up to 6.25 mg / ml to 50 mg / ml depending on conditions), which is an airway constrictor. Airway constrictor administration was sprayed through the inlet of the chamber for 3 minutes using an ultrasonic nebulizer. Airway hypersensitivity was analyzed using enhanced pause as an indicator of asthma.
  • asthma-induced mice OVA / DMSO
  • AC-1074 the compound of the present invention
  • the compound of the present invention (AC-1074) can suppress airway hyperresponsiveness in the asthma animal model and the compound (AC-1074) can alleviate the symptoms of asthma by inhibiting the production of inflammatory cytokine IL-4, anti It can be used as a pharmaceutical ingredient with an asthma effect.
  • the present invention relates to a novel compound that exhibits Leukotriene B4 receptor 2 (BLT2) inhibitory activity and a pharmaceutical composition for preventing or treating an inflammatory disease comprising the same.
  • BLT2 Leukotriene B4 receptor 2
  • the present inventors have identified a novel compound that exhibits BTL2 inhibitory activity in order to solve in vivo instability and difficulty in mass production, which are problems of conventional inflammatory disease treatment substances, and has excellent cancer cell death enhancement and metastasis suppression effect and chemotaxis inhibition of the compound.
  • the effects and anti-asthma effects have been confirmed experimentally, it is expected to be useful as a pharmaceutical composition for treating inflammatory diseases.

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Abstract

The present invention relates to a novel compound showing leukotriene B4 receptor 2 (BLT2) inhibitory activity and a pharmaceutical composition, for preventing or treating inflammatory diseases, comprising same as an active ingredient. In the present invention, a novel compound showing BLT2 inhibitory activity is investigated and the enhanced cancer cell death, metastasis suppression, chemotaxis inhibition, antiasthmatic effect and the like shown in the compound have been experimentally confirmed. Therefore, the present invention enables more fundamental approach and target treatment for treating or preventing inflammatory diseases.

Description

BLT 저해 활성을 갖는 신규 화합물 및 이를 유효성분으로 포함하는 염증성 질환 예방 또는 치료용 조성물Novel compounds having BLT inhibitory activity and compositions for preventing or treating inflammatory diseases comprising the same as active ingredients
본 발명은 신규 화합물 및 이의 용도에 관한 것으로서, 보다 구체적으로는 BLT2 (Leukotriene B4 receptor 2) 억제 활성을 나타내는 신규 화합물 및 이를 유효성분으로 포함하는 염증성 질환 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a novel compound and its use, and more particularly, to a novel compound exhibiting inhibitory activity of Leukotriene B4 receptor 2 (BLT2) and a pharmaceutical composition for preventing or treating inflammatory diseases comprising the same as an active ingredient.
염증반응은 생체나 조직에 물리적 작용이나 화학적 물질, 세균 감염, 면역학적 자극 등이 가해질 때, 이에 대해 방어할 수 있도록 다양한 작용기전을 통해 활성화되는 인체의 면역 시스템 중 하나이다. 다만, 이와 같은 염증반응이 지속되면 오히려 점막 손상을 촉진하게 되며, 이에 따라 발적, 발열, 종창, 동통, 기능장애 등으로 인한 류마티스 관절염, 동맥경화증, 위염, 천식 등의 염증성 질환을 유발하는 것을 알려져 있다. 이러한, 염증반응은 시간의 경과에 따라 급성염증과 만성염증으로 구분되며, 급성염증은 염증반응이 수 일 내지 수 주간 지속되고, 홍반, 발열, 통증, 부종과 같은 증상을 야기하는 반면, 만성염증은 장기간 염증상태가 지속되는 것으로 때로는 수 년 내지 수십 년에 걸쳐 나타나며, 단핵세포의 침윤, 섬유모세포 및 모세혈관의 증식, 결합조직의 증가로 인한 섬유화, 조직의 파괴 등의 조직학적 변화를 수반한다.Inflammatory reactions are one of the body's immune systems that are activated through various mechanisms of action to protect against physical or chemical agents, bacterial infections, and immunological stimuli. However, if such an inflammatory response persists, it promotes mucosal damage, thereby causing inflammatory diseases such as rheumatoid arthritis, arteriosclerosis, gastritis, and asthma due to redness, fever, swelling, pain, and dysfunction. have. These inflammatory reactions are classified into acute and chronic inflammations over time, and acute inflammations can cause symptoms such as erythema, fever, pain, and edema, while inflammatory reactions last several days to several weeks. Is a prolonged inflammatory state, sometimes over several years to decades, and is accompanied by histological changes such as invasion of monocytes, proliferation of fibroblasts and capillaries, fibrosis due to increased connective tissue, and tissue destruction. .
구체적으로, 생체 내 염증성 자극이 가해지면, 국소적으로 히스타민(histamine), 브레디키닌 (bradykinin), 프로스타글란딘 (prostaglandins), 산화질소(nitric oxide, NO), 각종 전염증성 사이토카인 (pro-inflammatory cytokines) 등이 합성, 분비되며, 이들은 혈관 확장 뿐 아니라 홍반, 발열, 통증, 부종을 유발시킨다. 특히, 체내 염증 과정에서 인터페론-감마 (interferon-γ, INF-γ), 종양괴사인자-알파 (tumor necrosis factor-α, TNF-α), 인터루킨-1 (interleukin-1, IL-1), 인터루킨-6(interleukin-6, IL-6) 등의 사이토카인과 같은 일반적인 면역 인자들 외에도 산화질소 (NO) 및 프로스타글란딘 E2 (prostaglandin E2, PGE2)이 주요 염증 유발 물질로 잘 알려져 있다.Specifically, when inflammatory stimuli are applied in vivo, histamine, bradykinin, prostaglandins, nitric oxide (NO), and various pro-inflammatory cytokines (pro-inflammatory cytokines) ) Are synthesized and secreted, and they cause vascular enlargement as well as erythema, fever, pain and edema. In particular, interferon-gamma (INF-γ), tumor necrosis factor-α (TNF-α), interleukin-1 (interleukin-1, IL-1), interleukin during inflammatory processes in the body In addition to common immune factors such as cytokines such as -6 (interleukin-6, IL-6), nitric oxide (NO) and prostaglandin E2 (PGE2) are well known as major inflammatory agents.
종래 염증 반응의 종결은 염증을 시작하는 물질들의 수준이 감소하면 자연적이고 수동적으로 일어나는 현상이라고 알려져 왔으나, Serhan 등이 lipoxin, resovin, protectin 류 등을 발견하여 이들에 의해 염증의 시작에 관여하는 프로스타글란딘 (prostaglandin)류처럼 염증의 종결이 능동적으로 촉진된다는 것을 발견하였다. 예를 들어, Resolvin E1은 통증에 효과적이며, RvE1는 염증의 종결을 유도하여 알레르기 염증 질환의 치료에 효과가 있다는 점이 보고된 바 있다. 또한, 만성 염증 질환에서 이러한 염증 종결을 능동적으로 촉진하는 인자들 즉, lipoxin A4, 아스피린에 의해 유도되는 lipoxin의 수준이 천식 환자 및 죽상동맥경화 환자에서 낮게 관찰됨이 보고된 바 있다. Conventionally, the termination of the inflammatory response has been known to occur naturally and passively when the level of inflammation-inducing substances decreases. However, Serhan et al. Found lipoxin, resovin, protectin, and the like, and prostaglandins are involved in the initiation of inflammation. Like prostaglandins, it has been found that the termination of inflammation is actively promoted. For example, it has been reported that Resolvin E1 is effective in pain and RvE1 is effective in treating allergic inflammatory diseases by inducing the termination of inflammation. In addition, it has been reported that the levels of the factors that actively promote the termination of inflammation in chronic inflammatory diseases, namely lipoxin A4 and aspirin-induced lipoxin, are low in asthma patients and atherosclerosis patients.
이에, 염증의 종결을 유도하는 신규 물질을 발굴하여, 염증 종결 이상과 관련된 질환을 치료하고자 하는 시도가 다양하게 진행되고 있으나 (한국공개특허 10-2015-0011875), lipoxin, resovin 등에 속한다고 알려진 화합물은 그 구조에 여러 개의 이중결합이 포함되어 있어 대사적으로 불안정하여 생체에서 빠르게 분해되는 등의 단점을 가지고 있으며, 물질을 대량생산하여 약으로 개발하기에는 다소 어려워, 약물성에 큰 문제점을 가지고 있다. Therefore, various attempts have been made to discover new substances that induce the termination of inflammation, and to treat diseases related to abnormal termination of inflammation (Korea Patent Publication No. 10-2015-0011875), compounds known to belong to lipoxin, resovin, etc. Since the structure contains a plurality of double bonds, such as metabolic instability and has a disadvantage of rapid decomposition in the living body, and mass production of the material is somewhat difficult to develop into a drug, has a big problem in drug properties.
한편, 류코트리엔 (Leukotriene B4; LTB4)은 급성 및 만성염증을 매개하는 5-리폭시제나제 경로에 의해 아라키돈산(AA)으로부터 합성되는 염증성 리피드 매개체 군이다. LTB4는 BLT1과 BLT2 의 두 가지 형태의 수용체들에 결합함으로써 생물학적 영향을 주는 것으로 알려져 있다. BLT2(Leukotriene B4 receptor 2)는 GPCR(G protein-coupled receptor) 군 중 하나로 LTB4에 대해 낮은 친화력을 갖는 수용체이며, 5-리폭시제나제 의존성 경로를 통해 유도된 아라키돈산(AA)의 리피드 매개체이다. On the other hand, leukotriene B4 (LTB 4 ) is a group of inflammatory lipid mediators synthesized from arachidonic acid (AA) by the 5-lipoxygenase pathway that mediates acute and chronic inflammation. LTB 4 is known to have a biological effect by binding to two types of receptors, BLT1 and BLT2. Leukotriene B4 receptor 2 (BLT2) is a group of G protein-coupled receptors (GPCRs) that has low affinity for LTB 4 and is a lipid mediator of arachidonic acid (AA) induced through a 5-lipoxygenase dependent pathway. to be.
이에, 본 발명자들은 상기와 같은 종래의 문제점을 해결하기 위하여, 보다 효과적인 염증의 종결을 유도하는 물질을 개발하기 위한 연구를 계속하던 중, BLT2 억제 활성을 나타내는 신규 화합물을 제조하였으며, 상기 화합물을 포함하는 염증성 질환 치료제를 최초로 고안하였다.Accordingly, the present inventors, while continuing to research to develop a substance that induces more effective termination of inflammation, in order to solve the conventional problems as described above, has produced a novel compound showing a BLT2 inhibitory activity, including the compound It was the first to develop an inflammatory disease treatment.
본 발명은 상기와 같은 문제점을 해결하기 위해 안출된 것으로서, 본 발명자들은 BLT2 억제 활성을 나타내는 신규 화합물의 염증성 질환 치료 효과를 확인하고 이에 기초하여 본 발명을 완성하게 되었다.The present invention has been made to solve the above problems, the present inventors have confirmed the therapeutic effect of the inflammatory disease of the novel compound showing the BLT2 inhibitory activity and completed the present invention based on this.
이에, 본 발명의 목적은 BLT2 억제 활성을 나타내는 신규 화합물 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.Accordingly, it is an object of the present invention to provide novel compounds or pharmaceutically acceptable salts thereof which exhibit BLT2 inhibitory activity.
또한, 본 발명의 다른 목적은 상기 신규 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 염증성 질환 예방 또는 치료용 약학적 조성물을 제공하는 것이다.In addition, another object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory diseases, comprising the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.
상기와 같은 본 발명의 목적을 달성하기 위하여, 본 발명은 BLT2 억제 활성을 나타내는 신규 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.In order to achieve the above object of the present invention, the present invention provides a novel compound or a pharmaceutically acceptable salt thereof exhibiting BLT2 inhibitory activity.
본 발명의 일 구현예로서, 상기 화합물은N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-(4'-((N-페닐펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; N-(3-플루오로페닐)-N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)펜탄아마이드; N-(4'-((N-3-플루오로페닐)펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; 1-(3-플루오로페닐)-1-((4'-메톡시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아; N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)-1-(4-메톡시페닐설폰일)메탄아마이드; 1-(3-플루오로페닐)-1-((4'-하이드록시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아; 2-(4'-((1-(3-플루오로페닐)-3-(3-(트리플루오로메틸)페닐)유레이도)메틸)바이페닐-4-일옥시)아세트산; 4-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)부탄산; 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)-2-메틸프로판산; (E)-3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아크릴산; 3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)프로판산; N-(3-플루오로페닐)-N-((4'-(2-(4-메틸피페라진-1-일)-2-옥소에톡시)바이페닐-4-일)메틸)펜탄아마이드; 프로프-2-인일 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트; N-(3-플루오로페닐)-N-((4'-(프로프-2-이닐옥시)바이페닐-4-일)메틸)펜탄아마이드; 4'-((N-(2-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산; 4'-((N-(4-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산; 4'-((N-(2-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산; 4'-((N-(3-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산; 4'-((N-(4-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산; N-((2'-(4-메톡시피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-((3'-(4-메틸피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-2-카복실산; 4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산; N-(3-플루오로페닐)-N-((4'-(몰폴린-4-카보닐)-[1,1'-바이페닐-4-일)메틸)펜탄아마이드; N-(3-플루오로페닐)-N-((4'-(4-메틸피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드; N-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-((4'-메톡시바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-((4'-하이드록시바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 2-(4'-((N-페닐펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드; N-(3-플루오로페닐)-N-((4'-하이드록시-[1,1'-바이페닐]-4-일)메틸)아세트아마이드; 2-((4'-((N-(3-플루오로페닐)아세트아미도)메틸)-[1,1'-바이페닐]-4-일)옥시)아세트산; N-(3-클로로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드; N-(3-클로로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드; 2-(4'-((N-(3-클로로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-(3-브로모페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드; N-((4'-(하이드록시바이페닐-4-일)메틸)-N-(3-(트리플루오로메틸)페닐)펜탄아마이드; 2-(4'-((N-(3-브로모페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-((4'-메톡시바이페닐-4-일)메틸)-N-(3-(트리플루오로메틸)페닐)펜탄아마이드; N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드; 2-(4'-((N-(3-(트리플루오로메틸)페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-((4'메톡시바이페닐-4-일)메틸)-N-m-톨릴펜탄아마이드; N-((4'-하이드록시페닐-4-일)메틸)-N-m-톨릴펜탄아마이드; 2-(4'-((N-m-톨릴펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-((4'-하이드록시페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드; 2-(4'-((N-(3-니트로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-(3-아이오도페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드; N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-아이오도페닐)펜탄아마이드; 2-(4'-((N-(3-아이오도페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)아세트아마이드; N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드; 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-(4-플루오로페닐)-N-((4'-(4-아이소프로필피페라진-1-카보닐)-[1,1'-바이페닐]-4-일)메틸)펜탄아마이드; N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 및 N-(4-플루오로페닐)-N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드.로 이루어진 군으로부터 선택될 수 있다.In one embodiment of the invention, the compound is N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentaneamide; N- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; N- (3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentaneamide; N- (4 '-(( N- 3-fluorophenyl) pentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; 1- (3-fluorophenyl) -1-((4'-methoxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea; N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methaneamide; 1- (3-fluorophenyl) -1-((4'-hydroxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea; 2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetic acid; 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoic acid; 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) -2-methylpropanoic acid; ( E ) -3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylic acid; 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) propanoic acid; N- (3-fluorophenyl) -N -((4 '-(2- (4-methylpiperazin-1-yl) -2-oxoethoxy) biphenyl-4-yl) methyl) pentaneamide; Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate; N- (3-fluorophenyl) -N -((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl) pentaneamide; 4 '-(( N- (2-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid; 4 '-(( N- (4-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid; 4 '-(( N- (2-methoxyphenyl) pentaneamido) methyl) biphenyl-3-carboxylic acid; 4 '-(( N- (3-methoxyphenyl) pentaneamido) methyl) biphenyl-3-carboxylic acid; 4 '-(( N- (4-methoxyphenyl) pentaneamido) methyl) biphenyl-3-carboxylic acid; N -((2 '-(4-methoxypiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentanamide; N -((3 '-(4-methylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentanamide; 4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-2-carboxylic acid; 4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid; N- (3-fluorophenyl) -N -((4 '-(morpholine-4-carbonyl)-[1,1'-biphenyl-4-yl) methyl) pentaneamide; N- (3-fluorophenyl) -N -((4 '-(4-methylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide; N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N-phenylpentanamide; N -((4'-methoxybiphenyl-4-yl) methyl) -N -phenylpentanamide; N -((4'-hydroxybiphenyl-4-yl) methyl) -N -phenylpentanamide; 2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid; N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide; N- (3-fluorophenyl) -N -((4'-hydroxy- [1,1'-biphenyl] -4-yl) methyl) acetamide; 2-((4 '-(( N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid; N- (3-chlorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide; N- (3-chlorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide; 2- (4 '-(( N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; N- (3-bromophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide; N -((4 '-(hydroxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide; 2- (4'-(( N- (3-bro Mophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; N -((4'-methoxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl ) pentane amide; N - ((4'- hydroxy-biphenyl-4-yl) methyl) - N - (3- nitrophenyl) pentane amide; 2- (4 '- (( N - (3- ( trifluoro Rhomethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid; N -((4'methoxybiphenyl-4-yl) methyl) -N - m -tolylpentaneamide; N- ( (4'-hydroxyphenyl-4-yl) methyl) -N - m -tolylpentanamide: 2- (4 '-(( Nm -tolylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid; N - ((4'- hydroxy-4-yl) methyl) - N - (3- nitrophenyl) pentane amide; 2- (4 '- (( N - (3- nitrophenyl) pentane amido) methyl ) Biphenyl-4-yloxy) acetic acid; N- (3-iodophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) phen Tan amide; N - ((4'- hydroxy-biphenyl-4-yl) methyl) - N - (3- iodo-phenyl) pentane amide; 2- (4 '- (( N - (3- iodo-phenyl ) Pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) acetamide; N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide; 2- (4 '-(( N- (3-fluorophenyl) pentanamido) Methyl) biphenyl-4-yloxy) acetic acid; N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentanamide; N- (4-fluorophenyl) - N - ((4 '- (4-isopropyl-piperazine-1-carbonyl) - [1,1'-biphenyl] -4-yl) methyl) pentane amide; N - ((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentanamide; and N- (4-fluorophenyl) -N -((3 Consisting of '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide. Can be selected from the group.
본 발명은 상기 신규 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 염증성 질환 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease, comprising the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일 구현예로서, 상기 염증성 질환은 천식, 죽상경화증, 암, 피부가려움증, 류마티스 관절염 및 염증성 장 질환으로 이루어진 군으로부터 선택될 수 있다. In one embodiment of the present invention, the inflammatory disease may be selected from the group consisting of asthma, atherosclerosis, cancer, itching of the skin, rheumatoid arthritis and inflammatory bowel disease.
본 발명의 다른 구현예로서, 상기 조성물은 BLT2 (Leukotriene B4 receptor 2) 활성을 저해시킬 수 있다. In another embodiment of the present invention, the composition may inhibit Leukotriene B4 receptor 2 (BLT2) activity.
상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 염증성 질환의 치료방법을 제공한다.It provides a method of treating an inflammatory disease comprising administering the pharmaceutical composition to a subject.
본 발명은 상기 신규 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물의 염증성 질환의 치료용도를 제공한다.The present invention provides a therapeutic use of an inflammatory disease of a composition comprising the novel compound or a pharmaceutically acceptable salt thereof.
본 발명은 BLT2 (Leukotriene B4 receptor 2) 억제 활성을 나타내는 신규 화합물 및 이를 포함하는 염증성 질환 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명자들은 종래의 염증성 질환 치료 물질의 문제점인 생체 내 불안정성 및 대량 생산의 어려움을 해소하기 위하여 BTL2 억제 활성을 나타내는 신규 화합물을 규명하였으며, 상기 화합물의 우수한 암세포 사멸 증진 및 전이 억제 효과, 주화성 억제 효과 및 항 천식 효과 등을 실험적으로 확인하였는바, 염증성 질환을 치료하기 위한 약학적 조성물로 유용하게 사용될 수 있을 것으로 기대된다.The present invention relates to a novel compound that exhibits Leukotriene B4 receptor 2 (BLT2) inhibitory activity and a pharmaceutical composition for preventing or treating an inflammatory disease comprising the same. The present inventors have identified a novel compound that exhibits BTL2 inhibitory activity in order to solve in vivo instability and difficulty in mass production, which are problems of conventional inflammatory disease treatment substances, and has excellent cancer cell death enhancement and metastasis suppression effect and chemotaxis inhibition of the compound. The effects and anti-asthma effects have been confirmed experimentally, it is expected to be useful as a pharmaceutical composition for treating inflammatory diseases.
도 1a 내지 도 1d는 BLT2가 발현된 세포 (CHO-BLT2)에서, 본 발명의 화합물 처리에 의한 성장 억제 효과를 확인한 결과이다.1A to 1D show the results of confirming the growth inhibitory effect of the compound of the present invention in cells expressing BLT2 (CHO-BLT2).
도 2a 내지 도 2c는 항암제 내성을 나타내는 난소암 세포 (SKOV-3 cells)에서, 본 발명의 화합물 및 항암제인 cisplatin 복합 처리에 의한 암세포 사멸 증진 여부를 확인한 결과이다. Figure 2a to 2c is a result of confirming whether cancer cell death enhanced by the treatment of the compound of the present invention and the anti-cancer drug cisplatin complex in ovarian cancer cells (SKOV-3 cells) showing anticancer drug resistance.
도 3a 내지 도 3d는 BLT2가 발현된 세포 (CHO-BLT2 cells)에서, 본 발명의 화합물 처리에 의한 세포의 주화성 억제 효과 및 IC50 (50% 억제 농도)를 확인한 결과이다.3A to 3D show results of confirming chemotaxis inhibitory effect and IC50 (50% inhibitory concentration) of cells by treatment with a compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells).
도 4a 및 도 4b는 BLT2가 발현된 세포 (CHO-BLT2 cells) 또는 BLT1이 발현된 세포 (CHO-BLT1)에서, 본 발명의 화합물 처리에 의한 세포의 주화성 억제 효과를 확인한 결과이다. 4A and 4B show the results of confirming the chemotaxis inhibitory effect of cells treated with the compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells) or cells expressing BLT1 (CHO-BLT1).
도 5은 BLT2가 발현된 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 처리에 의한 LTB4와 BLT2 결합 저해 효과를 확인한 결과이다. 5 is a result of confirming the inhibitory effect of LTB4 and BLT2 binding by the compound treatment of the present invention in BLT2-expressing cells (CHO-BLT2 cells).
도 6은 천식이 유도된 마우스에서, 본 발명의 화합물 처리에 의한 기도 과민성 감소 효과를 확인한 결과이다.6 is a result confirming the effect of reducing airway hypersensitivity by the compound treatment of the present invention in asthma-induced mice.
도 7은 중증 천식이 유도된 마우스에서, 본 발명의 화합물 처리에 의한 기도 과민성 감소 효과를 확인한 결과이다.Figure 7 is a result of confirming the effect of reducing airway hypersensitivity by the compound treatment of the present invention in mice with severe asthma induced.
도 8는 중증 천식이 유도된 마우스에서, 본 발명의 화합물 처리에 의한 IL-4 (interleukin-4) 생성 감소 효과를 확인한 결과이다.8 is a result confirming the effect of reducing IL-4 (interleukin-4) production by the compound treatment of the present invention in severe asthma induced mice.
본 발명자들은, 실시예에서 제조한 신규 화합물을 처리한 경우, BLT2 발현 세포의 성장을 현저히 억제시킬 수 있다는 점에 기반하여 상기 화합물의 암세포 사멸 증진, 암세포 전이 억제, BLT2 의존적인 주화성 저해, 및 항천식 효과 등을 구체적으로 확인하고, 이에 기초하여 본 발명을 완성하였다.The present inventors, based on the fact that the treatment of the novel compound prepared in the example can significantly inhibit the growth of BLT2 expressing cells, enhance the cancer cell death of the compound, inhibit cancer cell metastasis, inhibit BLT2-dependent chemotaxis, and The anti-asthma effect and the like have been specifically confirmed, and the present invention has been completed based on this.
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2016008070-appb-I000001
Figure PCTKR2016008070-appb-I000001
상기 화학식 1에서,In Chemical Formula 1,
R1은 C1~C10의 알킬,
Figure PCTKR2016008070-appb-I000002
또는
Figure PCTKR2016008070-appb-I000003
이고,R 1 is C 1 -C 10 alkyl,
Figure PCTKR2016008070-appb-I000002
or
Figure PCTKR2016008070-appb-I000003
ego,
R2는 수소,
Figure PCTKR2016008070-appb-I000004
,
Figure PCTKR2016008070-appb-I000005
,
Figure PCTKR2016008070-appb-I000006
또는
Figure PCTKR2016008070-appb-I000007
이고,R 2 is hydrogen,
Figure PCTKR2016008070-appb-I000004
,
Figure PCTKR2016008070-appb-I000005
,
Figure PCTKR2016008070-appb-I000006
or
Figure PCTKR2016008070-appb-I000007
ego,
R3는 수소,
Figure PCTKR2016008070-appb-I000008
,
Figure PCTKR2016008070-appb-I000009
,
Figure PCTKR2016008070-appb-I000010
또는
Figure PCTKR2016008070-appb-I000011
이고,R 3 is hydrogen,
Figure PCTKR2016008070-appb-I000008
,
Figure PCTKR2016008070-appb-I000009
,
Figure PCTKR2016008070-appb-I000010
or
Figure PCTKR2016008070-appb-I000011
ego,
R4는 수소,
Figure PCTKR2016008070-appb-I000012
,
Figure PCTKR2016008070-appb-I000013
,
Figure PCTKR2016008070-appb-I000014
,
Figure PCTKR2016008070-appb-I000015
또는
Figure PCTKR2016008070-appb-I000016
이고,R 4 is hydrogen,
Figure PCTKR2016008070-appb-I000012
,
Figure PCTKR2016008070-appb-I000013
,
Figure PCTKR2016008070-appb-I000014
,
Figure PCTKR2016008070-appb-I000015
or
Figure PCTKR2016008070-appb-I000016
ego,
여기서 Ra는 수소, C1~C10의 알킬, C1~C5의 카르복실, Where R a is hydrogen, C 1 -C 10 alkyl, C 1 -C 5 carboxyl,
Figure PCTKR2016008070-appb-I000017
Figure PCTKR2016008070-appb-I000017
R5, R6, 및 R7은 각각 독립적으로 수소, 할로겐, 니트로, 메틸, 트리플루오로메틸 또는 메톡시이며,R 5 , R 6 , and R 7 are each independently hydrogen, halogen, nitro, methyl, trifluoromethyl or methoxy,
단, R1은 부틸, R2는
Figure PCTKR2016008070-appb-I000018
, R3, R4, R5, R6, 및 R7은 수소인 경우;Provided that R 1 is butyl and R 2 is
Figure PCTKR2016008070-appb-I000018
When R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen;
R1은 부틸, R3는
Figure PCTKR2016008070-appb-I000019
, R2, R4, R5, R6, 및 R7은 수소인 경우;R 1 is butyl, R 3 is
Figure PCTKR2016008070-appb-I000019
When R 2 , R 4 , R 5 , R 6 , and R 7 are hydrogen;
R1은 부틸, R4는
Figure PCTKR2016008070-appb-I000020
, R2, R3, R5, R6, 및 R7은 수소인 경우;R 1 is butyl, R 4 is
Figure PCTKR2016008070-appb-I000020
, R 2 , R 3 , R 5 , R 6 , and R 7 are hydrogen;
R1은 부틸, R4는
Figure PCTKR2016008070-appb-I000021
, R2, R3, R5, R6, 및 R7은 수소인 경우;R 1 is butyl, R 4 is
Figure PCTKR2016008070-appb-I000021
, R 2 , R 3 , R 5 , R 6 , and R 7 are hydrogen;
R1은 부틸, R4는
Figure PCTKR2016008070-appb-I000022
, R6는 플루오르, R2, R3, R5, 및 R7은 수소인 경우;R 1 is butyl, R 4 is
Figure PCTKR2016008070-appb-I000022
When R 6 is fluorine, R 2 , R 3 , R 5 , and R 7 are hydrogen;
R1은 펜틸, R4는
Figure PCTKR2016008070-appb-I000023
, R6는 플루오르, R2, R3, R5, 및 R7은 수소인 경우; 및R 1 is pentyl, R 4 is
Figure PCTKR2016008070-appb-I000023
When R 6 is fluorine, R 2 , R 3 , R 5 , and R 7 are hydrogen; And
R1은 펜틸, R4는
Figure PCTKR2016008070-appb-I000024
, R6는 플루오르, R2, R3, R5, 및 R7은 수소인 경우는 제외한다.R 1 is pentyl, R 4 is
Figure PCTKR2016008070-appb-I000024
, Except that R 6 is fluorine, R 2 , R 3 , R 5 , and R 7 are hydrogen.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 바람직한 예는 하기와 같다:Preferred examples of the compound represented by Formula 1 according to the present invention are as follows:
N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentanamide;
N-(4'-((N-페닐펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; N- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide;
N-(3-플루오로페닐)-N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentaneamide;
N-(4'-((N-3-플루오로페닐)펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; N- (4 '-(( N- 3-fluorophenyl) pentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide;
1-(3-플루오로페닐)-1-((4'-메톡시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아;1- (3-fluorophenyl) -1-((4'-methoxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea;
N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)-1-(4-메톡시페닐설폰일)메탄아마이드; N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methaneamide;
1-(3-플루오로페닐)-1-((4'-하이드록시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아;1- (3-fluorophenyl) -1-((4'-hydroxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea;
2-(4'-((1-(3-플루오로페닐)-3-(3-(트리플루오로메틸)페닐)유레이도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetic acid;
4-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)부탄산;4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoic acid;
2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)-2-메틸프로판산;2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) -2-methylpropanoic acid;
(E)-3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아크릴산;( E ) -3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylic acid;
3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)프로판산;3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) propanoic acid;
N-(3-플루오로페닐)-N-((4'-(2-(4-메틸피페라진-1-일)-2-옥소에톡시)바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((4 '-(2- (4-methylpiperazin-1-yl) -2-oxoethoxy) biphenyl-4-yl) methyl) pentaneamide;
프로프-2-인일 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트;Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate;
N-(3-플루오로페닐)-N-((4'-(프로프-2-이닐옥시)바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl) pentaneamide;
4'-((N-(2-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산;4 '-(( N- (2-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid;
4'-((N-(4-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산;4 '-(( N- (4-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid;
4'-((N-(2-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산;4 '-(( N- (2-methoxyphenyl) pentaneamido) methyl) biphenyl-3-carboxylic acid;
4'-((N-(3-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산;4 '-(( N- (3-methoxyphenyl) pentaneamido) methyl) biphenyl-3-carboxylic acid;
4'-((N-(4-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산;4 '-(( N- (4-methoxyphenyl) pentaneamido) methyl) biphenyl-3-carboxylic acid;
N-((2'-(4-메톡시피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((2 '-(4-methoxypiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentanamide;
N-((3'-(4-메틸피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((3 '-(4-methylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentanamide;
4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-2-카복실산;4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-2-carboxylic acid;
4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산;4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid;
N-(3-플루오로페닐)-N-((4'-(몰폴린-4-카보닐)-[1,1'-바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((4 '-(morpholine-4-carbonyl)-[1,1'-biphenyl-4-yl) methyl) pentaneamide;
N-(3-플루오로페닐)-N-((4'-(4-메틸피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((4 '-(4-methylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide;
N-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N-phenylpentanamide;
N-((4'-메톡시바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((4'-methoxybiphenyl-4-yl) methyl) -N -phenylpentanamide;
N-((4'-하이드록시바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((4'-hydroxybiphenyl-4-yl) methyl) -N -phenylpentanamide;
2-(4'-((N-페닐펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide;
N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide;
2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
N-(3-클로로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드; N- (3-chlorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide;
N-(3-클로로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드; N- (3-chlorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide;
2-(4'-((N-(3-클로로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
N-(3-브로모페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드; N- (3-bromophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide;
N-((4'-(하이드록시바이페닐-4-일)메틸)-N-(3-(트리플루오로메틸)페닐)펜탄아마이드; N -((4 '-(hydroxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide;
2-(4'-((N-(3-브로모페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
N-((4'-메톡시바이페닐-4-일)메틸)-N-(3-(트리플루오로메틸)페닐)펜탄아마이드; N -((4'-methoxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide;
N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드; N - ((4'- hydroxy-biphenyl-4-yl) methyl) - N - (3- nitrophenyl) pentane amide;
2-(4'-((N-(3-(트리플루오로메틸)페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N- (3- (trifluoromethyl) phenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
N-((4'메톡시바이페닐-4-일)메틸)-N-m-톨릴펜탄아마이드; N -((4'methoxybiphenyl-4-yl) methyl) -N - m -tolylpentaneamide;
N-((4'-하이드록시페닐-4-일)메틸)-N-m-톨릴펜탄아마이드; N -((4'-hydroxyphenyl-4-yl) methyl) -N - m -tolylpentaneamide;
2-(4'-((N-m-톨릴펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( Nm -tolylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
N-((4'-하이드록시페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드; N - ((4'- hydroxy-4-yl) methyl) - N - (3- nitrophenyl) pentane amide;
2-(4'-((N-(3-니트로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
N-(3-아이오도페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드; N- (3-iodophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide;
N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-아이오도페닐)펜탄아마이드; N - ((4'- hydroxy-biphenyl-4-yl) methyl) - N - (3- iodo-phenyl) pentane amide;
2-(4'-((N-(3-아이오도페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)아세트아마이드; N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) acetamide;
N-(3-플루오로페닐)-N-((4'-하이드록시-[1,1'-바이페닐]-4-일)메틸)아세트아마이드; N- (3-fluorophenyl) -N -((4'-hydroxy- [1,1'-biphenyl] -4-yl) methyl) acetamide;
2-((4'-((N-(3-플루오로페닐)아세트아미도)메틸)-[1,1'-바이페닐]-4-일)옥시)아세트산;2-((4 '-(( N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid;
N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide;
N-(4-플루오로페닐)-N-((4'-(4-아이소프로필피페라진-1-카보닐)-[1,1'-바이페닐]-4-일)메틸)펜탄아마이드; N- (4-fluorophenyl) -N -((4 '-(4-isopropylpiperazin-1-carbonyl)-[1,1'-biphenyl] -4-yl) methyl) pentaneamide;
N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 및 N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide; And
N-(4-플루오로페닐)-N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드. N- (4-fluorophenyl) -N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide.
본 발명에서 사용되는 "약학적으로 허용되는"이라는 용어는 과도한 독성, 자극, 알러지 반응 또는 기타 문제점 또는 합병증 없이 이득/위험 비가 합리적이어서 대상체 (예: 인간)의 조직과 접촉하여 사용하기에 적합하며 건전한 의학적 판단의 범주 이내인 화합물 또는 조성물을 의미한다.As used herein, the term "pharmaceutically acceptable" is suitable for use in contact with the tissue of a subject (eg, a human being) because the benefit / risk ratio is reasonable without excessive toxicity, irritation, allergic reactions or other problems or complications. A compound or composition is within the scope of sound medical judgment.
본 발명에서 사용되는 용어 "염"은 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.As used herein, the term "salt" is useful for acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1로 표시되는 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.The acid addition salts according to the present invention can be dissolved in conventional methods, for example, by dissolving a compound represented by the formula (1) in an excess of an aqueous solution of an acid, which salt is a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation using. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수도 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면, 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염 (예, 질산은)과 반응시켜 얻는다.Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
본 발명의 일실시예에서는 BLT2 억제 활성을 나타내는 신규 화합물을 제조하였으며 (실시예 1 내지 57 참조), 상기 신규 화합물 처리에 의한 BLT2 발현 세포의 성장 억제를 확인하였다 (실험예 2 참조). 또한, 항암제인 cisplatin과 복합 처리에 의해 암세포 사멸 증진시키며, BLT2 발현 세포의 주화성을 억제시킬 수 있음을 확인하였으며 (실험예 3 내지 4 참조), 본 발명의 화합물을 이용하여 LTB4와 BLT2 결합 저해효과를 확인하고 (실험예 5 참조), 천식이 유도된 마우스에서, 기도 과민성 감소 및 IL-4 생성 억제 효과를 구체적으로 확인하였는바 (실험예 6 참조) 염증성 질환 약학적 조성물로 매우 유용하게 사용될 수 있음을 확인하였다.In one embodiment of the present invention was prepared a novel compound exhibiting BLT2 inhibitory activity (see Examples 1 to 57), and confirmed the growth inhibition of BLT2 expressing cells by the novel compound treatment (see Experimental Example 2). In addition, it was confirmed that cancer cell death may be enhanced by complex treatment with cisplatin, an anticancer agent, and that chemotaxis of BLT2 expressing cells may be inhibited (see Experimental Examples 3 to 4), and LTB4 and BLT2 binding inhibition using the compound of the present invention. The effect was confirmed (see Experimental Example 5), and in asthma-induced mice, the effect of reducing airway hypersensitivity and the inhibition of IL-4 production was specifically identified (see Experimental Example 6). Confirmed that it can.
이에, 본 발명은 상기 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 염증성 질환 예방 또는 치료용 약학적 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에서 사용되는 용어, "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 염증성 질환을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.As used herein, the term "prevention" means any action that inhibits or delays the development of an inflammatory disease by administration of a pharmaceutical composition according to the present invention.
본 발명에서 사용되는 용어, "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 염증성 질환에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term "treatment" means any action that improves or advantageously alters the symptoms of an inflammatory disease by administration of a pharmaceutical composition according to the present invention.
