WO2022149925A1 - Novel tryptophan hydroxylase inhibitor and use thereof - Google Patents

Novel tryptophan hydroxylase inhibitor and use thereof Download PDF

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Publication number
WO2022149925A1
WO2022149925A1 PCT/KR2022/000339 KR2022000339W WO2022149925A1 WO 2022149925 A1 WO2022149925 A1 WO 2022149925A1 KR 2022000339 W KR2022000339 W KR 2022000339W WO 2022149925 A1 WO2022149925 A1 WO 2022149925A1
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Prior art keywords
phenyl
amino
oxadiazol
propanoic acid
hydroxy
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PCT/KR2022/000339
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French (fr)
Korean (ko)
Inventor
배은정
최원일
김하일
이인규
전재한
오창주
안진희
Original Assignee
광주과학기술원
경북대학교 산학협력단
한국과학기술원
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Publication of WO2022149925A1 publication Critical patent/WO2022149925A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel oxadiazole phenylalanine derivatives and medicinal uses thereof.
  • Obesity refers to an abnormal or excessive accumulation of adipose tissue in the body. Obesity can be caused by excessive intake of nutrients relative to energy expenditure over a long period of time.
  • a simple index for measuring obesity is body mass index (BMI), which is defined as weight/height squared (kg/m 2 ). According to the World Health Organization, adults with a BMI of 30 or more are classified as overweight and obese. In addition, obesity has been classified as a disease since 2013, and may cause complications such as type 2 diabetes, cardiovascular disease, high blood pressure, stroke, colorectal cancer, breast cancer, and ovarian cancer.
  • the treatment methods for obesity include diet, exercise, drug treatment, and surgical methods.
  • the drug used for drug treatment can be classified into an anti-obesity agent acting on the central nerve and an anti-obesity agent acting on the peripheral nerve.
  • Existing obesity treatment is a treatment that suppresses appetite by suppressing serotonin present in the central nervous system.
  • serotonin present in the central nervous system, can affect mood, sleep and memory in addition to appetite.
  • side effects such as headache, agitation, tension, and depression have been reported for existing anti-obesity drugs acting on the central nervous system.
  • Serotonin is a monoamine-based compound that acts on the central nervous system and the peripheral nervous system, and its synthesis starts from tryptophan, an amino acid, and the synthesis proceeds in the order of hydroxylation and decarboxylation of tryptophan.
  • tryptophan hydroxlase TPH may act as a rate-regulating enzyme. This suggests that the synthesis of serotonin can be inhibited by inhibiting tryptophan hydroxylase.
  • This serotonin does not pass through the blood brain barrier (BBB), and is synthesized in the central nervous system and the peripheral nervous system, respectively.
  • BBB blood brain barrier
  • tryptophan hydroxylase 1 TPH1
  • tryptophan hydroxylase 2 TPH2
  • TPH1 tryptophan hydroxylase 1
  • TPH2 tryptophan hydroxylase 2
  • serotonin when serotonin is excessively secreted from peripheral tissues, it interferes with the activity of brown fat cells that burn energy. Therefore, inhibiting the synthesis of serotonin present in the peripheral nervous system can activate the metabolism of peripheral tissues. have.
  • One object of the present invention is to provide a novel oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a method for preparing the oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a composition for inhibiting tryptophan hydroxylase comprising the oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases comprising the oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a method for preventing or treating a metabolic disease comprising administering the pharmaceutical composition to an individual in need thereof.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising the oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a method for preventing or treating cancer, comprising administering the pharmaceutical composition to an individual in need thereof.
  • novel tryptophan hydroxylase inhibitor of the present invention and a pharmaceutical composition comprising the same inhibit the synthesis of serotonin in the peripheral nervous system by inhibiting the activity of tryptophan hydroxylase 1. Therefore, it does not stimulate the central nervous system and activates the metabolic activity of peripheral tissues, so it can be usefully used for the prevention or treatment of metabolic diseases.
  • a first aspect of the present invention provides a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof:
  • n is an integer from 0 to 2
  • R 1 is hydroxy, amino, C 1-6 alkoxy, hydroxy-C 1-4 alkoxy, or hydroxy-amino
  • R 2 To R 6 are each independently hydrogen, hydroxy, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-4 alkylamino, di( C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonylamino, C 6-10 arylcarbonylamino, C 6-14 aryl, C 6-10 aryl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkoxy, C 1-4 alkoxy-C 6-10 aryl, or
  • R 3 and R 4 are linked to each other to C 3-14 heterocyclyl, or form C 5-14 heteroaryl;
  • aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with hydroxy, oxo, C 1-4 alkoxy, or C 1-4 haloalkyl.
  • n may be 0 or 1, but is not limited thereto.
  • R 1 may be hydroxy, amino, ethoxy, hydroxyethoxy, or hydroxyamino, but is not limited thereto.
  • R 2 may be hydrogen, phenyl, hydroxyphenyl, or methoxyphenyl, but is not limited thereto.
  • R 3 may be hydrogen, bromo, nitro, methoxy, phenyl, hydroxyphenyl, or methoxyphenyl, but is not limited thereto.
  • R 4 is hydrogen, hydroxy, nitro, cyano, fluoro, bromo, iodo, methoxy, ethoxy, acetyl, methylcarbonylamino, phenylcarbonylamino, phenylmethoxy , phenylmethyl, dimethylamino, trifluoromethyl, or trifluoromethoxy, but is not limited thereto.
  • R 3 and R 4 may be connected to each other to form dioxolanyl, dioxanyl, pyrazolyl, pyrroline, or benzofuranyl, but is not limited thereto.
  • R 5 and R 6 may both be hydrogen, but is not limited thereto.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the compound of the present invention may exist in the form of a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt an acid value formed by a pharmaceutically acceptable free acid is useful.
  • pharmaceutically acceptable salt refers to a concentration having an effective action that is relatively non-toxic and harmless to a patient. any and all organic or inorganic addition salts.
  • Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and an acid or alcohol (eg glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Equal molar amounts of the compound and an acid or alcohol (eg glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
  • organic acids and inorganic acids can be used as free acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid as organic acids (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used. , but not limited to these.
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group
  • other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, and hydrogen phosphate.
  • the oxadiazole phenylalanine derivative or salt of an isomer thereof of the present invention is a pharmaceutically acceptable salt, if it is an oxadiazole phenylalanine derivative or a salt of an isomer thereof that exhibits pharmacological activity equivalent to that of the oxadiazole phenylalanine derivative or an isomer thereof. All are available without restrictions.
  • the compounds of the present invention include, without limitation, pharmaceutically acceptable salts thereof, as well as solvates such as possible hydrates and all possible stereoisomers that can be prepared therefrom.
  • Solvates and stereoisomers of the compounds can be prepared from the compounds of the present invention using methods known in the art.
  • the compounds of the present invention may be prepared in crystalline or amorphous form, and when prepared in crystalline form, may optionally be hydrated or solvated.
  • the present invention not only stoichiometric hydrates of the above compounds, but also compounds containing various amounts of water may be included.
  • Solvates of the compounds of the present invention include both stoichiometric and non-stoichiometric solvates.
  • a second aspect of the present invention is a first step of synthesizing a compound represented by Formula 4 by reacting a compound represented by Formula 2 with a compound represented by Formula 3; and a second step of converting the compound represented by Formula 4 obtained from the previous step into the compound represented by Formula 1; provides a method for preparing a compound represented by Formula 1, including:
  • n is an integer from 0 to 2
  • R 1 is hydroxy, amino, C 1-6 alkoxy, hydroxy-C 1-4 alkoxy, or hydroxy-amino
  • R 2 To R 6 are each independently hydrogen, hydroxy, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-4 alkylamino, di( C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonylamino, C 6-10 arylcarbonylamino, C 6-14 aryl, C 6-10 aryl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkoxy, C 1-4 alkoxy-C 6-10 aryl, or
  • R 3 and R 4 are linked to each other to C 3-14 heterocyclyl, or form C 5-14 heteroaryl;
  • R 2 ' to R 6 ' are each the same as R 2 to R 6 or a precursor thereof,
  • aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with hydroxy, oxo, C 1-4 alkoxy, or C 1-4 haloalkyl.
  • the reactant is reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (hydroxybenzotriazole; HOBt), and N,N-diisopropylethylamine (N,N-diisopropylethylamine; DIPEA) in the presence of 10 to 35 °C reacted for 12 to 24 hours, the obtained product was refluxed for 12 to 24 hours can be performed, but is not limited thereto.
  • the reaction may be performed on a solution dissolved in an organic solvent, and the solvents used in each reaction may be the same or different from each other.
  • a material produced as an intermediate may be isolated and/or purified and used in a subsequent reaction, or may be used in a subsequent reaction as a crude product without additional treatment.
  • the product obtained by reacting with EDCI, HOBt, and DIPEA in a dichloromethane solution is isolated and purified to obtain a white solid, and then it is dissolved in 1,4-dioxane to carry out the reaction did.
  • this is only an example of a synthesis method, and the scope of the present invention is not limited thereto.
  • a compound including a substituent bonded to R 2 ' to R 6 ' through an aryl group is a boronic acid derivative of R 2 ' to R 6 ', in which a halogen is It may be prepared by reaction with a substituted derivative of the compound of Formula 2, but is not limited thereto.
  • the reaction may be performed similarly to the series of reactions exemplified below, but is not limited thereto.