본 발명에서, 염증성 질환은 BLT2 (Leukotriene B4 receptor 2)의 과발현에 기인한 질병으로, 천식, 죽상경화증, 암, 피부가려움증, 류마티스 관절염 및 염증성 장 질환에서 선택되는 1종 이상일 수 있으나, 이로써 제한되는 것은 아니다. 본 명세서에서 예시한 상기 질환 외에도, 당업계에 알려져 있는 BLT2-연관된 염증성 질환은 모두 본 발명의 화학식 1의 구조를 갖는 화합물로 예방 또는 치료할 수 있는 염증성 질환에 포함되는 것으로 본다. 한 구체적인 예에서, 상기 암은 BLT2 또는 종양 유전자 Ras의 과발현에 의해 유발된 임의의 암일 수 있다. 이에 제한되는 것은 아니나, 상기 암은 방광암, 전립선암, 췌장암, 유방암, 뇌종양, 피부암 및 간암으로 이루어진 군으로부터 선택되는 것일 수 있으며, 이로써 제한되는 것은 아니다. In the present invention, the inflammatory disease is due to overexpression of Leukotriene B4 receptor 2 (BLT2), and may be at least one selected from asthma, atherosclerosis, cancer, skin itch, rheumatoid arthritis and inflammatory bowel disease, but is limited thereto. It is not. In addition to the diseases exemplified herein, all BLT2-associated inflammatory diseases known in the art are considered to be included in inflammatory diseases that can be prevented or treated with a compound having the structure of Formula 1 of the present invention. In one specific example, the cancer may be any cancer caused by overexpression of BLT2 or the oncogene Ras. Although not limited thereto, the cancer may be selected from the group consisting of bladder cancer, prostate cancer, pancreatic cancer, breast cancer, brain tumor, skin cancer, and liver cancer, but is not limited thereto.
본 발명에서, BLT2 Leukotriene B4 receptor 2)는 GPCR(G protein-coupled receptor) 군 중 하나로 LTB4 (Leukotriene B4; LTB4)에 대해 낮은 친화력을 갖는 수용체로서, 본 발명의 조성물은 BLT2에 의한 세포 성장을 억제함으로써, 염증성 질환을 예방 또는 치료할 수 있다. 보다 구체적으로 BLT2 활성으로 유도된 ROS의 생성을 저해하여 LTB4-유도된 주화성을 저해할 수 있다. In the present invention, BLT2 Leukotriene B4 receptor 2) is one of the group of G protein-coupled receptors (GPCR), which has a low affinity for LTB 4 ( Leukotriene B4; LTB 4 ), and the composition of the present invention is a cell growth by By inhibiting the inflammatory disease can be prevented or treated. More specifically, the inhibition of the production of ROS induced by BLT2 activity may inhibit LTB 4 -induced chemotaxis.
본 발명에서 사용되는 용어, "저해"는 유전자의 전사, mRNA 프로세싱, 번역, 전좌 및 성숙 중 임의의 단계를 저해하거나, 단백질과 단백질간의 결합, 단백질의 활성화 또는 이를 통한 신호전달의 저해를 의미한다. As used herein, the term "inhibition" means inhibiting any step of transcription, mRNA processing, translation, translocation, and maturation of a gene, or inhibition of protein-to-protein binding, activation of a protein, or signaling through it. .
본 발명의 약학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함할 수 있다. 이때, 약제학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세 결정성셀룰로스, 폴리비닐피로리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필 히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일등을 포함하나, 이에 한정되는 것은 아니다. 또한, 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. At this time, the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. In addition to the above components, it may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The pharmaceutical compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 얄려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래 의 치료제와는 순차적 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.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level refers to the type of disease, the severity, the activity of the drug, It may be determined according to the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently and other factors well known in the medical field. The pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1kg 당 0.001 내지 150mg, 바람직하게는 0.01내지 100mg을 매일 또는 격일 투여하거나, 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감 될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general 0.001 to 150 mg, preferably 0.01 to 100 mg, per kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day. However, since the dose may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention by any method.
또한, 본 발명은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 염증성 질환의 치료방법을 제공한다. 본 발명에서 "개체"란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말 및 소 등의 포유류를 의미한다.The present invention also provides a method of treating an inflammatory disease comprising administering the pharmaceutical composition to a subject. As used herein, "individual" means a subject in need of treatment for a disease, and more specifically, a mammal, such as a primate, mouse, dog, cat, horse and cow, which is human or non-human. .
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.
[실시예]EXAMPLE
실시예Example 1.  One. NN -((3'-(4--((3 '-(4- 메틸페닐설폰아미도Methylphenylsulfonamido )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((3'-(4-methylphenylsulfonamido)biphenyl-4-yl)methyl)--((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-1079)의 제조-phenylpentanamide) (AC-1079)
단계 1 : 3'-나이트로바이페닐-4-카브알데하이드 (3'-nitrobiphenyl-4-carbaldehyde) 의 제조Step 1: Preparation of 3'-nitrobiphenyl-4-carbaldehyde
3-브로모나이트로벤젠 (3-Bromonitrobenzene) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.01 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한 번 더 15분 동안 탈기한 후, 가열하여 3시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 3'-나이트로바이페닐-4-카브알데하이드 (3'-nitrobiphenyl-4-carbaldehyde)를 수득하였다 (91% 수율).3-Bromonitrobenzene (1.0 equiv) and 4-Formylphenylboronic acid (1.1 equiv) are mixed well with RBF and then 1,4 dioxane (1,4 dioxane) : Dissolved in a H 2 O (10: 1) mixed solution. Pd (dppf) Cl 2 .DCM (0.01 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 3 hours. The reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain 3'-nitrobiphenyl. 4-Carbaldehyde (3'-nitrobiphenyl-4-carbaldehyde) was obtained (91% yield).
단계 2 : Step 2: NN -((3'--((3'- 나이트로바이페닐Nitrobiphenyl -4-일)-4- days) 메틸methyl )아닐린 (Aniline ( NN -((3'--((3'- nitrobiphenylnitrobiphenyl -4--4- ylyl )methyl)aniline)의 제조Manufacture of methyl) aniline)
상기 단계 1에서 수득한 3'-나이트로바이페닐-4-카브알데하이드 (1.0 equiv)와 아닐린 (Aniline) (3.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv)이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산 마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, N-((3'-나이트로바이페닐-4-일)메틸)아닐린 (N-((3'-nitrobiphenyl-4-yl)methyl)aniline)을 수득하였다 (79% 수율).3'-nitrobiphenyl-4-carbaldehyde (1.0 equiv) and aniline (Aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. Purification of the concentrate by Medium Pressure Liquid Chromatography (MPLC), N - (( 3'-nitro-biphenyl-4-yl) methyl) aniline (N - ((3'-nitrobiphenyl -4-yl) methyl) aniline ) Was obtained (79% yield).
단계 3 : Step 3: NN -((3'--((3'- 나이트로바이페닐Nitrobiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((3'--((3'- nitrobiphenylnitrobiphenyl -4-yl)methyl)--4-yl) methyl)- NN -phenylpentanamide)의 제조-phenylpentanamide)
상기 단계 ２에서 수득한　N-((3'-나이트로바이페닐-4-일)메틸)아닐린을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(3.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 N-((3'-나이트로바이페닐-4-일)메틸)-N-페닐펜탄아마이드 (N-((3'-nitrobiphenyl-4-yl)methyl)-N-phenylpentanamide)를 수득하였다 (88% 수율). N -((3'-nitrobiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then on ice Cooled. Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. Purification of the concentrate by Medium Pressure Liquid Chromatography (MPLC) N - ((3'- nitro-biphenyl-4-yl) methyl) - N - phenyl pentane amide (N - ((3'-nitrobiphenyl -4-yl ) methyl) -N- phenylpentanamide) was obtained (88% yield).
단계 4 : Step 4: NN -((3'--((3'- 아미노바이페닐Aminobiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((3'--((3'- aminobiphenylaminobiphenyl -4-yl)methyl)--4-yl) methyl)- NN -phenylpentanamide)의 제조-phenylpentanamide)
상기 단계 3에서 수득한 N-((3'-나이트로바이페닐-4-일)메틸)-N-페닐펜탄아마이드 (1.0 equiv)를 RBF에 잘 섞은 후, 메탄올을 가하였다. RBF를 냉각시킨 후, 10 % Pd/C (20wt%)를 가하였으며, 혼합 용액을 실온, H2 공급 조건에서 밤새도록 교반하였다. 상기 반응을 마친 후, 실리카 패드를 통해 여과시킨 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 N-((3'-아미노바이페닐-4-일)메틸)-N-페닐펜탄아마이드 (N-((3'-aminobiphenyl-4-yl)methyl)-N-phenylpentanamide)를 수득하였다 (92% 수율). N -((3'-nitrobiphenyl-4-yl) methyl) -N-phenylpentanamide (1.0 equiv) obtained in step 3 above was mixed well with RBF, and methanol was added thereto. After cooling the RBF, 10% Pd / C (20 wt%) was added and the mixed solution was stirred overnight at room temperature, H 2 feed conditions. After the reaction was completed, the resultant was filtered through a pad of silica, and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((3'-aminobiphenyl-4-yl) methyl) -N-phenylpentaneamide (N-((3'-aminobiphenyl-4-yl) methyl) -N-phenylpentanamide) was obtained (92% yield).
단계 5 : Step 5: NN -((3'-(4--((3 '-(4- 메틸페닐설폰아미도Methylphenylsulfonamido )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((3'-(4-methylphenylsulfonamido)biphenyl-4-yl)methyl)--((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl)- NN -phenylpentanamide)의 제조-phenylpentanamide)
상기 4 단계에서 수득한 N-((3'-아미노바이페닐-4-일)메틸)-N-페닐펜탄아마이드(1.0 equiv)와 Triethylamine (2.0 equiv)을 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 이 후, 4-methoxybenzene sulfonyl chloride (1.5 equiv)를 가한 후, 실온에서 밤새도록 교반하였다. 상기 반응을 마친 후, DCM을 증발시켜 농축하였다. 상기 농축액을 컬럼 크로마토그래피로 정제하여 최종 생성물인 N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)-N-페닐펜탄아마이드 (N-((3'-(4-methylphenylsulfonamido)biphenyl-4-yl)methyl)-N-phenylpentanamide)을 수득하였다 (25% 수율). N -((3'-aminobiphenyl-4-yl) methyl) -N -phenylpentaneamide (1.0 equiv) and Triethylamine (2.0 equiv) obtained in step 4 were added to a dichloromethane (DCM) solution. After thawing, it was cooled on ice. Thereafter, 4-methoxybenzene sulfonyl chloride (1.5 equiv) was added, followed by stirring overnight at room temperature. After the reaction was completed, DCM was concentrated by evaporation. The concentrate was purified by column chromatography to give the final product, N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentanamide ( N -((3'- (4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N- phenylpentanamide) was obtained (25% yield).
1H-NMR (CDCl3, 400MHz) δ 7.67 (2H, d, J = 8.0 Hz); 7.39-7.31 (7H, m); 7.23 (3H, d, J = 8.4 Hz); 7.01 (3H, d, J = 8.4 Hz); 6.54 (1H, s); 4.90 (2H, s); 2.38 (3H, s); 2.09 (2H, t); 1.61-1.56 (2H, m); 1.26-1.20 (2H, m); 0.82 (3H, t). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.67 (2H, d, J = 8.0 Hz); 7.39-7. 31 (7H, m); 7.23 (3H, doublet, J = 8.4 Hz); 7.01 (3H, doublet, J = 8.4 Hz); 6.54 (1 H, s); 4.90 (2H, s); 2.38 (3 H, s); 2.09 (2H, t); 1.61-1.56 (2H, m); 1.26-1.20 (2H, m); 0.82 (3 H, t).
실시예Example 2.  2. NN -(4'-((N--(4 '-((N- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -3-일)-4-(-3- days) -4- ( 트리플루오로메틸Trifluoromethyl )) 벤즈아마이드Benzamide ( ( NN -(4'-((-(4'-(( NN -phenylpentanamido)methyl)biphenyl-3-yl)-4-(trifluoromethyl)benzamide) (AC-1310)의 제조Preparation of -phenylpentanamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide) (AC-1310)
상기 실시예 1의 단계 4에서 수득한 N-((3'-아미노바이페닐-4-일)메틸)-N-페닐펜탄아마이드, 트리플루오로메틸-p-톨루엔산 (Trifluromethyl-p-toluic acid) (1.2 equiv), EDC (1.2 equiv), HOBt (1.2 equiv), 및 N,N-다이아이소프로필에틸아민 (DIPEA) (1.2 equiv)을 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 실온에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였다. 에틸 아세테이트 (EA)로 수용성 층을 추출하였으며, 유기 용매층을 여과하고, 증발시켜 농축하였다. 상기 농축액을 컬럼 크로마토 그래피로 정제하여 최종 생성물인 N-(4'-((N-페닐펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드 (N-(4'-((N-phenylpentanamido)methyl)biphenyl-3-yl)-4-(trifluoromethyl)benzamide)를 수득하였다 (25% 수율).Obtained in Step 4 of Example 1 N - ((3'- amino-biphenyl-4-yl) methyl) - N - phenyl pentane amide, trifluoromethyl -p- toluic acid (p-toluic acid by-Trifluromethyl ) (1.2 equiv), EDC (1.2 equiv), HOBt (1.2 equiv), and N , N -diisopropylethylamine (DIPEA) (1.2 equiv) in a dichloromethane (DCM) solution, Stir overnight at. After the reaction was completed, water was added. The aqueous layer was extracted with ethyl acetate (EA) and the organic solvent layer was filtered, evaporated and concentrated. The concentrate was purified by column chromatography to give the final product, N- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide ( N- (4 '-(( N- phenylpentanamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide) was obtained (25% yield).
1H-NMR (CDCl3, 400MHz) δ 8.45 (1H, s); 8.03 (2H, d, J = 8.0 Hz); 7.89 (1H, s); 7.73 (2H, d, J = 8.4 Hz); 7.67 (1H, d, J = 7.6 Hz); 7.49 (2H, d, J = 8.0 Hz); 7.44-7.38 (2H, m); 7.36-7.31 (3H, m); 7.238 (2H, d, J = 8.4 Hz); 7.00-6.98 (2H, m); 4.89 (2H, s); 2.06 (2H, t); 1.58-1.54 (2H, m); 1.23-1.169 (2H, m); 0.78 (3H, t). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.45 (1H, s); 8.03 (2H, doublet, J = 8.0 Hz); 7.89 (1 H, s); 7.73 (2H, doublet, J = 8.4 Hz); 7.67 (1H, doublet, J = 7.6 Hz); 7.49 (2H, doublet, J = 8.0 Hz); 7.44-7.38 (2H, m); 7.36-7.31 (3H, m); 7.238 (2H, doublet, J = 8.4 Hz); 7.00-6.98 (2H, m); 4.89 (2H, s); 2.06 (2H, t); 1.58-1.54 (2H, m); 1.23-1.169 (2H, m); 0.78 (3H, t).
실시예Example 3.  3. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((3'-(4--((3 '-(4- 메틸페닐설폰아미도Methylphenylsulfonamido )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-fluorophenyl)--(3-fluorophenyl)- NN -((3'-(4-methylphenylsulfonamido)biphenyl-4-yl)methyl)pentanamide) (AC--((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentanamide) (AC- 1080)의1080 제조 Produce
단계 1 : (3-Step 1: (3- 플루오로Fluoro -((3'--((3'- 나이트로바이페닐Nitrobiphenyl -4-일)-4- days) 메틸methyl )아닐린 (3-Aniline (3- fluorofluoro -- NN -((3'--((3'- nitrobiphenylnitrobiphenyl -4-yl)methyl)aniline)의 제조 Preparation of -4-yl) methyl) aniline)
상기 실시예 1의 단계 1에서 수득한 3'-나이트로바이페닐-4-카브알데하이드 (1.0 equiv)와 3-플루오로아닐린 (3-fluoroaniline) (3.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv)이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산 마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, (3-플루오로-((3'-나이트로바이페닐-4-일)메틸)아닐린 (3-fluoro-N-((3'-nitrobiphenyl-4-yl)methyl)aniline)을 수득하였다 (81% 수율).3'-nitrobiphenyl-4-carbaldehyde (1.0 equiv) and 3-fluoroaniline (3-fluoroaniline) (3.0 equiv) obtained in step 1 of Example 1 were dissolved in methanol, and then at room temperature. Stir for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give (3-fluoro-((3'-nitrobiphenyl-4-yl) methyl) aniline (3-fluoro- N -((3'-nitrobiphenyl -4-yl) methyl) aniline) was obtained (81% yield).
단계 ２ : (Step 2: ( NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((3'--((3'- 나이트로바이페닐Nitrobiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-fluorophenyl)--(3-fluorophenyl)- NN -((3'-nitrobiphenyl-4-yl)methyl)pentanamide)의 제조Preparation of-((3'-nitrobiphenyl-4-yl) methyl) pentanamide)
상기 단계 1에서 수득한　(3-플루오로-((3'-나이트로바이페닐-4-일)메틸)아닐린을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(3.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산 마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 (N-(3-플루오로페닐)-N-((3'-나이트로바이페닐-4-일)메틸)펜탄아마이드 (N-(3-fluorophenyl)-N-((3'-nitrobiphenyl-4-yl)methyl)pentanamide)를 수득하였다 (8７% 수율).(3-fluoro-((3'-nitrobiphenyl-4-yl) methyl) aniline obtained in step 1 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. After the reaction was completed, valeroyl chloride (3.0 equiv) was added, followed by stirring at room temperature for 4 hours, after completion of the reaction, RBF was added thereto, and the organic solvent layer was added thereto. After washing with brine and separating, the organic solvent layers were combined, the water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered and evaporated to concentrate the concentrated solution by Medium Pressure Liquid Chromatography (MPLC). to (N - (3- fluorophenyl) - N - ((3'-nitro-biphenyl-4-yl) methyl) pentane amide (N - (3-fluorophenyl) - N - ((3'-nitrobiphenyl- 4-yl) methyl) pentanamide) was obtained (8 7% yield).
단계 3 : Step 3: NN -((3'--((3'- 아미노바이페닐Aminobiphenyl -4-일)-4- days) 메틸methyl )-)- NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아마이드Pentaneamide ( ( NN -((3'-aminobiphenyl-4-yl)methyl)--((3'-aminobiphenyl-4-yl) methyl)- NN -(3-fluorophenyl)pentanamide)의 제조Preparation of-(3-fluorophenyl) pentanamide)
상기 단계 2에서 수득한 (N-(3-플루오로페닐)-N-((3'-나이트로바이페닐-4-일)메틸)펜탄아마이드 (1.0 equiv)를 RBF에 잘 섞은 후, 메탄올을 가하였다. RBF를 냉각시킨 후, 10 % Pd/C (20wt%)를 가하였으며, 혼합 용액을 실온, H2 공급 조건에서 밤새도록 교반하였다. 상기 반응을 마친 후, 실리카 패드를 통해 여과시킨 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 N-((3'-아미노바이페닐-4-일)메틸)-N-(3-플루오로페닐)펜탄아마이드 (N-((3'-aminobiphenyl-4-yl)methyl)-N-(3-fluorophenyl)pentanamide)를 수득하였다 (89% 수율).( N- (3-fluorophenyl) -N -((3'-nitrobiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in step 2 was mixed well with RBF, and methanol After cooling the RBF, 10% Pd / C (20wt%) was added and the mixed solution was stirred overnight at room temperature, H 2 feed conditions, after completion of the reaction, filtered through a pad of silica ., and then concentrated by evaporation the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) N - ((3'- amino-biphenyl-4-yl) methyl) - N - pentane amide (3-fluorophenyl) (N - ((3'-aminobiphenyl-4 -yl) methyl) - N - (3-fluorophenyl) pentanamide a) was obtained (89% yield).
단계 4 : Step 4: NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((3'-(4--((3 '-(4- 메틸페닐설폰아미도Methylphenylsulfonamido )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-fluorophenyl)--(3-fluorophenyl)- NN -((3'-(4-methylphenylsulfonamido)biphenyl-4-yl)methyl)pentanamide)의 제조Preparation of-((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentanamide)
상기 단계 3에서 수득한 N-((3'-아미노바이페닐-4-일)메틸)-N-(3-플루오로페닐)펜탄아마이드(1.0 equiv)와 Triethylamine (2.0 equiv)을 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 이 후, 4-methoxybenzene sulfonyl chloride (1.5 equiv)를 가한 후, 실온에서 밤새도록 교반하였다. 상기 반응을 마친 후, DCM을 증발시켜 농축하였다. 상기 농축액을 컬럼크로마토그래피로 정제하여 최종 생성물인 N-(3-플루오로페닐)-N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)펜탄아마이드 (N-(3-fluorophenyl)-N-((3'-(4-methylphenylsulfonamido)biphenyl-4-yl)methyl)pentanamide)을 수득하였다 (25% 수율). N obtained in the Step 3 - ((3'-amino-biphenyl-4-yl) methyl) - N - (3-fluorophenyl) pentane amide (1.0 equiv) and Triethylamine (2.0 equiv) and dichloromethane ( dichloromethane, DCM) solution, and then cooled on ice. Thereafter, 4-methoxybenzene sulfonyl chloride (1.5 equiv) was added, followed by stirring overnight at room temperature. After the reaction was completed, DCM was concentrated by evaporation. The concentrate was purified by column chromatography to obtain the final product, N- (3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentaneamide ( N -(3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentanamide) was obtained (25% yield).
1H-NMR (CDCl3, 400MHz) δ 7.67 (2H, d, J = 8.0 Hz); 7.39-7.31 (7H, m); 7.23 (3H, d, J = 8.4 Hz); 7.01 (3H, d, J = 8.4 Hz); 6.54 (1H, s); 4.90 (2H, s); 2.38 (3H, s); 2.09 (2H, t); 1.61-1.56 (2H, m); 1.26-1.20 (2H, m); 0.82 (3H, t). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.67 (2H, d, J = 8.0 Hz); 7.39-7. 31 (7H, m); 7.23 (3H, doublet, J = 8.4 Hz); 7.01 (3H, doublet, J = 8.4 Hz); 6.54 (1 H, s); 4.90 (2H, s); 2.38 (3 H, s); 2.09 (2H, t); 1.61-1.56 (2H, m); 1.26-1.20 (2H, m); 0.82 (3 H, t).
실시예Example 4.  4. NN -(4'-((-(4'-(( NN -3--3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3-일)-4-(-3- days) -4- ( 트리플루오로메틸Trifluoromethyl )) 벤즈아마이드Benzamide ( ( NN -(4'-((-(4'-(( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )methyl)biphenyl-3-) methyl) biphenyl-3- ylyl )-4-()-4-( trifluoromethyltrifluoromethyl )) benzamidebenzamide ) (AC-1311)의 제조) (AC-1311) Preparation
상기 실시예 3의 단계 3에서 수득한 N-((3'-아미노바이페닐-4-일)메틸)-N-(3-플루오로페닐)펜탄아마이드, 트리플루오로메틸-p-톨루엔산 (Trifluromethyl-p-toluic acid) (1.2 equiv), EDC (1.2 equiv), HOBt (1.2 equiv), 및 N,N-다이아이소프로필에틸아민 (DIPEA) (1.2 equiv)을 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 실온에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였다. 에틸 아세테이트 (EA)로 수용성 층을 추출하였으며, 유기 용매층을 여과하고, 증발시켜 농축하였다. 상기 농축액을 컬럼크로마토그래피로 정제하여 최종 생성물인 N-(4'-((N-3-플루오로페닐)펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드 (N-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-3-yl)-4-(trifluoromethyl)benzamide)를 수득하였다 (25% 수율). N obtained in Step 3 in Example 3 - ((3'-amino-biphenyl-4-yl) methyl) - N - pentane amide, methyl -p- toluic acid trifluoroacetate (3-fluorophenyl) ( Trifluromethyl-p-toluic acid (1.2 equiv), EDC (1.2 equiv), HOBt (1.2 equiv), and N , N -diisopropylethylamine (DIPEA) (1.2 equiv) in dichloromethane, DCM After dissolving in solution, it was stirred overnight at room temperature. After the reaction was completed, water was added. The aqueous layer was extracted with ethyl acetate (EA) and the organic solvent layer was filtered, evaporated and concentrated. The concentrate was purified by column chromatography to give the final product, N- (4 '-(( N- 3-fluorophenyl) pentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide (N - (4 '- ( (N - (3-fluorophenyl) pentanamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide) was obtained (25% yield).
1H-NMR (CDCl3, 400MHz) δ 8.20 (1H, br, s); 8.03 (2H, d, J = 8.4 Hz); 7.89 (1H, m); 7.76 (2H. d. J = 8.0 Hz); 7.65 (1H, d, J = 8.0 Hz); 7.51 (2H, d, J = 8.0 Hz); 7.46-738 (2H, m); 7.34-7.28 (1H, m); 7.25 (2H, d, J = 8.4 Hz); 7.06-7.02 (1H, m); 6.81-6.74 (2H, m); 4.90 (2H, s); 2.08 (2H. t); 1.64-1.55 (2H, m); 1.33-1.19 (2H, m); 0.84 (3H,t). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.20 (1H, br, s); 8.03 (2H, doublet, J = 8.4 Hz); 7.89 (1 H, m); 7.76 (2H. D. J = 8.0 Hz); 7.65 (1H, doublet, J = 8.0 Hz); 7.51 (2H, doublet, J = 8.0 Hz); 7.46-738 (2H, m); 7.34-7.28 (1 H, m); 7.25 (2H, doublet, J = 8.4 Hz); 7.06-7.02 (1 H, m); 6.81-6.74 (2H, m); 4.90 (2H, s); 2.08 (2H. T); 1.64-1.55 (2H, m); 1.33-1.19 (2H, m); 0.84 (3H, t).
실시예Example 5. 1-(3- 5. 1- (3- 플루오로페닐Fluorophenyl )-1-((4'-) -1-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-3-(3-() -3- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)) Phenyl) 유레아Urea (1-(3- (1- (3- fluorophenylfluorophenyl )-1-((4'-) -1-((4'- methoxybiphenylmethoxybiphenyl -4--4- ylyl )methyl)-3-(3-() methyl) -3- (3- ( trifluoromethyltrifluoromethyl )phenyl)urea) (AC-1317)의 제조 Preparation of) phenyl) urea) (AC-1317)
단계 1 : 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)의 제조Step 1: Preparation of 4'-methoxybiphenyl-4-carbaldehyde
4-브로모아니솔 (4-Bromoanisole) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 dioxane : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.01 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한 번 더 15분 동안 탈기한 후, 가열하여 3시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 EA를 통해 여과, 추출한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)를 수득하였다 (63% 수율).4-Bromoanisole (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) were mixed well in RBF, followed by 1,4 dioxane: H 2 O (10: 1) It was dissolved in the mixed solution. Pd (dppf) Cl 2 .DCM (0.01 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 3 hours. After the reaction mixture was filtered and extracted through EA, water was removed with anhydrous magnesium sulfate (MgSO 4 ), concentrated by evaporation, and purified by Medium Pressure Liquid Chromatography (MPLC) to 4'-methoxybi. Phenyl-4-carbaldehyde (4'-methoxybiphenyl-4-carbaldehyde) was obtained (63% yield).
단계 step 2 : 32: 3 -- 플루오로Fluoro -- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )아닐린 (3-Aniline (3- fluorofluoro -- NN -((4'--((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)aniline)의 제조Preparation of -4-yl) methyl) aniline)
상기 단계 1에서 수득한 4-메톡시바이페닐-4-카브알데하이드 (1.0 equiv)와 3-플루오로아닐린 (3-fluroaniline) (3.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 3-플루오로-N-((4'-메톡시바이페닐-4-일)메틸)아닐린 (3-fluoro-N-((4'-methoxybiphenyl-4-yl)methyl)aniline)을 수득하였다 (63% 수율).4-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and 3-fluoroaniline (3-fluroaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. . The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give 3-fluoro-N-((4'-methoxybiphenyl-4-yl) methyl) aniline (3-fluoro-N-((4'- methoxybiphenyl-4-yl) methyl) aniline) was obtained (63% yield).
단계 step 3 : 13: 1 -(3--(3- 플루오로페닐Fluorophenyl )-1-((4'-) -1-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-3-(3-() -3- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)) Phenyl) 유레아Urea (1-(3- (1- (3- fluorophenylfluorophenyl )-1-((4'-) -1-((4'- methoxybiphenylmethoxybiphenyl -4--4- ylyl )methyl)-3-(3-() methyl) -3- (3- ( trifluoromethyltrifluoromethyl )phenyl)urea)의 제조Preparation of) phenyl) urea)
상기 단계 2에서 수득한 3-플루오로-N-((4-메톡시바이페닐-4-일)메틸)아닐린을 테트라하이드로퓨란 (tetrahydrofuran, THF) 용액에 녹인 후, 트리플루오로메틸페닐 이소시아네이트 (trifluromethylphenyl isocyanate) (1.0 equiv)를 가하고, 혼합 용액을 밤새도록 교반하였으며, 반응을 마친 후, silica를 가하여 RBF와 조생성물(crude product)를 흡착시켰으며, Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 최종 생성물인 1-(3-플루오로페닐)-1-((4'-메톡시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아 (1-(3-fluorophenyl)-1-((4'-methoxybiphenyl-4-yl)methyl)-3-(3-(trifluoromethyl)phenyl)urea)를 수득하였다 (23.4% 수율).3-fluoro- N -((4-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in tetrahydrofuran (THF) solution, and then trifluoromethylphenyl isocyanate (trifluromethylphenyl isocyanate) (1.0 equiv) was added, the mixed solution was stirred overnight, and after completion of the reaction, silica was added to adsorb RBF and the crude product, which was purified by Medium Pressure Liquid Chromatography (MPLC). Product 1- (3-fluorophenyl) -1-((4'-methoxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea (1- (3 -fluorophenyl) -1-((4'-methoxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea) was obtained (23.4% yield).
1H-NMR (CDCl3, 400MHz)δ 7.61 (1H, s); 7.53-7.48 (5H, m); 7.45-7.35 (2H, m); 7.32-7.29 (3H, m); 7.14-7.09 (1H, m); 7.02 (1H, d, J = 8.4 Hz); 6.96 (3H, d, J = 8.8 Hz); 6.32 (1H, s, br); 4.96 (2H, s); 3.85 (3H, s). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.61 (1H, s); 7.53-7.48 (5H, m); 7.45-7.35 (2H, m); 7.32-7.29 (3H, m); 7.14-7.09 (1 H, m); 7.02 (1H, doublet, J = 8.4 Hz); 6.96 (3H, doublet, J = 8.8 Hz); 6.32 (1H, s, br); 4.96 (2H, s); 3.85 (3 H, s).
실시예Example 6.  6. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-1-(4-) -1- (4- 메톡시페닐설폰일Methoxyphenylsulfonyl )) 메탄아마이드Methane amide ( ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'--((4'- methoxybiphenylmethoxybiphenyl -4--4- ylyl )methyl)-1-(4-methoxyphenylsulfonyl)methanamide) (AC-1312)의 제조 Preparation of) methyl) -1- (4-methoxyphenylsulfonyl) methanamide) (AC-1312)
상기 실시예 5의 단계 2에서 수득한 3-플루오로-N-((4-메톡시바이페닐-4-일)메틸)아닐린과 TEA (2.0 equiv)를 RBF에 녹인 후, DCM 을 가하였다. 상기 혼합 용액을 0℃에서 교반하면서 냉각시켰다. 이후, 4-메톡시벤젠-1-설폰일 클로라이드 (4-methoxybenzen-1-sulfonyl chloride) (1.5 equiv)를 가하고, 실온에서 밤새도록 교반하였다. 상기 혼합 용액에서 DCM을 진공 상태에서 증발시켜 농축시켰다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)-1-(4-메톡시페닐설폰일)메탄아마이드 (N-(3-fluorophenyl)-N-((4'-methoxybiphenyl-4-yl)methyl)-1-(4-methoxyphenylsulfonyl)methanamide)를 수득하였다 (61% 수율).3-fluoro- N -((4-methoxybiphenyl-4-yl) methyl) aniline and TEA (2.0 equiv) obtained in step 2 of Example 5 were dissolved in RBF, and DCM was added thereto. The mixed solution was cooled with stirring at 0 ° C. Then 4-methoxybenzen-1-sulfonyl chloride (1.5 equiv) was added and stirred overnight at room temperature. In the mixed solution, DCM was concentrated by evaporation in vacuo. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final product N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4- Methoxyphenylsulfonyl) methaneamide ( N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methanamide) was obtained (61% yield). .
1H-NMR (CDCl3, 400MHz)δ 7.62-7.59 (2H, m); 7.48-7.45 (2H, m); 7.43 (2H, d, J = 8.0 Hz); 7.26 (2H, d, J = 0.8 Hz); 7.21-7.15 (1H, m); 6.99-6.89 (5H, m); 6.85-6.83 (1H, m); 6.79-6.76 (1H, m); 4.72 (2H, s); 3.91 (3H, s); 3.83 (3H, s). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.62-7.59 (2H, m); 7.48-7.45 (2H, m); 7.43 (2H, doublet, J = 8.0 Hz); 7.26 (2H, doublet, J = 0.8 Hz); 7.21-7.15 (1 H, m); 6.99-6.89 (5H, m); 6.85-6.83 (1 H, m); 6.79-6.76 (1 H, m); 4.72 (2H, s); 3.91 (3H, s); 3.83 (3 H, s).
실시예Example 7. 1-(3- 7. 1- (3- 플루오로페닐Fluorophenyl )-1-((4'-) -1-((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-3-(3-() -3- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)유레아 (1-(3-) Phenyl) urea (1- (3- fluorophenylfluorophenyl )-1-((4'-) -1-((4'- hydroxybiphenylhydroxybiphenyl -4--4- ylyl )methyl)-3-(3-(trifluoromethyl)phenyl)urea) (AC-1318)의 제조Preparation of) methyl) -3- (3- (trifluoromethyl) phenyl) urea) (AC-1318)
상기 실시예 5에서 수득한 1-(3-플루오로페닐)-1-((4'-메톡시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아 (1.0 equiv)를 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 0℃에서, BBr3를 천천히 가하였으며, 실온에서 3시간 동안 혼합 용액을 교반하였다. 상기 반응을 TLC (thin Layer Chromatography)로 관찰하였다. 반응을 마친 후, RBF에 얼음을 가하고, DCM에서 추출하였다. 유기 용매층을 분리하고. 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하였으며, 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 1-(3-플루오로페닐)-1-((4'-하이드록시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아 (1-(3-fluorophenyl)-1-((4'-hydroxybiphenyl-4-yl)methyl)-3-(3-(trifluoromethyl)phenyl)urea)를 수득하였다 (55% 수율).1- (3-fluorophenyl) -1-((4'-methoxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea obtained in Example 5 above (1.0 equiv) was dissolved in dichloromethane (DCM) solution and cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final product 1- (3-fluorophenyl) -1-((4'-hydroxybiphenyl-4-yl) methyl) -3- (3- (Trifluoromethyl) phenyl) urea (1- (3-fluorophenyl) -1-((4'-hydroxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea) was obtained ( 55% yield).
1H-NMR (CDCl3, 400MHz) δ 7.60 (1H, s); 7.53 (1H, d, J = 7.4 Hz); 7.48-7.45 (4H, m); 7.43-7.35 (2H, m); 7.31 (3H, d, J = 8.0 Hz); 7.14-7.09 (1H, m); 7.02 (1H, d, J = 8.0 Hz); 6.98-6.95 (1H, m); 6.91-6.88 (2H, m); 6.33 (1H, s); 4.96 (2H, s); 4.85 (1H, s). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.60 (1H, s); 7.53 (1H, doublet, J = 7.4 Hz); 7.48-7.45 (4H, m); 7.43-7.35 (2H, m); 7.31 (3H, doublet, J = 8.0 Hz); 7.14-7.09 (1 H, m); 7.02 (1H, doublet, J = 8.0 Hz); 6.98-6.95 (1 H, m); 6.91-6.88 (2H, m); 6.33 (1 H, s); 4.96 (2H, s); 4.85 (1 H, s).
실시예Example 8. 2-(4'-((1-(3- 8. 2- (4 '-((1- (3- 플루오로페닐Fluorophenyl )-3-(3-() -3- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)) Phenyl) 유레이도Eureido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((1-(3-Acetic acid (2- (4 '-((1- (3- fluorophenylfluorophenyl )-3-(3-() -3- (3- ( trifluoromethyltrifluoromethyl )phenyl)) phenyl) ureidoureido )methyl)biphenyl-4-yloxy)acetic acid) (AC-1320)의 제조Preparation of) methyl) biphenyl-4-yloxy) acetic acid) (AC-1320)
단계 1 : 에틸-2-(4'-((1-(3-Step 1: ethyl-2- (4 '-((1- (3- 플루오로페닐Fluorophenyl )-3-(3-() -3- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)) Phenyl) 유레이도Eureido )) 메틸methyl )) 바이페닐Biphenyl -4-일옥시)아세테이트 (Ethyl-2-(4'-((1-(3-4-yloxy) acetate (Ethyl-2- (4 '-((1- (3- fluorophenylfluorophenyl )-3-(3-(trifluoromethyl)phenyl)ureido)methyl)biphenyl-4-yloxy)acetate)의 제조) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetate)
상기 실시예 7에서 수득한 1-(3-플루오로페닐)-1-((4'-하이드록시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아 (1.0 equiv)와 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 에틸클로로아세테이트 (Ethylchloroacetate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산 마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 에틸-2-(4'-((1-(3-플루오로페닐)-3-(3-(트리플루오로메틸)페닐)유레이도)메틸)바이페닐-4-일옥시)아세테이트 (Ethyl-2-(4'-((1-(3-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)ureido)methyl)biphenyl-4-yloxy)acetate)수득하였다 (96% 수율).1- (3-fluorophenyl) -1-((4'-hydroxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea obtained in Example 7 above (1.0 equiv) and K 2 CO 3 (3.0 equiv) were dissolved in N, N -dimethylformamide (DMF) solution and then cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl-2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl ) Biphenyl-4-yloxy) acetate (Ethyl-2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetate ) (96% yield).