  • the reaction exemplified below is a synthesis example for a compound having a specific substituent, and the scope of the present invention is not limited thereto.
  • the compound represented by Formula 3 may be prepared from (S)-2-amino-3-(4-cyanophenyl)propanoic acid, but is not limited thereto.
  • the reaction may be performed similarly to the series of reactions exemplified below, but is not limited thereto.
  • the reaction exemplified below is a synthesis example for a compound having a specific substituent, and the scope of the present invention is not limited thereto.
  • a third aspect of the present invention provides a composition for inhibiting tryptophan hydroxylase, comprising the compound of the first aspect, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a fourth aspect of the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, comprising the compound of the first aspect, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a fifth aspect of the present invention provides a method for preventing or treating a metabolic disease, comprising administering the pharmaceutical composition of the fourth aspect to an individual in need thereof.
  • a sixth aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound of the first aspect, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a seventh aspect of the present invention provides a method for preventing or treating cancer, comprising administering the pharmaceutical composition of the sixth aspect to an individual in need thereof.
  • prevention refers to any action that inhibits or delays the occurrence, spread, and recurrence of metabolic or cancer diseases by administration of the composition of the present invention
  • treatment refers to any action by administration of the composition of the present invention. It refers to any action that improves or beneficially changes the symptoms of the above disease.
  • the pharmaceutical composition of the present invention can prevent or treat diseases related thereto by inhibiting the activity of tryptophan hydroxylase.
  • the pharmaceutical composition of the present invention can activate metabolism by inhibiting the activity of tryptophan hydroxylase, in particular, TPH1, thereby inhibiting serotonin synthesis in the peripheral nervous system. Therefore, the pharmaceutical composition of the present invention can exhibit the effect of suppressing weight gain without stimulating the brain or suppressing appetite through the above mechanism.
  • tryrotonin is known to promote the progression of cancer diseases by various mechanisms. As described above, inhibition of serotonin expression through inhibition of TPH1 activity prevents or treats cancer diseases by inhibiting the promotion of cancer diseases by serotonin. can
  • tryptophan hydroxylase refers to an enzyme involved in the synthesis of serotonin (5-hydroxytryptamine; 5-HT), a monoamine neurotransmitter, which hydroxylates tryptophan to 5 -Can produce hydroxytryptophan.
  • 5-HT serotonin
  • TPH1 and TPH2 there are two distinct TPH genes, TPH1 and TPH2 , in humans as well as other mammals, which are present on chromosomes 11 and 12 and encode two other different homologous enzymes, TPH1 and TPH2, respectively.
  • TPH1 is expressed in tissues that express serotonin in the periphery (eg, skin, gut and pineal gland, etc.) but is also expressed in the central nervous system, whereas TPH2 is exclusively expressed in neuronal cell types. It is the predominant isoform in the central nervous system.
  • metabolic diseases that can be prevented or treated with the pharmaceutical composition of the present invention may be obesity, hypertension, arteriosclerosis, diabetes, insulin resistance, hepatic steatosis, fatty liver disease, dyslipidemia, and the like.
  • cancer diseases that can be prevented or treated by the pharmaceutical composition of the present invention include colorectal cancer, colon cancer, cholangiocarcinoma, bile duct carcinoma, lung cancer, gastric cancer. , breast cancer, pancreatic cancer, urinary bladder cancer, prostate cancer, ovarian cancer, placental cancer, choriocarcinoma, squamous epithelium Esophageal squamous cell cancer, glioblastomas, melanomas, renal carcinomas, cervical squamous cell carcinomas, hepatocellular carcinomas, and cervical intraepithelial tumors (cervical intraepithelial neoplasia), etc.
  • diseases that can be prevented or treated using the pharmaceutical composition of the present invention are not limited thereto, and any disease capable of exhibiting a preventive or therapeutic effect by inhibiting tryptophan hydroxylase activity may be included in the scope of the present invention.
  • the pharmaceutical composition according to the present invention contains, as an active ingredient, the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof in an amount of 0.1 to 75% by weight based on the total weight of the composition, more preferably may be contained in an amount of 1 to 50% by weight.
  • composition of the present invention may further include a pharmaceutically acceptable carrier, diluent, or excipient, and may include powders, granules, tablets, capsules, suspensions, emulsions, syrups, It can be formulated and used in various forms such as oral dosage forms such as aerosols, injections of sterile injection solutions, etc., and can be administered orally or administered through various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like.
  • compositions examples include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, and cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • the composition of the present invention may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a fragrance, an emulsifier, a preservative, and the like.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. are mixed and formulated.
  • excipients for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc may be used.
  • Liquid formulations for oral use may include suspensions, solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents, may be included.
  • excipients such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents, may be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • the suppositories are Witepsol, Macrogol, and Twin61. Cacao butter, laurin fat, glycerogelatin, etc. may be used.
  • injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.
  • the composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level depends on the patient's health condition, disease type, severity, drug activity, sensitivity to drug, administration method, administration time, administration route and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other factors well known in the medical field.
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the dosage may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., and thus the dosage is not intended to limit the scope of the present invention in any way.
  • the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and weight of the patient, and generally 1 to 100 mg per kg of body weight, preferably 5 to 60 mg, is administered daily or every other day, or 1 It can be administered in divided doses 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, disease severity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
  • the term "individual” means monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, It means all animals, including cats, dogs, mice, mice, rabbits, or guinea pigs, and by administering the pharmaceutical composition of the present invention to an individual, the disease can be effectively prevented or treated.
  • the pharmaceutical composition of the present invention may be administered in parallel with a conventional therapeutic agent.
  • administration means providing a predetermined substance to a patient by any suitable method, and the administration route of the composition of the present invention may be administered through any general route as long as it can reach the target tissue.
  • Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration may be administered intrarectally, but is not limited thereto.
  • the pharmaceutical composition of the present invention may be administered by any device capable of transporting an active substance to a target cell.
  • Preferred administration modes and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections, and the like.
  • aqueous solvents such as physiological saline solution and Ringer's solution, vegetable oil, higher fatty acid esters (eg, ethyl oleate), and non-aqueous solvents such as alcohols (eg, ethanol, benzyl alcohol, propylene glycol, glycerin, etc.)
  • Stabilizers for preventing deterioration e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.
  • emulsifiers e.g., buffers for pH control, to inhibit microbial growth
  • Pharmaceutical carriers such as preservatives (eg, phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.
  • terapéuticaally effective amount used in combination with an active ingredient in the present invention means an amount of an oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof effective for preventing or treating a target disease.
  • the pharmaceutical composition of the present invention may be used for the prevention or treatment of known diseases other than oxadiazole phenylalanine derivatives, isomers thereof, or pharmaceutically acceptable salts thereof as an active ingredient, depending on the type of disease to be prevented or treated. It may further include a known drug used. For example, when used for the prevention or treatment of cancer diseases, as an active ingredient, an oxadiazole phenylalanine derivative, an isomer thereof, or a known drug in addition to a pharmaceutically acceptable salt thereof may be additionally included, and the treatment of these diseases It can be used in combination with other treatments known for
  • Step 1-1 Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid
  • Step 1-2 Preparation of ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoate
  • Step 1-3 Preparation of (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(4-(N'-hydroxycarbamimidoyl)phenyl)propanoate
  • the product was purified by silica gel column chromatography with ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(N-hydroxycarbamiimidoyl)phenyl)propanoate (2.49 g , 90%) as a white solid.
  • Step 1-4 Preparation of methyl 4'-hydroxy-6-methoxybiphenyl-3-carboxylate
  • Step 1-5 Preparation of 4'-hydroxy-6-methoxybiphenyl-3-carboxylic acid
  • Step 1-6 Preparation of 4'-acetoxy-6-methoxybiphenyl-3-carboxylic acid
  • Step 1-7 (S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamimidoyl)phenyl)-2-(tert-butoxy Preparation of carbonylamino) propanoate
  • Step 1-8 (S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamimidoyl)phenyl)-2-(tert-butoxy Preparation of carbonylamino) propanoate
  • reaction mixture was purified by column chromatography (S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamimidoyl)phenyl)-2-( tert-butoxycarbonylamino)propanoate (1.94 g, 78%) was obtained as a white solid.
  • Step 1-9 (S)-2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1, Preparation of 2,4-oxadiazol-3-yl)phenyl)propanoic acid
  • Step 1-10 (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole- Preparation of 3-yl)phenyl)propanoic acid hydrochloride
  • Step 2-1 (S)-Ethyl 2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1 Preparation of ,2,4-oxadiazol-3-yl)phenyl)propanoate
  • Step 2-2 (S)-Ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole Preparation of -3-yl)phenyl)propanoate hydrochloride
  • Step 3-1 (S)-tert-Butyl 1-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxa Preparation of diazol-3-yl)phenyl)-1-oxopropan-2-ylcarbamate
  • Step 3-2 (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole- Preparation of 3-yl)phenyl)propanamide hydrochloride
  • Examples 1 to 43 were prepared in a manner similar to Preparation Examples 1 to 3, and the chemical structural formulas and compound names of the synthesized compounds are shown in Table 1 below.
  • TPH1 TRYPTOPHAN HYDROXYLASE 1 Inhibitor Screening Assay Kit (BPS Bioscience, Catalog # 72053) was used. and tested.
  • the TPH1 Inhibitor Screening Assay Kit was used according to the manufacturer's manual, and the results are shown in Table 3 below.
  • the synthesized compound was placed in a 96-well microplate, and 40 ⁇ L of TPH1 enzyme was added. Then, after adding 50 ⁇ L of TPH1 reaction solution, the microplate was shielded from light with aluminum foil. The microplate was transferred to a 4°C environment, shaken carefully, and incubated for 4 hours. Then, 10 ⁇ L of quench solution was added and TPH1 activity was measured by reading the degree of fluorescence in a Flexstation3 microplate reader. At this time, the excitation spectrum was measured at a wavelength of 300 nm, and the emission spectrum was measured at a wavelength of 360 nm.
  • Example TPH1 activity (% inhibition at 1 ⁇ M)
  • Example TPH1 activity (% inhibition at 1 ⁇ M)
  • One ⁇ 5 23 ⁇ 5 2 53.5 24 80.7 3 ⁇ 5 25 90.7 4 ⁇ 5 26 96.7 5 ⁇ 5 27 98.8 6 67.6 28 97.0 7 47.0 29 30.1 8 86.3 30 44.8 9 84.9 31 43.5 10
  • 39.3 32 ⁇ 5 11 ⁇ 5 33 ⁇ 5 12 6.1 34 ⁇ 5 13 ⁇ 5 35 ⁇ 5 14 41.5 36 12.2 15 42.4
  • 40 ⁇ 5 19 100 41 ⁇ 5 20 32.2 42 17.7 21 100 43 78.7 22 7.4
  • the compound represented by Formula 1 according to the present invention has an excellent inhibitory effect on TPH1, so it is useful for preventing or treating metabolic diseases, cancer, digestive system diseases, or circulatory system diseases, which are diseases related to TPH1 activity. can be used

Abstract

The present invention relates to a novel oxadiazole phenylalanine derivative and a medical use thereof. A novel tryptophan hydroxylase inhibitor and a pharmaceutical composition, which contain same, inhibit the synthesis of serotonin in the peripheral nervous system by inhibiting the activity of tryptophan hydroxylase 1. Therefore, the present invention does not stimulate the central nervous system and activates metabolic activity in the peripheral tissues, and thus can be effectively used in the prevention or treatment of metabolic diseases.

Description

신규한 트립토판 수산화효소 저해제 및 이의 용도Novel tryptophan hydroxylase inhibitors and uses thereof
본 발명은 신규한 옥사디아졸 페닐알라닌 유도체 및 이의 의약 용도에 관한 것이다.The present invention relates to novel oxadiazole phenylalanine derivatives and medicinal uses thereof.
비만이란 체내에 지방조직이 비정상적이거나 과다하게 축적된 상태를 의미한다. 비만은 오랜 기간 동안 에너지 소비량에 비해 영양소를 과다 섭취할 경우 유발될 수 있다. 비만을 측정하는 간단한 지수로는 체중/키의 제곱(kg/m2)으로 정의되는 체질량지수(BMI: Body Mass Index)가 있다. 세계보건기구(World Health Organization)에 따르면 상기 BMI가 30 이상의 성인은 과체중 및 비만으로 분류된다. 또한, 비만은 2013년 이후로 비만은 질병으로 분류되었으며, 제2형 당뇨병, 심혈관 질환, 고혈압, 뇌졸중, 대장암, 유방암, 난소암 등과 같은 합병증을 유발할 수 있다.Obesity refers to an abnormal or excessive accumulation of adipose tissue in the body. Obesity can be caused by excessive intake of nutrients relative to energy expenditure over a long period of time. A simple index for measuring obesity is body mass index (BMI), which is defined as weight/height squared (kg/m 2 ). According to the World Health Organization, adults with a BMI of 30 or more are classified as overweight and obese. In addition, obesity has been classified as a disease since 2013, and may cause complications such as type 2 diabetes, cardiovascular disease, high blood pressure, stroke, colorectal cancer, breast cancer, and ovarian cancer.
이러한 비만의 치료방법으로는 식이요법, 운동, 약물 치료, 외과적 수술 방법이 있다. 구체적으로, 약물 치료에 사용되는 약물은 중추 신경에 작용하는 비만 치료제와 말초 신경에 작용하는 비만 치료제로 분류할 수 있다. 기존의 비만 치료제는 중추 신경계에 존재하는 세로토닌을 억제하여 식욕을 억제하는 치료제이다. 하지만, 중추 신경에 존재하는 세로토닌은 식욕 이외에도 기분, 수면 및 기억에 영향을 미칠 수 있다. 한편, 중추 신경계에 작용하는 기존의 비만 치료제의 경우 두통, 초조, 긴장감, 우울증과 같은 부작용이 보고된 바 있다.The treatment methods for obesity include diet, exercise, drug treatment, and surgical methods. Specifically, the drug used for drug treatment can be classified into an anti-obesity agent acting on the central nerve and an anti-obesity agent acting on the peripheral nerve. Existing obesity treatment is a treatment that suppresses appetite by suppressing serotonin present in the central nervous system. However, serotonin, present in the central nervous system, can affect mood, sleep and memory in addition to appetite. On the other hand, side effects such as headache, agitation, tension, and depression have been reported for existing anti-obesity drugs acting on the central nervous system.
세로토닌은 중추 신경계 및 말초 신경계에 작용하는 모노아민계 화합물로서, 이의 합성은 아미노산인 트립토판으로부터 시작되는데, 통상 트립토판의 수산화, 탈카르복실화 순으로 합성이 진행된다. 이러한 과정에서 트립토판 수산화 효소(tryptophan hydroxlase; TPH)가 속도조절 효소로 작용할 수 있다. 이는, 트립토판 수산화효소를 억제함으로써 세로토닌의 합성을 억제할 수 있음을 시사한다.Serotonin is a monoamine-based compound that acts on the central nervous system and the peripheral nervous system, and its synthesis starts from tryptophan, an amino acid, and the synthesis proceeds in the order of hydroxylation and decarboxylation of tryptophan. In this process, tryptophan hydroxlase (TPH) may act as a rate-regulating enzyme. This suggests that the synthesis of serotonin can be inhibited by inhibiting tryptophan hydroxylase.
이러한 세로토닌은 혈액뇌장벽(blood brain barrier; BBB)를 통과하지 못하며, 중추 신경계와 말초 신경계에서 각각 합성된다. 트립토판 수산화효소에는 두 가지 동형 단백질이 존재하는데, 이중 트립토판 수산화효소 1(tryptophan hydroxylase 1; TPH1)은 주로 말초 조직에서 발현되며, 트립토판 수산화효소 2(tryptophan hydroxylase 2; TPH2)는 장 및 중추신경계의 신경세포에서 발현된다. 상기 세로토닌은 혈액뇌장벽(BBB)을 통과할 수 없으므로 말초 세로토닌 시스템은 중추 세로토닌 시스템과 기능적으로 별개이다. 말초신경계에서 세로토닌은 말초 조직의 대사 조절에 중요한 역할을 한다.This serotonin does not pass through the blood brain barrier (BBB), and is synthesized in the central nervous system and the peripheral nervous system, respectively. There are two isoforms of tryptophan hydroxylase. Of these, tryptophan hydroxylase 1 (TPH1) is mainly expressed in peripheral tissues, and tryptophan hydroxylase 2 (TPH2) is a neurotransmitter in the intestine and central nervous system. expressed in cells. Since the serotonin cannot cross the blood-brain barrier (BBB), the peripheral serotonin system is functionally distinct from the central serotonin system. In the peripheral nervous system, serotonin plays an important role in the metabolic regulation of peripheral tissues.
구체적으로, 말초 조직에서 세로토닌이 과다 분비될 경우, 에너지를 연소시키는 갈색지방 세포의 활동을 방해한다. 따라서, 말초신경계에 존재하는 세로토닌의 합성을 억제하면 말초 조직의 대사를 활성화시킬 수 있고, 따라서 말초신경 내 세로토닌의 합성 억제는 뇌를 자극하거나 식욕을 억제하지 않으면서 체중 증가 억제에 도움을 줄 수 있다.Specifically, when serotonin is excessively secreted from peripheral tissues, it interferes with the activity of brown fat cells that burn energy. Therefore, inhibiting the synthesis of serotonin present in the peripheral nervous system can activate the metabolism of peripheral tissues. have.
본 발명의 하나의 목적은 신규한 옥사디아졸 페닐알라닌 유도체, 이의 이성질체, 또는 이들의 약학적으로 허용 가능한 염을 제공하는 것이다.One object of the present invention is to provide a novel oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof.
본 발명의 다른 하나의 목적은 상기 옥사디아졸 페닐알라닌 유도체, 이의 이성질체, 또는 이들의 약학적으로 허용 가능한 염의 제조방법을, 제공하는 것이다.Another object of the present invention is to provide a method for preparing the oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 하나의 목적은 상기 옥사디아졸 페닐알라닌 유도체, 이의 이성질체, 또는 이들의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 트립토판 수산화효소 저해용 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for inhibiting tryptophan hydroxylase comprising the oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 하나의 목적은 상기 옥사디아졸 페닐알라닌 유도체, 이의 이성질체, 또는 이들의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 대사성 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases comprising the oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 하나의 목적은 상기 약학적 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는 대사성 질환의 예방 또는 치료 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating a metabolic disease comprising administering the pharmaceutical composition to an individual in need thereof.