단계 step 2 : 22: 2 -(4'-((1-(3--(4 '-((1- (3- 플루오로페닐Fluorophenyl )-3-(3-() -3- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)) Phenyl) 유레이도Eureido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((1-(3-Acetic acid (2- (4 '-((1- (3- fluorophenylfluorophenyl )-3-(3-() -3- (3- ( trifluoromethyltrifluoromethyl )phenyl)) phenyl) ureidoureido )methyl)biphenyl-4-yloxy)acetic acid)의 제조) methyl) biphenyl-4-yloxy) acetic acid)
상기 단계 1에서 수득한 에틸-2-(4'-((1-(3-플루오로페닐)-3-(3-(트리플루오로메틸)페닐)유레이도)메틸)바이페닐-4-일옥시)아세테이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 최종 생성물인 2-(4'-((1-(3-플루오로페닐)-3-(3-(트리플루오로메틸)페닐)유레이도)메틸)바이페닐-4-일옥시)아세트산 (2-(4'-((1-(3-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)ureido)methyl)biphenyl-4-yloxy)acetic acid)을 수득하였다 (96% 수율).Ethyl-2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yljade obtained in step 1 above. C) acetate (1.0 equiv) was mixed well with tetrahydrofuran (THF), then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and the final product 2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl 4-yloxy) acetic acid (2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetic acid) was obtained. (96% yield).
1H-NMR (CDCl3, 400MHz) δ 7.61 (1H, s); 7.52-7.47 (5H, m); 7.45-7.35 (2H, m); 7.32-7.26 (3H, m); 7.09-7.15 (1H, m); 7.02-7.00 (1H, d, J = 8.4 Hz); 6.98-6.96 (3H, d, J = 8.4 Hz); 6.32 (1H, s); 4.96 (2H, s); 4.66 (2H, s); 4.31-4.26 (2H, q); 1.26 (3H, t). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.61 (1H, s); 7.52-7.47 (5H, m); 7.45-7.35 (2H, m); 7.32-7.26 (3H, m); 7.09-7.15 (1 H, m); 7.02-7.00 (1H, doublet, J = 8.4 Hz); 6.98-6.96 (3H, d, J = 8.4 Hz); 6.32 (1 H, s); 4.96 (2H, s); 4.66 (2H, s); 4.31-4.26 (2H, q); 1.26 (3 H, t).
실시예Example 9. 4-(4'-(( 9. 4- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )부탄산 (4-(4'-((Butanoic acid (4- (4 '-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)butanoic acid) (AC-1322)의 제조Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoic acid) (AC-1322)
단계 1 : Step 1: NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-fluorophenyl)--(3-fluorophenyl)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide)의 제조Preparation of-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
상기 실시예 5의 단계 ２에서 수득한 3-플루오로-N-((4'-메톡시바이페닐-4-일)메틸)아닐린을다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride) (3.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후 유개 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (N-(3-fluorophenyl)-N-((4'-methoxybiphenyl-4-yl)methyl)pentanamide)를 수득하였다 (100% 수율).3-fluoro- N -((4'-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 of Example 5 was dissolved in dichloromethane (DCM) and triethanolamine , TEA) was added and then cooled on ice. Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide ( N- (3-fluorophenyl ) -N -((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (100% yield).
단계 2 : Step 2: NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-fluorophenyl)--(3-fluorophenyl)- NN -((4'-hydroxybiphenyl-4-yl)methyl)pentanamide)의 제조Preparation of-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide)
상기 단계 1에서 수득한 N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (1.0 equiv)를 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 0℃에서, BBr3를 천천히 가하였으며, 실온에서 3시간 동안 혼합 용액을 교반하였다. 상기 반응을 TLC (thin Layer Chromatography)로 관찰하였다. 반응을 마친 후, RBF에 얼음을 가하고, DCM에서 추출하였다. 유기 용매층을 분리하고. 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하였으며, 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드 (N-(3-fluorophenyl)-N-((4'-hydroxybiphenyl-4-yl)methyl)pentanamide)를 수득하였다 (85% 수율). N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in step 1 was diluted with dichloromethane (DCM). After melting in, cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide ( N- (3-fluorophenyl ) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) was obtained (85% yield).
단계 3 : 에틸 4-(4'-((Step 3: ethyl 4- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )) 부타노에이트Butanoate (Ethyl 4-(4'-(( (Ethyl 4- (4 '-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)butanoate)의 제조Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoate)
상기 단계　２에서 수득한 N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드 (1.0 equiv)와 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 에틸 4-클로로부타노에이트 (Ethyl 4-chlorobutanoate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트 (EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산 마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 에틸 4-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)부타노에이트 (Ethyl 4-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)butanoate)를 수득하였다 (92% 수율). N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in step 2 were prepared. It was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. Ethyl 4-chlorobutanoate (3.0 equiv) was added and the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoate (Ethyl 4- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoate) was obtained (92% yield).
단계 step 4 : 44: 4 -(4'-((-(4'-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )부탄산 (4-(4'-((Butanoic acid (4- (4 '-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)butanoic acid)의 제조Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoic acid)
상기 단계 3에서 수득한 에틸 4-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)부타노에이트 (Ethyl 4-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)butanoate)를 테트라하이드로퓨란 (tetrahydrofuran, THF) 용액에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 상기 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 최종 생성물인 4-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)부탄산 (4-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)butanoic acid)를 수득하였다 (100% 수율)Ethyl 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoate obtained in step 3 (Ethyl 4- (4'-( ( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoate) was mixed well with tetrahydrofuran (THF) solution, LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and the final product was 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoic acid (4- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoic acid) was obtained (100% yield).
1H-NMR (DMSO-D6, 400 MHz) δ 12.2 (1H, br, s); 7.58-7.53 (4H, m); 7.43-7.41 (1H, m); 7.23 (2H, d, J = 8.0 Hz); 7.20-7.17 (2H, m); 7.05 (1H, d, J = 8.4 Hz); 7.00 (2H, d, J = 8.8 Hz); 4.91 (2H, s); 4.02 (2H, t); 2.51 (2H, t); 2.40 (2H, t); 1.98-1.94 (2H, m); 1.52-1.48(2H, m); 1.24-1.18 (2H, m); 0.79 (3H, t). 1 H-NMR (DMSO-D6, 400 MHz) δ 12.2 (1H, br, s); 7.58-7.53 (4H, m); 7.43-7.41 (1 H, m); 7.23 (2H, doublet, J = 8.0 Hz); 7.20-7.17 (2H, m); 7.05 (1H, doublet, J = 8.4 Hz); 7.00 (2H, doublet, J = 8.8 Hz); 4.91 (2H, s); 4.02 (2H, t); 2.51 (2H, t); 2.40 (2H, t); 1.98-1.94 (2H, m); 1.52-1.48 (2H, m); 1.24-1.18 (2H, m); 0.79 (3H, t).
실시예Example 10. 2-(4'-(( 10. 2- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )-2-)-2- 메틸프로판산Methylpropanoic acid (2-(4'-(( (2- (4 '-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)-2-methylpropanoic acid) (AC--(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) -2-methylpropanoic acid) (AC- 1321)의1321's 제조  Produce
상기 실시예 9의 단계 3에서 에틸 4-클로로부타노에이트 (Ethyl 4-chlorobutanoate) 대신 에틸 2-클로로-2-메틸프로파노에이트 (Ethyl 2-chloro-2-methylpropanoate) (3.0 equiv)를 이용하여, 에틸 4-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)butanoate (Ethyl 4-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)butanoate)를 제조하였으며(수율 92%), 실시예 9의 단계 4와 동일한 방법으로 최종 생성물인 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)-2-메틸프로판산 2-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)-2-methylpropanoic acid를 수득하였다 (100% 수율).In step 3 of Example 9 using ethyl 2-chloro-2-methylpropanoate (3.0 equiv) instead of ethyl 4-chlorobutanoate (Ethyl 4-chlorobutanoate) , Ethyl 4- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoate (Ethyl 4- (4'-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl -4-yloxy) butanoate) was obtained (yield 92%), and the final product 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) in the same manner as in step 4 of Example 9 Methyl) biphenyl-4-yloxy) -2-methylpropanoic acid 2- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) -2-methylpropanoic acid was obtained ( 100% yield).
1H-NMR (DMSO-D6, 400MHz) δ 7.54-7.51 (4H, m); 7.40-7.39 (1H, m); 7.21 (2H, d, J = 8.0 Hz); 7.16 (2H, d, J = 10.0 Hz); 7.02 (1H, d, J = 7.6 Hz); 6.87 (2H, d, J = 9.2 Hz); 4.88 (2H, s); 2.49 (2H, t); 1.52 (6H, s); 1.49-1.45 (2H, m); 1.22-1.15 (2H, m); 0.77 (3H, t). 1 H-NMR (DMSO-D 6 , 400 MHz) δ 7.54-7.51 (4H, m); 7.40-7.39 (1 H, m); 7.21 (2H, doublet, J = 8.0 Hz); 7.16 (2H, doublet, J = 10.0 Hz); 7.02 (1H, doublet, J = 7.6 Hz); 6.87 (2H, doublet, J = 9.2 Hz); 4.88 (2H, s); 2.49 (2H, t); 1.52 (6H, s); 1.49-1.45 (2H, m); 1.22-1.15 (2H, m); 0.77 (3H, t).
실시예Example 11. ( 11. ( EE )-3-(4'-(() -3- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아크릴산 ((E)-3-(4'-((Acrylic Acid ((E) -3- (4 '-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acrylic acid) (AC-1323)의 제조 Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acrylic acid) (AC-1323)
상기 실시예 9의 단계 3에서 에틸 4-클로로부타노에이트 (Ethyl 4-chlorobutanoate) 대신 메틸 (2E)-3-클로로아크릴레이트 (Methyl (2E)-3-chloroacrylate) (3.0 equiv)를 이용하여, (E)-메틸 3-(4'-((N-(3-플로오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아크릴레이트 ((E)-methyl 3-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acrylate)를 제조하였으며 (수율 100%), 실시예 9의 단계 4와 동일한 방법으로 최종 생성물인 (E)-3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아크릴산 ((E)-3-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acrylic acid)을 수득하였다 (29% 수율)In step 3 of Example 9 using methyl (2E) -3-chloroacrylate (3.0 equiv) instead of ethyl 4-chlorobutanoate, (E) -methyl 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylate ((E) -methyl 3- (4'- (( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acrylate) was prepared (yield 100%), and the final product (E) -3- ( 4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylic acid ((E) -3- (4'-(( N- (3-fluorophenyl) pentanamido ) methyl) biphenyl-4-yloxy) acrylic acid) was obtained (29% yield).
1H-NMR (DMSO-D6, 400 MHz) δ 12.1 (1H, s, br); 7.80 (1H, d, J = 12.0 Hz); 7.68 (2H, d, J = 8.4 Hz); 7.58 (2H, d, J = 8.0 Hz); 7.41-7.26 (1H, m); 7.24-7.19 (4H, m); 7.18-7.16 (2H, m); 7.04 (1H, d, J = 8.0 Hz); 5.52 (1H, d, J = 11.2 Hz); 4.90 (2H, s); 2.49 (2H, t); 1.50-1.44 (2H, m); 1.21-1.14 (2H, m); 0.77 (3H,t). 1 H-NMR (DMSO-D 6 , 400 MHz) δ 12.1 (1H, s, br); 7.80 (1H, doublet, J = 12.0 Hz); 7.68 (2H, doublet, J = 8.4 Hz); 7.58 (2H, doublet, J = 8.0 Hz); 7.41-7.26 (1 H, m); 7.24-7.19 (4H, m); 7.18-7.16 (2H, m); 7.04 (1H, doublet, J = 8.0 Hz); 5.52 (1H, doublet, J = 11.2 Hz); 4.90 (2H, s); 2.49 (2H, t); 1.50-1.44 (2H, m); 1.21-1.14 (2H, m); 0.77 (3H, t).
실시예Example 12. 3-(4'-(( 12. 3- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )프로판산 (3-(4'-((Propanoic acid (3- (4 '-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)propanoic acid) (AC-1324)의 제조 Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) propanoic acid) (AC-1324)
상기 실시예 9의 단계 3에서 에틸 4-클로로부타노에이트 (Ethyl 4-chlorobutanoate) 대신 메틸 3-클로로아세테이트 (Methyl 3-choloroacetate) (3.0 equiv)를 이용하여, 메틸 3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)프로파노에이트 (Methyl 3-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)propanoate)를 제조하였으며 (수율 26.2%), 실시예 9의 단계 4와 동일한 방법으로 최종 생성물인 3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)프로판산 (3-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)propanoic acid)을 수득하였다 (45% 수율).In step 3 of Example 9, using methyl 3-chloroacetate (3.0 equiv) instead of ethyl 4-chlorobutanoate, methyl 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) propanoate (Methyl 3- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4 -yloxy) propanoate) (yield 26.2%), and the final product 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) in the same manner as in step 4 of Example 9 Biphenyl-4-yloxy) propanoic acid (3- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) propanoic acid) was obtained (45% yield).
1H-NMR (CDCl3, 400MHz) δ 7.57-7.51 (4H, m); 7.43-7.38 (1H, m); 7.21 (2H, d, J = 8.0 Hz); 7.16 (2H, d, J = 10.0 Hz); 7.03 (2H, d, J = 8.0 Hz); 6.98 (2H, d, J = 8.4 Hz); 4.88 (2H, s); 4.18 (2H, t); 2.68 (2H, t); 2.12 (2H, t); 1.51-1.44 (2H, m); 1.24-1.15 (2H, m); 0.77 (3H,t). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.57-7.51 (4H, m); 7.43-7.38 (1 H, m); 7.21 (2H, doublet, J = 8.0 Hz); 7.16 (2H, doublet, J = 10.0 Hz); 7.03 (2H, doublet, J = 8.0 Hz); 6.98 (2H, doublet, J = 8.4 Hz); 4.88 (2H, s); 4.18 (2H, t); 2.68 (2H, t); 2.12 (2H, t); 1.51-1.44 (2H, m); 1.24-1.15 (2H, m); 0.77 (3H, t).
실시예Example 13.  13. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(2-(4--((4 '-(2- (4- 메틸피페라진Methylpiperazine -1-일)-2--1-yl) -2- 옥소에톡시Oxoethoxy )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )펜탄아마이드 (Pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'-(2-(4--((4 '-(2- (4- methylpiperazinmethylpiperazin -1--One- ylyl )-2-)-2- oxoethoxyoxoethoxy )biphenyl-4-yl)methyl)pentanamide) (AC-1309)의 제조 Preparation of) biphenyl-4-yl) methyl) pentanamide) (AC-1309)
단계 1 : Step 1: 메틸methyl 2-(4'-(( 2- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세테이트 (Methyl 2-(4'-((Acetate (Methyl 2- (4 '-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)의 제조Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
상기 실시예 9의 단계 2에서 수득한 N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드와 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 메틸 브로모아세테이트 (Methyl bromoacetate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 메틸 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (Methyl 2-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)를 수득하였다. N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide and K 2 CO 3 (3.0 equiv) obtained in step 2 of Example 9 were prepared. It was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. Methyl bromoacetate (3.0 equiv) was added and the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to prepare methyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (Methyl 2- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained.
단계 step 2 : 22: 2 -(4'-((-(4'-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)의 제조Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
상기 단계 1에서 수득한 메틸 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트를 테트라하이드로퓨란 (tetrahydrofuran, THF) 용액에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 상기 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트(EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하여 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산 (2-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)을 수득하였다 (80% 수율).Methyl 2- (4 ′-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate obtained in step 1 above was added to a tetrahydrofuran (THF) solution. After mixing well, LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo to afford 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid (2- (4'-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) was obtained (80% yield).
단계 3 : Step 3: NN -(3--(3- 플루오로페닐Fluorophenyl )) -N-N -((4'-(2-(4--((4 '-(2- (4- 메틸피페라진Methylpiperazine -1-일)-2--1-yl) -2- 옥소에톡시Oxoethoxy )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )펜탄아마이드 (Pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'-(2-(4--((4 '-(2- (4- methylpiperazinmethylpiperazin -1--One- ylyl )-2-)-2- oxoethoxyoxoethoxy )biphenyl-4-yl)methyl)pentanamide)의 제조) biphenyl-4-yl) methyl) pentanamide)
상기 단계 2에서 수득한 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산 (1.0 equiv)과 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 프로파길 브로마이드(Propargyl bromide) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-(3-플루오로페닐)-N-((4'-(2-(4-메틸피페라진-1-일)-2-옥소에톡시)바이페닐-4-일)메틸)펜탄아마이드 (N-(3-fluorophenyl)-N-((4'-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)biphenyl-4-yl)methyl)pentanamide)를 수득하였다 (65% 수율).2- (4 '-((N-(3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid (1.0 equiv) and K2CO3 (3.0 equiv)N,NDissolve in dimethylformamide (DMF) solution and cool on ice. After adding propargyl bromide (3.0 equiv), the mixed solution was cooled to room temperature, N2 Stir overnight at feed conditions. After the reaction was completed, water was added and extracted with ethyl acetate (EA). The organic solvent layer was washed with brine and dried over anhydrous magnesium sulfate (MgSO4Water was removed, and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield N- (3-fluorophenyl)-, the final product.N-((4 '-(2- (4-methylpiperazin-1-yl) -2-oxoethoxy) biphenyl-4-yl) methyl) pentaneamide (N-(3-fluorophenyl)-N-((4 '-(2- (4-methylpiperazin-1-yl) -2-oxoethoxy) biphenyl-4-yl) methyl) pentanamide) was obtained (65% yield).
1H-NMR (CDCl3, 400MHz) δ 7.52-7.51 (2H, m); 7.458 (2H, d, J = 8.0 Hz); 7.33-7.27 (1H, m); 7.24 (2H, d, J = 8.4 Hz); 7.05-6.99 (3H, m); 6.88-6.75 (2H, m); 4.89 (2H, s); 4.68 (2H, s); 3.67-3.60 (4H, m); 2.43-2.38 (4H, m); 2.30 (3H, s); 2.10 (2H, t); 1.64-1.57 (2H, m); 1.30-1.22 (2H, m); 0.83 (3H, t). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.52-7.51 (2H, m); 7.458 (2H, doublet, J = 8.0 Hz); 7.33-7. 27 (1 H, m); 7.24 (2H, doublet, J = 8.4 Hz); 7.05-6.99 (3H, m); 6.88-6.75 (2H, m); 4.89 (2H, s); 4.68 (2H, s); 3.67-3.60 (4H, m); 2.43-2.38 (4H, m); 2.30 (3H, s); 2.10 (2H, t); 1.64-1.57 (2H, m); 1.30-1.22 (2H, m); 0.83 (3H, t).
실시예Example 14.  14. 프로프Prof -2-인일 2-(4'-((2-person 2- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세테이트 (Prop-2-Acetate (Prop-2- ynylynyl 2-(4'-(( 2- (4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )acetate) (AC-) acetate) (AC- 1390)의1390) 제조  Produce
상기 실시예 10에서 수득한 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)-2-메틸프로판산과 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 메틸프로피오레이트 (Methyl propiolate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 프로프-2-인일 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (Prop-2-ynyl 2-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)를 수득하였다 (61.3% 수율).2- (4 ′-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) -2-methylpropanoic acid and K 2 CO 3 (3.0 obtained in Example 10 above) equiv) was dissolved in N, N-dimethylformamide (DMF) solution and then cooled on ice. After adding methyl propiolate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final product, Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4- Iloxy) acetate (Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (61.3% yield).
1H-NMR (CDCl3, 400MHz) δ 7.51 (2H, d, J = 8.4 Hz); 7.45 (2H, d, J = 8.0 Hz); 7.33-7.28 (1H, m); 7.21 (2H, d, J = 8.0 Hz); 7.05-7.01 (1H, m); 6.97 (2H, d, J = 8.4 Hz); 6.82-6.75 (2H, m); 4.89 (2H, s); 4.83 (2H, d, J = 1.6 Hz); 4.72 (2H, s); 2.53 (1H, s); 2.09 (2H, t); 1.64-1.58 (2H, m); 1.27-1.20 (2H, m); 0.831 (3H, t). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (2H, doublet, J = 8.4 Hz); 7.45 (2H, doublet, J = 8.0 Hz); 7.33-7.28 (1 H, m); 7.21 (2H, doublet, J = 8.0 Hz); 7.05-7.01 (1 H, m); 6.97 (2H, doublet, J = 8.4 Hz); 6.82-6.75 (2H, m); 4.89 (2H, s); 4.83 (2H, doublet, J = 1.6 Hz); 4.72 (2H, s); 2.53 (1 H, s); 2.09 (2H, t); 1.64-1.58 (2H, m); 1.27-1.20 (2H, m); 0.831 (3H, t).
실시예Example 15.  15. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(-((4'-( 프로프Prof -2--2- 이닐옥시Iniloxy )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-fluorophenyl)--(3-fluorophenyl)- NN -((4'-(prop-2-ynyloxy)biphenyl-4-yl)methyl)pentanamide)의 (AC-1389) 제조 (AC-1389) Preparation of-((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl) pentanamide)
상기 실시예 9의 단계 2에서 수득한 N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드와 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 메틸 프로피오레이트 (Methyl propiolate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산 마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-(3-플루오로페닐)-N-((4'-(프로프-2-이닐옥시)바이페닐-4-일)메틸)펜탄아마이드 (N-(3-fluorophenyl)-N-((4'-(prop-2-ynyloxy)biphenyl-4-yl)methyl)pentanamide)를 수득하였다 (58.2% 수율). N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide and K 2 CO 3 (3.0 equiv) obtained in step 2 of Example 9 were prepared. It was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. After adding methyl propiolate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N -((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl as the final product. ) Pentaneamide ( N- (3-fluorophenyl) -N -((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl) pentanamide) was obtained (58.2% yield).
1H-NMR (CDCl3, 400MHz) δ 7.54-7.50 (2H, m); 7.46 (2H, d, J = 8.4 Hz); 7.33-7.28 (1H, m); 7.23 (2H, d, J = 8.4 Hz); 7.06-7.03 (3H, m); 6.82-6.75 (2H, m); 4.89 (2H, s); 4.73 (2H, d, J = 2.0 Hz); 2.54 (1H. t); 2.09 (2H, t); 1.64-1.57 (2H, m); 1.29-1.20 (2H, m); 0.83 (3H, m). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.54-7.50 (2H, m); 7.46 (2H, doublet, J = 8.4 Hz); 7.33-7.28 (1 H, m); 7.23 (2H, doublet, J = 8.4 Hz); 7.06-7.03 (3H, m); 6.82-6.75 (2H, m); 4.89 (2H, s); 4.73 (2H, doublet, J = 2.0 Hz); 2.54 (1 H. t); 2.09 (2H, t); 1.64-1.57 (2H, m); 1.29-1.20 (2H, m); 0.83 (3 H, m).
실시예Example 16. 4'-(( 16. 4 '-(( NN -(2--(2- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(2-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid) (AC-1071)의 제조Preparation of-(2-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) (AC-1071)
단계 1 : Step 1: 메틸methyl 4'-((2- 4 '-((2- 플루오로페닐아미노Fluorophenylamino )) 메틸methyl )) 바이페닐Biphenyl -2--2- 카복실레이트Carboxylate (Methyl 4'-((2-fluorophenylamino)methyl)biphenyl-2-carboxylate)의 제조 Preparation of (Methyl 4 '-((2-fluorophenylamino) methyl) biphenyl-2-carboxylate)
메틸 4'-포밀바이페닐-4-카복실레이트 (Methyl 4'-formylbiphenyl-4-carboxylate) (1.0 equiv)와 2-플루오로아닐린 (2-fluoroaniline) (3.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv)이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 메틸 4'-((2-플루오로페닐아미노)메틸)바이페닐-4-카복실레이트 (Methyl 4'-((2-fluorophenylamino)methyl)biphenyl-4-carboxylate)을 수득하였다 (95% 수율).Methyl 4'-formylbiphenyl-4-carboxylate (1.0 equiv) and 2-fluoroaniline (3.0 equiv) were dissolved in methanol, and then at room temperature. Stirred for 4 h. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to remove methyl 4 '-((2-fluorophenylamino) methyl) biphenyl-4-carboxylate (Methyl 4'-((2-fluorophenylamino) methyl) biphenyl -4-carboxylate) (95% yield).
단계 2 : Step 2: 메틸methyl 4'-(( 4'-(( NN -(2--(2- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실레이트Carboxylate (Methyl 4'-(( (Methyl 4 '-(( NN -(1-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylate)-(1-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate)
상기 단계 1에서 수득한 메틸 4'-((2-플루오로페닐아미노)메틸)바이페닐-4-카복실레이트를 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(3.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 메틸 4'-((N-(2-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실레이트 (Methyl 4'-((N-(1-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylate)를 수득하였다 (95% 수율).Methyl 4 '-((2-fluorophenylamino) methyl) biphenyl-4-carboxylate obtained in step 1 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. , Cooled on ice. Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4 '-(( N- (2-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylate (Methyl 4'-(( N- (1-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate) was obtained (95% yield).
단계 step 3 : 43: 4 '-(('-(( NN -(2--(2- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(2-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid)의 제조Preparation of-(2-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid)
상기 단계 2에서 수득한 4'-((N-(2-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실레이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액를 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 상기 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트(EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 최종 생성물인 4'-((N-(2-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산 (4'-((N-(2-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid)을 수득하였다 (94 % 수율).4 '-(( N- (2-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylate (1.0 equiv) obtained in step 2 was mixed well with tetrahydrofuran (THF) , LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and the final product was 4 '-(( N- (2-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid (4'-(( N- (2-fluorophenyl ) pentanamido) methyl) biphenyl-4-carboxylic acid) was obtained (94% yield).
1H-NMR (CDCl3, 400MHz) δ 8.16 (2H, d, J = 8.4 Hz); 7.67 (2H, d, J = 8.4 Hz); 7.54 (2H, d, J = 7.6 Hz); 7.31 (2H, d, J = 8.4 Hz); 7.18-7.08 (3H, m); 7.00-6.96 (1H, t); 5.28 (1H, d, J = 14.4 Hz); 4.56 (1H, d, J = 14.4 Hz); 2.09 (2H, t); 1.63-1.59 (2H, m); 1.27-1.22 (2H, m); 0.83 (3H, t). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.16 (2H, d, J = 8.4 Hz); 7.67 (2H, doublet, J = 8.4 Hz); 7.54 (2H, doublet, J = 7.6 Hz); 7.31 (2H, doublet, J = 8.4 Hz); 7.18-7.08 (3H, m); 7.00-6.96 (1 H, t); 5.28 (1H, doublet, J = 14.4 Hz); 4.56 (1H, doublet, J = 14.4 Hz); 2.09 (2H, t); 1.63-1.59 (2H, m); 1.27-1.22 (2H, m); 0.83 (3H, t).
실시예Example 17. 4'-(( 17. 4 '-(( NN -(4--(4- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(4-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid) (AC-1072)의 제조Preparation of-(4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) (AC-1072)
2-플루오로아닐린 (2-fluoroaniline) 대신 4-플루오로아닐린 (2-fluoroaniline)을 이용하여 상기 실시예 16의 단계 1과 동일한 방법으로 4'-((2-플루오로페닐아미노)메틸)바이페닐-4-카복실레이트 (Methyl 4'-((4-fluorophenylamino)methyl)biphenyl-2-carboxylate)를 제조하고, 메틸 4'-((N-(4-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실레이트 (Methyl 4'-((N-(1-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylate)를 제조하여 최종 생성물인 4'-((N-(4-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산 (4'-((N-(4-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid)을 수득하였다 (90% 수율)4 '-((2-fluorophenylamino) methyl) bi by the same method as Step 1 of Example 16 using 4-fluoroaniline instead of 2-fluoroaniline Phenyl-4-carboxylate (Methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-2-carboxylate) was prepared and methyl 4'-(( N- (4-fluorophenyl) pentaneamido) methyl) Biphenyl-4-carboxylate (Methyl 4 '-(( N- (1-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate) was prepared, resulting in 4'-(( N- (4-fluorophenyl). ) Pentaneamido) methyl) biphenyl-4-carboxylic acid (4 '-(( N- (4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) was obtained (90% yield)
1H-NMR (CDCl3, 400MHz) δ 8.17 (2H, d, J = 8.4 Hz); 7.68 (2H, d, J = 8 Hz); 7.56 (2H, d, J = 8.0 Hz); 7.30 (2H, d, J = 7.6 Hz); 7.04-6.98 (4H, m); 4.91 (2H, s); 2.07 (2H, t); 1.62-1.58 (2H, m); 1.25-1.23 (2H, m); 0.83 (3H, t). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.17 (2H, d, J = 8.4 Hz); 7.68 (2H, doublet, J = 8 Hz); 7.56 (2H, doublet, J = 8.0 Hz); 7.30 (2H, doublet, J = 7.6 Hz); 7.04-6.98 (4H, m); 4.91 (2H, s); 2.07 (2H, t); 1.62-1.58 (2H, m); 1.25-1.23 (2H, m); 0.83 (3H, t).
실시예Example 18. 4'-(( 18.4 '-(( NN -(2--(2- 메톡시페닐Methoxyphenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(2-methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylic acid) (AC-1076)의 제조Preparation of-(2-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) (AC-1076)
메틸 4'-포밀바이페닐-4-카복실레이트 대신 메틸 4'-포밀바이페닐-3-카복실레이트(Methyl 4'-formylbiphenyl-3-carboxylate), 2-플루오로아닐린 대신 2-메톡시아닐린(2-Methoxyaniline)을 이용하여 상기 실시예 16의 단계 1과 동일한 방법으로 4'-((2-메톡시페닐아미노)메틸)바이페닐-3-카복실레이트 (Methyl 4'-((2-Methoxyphenylamino)methyl)biphenyl-3-carboxylate)를 제조하고, 실시예 16의 단계 2 및 단계 3과 동일한 방법으로 메틸 4'-((N-(2-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실레이트 (Methyl 4'-((N-(2-Methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylate)를 제조하여 최종 생성물인 4'-((N-(2-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산 (4'-((N-(2-methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylic acid)을 수득하였다 (90% 수율).Methyl 4'-formylbiphenyl-3-carboxylate instead of methyl 4'-formylbiphenyl-4-carboxylate, 2-methoxyaniline instead of 2-fluoroaniline (2 4 '-((2-methoxyphenylamino) methyl) biphenyl-3-carboxylate (Methyl 4'-((2-Methoxyphenylamino) methyl) in the same manner as in Step 1 of Example 16 using -Methoxyaniline ) biphenyl-3-carboxylate) and methyl 4 '-(( N- (2-methoxyphenyl) pentaneamido) methyl) biphenyl-3- in the same manner as in steps 2 and 3 of Example 16 Carboxylate (Methyl 4 '-(( N- (2-Methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylate) was prepared, resulting in 4'-(( N- (2-methoxyphenyl) pentaneamido) Methyl) biphenyl-3-carboxylic acid (4 '-(( N- (2-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) was obtained (90% yield).
1H-NMR (400 MHz, CDCl3) δ 8.13 (1H, s); 7.90-7.86 (2H, m); 7.62-7.54 (3H, m); 7.26 (2H, d, J = 7.6 Hz); 7.06 (2H, d, J = 8.8 Hz); 6.89 (2H, d, J = 8.8 Hz); 4.83 (2H, s); 3.70 (3H, s); 2.05-2.01 (2H, m); 1.46-1.41 (2H, m); 0.75 (3H, t). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.13 (1 H, s); 7.90-7.86 (2H, m); 7.62-7.54 (3H, m); 7.26 (2H, doublet, J = 7.6 Hz); 7.06 (2H, doublet, J = 8.8 Hz); 6.89 (2H, doublet, J = 8.8 Hz); 4.83 (2H, s); 3.70 (3H, s); 2.05-2.01 (2H, m); 1.46-1.41 (2H, m); 0.75 (3H, t).
실시예Example 19. 4'-(( 19. 4 '-(( NN -(3--(3- 메톡시페닐Methoxyphenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(3-methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylic acid) (AC-1077)의 제조Preparation of-(3-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) (AC-1077)
메틸 4'-포밀바이페닐-4-카복실레이트 대신 메틸 4'-포밀바이페닐-3-카복실레이트(Methyl 4'-formylbiphenyl-3-carboxylate), 2-플루오로아닐린 대신 3-메톡시아닐린(3-Methoxyaniline)을 이용하여 상기 실시예 16의 단계 1과 동일한 방법으로 4'-((3-메톡시페닐아미노)메틸)바이페닐-3-카복실레이트 (Methyl 4'-((3-Methoxyphenylamino)methyl)biphenyl-3-carboxylate)를 제조하고, 실시예 16의 단계 2 및 단계 3과 동일한 방법으로 메틸 4'-((N-(3-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실레이트 (Methyl 4'-((N-(3-Methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylate)를 제조하여 최종 생성물인 4'-((N-(3-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산 (4'-((N-(3-methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylic acid)을 수득하였다 (92% 수율).Methyl 4'-formylbiphenyl-3-carboxylate instead of methyl 4'-formylbiphenyl-4-carboxylate, 3-methoxyaniline instead of 2-fluoroaniline (3 4 '-((3-methoxyphenylamino) methyl) biphenyl-3-carboxylate (Methyl 4'-((3-Methoxyphenylamino) methyl) in the same manner as in Step 1 of Example 16 using -Methoxyaniline ) biphenyl-3-carboxylate) and methyl 4 '-(( N- (3-methoxyphenyl) pentaneamido) methyl) biphenyl-3- in the same manner as in steps 2 and 3 of Example 16. Carboxylate (Methyl 4 '-(( N- (3-Methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylate) was prepared, resulting in 4'-(( N- (3-methoxyphenyl) pentaneamido) Methyl) biphenyl-3-carboxylic acid (4 '-(( N- (3-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) was obtained (92% yield).
1H-NMR (400MHz, CDCl3) δ 8.24 (1H, s); 7.89 (1H, d, J = 7.2 Hz); 7.84 (1H, d, J = 7.2 Hz); 7.59-7.52 (3H, m); 7.29 (2H, d, J = 7.6 Hz); 7.00-6.60 (4H, m); 4.89 (2H, s); 3.78 (3H. s); 2.13 (2H, t); 1.62-1.52 (2H, m); 1.19-1.16 (2H, m); 0.83 (3H, t). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.24 (1H, s); 7.89 (1H, doublet, J = 7.2 Hz); 7.84 (1H, doublet, J = 7.2 Hz); 7.59-7.52 (3H, m); 7.29 (2H, doublet, J = 7.6 Hz); 7.00-6.60 (4H, m); 4.89 (2H, s); 3.78 (3 H. s); 2.13 (2H, t); 1.62-1.52 (2H, m); 1.19-1.16 (2H, m); 0.83 (3H, t).
실시예Example 20. 4'-(( 20. 4 '-(( NN -(4--(4- 메톡시페닐Methoxyphenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(4-methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylic acid) (AC-1078)의 제조Preparation of-(4-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) (AC-1078)
메틸 4'-포밀바이페닐-4-카복실레이트 대신 메틸 4'-포밀바이페닐-3-카복실레이트(Methyl 4'-formylbiphenyl-3-carboxylate), 2-플루오로아닐린 대신 4-메톡시아닐린(4-Methoxyaniline)을 이용하여 상기 실시예 16의 단계 1과 동일한 방법으로 4'-((4-메톡시페닐아미노)메틸)바이페닐-3-카복실레이트 (Methyl 4'-((4-Methoxyphenylamino)methyl)biphenyl-3-carboxylate)를 제조하고, 실시예 16의 단계 2 및 단계 3과 동일한 방법으로 메틸 4'-((N-(4-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실레이트 (Methyl 4'-((N-(4-Methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylate)를 제조하여 최종 생성물인 4'-((N-(4-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산 (4'-((N-(4-methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylic acid)을 수득하였다 (92% 수율).Methyl 4'-formylbiphenyl-3-carboxylate instead of methyl 4'-formylbiphenyl-4-carboxylate, 4-methoxyaniline instead of 2-fluoroaniline (4 4 '-((4-methoxyphenylamino) methyl) biphenyl-3-carboxylate (Methyl 4'-((4-Methoxyphenylamino) methyl) in the same manner as in Step 1 of Example 16 using -Methoxyaniline ) biphenyl-3-carboxylate) and methyl 4 '-(( N- (4-methoxyphenyl) pentaneamido) methyl) biphenyl-3- in the same manner as in Step 2 and Step 3 of Example 16 A carboxylate (Methyl 4 '-(( N- (4-Methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylate) was prepared, resulting in 4'-(( N- (4-methoxyphenyl) pentaneamido). Methyl) biphenyl-3-carboxylic acid (4 '-(( N- (4-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) was obtained (92% yield).
1H-NMR (400 MHz, CDCl3) δ 8.32 (1H, s); 8.07 (1H, d, J = 7.6 Hz); 7.82 (1H, d, J = 8.0 Hz); 7.55-7.53 (3H, m); 7.30 (2H, d, J = 7.6 Hz) 6.92-6.83 (4H, m); 4.90 (2H, s); 3.81 (3H, s); 2.09 (2H, t); 1.59-1.56 (2H, m); 1.25-1.20 (2H, m); 0.83 (3H, t). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.32 (1H, s); 8.07 (1H, doublet, J = 7.6 Hz); 7.82 (1H, doublet, J = 8.0 Hz); 7.55-7.53 (3H, m); 7.30 (2H, doublet, J = 7.6 Hz) 6.92-6.83 (4H, m); 4.90 (2H, s); 3.81 (3 H, s); 2.09 (2H, t); 1.59-1.56 (2H, m); 1.25-1.20 (2H, m); 0.83 (3H, t).
실시예Example 21.  21. NN -((2'-(4--((2 '-(4- 메톡시피페라진Methoxypiperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((2'-(4-methylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)--((2 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-888)의 제조-phenylpentanamide) (AC-888) Preparation
4'-((N-페닐펜탄아미도)메틸)바이페닐-2-카복실산 (1.0 equiv)과 1-메틸피페라진 (1-methyl piperazine)(0.9 equiv), HATU (1.2 equiv) 및 N,N-다이아이소프로필에틸아민 (DIPEA) (2.5 equiv)을 N,N-다이메틸포름아마이드(DMF)에 용해시켰으며, 상기 혼합 용액을 상온에서 밤새도록 교반하였다. 상기 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트 (EA)로 수용성 층을 추출하였다. 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 컬럼크로마토그래피로 정제하여 최종 생성물인 N-((2'-(4-메톡시피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드 (N-((2'-(4-methylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)-N-phenylpentanamide)를 수득하였다 (93% 수율).4 '-(( N -phenylpentaneamido) methyl) biphenyl-2-carboxylic acid (1.0 equiv) and 1-methyl piperazine (0.9 equiv), HATU (1.2 equiv) and N, N -Diisopropylethylamine (DIPEA) (2.5 equiv) was dissolved in N, N -dimethylformamide (DMF) and the mixed solution was stirred overnight at room temperature. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was filtered and then concentrated by evaporation. The concentrated solution was purified by column chromatography to obtain the final product, N -((2 '-(4-methoxypiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide ( N- ((2 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) -N- phenylpentanamide) was obtained (93% yield).
1H-NMR (DMSO-d6, 500MHz) δ 7.71 (m, 1H), 7.61 (m, 3H), 7.51 (m, 1H), 7.39 (m, 2H), 7.34 (m, 2H), 7.27 (m, 2H), 7.19 (m, 2H), 4.90 (s, 2H), 3.6 (d, 4H), 2.36 (d, 4H), 2.19 (s, 3H), 2.07 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H). 1 H-NMR (DMSO-d 6 , 500 MHz) δ 7.71 (m, 1H), 7.61 (m, 3H), 7.51 (m, 1H), 7.39 (m, 2H), 7.34 (m, 2H), 7.27 ( m, 2H), 7.19 (m, 2H), 4.90 (s, 2H), 3.6 (d, 4H), 2.36 (d, 4H), 2.19 (s, 3H), 2.07 (m, 2H), 1.48 (m , 2H), 1.18 (m, 2H), 0.76 (t, 3H).
실시예Example 22.  22. NN -((3'-(4--((3 '-(4- 메틸피페라진Methylpiperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide (( NN -((3'-(4-methylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)--((3 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-889)의 제조-phenylpentanamide) (AC-889) Preparation
단계 1 : 메틸 4'-포밀바이페닐-3-카복실레이트 (methyl 4'-formylbiphenyl-3-carboxylate)의 제조Step 1: Preparation of Methyl 4'-formylbiphenyl-3-carboxylate
메틸 3-브로모벤조에이트 (Methyl 3-bromobenzoate) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (5:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기(degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한 번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, 컬럼크로마토그래피로 정제하여 메틸 4'-포밀바이페닐-2-카복실레이트 (methyl 4'-formylbiphenyl-3-carboxylate)를 수득하였다 (90% 수율).Methyl 3-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane). ): H 2 O (5: 1) was dissolved in a mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. After the reaction mixture was filtered and extracted with ethyl acetate (EA), water was removed with anhydrous MgSO 4 , concentrated by evaporation, purified by column chromatography, and methyl 4'-formylbiphenyl-2-carboxyl. Yield (methyl 4'-formylbiphenyl-3-carboxylate) was obtained (90% yield).
단계 2 : Step 2: 메틸methyl 4'-(( 4'-(( 페닐아미노Phenylamino )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실레이트 (methyl 4'-(Carboxylate (methyl 4 '-( (phenylamino)methyl)biphenyl-2-carboxylate)의 제조Preparation of (phenylamino) methyl) biphenyl-2-carboxylate)
상기 단계 1에서 수득한 메틸 4'-포밀바이페닐-3-카복실레이트 (1.0 equiv)와 아닐린 (aniline) (3.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 컬럼크로마토그래피로 정제하여, 메틸 4'-((페닐아미노)메틸)바이페닐-2-카복실레이트 (methyl 4'-((phenylamino)methyl)biphenyl-3-carboxylate)을 수득하였다 (86% 수율). Methyl 4′-formylbiphenyl-3-carboxylate (1.0 equiv) and aniline (aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by column chromatography to give methyl 4 '-((phenylamino) methyl) biphenyl-2-carboxylate (methyl 4'-((phenylamino) methyl) biphenyl-3-carboxylate) (86 % Yield).
단계 3 : Step 3: 메틸methyl 4'-((N- 4 '-((N- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실레이트Carboxylate (methyl 4'-((N-phenylpentanamido)methyl)biphenyl-3-carboxylate)의 제조Preparation of (methyl 4 '-((N-phenylpentanamido) methyl) biphenyl-3-carboxylate)
상기 2 단계에서 수득한 4'-((페닐아미노)메틸)바이페닐-3-카복실레이트을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 컬럼크로마토그래피로 정제하여, 메틸 4'-((N-페닐펜탄아미도)메틸)바이페닐-3-카복실레이트 (methyl 4'-((N-phenylpentanamido)methyl)biphenyl-3-carboxylate)를 수득하였다 (92% 수율).4 '-((phenylamino) methyl) biphenyl-3-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrate was purified by column chromatography, methyl 4 '-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylate (methyl 4'-((N-phenylpentanamido) methyl) biphenyl-3-carboxylate ) Was obtained (92% yield).
단계 step 4 : 44: 4 '-((N-'-((N- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실산Carboxylic acid (4'-((N-phenylpentanamido)methyl)biphenyl-3-carboxylic acid)의 제조 Preparation of (4 '-((N-phenylpentanamido) methyl) biphenyl-3-carboxylic acid)
상기 단계 3에서 수득한 메틸 4'-((N-페닐펜탄아미도)메틸)바이페닐-3-카복실레이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 컬럼크로마토그래피로 정제하여, 4'-((N-페닐펜탄아미도)메틸)바이페닐-3-카복실산 (4'-((N-phenylpentanamido)methyl)biphenyl-3-carboxylic acid)을 수득하였다 (94% 수율). Methyl 4 ′-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF), and then LiOH solution was added thereto. , Was stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and purified by column chromatography to obtain 4 '-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylic acid (4'-((N-phenylpentanamido) methyl) biphenyl- 3-carboxylic acid) was obtained (94% yield).
단계 5 : N-((３'-(4-메톡시피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드 (N-((３'-(4-methylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)-N-phenylpentanamide) 의 제조Step 5: N-((3 '-(4-methoxypiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide (N-((3'-(4-methylpiperazine -1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide)
상기 단계 4에서 수득한 4'-((N-페닐펜탄아미도)메틸)바이페닐-3-카복실산 (1.0 equiv)과 1-메틸피페라진 (1-methyl piperazine)(0.9 equiv), HATU (1.2 equiv) 및 N,N-다이아이소프로필에틸아민 (DIPEA) (2.5 equiv)을 N,N-다이메틸포름아마이드 (DMF)에 용해시켰으며, 상기 혼합 용액을 상온에서 밤새도록 교반하였다. 상기 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트 (EA)로 수용성 층을 추출하였다. 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 컬럼 크로마토 그래피로 정제하여 최종 생성물인 N-((3'-(4-메톡시피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드 (N-((3'-(4-methylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)-N-phenylpentanamide)를 수득하였다 (93% 수율).4 '-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylic acid (1.0 equiv), 1-methyl piperazine (0.9 equiv) and HATU (1.2) obtained in step 4 above. equiv) and N, N-diisopropylethylamine (DIPEA) (2.5 equiv) were dissolved in N, N-dimethylformamide (DMF) and the mixed solution was stirred overnight at room temperature. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by column chromatography to obtain N-((3 '-(4-methoxypiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide (N- ((3 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide) was obtained (93% yield).
1H-NMR (DMSO-d6, 500 MHz) δ 7.71 (m, 1H), 7.61 (m, 3H), 7.51 (m, 1H), 7.42 (m, 2H), 7.30 (m, 2H), 7.25 (m, 2H), 7.19 (m, 2H), 4.90 (s, 2H), 3.16 (d, 4H), 2.38 (d, 4H), 2.18 (s, 3H), 2.07 (m, 2H) 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H). 1 H-NMR (DMSO-d 6 , 500 MHz) δ 7.71 (m, 1H), 7.61 (m, 3H), 7.51 (m, 1H), 7.42 (m, 2H), 7.30 (m, 2H), 7.25 (m, 2H), 7.19 (m, 2H), 4.90 (s, 2H), 3.16 (d, 4H), 2.38 (d, 4H), 2.18 (s, 3H), 2.07 (m, 2H) 1.48 (m , 2H), 1.18 (m, 2H), 0.76 (t, 3H).
실시예Example 23. 4'-(( 23. 4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -2--2- 카복실산Carboxylic acid (4'-(((4'-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-2-carboxylic acid) (AC-891)의 제조Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylic acid) (AC-891)
단계 1 : 메틸 4'-포밀바이페닐-2-카복실레이트 (methyl 4'-formylbiphenyl-2-carboxylate)의 제조Step 1: Preparation of Methyl 4'-formylbiphenyl-2-carboxylate
메틸 2-브로모벤조에이트 (Methyl 3-bromobenzoate) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (5:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한 번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, 컬럼크로마토그래피로 정제하여 메틸 4'-포밀바이페닐-2-카복실레이트 (methyl 4'-formylbiphenyl-2-carboxylate)를 수득하였다 (90% 수율).Methyl 3-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane). ): H 2 O (5: 1) was dissolved in a mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. After the reaction mixture was filtered and extracted with ethyl acetate (EA), water was removed with anhydrous MgSO 4 , concentrated by evaporation, purified by column chromatography, and methyl 4'-formylbiphenyl-2-carboxyl. Yield (methyl 4'-formylbiphenyl-2-carboxylate) was obtained (90% yield).
단계 step 2 : 42: 4 '-((3-'-((3- 플루오로페닐아미노Fluorophenylamino ) ) 메틸methyl ) ) 바이페닐Biphenyl -2--2- 카복실레이트 (4'-(Carboxylate (4 '-( (3-fluorophenylamino) methyl) biphenyl-2-carboxylate)의 제조Preparation of (3-fluorophenylamino) methyl) biphenyl-2-carboxylate)
상기 단계 1에서 수득한 메틸 4'-포밀바이페닐-2-카복실레이트 (1.0 equiv)와 3-플루오로아닐린 (3-fluoroaniline ) (3.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 컬럼크로마토그래피로 정제하여, 4'-((3-플루오로페닐아미노) 메틸) 바이페닐-2-카복실레이트 (4'-((3-fluorophenylamino) methyl) biphenyl-2-carboxylate)을 수득하였다 (86% 수율). Methyl 4'-formylbiphenyl-2-carboxylate (1.0 equiv) and 3-fluoroaniline (3-fluoroaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by column chromatography to obtain 4 '-((3-fluorophenylamino) methyl) biphenyl-2-carboxylate (4'-((3-fluorophenylamino) methyl) biphenyl-2-carboxylate). Obtained (86% yield).
단계 3 : Methyl 4'-((N-(3- 플루오로페닐 ) 펜탄아미도 ) 메틸 ) 바이페닐 -2- 카복실레이트 (Methyl 4'-((N-(3-fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylate)의 제조 Step 3: Methyl 4 '- (( N- (3- fluorophenyl) pentane amido) methyl) biphenyl-2-carboxylate (Methyl 4' - ((N- (3-fluorophenyl) pentanamido) methyl) biphenyl -2-carboxylate)
상기 2 단계에서 수득한 4'-((3-플루오로페닐아미노) 메틸) 바이페닐-2-카복실레이트을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 컬럼크로마토그래피로 정제하여, 메틸 4'-((N-(3-플루오로페닐) 펜탄아미도) 메틸) 바이페닐-2-카복실레이트 (Methyl 4'-((N-(3-fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylate)를 수득하였다 (92% 수율).4 '-((3-fluorophenylamino) methyl) biphenyl-2-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then ice Cooled in. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrate was purified by column chromatography to prepare methyl 4 '-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-2-carboxylate (Methyl 4'-((N- (3- fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylate) was obtained (92% yield).
단계 step 4 : 44: 4 '-((N-(3-'-((N- (3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -2--2- 카복실산Carboxylic acid (4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-2-carboxylic acid)의 제조 Preparation of (4 '-((N- (3-fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylic acid)
상기 단계 3에서 수득한 메틸 4'-((N-(3-플루오로페닐) 펜탄아미도) 메틸) 바이페닐-2-카복실레이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 컬럼크로마토그래피로 정제하여, 4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-2-카복실산 (4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-2-carboxylic acid)을 수득하였다 (94% 수율). Methyl 4 ′-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-2-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF). Then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and purified by column chromatography to give 4 '-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-2-carboxylic acid (4'-((N- (3-fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylic acid) was obtained (94% yield).
1H-NMR (DMSO-d6, 500 MHz) δ 12.8 (s, br, 1H), 7.7 (m, 1H), 7.55 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.25 (m, 2H), 7.20 (m, 3H), 7.05 (m, 1H), 4.93 (s, 2H), 2.14 (m, 2H), 1.49 (m, 2H), 1.20 (m, 2H), 0.78 (t, 3H). 1 H-NMR (DMSO-d6, 500 MHz) δ 12.8 (s, br, 1H), 7.7 (m, 1H), 7.55 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.25 (m, 2H), 7.20 (m, 3H), 7.05 (m, 1H), 4.93 (s, 2H), 2.14 (m, 2H), 1.49 (m, 2H), 1.20 (m, 2H), 0.78 (t, 3H).
실시예Example 24. 4'-(( 24. 4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid) (AC-893)의 제조Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) (AC-893)
단계 1 : 메틸 4'-포밀바이페닐-4-카복실레이트 (methyl 4'-formylbiphenyl-4-carboxylate)의 제조Step 1: Preparation of Methyl 4'-formylbiphenyl-4-carboxylate
메틸 4-브로모벤조에이트 (Methyl 3-bromobenzoate) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (5:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한 번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, 컬럼크로마토그래피로 정제하여 메틸 4'-포밀바이페닐-4-카복실레이트 (methyl 4'-formylbiphenyl-2-carboxylate)를 수득하였다 (90% 수율).Methyl 3-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane). ): H 2 O (5: 1) was dissolved in a mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. After the reaction mixture was filtered and extracted with ethyl acetate (EA), water was removed with anhydrous MgSO 4 , concentrated by evaporation, purified by column chromatography, and methyl 4'-formylbiphenyl-4-carboxyl. Yield (methyl 4'-formylbiphenyl-2-carboxylate) was obtained (90% yield).
단계 2 : Step 2: 메틸methyl 4'-((3- 4 '-((3- 플루오로아미노Fluoroamino ) ) 메틸methyl ) ) 바이페닐Biphenyl -4--4- 카복실레이트 (Methyl 4'-(Carboxylate (Methyl 4 '-( (3-fluorophenylamino) methyl) biphenyl-4-carboxylate)의 제조 Preparation of (3-fluorophenylamino) methyl) biphenyl-4-carboxylate)
상기 단계 1에서 수득한 메틸 4'-포밀바이페닐-4-카복실레이트 (1.0 equiv)와 3-플루오로아닐린 (3-fluoroaniline ) (3.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 컬럼크로마토그래피로 정제하여, 메틸 4'-((3-플루오로아미노) 메틸) 바이페닐-4-카복실레이트 (Methyl 4'-((3-fluorophenylamino) methyl) biphenyl-4-carboxylate)을 수득하였다 (86% 수율). Methyl 4'-formylbiphenyl-4-carboxylate (1.0 equiv) and 3-fluoroaniline (3-fluoroaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by column chromatography, methyl 4 '-((3-fluoroamino) methyl) biphenyl-4-carboxylate (Methyl 4'-((3-fluorophenylamino) methyl) biphenyl-4-carboxylate) Obtained (86% yield).
단계 3 : Step 3: 메틸methyl 4'-((N-(3- 4 '-((N- (3- 플루오로페닐Fluorophenyl ) ) 펜탄아미도Pentanamido ) ) 메틸methyl ) ) 바이페닐Biphenyl -4--4- 카보실레이트Carbosylate (Methyl 4'-((N-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate)의 제조 Preparation of (Methyl 4 '-((N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate)
상기 2 단계에서 수득한 메틸 4'-((3-플루오로아미노) 메틸) 바이페닐-4-카복실레이트을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 컬럼크로마토그래피로 정제하여, 메틸 4'-((N-(3-플루오로페닐) 펜탄아미도) 메틸) 바이페닐-4-카보실레이트 (Methyl 4'-((N-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate)를 수득하였다 (92% 수율).Methyl 4 '-((3-fluoroamino) methyl) biphenyl-4-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then ice Cooled at. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrated solution was purified by column chromatography, methyl 4 '-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-carbolate (Methyl 4'-((N- (3 -fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate) was obtained (92% yield).
단계 step 4 : 44: 4 '-((N-(3-'-((N- (3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid)의 제조 Preparation of (4 '-((N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid)
상기 단계 3에서 수득한 메틸 4'-((N-(3-플루오로페닐) 펜탄아미도) 메틸) 바이페닐-4-카보실레이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 컬럼크로마토그래피로 정제하여, 4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산 (4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid)을 수득하였다 (94% 수율). Methyl 4 ′-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-carbosylate (1.0 equiv) obtained in step 3 above was added to tetrahydrofuran (THF). After mixing, LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and purified by column chromatography to obtain 4 '-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid (4'-((N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) was obtained (94% yield).
1H-NMR (DMSO-d6, 500 MHz) δ 13.1 (s, br, 1H), 8.12 (d, 1H), 7.85 (d, 2H), 7.66 (d, 2H), 7.56 (m, 2H), 7.20 (m, 2H), 7.20 (m, 2H,) 7.05 (m, 1H), 4.91 (s, 2H), 2.08 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H). 1 H-NMR (DMSO-d6, 500 MHz) δ 13.1 (s, br, 1H), 8.12 (d, 1H), 7.85 (d, 2H), 7.66 (d, 2H), 7.56 (m, 2H), 7.20 (m, 2H), 7.20 (m, 2H,) 7.05 (m, 1H), 4.91 (s, 2H), 2.08 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H).
실시예Example 25.  25. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(-((4'-( 몰폴린Morpholine -4--4- 카보닐Carbonyl )-[1,1'-)-[1,1'- 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( N-N- (3-fluorophenyl)-(3-fluorophenyl)- NN -((4'-(morpholine-4-carbonyl)-[1,1'-biphenyl]-4-yl)methyl)pentanamide) (AC-950)의 제조Preparation of-((4 '-(morpholine-4-carbonyl)-[1,1'-biphenyl] -4-yl) methyl) pentanamide) (AC-950)
상기 실시예 24에서 수득한 4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산 (1.0 equiv)과 몰폴린 (morpholine)(0.9 equiv), HATU (1.2 equiv) 및 N,N-다이아이소프로필에틸아민 (DIPEA) (2.5 equiv)을 N,N-다이메틸포름아마이드 (DMF)에 용해시켰으며, 상기 혼합 용액을 상온에서 밤새도록 교반하였다. 상기 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트 (EA)로 수용성 층을 추출하였다. 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 컬럼 크로마토 그래피로 정제하여 최종 생성물인 N-(3-플루오로페닐)-N-((4'-(몰폴린-4-카보닐)-[1,1'-바이페닐-4-일)메틸)펜탄아마이드 (N-(3-fluorophenyl)-N-((4'-(morpholine-4-carbonyl)-[1,1'-biphenyl]-4-yl)methyl)pentanamide)를 수득하였다 (93% 수율).4 '-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid (1.0 equiv), morpholine (0.9 equiv) obtained in Example 24, and HATU ( 1.2 equiv) and N, N-diisopropylethylamine (DIPEA) (2.5 equiv) were dissolved in N, N-dimethylformamide (DMF) and the mixed solution was stirred overnight at room temperature. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by column chromatography to give the final product N- (3-fluorophenyl) -N-((4 '-(morpholine-4-carbonyl)-[1,1'-biphenyl-4- Il) methyl) pentaneamide (N- (3-fluorophenyl) -N-((4 '-(morpholine-4-carbonyl)-[1,1'-biphenyl] -4-yl) methyl) pentanamide) was obtained. (93% yield).
1H-NMR (DMSO-d6, 500 MHz) δ 7.95 (m, 1H), 7.70 (d, 2H), 7.62 (d, 2H), 7.44 (d, 2H), 7.36 m, 2H), 7.27 (m, 2H), 7.19 (d, 2H), 4.90 (s, 2H), 3.01 (d, 4H), 2.5 (s, 3H), 2.36 (d, 4H), 2.07 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H). 1 H-NMR (DMSO-d6, 500 MHz) δ 7.95 (m, 1H), 7.70 (d, 2H), 7.62 (d, 2H), 7.44 (d, 2H), 7.36 m, 2H), 7.27 (m , 2H), 7.19 (d, 2H), 4.90 (s, 2H), 3.01 (d, 4H), 2.5 (s, 3H), 2.36 (d, 4H), 2.07 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H).
실시예Example 26.  26. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(4--((4 '-(4- 메틸피페라진Methylpiperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'-(4--((4 '-(4- methylpiperazinemethylpiperazine -1-carbonyl)biphenyl-4--1-carbonyl) biphenyl-4- ylyl )methyl)methyl) pentanamidepentanamide ) (AC-951)의 제조Preparation of (AC-951)
단계 step 1 : 41: 4 '-(('-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid)의 제조Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid)
2-플루오로아닐린 대신 3-메톡시아닐린(3-Methoxyaniline)을 이용하여 상기 실시예 16의 단계 1과 동일한 방법으로 4'-((3-메톡시페닐아미노)메틸)바이페닐-4-카복실레이트 (Methyl 4'-((3-Methoxyphenylamino)methyl)biphenyl-4-carboxylate)를 제조하고, 실시예 16의 단계 2 및 단계 3과 동일한 방법으로 메틸 4'-((N-(3-메톡시페닐)펜탄아미도)메틸)바이페닐-4-카복실레이트 (Methyl 4'-((N-(3-Methoxyphenyl)pentanamido)methyl)biphenyl-4-carboxylate)를 제조하고 4'-((N-(3-메톡시페닐)펜탄아미도)메틸)바이페닐-4-카복실산 (4'-((N-(3-methoxyphenyl)pentanamido)methyl)biphenyl-4-carboxylic acid)을 수득하였다 (94% 수율).4 '-((3-methoxyphenylamino) methyl) biphenyl-4-carboxyl in the same manner as in Step 1 of Example 16, using 3-methoxyaniline instead of 2-fluoroaniline Methyl 4 '-((3-Methoxyphenylamino) methyl) biphenyl-4-carboxylate) was prepared, and methyl 4'-(( N- (3-methoxy was prepared in the same manner as in Step 2 and Step 3 of Example 16. Phenyl) pentaneamido) methyl) biphenyl-4-carboxylate (Methyl 4 '-(( N- (3-Methoxyphenyl) pentanamido) methyl) biphenyl-4-carboxylate) was prepared and 4'-(( N- ( 3-methoxyphenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid (4 '-(( N- (3-methoxyphenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) was obtained (94% yield). .
단계 2 : Step 2: NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(4--((4 '-(4- 메틸피페라진Methylpiperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-fluorophenyl)--(3-fluorophenyl)- NN -((4'-(4-methylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)pentanamide)의 제조Preparation of-((4 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide)
상기 단계 1에서 수득한 4'-((N-(3-메톡시페닐)펜탄아미도)메틸)바이페닐-4-카복실산 (1.0 equiv)과 1-메틸 피페라진(1-Methyl piperazine)(0.9 equiv), EDC (1.2 equiv), HoBt (1.2 equiv), 및 N,N-다이아이소프로필에틸아민 (DIPEA) (2.5 equiv)을 N,N-다이메틸포름아마이드 (DMF)에 용해시켰으며, 상기 혼합 용액을 상온에서 밤새도록 교반하였다. 상기 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트 (EA)로 수용성 층을 추출하였다. 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 컬럼 크로마토 그래피로 정제하여 최종 생성물인 N-(3-플루오로페닐)-N-((4'-(4-메틸피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드 (N-(3-fluorophenyl)-N-((4'-(4-methylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)pentanamide)를 수득하였다 (93% 수율).4 '-(( N- (3-methoxyphenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid (1.0 equiv) and 1-methyl piperazine (0.9 obtained in step 1) equiv), EDC (1.2 equiv), HoBt (1.2 equiv), and N , N -diisopropylethylamine (DIPEA) (2.5 equiv) were dissolved in N , N -dimethylformamide (DMF) The mixed solution was stirred overnight at room temperature. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by column chromatography to give the final product N- (3-fluorophenyl) -N -((4 '-(4-methylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) Pentaneamide (N- (3-fluorophenyl) -N -((4 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) was obtained (93% yield).
1H-NMR (DMSO-d6, 500MHz) δ 7.95 (1H, m), 7.70 (2H, d), 7.62 (2H, d), 7.44 (2H, d), 7.36 (2H, m), 7.27 (2H, m), 7.19 (2H, d), 4.90 (2H, s), 3.01 (4H, d), 2.5 (3H, s), 2.36 (4H, d), 2.07 (2H, m), 1.48 (2H, m), 1.18 (2H, m), 0.76 (3H, t). 1 H-NMR (DMSO-d 6 , 500 MHz) δ 7.95 (1H, m), 7.70 (2H, d), 7.62 (2H, d), 7.44 (2H, d), 7.36 (2H, m), 7.27 ( 2H, m), 7.19 (2H, d), 4.90 (2H, s), 3.01 (4H, d), 2.5 (3H, s), 2.36 (4H, d), 2.07 (2H, m), 1.48 (2H , m), 1.18 (2H, m), 0.76 (3H, t).
실시예Example 27.  27. NN -((2'-(1H--((2 '-(1H- 테트라졸Tetrazole -5-일)-5 days) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)--((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-952)의 제조 -phenylpentanamide) (AC-952)
단계 step 1 : 41: 4 '-(('-(( 페닐아미노Phenylamino )) 메틸methyl )) 바이페닐Biphenyl -2--2- 카보나이트릴Carbon Nitrile (4'-(( (4'-(( phenylaminophenylamino )methyl)biphenyl-2-carbonitrile)의 제조) methyl) biphenyl-2-carbonitrile)
Aniline (1.0 equiv)과 K2CO3 (3.0 equiv)을 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 이후, 4'-(브로모메틸)-2-바이페닐카보나이트릴 (4'-(Bromomethyl)-2-biphenylcarbonitrile) (3.0 equiv)을 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 상기 반응을 마친 혼합물을 EA를 통해 여과, 추출한 후, 유기 용매층을 여과하고, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 4'-((페닐아미노)메틸)바이페닐-2-카보나이트릴 (4'-((phenylamino)methyl)biphenyl-2-carbonitrile)을 수득하였다 (86% 수율).Aniline (1.0 equiv) and K 2 CO 3 (3.0 equiv) were dissolved in dichloromethane (DCM) solution and then cooled on ice. Then, 4 '-(bromomethyl) -2-biphenylcarbonitrile (4'-(Bromomethyl) -2-biphenylcarbonitrile) (3.0 equiv) was added, and then the mixed solution was stirred overnight at room temperature and N 2 supply conditions. It was. After the reaction mixture was filtered and extracted through EA, the organic solvent layer was filtered and evaporated to concentrate. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give 4 '-((phenylamino) methyl) biphenyl-2-carbonitrile (4'-((phenylamino) methyl) biphenyl-2-carbonitrile) ( 86% yield).
단계 2 : Step 2: NN -((2'--((2'- 시아노페닐Cyanophenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide (N-((2'- (N-((2'- cyanobiphenylcyanobiphenyl -4--4- ylyl )methyl)-N-phenylpentanamide)의 제조Preparation of Methyl) -N-phenylpentanamide)
상기 단계 1에서 수득한 4'-((페닐아미노)메틸)바이페닐-2-카보나이트릴을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(3.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 N-((2'-시아노페닐-4-일)메틸)-N-페닐펜탄아마이드 (N-((2'-cyanobiphenyl-4-yl)methyl)-N-phenylpentanamide)을 수득하였다 (92%).4 '-((phenylamino) methyl) biphenyl-2-carbonitrile obtained in step 1 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then cooled on ice. . Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N -((2'-cyanophenyl-4-yl) methyl) -N -phenylpentanamide (N-((2'-cyanobiphenyl-4-yl) methyl) -N-phenylpentanamide) was obtained (92%).
단계 3 : Step 3: NN -((2'-(1H--((2 '-(1H- 테트라졸Tetrazole -5-일)-5 days) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)--((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl)- NN -phenylpentanamide)의 제조-phenylpentanamide)
상기 단계 2에서 수득한 N-((2'-시아노페닐-4-일)메틸)-N-페닐펜탄아마이드(1.0 equiv)과 트리부틸틴 클로라이드 (Tributyltin Chloride)(2.0 equiv), 및 Sodium Azide (2.0 equiv)를 RBF에 잘 섞은 후, O-xylene (10 V)에 녹였다. 상기 혼합 용액을 12시간 동안 환류시킨 후, 용매를 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-N-페닐펜탄아마이드 (N-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-N-phenylpentanamide)을 수득하였다 (92% 수율). N -((2'-cyanophenyl-4-yl) methyl) -N -phenylpentaneamide (1.0 equiv) and tributyltin chloride (2.0 equiv) obtained in step 2, and Sodium Azide (2.0 equiv) was mixed well in RBF and dissolved in O-xylene (10 V). The mixed solution was refluxed for 12 hours, and then the solvent was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N -phenylpentanamide ( N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N- phenylpentanamide) was obtained (92% yield).
1H-NMR (MeOD, 500 MHz) δ 8.16 (1H, d, J = 6.0 Hz); 7.60 -7.52 (2H, m); 7.43-7.39 (3H, m); 7.34 (1H, t); 7.25 (2H, t); 7.15 (2H, d, J = 6.4 Hz); 7.03 (2H, d, J = 6.0 Hz); 4.90 (2H, s); 2.09 (2H, t); 1.57-1.50 (2H, m); 1.22-1.18 (2H, m); 0.79 (3H, t). 1 H-NMR (MeOD, 500 MHz) δ 8.16 (1H, d, J = 6.0 Hz); 7.60 -7.52 (2H, m); 7.43-7.39 (3H, m); 7.34 (1 H, t); 7.25 (2H, t); 7.15 (2H, doublet, J = 6.4 Hz); 7.03 (2H, doublet, J = 6.0 Hz); 4.90 (2H, s); 2.09 (2H, t); 1.57-1.50 (2H, m); 1.22-1.18 (2H, m); 0.79 (3H, t).
실시예Example 28.  28. NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((4'--((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)--4-yl) methyl)- NN -phenylpentanamide) (AC-1067)의 제조-phenylpentanamide) (AC-1067)
단계 1 : 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)의 제조Step 1: Preparation of 4'-methoxybiphenyl-4-carbaldehyde
4-브로모아니솔 (4-Bromoanisole) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.01 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한 번 더 15분 동안 탈기한 후, 가열하여 3시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)를 수득하였다 (73% 수율).4-Bromoanisole (1.0 equiv) and 4-Formylphenylboronic acid (1.1 equiv) are mixed well with RBF, then 1,4 dioxane (1,4 dioxane): Dissolved in H 2 O (10: 1) mixed solution. Pd (dppf) Cl 2 .DCM (0.01 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 3 hours. After the reaction mixture was filtered and extracted with ethyl acetate (EA), water was removed with anhydrous MgSO 4 , concentrated by evaporation, and purified by Medium Pressure Liquid Chromatography (MPLC) to 4'-methoxybiphenyl. 4-Carbaldehyde (4'-methoxybiphenyl-4-carbaldehyde) was obtained (73% yield).
단계 2 : Step 2: NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )아닐린 (Aniline ( NN -((4'--((4'- methoxybiphenylmethoxybiphenyl -4--4- ylyl )methyl)aniline)의 제조Manufacture of methyl) aniline)
상기 단계 1에서 수득한 4'-메톡시바이페닐-4-카브알데하이드 (1.0 equiv)와 아닐린 (aniline) (3.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, N-((4'-메톡시바이페닐-4-일)메틸)아닐린 (N-((4'-methoxybiphenyl-4-yl)methyl)aniline)을 수득하였다. 4'-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and aniline (aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. Purification of the concentrate by Medium Pressure Liquid Chromatography (MPLC), N - ((4'- methoxy-biphenyl-4-yl) methyl) aniline (N - ((4'-methoxybiphenyl -4-yl) methyl) aniline ) Was obtained.
단계 3 : Step 3: NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((4'--((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)--4-yl) methyl)- NN -phenylpentanamide)의 제조-phenylpentanamide)
상기 2 단계에서 수득한 N-((4'-메톡시바이페닐-4-일)메틸)아닐린을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(3.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인N-((4'-메톡시바이페닐-4-일)메틸)-N-페닐펜탄아마이드 (N-((4'-methoxybiphenyl-4-yl)methyl)-N-phenylpentanamide)를 수득하였다 (100% 수율). N -((4'-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then on ice Cooled. Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final product, N -((4'-methoxybiphenyl-4-yl) methyl) -N -phenylpentaneamide ( N -((4'-methoxybiphenyl- 4-yl) methyl) -N- phenylpentanamide) was obtained (100% yield).
1H NMR (400 MHz, CDCl3) δ 7.51 (2H, d, J = 8.4 Hz); 7.45 (2H, d, J = 8.0 Hz); 7.34-7.30 (3H, m); 7.24 (2H, d, J = 8.0 Hz); 7.01 (2H, d, J = 7.2 Hz); 6.96 (2H, d, J = 8.8 Hz); 4.90 (2H, s); 3.85 (3H, s); 2.08 (2H, t); 1.63-1.57 (2H, m); 1.26-1.20 (2H, m); 0.83 (3H, t). 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (2H, doublet, J = 8.4 Hz); 7.45 (2H, doublet, J = 8.0 Hz); 7.34-7.30 (3H, m); 7.24 (2H, doublet, J = 8.0 Hz); 7.01 (2H, doublet, J = 7.2 Hz); 6.96 (2H, doublet, J = 8.8 Hz); 4.90 (2H, s); 3.85 (3 H, s); 2.08 (2H, t); 1.63-1.57 (2H, m); 1.26-1.20 (2H, m); 0.83 (3H, t).
실시예Example 29.  29. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((4'--((4'- hydroxybiphenylhydroxybiphenyl -4-yl)methyl)--4-yl) methyl)- NN -phenylpentanamide) (AC-1069)의 제조-phenylpentanamide) (AC-1069)
상기 실시예 28에서 수득한 N-((4'-메톡시바이페닐-4-일)메틸)-N-페닐펜탄아마이드 (1.0 equiv)를 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 0℃에서, BBr3를 천천히 가하였으며, 실온에서 3시간 동안 혼합 용액을 교반하였다. 상기 반응을 TLC (thin Layer Chromatography)로 관찰하였다. 반응을 마친 후, RBF에 얼음을 가하고, DCM에서 추출하였다. 유기 용매층을 분리하고. 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하였으며, 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-((4'-하이드록시바이페닐-4-일)메틸)-N-페닐펜탄아마이드 (N-((4'-hydroxybiphenyl-4-yl)methyl)-N-phenylpentanamide)를 수득하였다 (80% 수율). N -((4'-methoxybiphenyl-4-yl) methyl) -N -phenylpentaneamide (1.0 equiv) obtained in Example 28 was dissolved in a dichloromethane (DCM) solution, and then iced. Cooled at. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N -((4'-hydroxybiphenyl-4-yl) methyl) -N -phenylpentanamide ( N -((4'-hydroxybiphenyl-) as a final product. 4-yl) methyl) -N- phenylpentanamide) was obtained (80% yield).
1H-NMR (CDCl3, 400MHz) δ 7.44-7.37 (4H, m); 7.35-7.31 (3H, m); 7.26 (2H, d, J = 8.4 Hz); 7.03 (2H, d, J = 6.8 Hz); 6.88 (2H, d, J = 8.4 Hz); 5.37 (1H, br, s); 4.91 (2H, s); 2.10 (2H, t); 1.63-1.57 (2H, m); 1.25-1.20 (2H, m); 0.83 (3H, t). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.44-7.37 (4H, m); 7.35-7.31 (3H, m); 7.26 (2H, doublet, J = 8.4 Hz); 7.03 (2H, doublet, J = 6.8 Hz); 6.88 (2H, doublet, J = 8.4 Hz); 5.37 (1H, broad singlet, s); 4.91 (2H, s); 2.10 (2H, t); 1.63-1.57 (2H, m); 1.25-1.20 (2H, m); 0.83 (3H, t).