본 발명의 또 다른 하나의 목적은 상기 옥사디아졸 페닐알라닌 유도체, 이의 이성질체, 또는 이들의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 암 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising the oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 하나의 목적은 상기 약학적 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는 암 질환의 예방 또는 치료 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating cancer, comprising administering the pharmaceutical composition to an individual in need thereof.
본 발명의 신규한 트립토판 수산화효소 저해제 및 이를 포함하는 약학 조성물은 트립토판 수산화효소 1의 활성을 억제함으로써 말초신경계에서 세로토닌의 합성을 억제한다. 따라서, 중추신경계를 자극하지 않으며, 말초 조직의 대사 활동을 활성화시키므로 대사성 질환의 예방 또는 치료에 유용하게 사용될 수 있다.The novel tryptophan hydroxylase inhibitor of the present invention and a pharmaceutical composition comprising the same inhibit the synthesis of serotonin in the peripheral nervous system by inhibiting the activity of tryptophan hydroxylase 1. Therefore, it does not stimulate the central nervous system and activates the metabolic activity of peripheral tissues, so it can be usefully used for the prevention or treatment of metabolic diseases.
본 발명에서 개시되는 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본 발명에서 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기 기술되는 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 할 수 없다.Each description and embodiment disclosed in the present invention is also applicable to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be said that the scope of the present invention is limited by the specific descriptions described below.
또한, 당해 기술분야의 통상의 지식을 가진 자는 통상의 실험만을 사용하여 본 발명에 기재된 본 발명의 특정 양태에 대한 다수의 등가물을 인지하거나 확인할 수 있다. 또한, 이러한 등가물은 본 발명에 포함되는 것으로 의도된다.In addition, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Also, such equivalents are intended to be encompassed by the present invention.
아울러, 본 발명의 명세서 전체에 있어서, 어떤 부분이 어떤 구성 요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In addition, throughout the specification of the present invention, when a part "includes" a certain component, it does not exclude other components unless otherwise stated, but may further include other components. it means.
이하, 본 발명을 보다 자세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 제1양태는 하기 화학식 1로 표시되는 화합물, 이의 이성질체, 또는 이들의 약학적으로 허용 가능한 염을 제공한다:A first aspect of the present invention provides a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2022000339-appb-img-000001
Figure PCTKR2022000339-appb-img-000001
상기 화학식 1에서,In Formula 1,
n은 0 내지 2의 정수,n is an integer from 0 to 2,
R1은 히드록시, 아미노, C1-6 알콕시, 히드록시-C1-4 알콕시, 또는 히드록시-아미노,R 1 is hydroxy, amino, C 1-6 alkoxy, hydroxy-C 1-4 alkoxy, or hydroxy-amino,
R2 내지 R6은 각각 독립적으로 수소, 히드록시, 니트로, 시아노, 할로, C1-6 할로알킬, C1-6 알콕시, C1-6 할로알콕시, C1-4 알킬아미노, 디(C1-4 알킬)아미노, C1-4 알킬카보닐, C1-4 알킬카보닐아미노, C6-10 아릴카보닐아미노, C6-14 아릴, C6-10 아릴-C1-4 알킬, C6-10 아릴-C1-4 알콕시, C1-4 알콕시-C6-10 아릴, 또는R 2 To R 6 are each independently hydrogen, hydroxy, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-4 alkylamino, di( C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonylamino, C 6-10 arylcarbonylamino, C 6-14 aryl, C 6-10 aryl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkoxy, C 1-4 alkoxy-C 6-10 aryl, or
R3 및 R4가 서로 연결되어 C3-14 헤테로사이클릴, 또는 C5-14 헤테로아릴을 형성하고,R 3 and R 4 are linked to each other to C 3-14 heterocyclyl, or form C 5-14 heteroaryl;
상기 아릴, 헤테로아릴 및 헤테로사이클릴은 각각 독립적으로 비치환 또는 히드록시, 옥소, C1-4 알콕시, 또는 C1-4 할로알킬로 치환됨.wherein said aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with hydroxy, oxo, C 1-4 alkoxy, or C 1-4 haloalkyl.
예컨대, 상기 화학식 1에서, n은 0 또는 1일 수 있으나, 이에 제한되지 않는다.For example, in Formula 1, n may be 0 or 1, but is not limited thereto.
예컨대, 상기 화학식 1에서, R1은 히드록시, 아미노, 에톡시, 히드록시에톡시, 또는 히드록시아미노일 수 있으나, 이에 제한되지 않는다.For example, in Formula 1, R 1 may be hydroxy, amino, ethoxy, hydroxyethoxy, or hydroxyamino, but is not limited thereto.
예컨대, 상기 화학식 1에서, R2는 수소, 페닐, 히드록시페닐, 또는 메톡시페닐일 수 있으나, 이에 제한되지 않는다.For example, in Formula 1, R 2 may be hydrogen, phenyl, hydroxyphenyl, or methoxyphenyl, but is not limited thereto.
예컨대, 상기 화학식 1에서, R3은 수소, 브로모, 니트로, 메톡시, 페닐, 히드록시페닐, 또는 메톡시페닐일 수 있으나, 이에 제한되지 않는다.For example, in Formula 1, R 3 may be hydrogen, bromo, nitro, methoxy, phenyl, hydroxyphenyl, or methoxyphenyl, but is not limited thereto.
예컨대, 상기 화학식 1에서, R4는 수소, 히드록시, 니트로, 시아노, 플루오로, 브로모, 아이오도, 메톡시, 에톡시, 아세틸, 메틸카보닐아미노, 페닐카보닐아미노, 페닐메톡시, 페닐메틸, 디메틸아미노, 트리플루오로메틸, 또는 트리플루오로메톡시일 수 있으나, 이에 제한되지 않는다.For example, in Formula 1, R 4 is hydrogen, hydroxy, nitro, cyano, fluoro, bromo, iodo, methoxy, ethoxy, acetyl, methylcarbonylamino, phenylcarbonylamino, phenylmethoxy , phenylmethyl, dimethylamino, trifluoromethyl, or trifluoromethoxy, but is not limited thereto.
또는, 상기 R3 및 R4는 서로 연결되어 디옥솔라닐, 디옥사닐, 피라졸릴, 피롤린, 또는 벤조퓨라닐을 형성할 수 있으나, 이에 제한되지 않는다.Alternatively, R 3 and R 4 may be connected to each other to form dioxolanyl, dioxanyl, pyrazolyl, pyrroline, or benzofuranyl, but is not limited thereto.
예컨대, 상기 화학식 1에서, R5 및 R6은 모두 수소일 수 있으나, 이에 제한되지 않는다.For example, in Formula 1, R 5 and R 6 may both be hydrogen, but is not limited thereto.