실시예Example 30. 2-(4'-(( 30. 2- (4 '-(( NN -- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -phenylpentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1073)의 제조Preparation of -phenylpentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1073)
단계 1 : 에틸 (2-(4'-((Step 1: ethyl (2- (4 '-(( NN -- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세테이트 (Ethyl (2-(4'-((Acetate (Ethyl (2- (4 '-(( NN -phenylpentanamido)methyl)biphenyl-4-yloxy)acetate)의 제조-phenylpentanamido) methyl) biphenyl-4-yloxy) acetate)
상기 실시예 29에서 수득한 N-((4'-하이드록시바이페닐-4-일)메틸)-N-페닐펜탄아마이드 (1.0 equiv)와 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 에틸브로모아세테이트 (Ethylbromoacetate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 에틸 (2-(4'-((N-페닐펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (Ethyl (2-(4'-((N-phenylpentanamido)methyl)biphenyl-4-yloxy)acetate)를 수득하였다. N -((4'-hydroxybiphenyl-4-yl) methyl) -N -phenylpentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 29 were replaced with N , N -di Dissolved in methylformamide (DMF) solution and cooled on ice. Ethylbromoacetate (3.0 equiv) was added and the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl (2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetate (Ethyl (2- (4'- (( N- phenylpentanamido) methyl) biphenyl-4-yloxy) acetate was obtained.
단계 step 2 : 22: 2 -(4'-((-(4'-(( NN -- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -phenylpentanamido)methyl)biphenyl-4-yloxy)acetic acid)의 제조-phenylpentanamido) methyl) biphenyl-4-yloxy) acetic acid)
상기 단계 1에서 수득한 에틸 (2-(4'-((N-페닐펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 최종 생성물인 2-(4'-((N-페닐펜탄아미도)메틸)바이페닐-4-일옥시)아세트산 (2-(4'-((N-phenylpentanamido)methyl)biphenyl-4-yloxy)acetic acid)을 수득하였다 (85% 수율).Ethyl (2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was mixed well with tetrahydrofuran (THF). Then, LiOH solution was added and stirred for 4 hours After completion of the reaction, the mixed solution was concentrated and 2N HCl was added until acidic and extracted with ethyl acetate (EA) in vacuo. The solvent layer was removed and the final product 2- (4 '-(( N- phenylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid (2- (4'-(( N -phenylpentanamido) methyl) biphenyl -4-yloxy) acetic acid) was obtained (85% yield).
1H-NMR (CDCl3, 400MHz) δ 7.49 (2H, d, J = 8.0 Hz); 7.41 (2H, d, J = 8.0 Hz); 7.34-7.32 (3H, m); 7.22 (2H, d, J = 8.0 Hz); 7.01-6.95 (4H, m); 4.91 (2H, s); 4.97 (2H, s); 2.10 (2H, t); 1.65-1.55 (2H, m); 1.26-1.17 (2H, m); 0.80 (3H, t). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.49 (2H, d, J = 8.0 Hz); 7.41 (2H, doublet, J = 8.0 Hz); 7.34-7.32 (3H, m); 7.22 (2H, doublet, J = 8.0 Hz); 7.01-6.95 (4H, m); 4.91 (2H, s); 4.97 (2H, s); 2.10 (2H, t); 1.65-1.55 (2H, m); 1.26-1.17 (2H, m); 0.80 (3H, t).
실시예Example 31.  31. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-fluorophenyl)--(3-fluorophenyl)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide) (AC-1068)의 제조Preparation of-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1068)
아닐린 대신 3-플루오로아닐린 (3-fluoroaniline)를 이용하여 3-플루오로-N-((4'-메톡시바이페닐-4-일)메틸)아닐린 (3-fluoro-N-((4'-methoxybiphenyl-4-yl)methyl)aniline)을 제조하고, 최종 생성물인 N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (N-(3-fluorophenyl)-N-((4'-methoxybiphenyl-4-yl)methyl)pentanamide)를 수득하였다. (100% 수율).3-fluoro- N -((4'-methoxybiphenyl-4-yl) methyl) aniline (3-fluoro- N -((4 ') using 3-fluoroaniline instead of aniline -methoxybiphenyl-4-yl) methyl) aniline) and the final product is N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide ( N -(3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained. (100% yield).
1H NMR (400 MHz, CDCl3) δ 7.52-7.45 (4H, m); 7.31-7.30 (1H, m); 7.23 (2H, d, J = 8.4 Hz); 7.03-7.03 (1H, m); 6.97 (2H, d, J = 8.8 Hz); 6.82-6.80 (2H, m); 4.89 (2H, s); 3.85 (3H, s); 2.10 (2H, t); 1.62-1.57 (2H, m); 1.27-1.22 (2H, m); 0.83 (3H, t). 1 H NMR (400 MHz, CDCl 3 ) δ 7.52-7.45 (4H, m); 7.31-7.30 (1H, m); 7.23 (2H, doublet, J = 8.4 Hz); 7.03-7.03 (1 H, m); 6.97 (2H, doublet, J = 8.8 Hz); 6.82-6.80 (2H, m); 4.89 (2H, s); 3.85 (3 H, s); 2.10 (2H, t); 1.62-1.57 (2H, m); 1.27-1.22 (2H, m); 0.83 (3H, t).
실시예Example 32.  32. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-fluorophenyl)--(3-fluorophenyl)- NN -((4'-hydroxybiphenyl-4-yl)methyl)pentanamide) (AC-1070)의 제조Preparation of-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) (AC-1070)
상기 실시예 31에서 수득한 N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (1.0 equiv)를 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 0℃에서, BBr3를 천천히 가하였으며, 실온에서 3시간 동안 혼합 용액을 교반하였다. 상기 반응을 TLC (thin Layer Chromatography)로 관찰하였다. 반응을 마친 후, RBF에 얼음을 가하고, DCM에서 추출하였다. 유기 용매층을 분리하고. 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하였으며, 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드 (N-(3-fluorophenyl)-N-((4'-hydroxybiphenyl-4-yl)methyl)pentanamide)를 수득하였다 (85% 수율). N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in Example 31 was converted to dichloromethane (DCM). After dissolving in solution, it was cooled in ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide ( N- ( 3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) was obtained (85% yield).
1H-NMR (400 MHz, CDCl3) δ 7.44-7.42 (4H, m); 7.35-7.29 (1H, m); 7.22 (2H, d, J = 8.0 Hz); 7.06-7.02 (1H, m); 6.88 (2H, d, J = 8.0 Hz); 6.85-6.78 (2H, m); 5.60 (1H, br, s); 4.90 (2H, s); 2.12 (2H, t); 1.65-1.57 (2H, m); 1.30-1.20 (2H, m); 0.83 (3H, t). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.44-7.42 (4H, m); 7.35-7.29 (1 H, m); 7.22 (2H, doublet, J = 8.0 Hz); 7.06-7.02 (1 H, m); 6.88 (2H, doublet, J = 8.0 Hz); 6.85-6.78 (2H, m); 5.60 (1H, broad singlet, s); 4.90 (2H, s); 2.12 (2H, t); 1.65-1.57 (2H, m); 1.30-1.20 (2H, m); 0.83 (3H, t).
실시예Example 33. 2-(4'-(( 33. 2- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1074)의 제조Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1074)
상기 실시예 32에서 수득한 N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드를 이용하여 실시예 30과 동일한 방법으로 에틸 (2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (Ethyl (2-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)을 제조하여 최종 생성물인 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산 (2-(4'-((N-(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)을 수득하였다 (80% 수율).In the same manner as in Example 30 using N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide obtained in Example 32, ethyl (2 -(4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (Ethyl (2- (4'-(( N- (3-fluorophenyl) pentanamido ) methyl) biphenyl-4-yloxy) acetate) to produce the final product 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid ( 2- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) was obtained (80% yield).
1H-NMR (CDCl3, 400MHz) δ 7.49-7.46 (4H, t); 7.39-7.37 (1H, m); 7.18-7.14 (4H, m); 7.01 (1H, d, J = 8.0 Hz); 6.88 (2H, d, J = 8.4 Hz); 4.86 (2H, s); 4.38 (2H, s); 2.09 (2H, m); 1.47-1.44 (2H, m); 1.19-1.13 (2H, m); 0.75 (3H, t). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.49-7.46 (4H, t); 7.39-7.37 (1 H, m); 7.18-7.14 (4H, m); 7.01 (1H, doublet, J = 8.0 Hz); 6.88 (2H, doublet, J = 8.4 Hz); 4.86 (2H, s); 4.38 (2H, s); 2.09 (2H, m); 1.47-1.44 (2H, m); 1.19-1.13 (2H, m); 0.75 (3H, t).
실시예Example 34.  34. NN -(3--(3- 클로로페닐Chlorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-chlorophenyl)--(3-chlorophenyl)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide) (AC-1628)의 제조Preparation of-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1628)
단계 1 : 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)의 제조Step 1: Preparation of 4'-methoxybiphenyl-4-carbaldehyde
1-브로모-4-메톡시벤젠 (1-bromo-4-methoxybenzene) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)를 수득하였다 (73% 수율).1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. After the reaction mixture was filtered and extracted with ethyl acetate (EA), water was removed with anhydrous MgSO 4 , concentrated by evaporation, and purified by Medium Pressure Liquid Chromatography (MPLC) to 4'-methoxybiphenyl. 4-Carbaldehyde (4'-methoxybiphenyl-4-carbaldehyde) was obtained (73% yield).
단계 step 2 : 32: 3 -- 클로로Chloro -N--N- ((4'-메톡시페닐-4-일)메틸)아닐린 ((4'-methoxyphenyl-4-yl) methyl) aniline (3-(3- chlorochloro -N-((4'--N-((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)aniline)의 제조Preparation of -4-yl) methyl) aniline)
상기 단계 1에서 수득한 4'-메톡시바이페닐-4-카브알데하이드 (1.0 equiv)와 3-클로로아닐린 (3-chloroaniline) (2.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 3-클로로-N-((4'-메톡시페닐-4-일)메틸)아닐린 (3-chloro-N-((4'-methoxybiphenyl-4-yl)methyl)aniline)을 수득하였다 (97% 수율).4'-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and 3-chloroaniline (3-chloroaniline) (2.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. . The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give 3-chloro-N-((4'-methoxyphenyl-4-yl) methyl) aniline (3-chloro-N-((4'-methoxybiphenyl- 4-yl) methyl) aniline) was obtained (97% yield).
단계 3 : N-(3-Step 3: N- (3- 클로로페닐Chlorophenyl )-N-) -N- ((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3-(3- chlorophenylchlorophenyl )-N-((4'-methoxybiphenyl-4-yl)methyl)pentanamide)의 제조) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
상기 2 단계에서 수득한 3-클로로-N-((4'-메톡시페닐-4-일)메틸)아닐린을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 화합물인 N-(3-클로로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (N-(3-chlorophenyl)-N-((4'-methoxybiphenyl-4-yl)methyl)pentanamide)를 수득하였다 (85% 수율).3-chloro-N-((4'-methoxyphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM), and triethanolamine (TEA) was added thereto. , Cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final compound, N- (3-chlorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3 -chlorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (85% yield).
1H-NMR (CDCl3, 400MHz) δ 7.52-7.49 (m, 2H); 7.46 (d, J = 8.0 Hz, 2H); 7.30 (d, J = 8.0 Hz, 2H) 7.22 (d, J = 8.4 Hz, 2H); 7.06 (s, 1H); 6.98-6.94 (m, 2H); 6.88 (d, J = 7.6 Hz, 1H); 4.88 (s, 2H); 3.84 (s, 3H); 2.08 (t, J = 7.0 Hz, 2H); 1.65-1.56 (m, 2H); 1.29-1.20 (m, 2H); 0.83 (t, J = 7.2 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.52-7.49 (m, 2H); 7.46 (d, J = 8.0 Hz, 2H); 7.30 (d, J = 8.0 Hz, 2H) 7.22 (d, J = 8.4 Hz, 2H); 7.06 (s, 1 H); 6.98-6.94 (m, 2 H); 6.88 (d, J = 7.6 Hz, 1 H); 4.88 (s, 2 H); 3.84 (s, 3 H); 2.08 (t, J = 7.0 Hz, 2H); 1.65-1.56 (m, 2 H); 1.29-1.20 (m, 2 H); 0.83 (t, J = 7.2 Hz, 3H).
실시예Example 35.  35. NN -(3--(3- 클로로페닐Chlorophenyl )-)- NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-chlorophenyl)--(3-chlorophenyl)- NN -((4'-hydroxybiphenyl-4-yl)methyl)pentanamide) (AC-1629)의 제조Preparation of-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) (AC-1629)
상기 실시예 34에서 수득한 N-(3-클로로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (1.0 equiv)를 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 0℃에서, BBr3를 천천히 가하였으며, 실온에서 3시간 동안 혼합 용액을 교반하였다. 상기 반응을 TLC (thin Layer Chromatography)로 관찰하였다. 반응을 마친 후, RBF에 얼음을 가하고, DCM에서 추출하였다. 유기 용매층을 분리하고. 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하였으며, 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-(3-클로로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드 (N-(3-chlorophenyl)-N-((4'-hydroxybiphenyl-4-yl)methyl)pentanamide)를 수득하였다 (88% 수율).N- (3-chlorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in Example 34 was diluted with dichloromethane (DCM). After melting in, cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-chlorophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (N- (3) as a final product. -chlorophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) was obtained (88% yield).
1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.4 Hz, 4H); 7.32-7.25 (m, 2H); 7.21(d, J = 8.0 Hz, 2H); 7.08 (s, 1H); 6.91-6.85 (m, 3H); 5.49 (s, 1H); 4.88 (s, 2H); 2.10 (t, J = 7.2 Hz, 2H); 1.64-1.57 (m, 2H); 1.27-1.22 (m, 2H); 0.83 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (d, J = 8.4 Hz, 4H); 7.32-7.25 (m, 2 H); 7.21 (d, J = 8.0 Hz, 2H); 7.08 (s, 1 H); 6.91-6.85 (m, 3 H); 5.49 (s, 1 H); 4.88 (s, 2 H); 2.10 (t, J = 7.2 Hz, 2H); 1.64-1.57 (m, 2 H); 1.27-1.22 (m, 2 H); 0.83 (t, J = 7.2 Hz, 3H).
실시예Example 36. 2-(4'-(( 36. 2- (4 '-(( NN -(3--(3- 클로로페닐Chlorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (Acetic acid ( N-N- (3-bromophenyl)-(3-bromophenyl)- NN -((4'-hydroxybiphenyl-4-yl)methyl)pentanamide) (AC-1630)의 제조Preparation of-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) (AC-1630)
단계 1 : 에틸 2-(4'-((N-(3-Step 1: ethyl 2- (4 ′-((N- (3- 클로로페닐Chlorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세테이트 (ethyl 2-(4'-((N-(3-chlorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)의 제조Preparation of Acetate (ethyl 2- (4 '-((N- (3-chlorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
상기 실시예 35에서 수득한 N-(3-클로로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드 (1.0 equiv)와 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 에틸클로로아세테이트 (Ethylchloroacetate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 에틸 2-(4'-((N-(3-클로로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (ethyl 2-(4'-((N-(3-chlorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)를 수득하였다(75% 수율).N- (3-chlorophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 35 were prepared. It was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain ethyl 2- (4 '-((N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- ( 4 '-((N- (3-chlorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (75% yield).
단계 step 2 : 22: 2 -(4'-((N-(3--(4 '-((N- (3- 클로로페닐Chlorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((N-(3-chlorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)의 제조Preparation of acetic acid (2- (4 '-((N- (3-chlorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
상기 단계 1에서 수득한 에틸 2-(4'-((N-(3-클로로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 최종 생성물인 2-(4'-((N-(3-클로로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산 (2-(4'-((N-(3-chlorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)을 수득하였다 (98% 수율).Ethyl 2- (4 '-((N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was added with tetrahydrofuran (THF). After mixing well), LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed under vacuum and the final product 2- (4 '-((N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid (2- (4'- ((N- (3-chlorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) was obtained (98% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.40-7.37 (m, 3H); 7.23 (d, J = 8.4 Hz, 2H); 7.16 (s, 1H); 6.97 (d, J = 8.0 Hz, 2H); 4.89 (s, 2H); 4.70 (s, 2H); 2.11 (t, 2H); 1.52-1.45 (m, 2H); 1.23-1.16 (m, 2H); 0.78 (d, J = 7.6 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.40-7.37 (m, 3H); 7.23 (d, J = 8.4 Hz, 2H); 7.16 (s, 1 H); 6.97 (d, J = 8.0 Hz, 2H); 4.89 (s, 2 H); 4.70 (s, 2 H); 2.11 (t, 2 H); 1.52-1.45 (m, 2 H); 1.23-1.16 (m, 2 H); 0.78 (d, J = 7.6 Hz, 3H).
실시예Example 37.  37. NN -(3--(3- 브로모페닐Bromophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3--(3- bromophenylbromophenyl )-)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide) (AC-1631)의 제조Preparation of-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1631)
단계 1 : 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)의 제조Step 1: Preparation of 4'-methoxybiphenyl-4-carbaldehyde
1-브로모-4-메톡시벤젠 (1-bromo-4-methoxybenzene) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한 번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)를 수득하였다 (73% 수율).1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. After the reaction mixture was filtered and extracted with ethyl acetate (EA), water was removed with anhydrous MgSO 4 , concentrated by evaporation, and purified by Medium Pressure Liquid Chromatography (MPLC) to 4'-methoxybiphenyl. 4-Carbaldehyde (4'-methoxybiphenyl-4-carbaldehyde) was obtained (73% yield).
단계 step 2 : 32: 3 -- 브로모Bromo -N--N- ((4'-메톡시페닐-4-일)메틸)아닐린 ((4'-methoxyphenyl-4-yl) methyl) aniline (3-(3- chlorochloro -N-((4'--N-((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)aniline)의 제조 Preparation of -4-yl) methyl) aniline)
상기 단계 1에서 수득한 4'-메톡시바이페닐-4-카브알데하이드 (1.0 equiv)와 3-브로모아닐린 (3-bromoaniline) (2.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 3-브로모-N-((4'-메톡시페닐-4-일)메틸)아닐린 (3-chloro-N-((4'-methoxybiphenyl-4-yl)methyl)aniline)을 수득하였다 (97% 수율). 4'-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and 3-bromoaniline (3-bromoaniline) (2.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield 3-bromo-N-((4'-methoxyphenyl-4-yl) methyl) aniline (3-chloro-N-((4'-methoxybiphenyl). -4-yl) methyl) aniline) was obtained (97% yield).
단계 3 : N-(3-Step 3: N- (3- 브로모페닐Bromophenyl )-N-) -N- ((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3-(3- bromophenylbromophenyl )-N-((4'-methoxybiphenyl-4-yl)methyl)pentanamide)의 제조) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
상기 2 단계에서 수득한 3-브로모-N-((4'-메톡시페닐-4-일)메틸)아닐린을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 화합물인 N-(3-브로모페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (N-(3-bromophenyl)-N-((4'-methoxybiphenyl-4-yl)methyl)pentanamide)를 수득하였다 (73% 수율).3-bromo-N-((4'-methoxyphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. Then cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrated solution was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain a final compound, N- (3-bromophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- ( 3-bromophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (73% yield).
1H-NMR (CDCl3, 400MHz) δ 7.51 (d, J = 8.8 Hz, 2H); 7.46 (d, J = 8.4 Hz, 3H); 7.23-7.18 (m, 4H); 6.96 (d, J = 8.8 Hz, 2H); 6.91(d, J = 7.6 Hz, 1H); 4.88 (s, 2H); 3.84 (s, 3H); 2.08 (t, J = 7.2 Hz, 2H); 1.61 -1.55 (m, 2H); 1.27-1.21 (m, 2H); 0.83 (t, J = 7.2 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H); 7.46 (d, J = 8.4 Hz, 3H); 7.23-7.18 (m, 4H); 6.96 (d, J = 8.8 Hz, 2H); 6.91 (d, J = 7.6 Hz, 1 H); 4.88 (s, 2 H); 3.84 (s, 3 H); 2.08 (t, J = 7.2 Hz, 2H); 1.61 -1.55 (m, 2 H); 1.27-1.21 (m, 2 H); 0.83 (t, J = 7.2 Hz, 3H).
실시예Example 38.  38. N-N- (3-(3- 브로모페닐Bromophenyl )-)- N-N- ((4'-((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-bromophenyl)--(3-bromophenyl)- NN -((4'-hydroxybiphenyl-4-yl)methyl)pentanamide) (AC-1632)의 제조Preparation of-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) (AC-1632)
상기 실시예 37에서 수득한 N-(3-브로모페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (1.0 equiv)를 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 0℃에서, BBr3를 천천히 가하였으며, 실온에서 3시간 동안 혼합 용액을 교반하였다. 상기 반응을 TLC (thin Layer Chromatography)로 관찰하였다. 반응을 마친 후, RBF에 얼음을 가하고, DCM에서 추출하였다. 유기 용매층을 분리하고. 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하였으며, 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-(3-브로모페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드 (N-(3-bromophenyl)-N-((4'-hydroxybiphenyl-4-yl)methyl)pentanamide)를 수득하였다 (89% 수율).N- (3-bromophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in Example 37 was converted to dichloromethane (DCM). After dissolving in solution, it was cooled in ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield N- (3-bromophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (N- ( 3-bromophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) was obtained (89% yield).
1H-NMR (400 MHz, CDCl3) δ 7.47-7.42 (m, 5H); 7.24-7.19 (m, 4H); 6.94 (d, J = 7.6 Hz, 1H); 6.87 (d, J = 8.0 Hz, 2H); 5.49 (s, 1H); 4.88 (s, 2H); 2.10 (t, J = 7.2 Hz, 2H); 1.64-1.58 (m, 2H); 1.29-1.20 (m, 2H); 0.83 (t, J = 7.2 Hz, 3H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.47-7.42 (m, 5H); 7.24-7.19 (m, 4 H); 6.94 (d, J = 7.6 Hz, 1 H); 6.87 (d, J = 8.0 Hz, 2H); 5.49 (s, 1 H); 4.88 (s, 2 H); 2.10 (t, J = 7.2 Hz, 2H); 1.64-1.58 (m, 2 H); 1.29-1.20 (m, 2 H); 0.83 (t, J = 7.2 Hz, 3H).
실시예Example 39. 2-(4'-(( 39. 2- (4 '-(( NN -(3--(3- 브로모페닐Bromophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3-bromophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1633)의 제조Preparation of-(3-bromophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1633)
단계 1 : 에틸 2-(4'-((N-(3-Step 1: ethyl 2- (4 ′-((N- (3- 브로모페닐Bromophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세테이트 (ethyl 2-(4'-((N-(3-bromophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)의 제조Preparation of Acetate (ethyl 2- (4 '-((N- (3-bromophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
상기 실시예 38에서 수득한 N-(3-브로모페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드 (1.0 equiv)와 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 에틸클로로아세테이트 (Ethylchloroacetate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 에틸 2-(4'-((N-(3-브로모페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (ethyl 2-(4'-((N-(3-bromophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)를 수득하였다(85% 수율).N- (3-bromophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 38. Was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 2- (4 '-((N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4 '-((N- (3-bromophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (85% yield).
단계 step 2 : 22: 2 -(4'-((N-(3--(4 '-((N- (3- 브로모페닐Bromophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((N-(3-bromophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)의 제조Preparation of acetic acid (2- (4 '-((N- (3-bromophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
상기 단계 1에서 수득한 에틸 2-(4'-((N-(3-브로모페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 최종 생성물인 2-(4'-((N-(3-브로모페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산 (2-(4'-((N-(3-bromophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)을 수득하였다 (87% 수율).Ethyl 2- (4 '-((N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was converted to tetrahydrofuran, THF) was mixed well, then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and the final product 2- (4 '-((N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid (2- (4') -((N- (3-bromophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) was obtained (87% yield).
1H-NMR (CDCl3, 400MHz) δ 7.51 (d, J = 8.8 Hz, 2H); 7.44 (d, J = 8.8 Hz, 3H); 7.23-7.18 (m, 4H); 6.98 (d, J = 8.0 Hz, 2H); 6.92 (d, J = 8.0 Hz, 1H); 4.88 (s, 2H); 4.71 (s, 2H); 2.09 (t, 2H); 1.63-1.57 (m, 2H); 1.25-1.21 (m, 2H); 0.83 (t, J = 7.2 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H); 7.44 (d, J = 8.8 Hz, 3H); 7.23-7.18 (m, 4H); 6.98 (d, J = 8.0 Hz, 2H); 6.92 (d, J = 8.0 Hz, 1 H); 4.88 (s, 2 H); 4.71 (s, 2 H); 2.09 (t, 2 H); 1.63-1.57 (m, 2 H); 1.25-1.21 (m, 2 H); 0.83 (t, J = 7.2 Hz, 3H).
실시예Example 40.  40. NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- (3-(3- (( 트리플루오로메틸Trifluoromethyl )페닐)) Phenyl) 펜탄아마이드Pentaneamide (( NN -((4'-methoxybiphenyl-4-yl)methyl)--((4'-methoxybiphenyl-4-yl) methyl)- NN -(3-(trifluoromethyl)phenyl)pentanamide) (AC-1634)의 제조Preparation of-(3- (trifluoromethyl) phenyl) pentanamide) (AC-1634)
단계 1 : 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)의 제조Step 1: Preparation of 4'-methoxybiphenyl-4-carbaldehyde
1-브로모-4-메톡시벤젠 (1-bromo-4-methoxybenzene) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)를 수득하였다 (73% 수율).1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. After the reaction mixture was filtered and extracted with ethyl acetate (EA), water was removed with anhydrous MgSO 4 , concentrated by evaporation, and purified by Medium Pressure Liquid Chromatography (MPLC) to 4'-methoxybiphenyl. 4-Carbaldehyde (4'-methoxybiphenyl-4-carbaldehyde) was obtained (73% yield).
단계 2 : N-((4'-Step 2: N-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-3-) -3- (트리플루오로메틸)아닐린 (N-((Trifluoromethyl) aniline (N- ( (4'-methoxybiphenyl-4-yl)methyl)-3-(trifluoromethyl)aniline)의 제조Preparation of (4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline)
상기 단계 1에서 수득한 4'-메톡시바이페닐-4-카브알데하이드 (1.0 equiv)와 3-(트리플루오로메틸)아닐린 (3-(trifluoromethyl)aniline) (2.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, N-((4'-메톡시바이페닐-4-일)메틸)-3-(트리플루오로메틸)아닐린 (N-((4'-methoxybiphenyl-4-yl)methyl)-3-(trifluoromethyl)aniline)을 수득하였다 (93% 수율). 4'-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and 3- (trifluoromethyl) aniline (2.0 equiv) obtained in step 1 were dissolved in methanol. And stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline (N-((4'- methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline) was obtained (93% yield).
단계 3 : N-((4'-Step 3: N-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-N-) -N- (3-(3- (( 트리플루오로메틸Trifluoromethyl )페닐)) Phenyl) 펜탄아마이드Pentaneamide (N-((4'-methoxybiphenyl-4-yl)methyl)-N-(3-(trifluoromethyl)phenyl)pentanamide)의 제조Preparation of (N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentanamide)
상기 2 단계에서 수득한 N-((4'-메톡시바이페닐-4-일)메틸)-3-(트리플루오로메틸)아닐린을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 화합물인 N-((4'-메톡시바이페닐-4-일)메틸)-N-(3-(트리플루오로메틸)페닐)펜탄아마이드(N-((4'-methoxybiphenyl-4-yl)methyl)-N-(3-(trifluoromethyl)phenyl)pentanamide)를 수득하였다 (75% 수율).N-((4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine , TEA) was added and then cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide as a final compound. (N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentanamide) was obtained (75% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.58 (d, J = 7.6 Hz, 1H); 7.5 (dd, J = 3.0, 11.8 Hz, 2H); 7.46 (d, J = 7.6 Hz, 3H); 7.28 (s, 1H); 7.21 (d , J = 8.0 Hz, 2H); 7.17 (d, J = 7.2 Hz, 1H); 6.97 (dd, J = 3.0, 11.8 Hz, 2H); 4.91 (s, 2H); 3.84 (s, 3H); 2.05 (s, 2H); 1.64-1.56 (m, 2H); 1.28-1.19 (m, 2H); 0.82 (t, J = 7.6 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.58 (d, J = 7.6 Hz, 1H); 7.5 (dd, J = 3.0, 11.8 Hz, 2H); 7.46 (d, J = 7.6 Hz, 3H); 7.28 (s, 1 H); 7.21 (d, J = 8.0 Hz, 2H); 7.17 (d, J = 7.2 Hz, 1H); 6.97 (dd, J = 3.0, 11.8 Hz, 2H); 4.91 (s, 2 H); 3.84 (s, 3 H); 2.05 (s, 2 H); 1.64-1.56 (m, 2 H); 1.28-1.19 (m, 2 H); 0.82 (t, J = 7.6 Hz, 3H).
실시예Example 41.  41. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- N-N- (3-(3- (( 트리플루오로메틸Trifluoromethyl )페닐)) Phenyl) 펜탄아마이드Pentaneamide (( NN -((4'-hydroxybiphenyl-4-yl)methyl)--((4'-hydroxybiphenyl-4-yl) methyl)- NN -(3-(trifluoromethyl)phenyl)pentanamide) (AC-1635)의 제조Preparation of-(3- (trifluoromethyl) phenyl) pentanamide) (AC-1635)
상기 실시예 40에서 수득한 N-((4'-메톡시바이페닐-4-일)메틸)-N-(3-(트리플루오로메틸)페닐)펜탄아마이드 (1.0 equiv)를 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 0℃에서, BBr3를 천천히 가하였으며, 실온에서 3시간 동안 혼합 용액을 교반하였다. 상기 반응을 TLC (thin Layer Chromatography)로 관찰하였다. 반응을 마친 후, RBF에 얼음을 가하고, DCM에서 추출하였다. 유기 용매층을 분리하고. 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하였으며, 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-(트리플루오로메틸)페닐)펜탄아마이드(N-((4'-hydroxybiphenyl-4-yl)methyl)-N-(3-(trifluoromethyl)phenyl)pentanamide를 수득하였다 (96% 수율).N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide (1.0 equiv) obtained in Example 40 was converted to dichloromethane ( dichloromethane, DCM) solution, and then cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide as a final product. (N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentanamide was obtained (96% yield).
1H-NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.6 Hz, 1H); 7.48 (d, J = 7.6 Hz, 1H); 7.44 (d, J = 8.4 Hz, 4H); 7.29 (s, 1H); 7.21 (q, 3H); 6.89 (d, J = 11.6 Hz, 2H); 5.14 (s, 1H); 4.91 (s, 2H); 2.06 (t, 2H); 1.64-1.58 (m, 2H); 1.28-1.2 (m, 2H); 0.82 (t, J = 7.4 Hz, 3H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 7.6 Hz, 1H); 7.48 (d, J = 7.6 Hz, 1 H); 7.44 (d, J = 8.4 Hz, 4H); 7.29 (s, 1 H); 7.21 (q, 3 H); 6.89 (d, J = 11.6 Hz, 2H); 5.14 (s, 1 H); 4.91 (s, 2 H); 2.06 (t, 2 H); 1.64-1.58 (m, 2 H); 1.28-1.2 (m, 2 H); 0.82 (t, J = 7.4 Hz, 3H).
실시예Example 42. 2-(4'-(( 42. 2- (4 '-(( NN -(3-(-(3- ( 트리플루오로메틸Trifluoromethyl )페닐)) Phenyl) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3-(trifluoromethyl)phenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC--(3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC- 1636)의1636) 제조 Produce
단계 1 : 에틸 2-(4'-((N-(3-(Step 1: ethyl 2- (4 ′-((N- (3- ( 트리플루오로Trifluoro )페닐)) Phenyl) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세테이트 (ethyl 2-(4'-((N-(3-(trifluoromethyl)phenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)의 제조Preparation of Acetate (ethyl 2- (4 '-((N- (3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
상기 실시예 41에서 수득한 N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-(트리플루오로메틸)페닐)펜탄아마이드 (1.0 equiv)와 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 에틸브로모아세테이트 (Ethylbromoacetate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 2-(4'-((N-(3-(트리플루오로)페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (ethyl 2-(4'-((N-(3-(trifluoromethyl)phenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)를 수득하였다 (100% 수율).N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide (1.0 equiv) and K 2 CO 3 obtained in Example 41 above. (3.0 equiv) was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. Ethylbromoacetate (3.0 equiv) was added and the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give 2- (4 '-((N- (3- (trifluoro) phenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4 '-((N- (3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (100% yield).
단계 step 2 : 22: 2 -(4'-((N-(3-(-(4 '-((N- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)) Phenyl) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((N-(3-(trifluoromethyl)phenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)의 제조Preparation of acetic acid (2- (4 '-((N- (3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
상기 1단계에서 수득한 2-(4'-((N-(3-(트리플루오로)페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 최종 생성물인 2-(4'-((N-(3-(트리플루오로메틸)페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산 (2-(4'-((N-(3-(trifluoromethyl)phenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)을 수득하였다 (69% 수율).2- (4 '-((N- (3- (trifluoro) phenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was added with tetrahydrofuran ( After tetrahydrofuran (THF) was mixed well, LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and the final product 2- (4 '-((N- (3- (trifluoromethyl) phenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid (2 -(4 '-((N- (3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) was obtained (69% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.59 (d, J = 7.2 Hz, 1H); 7.52-7.43 (m, 5H); 7.28 (s, 1H); 7.21 (d, J = 7.6 Hz, 3H); 6.99 (d, J = 8.8 Hz, 2H); 4.93 (s, 2H); 4.77 (s, 2H); 2.08 (t, 2H); 1.62-1.54 (m, 2H); 1.23-1.19 (m, 2H); 0.82 (t, J = 7.0 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.59 (d, J = 7.2 Hz, 1H); 7.52-7.43 (m, 5 H); 7.28 (s, 1 H); 7.21 (d, J = 7.6 Hz, 3H); 6.99 (d, J = 8.8 Hz, 2H); 4.93 (s, 2 H); 4.77 (s, 2 H); 2.08 (t, 2 H); 1.62-1.54 (m, 2 H); 1.23-1.19 (m, 2 H); 0.82 (t, J = 7.0 Hz, 3H).
실시예Example 43.  43. N-N- (((( 4'메톡시바이페닐4'methoxybiphenyl -4-일)-4- days) 메틸methyl )-)- N-m-N-m- 톨릴펜탄아마이드Tolylpentaneamide ( ( NN -((4'--((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)--4-yl) methyl)- N-mN-m -tolylpentanamide) (AC-1637)의 제조-tolylpentanamide) (AC-1637)
단계 1 : 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)의 제조Step 1: Preparation of 4'-methoxybiphenyl-4-carbaldehyde
1-브로모-4-메톡시벤젠 (1-bromo-4-methoxybenzene) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)를 수득하였다 (73% 수율).1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. After the reaction mixture was filtered and extracted with ethyl acetate (EA), water was removed with anhydrous MgSO 4 , concentrated by evaporation, and purified by Medium Pressure Liquid Chromatography (MPLC) to 4'-methoxybiphenyl. 4-Carbaldehyde (4'-methoxybiphenyl-4-carbaldehyde) was obtained (73% yield).
단계 2 : N-((4'-Step 2: N-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-3-) -3- (트리플루오로메틸)아닐린 (N-((Trifluoromethyl) aniline (N- ( (4'-methoxybiphenyl-4-yl)methyl)-3-(trifluoromethyl)aniline)의 제조Preparation of (4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline)
상기 단계 1에서 수득한 4'-메톡시바이페닐-4-카브알데하이드 (1.0 equiv)와 m-톨리딘 (m-toluidine) (2.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, N-((4'-메톡시바이페닐-4-일)메틸)-3-(트리플루오로메틸)아닐린 (N-((4'-methoxybiphenyl-4-yl)methyl)-3-(trifluoromethyl)aniline)을 수득하였다 (98% 수율). 4'-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and m-toluidine (2.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. . The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline (N-((4'- methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline) was obtained (98% yield).
단계 3 : N-((4'-Step 3: N-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-N-m-) -N-m- 톨릴펜탄아마이드Tolylpentaneamide (N-((4'- (N-((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)-N-m-tolylpentanamide)의 제조Preparation of -4-yl) methyl) -N-m-tolylpentanamide)
상기 2 단계에서 수득한 N-((4'-메톡시바이페닐-4-일)메틸)-3-(트리플루오로메틸)아닐린 을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 화합물인 N-((4'-메톡시바이페닐-4-일)메틸)-N-m-톨릴펜탄아마이드 (N-((4'-methoxybiphenyl-4-yl)methyl)-N-m-tolylpentanamide)를 수득하였다 (90% 수율).N-((4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine , TEA) was added and then cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain the final compound, N-((4'-methoxybiphenyl-4-yl) methyl) -Nm-tolylpentaneamide (N-((4'-methoxybiphenyl- 4-yl) methyl) -Nm-tolylpentanamide) was obtained (90% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.51 (d, J = 7.6 Hz, 2H); 7.45 (d, J = 7.6 Hz, 2H); 7.21 (t, J = 10.0 Hz, 3H); 7.11 (d, J = 7.2 Hz, 1H); 6.97 (d, J = 7.6 Hz, 2H); 6.84 (s, 1H); 6.78 (d, J = 8.0 Hz, 1H); 4.88 (s, 2H); 3.848 (s, 3H); 2.31 (s, 3H); 2.08 (t, J = 7.4 Hz, 2H); 1.63-1.55 (m, 2H); 1.26-1.20 (m, 2H); 0.82 (t, J = 7.4 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (d, J = 7.6 Hz, 2H); 7.45 (d, J = 7.6 Hz, 2H); 7.21 (t, J = 10.0 Hz, 3H); 7.11 (d, J = 7.2 Hz, 1H); 6.97 (d, J = 7.6 Hz, 2H); 6.84 (s, 1 H); 6.78 (d, J = 8.0 Hz, 1H); 4.88 (s, 2 H); 3.848 (s, 3 H); 2.31 (s, 3 H); 2.08 (t, J = 7.4 Hz, 2H); 1.63-1.55 (m, 2 H); 1.26-1.20 (m, 2 H); 0.82 (t, J = 7.4 Hz, 3H).