구체적으로, 상기 화합물은Specifically, the compound is
1. (S)-2-아미노-3-(4-(5-페닐-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),1. (S)-2-amino-3-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2-amino-3-( 4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
2. (S)-2-아미노-3-(4-(5-(4-메톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),2. (S)-2-amino-3-(4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
3. (S)-2-아미노-3-(4-(5-(3-메톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),3. (S)-2-amino-3-(4-(5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
4. (S)-2-아미노-3-(4-(5-(4-히드록시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),4. (S)-2-amino-3-(4-(5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
5. (S)-2-아미노-3-(4-(5-(4-에톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),5. (S)-2-amino-3-(4-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
6. (S)-2-아미노-3-(4-(5-(3,4-디메톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),6. (S)-2-amino-3-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S) -2-amino-3-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
7. (S)-2-아미노-3-(4-(5-(4-플루오로페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),7. (S)-2-amino-3-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
8. (S)-2-아미노-3-(4-(5-(4-브로모페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),8. (S)-2-amino-3-(4-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
9. (S)-2-아미노-3-(4-(5-(4-아이오도페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-iodophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),9. (S)-2-amino-3-(4-(5-(4-iodophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-iodophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
10. (S)-2-아미노-3-(4-(5-(4-(트리플루오로메틸)페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),10. (S)-2-amino-3-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (( S)-2-amino-3-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
11. (S)-2-아미노-3-(4-(5-(4-(트리플루오로메톡시)페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),11. (S)-2-amino-3-(4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (( S)-2-amino-3-(4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
12. (S)-2-아미노-3-(4-(5-(4-시아노페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),12. (S)-2-amino-3-(4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
13. (S)-3-(4-(5-(4-아세틸페닐)-1,2,4-옥사디아졸-3-일)페닐)-2-아미노프로판산((S)-3-(4-(5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),13. (S)-3-(4-(5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S)-3- (4-(5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),
14. (S)-2-아미노-3-(4-(5-(4-니트로페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),14. (S)-2-amino-3-(4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2- amino-3-(4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
15. (S)-2-아미노-3-(4-(5-(4-메톡시-3-니트로페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-methoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),15. (S)-2-amino-3-(4-(5-(4-methoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (( S)-2-amino-3-(4-(5-(4-methoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
16. (S)-2-아미노-3-(4-(5-(4-메톡시벤질)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),16. (S)-2-amino-3-(4-(5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
17. (S)-2-아미노-3-(4-(5-(3-브로모-4-메톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(3-bromo-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),17. (S)-2-amino-3-(4-(5-(3-bromo-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ( (S)-2-amino-3-(4-(5-(3-bromo-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
18. (S)-2-아미노-3-(4-(5-(6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),18. (S)-2-amino-3-(4-(5-(6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ( (S)-2-amino-3-(4-(5-(6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
19. (S)-2-아미노-3-(4-(5-(4',6-디메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),19. (S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
20. (S)-2-아미노-3-(4-(5-(4'-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4'-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),20. (S)-2-amino-3-(4-(5-(4'-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(4'-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
21. (S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),21. (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),
22. (S)-2-아미노-3-(4-(5-(4',6-디메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판아미드((S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide),22. (S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanamide ((S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide),
23. (S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판아미드((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide),23. (S)-2-Amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanamide ((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl )propanamide),
24. (S)-에틸 2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로파노에이트((S)-ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate),24. (S)-Ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole-3- yl)phenyl)propanoate ((S)-ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3- yl)phenyl)propanoate),
25. (S)-2-아미노-3-(4-(5-(3',6-디메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(3',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),25. (S)-2-amino-3-(4-(5-(3',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(3',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
26. (S)-2-아미노-3-(4-(5-(3'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(3'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),26. (S)-2-amino-3-(4-(5-(3'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(3'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),
27. (S)-2-아미노-3-(4-(5-(2',6-디메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(2',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),27. (S)-2-amino-3-(4-(5-(2',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(2',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
28. (S)-2-아미노-3-(4-(5-(2'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(2'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),28. (S)-2-amino-3-(4-(5-(2'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(2'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),
29. (S)-2-아미노-3-(4-(5-(5-메톡시바이페닐-2-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),29. (S)-2-amino-3-(4-(5-(5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ( (S)-2-amino-3-(4-(5-(5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
30. (S)-2-아미노-3-(4-(5-(4',5-디메톡시바이페닐-2-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4',5-dimethoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),30. (S)-2-amino-3-(4-(5-(4',5-dimethoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(4',5-dimethoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
31. (S)-2-아미노-3-(4-(5-(4'-히드록시-5-메톡시바이페닐-2-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4'-hydroxy-5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),31. (S)-2-amino-3-(4-(5-(4'-hydroxy-5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(4'-hydroxy-5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),
32. (S)-3-(4-(5-(1H-인돌-6-일)-1,2,4-옥사디아졸-3-일)페닐)-2-아미노프로판산((S)-3-(4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),32. (S)-3-(4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S) -3-(4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),
33. (S)-3-(4-(5-(1H-인다졸-6-일)-1,2,4-옥사디아졸-3-일)페닐)-2-아미노프로판산((S)-3-(4-(5-(1H-indazol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),33. (S)-3-(4-(5-(1H-indazol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S) )-3-(4-(5-(1H-indazol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),
34. (S)-2-아미노-3-(4-(5-(2,3-디하이드로벤조[b][1,4]디옥신-6-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),34. (S)-2-amino-3-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,4-oxadia zol-3-yl)phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1, 2,4-oxadiazol-3-yl)phenyl)propanoic acid),
35. (S)-2-아미노-3-(4-(5-(벤조[d][1,3]디옥솔-5-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),35. (S)-2-amino-3-(4-(5-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-3-yl) Phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-3-yl) phenyl) propanoic acid),
36. (S)-2-아미노-3-(4-(5-(디벤조[b,d]퓨란-2-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(dibenzo[b,d]furan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),36. (S)-2-amino-3-(4-(5-(dibenzo[b,d]furan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propane acid ((S)-2-amino-3-(4-(5-(dibenzo[b,d]furan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
37. (S)-2-아미노-3-(4-(5-(4-(디메틸아미노)페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-(dimethylamino)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),37. (S)-2-amino-3-(4-(5-(4-(dimethylamino)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S) -2-amino-3-(4-(5-(4-(dimethylamino)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
38. (S)-2-아미노-3-(4-(5-(4-벤질페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),38. (S)-2-amino-3-(4-(5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2- amino-3-(4-(5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
39. (S)-2-아미노-3-(4-(5-(4-(벤질옥시)페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),39. (S)-2-amino-3-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S) -2-amino-3-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
40. (S)-3-(4-(5-(4-아세트아미도페닐)-1,2,4-옥사디아졸-3-일)페닐)-2-아미노프로판산((S)-3-(4-(5-(4-acetamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),40. (S)-3-(4-(5-(4-acetamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S)- 3-(4-(5-(4-acetamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),
41. (S)-2-아미노-3-(4-(5-(4-벤즈아미도페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-benzamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),41. (S)-2-amino-3-(4-(5-(4-benzamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)- 2-amino-3-(4-(5-(4-benzamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
42. (S)-2-아미노-N-히드록시-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판아미드((S)-2-amino-N-hydroxy-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide), 또는42. (S)-2-Amino-N-hydroxy-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadia zol-3-yl)phenyl)propanamide ((S)-2-amino-N-hydroxy-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2, 4-oxadiazol-3-yl)phenyl)propanamide), or
43. (S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)-N-(2-히드록시에톡시)프로판아미드((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(2-hydroxyethoxy)propanamide)일 수 있으나, 이에 제한되지 않는다.43. (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)-N-(2-hydroxyethoxy)propanamide ((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1, 2,4-oxadiazol-3-yl)phenyl)-N-(2-hydroxyethoxy)propanamide), but is not limited thereto.
예컨대, 본 발명의 화합물은 약학적으로 허용 가능한 염의 형태로 존재할 수 있다. 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산가염이 유용하다. 본 발명의 용어 "약학적으로 허용 가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 상기 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기 또는 무기 부가염을 의미한다.For example, the compound of the present invention may exist in the form of a pharmaceutically acceptable salt. As the salt, an acid value formed by a pharmaceutically acceptable free acid is useful. As used herein, the term "pharmaceutically acceptable salt" refers to a concentration having an effective action that is relatively non-toxic and harmless to a patient. any and all organic or inorganic addition salts.
산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올(예, 글리콜 모노메틸에테르)을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and an acid or alcohol (eg glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 요오드화수소산(hydroiodic acid) 등을 사용할 수 있으며, 이들에 제한되지 않는다.At this time, organic acids and inorganic acids can be used as free acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid as organic acids (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used. , but not limited to these.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto. Also, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
본 발명의 화합물의 약학적으로 허용 가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용 가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용 가능한 염으로는 히드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄술포네이트(메실레이트) 및 p-톨루엔술포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group, and other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, and hydrogen phosphate. , dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and the like, and preparation of salts known in the art It can be prepared through a method.
본 발명의 옥사디아졸 페닐알라닌 유도체, 또는 이의 이성질체의 염은 약학적으로 허용 가능한 염으로서, 옥사디아졸 페닐알라닌 유도체, 또는 이의 이성질체와 동등한 약리활성을 나타내는 옥사디아졸 페닐알라닌 유도체, 또는 이의 이성질체의 염이면 제한없이 모두 사용 가능하다.The oxadiazole phenylalanine derivative or salt of an isomer thereof of the present invention is a pharmaceutically acceptable salt, if it is an oxadiazole phenylalanine derivative or a salt of an isomer thereof that exhibits pharmacological activity equivalent to that of the oxadiazole phenylalanine derivative or an isomer thereof. All are available without restrictions.
또한, 본 발명의 화합물은, 이의 약학적으로 허용 가능한 염뿐만 아니라 이로부터 제조될 수 있는 가능한 수화물 등의 용매화물 및 가능한 모든 입체 이성질체를 제한없이 포함한다. 상기 화합물의 용매화물 및 입체이성질체는 당업계에 공지된 방법을 사용하여 본 발명의 화합물로부터 제조할 수 있다.In addition, the compounds of the present invention include, without limitation, pharmaceutically acceptable salts thereof, as well as solvates such as possible hydrates and all possible stereoisomers that can be prepared therefrom. Solvates and stereoisomers of the compounds can be prepared from the compounds of the present invention using methods known in the art.
나아가, 본 발명의 화합물은 결정 형태 또는 비결정 형태로 제조될 수 있으며, 결정 형태로 제조될 경우 임의로 수화되거나 용매화될 수 있다. 본 발명에서는 상기 화합물의 화학양론적 수화물뿐만 아니라 다양한 양의 물을 함유하는 화합물이 포함될 수 있다. 본 발명의 화합물의 용매화물은 화학양론적 용매화물 및 비화학양론적 용매화물 모두를 포함한다.Furthermore, the compounds of the present invention may be prepared in crystalline or amorphous form, and when prepared in crystalline form, may optionally be hydrated or solvated. In the present invention, not only stoichiometric hydrates of the above compounds, but also compounds containing various amounts of water may be included. Solvates of the compounds of the present invention include both stoichiometric and non-stoichiometric solvates.
본 발명의 제2양태는 하기 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 합성하는 제1단계; 및 이전 단계로부터 수득한 화학식 4로 표시되는 화합물을 화학식 1로 표시되는 화합물로 전환하는 제2단계;를 포함하는, 화학식 1로 표시되는 화합물의 제조방법을 제공한다:A second aspect of the present invention is a first step of synthesizing a compound represented by Formula 4 by reacting a compound represented by Formula 2 with a compound represented by Formula 3; and a second step of converting the compound represented by Formula 4 obtained from the previous step into the compound represented by Formula 1; provides a method for preparing a compound represented by Formula 1, including:
[화학식 1][Formula 1]
Figure PCTKR2022000339-appb-img-000002
Figure PCTKR2022000339-appb-img-000002
[화학식 2][Formula 2]
Figure PCTKR2022000339-appb-img-000003
Figure PCTKR2022000339-appb-img-000003
[화학식 3][Formula 3]
Figure PCTKR2022000339-appb-img-000004
Figure PCTKR2022000339-appb-img-000004
[화학식 4][Formula 4]
Figure PCTKR2022000339-appb-img-000005
Figure PCTKR2022000339-appb-img-000005
상기 화학식 1 내지 4에 있어서,In Formulas 1 to 4,
n은 0 내지 2의 정수,n is an integer from 0 to 2,
R1은 히드록시, 아미노, C1-6 알콕시, 히드록시-C1-4 알콕시, 또는 히드록시-아미노,R 1 is hydroxy, amino, C 1-6 alkoxy, hydroxy-C 1-4 alkoxy, or hydroxy-amino,
R2 내지 R6은 각각 독립적으로 수소, 히드록시, 니트로, 시아노, 할로, C1-6 할로알킬, C1-6 알콕시, C1-6 할로알콕시, C1-4 알킬아미노, 디(C1-4 알킬)아미노, C1-4 알킬카보닐, C1-4 알킬카보닐아미노, C6-10 아릴카보닐아미노, C6-14 아릴, C6-10 아릴-C1-4 알킬, C6-10 아릴-C1-4 알콕시, C1-4 알콕시-C6-10 아릴, 또는R 2 To R 6 are each independently hydrogen, hydroxy, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-4 alkylamino, di( C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonylamino, C 6-10 arylcarbonylamino, C 6-14 aryl, C 6-10 aryl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkoxy, C 1-4 alkoxy-C 6-10 aryl, or
R3 및 R4가 서로 연결되어 C3-14 헤테로사이클릴, 또는 C5-14 헤테로아릴을 형성하고,R 3 and R 4 are linked to each other to C 3-14 heterocyclyl, or form C 5-14 heteroaryl;
R2' 내지 R6'은 각각 R2 내지 R6와 동일하거나, 이들의 전구체이며,R 2 ' to R 6 ' are each the same as R 2 to R 6 or a precursor thereof,
상기 아릴, 헤테로아릴 및 헤테로사이클릴은 각각 독립적으로 비치환 또는 히드록시, 옥소, C1-4 알콕시, 또는 C1-4 할로알킬로 치환됨.wherein said aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with hydroxy, oxo, C 1-4 alkoxy, or C 1-4 haloalkyl.
본 발명의 용어, "약학적으로 허용 가능한 염"은 상기에서 설명한 바와 같다.As used herein, the term "pharmaceutically acceptable salt" is as described above.
예컨대, 제1단계의 반응은, 상기 반응물을 1-에틸-3-(3-디메틸아미노프로필)카보디이미드(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDCI), 히드록시벤조트리아졸(hydroxybenzotriazole; HOBt), 및 N,N-디이소프로필에틸아민(N,N-diisopropylethylamine; DIPEA) 존재 하에 10 내지 35℃에서 12 내지 24시간 동안 반응시키고, 수득한 생성물을 12 내지 24시간 동안 환류시켜 수행할 수 있으나, 이에 제한되지 않는다. 상기 반응은 유기 용매에 용해시킨 용액 상에서 수행할 수 있으며, 각 반응에 사용되는 용매는 서로 같거나 상이할 수 있다. 예컨대, 중간체로서 생성되는 물질은 분리, 및/또는 정제하여 이후 반응에 사용하거나, 추가적인 처리 공정 없이 조 생성물 상태로 이후 반응에 사용할 수 있다. 예컨대, 본 발명의 일 실시예에서는 디클로로메탄 용액 상에서 EDCI, HOBt, 및 DIPEA와 반응시켜 수득한 생성물을 분리 및 정제하여 흰색 고체로 수득한 후, 이를 1,4-다이옥산에 용해시켜 이후 반응을 수행하였다. 그러나, 이는 합성방법의 예시일 뿐, 본 발명의 범주가 이에 제한되는 것은 아니다.For example, in the reaction of the first step, the reactant is reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (hydroxybenzotriazole; HOBt), and N,N-diisopropylethylamine (N,N-diisopropylethylamine; DIPEA) in the presence of 10 to 35 ℃ reacted for 12 to 24 hours, the obtained product was refluxed for 12 to 24 hours can be performed, but is not limited thereto. The reaction may be performed on a solution dissolved in an organic solvent, and the solvents used in each reaction may be the same or different from each other. For example, a material produced as an intermediate may be isolated and/or purified and used in a subsequent reaction, or may be used in a subsequent reaction as a crude product without additional treatment. For example, in one embodiment of the present invention, the product obtained by reacting with EDCI, HOBt, and DIPEA in a dichloromethane solution is isolated and purified to obtain a white solid, and then it is dissolved in 1,4-dioxane to carry out the reaction did. However, this is only an example of a synthesis method, and the scope of the present invention is not limited thereto.
예컨대, 상기 화학식 2로 표시되는 화합물 중 R2' 내지 R6'에 아릴기를 통해 결합된 치환기를 포함하는 화합물은 R2' 내지 R6'의 보론산 유도체를 해당 치환기가 결합된 자리에 할로겐이 치환된 화학식 2의 화합물의 유도체와 반응시켜 준비할 수 있으나, 이에 제한되지 않는다.For example, in the compound represented by Formula 2, a compound including a substituent bonded to R 2 ' to R 6 ' through an aryl group is a boronic acid derivative of R 2 ' to R 6 ', in which a halogen is It may be prepared by reaction with a substituted derivative of the compound of Formula 2, but is not limited thereto.
상기 반응의 하기 예시한 일련의 반응과 유사하게 수행될 수 있으나, 이에 제한되지 않는다. 아래 예시한 반응은 특정 치환기를 갖는 화합물에 대한 합성예로서, 본 발명의 범주는 이에 제한되지 않는다.The reaction may be performed similarly to the series of reactions exemplified below, but is not limited thereto. The reaction exemplified below is a synthesis example for a compound having a specific substituent, and the scope of the present invention is not limited thereto.
[단계 a1][Step a1]
Figure PCTKR2022000339-appb-img-000006
Figure PCTKR2022000339-appb-img-000006
[단계 a2][Step a2]
Figure PCTKR2022000339-appb-img-000007
Figure PCTKR2022000339-appb-img-000007
[단계 a3][Step a3]
Figure PCTKR2022000339-appb-img-000008
Figure PCTKR2022000339-appb-img-000008
예컨대, 상기 화학식 3으로 표시되는 화합물은 (S)-2-아미노-3-(4-시아노페닐)프로판산으로부터 준비될 수 있으나, 이에 제한되지 않는다.For example, the compound represented by Formula 3 may be prepared from (S)-2-amino-3-(4-cyanophenyl)propanoic acid, but is not limited thereto.
상기 반응의 하기 예시한 일련의 반응과 유사하게 수행될 수 있으나, 이에 제한되지 않는다. 아래 예시한 반응은 특정 치환기를 갖는 화합물에 대한 합성예로서, 본 발명의 범주는 이에 제한되지 않는다.The reaction may be performed similarly to the series of reactions exemplified below, but is not limited thereto. The reaction exemplified below is a synthesis example for a compound having a specific substituent, and the scope of the present invention is not limited thereto.
[단계 b1][Step b1]
Figure PCTKR2022000339-appb-img-000009
Figure PCTKR2022000339-appb-img-000009
[단계 b2][Step b2]
Figure PCTKR2022000339-appb-img-000010
Figure PCTKR2022000339-appb-img-000010
[단계 b3][Step b3]
Figure PCTKR2022000339-appb-img-000011
Figure PCTKR2022000339-appb-img-000011
본 발명의 화합물, 이의 이성질체, 또는 이들의 약학적으로 허용 가능한 염은 하기 반응식 1 또는 2로 예시되는 일련의 반응을 통해 제조될 수 있으나, 이에 제한되지 않는다:The compound of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof may be prepared through a series of reactions exemplified by Scheme 1 or 2 below, but is not limited thereto:
[반응식 1][Scheme 1]
Figure PCTKR2022000339-appb-img-000012
Figure PCTKR2022000339-appb-img-000012
[반응식 2][Scheme 2]
Figure PCTKR2022000339-appb-img-000013
.
Figure PCTKR2022000339-appb-img-000013
.
상기 반응식 1 및 2는 제조방법의 구체적인 예시일 뿐 본 발명의 범주가 이에 제한되는 것은 아니다.Schemes 1 and 2 are only specific examples of the preparation method, and the scope of the present invention is not limited thereto.
본 발명의 제3양태는 제1양태의 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 트립토판 수산화효소(tryptophan hydroxylase) 저해용 조성물을 제공한다.A third aspect of the present invention provides a composition for inhibiting tryptophan hydroxylase, comprising the compound of the first aspect, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 제4양태는 제1양태의 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 대사성 질환의 예방 또는 치료용 약학적 조성물을 제공한다.A fourth aspect of the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, comprising the compound of the first aspect, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 제5양태는 제4양태의 약학적 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는 대사성 질환의 예방 또는 치료 방법을 제공한다.A fifth aspect of the present invention provides a method for preventing or treating a metabolic disease, comprising administering the pharmaceutical composition of the fourth aspect to an individual in need thereof.