실시예Example 44.  44. NN -((4'--((4'- 하이드록시페닐Hydroxyphenyl -4-일)-4- days) 메틸methyl )-)- NN -- mm -- 톨릴펜탄아마이드Tolylpentaneamide ( ( NN -((4'--((4'- hydroxybiphenylhydroxybiphenyl -4-yl)methyl)-4-yl) methyl) -N-m--N-m- tolylpentanamide) (AC-1638)의 제조Preparation of tolylpentanamide) (AC-1638)
상기 실시예 43에서 수득한 N-((4'-메톡시바이페닐-4-일)메틸)-N-m-톨릴펜탄아마이드 (1.0 equiv)를 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 0℃에서, BBr3를 천천히 가하였으며, 실온에서 3시간 동안 혼합 용액을 교반하였다. 상기 반응을 TLC (thin Layer Chromatography)로 관찰하였다. 반응을 마친 후, RBF에 얼음을 가하고, DCM에서 추출하였다. 유기 용매층을 분리하고. 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하였으며, 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-((4'-하이드록시페닐-4-일)메틸)-N-m-톨릴펜탄아마이드 (N-((4'-hydroxybiphenyl-4-yl)methyl)-N-m-tolylpentanamide)를 수득하였다 (83% 수율).N-((4'-methoxybiphenyl-4-yl) methyl) -Nm-tolylpentanamide (1.0 equiv) obtained in Example 43 was dissolved in a dichloromethane (DCM) solution, and then iced. Cooled at. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-hydroxyphenyl-4-yl) methyl) -Nm-tolylpentaneamide (N-((4'-hydroxybiphenyl-4) as a final product. -yl) methyl) -Nm-tolylpentanamide) was obtained (83% yield).
1H-NMR (400 MHz, CDCl3) δ 7.41-7.36 (m, 4H); 7.25-7.21 (m, 3H), 7.13 (d, J = 7.6 Hz, 1H); 6.97 (s, br, 1H); 6.89 (s, 1H); 6.85 (d, J = 6.8 Hz, 3H); 4.89 (s, 2H); 2.33 (s, 3H); 2.14 (t, J = 7.6 Hz, 2H); 1.64-1.56 (m, 2H); 1.28-1.18 (m, 2H); 0.81 (t, J = 7.2 Hz, 3H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.41-7.36 (m, 4H); 7.25-7.21 (m, 3 H), 7.13 (d, J = 7.6 Hz, 1 H); 6.97 (s, br, 1 H); 6.89 (s, 1 H); 6.85 (d, J = 6.8 Hz, 3H); 4.89 (s, 2 H); 2.33 (s, 3 H); 2.14 (t, J = 7.6 Hz, 2H); 1.64-1.56 (m, 2 H); 1.28-1.18 (m, 2 H); 0.81 (t, J = 7.2 Hz, 3H).
실시예Example 45. 2-(4'-(( 45. 2- (4 '-(( N-m-N-m- 톨릴펜탄아미도Tolylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( N-m-N-m- tolylpentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1639)의 제조Preparation of tolylpentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1639)
단계 1 : 에틸 2-(4'-((N-m-Step 1: ethyl 2- (4 '-((N-m- 톨릴펜탄아미도Tolylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세테이트 (ethyl 2-(4'-((N-m-tolylpentanamido)methyl)biphenyl-4-yloxy)acetate)의 제조Preparation of Acetate (ethyl 2- (4 '-((N-m-tolylpentanamido) methyl) biphenyl-4-yloxy) acetate)
상기 실시예 44에서 수득한 N-((4'-하이드록시페닐-4-일)메틸)-N-m-톨릴펜탄아마이드 (1.0 equiv)와 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 에틸클로로아세테이트 (Ethylchloroacetate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 에틸 2-(4'-((N-m-톨릴펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (ethyl 2-(4'-((N-m-tolylpentanamido)methyl)biphenyl-4-yloxy)acetate)를 수득하였다(100% 수율).N-((4'-hydroxyphenyl-4-yl) methyl) -Nm-tolylpentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 44 were replaced with N , N -dimethyl. It was dissolved in formamide (DMF) solution and then cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain ethyl 2- (4 '-((Nm-tolylpentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4'-(( Nm-tolylpentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (100% yield).
단계 step 2 : 22: 2 -(4'-((N-m--(4 '-((N-m- 톨릴펜탄아미도Tolylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((N-m-tolylpentanamido)methyl)biphenyl-4-yloxy)acetic acid)의 제조Preparation of acetic acid (2- (4 '-((N-m-tolylpentanamido) methyl) biphenyl-4-yloxy) acetic acid)
상기 단계 1에서 수득한 에틸 2-(4'-((N-m-톨릴펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 최종 생성물인 2-(4'-((N-m-톨릴펜탄아미도)메틸)바이페닐-4-일옥시)아세트산 (2-(4'-((N-m-tolylpentanamido)methyl)biphenyl-4-yloxy)acetic acid)을 수득하였다 (62% 수율).Ethyl 2- (4 '-((Nm-tolylpentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was mixed well with tetrahydrofuran (THF). , LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and the final product 2- (4 '-((Nm-tolylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid (2- (4'-((Nm-tolylpentanamido) ) methyl) biphenyl-4-yloxy) acetic acid) was obtained (62% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.50 (d, J = 8.8 Hz, 2H); 7.42 (s, 2H); 7.23 (t, J = 7.4 Hz, 3H); 7.11 (d, J = 7.2 Hz, 1H); 6.98 (d, J = 8.4 Hz, 2H); 6.83 (s, 1H); 6.78 (d, J = 7.6 Hz, 1H); 5.00 (s, 2H); 4.767 (s, 2H); 2.35 (s, 3H); 2.10 (t, J = 7.6 Hz, 2H); 1.64-1.53 (m, 2H); 1.26-1.25 (m, 2H); 0.81 (t, J = 6.0 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.50 (d, J = 8.8 Hz, 2H); 7.42 (s, 2 H); 7.23 (t, J = 7.4 Hz, 3H); 7.11 (d, J = 7.2 Hz, 1H); 6.98 (d, J = 8.4 Hz, 2H); 6.83 (s, 1 H); 6.78 (d, J = 7.6 Hz, 1 H); 5.00 (s, 2 H); 4.767 (s, 2 H); 2.35 (s, 3 H); 2.10 (t, J = 7.6 Hz, 2H); 1.64-1.53 (m, 2 H); 1.26-1.25 (m, 2 H); 0.81 (t, J = 6.0 Hz, 3H).
실시예Example 46.  46. N-N- ((4'-((4'- 하이드록시페닐Hydroxyphenyl -4-일)-4- days) 메틸methyl )-)- NN -(3--(3- 니트로페닐Nitrophenyl )) 펜탄아마이드Pentaneamide ( ( NN -((4'-hydroxybiphenyl-4-yl)methyl)--((4'-hydroxybiphenyl-4-yl) methyl)- NN -(3-nitrophenyl)pentanamide) (AC-1641)의 제조Preparation of-(3-nitrophenyl) pentanamide) (AC-1641)
단계 1 : 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)의 제조Step 1: Preparation of 4'-methoxybiphenyl-4-carbaldehyde
1-브로모-4-메톡시벤젠 (1-bromo-4-methoxybenzene) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)를 수득하였다 (73% 수율).1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. After the reaction mixture was filtered and extracted with ethyl acetate (EA), water was removed with anhydrous MgSO 4 , concentrated by evaporation, and purified by Medium Pressure Liquid Chromatography (MPLC) to 4'-methoxybiphenyl. 4-Carbaldehyde (4'-methoxybiphenyl-4-carbaldehyde) was obtained (73% yield).
단계 2 : N-((4'-Step 2: N-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-3-) -3- 니트로아닐린(N-(Nitroaniline (N- ( (4'-(4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)-3-nitroaniline)의 제조Preparation of -4-yl) methyl) -3-nitroaniline)
상기 단계 1에서 수득한 4'-메톡시바이페닐-4-카브알데하이드 (1.0 equiv)와 3-니트로아닐린 (3-nitroaniline) (2.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 노랑색 고체의 N-((4'-메톡시바이페닐-4-일)메틸)-3-니트로아닐린 (N-((4'-methoxybiphenyl-4-yl)methyl)-3-nitroaniline)을 수득하였다 (97% 수율). 4'-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and 3-nitroaniline (2.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. . The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give yellow solid N-((4'-methoxybiphenyl-4-yl) methyl) -3-nitroaniline (N-((4'-methoxybiphenyl- 4-yl) methyl) -3-nitroaniline) was obtained (97% yield).
단계 3 : N-((4'-Step 3: N-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-N-) -N- (3-니트로페닐)펜탄아마이드(3-nitrophenyl) pentaneamide (N-((4'-methoxybiphenyl-4-yl)methyl)-N-(3-nitrophenyl)pentanamide)의 제조Preparation of (N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide)
상기 2 단계에서 수득한 N-((4'-메톡시바이페닐-4-일)메틸)-3-니트로아닐린을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, N-((4'-메톡시바이페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드(N-((4'-methoxybiphenyl-4-yl)methyl)-N-(3-nitrophenyl)pentanamide)를 수득하였다 (91% 수율).N-((4'-methoxybiphenyl-4-yl) methyl) -3-nitroaniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. Then cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentaneamide (N-((4 '). -methoxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide) was obtained (91% yield).
단계 4 : N-((4'-Step 4: N-((4'- 하이드록시페닐Hydroxyphenyl -4-일)-4- days) 메틸methyl )-N-(3-) -N- (3- 니트로페닐Nitrophenyl )) 펜탄아마이드Pentaneamide (N-((4'-hydroxybiphenyl-4-yl)methyl)-N-(3-nitrophenyl)pentanamide)의 제조 Preparation of (N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide)
상기 3단계에서 수득한 N-((4'-메톡시바이페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드 (1.0 equiv)를 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 0℃에서, BBr3를 천천히 가하였으며, 실온에서 3시간 동안 혼합 용액을 교반하였다. 상기 반응을 TLC (thin Layer Chromatography)로 관찰하였다. 반응을 마친 후, RBF에 얼음을 가하고, DCM에서 추출하였다. 유기 용매층을 분리하고. 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하였으며, 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-((4'-하이드록시페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드 (N-((4'-hydroxybiphenyl-4-yl)methyl)-N-(3-nitrophenyl)pentanamide) 를 수득하였다 (30% 수율).N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentaneamide (1.0 equiv) obtained in step 3 was added to a dichloromethane (DCM) solution. After thawing, it was cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield N-((4'-hydroxyphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentaneamide (N-((4 '-hydroxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide) Was obtained (30% yield).
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.8 Hz, 1H); 7.95 (s, 1H); 7.52 (t, J = 8.2 Hz, 1H); 7.44 (d, J = 8.0 Hz, 4H); 7.33 (s, 1H); 7.21 (d, J = 8.0 Hz, 2H); 6.97 (d, J = 8.0 Hz, 2H); 4.95 (s, 2H); 4.89 (s, 1H); 2.09 (t, 2H); 1.66-1.54 (m, 2H); 1.27-1.22 (m, 2H); 0.86 (t, J = 9.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (d, J = 8.8 Hz, 1H); 7.95 (s, 1 H); 7.52 (t, J = 8.2 Hz, 1H); 7.44 (d, J = 8.0 Hz, 4H); 7.33 (s, 1 H); 7.21 (d, J = 8.0 Hz, 2H); 6.97 (d, J = 8.0 Hz, 2H); 4.95 (s, 2 H); 4.89 (s, 1 H); 2.09 (t, 2 H); 1.66-1.54 (m, 2 H); 1.27-1.22 (m, 2 H); 0.86 (t, J = 9.2 Hz, 3H).
실시예Example 47. 2-(4'-(( 47. 2- (4 '-(( NN -(3--(3- 니트로페닐Nitrophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3-nitrophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1642)의 제조Preparation of-(3-nitrophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1642)
단계 1 : 에틸 2-(4'-((N-(3-Step 1: ethyl 2- (4 ′-((N- (3- 니트로페닐Nitrophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세테이트 (ethyl 2-(4'-((N-(3-nitrophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)의 제조Preparation of Acetate (ethyl 2- (4 '-((N- (3-nitrophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
상기 실시예 46에서 수득한 N-((4'-하이드록시페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드 (1.0 equiv)와 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 에틸클로로아세테이트 (Ethylchloroacetate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 에틸 2-(4'-((N-(3-니트로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (ethyl 2-(4'-((N-(3-nitrophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)를 수득하였다(91% 수율).N-((4'-hydroxyphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 46 were added to N. , Dissolved in N -dimethylformamide (DMF) solution and cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 2- (4 '-((N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- ( 4 '-((N- (3-nitrophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (91% yield).
단계 step 2 : 22: 2 -(4'-((N-(3--(4 '-((N- (3- 니트로페닐Nitrophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((N-(3-nitrophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)의 제조Preparation of acetic acid (2- (4 '-((N- (3-nitrophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
상기 단계 1에서 수득한 에틸 2-(4'-((N-(3-니트로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 최종 생성물인 2-(4'-((N-(3-니트로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산 (2-(4'-((N-(3-nitrophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)을 수득하였다 (49% 수율).Ethyl 2- (4 ′-((N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was added to tetrahydrofuran (THF). After mixing well), LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and the final product 2- (4 '-((N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid (2- (4'- ((N- (3-nitrophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) was obtained (49% yield).
1H-NMR (CDCl3, 400 MHz) δ 8.15 (d, J = 7.2 Hz, 1H); 8.10 (s, 1H); 7.69-7.63 (m, 2H); 7.55 (t, J = 8.2 Hz, 4H); 7.25 (d, J = 8.0 Hz, 2H); 6.97 (d, J = 8.4 Hz, 2H); 4.97 (s, 2H); 4.70 (s, 2H); 2.15 (t, 2H); 1.53-1.46 (m, 2H); 1.24-1.17 (m, 2H); 0.78 (t, J = 7.2 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.15 (d, J = 7.2 Hz, 1H); 8.10 (s, 1 H); 7.69-7.63 (m, 2 H); 7.55 (t, J = 8.2 Hz, 4H); 7.25 (d, J = 8.0 Hz, 2H); 6.97 (d, J = 8.4 Hz, 2H); 4.97 (s, 2 H); 4.70 (s, 2 H); 2.15 (t, 2 H); 1.53-1.46 (m, 2 H); 1.24-1.17 (m, 2 H); 0.78 (t, J = 7.2 Hz, 3H).
실시예Example 48.  48. NN -(3--(3- 아이오도페닐Iodophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-iodophenyl)--(3-iodophenyl)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide) (AC-1643)의 제조Preparation of-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1643)
단계 1 : 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)의 제조Step 1: Preparation of 4'-methoxybiphenyl-4-carbaldehyde
1-브로모-4-메톡시벤젠 (1-bromo-4-methoxybenzene) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)를 수득하였다 (73% 수율).1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. After the reaction mixture was filtered and extracted with ethyl acetate (EA), water was removed with anhydrous MgSO 4 , concentrated by evaporation, and purified by Medium Pressure Liquid Chromatography (MPLC) to 4'-methoxybiphenyl. 4-Carbaldehyde (4'-methoxybiphenyl-4-carbaldehyde) was obtained (73% yield).
단계 step 2 : 32: 3 -- 아이오도Iodo -N-((4'--N-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )아닐린 (3-Aniline (3- iodoiodo -N-((4'--N-((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)aniline)의 제조Preparation of -4-yl) methyl) aniline)
상기 단계 1에서 수득한 4'-메톡시바이페닐-4-카브알데하이드 (1.0 equiv)와 3-아이오도아닐린 (3-iodoaniline) (2.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 3-아이오도-N-((4'-메톡시바이페닐-4-일)메틸)아닐린 (3-iodo-N-((4'-methoxybiphenyl-4-yl)methyl)aniline)을 수득하였다 (95% 수율). 4'-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and 3-iodoaniline (2.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give 3-iodo-N-((4'-methoxybiphenyl-4-yl) methyl) aniline (3-iodo-N-((4'- methoxybiphenyl-4-yl) methyl) aniline) was obtained (95% yield).
단계 3 : N-(3-Step 3: N- (3- 아이오도페닐Iodophenyl )-N-((4'-) -N-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide (N-(3- (N- (3- iodophenyliodophenyl )-N-((4'-methoxybiphenyl-4-yl)methyl)pentanamide)의 제조) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
상기 2 단계에서 수득한 3-아이오도-N-((4'-메톡시바이페닐-4-일)메틸)아닐린을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 최종화합물인 N-(3-아이오도페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (N-(3-iodophenyl)-N-((4'-methoxybiphenyl-4-yl)methyl)pentanamide)를 수득하였다 (80% 수율).3-iodo-N-((4'-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) After addition, it was cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrated solution was purified by Medium Pressure Liquid Chromatography (MPLC), and the final compound, N- (3-iodophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3-iodophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (80% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.64 (d, J = 8.0 Hz, 1H); 7.51 (d, J = 8.8 Hz, 2H); 7.46 (d, J = 8.4 Hz, 2H); 7.41 (s, 1H); 7.21 (d, J = 8.0 Hz, 2H); 7.06 (t, J = 8.0 Hz, 1H); 6.96 (d, J = 8.8 Hz, 3H); 4.87 (s, 2H); 3.84 (s, 3H); 2.07 (t, J = 7.0 Hz, 2H); 1.63-4.57 (m, 2H); 1.29-1.2(m, 2H); 0.83 (t, J = 7.4 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.64 (d, J = 8.0 Hz, 1H); 7.51 (d, J = 8.8 Hz, 2H); 7.46 (d, J = 8.4 Hz, 2H); 7.41 (s, 1 H); 7.21 (d, J = 8.0 Hz, 2H); 7.06 (t, J = 8.0 Hz, 1 H); 6.96 (d, J = 8.8 Hz, 3H); 4.87 (s, 2 H); 3.84 (s, 3 H); 2.07 (t, J = 7.0 Hz, 2H); 1.63-4.57 (m, 2 H); 1.29-1.2 (m, 2 H); 0.83 (t, J = 7.4 Hz, 3H).
실시예Example 49.  49. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- (3-아이오도페닐)펜탄아마이드((3-iodophenyl) pentaneamide ( NN -(-( (4'-hydroxybiphenyl-4-yl)methyl)-(4'-hydroxybiphenyl-4-yl) methyl)- NN -(3-iodophenyl)pentanamide) (AC-1644)의 제조Preparation of-(3-iodophenyl) pentanamide) (AC-1644)
상기 실시예 48에서 수득한 N-(3-아이오도페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (1.0 equiv)를 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 0℃에서, BBr3를 천천히 가하였으며, 실온에서 3시간 동안 혼합 용액을 교반하였다. 상기 반응을 TLC (thin Layer Chromatography)로 관찰하였다. 반응을 마친 후, RBF에 얼음을 가하고, DCM에서 추출하였다. 유기 용매층을 분리하고. 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하였으며, 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-아이오도페닐)펜탄아마이드(N-((4'-hydroxybiphenyl-4-yl)methyl)-N-(3-iodophenyl)pentanamide)를 수득하였다 (90% 수율).N- (3-iodophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in Example 48 was converted to dichloromethane (DCM). After dissolving in solution, it was cooled in ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3-iodophenyl) pentaneamide (N- ( (4'-hydroxybiphenyl-4-yl) methyl) -N- (3-iodophenyl) pentanamide) was obtained (90% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.65 (d, J = 8.0 Hz, 1H); 7.46-7.43 (m, 5H); 7.21 (d, J = 7.6 Hz, 2H); 7.06 (t, J = 8.0 Hz, 1H); 6.95 (d, J = 8.8 Hz, 1H); 6.86 (d, J = 8.4 Hz, 2H); 5.08 (s, 1H); 4.871 (s, 2H); 2.07 (t, 2H); 1.63-1.59 (m, 2H); 1.29-1.21 (m, 2H); 0.86 (t, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.65 (d, J = 8.0 Hz, 1H); 7.46-7.43 (m, 5 H); 7.21 (d, J = 7.6 Hz, 2H); 7.06 (t, J = 8.0 Hz, 1 H); 6.95 (d, J = 8.8 Hz, 1H); 6.86 (d, J = 8.4 Hz, 2H); 5.08 (s, 1 H); 4.871 (s, 2 H); 2.07 (t, 2 H); 1.63-1.59 (m, 2 H); 1.29-1.21 (m, 2 H); 0.86 (t, 3 H).
실시예Example 50. 2-(4'-(( 50. 2- (4 '-(( NN -(3--(3- 아이오도페닐Iodophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3-iodophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1645)의 제조Preparation of-(3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1645)
단계 1 : 에틸 2-(4'-((N-(3-Step 1: ethyl 2- (4 ′-((N- (3- 아이오도페닐Iodophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세테이트 (ethyl 2-(4'-((N-(3-iodophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)의 제조Preparation of Acetate (ethyl 2- (4 '-((N- (3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
N-(3-아이오도페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드 (1.0 equiv)와 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 에틸클로로아세테이트 (Ethylchloroacetate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 에틸 2-(4'-((N-(3-아이오도페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (ethyl 2-(4'-((N-(3-iodophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate)를 수득하였다(89% 수율).N- (3- iodo-phenyl) -N - ((4'- hydroxy-biphenyl-4-yl) methyl) pentane amide (1.0 equiv) and K 2 CO 3 to (3.0 equiv) N, N - dimethyl It was dissolved in formamide (DMF) solution and then cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 2- (4 '-((N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4 '-((N- (3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (89% yield).
단계 step 2 : 22: 2 -(4'-((N-(3--(4 '-((N- (3- 아이오도페닐Iodophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((N-(3-iodophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)의 제조Preparation of acetic acid (2- (4 '-((N- (3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
상기 단계 1에서 수득한 에틸 2-(4'-((N-(3-아이오도페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 최종 생성물인 2-(4'-((N-(3-아이오도페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산 (2-(4'-((N-(3-iodophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid)을 수득하였다 (94% 수율).Ethyl 2- (4 '-((N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was converted to tetrahydrofuran, THF) was mixed well, then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and the final product 2- (4 '-((N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid (2- (4') -((N- (3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) was obtained (94% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.65 (d, J = 7.6 Hz, 1H); 7.51 (d, J = 8.8 Hz, 2H); 7.43 (t, J = 8.8 Hz, 3H); 7.21 (d, J = 8.0 Hz, 2H); 7.06 (t, J = 7.8 Hz, 1H); 6.98 (d, J = 8.4 Hz, 2H); 6.94 (d, J = 8.0 Hz, 1H); 4.87 (s, 2H); 4.71 (s, 2H); 2.1 (t, 2H); 1.63-1.55 (m, 2H); 1.26-1.19 (m, 2H); 0.83 (t, J = 7.2 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.65 (d, J = 7.6 Hz, 1H); 7.51 (d, J = 8.8 Hz, 2H); 7.43 (t, J = 8.8 Hz, 3H); 7.21 (d, J = 8.0 Hz, 2H); 7.06 (t, J = 7.8 Hz, 1H); 6.98 (d, J = 8.4 Hz, 2H); 6.94 (d, J = 8.0 Hz, 1 H); 4.87 (s, 2 H); 4.71 (s, 2 H); 2.1 (t, 2 H); 1.63-1.55 (m, 2 H); 1.26-1.19 (m, 2 H); 0.83 (t, J = 7.2 Hz, 3H).
실시예Example 51.  51. NN -(3--(3- 플로오로페닐Fluorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 아세트아마이드Acetamide ( ( NN -(3-fluorophenyl)--(3-fluorophenyl)- N-N- ((4'-methoxybiphenyl-4-yl)methyl)acetamide) (AC-1646)의 제조Preparation of ((4'-methoxybiphenyl-4-yl) methyl) acetamide) (AC-1646)
단계 1 : 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)의 제조Step 1: Preparation of 4'-methoxybiphenyl-4-carbaldehyde
1-브로모-4-메톡시벤젠 (1-bromo-4-methoxybenzene) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 4'-메톡시바이페닐-4-카브알데하이드 (4'-methoxybiphenyl-4-carbaldehyde)를 수득하였다 (73% 수율).1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. After the reaction mixture was filtered and extracted with ethyl acetate (EA), water was removed with anhydrous MgSO 4 , concentrated by evaporation, and purified by Medium Pressure Liquid Chromatography (MPLC) to 4'-methoxybiphenyl. 4-Carbaldehyde (4'-methoxybiphenyl-4-carbaldehyde) was obtained (73% yield).
단계 step 2 : 32: 3 -- 플루오로Fluoro -N-((4'--N-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )아닐린 (3-Aniline (3- fluorofluoro -N-((4'--N-((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)aniline)의 제조Preparation of -4-yl) methyl) aniline)
상기 단계 1에서 수득한 4'-메톡시바이페닐-4-카브알데하이드 (1.0 equiv)와 3-플루오로도아닐린 (3-fluoroaniline) (2.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 3-플루오로-N-((4'-메톡시바이페닐-4-일)메틸)아닐린 (3-fluoro-N-((4'-methoxybiphenyl-4-yl)methyl)aniline)을 수득하였다 (63% 수율). 4'-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and 3-fluoroaniline (3-fluoroaniline) (2.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give 3-fluoro-N-((4'-methoxybiphenyl-4-yl) methyl) aniline (3-fluoro-N-((4'- methoxybiphenyl-4-yl) methyl) aniline) was obtained (63% yield).
단계 3 : N-(3-Step 3: N- (3- 플루오로페닐Fluorophenyl )-N-((4'-) -N-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide (N-(3-fluorophenyl)-N-((4'-methoxybiphenyl-4-yl)methyl)pentanamide)의 제조 Preparation of (N- (3-fluorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
상기 2 단계에서 수득한 3-플루오로-N-((4'-메톡시바이페닐-4-일)메틸)아닐린을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 최종화합물인 N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드 (N-(3-fluorophenyl)-N-((4'-methoxybiphenyl-4-yl)methyl)pentanamide)를 수득하였다 (81% 수율).3-fluoro-N-((4'-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) After addition, it was cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain N- (3-fluorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3-fluorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (81% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H); 7.46 (d, J = 8.0 Hz, 2H); 7.31 (q, J = 7.6 Hz, 1H); 7.25 (d, J = 8.4 Hz, 2H); 7.03 (t, J = 7.6 Hz, 1H); 6.97 (d, J = 8.8 Hz, 2H); 6.81 (dd, J = 8.4, 20.0 Hz, 2H); 4.90 (s, 2H); 3.85 (s, 3H); 1.93 (s, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H); 7.46 (d, J = 8.0 Hz, 2H); 7.31 (q, J = 7.6 Hz, 1 H); 7.25 (d, J = 8.4 Hz, 2H); 7.03 (t, J = 7.6 Hz, 1H); 6.97 (d, J = 8.8 Hz, 2H); 6.81 (dd, J = 8.4, 20.0 Hz, 2H); 4.90 (s, 2 H); 3.85 (s, 3 H); 1.93 (s, 3 H).
실시예Example 52.  52. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -- (( (4'-(4'- 하이드록시Hydroxy -[1,1'--[1,1'- 바이페닐Biphenyl ]-4-일)] -4-day) 메틸methyl )) 아세트아마이드Acetamide (( NN -(3-fluorophenyl)--(3-fluorophenyl)- N-N- ((4'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)acetamide) (AC-1647)의 제조Preparation of ((4'-hydroxy- [1,1'-biphenyl] -4-yl) methyl) acetamide) (AC-1647)
상기 실시예 51에서 수득한 N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-아이오도페닐)펜탄아마이드 (1.0 equiv)를 다이클로로메탄 (dichloromethane, DCM) 용액에 녹인 후, 얼음에서 냉각시켰다. 0℃에서, BBr3를 천천히 가하였으며, 실온에서 3시간 동안 혼합 용액을 교반하였다. 상기 반응을 TLC (thin Layer Chromatography)로 관찰하였다. 반응을 마친 후, RBF에 얼음을 가하고, DCM에서 추출하였다. 유기 용매층을 분리하고. 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하였으며, 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 최종 생성물인 N-(3-플루오로페닐)-N-((4'-하이드록시-[1,1'-바이페닐]-4-일)메틸)아세트아마이드(N-(3-fluorophenyl)-N-((4'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)acetamide)를 수득하였다 (69% 수율).N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3-iodophenyl) pentaneamide (1.0 equiv) obtained in Example 51 was converted to dichloromethane (DCM). After dissolving in solution, it was cooled in ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N-((4'-hydroxy- [1,1'-biphenyl] -4-yl) as a final product. Methyl) acetamide (N- (3-fluorophenyl) -N-((4'-hydroxy- [1,1'-biphenyl] -4-yl) methyl) acetamide) was obtained (69% yield).
1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.8 Hz, 4H); 7.32 (q, J = 7.3 Hz, 1H); 7.24 (d, J = 8.0 Hz, 2H); 7.04 (t, J = 8.2 Hz, 1H); 6.89 (d, J = 7.2 Hz, 2H); 6.84 (d, J = 7.2 Hz, 1H); 6.79 (d, J = 8.8 Hz, 1H) ; 5.013 (s, 1H); 4.90 (s, 2H); 1.93 (s, 3H) 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (d, J = 8.8 Hz, 4H); 7.32 (q, J = 7.3 Hz, 1 H); 7.24 (d, J = 8.0 Hz, 2H); 7.04 (t, J = 8.2 Hz, 1H); 6.89 (d, J = 7.2 Hz, 2H); 6.84 (d, J = 7.2 Hz, 1H); 6.79 (d, J = 8.8 Hz, 1H); 5.013 (s, 1 H); 4.90 (s, 2 H); 1.93 (s, 3 H)
실시예Example 53. 2-((4'-(( 53. 2-((4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 아세트아미도Acetamido )) 메틸methyl )-[1,1'-)-[1,1'- 바이페닐Biphenyl ]-4-일)] -4-day) 옥시Oxy )아세트산 (2-((4'-((Acetic acid (2-((4 '-(( NN -(3-fluorophenyl)acetamido)methyl)-[1,1'-biphenyl]-4-yl)oxy)acetic acid) (AC--(3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid) (AC- 1648)의1648 of 제조 Produce
단계 1 : 에틸 2-(4'-((N-(3-Step 1: ethyl 2- (4 ′-((N- (3- 플루오로페닐Fluorophenyl )) 아세토아미도Acetoamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세테이트 (ethyl 2-(4'-((N-(3-fluorophenyl)acetamido)methyl)biphenyl-4-yloxy)acetate)의 제조Preparation of Acetate (ethyl 2- (4 '-((N- (3-fluorophenyl) acetamido) methyl) biphenyl-4-yloxy) acetate)
상기 실시예 32에서 수득한 N-(3-플루오로페닐)-N-((4'-하이드록시-[1,1'-바이페닐]-4-일)메틸)아세트아마이드 (1.0 equiv)와 K2CO3 (3.0 equiv)를 N,N-다이메틸포름아마이드 (DMF) 용액에 녹인 후, 얼음에서 냉각시켰다. 에틸클로로아세테이트 (Ethylchloroacetate) (3.0 equiv)를 가한 후, 혼합 용액을 실온, N2 공급 조건에서 밤새도록 교반하였다. 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트(EA)로 수용성 층을 추출하였다. 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 에틸 2-(4'-((N-(3-플루오로페닐)아세토아미도)메틸)바이페닐-4-일옥시)아세테이트 (ethyl 2-(4'-((N-(3-fluorophenyl)acetamido)methyl)biphenyl-4-yloxy)acetate)를 수득하였다(91% 수율).N- (3-fluorophenyl) -N-((4'-hydroxy- [1,1'-biphenyl] -4-yl) methyl) acetamide (1.0 equiv) obtained in Example 32 above; K 2 CO 3 (3.0 equiv) was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 2- (4 '-((N- (3-fluorophenyl) acetoamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4 '-((N- (3-fluorophenyl) acetamido) methyl) biphenyl-4-yloxy) acetate) was obtained (91% yield).
단계 step 2 : 22: 2 -((4'-((N-(3--((4 '-((N- (3- 플루오로페닐Fluorophenyl )) 아세트아미도Acetamido )) 메틸methyl )-[1,1'-)-[1,1'- 바이페닐Biphenyl ]-4-일)] -4-day) 옥시Oxy )아세트산 (2-((4'-((N-(3-fluorophenyl)acetamido)methyl)-[1,1'-biphenyl]-4-yl)oxy)acetic acid)의 제조Preparation of acetic acid (2-((4 '-((N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid)
상기 단계 1에서 수득한 에틸 2-(4'-((N-(3-플루오로페닐)아세토아미도)메틸)바이페닐-4-일옥시)아세테이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 최종 생성물인 2-((4'-((N-(3-플루오로페닐)아세트아미도)메틸)-[1,1'-바이페닐]-4-일)옥시)아세트산 (2-((4'-((N-(3-fluorophenyl)acetamido)methyl)-[1,1'-biphenyl]-4-yl)oxy)acetic acid)을 수득하였다 (67% 수율).Ethyl 2- (4 '-((N- (3-fluorophenyl) acetoamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was converted to tetrahydrofuran, THF) was mixed well, then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and the final product 2-((4 '-((N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl ) Oxy) acetic acid (2-((4 '-((N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid) was obtained (67% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.54 (d, J = 8.0 Hz, 2H); 7.50 (d, J = 8.4 Hz, 2H); 7.39 (q, J = 7.3 Hz, 1H); 7.24 (d, J = 8.0 Hz, 2H); 7.11 (t, J = 9.2 Hz, 1H); 7.00 (d, J = 8.4 Hz, 2H); 6.96 (d, J = 7.6 Hz, 2H); 4.93 (s, 2H); 4.69 (s, 2H); 1.93 (s, 3H) 1 H-NMR (CDCl 3 , 400 MHz) δ 7.54 (d, J = 8.0 Hz, 2H); 7.50 (d, J = 8.4 Hz, 2H); 7.39 (q, J = 7.3 Hz, 1 H); 7.24 (d, J = 8.0 Hz, 2H); 7.11 (t, J = 9.2 Hz, 1 H); 7.00 (d, J = 8.4 Hz, 2H); 6.96 (d, J = 7.6 Hz, 2H); 4.93 (s, 2 H); 4.69 (s, 2 H); 1.93 (s, 3 H)
실시예Example 54.  54. NN -((4'-(4--((4 '-(4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide (( NN -((4'-(4-isopropylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)--((4 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-1649)의 제조-phenylpentanamide) (AC-1649)
단계 1 : 메틸 4'-포밀바이페닐-4-카복실레이트 (methyl 4'-formylbiphenyl-4-carboxylate)의 제조Step 1: Preparation of Methyl 4'-formylbiphenyl-4-carboxylate
1-브로모-4-메톡시벤젠 (1-bromo-4-methoxybenzene) (1.0 equiv)과 메틸 4-브로모벤조에이트 (methyl 4-bromobenzoate) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 메틸 4'-포밀바이페닐-4-카복실레이트 (methyl 4'-formylbiphenyl-4-carboxylate)를 수득하였다 (73% 수율).1-bromo-4-methoxybenzene (1.0 equiv) and methyl 4-bromobenzoate (1.1 equiv) were mixed well in RBF, and then 1, 4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. The reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4'-formylbiphenyl. 4-carboxylate (methyl 4'-formylbiphenyl-4-carboxylate) was obtained (73% yield).
단계 2 : Step 2: 메틸methyl 4'-(( 4'-(( 페닐아미노Phenylamino )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실레이트Carboxylate (methyl 4'-((phenylamino)methyl)biphenyl-4-carboxylate)의 제조Preparation of (methyl 4 '-((phenylamino) methyl) biphenyl-4-carboxylate)
상기 단계 1에서 수득한 메틸 4'-포밀바이페닐-4-카복실레이트 (1.0 equiv)와 아닐린 (aniline) (3.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 메틸 4'-((페닐아미노)메틸)바이페닐-4-카복실레이트 (methyl 4'-((phenylamino)methyl)biphenyl-4-carboxylate )을 수득하였다 (51% 수율). Methyl 4′-formylbiphenyl-4-carboxylate (1.0 equiv) and aniline (aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to prepare methyl 4 '-((phenylamino) methyl) biphenyl-4-carboxylate (methyl 4'-((phenylamino) methyl) biphenyl-4-carboxylate). Obtained (51% yield).
단계 3 : Step 3: 메틸methyl 4'-((N- 4 '-((N- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실레이트 (methyl 4'-(Carboxylate (methyl 4 '-( (N-phenylpentanamido)methyl)biphenyl-4-carboxylate )의 제조Preparation of (N-phenylpentanamido) methyl) biphenyl-4-carboxylate)
상기 2 단계에서 수득한 메틸 4'-((페닐아미노)메틸)바이페닐-4-카복실레이트을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 메틸 4'-((N-페닐펜탄아미도)메틸)바이페닐-4-카복실레이트 (methyl 4'-((N-phenylpentanamido)methyl)biphenyl-4-carboxylate )를 수득하였다 (57% 수율).Methyl 4 '-((phenylamino) methyl) biphenyl-4-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then cooled on ice. . Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrated solution was purified by Medium Pressure Liquid Chromatography (MPLC), and methyl 4 '-((N-phenylpentaneamido) methyl) biphenyl-4-carboxylate (methyl 4'-((N-phenylpentanamido) methyl) biphenyl -4-carboxylate) was obtained (57% yield).