본 발명의 제6양태는 제1양태의 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암 질환의 예방 또는 치료용 약학적 조성물을 제공한다.A sixth aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound of the first aspect, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 제7양태는 제6양태의 약학적 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는 암 질환의 예방 또는 치료 방법을 제공한다.A seventh aspect of the present invention provides a method for preventing or treating cancer, comprising administering the pharmaceutical composition of the sixth aspect to an individual in need thereof.
본 발명의 용어, "예방"이란 본 발명의 조성물의 투여로 대사질환 또는 암질환의 발생, 확산 및 재발을 억제시키거나 지연시키는 모든 행위를 의미하고, "치료"란 본 발명의 조성물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term "prevention" refers to any action that inhibits or delays the occurrence, spread, and recurrence of metabolic or cancer diseases by administration of the composition of the present invention, and "treatment" refers to any action by administration of the composition of the present invention. It refers to any action that improves or beneficially changes the symptoms of the above disease.
본 발명의 약학적 조성물은 트립토판 수산화효소의 활성을 억제함으로써 이와 관련 질환을 예방 또는 치료할 수 있다. 구체적으로, 본 발명의 약학적 조성물은 트립토판 수산화효소, 특히, TPH1의 활성을 억제하여 말초 신경계에서 세로토닌 합성을 저해함으로써 대사를 활성화시킬 수 있다. 따라서, 본 발명의 약학적 조성물은 상기 기전을 통해 뇌를 자극하거나 식욕을 억제하지 않으면서 체중 증가를 억제하는 효과를 나타낼 수 있다. 한편, 세로토닌은 다양한 기전에 의해 암 질환의 진행을 촉진하는 것으로 알려져 있는 바, 상기와 같이 TPH1 활성 억제를 통한 세로토닌 발현의 억제는 세로토닌에 의한 암 질환의 진행 촉진을 저해함으로써 암 질환을 예방 또는 치료할 수 있다.The pharmaceutical composition of the present invention can prevent or treat diseases related thereto by inhibiting the activity of tryptophan hydroxylase. Specifically, the pharmaceutical composition of the present invention can activate metabolism by inhibiting the activity of tryptophan hydroxylase, in particular, TPH1, thereby inhibiting serotonin synthesis in the peripheral nervous system. Therefore, the pharmaceutical composition of the present invention can exhibit the effect of suppressing weight gain without stimulating the brain or suppressing appetite through the above mechanism. On the other hand, serotonin is known to promote the progression of cancer diseases by various mechanisms. As described above, inhibition of serotonin expression through inhibition of TPH1 activity prevents or treats cancer diseases by inhibiting the promotion of cancer diseases by serotonin. can
본 발명의 용어, "트립토판 수산화효소"란, 모노아민 신경전달물질(neurotransmitter)인 세로토닌(serotonin, 5-hydroxytryptamine; 5-HT)의 합성에 관여하는 효소를 의미하는 것으로, 이는 트립토판을 수산화시켜 5-히드록시트립토판을 생성할 수 있다. 상기 트립토판 수산화효소는 타이로신 수산화효소 및 페닐알라닌 수산화효소와 함께 바이오프테린-의존적 방향족 아미노산 수산화효소 패밀리를 구성한다. 다른 포유류는 물론 인간에는 2개 구분되는 TPH 유전자, TPH1 및TPH2가 존재하며, 이들 유전자는 염색체 11 및 12 상에 존재하고, 2개 다른 상이한 상동(homologous) 효소, TPH1 및 TPH2를 각각 인코딩한다. 예컨대, TPH1은 말초(예컨대, 피부(skin), 소화관(gut) 및 송과선(pineal gland) 등)에서 세로토닌을 발현하는 조직에서 발현되나 중추신경계에서도 발현되는 반면, TPH2는 신경 세포 유형에서만 독점적으로 발현되며 중추 신경계에서 우세한 동형(isoform)이다.As used herein, the term "tryptophan hydroxylase" refers to an enzyme involved in the synthesis of serotonin (5-hydroxytryptamine; 5-HT), a monoamine neurotransmitter, which hydroxylates tryptophan to 5 -Can produce hydroxytryptophan. The tryptophan hydroxylase, together with tyrosine hydroxylase and phenylalanine hydroxylase, constitute a family of biopterin-dependent aromatic amino acid hydroxylases. There are two distinct TPH genes, TPH1 and TPH2 , in humans as well as other mammals, which are present on chromosomes 11 and 12 and encode two other different homologous enzymes, TPH1 and TPH2, respectively. For example, TPH1 is expressed in tissues that express serotonin in the periphery (eg, skin, gut and pineal gland, etc.) but is also expressed in the central nervous system, whereas TPH2 is exclusively expressed in neuronal cell types. It is the predominant isoform in the central nervous system.
예컨대, 본 발명의 약학적 조성물로 예방 또는 치료할 수 있는 대사성 질환은 비만, 고혈압, 동맥경화, 당뇨, 인슐린저항성, 간지방증(hepatic steatosis), 지방간(fatty liver) 질환, 이상지질혈증 등일 수 있다.For example, metabolic diseases that can be prevented or treated with the pharmaceutical composition of the present invention may be obesity, hypertension, arteriosclerosis, diabetes, insulin resistance, hepatic steatosis, fatty liver disease, dyslipidemia, and the like.
예컨대, 본 발명의 약학적 조성물로 예방 또는 치료할 수 있는 암 질환은 직장암(colorectal cancer), 결장암(colon cancer), 담관암종(cholangiocarcinoma, bile duct carcinoma), 폐암(lung cancer), 위암(gastric cancer), 유방암(breast cancer), 췌장암(pancreatic cancer), 비뇨기 방광암(urinary bladder cancer), 전립선암(prostate cancer), 난소암(ovarian cancer), 태반암종(placental cancer), 융모암종(choriocarcinoma), 편평상피세포식도암(esophageal squamous cell cancer), 교아세포종(glioblastomas), 흑색종(melanomas), 신장암(renal carcinomas) 경부편평세포암(cervical squamous cell carcinomas), 간세포암종(hepatocellular carcinomas), 및 자궁경부상피내종양(cervical intraepithelial neoplasia) 등일 수 있다.For example, cancer diseases that can be prevented or treated by the pharmaceutical composition of the present invention include colorectal cancer, colon cancer, cholangiocarcinoma, bile duct carcinoma, lung cancer, gastric cancer. , breast cancer, pancreatic cancer, urinary bladder cancer, prostate cancer, ovarian cancer, placental cancer, choriocarcinoma, squamous epithelium Esophageal squamous cell cancer, glioblastomas, melanomas, renal carcinomas, cervical squamous cell carcinomas, hepatocellular carcinomas, and cervical intraepithelial tumors (cervical intraepithelial neoplasia), etc.
그러나, 본 발명의 약학적 조성물을 이용하여 예방 또는 치료할 수 있는 질환은 이에 제한되는 것은 아니며, 트립토판 수산화효소 활성을 억제하여 예방 또는 치료 효과를 나타낼 수 있는 질환이면 본 발명의 범주에 포함될 수 있다.However, diseases that can be prevented or treated using the pharmaceutical composition of the present invention are not limited thereto, and any disease capable of exhibiting a preventive or therapeutic effect by inhibiting tryptophan hydroxylase activity may be included in the scope of the present invention.
바람직하게, 본 발명에 따른 약학적 조성물은 유효성분으로서 화학식 1로 표시되는 화합물, 이의 이성질체, 또는 이들의 약학적으로 허용가능한 염을 조성물의 총중량을 기준으로 0.1 내지 75 중량%로, 보다 바람직하게는 1 내지 50 중량%로 함유할 수 있다.Preferably, the pharmaceutical composition according to the present invention contains, as an active ingredient, the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof in an amount of 0.1 to 75% by weight based on the total weight of the composition, more preferably may be contained in an amount of 1 to 50% by weight.
본 발명의 조성물은 약학적으로 허용가능한 담체, 희석제 또는 부형제를 추가로 포함할 수 있으며, 각각의 사용 목적에 맞게 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁제, 에멀젼, 시럽, 에어로졸 등의 경구 제형, 멸균 주사 용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여하거나 정맥내, 복강내, 피하, 직장, 국소 투여 등을 포함한 다양한 경로를 통해 투여될 수 있다. 이러한 조성물에 포함될 수 있는 적합한 담체, 부형제 또는 희석제의 예로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸셀룰로즈, 미정질셀룰로스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수 있다. 또한, 본 발명의 조성물은 충전제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.The composition of the present invention may further include a pharmaceutically acceptable carrier, diluent, or excipient, and may include powders, granules, tablets, capsules, suspensions, emulsions, syrups, It can be formulated and used in various forms such as oral dosage forms such as aerosols, injections of sterile injection solutions, etc., and can be administered orally or administered through various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like. Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, and cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, the composition of the present invention may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a fragrance, an emulsifier, a preservative, and the like.
경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로스, 락토즈, 젤라틴 등을 혼합하여 제형화한다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크와 같은 윤활제가 사용될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used.
경구용 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 예시될 수 있으며, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Liquid formulations for oral use may include suspensions, solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents, may be included. can
비경구 투여를 위한 제제에는 멸균된 수용액제, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈61. 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 한편, 주사제에는 용해제, 등장화제, 현탁화제, 유화제, 안정화제, 방부제 등과 같은 종래의 첨가제가 포함될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. The suppositories are Witepsol, Macrogol, and Twin61. Cacao butter, laurin fat, glycerogelatin, etc. may be used. On the other hand, injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.