단계 step 4 : 44: 4 '-((N-'-((N- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-((N-phenylpentanamido)methyl)biphenyl-4-carboxylic acid )의 제조Preparation of (4 '-((N-phenylpentanamido) methyl) biphenyl-4-carboxylic acid)
상기 단계 3에서 수득한 메틸 4'-((N-페닐펜탄아미도)메틸)바이페닐-4-카복실레이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 재결정하여, 4'-((N-페닐펜탄아미도)메틸)바이페닐-4-카복실산(4'-((N-phenylpentanamido)methyl)biphenyl-4-carboxylic acid )을 수득하였다 (97% 수율). Methyl 4 ′-((N-phenylpentaneamido) methyl) biphenyl-4-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF), and then LiOH solution was added thereto. , Was stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and recrystallized to give 4 '-((N-phenylpentaneamido) methyl) biphenyl-4-carboxylic acid (4'-((N-phenylpentanamido) methyl) biphenyl-4-carboxylic acid ) Was obtained (97% yield).
단계 step 5 : 45: 4 '-((N-'-((N- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-((N-phenylpentanamido)methyl)biphenyl-4-carboxylic acid)의 제조Preparation of (4 '-((N-phenylpentanamido) methyl) biphenyl-4-carboxylic acid)
상기 단계 4에서 수득한 4'-((N-페닐펜탄아미도)메틸)바이페닐-4-카복실산(1.0 equiv)과 1-아이소프로필피페라진 (1-isopropylpiperazine)(0.9 equiv), HATU (1.2 equiv) 및 N,N-다이아이소프로필에틸아민 (DIPEA) (2.5 equiv)을 N,N-다이메틸포름아마이드 (DMF)에 용해시켰으며, 상기 혼합 용액을 상온에서 밤새도록 교반하였다. 상기 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트 (EA)로 수용성 층을 추출하였다. 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 컬럼 크로마토 그래피로 정제하여 최종 생성물인 4'-((N-페닐펜탄아미도)메틸)바이페닐-4-카복실산(4'-((N-phenylpentanamido)methyl)biphenyl-4-carboxylic acid)를 수득하였다 (50% 수율).4 '-((N-phenylpentaneamido) methyl) biphenyl-4-carboxylic acid (1.0 equiv) and 1-isopropylpiperazine (0.9 equiv) obtained in step 4, HATU (1.2 equiv) and N, N-diisopropylethylamine (DIPEA) (2.5 equiv) were dissolved in N, N-dimethylformamide (DMF) and the mixed solution was stirred overnight at room temperature. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by column chromatography to obtain 4 '-((N-phenylpentaneamido) methyl) biphenyl-4-carboxylic acid (4'-((N-phenylpentanamido) methyl) biphenyl-4-carboxylic acid ) Was obtained (50% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.60 (d, J = 8.0 Hz, 2H), 7.49 (m, J = 4.8 Hz, 4H), 7.36 (d, J = 6.4 Hz, 3H), 7.29 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 6.8 Hz, 2H), 4.92 (s, 2H), 3.65 (d, 4H), 2.74 (m, 1H), 2.55 (d, 4H), 2.09 (t, J = 7.6 Hz, 2H), 1.60 (m, 2H), 1.22 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.4 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.60 (d, J = 8.0 Hz, 2H), 7.49 (m, J = 4.8 Hz, 4H), 7.36 (d, J = 6.4 Hz, 3H), 7.29 ( d, J = 8.4 Hz, 2H), 7.02 (d, J = 6.8 Hz, 2H), 4.92 (s, 2H), 3.65 (d, 4H), 2.74 (m, 1H), 2.55 (d, 4H), 2.09 (t, J = 7.6 Hz, 2H), 1.60 (m, 2H), 1.22 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.4 Hz, 3H).
실시예Example 55.  55. NN -(4-플루오로페닐)--(4-fluorophenyl)- NN -((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드(-((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide ( NN -(4-fluorophenyl)--(4-fluorophenyl)- NN -((4'-(4-isopropylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)pentanamide)의 제조(AC-1650)Preparation of-((4 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) (AC-1650)
단계 1 : Step 1: 메틸methyl 4'- 4'- 포밀바이페닐Formylbiphenyl -4--4- 카복실레이트Carboxylate (methyl 4'- (methyl 4'- formylbiphenylformylbiphenyl -4--4- carboxylatecarboxylate ) 의 제조Manufacture of
1-브로모4-메톡시벤젠 (1-bromo-4-methoxybenzen) (1.0 equiv)과 메틸 4-b브로모벤조에이트 (methyl 4-bromobenzoate) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한 번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 메틸 4'-포밀바이페닐-4-카복실레이트 (methyl 4'-formylbiphenyl-4-carboxylate)를 수득하였다 (73% 수율).After mixing 1-bromo4-methoxybenzene (1.0 equiv) and methyl 4-bbromobenzoate (1.1 equiv) well to RBF, 4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution. Pd (dppf) Cl2.DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. The reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4'-formylbiphenyl. 4-carboxylate (methyl 4'-formylbiphenyl-4-carboxylate) was obtained (73% yield).
단계 2 : Step 2: 메틸methyl 4'-((4- 4 '-((4- 플루오로페닐아미노Fluorophenylamino )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실레이트Carboxylate (methyl 4'-((4-fluorophenylamino)methyl)biphenyl-4-carboxylate)의 제조 Preparation of (methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-4-carboxylate)
상기 단계 1에서 수득한 4'-포밀바이페닐-4-카복실레이트 (1.0 equiv)와 3-브로모아닐린 (3-bromoaniline) (3.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv)이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산 마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 메틸 4'-((4-플루오로페닐아미노)메틸)바이페닐-4-카복실레이트 (methyl 4'-((4-fluorophenylamino)methyl)biphenyl-4-carboxylate)을 수득하였다 (51% 수율).4'-formylbiphenyl-4-carboxylate (1.0 equiv) and 3-bromoaniline (3-bromoaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. . The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, a methanol solution in which 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 (1.0 equiv) were mixed in the solution Was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to prepare methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-4-carboxylate (methyl 4'-((4-fluorophenylamino) methyl) biphenyl -4-carboxylate) was obtained (51% yield).
단계 3 : Step 3: 메틸methyl 4'-((N-(4- 4 '-((N- (4- 플루오로페닐Fluorophenyl )펜타아미도)Pentaamido) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실레이트 (methyl 4'-((N-Carboxylate (methyl 4 '-((N- (4-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylate)의 제조Preparation of (4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate)
상기 단계 ２에서 수득한　4'-((4-플루오로페닐아미노)메틸)바이페닐-4-카복실레이트을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 12시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여 메틸 4'-((N-(4-플루오로페닐)펜타아미도)메틸)바이페닐-4-카복실레이트 (methyl 4'-((N-(4-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylate)를 수득하였다 (85% 수율).4 '-((4-fluorophenylamino) methyl) biphenyl-4-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then ice Cooled in. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 12 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give methyl 4 '-((N- (4-fluorophenyl) pentamido) methyl) biphenyl-4-carboxylate (methyl 4'-((N- (4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate) was obtained (85% yield).
단계 step 4 : 44: 4 '-((N-(4-'-((N- (4- 플루오로페닐Fluorophenyl )펜타아미도)Pentaamido) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-((N-(4-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid)의 제조 Preparation of (4 '-((N- (4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid)
상기 단계 3에서 수득한 메틸 4'-((N-(4-플루오로페닐)펜타아미도)메틸)바이페닐-4-카복실레이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하여 4'-((N-(4-플루오로페닐)펜타아미도)메틸)바이페닐-4-카복실산 (4'-((N-(4-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid)을 수득하였다 (90% 수율). Methyl 4 ′-((N- (4-fluorophenyl) pentamido) methyl) biphenyl-4-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF). Then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). Remove the organic solvent layer in vacuo to remove 4 '-((N- (4-fluorophenyl) pentamido) methyl) biphenyl-4-carboxylic acid (4'-((N- (4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) was obtained (90% yield).
단계 5 : Step 5: NN -(4-플루로로페닐)-N-((4'-(4-아이소프로필리페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드(-(4-fluorofluorophenyl) -N-((4 '-(4-isopropylliprazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide ( NN -(4-fluorophenyl)-N-((4'-(4-isopropylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)pentanamide)의 제조Preparation of-(4-fluorophenyl) -N-((4 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide)
상기 단계 4에서 수득한 4'-((N-(4-플루오로페닐)펜타아미도)메틸)바이페닐-4-카복실산 (1.0 equiv)과 1-아이소프로필리페라진 (1-isopropylpiperazine)(0.9 equiv), EDC (1.2 equiv), HoBt (1.2 equiv), 및 N,N-다이아이소프로필에틸아민 (DIPEA) (2.5 equiv)을 N,N-다이메틸포름아마이드 (DMF)에 용해시켰으며, 상기 혼합 용액을 상온에서 밤새도록 교반하였다. 상기 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트 (EA)로 수용성 층을 추출하였다. 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 컬럼 크로마토 그래피로 정제하여 최종 생성물인 N-(4-플루로로페닐)-N-((4'-(4-아이소프로필리페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드(N-(4-fluorophenyl)-N-((4'-(4-isopropylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)pentanamide)를 수득하였다 (41% 수율).4 ′-((N- (4-fluorophenyl) pentamido) methyl) biphenyl-4-carboxylic acid (1.0 equiv) and 1-isopropylpiperazine (0.9 obtained in step 4) (0.9 equiv), EDC (1.2 equiv), HoBt (1.2 equiv), and N , N -diisopropylethylamine (DIPEA) (2.5 equiv) were dissolved in N , N -dimethylformamide (DMF) The mixed solution was stirred overnight at room temperature. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by column chromatography to give the final product, N- (4-flurophenyl) -N-((4 '-(4-isopropylliprazin-1-carbonyl) biphenyl-4-yl) Methyl) pentaneamide ( N- (4-fluorophenyl) -N-((4 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) was obtained (41% yield).
1H-NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.4 Hz, 2H), 7.49 (m, J = 6.0 Hz, 4H), 7.27 (d, J = 8.0 Hz, 2H), 7.00 (m, J = 6.7 Hz, 4H), 4.89 (s, 2H), 3.67 (d, 4H), 2.77 (m, 1H), 2.57 (d, 4H), 2.07 (t, J = 7.2 Hz, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.07 (d, J = 6.0 Hz, 6H); 0.83 (t, J = 7.4 Hz, 3H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 8.4 Hz, 2H), 7.49 (m, J = 6.0 Hz, 4H), 7.27 (d, J = 8.0 Hz, 2H), 7.00 ( m, J = 6.7 Hz, 4H), 4.89 (s, 2H), 3.67 (d, 4H), 2.77 (m, 1H), 2.57 (d, 4H), 2.07 (t, J = 7.2 Hz, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.07 (d, J = 6.0 Hz, 6H); 0.83 (t, J = 7.4 Hz, 3H).
실시예Example 56.  56. NN -((3'-(4--((3 '-(4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide (( N-N- ((3'-(4-isopropylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)-((3 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-1651)의 제조Preparation of -phenylpentanamide) (AC-1651)
단계 1 : 메틸 4'-포밀바이페닐-3-카복실레이트 (methyl 4'-formylbiphenyl-4-carboxylate)의 제조Step 1: Preparation of Methyl 4'-formylbiphenyl-3-carboxylate
메틸 3-브로모벤조에이트 (Methyl 2-bromobenzoate) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 메틸 4'-포밀바이페닐-3-카복실레이트 (methyl 4'-formylbiphenyl-3-carboxylate)를 수득하였다 (91% 수율).Methyl 2-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane). ): H 2 O (10: 1) was dissolved in a mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. The reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4'-formylbiphenyl. 3-carboxylate (methyl 4'-formylbiphenyl-3-carboxylate) was obtained (91% yield).
단계 2 : Step 2: 메틸methyl 4'-(( 4'-(( 페닐아미노Phenylamino )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실레이트Carboxylate (methyl 4'-((phenylamino)methyl)biphenyl-4-carboxylate)의 제조Preparation of (methyl 4 '-((phenylamino) methyl) biphenyl-4-carboxylate)
상기 단계 1에서 수득한 메틸 4'-포밀바이페닐-3-카복실레이트 (1.0 equiv)와 아닐린 (aniline ) (3.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 메틸 4'-((페닐아미노)메틸)바이페닐-3-카복실레이트(methyl 4'-((phenylamino)methyl)biphenyl-3-carboxylate )을 수득하였다 (95% 수율). Methyl 4′-formylbiphenyl-3-carboxylate (1.0 equiv) and aniline (aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to prepare methyl 4 '-((phenylamino) methyl) biphenyl-3-carboxylate (methyl 4'-((phenylamino) methyl) biphenyl-3-carboxylate). Obtained (95% yield).
단계 3 : Step 3: 메틸methyl 4'-((N- 4 '-((N- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실레이트Carboxylate (methyl 4'-((N-phenylpentanamido)methyl)biphenyl-3-carboxylate )의 제조 Preparation of (methyl 4 '-((N-phenylpentanamido) methyl) biphenyl-3-carboxylate)
상기 2 단계에서 수득한 메틸 4'-((페닐아미노)메틸)바이페닐-3-카복실레이트을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 메틸 4'-((N-페닐펜탄아미도)메틸)바이페닐-3-카복실레이트 (methyl 4'-((N-phenylpentanamido)methyl)biphenyl-3-carboxylate )를 수득하였다 (96% 수율).Methyl 4 '-((phenylamino) methyl) biphenyl-3-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then cooled on ice. . Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrated solution was purified by Medium Pressure Liquid Chromatography (MPLC), and methyl 4 '-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylate (methyl 4'-((N-phenylpentanamido) methyl) biphenyl -3-carboxylate) was obtained (96% yield).
단계 step 4 : 44: 4 '-((N-'-((N- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실산Carboxylic acid (4'-((N-phenylpentanamido)methyl)biphenyl-3-carboxylic acid )의 제조Preparation of (4 '-((N-phenylpentanamido) methyl) biphenyl-3-carboxylic acid)
상기 단계 3에서 수득한 메틸 4'-((N-페닐펜탄아미도)메틸)바이페닐-3-카복실레이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 재결정하여, 4'-((N-페닐펜탄아미도)메틸)바이페닐-3-카복실산(4'-((N-phenylpentanamido)methyl)biphenyl-3-carboxylic acid )을 수득하였다 (95% 수율). Methyl 4 ′-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF), and then LiOH solution was added thereto. , Was stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and recrystallized to obtain 4 '-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylic acid (4'-((N-phenylpentanamido) methyl) biphenyl-3-carboxylic acid ) Was obtained (95% yield).
단계 5 : N-((3'-(4-Step 5: N-((3 '-(4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-N-) -N- 페닐펜탄아마이드Phenylpentaneamide (N-((3'-(4-isopropylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)-N-phenylpentanamide)의 제조Preparation of (N-((3 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide)
상기 단계 4에서 수득한 4'-((N-페닐펜탄아미도)메틸)바이페닐-3-카복실산(1.0 equiv)과 1-아이소프로필피페라진 (1-isopropylpiperazine)(0.9 equiv), EDC (1.2 equiv), HoBt (1.2 equiv) 및 N,N-다이아이소프로필에틸아민 (DIPEA) (2.5 equiv)을 N,N-다이메틸포름아마이드 (DMF)에 용해시켰으며, 상기 혼합 용액을 상온에서 밤새도록 교반하였다. 상기 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트 (EA)로 수용성 층을 추출하였다. 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 컬럼 크로마토 그래피로 정제하여 최종 생성물인 N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드(N-((3'-(4-isopropylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)-N-phenylpentanamide)를 수득하였다 (70% 수율).4 '-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylic acid (1.0 equiv) and 1-isopropylpiperazine (0.9 equiv) obtained in the step 4, EDC (1.2 equiv), HoBt (1.2 equiv) and N, N-diisopropylethylamine (DIPEA) (2.5 equiv) were dissolved in N, N-dimethylformamide (DMF) and the mixed solution overnight at room temperature Stirred. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by column chromatography to obtain N-((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentaneamide (N- ((3 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide) was obtained (70% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.61 (d, J = 6.8 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.45 (d, 1H), 7.354 (m, 4H), 7.28 (s, 2H), 7.01 (d, J = 7.2 Hz, 2H,), 4.92 (s, 2H), 3.64 (d, 4H), 2.72 (m, 1H), 2.53 (d, 4H), 2.09 (t, J = 7.4 Hz, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.05 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.2 Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.61 (d, J = 6.8 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.45 (d, 1H), 7.354 (m, 4H), 7.28 (s, 2H), 7.01 (d, J = 7.2 Hz, 2H,), 4.92 (s, 2H), 3.64 (d, 4H), 2.72 (m, 1H), 2.53 (d, 4H), 2.09 ( t, J = 7.4 Hz, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.05 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.2 Hz, 3H).
실시예Example 57.  57. NN -(4-플루오로페닐)--(4-fluorophenyl)- NN -((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드(-((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide ( N-N- (4-fluorophenyl)-(4-fluorophenyl)- NN -((3'-(4-isopropylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)pentanamide) (AC-1652)의 제조Preparation of-((3 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) (AC-1652)
단계 1 : 메틸 4'-포밀바이페닐-3-카복실레이트 (methyl 4'-formylbiphenyl-4-carboxylate)의 제조Step 1: Preparation of Methyl 4'-formylbiphenyl-3-carboxylate
메틸 3-브로모벤조에이트 (Methyl 2-bromobenzoate) (1.0 equiv)과 4-포밀페닐보론산 (4-Formylphenylboronic acid) (1.1 equiv)를 RBF에 잘 섞은 후, 1,4 다이옥산 (1,4 dioxane) : H2O (10:1) 혼합 용액에 녹였다. 상기 혼합 용액에 Pd(dppf)Cl2.DCM (0.05 equiv)를 가하여 20분 동안 탈기 (degassing)하였으며, Na2CO3를 가하여 재차 20분 동안 탈기하였다. 다시 한번 더 15분 동안 탈기한 후, 가열하여 4시간 동안 환류시켰다. 상기 반응을 마친 혼합물을 에틸 아세테이트 (EA)로 여과, 추출한 후, 무수의 MgSO4로 수분을 제거하고, 증발시켜 농축시킨 후, Medium Pressure Liquid Chromatography (MPLC)로 정제하여 메틸 4'-포밀바이페닐-3-카복실레이트 (methyl 4'-formylbiphenyl-3-carboxylate)를 수득하였다 (91% 수율).Methyl 2-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane). ): H 2 O (10: 1) was dissolved in a mixed solution. Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours. The reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4'-formylbiphenyl. 3-carboxylate (methyl 4'-formylbiphenyl-3-carboxylate) was obtained (91% yield).
단계 2 : Step 2: 메틸methyl 4'-((4- 4 '-((4- 플루오로페닐아미노Fluorophenylamino )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실레이트Carboxylate (methyl 4'-((4-fluorophenylamino)methyl)biphenyl-3-carboxylate)의 제조Preparation of (methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-3-carboxylate)
상기 단계 1에서 수득한 메틸 4'-포밀바이페닐-3-카복실레이트 (1.0 equiv)와 4-플루오로아닐린 (4-fluoroaniline) (3.0 equiv)을 메탄올에 용해시킨 후, 상온에서 4 시간 동안 교반하였다. 이민 (imine)이 형성되기까지의 반응을 TLC (thin Layer Chromatography)로 관찰하였으며, 이민이 형성된 후, 상기 용액에 1M NaCNBH3 (1.0 equiv)와 0.5M ZnCl2 (1.0 equiv) 이 혼합된 메탄올 용액을 가하고, 상온에서 밤새도록 교반하였다. 반응을 마친 후, 진공 상태에서 메탄올을 제거하였으며, 남은 용액을 에틸 아세테이트 (EA)로 희석하고, 유기 용매층을 소금물 (Brine)로 세척한 후, 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 유기 용매층을 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 메틸 4'-((4-플루오로페닐아미노)메틸)바이페닐-3-카복실레이트 (methyl 4'-((4-fluorophenylamino)methyl)biphenyl-3-carboxylate)을 수득하였다 (97% 수율). Methyl 4'-formylbiphenyl-3-carboxylate (1.0 equiv) and 4-fluoroaniline (4-fluoroaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature. After the reaction was completed, methanol was removed in vacuo, the remaining solution was diluted with ethyl acetate (EA), the organic solvent layer was washed with brine, and water was removed with anhydrous magnesium sulfate (MgSO 4 ). The organic solvent layer was evaporated and concentrated. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to prepare methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-3-carboxylate (methyl 4'-((4-fluorophenylamino) methyl) biphenyl -3-carboxylate) was obtained (97% yield).
단계 3 : Step 3: 메틸methyl 4'-((N-(4- 4 '-((N- (4- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실레이트 (methyl 4'-((N-Carboxylate (methyl 4 '-((N- (4-fluorophenyl)pentanamido)methyl)biphenyl-3-carboxylate)의 제조Preparation of (4-fluorophenyl) pentanamido) methyl) biphenyl-3-carboxylate)
상기 2 단계에서 수득한 메틸 4'-((4-플루오로페닐아미노)메틸)바이페닐-3-카복실레이트을 다이클로로메탄 (dichloromethane, DCM)에 녹이고, 트리에탄올아민 (triethanolamine, TEA)을 가한 후, 얼음에서 냉각시켰다. 상기 혼합 용액에 발레로일 클로라이드 (valeroyl chloride)(2.0 equiv)를 가한 후, 실온에서 4시간 동안 교반하였다. 상기 반응을 마친 후, RBF를 가하였으며, 유기 용매층을 소금물로 세척하고 분리하였다. 이 후, 유기 용매층을 모아 무수의 황산마그네슘 (MgSO4)으로 수분을 제거하고, 여과한 후, 증발시켜 농축하였다. 상기 농축액을 Medium Pressure Liquid Chromatography (MPLC)로 정제하여, 메틸 4'-((N-(4-플루오로페닐)펜탄아미도)메틸)바이페닐-3-카복실레이트 (methyl 4'-((N-(4-fluorophenyl)pentanamido)methyl)biphenyl-3-carboxylate)를 수득하였다 (96% 수율).Methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-3-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. Cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation. The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give methyl 4 '-((N- (4-fluorophenyl) pentaneamido) methyl) biphenyl-3-carboxylate (methyl 4'-((N -(4-fluorophenyl) pentanamido) methyl) biphenyl-3-carboxylate) was obtained (96% yield).
단계 step 4 : 44: 4 '-((N-(4-'-((N- (4- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실산Carboxylic acid (4'-((N-(4-fluorophenyl)pentanamido)methyl)biphenyl-3-carboxylic acid)의 제조 Preparation of (4 '-((N- (4-fluorophenyl) pentanamido) methyl) biphenyl-3-carboxylic acid)
상기 단계 3에서 수득한 메틸 4'-((N-(4-플루오로페닐)펜탄아미도)메틸)바이페닐-3-카복실레이트 (1.0 equiv)를 테트라하이드로퓨란 (tetrahydrofuran, THF)에 잘 섞은 후, LiOH 용액을 가하고, 4시간 동안 교반하였다. 상기 반응을 마친 후, 혼합 용액을 농축시키고, 산성 상태가 될 때까지 2N HCl을 가한 후, 에틸 아세테이트 (EA)로 추출하였다. 진공 상태에서 유기 용매층을 제거하고 재결정하여, 4'-((N-(4-플루오로페닐)펜탄아미도)메틸)바이페닐-3-카복실산 (4'-((N-(4-fluorophenyl)pentanamido)methyl)biphenyl-3-carboxylic acid ) 을 수득하였다 (95% 수율). Methyl 4 ′-((N- (4-fluorophenyl) pentaneamido) methyl) biphenyl-3-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF). Then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA). The organic solvent layer was removed in vacuo and recrystallized to give 4 '-((N- (4-fluorophenyl) pentaneamido) methyl) biphenyl-3-carboxylic acid (4'-((N- (4-fluorophenyl ) pentanamido) methyl) biphenyl-3-carboxylic acid ) was obtained (95% yield).
단계 5 : N-(4-Step 5: N- (4- fluorophenylfluorophenyl )-N-((3'-(4-) -N-((3 '-(4- isopropylpiperazineisopropylpiperazine -1-carbonyl)biphenyl-4-yl)methyl)pentanamide (N-(4--1-carbonyl) biphenyl-4-yl) methyl) pentanamide (N- (4- fluorophenylfluorophenyl )-N-((3'-(4-) -N-((3 '-(4- isopropylpiperazineisopropylpiperazine -1-carbonyl)biphenyl-4-yl)methyl)pentanamide)의 제조-1-carbonyl) biphenyl-4-yl) methyl) pentanamide)
상기 단계 4에서 수득한 4'-((N-(4-플루오로페닐)펜탄아미도)메틸)바이페닐-3-카복실산 (1.0 equiv)과 1-아이소프로필피페라진 (1-isopropylpiperazine)(0.9 equiv), HATU (1.2 equiv) 및 N,N-다이아이소프로필에틸아민 (DIPEA) (2.5 equiv)을 N,N-다이메틸포름아마이드 (DMF)에 용해시켰으며, 상기 혼합 용액을 상온에서 밤새도록 교반하였다. 상기 반응을 마친 후, 물을 가하였으며, 에틸 아세테이트 (EA)로 수용성 층을 추출하였다. 유기 용매 층이 여과된 후, 증발시켜 농축하였다. 상기 농축액을 컬럼 크로마토 그래피로 정제하여 최종 생성물인 메틸 4'-((4-플루오로페닐아미노)메틸)바이페닐-3-카복실레이트N-(4-fluorophenyl)-N-((3'-(4-isopropylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)pentanamide (N-(4-fluorophenyl)-N-((3'-(4-isopropylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)pentanamide)를 수득하였다 (70% 수율).4 '-((N- (4-fluorophenyl) pentaneamido) methyl) biphenyl-3-carboxylic acid (1.0 equiv) and 1-isopropylpiperazine (0.9 obtained in step 4) (0.9 equiv), HATU (1.2 equiv) and N, N-diisopropylethylamine (DIPEA) (2.5 equiv) were dissolved in N, N-dimethylformamide (DMF) and the mixed solution overnight at room temperature Stirred. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA). The organic solvent layer was filtered and then concentrated by evaporation. The concentrate was purified by column chromatography to obtain the final product, methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-3-carboxylate N- (4-fluorophenyl) -N-((3'-( 4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide (N- (4-fluorophenyl) -N-((3 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) was obtained (70% yield).
1H-NMR (CDCl3, 400 MHz) δ 7.61 (q, 2H), 7.47 (m, J = 6.0 Hz, 3H), 7.34 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 7.6 Hz, 2H), 7.03 (m, 2H), 6.96 (m, 2H), 4.88 (s, 2H), 3.65 (d, 4H), 2.74 (m, 1H), 2.54 (d, 4H), 2.06 (t, J = 7.6 Hz, 2H), 1.58 (m, 2H), 1.25 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H) 1 H-NMR (CDCl 3 , 400 MHz) δ 7.61 (q, 2H), 7.47 (m, J = 6.0 Hz, 3H), 7.34 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 7.6 Hz, 2H), 7.03 (m, 2H), 6.96 (m, 2H), 4.88 (s, 2H), 3.65 (d, 4H), 2.74 (m, 1H), 2.54 (d, 4H), 2.06 (t , J = 7.6 Hz, 2H), 1.58 (m, 2H), 1.25 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H)
[실험예]Experimental Example
실험예 1. BLT2가 발현된 세포 또는 BLT2가 발현되지 않은 세포의 준비Experimental Example 1. Preparation of cells expressing BLT2 or cells not expressing BLT2
본 실험을 위하여, BLT2가 발현되지 않은 세포 및 BLT2가 발현된 세포 (CHO-BLT2 cells)를 하기와 같은 방법으로 준비하였다. For this experiment, cells without BLT2 expression and cells with BLT2 expression (CHO-BLT2 cells) were prepared in the following manner.
CHO 세포는 한국세포주은행 (KCLB, 10061)으로부터 얻었으며, 이를 10%의 FBS (fetal bovine serum; Life technologies, Inc.), 페니실린 (50 units/mL) 및 antibiotic antimycotic solution (Life technologies, Inc.)이 포함된 RPMI 1640 medium (Invitrogen) 에서 37 ℃, 5% CO2 조건에서 배양하였다. 상기 세포를 3일간 각각 Trypsin-EDTA를 사용하여 나누어 (splitting) 성장 단계로 유지시켰으며, PBS (phosphate-buffered saline; 137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4,2mMKH2PO4)로 세척하고, 이 후 새로운 배지에 첨가하여 BLT2가 발현되지 않은 세포를 준비하였다. CHO cells were obtained from the Korea Cell Line Bank (KCLB, 10061), which contained 10% FBS (fetal bovine serum; Life technologies, Inc.), penicillin (50 units / mL), and antibiotic antimycotic solution (Life technologies, Inc.). It was incubated at 37 ℃, 5% CO 2 conditions in RPMI 1640 medium (Invitrogen) containing the. The cells were maintained in the growth phase by splitting with Trypsin-EDTA for 3 days, respectively, in PBS (phosphate-buffered saline; 137 mM NaCl, 2.7 mM KCl, 10 mM Na 2 HPO 4 , 2mMKH 2 PO 4 ) Washed and then added to fresh medium to prepare cells free of BLT2 expression.
또한, 안정된 CHO/BLT2 클론 (stable CHO/BLT2 clones)의 제조를 위해, CHO-K1 세포를 HA-tagged human BLT2를 코딩하는 pcDNA3-long form BLT2로 형질전환하고, 0.4 mg/ml의 G418 (Invitrogen, Carlsbad, CA, USA)로 선별하였다. BLT2 발현을 스크리닝하기 위해, 상기 선별된 클론을 인간-특이적 BLT2 프라이머를 사용하는 RT-PCR로 분석하였고, 대표적인 클론을 BLT2가 발현된 세포(CHO-BLT2)로 실험에 사용하였다. In addition, for the preparation of stable CHO / BLT2 clones, CHO-K1 cells were transformed with pcDNA3-long form BLT2 encoding HA-tagged human BLT2, and 0.4 mg / ml of G418 (Invitrogen). , Carlsbad, CA, USA). To screen for BLT2 expression, the selected clones were analyzed by RT-PCR using human-specific BLT2 primers, and representative clones were used in the experiments with cells expressing BLT2 (CHO-BLT2).
실험예 2. BLT2가 발현된 세포에 대한 성장 억제효과 확인 Experimental Example 2. Confirmation of growth inhibitory effect on cells expressing BLT2
상기 실시예에서 제조한 화합물의 처리에 따른 세포 생존율을 3-(4,5-디메틸티아졸-2-일)-2,5-디페닐테트라졸륨 브로마이드 (MTT) 방법으로 측정하였다.Cell viability according to the treatment of the compound prepared in the above Example was measured by the 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) method.
보다 구체적으로, 상기 실험예 1에서 준비한 1 × 104개의 BLT2가 발현되지 않은 세포 (CHO-pcDNA3.1 cells) 및 BLT2가 발현된 세포 (CHO-BLT2 cells)를 96 mm 배양 접시 (culture dish)에 분주하고 24시간 동안 세포를 배양시켰다. 이 후, 배양액을 제거하고 무혈청 RPMI 배지를 첨가하였으며. 2시간 후, 상기 실시예에서 준비한 화합물 10 μM, 대조군인 DMSO (화합물 용매) 10 μM, 양성 대조군인 LY255283 ((1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)heptyl]oxy]phenyl]-ethanone) (Cayman) 10 μM을 각각의 세포에 1시간 전 처리하였다. 이 후, LTB4 (300nM)를 처리한 후 24시간 동안 배양하였다. 20μL의 MTT 용액 (5 mg/mL, Sigma-Aldrich)을 각 웰에 가하고 습한 CO2 인큐베이터에서 37 ℃, 4시간 동안 배양한 후, 상층액을 제거하고, 200μL의 DMSO를 각 웰에 가해 불용성 보라색 포마잔 결정을 용해시켰다. 550 nm에서의 흡광도를 마이크로플레이트 리더(Molecular Devices, Sunnyvale, CA)를 이용하여 측정하였으며, 모든 측정은 3회 반복 수행하였다.More specifically, 1 × 10 4 prepared in Experimental Example 1 Cells without BLT2 expression (CHO-pcDNA3.1 cells) and cells with BLT2 expression (CHO-BLT2 cells) were dispensed into a 96 mm culture dish and cultured for 24 hours. Thereafter, the culture was removed and serum-free RPMI medium was added. After 2 hours, 10 μM of the compound prepared in the above example, 10 μM of DMSO (compound solvent) as a control, LY255283 ((1- [5-ethyl-2-hydroxy-4-[[6-methyl-6-) as a positive control 10 μM of (1H-tetrazol-5-yl) heptyl] oxy] phenyl] -ethanone (Cayman) was treated with each cell 1 hour prior to LTB 4 (300nM) was treated and incubated for 24 hours. 20 μL of MTT solution (5 mg / mL, Sigma-Aldrich) was added to each well and incubated for 4 hours at 37 ° C. in a humid CO 2 incubator, then the supernatant was removed and 200 μL of DMSO was added to each well to insoluble purple Formazan crystals were dissolved. Absorbance at 550 nm was measured using a microplate reader (Molecular Devices, Sunnyvale, Calif.), And all measurements were repeated three times.
그 결과, 도 1a 내지 도 1d에 나타낸 바와 같이, BLT2가 발현된 세포(CHO-BLT2 cells)에 BLT2의 리간드인 LTB4 (300nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 성장이 20%에서 35%까지 증가하였고, BLT2가 발현된 세포 (CHO-BLT2)에서, 양성 대조군인 LY255283을 전 처리한 경우, 대조군인 DMSO를 처리한 경우와 비교하여 약 90%의 세포 성장을 나타냈으며, 상기 실시예의 화합물 처리에 따른 세포 성장 억제 효과를 확인하였다. 구체적으로, 본 발명의 화합물 AC-1632 (78.7%), AC-1635 (71.6%), AC-1646 (72.1%) 및 AC-1650 (82.2%)의 화합물에서 성장 억제효과를 확인하였다.As a result, as shown in FIGS. 1A to 1D, LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +) and ethanol treated (DMSO-) cell growth increased from 20% to 35%, and in BLT2 expressed cells (CHO-BLT2), positive control Phosphorus LY255283 pre-treated, showed about 90% cell growth compared to the control group treated with DMSO, confirming the effect of inhibiting cell growth according to the compound treatment of the Example. Specifically, the growth inhibitory effect of the compounds of the present invention AC-1632 (78.7%), AC-1635 (71.6%), AC-1646 (72.1%) and AC-1650 (82.2%) was confirmed.
상기 실험결과는, 본 발명의 화합물 (AC-1632, AC-1635, AC-1646 및 AC-1650)은 BLT2로 유도된 세포 증식을 매우 우수한 효율로 억제할 수 있으며, 상기 화합물은 항암, 항천식 또는 다른 형태의 BLT2 관련 염증성 질환의 억제를 위한 치료제로 활용 가능한 약학적 성분 (BLT2-blocking pharmacological molecules)으로 이용될 수 있음을 의미한다.The results of the experiment, the compounds of the present invention (AC-1632, AC-1635, AC-1646 and AC-1650) can inhibit the cell proliferation induced by BLT2 with very good efficiency, the compound is anti-cancer, anti-asthma Or BLT2-blocking pharmacological molecules, which can be used as therapeutic agents for the inhibition of other forms of BLT2-related inflammatory diseases.
실험예 3. BLT2 억제를 통한 암세포사멸 유도효과 확인Experimental Example 3. Confirmation of cancer cell death induction effect through BLT2 inhibition
본 발명자들은 BLT2의 발현은 항암제 내성 정도에 따라 비례적으로 증가하며, BLT2 억제에 의하여 항암제 내성이 현저히 감소됨을 실험적으로 확인한 바가 있다. 따라서 항암제 내성을 나타내는 난소암세포 (SKOV-3 cells)에서, 본 발명의 화합물을 항암제인 cisplatin과 복합 처리 시, 항암제 내성에도 불구하고 암세포 사멸이 유도 되는지 여부를 확인하고자 하였다.The inventors have experimentally confirmed that the expression of BLT2 increases proportionally with the degree of anticancer drug resistance, and the anticancer drug resistance is significantly reduced by BLT2 inhibition. Therefore, in the ovarian cancer cells (SKOV-3 cells) exhibiting anticancer drug resistance, when the compound of the present invention in combination with the anticancer drug cisplatin, to determine whether cancer cell death is induced despite the anticancer drug resistance.
암세포 사멸여부는 3-(4,5-디메틸티아졸-2-일)-2,5-디페닐테트라졸륨 브로마이드 (MTT) 방법을 이용하여 측정하였다. 보다 구체적으로, 항암제 내성을 나타내는 1 × 105개의 난소 암세포 (SKOV-3 cells)를 12웰 배양 접시(12-well culture dish) 상에 분주하고 24시간 동안 세포를 배양하였다. 상기 실시예에서 제조한 화합물 10 μM, 대조군인 DMSO (화합물의 용매) 10 μM, 양성 대조군인 LY255283 10 μM를 각각 0.5% 혈청 RPMI 배지에 30분간 전 처리하였다. 이 후, 항암제인 cisplatin을 50μM를 처리한 후, 24시간 동안 배양하였다. 20 μL의 MTT 용액(5 mg/mL, Sigma-Aldrich)을 각 웰에 가하고 습한 CO2 인큐베이터에서 37℃, 4시간 동안 배양하였다. 이 후, 상층액을 제거하고, 500 μL의 DMSO를 각 웰에 가해 불용성 보라색 포마잔 결정을 용해시켰다. 550 nm에서의 흡광도를 마이크로플레이트 리더 (Molecular Devices, Sunnyvale, CA)를 이용하여 측정하였으며, 모든 측정은 3회 반복 수행하였다. Cancer cell death was measured using 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) method. More specifically, 1 × 10 5 showing anticancer drug resistance Ovarian cancer cells (SKOV-3 cells) were dispensed onto a 12-well culture dish and incubated for 24 hours. 10 μM of the compound prepared in the above example, 10 μM of the control DMSO (solvent of the compound) and 10 μM of the positive control LY255283 were each pretreated in 0.5% serum RPMI medium for 30 minutes. Subsequently, cisplatin, an anticancer agent, was treated with 50 μM and then cultured for 24 hours. 20 μL of MTT solution (5 mg / mL, Sigma-Aldrich) was added to each well and incubated for 4 hours at 37 ° C. in a humid CO 2 incubator. The supernatant was then removed and 500 μL of DMSO was added to each well to dissolve insoluble purple formazan crystals. Absorbance at 550 nm was measured using a microplate reader (Molecular Devices, Sunnyvale, Calif.) And all measurements were repeated three times.
그 결과, 도 2a 내지 도 2c에 나타낸 바와 같이, 항암제 내성을 나타내는 난소암 세포 (SKOV-3 cells)에서, 양성 대조군인 LY255283과 cisplatin을 복합 처리한 경우, 항암제인 cisplatin을 단독 처리와 비교하여 암세포 사멸이 증가함을 확인하였다. 또한, AC-1070, AC-1072, AC-1073 및 AC-1074의 화합물을 cisplatin을 복합 처리한 경우에 양성 대조군인 LY255283 복합 처리와 비교하여 매우 우수한 암세포 사멸 증가를 확인하였다.As a result, as shown in Fig. 2a to 2c, in the combination of the positive control group LY255283 and cisplatin in the ovarian cancer cells (SKOV-3 cells) showing anti-cancer drug resistance, cisplatin as an anticancer drug compared to the treatment alone It was confirmed that death was increased. In addition, when the compound of AC-1070, AC-1072, AC-1073 and AC-1074 was treated with cisplatin, it was confirmed that a very good increase in cancer cell death compared to the positive control LY255283 complex treatment.
상기 결과는, 본 발명의 화합물 (AAC-1070, AC-1072, AC-1073 및 AC-1074)은 항암제 내성을 감소시켜 항암제인 cisplatin에 의한 암세포사멸을 우수한 효율로 유도할 수 있는바, 항암 효과 증진을 위한 약학적 성분으로 이용될 수 있음을 의미한다.The results, the compounds of the present invention (AAC-1070, AC-1072, AC-1073 and AC-1074) can reduce the cancer drug resistance to induce cancer cell death by cisplatin, an anticancer drug with excellent efficiency, anticancer effect It can be used as a pharmaceutical ingredient for enhancement.
실험예 4. LTB4로 유도된 BLT2 의존적인 주화성 저해효과 확인Experimental Example 4 Confirmation of BLT2-dependent Chemotaxis Inhibition Induced by LTB 4
주화성 (Chemotactic motility)은 6.5-mm 직경의 폴리카보네이트 필터 (8-μm 의 공극 크기, Corning Costar)를 구비한 Transwell 챔버를 이용하여 분석하였다. 구체적으로, 필터의 아래쪽 표면을 37 ℃에서 1시간 동안 무혈청 RPMI 1640 배지 중의 10 μg/mL 파이브로넥틴으로 코팅하였다. 다양한 양의 LTB4를 포함한 RPMI 1640 배지와 함께 건조, 코팅된 필터를 Transwell 챔버의 아래쪽 웰에 두고, 무혈청 RPMI 1640 배지에 BLT1 및 BLT2를 안정적으로 발현하는 CHO 세포를 최종적으로 2 × 104cells/100μL로 윗쪽 웰에 로딩하여 실험하였다. 저해제들의 효과를 평가할 때 세포들은 분주 전 30분 동안 각각의 저해제로 전 처리하였다. 37℃, 5% CO2에서 3시간 동안 배양한 후, 필터들을 메탄올로 3분 동안 고정시키고, 헤마톡실린 및 에오신으로 10분 동안 염색했다. 본 실험에서, 세포는 BLT2가 발현된 세포(CHO-BLT2 cells) 및 BLT1이 발현된 세포(CHO-BLT1)를 이용하였으며, 양성 대조군으로 각각 LY255283 및 U75302를, 비교 대조군으로 BLT2의 리간드인 LTB4 , (300 nM), BLT1의 리간드인 LTB4 (10nM), LPA (lysophosphatidicacid;100nM)를 이용하였다. 주화성은 광학 현미경 하에서 (배율, ×200), 필터의 아래쪽 측면 상의 세포를 계수함으로써 정량하였다. 각 분석에서 6개의 필드를 계수하였고, 각각의 샘플은 2회씩 분석하였으며, 상기 분석은 3회씩 반복 수행하였다.Chemotactic motility was analyzed using a Transwell chamber equipped with a 6.5-mm diameter polycarbonate filter (8-μm pore size, Corning Costar). Specifically, the bottom surface of the filter was coated with 10 μg / mL fibronectin in serum free RPMI 1640 medium at 37 ° C. for 1 hour. A dry, coated filter with RPMI 1640 medium containing varying amounts of LTB 4 is placed in the bottom well of the Transwell chamber and finally 2 × 10 4 cells of CHO cells stably expressing BLT1 and BLT2 in serum-free RPMI 1640 medium. Experiments were performed by loading into the upper wells at / 100 μL. When evaluating the effects of the inhibitors, the cells were pretreated with each inhibitor for 30 minutes before dispensing. After 3 hours of incubation at 37 ° C., 5% CO 2 , the filters were fixed with methanol for 3 minutes and stained with hematoxylin and eosin for 10 minutes. In the present experiment, the cells used BLT2-expressing cells (CHO-BLT2 cells) and BLT1-expressing cells (CHO-BLT1), LY255283 and U75302 as positive controls, respectively, and LTB 4 , a ligand of BLT2 as a comparative control. , (300 nM), LTB 4 , the ligand of BLT1 (10 nM) and LPA (lysophosphatidic acid; 100 nM) were used. Chemotaxis was quantified by counting cells on the lower side of the filter under an optical microscope (magnification, x200). Six fields were counted in each assay, each sample analyzed twice, and the assay was repeated three times.
그 결과, 도 3a 내지 도 3d 및 하기 표 1에 나타낸 바와 같이, BLT2를 발현하는 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 (AC-1074)의 농도가 증가함에 따라 (10-4, 10-3, 10-2, 10-1, 1, 10 및 102), 무 혈청 조건 하에서 CHO-BLT2 세포의 주화성이 억제됨을 확인하였으며, AC-1074의 화합물의 IC50 (50% 억제 농도)는 6.024 μM 이었다.As a result, as shown in FIGS. 3A to 3D and Table 1 below, in the cells expressing BLT2 (CHO-BLT2 cells), as the concentration of the compound (AC-1074) of the present invention was increased (10 −4 , 10 -3 , 10 -2 , 10 -1 , 1, 10 and 10 2 ), it was confirmed that chemotaxis of CHO-BLT2 cells under serum-free conditions, IC 50 (50% inhibitory concentration of the compound of AC-1074) ) Was 6.024 μΜ.
Figure PCTKR2016008070-appb-T000001
Figure PCTKR2016008070-appb-T000001
또한, 도 4a에 나타낸 바와 같이, BLT2가 발현된 세포(CHO-BLT2 cells)에 BLT2의 리간드인 LTB4 (300nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 2.9배 증가되었고, 양성 대조군으로 사용된 LY255283를 10 μM 전처리한 경우, 리간드인 LTB4를 처리한 경우와 비교하여 90% 의 주화성을 나타내었으며, 본 발명의 화합물 (AC-1074)을 BLT2가 발현된 세포에 10 μM 전처리한 경우, 리간드인 LTB4를 처리한 경우 (DMSO+)와 비교하여 주화성이 53% 억제됨을 확인하였다.In addition, as shown in Figure 4a, LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +), ethanol treated compared to (DMSO-), the cell chemotaxis was increased 2.9-fold, and 10 μM pretreatment of LY255283 used as a positive control, the ligand LTB 4 To It showed 90% chemotaxis compared to the treatment, and when the compound of the present invention (AC-1074) was pretreated with 10 μM of cells expressing BLT2, the ligand was treated with LTB 4 (DMSO +). It was confirmed that 53% inhibition of chemotaxis.
또한, 도 4b에 나타낸 바와 같이, BLT1이 발현된 세포(CHO-BLT1 cells)에 BLT1의 리간드인 LTB4 (10nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 2.8배 증가되었고, 본 발명의 화합물 (AC-1074)을 BLT2가 발현된 세포에 10 μM 전처리한 경우, 리간드인 LTB4를 처리한 경우 (DMSO+)와 비교하여 주화성의 변화가 없음을 확인하였다.In addition, as shown in Figure 4b, LTB 4 which is a ligand of BLT1 to BLT1-expressing cells (CHO-BLT1 cells) When treated with (10 nM) (DMSO +), compared with (DMSO-) with ethanol, the cell chemotaxis was increased by 2.8-fold, and the compound (AC-1074) of the present invention was added to cells expressing BLT2 10. In case of pretreatment with M, it was confirmed that there was no change in chemotaxis compared to (DMSO +) when the ligand LTB 4 was treated.
또한, 도 4c에 나타낸 바와 같이, BLT2가 발현된 세포(CHO-BLT2 cells)에 LPA (lysophosphatidicacid)(100nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 3.4배 증가되었고, 본 발명의 화합물 (AC-1074)을 BLT2가 발현된 세포에 10 μM 전처리한 경우, 리간드인 LPA를 처리한 경우 (DMSO+)와 비교하여 주화성의 변화가 없음을 확인하였다.In addition, as shown in Figure 4c, BLT2-expressing cells (CHO-BLT2 cells) treated with LPA (lysophosphatidic acid) (100nM) (DMSO +), ethanol treated (DMSO-) cells, compared to Chemotaxis was increased 3.4 times, and when the compound of the present invention (AC-1074) was pretreated with 10 μM of cells expressing BLT2, there was no change in chemotaxis compared to LPA treated with ligand (DMSO +). Confirmed.
상기 결과는, BLT2가 안정하게 발현되고 있는 세포 (CHO-BLT2)에서, 주화성 활성은 LTB4 자극에 인해 증가되며, 본 발명의 화합물 (AC-1074)은 이러한 주화성을 현저히 저해시킬 수 있는바, LTB4에 의해 유도된 BLT2-의존적 주화성을 저해시키기 위한 약학적 성분으로 이용될 수 있음을 의미한다.The results indicate that chemotactic activity is LTB 4 in cells stably expressing BLT2 (CHO-BLT2). Increased due to stimulation, the compound of the present invention (AC-1074) can significantly inhibit this chemotaxis, can be used as a pharmaceutical component for inhibiting BLT2-dependent chemotaxis induced by LTB 4 Means.
실험예 5. LTB4와 BLT2 결합 저해효과 확인Experimental Example 5. Confirmation of the inhibitory effect of LTB 4 and BLT2 binding
LTB4와 BLT2 결합 (ligand binding affinity) 저해는 동위원소 트리튬(H3)이 표기표 LTB4([3H]LTB4, ARC)(specific activity 160.0 Ci/mmol)를 사용하여 분석하였다. 실험방법은 CHO-BLT2 세포 2 × 106개를 100 mm 배양접시에 깔고 48시간 동안 배양한 후 다음 과정을 진행한다. 수확한 세포를 균질기(homogenizer)로 1분씩 총 5회 사용하여 세포막의 단백질들을 분리한다. 그 후 4℃에서 45,000 RPM으로 40 분간 원심분리를 진행하여 세포막의 단백질만 수확하고 이를 40 μg/45 μL 농도로 정량하였다. 동일하게 정량된 BLT2가 포함된 세포막 단백질에 각각 동일한 양의 [3H]LTB4(5 nM)를 처리하고 농도별(10-9, 10-8, 10-7, 10-6 및 10-5 M)로 화합물질을 처리하였을 때, 트리튬이 표기된 LTB4와 BLT2의 결합 억제정도를 Hidex 300sL 액체섬광계수기를 사용하여 측정하였다.LTB 4 and BLT2 binding (ligand binding affinity) inhibition was analyzed by isotope tritium (H3) using the label LTB 4 ([3H] LTB 4, ARC) (specific activity 160.0 Ci / mmol). Experimental method is to put 2 × 10 6 CHO-BLT2 cells in a 100 mm culture dish and incubate for 48 hours before proceeding. The harvested cells are used five times for one minute in a homogenizer to separate the proteins of the cell membrane. Thereafter, centrifugation was performed for 40 minutes at 45,000 RPM at 4 ° C to harvest only proteins of the cell membrane and quantitate them at a concentration of 40 μg / 45 μL. Cell membrane proteins containing equally quantified BLT2 were treated with the same amount of [3H] LTB 4 (5 nM), respectively, and at different concentrations (10 -9 , 10 -8 , 10 -7 , 10 -6 and 10 -5 M). ), The degree of inhibition of the binding of tritium-labeled LTB 4 to BLT2 was measured using a Hidex 300sL liquid scintillation counter.
그 결과, 도 5에 나타낸 바와 같이, BLT2를 발현하는 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 (AC-1074)의 농도가 증가함에 따라 (10-9, 10-8, 10-7, 10-6 및 10-5) LTB4와 BLT2의 결합이 억제됨을 확인하였으며, AC-1074 화합물의 IC50 (50% 결합 억제 농도)는 140.35 nM 이었다.As a result, as shown in Figure 5, in the BLT2 expressing cells (CHO-BLT2 cells), as the concentration of the compound (AC-1074) of the present invention increases (10 -9 , 10 -8 , 10 -7) , 10 -6 and 10 -5 ) LTB 4 and BLT2 inhibition was confirmed, IC 50 (50% binding inhibition concentration) of the AC-1074 compound was 140.35 nM.
실험예 6. BLT2 억제를 통한 항천식 효과 확인Experimental Example 6. Confirmation of anti-asthma effect through BLT2 inhibition
천식의 초기 반응에서는 mast cell이 중요한 역할을 하며, 외부에서 allergen이 기도를 통해 체내에 들어오면 mast cell이 활성화되어 여러 가지 싸이토카인 (interlukin-4, interlukin-13)들을 분비하게 된다. 이러한 싸이토카인에 의해 염증세포들의 유입, 점액의 생성, 기도가 수축하는 등의 현상이 나타나게 된다. 본 발명자들은 항 천식효과를 확인하기 위해 7주령(18-20g)이 된 암컷 BALB/c 마우스를 오리엔트 (Seoungnam, Korea)로부터 공급받아 실험에 사용하였으며, 천식을 유도하였다. 1 및 14일에 암컷 C57BL/6 마우스에 보조제인 알루미늄 하이드로퍼 겔 (alum)(Pierce, Rockford, IL) 2.5 mg을 20 mg의 난백 알부민(OVA)에 포함시켜 복강 내 감작시켰다. 두 번의 초기 감작 후 21, 22 및 23 일에 초음파 분무기를 사용하여 1% OVA를 마우스에 분사하였다. 본 발명의 화합물 (AC-1074)(5 ㎎/㎏), LY255283 (5 ㎎/㎏, Cayman) 또는 DMSO는 1% OVA를 분사하기 1 시간 전에 복강주사 하였다. 초기 감작 후 24일에 기도과민성 (AHR)를 측정하였고, 25일에 천식표현형인 염증성 싸이토카인 IL-4 발현 및 염증세포(호중구; neutrophil)의 유입을 관찰하기 위해 마우스를 해부하였다. 또한, 기도과민성 측정은 마우스에 기도수축제인 metacholine (조건에 따라 6.25 mg/ml ~ 50 mg/ml까지)을 투여한 후 수행하였다. 기도 수축제 투여는 초음파 분무기를 사용하여 3분 동안 챔버의 입구를 통해 분사하였다. 기도의 과민성은 enhanced pause를 천식현상의 지표로 사용하여 분석하였다.In the early reaction of asthma, mast cells play an important role. When allergen enters the body through the airway, mast cells are activated to release various cytokines (interlukin-4 and interlukin-13). The cytokine causes phenomena such as influx of inflammatory cells, mucus production, and airway contraction. To confirm the anti-asthma effect, the present inventors received female BALB / c mice that were 7 weeks old (18-20 g) from Orient (Seoungnam, Korea) and used them in the experiments to induce asthma. On day 1 and 14 2.5 mg of aluminum hydropergel (alum) (Pierce, Rockford, IL), a supplement to female C57BL / 6 mice, was intraperitoneally sensitized to 20 mg of egg white albumin (OVA). Mice were sprayed with 1% OVA using an ultrasonic nebulizer on days 21, 22 and 23 after two initial sensitizations. Compound (AC-1074) (5 mg / kg), LY255283 (5 mg / kg, Cayman) or DMSO of the present invention was intraperitoneally injected 1 hour prior to 1% OVA injection. Airway hypersensitivity (AHR) was measured 24 days after initial sensitization, and mice were dissected on day 25 to observe the asthma phenotype of inflammatory cytokine IL-4 expression and the influx of inflammatory cells (neutrophils). In addition, airway hypersensitivity measurement was performed after the administration of metacholine (up to 6.25 mg / ml to 50 mg / ml depending on conditions), which is an airway constrictor. Airway constrictor administration was sprayed through the inlet of the chamber for 3 minutes using an ultrasonic nebulizer. Airway hypersensitivity was analyzed using enhanced pause as an indicator of asthma.
그 결과, 도 6에 나타낸 바와 같이, 천식이 유도된 마우스 (OVA/DMSO)에서 천식이 유도 되지 않은 마우스 (Normal)에 비해 12배가량 기도 저항성이 증가되었으며, 본 발명의 화합물 (AC-1074)을 10 μM 전처리한 경우, 기도수축제 50 mg/ml를 투여한 마우스와 비교하여, 기도 과민성이 42%, 감소됨을 확인하였다.As a result, as shown in Figure 6, asthma-induced mice (OVA / DMSO) increased as much as 12 times in airway resistance compared to non-asthma-induced mice (Normal), the compound of the present invention (AC-1074) When 10 μM pretreatment was compared with mice administered 50 mg / ml of airway constrictor, it was confirmed that airway hypersensitivity was reduced by 42%.
또한, 도 7 및 도 8에서 나타낸 바와 같이, 양성 대조군인 LY255283을 10 μM 전 처리한 경우, 기도수축제 50 mg/ml를 투여한 중증천식이 유도된 마우스에서 기도과민성이 69.2% 감소되었으며, 마우스 복강에서 분리된 세포들의 IL-4 생성이 67.2% 감소됨을 확인하였다. 나아가, 본 발명의 화합물 (AC-1074)을 10 μM 전처리한 경우, 기도수축제 50 mg/ml를 투여한 중증천식이 유도된 마우스에서 기도 과민성이 59% 감소되었으며, 마우스 복강에서 분리된 세포들의 IL-4 생성이 35.5% 감소됨을 확인하였다.In addition, as shown in FIGS. 7 and 8, when 10 μM of the positive control LY255283 was pretreated, airway hypersensitivity was reduced by 69.2% in severe asthma-induced mice administered with 50 mg / ml of airway constrictor. It was confirmed that IL-4 production of cells isolated from the abdominal cavity was reduced by 67.2%. Furthermore, when 10 μM of the compound of the present invention (AC-1074) was pretreated, airway hyperresponsiveness was reduced by 59% in severe asthma-induced mice administered with 50 mg / ml of airway constrictor. It was confirmed that IL-4 production was reduced by 35.5%.
상기 결과는, 본 발명의 화합물(AC-1074)은 천식 동물모델에서 기도과민성을 억제하고 화합물(AC-1074)은 염증성 싸이토카인 IL-4 생성을 억제시켜 천식의 증상을 완화시킬 수 있는바, 항천식 효과를 갖는 약학적 성분으로 이용될 수 있음을 의미한다.The above results, the compound of the present invention (AC-1074) can suppress airway hyperresponsiveness in the asthma animal model and the compound (AC-1074) can alleviate the symptoms of asthma by inhibiting the production of inflammatory cytokine IL-4, anti It can be used as a pharmaceutical ingredient with an asthma effect.
본 발명은 BLT2 (Leukotriene B4 receptor 2) 억제 활성을 나타내는 신규 화합물 및 이를 포함하는 염증성 질환 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명자들은 종래의 염증성 질환 치료 물질의 문제점인 생체 내 불안정성 및 대량 생산의 어려움을 해소하기 위하여 BTL2 억제 활성을 나타내는 신규 화합물을 규명하였으며, 상기 화합물의 우수한 암세포 사멸 증진 및 전이 억제 효과, 주화성 억제 효과 및 항 천식 효과 등을 실험적으로 확인하였는바, 염증성 질환을 치료하기 위한 약학적 조성물로 유용하게 사용될 수 있을 것으로 기대된다.The present invention relates to a novel compound that exhibits Leukotriene B4 receptor 2 (BLT2) inhibitory activity and a pharmaceutical composition for preventing or treating an inflammatory disease comprising the same. The present inventors have identified a novel compound that exhibits BTL2 inhibitory activity in order to solve in vivo instability and difficulty in mass production, which are problems of conventional inflammatory disease treatment substances, and has excellent cancer cell death enhancement and metastasis suppression effect and chemotaxis inhibition of the compound. The effects and anti-asthma effects have been confirmed experimentally, it is expected to be useful as a pharmaceutical composition for treating inflammatory diseases.

Claims (7)

  1. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염:A compound represented by formula (1) or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2016008070-appb-I000025
    Figure PCTKR2016008070-appb-I000025
    상기 화학식 1에서,In Chemical Formula 1,
    R1은 C1~C10의 알킬,
    Figure PCTKR2016008070-appb-I000026
    또는
    Figure PCTKR2016008070-appb-I000027
    이고,    R 1 is C 1 -C 10 alkyl,
    Figure PCTKR2016008070-appb-I000026
    or
    Figure PCTKR2016008070-appb-I000027
    ego,
    R2는 수소,
    Figure PCTKR2016008070-appb-I000028
    ,
    Figure PCTKR2016008070-appb-I000029
    ,
    Figure PCTKR2016008070-appb-I000030
    또는
    Figure PCTKR2016008070-appb-I000031
    이고,    R 2 is hydrogen,
    Figure PCTKR2016008070-appb-I000028
    ,
    Figure PCTKR2016008070-appb-I000029
    ,
    Figure PCTKR2016008070-appb-I000030
    or
    Figure PCTKR2016008070-appb-I000031
    ego,
    R3는 수소,
    Figure PCTKR2016008070-appb-I000032
    ,
    Figure PCTKR2016008070-appb-I000033
    ,
    Figure PCTKR2016008070-appb-I000034
    또는
    Figure PCTKR2016008070-appb-I000035
    이고,    R 3 is hydrogen,
    Figure PCTKR2016008070-appb-I000032
    ,
    Figure PCTKR2016008070-appb-I000033
    ,
    Figure PCTKR2016008070-appb-I000034
    or
    Figure PCTKR2016008070-appb-I000035
    ego,
    R4는 수소,
    Figure PCTKR2016008070-appb-I000036
    ,
    Figure PCTKR2016008070-appb-I000037
    ,
    Figure PCTKR2016008070-appb-I000038
    ,
    Figure PCTKR2016008070-appb-I000039
    또는
    Figure PCTKR2016008070-appb-I000040
    이고,    R 4 is hydrogen,
    Figure PCTKR2016008070-appb-I000036
    ,
    Figure PCTKR2016008070-appb-I000037
    ,
    Figure PCTKR2016008070-appb-I000038
    ,
    Figure PCTKR2016008070-appb-I000039
    or
    Figure PCTKR2016008070-appb-I000040
    ego,
    여기서 Ra는 수소, C1~C10의 알킬, C1~C5의 카르복실,Where R a is hydrogen, C 1 -C 10 alkyl, C 1 -C 5 carboxyl,
    Figure PCTKR2016008070-appb-I000041
    Figure PCTKR2016008070-appb-I000041
    R5, R6, 및 R7은 각각 독립적으로 수소, 할로겐, 니트로, 메틸, 트리플루오로메틸 또는 메톡시이며,R 5 , R 6 , and R 7 are each independently hydrogen, halogen, nitro, methyl, trifluoromethyl or methoxy,
    단, R1은 부틸, R2는
    Figure PCTKR2016008070-appb-I000042
    , R3, R4, R5, R6, 및 R7은 수소인 경우;    Provided that R 1 is butyl and R 2 is
    Figure PCTKR2016008070-appb-I000042
    When R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen;
    R1은 부틸, R3는
    Figure PCTKR2016008070-appb-I000043
    , R2, R4, R5, R6, 및 R7은 수소인 경우;    R 1 is butyl, R 3 is
    Figure PCTKR2016008070-appb-I000043
    When R 2 , R 4 , R 5 , R 6 , and R 7 are hydrogen;
    R1은 부틸, R4는
    Figure PCTKR2016008070-appb-I000044
    , R2, R3, R5, R6, 및 R7은 수소인 경우;    R 1 is butyl, R 4 is
    Figure PCTKR2016008070-appb-I000044
    , R 2 , R 3 , R 5 , R 6 , and R 7 are hydrogen;
    R1은 부틸, R4는
    Figure PCTKR2016008070-appb-I000045
    , R2, R3, R5, R6, 및 R7은 수소인 경우;    R 1 is butyl, R 4 is
    Figure PCTKR2016008070-appb-I000045
    , R 2 , R 3 , R 5 , R 6 , and R 7 are hydrogen;
    R1은 부틸, R4는
    Figure PCTKR2016008070-appb-I000046
    , R6는 플루오르, R2, R3, R5, 및 R7은 수소인 경우;    R 1 is butyl, R 4 is
    Figure PCTKR2016008070-appb-I000046
    When R 6 is fluorine, R 2 , R 3 , R 5 , and R 7 are hydrogen;
    R1은 펜틸, R4는
    Figure PCTKR2016008070-appb-I000047
    , R6는 플루오르, R2, R3, R5, 및 R7은 수소인 경우; 및    R 1 is pentyl, R 4 is
    Figure PCTKR2016008070-appb-I000047
    When R 6 is fluorine, R 2 , R 3 , R 5 , and R 7 are hydrogen; And
    R1은 펜틸, R4는
    Figure PCTKR2016008070-appb-I000048
    , R6는 플루오르, R2, R3, R5, 및 R7은 수소인 경우는 제외한다.    R 1 is pentyl, R 4 is
    Figure PCTKR2016008070-appb-I000048
    , Except that R 6 is fluorine, R 2 , R 3 , R 5 , and R 7 are hydrogen.
  2. 제 1항에 있어서,The method of claim 1,
    상기 화학식 1로 표시되는 화합물은 하기 화합물들로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염:The compound represented by Formula 1 is selected from the group consisting of the compound, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
    N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentanamide;
    N-(4'-((N-페닐펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; N- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide;
    N-(3-플루오로페닐)-N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentaneamide;
    N-(4'-((N-3-플루오로페닐)펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; N- (4 '-(( N- 3-fluorophenyl) pentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide;
    1-(3-플루오로페닐)-1-((4'-메톡시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아;1- (3-fluorophenyl) -1-((4'-methoxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea;
    N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)-1-(4-메톡시페닐설폰일)메탄아마이드; N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methaneamide;
    1-(3-플루오로페닐)-1-((4'-하이드록시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아;1- (3-fluorophenyl) -1-((4'-hydroxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea;
    2-(4'-((1-(3-플루오로페닐)-3-(3-(트리플루오로메틸)페닐)유레이도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetic acid;
    4-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)부탄산;4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoic acid;
    2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)-2-메틸프로판산;2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) -2-methylpropanoic acid;
    (E)-3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아크릴산;( E ) -3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylic acid;
    3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)프로판산;3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) propanoic acid;
    N-(3-플루오로페닐)-N-((4'-(2-(4-메틸피페라진-1-일)-2-옥소에톡시)바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((4 '-(2- (4-methylpiperazin-1-yl) -2-oxoethoxy) biphenyl-4-yl) methyl) pentaneamide;
    프로프-2-인일 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트;Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate;
    N-(3-플루오로페닐)-N-((4'-(프로프-2-이닐옥시)바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl) pentaneamide;
    4'-((N-(2-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산;4 '-(( N- (2-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid;
    4'-((N-(4-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산;4 '-(( N- (4-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid;
    4'-((N-(2-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산;4 '-(( N- (2-methoxyphenyl) pentaneamido) methyl) biphenyl-3-carboxylic acid;
    4'-((N-(3-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산;4 '-(( N- (3-methoxyphenyl) pentaneamido) methyl) biphenyl-3-carboxylic acid;
    4'-((N-(4-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산;4 '-(( N- (4-methoxyphenyl) pentaneamido) methyl) biphenyl-3-carboxylic acid;
    N-((2'-(4-메톡시피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((2 '-(4-methoxypiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentanamide;
    N-((3'-(4-메틸피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((3 '-(4-methylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentanamide;
    4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-2-카복실산;4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-2-carboxylic acid;
    4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산;4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid;
    N-(3-플루오로페닐)-N-((4'-(몰폴린-4-카보닐)-[1,1'-바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((4 '-(morpholine-4-carbonyl)-[1,1'-biphenyl-4-yl) methyl) pentaneamide;
    N-(3-플루오로페닐)-N-((4'-(4-메틸피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((4 '-(4-methylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide;
    N-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N-phenylpentanamide;
    N-((4'-메톡시바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((4'-methoxybiphenyl-4-yl) methyl) -N -phenylpentanamide;
    N-((4'-하이드록시바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((4'-hydroxybiphenyl-4-yl) methyl) -N -phenylpentanamide;
    2-(4'-((N-페닐펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
    N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide;
    N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드; N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide;
    2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
    N-(3-클로로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드; N- (3-chlorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide;
    N-(3-클로로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드; N- (3-chlorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide;
    2-(4'-((N-(3-클로로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
    N-(3-브로모페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드; N- (3-bromophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide;
    N-((4'-(하이드록시바이페닐-4-일)메틸)-N-(3-(트리플루오로메틸)페닐)펜탄아마이드; N -((4 '-(hydroxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide;
    2-(4'-((N-(3-브로모페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
    N-((4'-메톡시바이페닐-4-일)메틸)-N-(3-(트리플루오로메틸)페닐)펜탄아마이드; N -((4'-methoxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide;
    N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드; N - ((4'- hydroxy-biphenyl-4-yl) methyl) - N - (3- nitrophenyl) pentane amide;
    2-(4'-((N-(3-(트리플루오로메틸)페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N- (3- (trifluoromethyl) phenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
    N-((4'메톡시바이페닐-4-일)메틸)-N-m-톨릴펜탄아마이드; N -((4'methoxybiphenyl-4-yl) methyl) -N - m -tolylpentaneamide;
    N-((4'-하이드록시페닐-4-일)메틸)-N-m-톨릴펜탄아마이드; N -((4'-hydroxyphenyl-4-yl) methyl) -N - m -tolylpentaneamide;
    2-(4'-((N-m-톨릴펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( Nm -tolylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
    N-((4'-하이드록시페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드; N - ((4'- hydroxy-4-yl) methyl) - N - (3- nitrophenyl) pentane amide;
    2-(4'-((N-(3-니트로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
    N-(3-아이오도페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드; N- (3-iodophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide;
    N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-아이오도페닐)펜탄아마이드; N - ((4'- hydroxy-biphenyl-4-yl) methyl) - N - (3- iodo-phenyl) pentane amide;
    2-(4'-((N-(3-아이오도페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;2- (4 '-(( N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid;
    N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)아세트아마이드; N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) acetamide;
    N-(3-플루오로페닐)-N-((4'-하이드록시-[1,1'-바이페닐]-4-일)메틸)아세트아마이드; N- (3-fluorophenyl) -N -((4'-hydroxy- [1,1'-biphenyl] -4-yl) methyl) acetamide;
    2-((4'-((N-(3-플루오로페닐)아세트아미도)메틸)-[1,1'-바이페닐]-4-일)옥시)아세트산;2-((4 '-(( N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid;
    N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide;
    N-(4-플루오로페닐)-N-((4'-(4-아이소프로필피페라진-1-카보닐)-[1,1'-바이페닐]-4-일)메틸)펜탄아마이드; N- (4-fluorophenyl) -N -((4 '-(4-isopropylpiperazin-1-carbonyl)-[1,1'-biphenyl] -4-yl) methyl) pentaneamide;
    N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 및 N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide; And
    N-(4-플루오로페닐)-N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드. N- (4-fluorophenyl) -N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide.
  3. 제 1항 또는 제 2항의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 염증성 질환 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating inflammatory diseases, comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.
  4. 제 3항에 있어서,The method of claim 3, wherein
    상기 염증성 질환은 천식, 죽상경화증, 암, 피부가려움증, 류마티스 관절염 및 염증성 장 질환으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 조성물.Wherein said inflammatory disease is selected from the group consisting of asthma, atherosclerosis, cancer, itching of the skin, rheumatoid arthritis and inflammatory bowel disease.
  5. 제 3항에 있어서,The method of claim 3, wherein
    상기 조성물은 BLT2 (Leukotriene B4 receptor 2) 활성을 저해시키는 것을 특징으로 하는, 조성물.Said composition is characterized in that it inhibits Leukotriene B4 receptor 2 (BLT2) activity.
  6. 제 1항 또는 제 2항의 화합물 또는 이의 약학적으로 허용가능한 염을 개체에 투여하는 단계를 포함하는, 염증성 질환의 예방 또는 치료 방법.A method of preventing or treating an inflammatory disease comprising administering to a subject a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof.
  7. 제 1항 또는 제 2항의 화합물 또는 이의 약학적으로 허용가능한 염의 염증성 질환의 예방 또는 치료 용도.Use of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof for the prophylaxis or treatment of an inflammatory disease.
PCT/KR2016/008070 2015-07-24 2016-07-23 Novel compound having blt inhibitory activity and composition, for preventing or treating inflammatory diseases, comprising same as active ingredient WO2017018751A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018170165A1 (en) * 2017-03-15 2018-09-20 Metacrine, Inc. Farnesoid x receptor agonists and uses thereof
WO2018170173A1 (en) * 2017-03-15 2018-09-20 Metacrine, Inc. Farnesoid x receptor agonists and uses thereof
WO2018170167A1 (en) * 2017-03-15 2018-09-20 Metacrine, Inc. Farnesoid x receptor agonists and uses thereof
WO2018170166A1 (en) * 2017-03-15 2018-09-20 Metacrine, Inc. Farnesoid x receptor agonists and uses thereof
WO2018170182A1 (en) * 2017-03-15 2018-09-20 Metacrine, Inc. Farnesoid x receptor agonists and uses thereof
US11084817B2 (en) 2018-09-18 2021-08-10 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006083477A2 (en) * 2005-01-07 2006-08-10 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US20080132574A1 (en) * 2004-04-26 2008-06-05 Shinji Nakade Novel Blt2-Mediated Disease, Blt2 Binding Agent And the Compound
WO2008073929A1 (en) * 2006-12-11 2008-06-19 Wyeth Ion channel modulators
KR20090125837A (en) * 2007-03-23 2009-12-07 고려대학교 산학협력단 Use of inhibitors of leukotriene Ｂ4 receptor TLT2 for the treatment of asthma
KR20130017073A (en) * 2011-08-05 2013-02-19 동국대학교 산학협력단 New biphenyl derivative or pharmaceutically acceptable salt thereof, and pharmaceutical composition for treating or preventing inflammatory diseases or autoimmune diseases containing the same as an active ingredient

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080132574A1 (en) * 2004-04-26 2008-06-05 Shinji Nakade Novel Blt2-Mediated Disease, Blt2 Binding Agent And the Compound
WO2006083477A2 (en) * 2005-01-07 2006-08-10 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
WO2008073929A1 (en) * 2006-12-11 2008-06-19 Wyeth Ion channel modulators
KR20090125837A (en) * 2007-03-23 2009-12-07 고려대학교 산학협력단 Use of inhibitors of leukotriene Ｂ4 receptor TLT2 for the treatment of asthma
KR20130017073A (en) * 2011-08-05 2013-02-19 동국대학교 산학협력단 New biphenyl derivative or pharmaceutically acceptable salt thereof, and pharmaceutical composition for treating or preventing inflammatory diseases or autoimmune diseases containing the same as an active ingredient

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10927082B2 (en) 2017-03-15 2021-02-23 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US10961198B2 (en) 2017-03-15 2021-03-30 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
WO2018170167A1 (en) * 2017-03-15 2018-09-20 Metacrine, Inc. Farnesoid x receptor agonists and uses thereof
WO2018170166A1 (en) * 2017-03-15 2018-09-20 Metacrine, Inc. Farnesoid x receptor agonists and uses thereof
WO2018170182A1 (en) * 2017-03-15 2018-09-20 Metacrine, Inc. Farnesoid x receptor agonists and uses thereof
KR20190121399A (en) * 2017-03-15 2019-10-25 메타크린, 인크. Panesoid X Receptor Agonists and Uses thereof
WO2018170173A1 (en) * 2017-03-15 2018-09-20 Metacrine, Inc. Farnesoid x receptor agonists and uses thereof
CN110637015A (en) * 2017-03-15 2019-12-31 梅塔科林公司 Farnesoid X receptor agonists and their uses
WO2018170165A1 (en) * 2017-03-15 2018-09-20 Metacrine, Inc. Farnesoid x receptor agonists and uses thereof
CN110637011A (en) * 2017-03-15 2019-12-31 梅塔科林公司 Farnesoid X receptor agonists and their uses
CN110637011B (en) * 2017-03-15 2024-05-14 奥加诺沃公司 Farnesoid X receptor agonists and uses thereof
US11236071B1 (en) 2017-03-15 2022-02-01 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
CN110637015B (en) * 2017-03-15 2024-04-02 奥加诺沃公司 Fanisole X receptor agonist and application thereof
KR102588982B1 (en) 2017-03-15 2023-10-12 오가노보, 인크. Farnesoid X receptor agonists and uses thereof
US11773094B2 (en) 2018-09-18 2023-10-03 Organovo, Inc. Farnesoid X receptor agonists and uses thereof
US11084817B2 (en) 2018-09-18 2021-08-10 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof

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