이때, 본 발명의 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명의 용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.At this time, the composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level depends on the patient's health condition, disease type, severity, drug activity, sensitivity to drug, administration method, administration time, administration route and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other factors well known in the medical field. can The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
예컨대, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.For example, the dosage may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., and thus the dosage is not intended to limit the scope of the present invention in any way.
구체적으로, 본 발명의 조성물에서 화합물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 kg 당 1 내지 100 mg, 바람직하게는 5 내지 60 mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and weight of the patient, and generally 1 to 100 mg per kg of body weight, preferably 5 to 60 mg, is administered daily or every other day, or 1 It can be administered in divided doses 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, disease severity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
본 발명의 용어 "개체"란, 상기 트립토판 수산화효소 활성 관련 질환, 대사성 질환 및/또는 암 질환이 발명하였거나 발병할 수 있는 인간을 포함한 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미하고, 본 발명의 약학적 조성물을 개체에게 투여함으로써 상기 질환을 효과적으로 예방 또는 치료할 수 있다. 본 발명의 약학적 조성물은 기존의 치료제와 병행하여 투여될 수 있다.As used herein, the term "individual" means monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, It means all animals, including cats, dogs, mice, mice, rabbits, or guinea pigs, and by administering the pharmaceutical composition of the present invention to an individual, the disease can be effectively prevented or treated. The pharmaceutical composition of the present invention may be administered in parallel with a conventional therapeutic agent.
본 발명의 용어 "투여"란, 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내투여, 직장내 투여될 수 있으나, 이에 제한되지는 않는다. 또한, 본 발명의 약학적 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥 주사제, 피하 주사제, 피내 주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성 용제, 식물유, 고급 지방산 에스테르(예, 올레인산에칠 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물 발육을 저지하기 위한 보존제(예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.The term "administration" of the present invention means providing a predetermined substance to a patient by any suitable method, and the administration route of the composition of the present invention may be administered through any general route as long as it can reach the target tissue. have. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, may be administered intrarectally, but is not limited thereto. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of transporting an active substance to a target cell. Preferred administration modes and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections, and the like. For injections, aqueous solvents such as physiological saline solution and Ringer's solution, vegetable oil, higher fatty acid esters (eg, ethyl oleate), and non-aqueous solvents such as alcohols (eg, ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) Stabilizers for preventing deterioration (e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH control, to inhibit microbial growth Pharmaceutical carriers such as preservatives (eg, phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.
본 발명에서 유효성분과 결합하여 사용된 "치료학적으로 유효한 양"이란 용어는 대상 질환을 예방 또는 치료하는데 유효한 옥사디아졸 페닐알라닌 유도체, 이의 이성질체, 또는 이들의 약학적으로 허용가능한 염의 양을 의미한다.The term "therapeutically effective amount" used in combination with an active ingredient in the present invention means an amount of an oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof effective for preventing or treating a target disease.
본 발명의 약학적 조성물은 예방 또는 치료하고자 하는 질환의 종류에 따라, 유효성분으로서 옥사디아졸 페닐알라닌 유도체, 이의 이성질체, 또는 이들의 약학적으로 허용가능한 염 이외의 공지된 각 질환의 예방 또는 치료에 사용되는 공지의 약물을 추가로 포함할 수 있다. 예컨대, 암질환의 예방 또는 치료에 사용되는 경우 유효성분으로서 옥사디아졸 페닐알라닌 유도체, 이의 이성질체, 또는 이들의 약학적으로 허용가능한 염 이외에 공지된 약물을 추가로 포함할 수 있고, 이들 질환의 치료를 위해 공지된 다른 치료와 병용될 수 있다.The pharmaceutical composition of the present invention may be used for the prevention or treatment of known diseases other than oxadiazole phenylalanine derivatives, isomers thereof, or pharmaceutically acceptable salts thereof as an active ingredient, depending on the type of disease to be prevented or treated. It may further include a known drug used. For example, when used for the prevention or treatment of cancer diseases, as an active ingredient, an oxadiazole phenylalanine derivative, an isomer thereof, or a known drug in addition to a pharmaceutically acceptable salt thereof may be additionally included, and the treatment of these diseases It can be used in combination with other treatments known for
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.
제조예 1: (S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염의 제조Preparation Example 1: (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole-3 Preparation of -yl)phenyl)propanoic acid hydrochloride
단계 1-1: (S)-2-((tert-부톡시카보닐)아미노)-3-(4-시아노페닐)프로판산의 제조Step 1-1: Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid
Figure PCTKR2022000339-appb-img-000014
Figure PCTKR2022000339-appb-img-000014
(S)-2-아미노-3-(4-시아노페닐)프로판산(3.0 g, 15.773 mmol) 및 탄산수소나트륨(3.98 g, 47.32 mmol)을 20 mL의 1,4-다이옥산에 용해시켰다. 반응 혼합물을 0℃로 냉각시키고 디-tert-부틸 디카보네이트(5.16 g, 23.66 mmol)를 용해한 1,4-다이옥산(200 mL)을 0℃에서 1시간에 걸쳐 반응 혼합물에 천천히 적가하였다. 반응 혼합물을 실온에 도달하도록 허용하고 18시간 동안 교반하였다. 반응 완료 후, 용매를 진공에서 제거하고 남은 잔류 물에 5% KHSO4 수용액을 첨가하고 에틸 아세테이트로 추출하였다. 상기 추출물의 유기상을 염수로 세척한 후, 무수 황산나트륨으로 건조시켰다. 상기 건조시킨 추출물을 진공 하에 농축시켜 여과에 의해 (S)-2-((tert-부톡시카보닐)아미노)-3-(4-시아노페닐)프로판산(3.31 g, 70%)를 베이지 고체로 수득하였다.(S)-2-amino-3-(4-cyanophenyl)propanoic acid (3.0 g, 15.773 mmol) and sodium hydrogen carbonate (3.98 g, 47.32 mmol) were dissolved in 20 mL of 1,4-dioxane. The reaction mixture was cooled to 0 °C and 1,4-dioxane (200 mL) in di-tert-butyl dicarbonate (5.16 g, 23.66 mmol) was slowly added dropwise to the reaction mixture at 0 °C over 1 hour. The reaction mixture was allowed to reach room temperature and stirred for 18 h. After completion of the reaction, the solvent was removed in vacuo, and 5% KHSO 4 aqueous solution was added to the remaining water, followed by extraction with ethyl acetate. The organic phase of the extract was washed with brine and dried over anhydrous sodium sulfate. The dried extract was concentrated in vacuo and filtered to beige (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid (3.31 g, 70%) by filtration. obtained as a solid.
단계 1-2: 에틸 (S)-2-((tert-부톡시카보닐)아미노)-3-(4-시아노페닐)프로파노에이트의 제조Step 1-2: Preparation of ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoate
Figure PCTKR2022000339-appb-img-000015
Figure PCTKR2022000339-appb-img-000015
상기 수득한 (S)-2-((tert-부톡시카보닐)아미노)-3-(4-시아노페닐)프로판산(3.31 g, 11.40 mmol) 및 탄산칼륨(3.15 g, 22.80 mmol)를 DMF(10 mL)에 넣은 용액에 0℃에서 순차적으로 첨가하였다. 이 혼합물에 아이오도에탄(1.1 mL, 13.68 mmol)을 천천히 첨가하고 반응 혼합물을 실온에 도달하도록 허용하고 16시간 동안 교반하였다. 반응 완료 후 생성된 혼합물에 물을 첨가하고 에틸 아세테이트로 추출 하였다. 합한 유기상을 무수 황산나트륨상에서 건조시키고, 감압하에 농축시켰다. 반응 혼합물을 컬럼 크로마토 그래피로 정제하여 에틸 (S)-2-((tert-부톡시카보닐)아미노)-3-(4-시아노페닐)프로파노에이트(3.42g, 94%)를 백색 고체로 수득했다.(S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid (3.31 g, 11.40 mmol) and potassium carbonate (3.15 g, 22.80 mmol) obtained above were It was sequentially added to a solution in DMF (10 mL) at 0 °C. To this mixture was added iodoethane (1.1 mL, 13.68 mmol) slowly and the reaction mixture was allowed to reach room temperature and stirred for 16 h. After completion of the reaction, water was added to the resulting mixture, followed by extraction with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The reaction mixture was purified by column chromatography to give ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoate (3.42 g, 94%) as a white solid. was obtained with
단계 1-3: (S)-에틸 2-(tert-부톡시카보닐아미노)-3-(4-(N'-히드록시카밤이미도일)페닐)프로파노에이트의 제조Step 1-3: Preparation of (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(4-(N'-hydroxycarbamimidoyl)phenyl)propanoate
Figure PCTKR2022000339-appb-img-000016
Figure PCTKR2022000339-appb-img-000016
에틸 (S)-2-((tert-부톡시카보닐)아미노)-3-(4-시아노페닐)프로파노에이트(2.5 g, 7.85 mmol), 히드록실아민 염산염(1.64 g, 23.56 mmol) 및 트리에틸아민(5.48 mL, 39.26 mmol)의 혼합물을 에탄올(20 mL)에 용해시켜 환류 하에 2시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시킨 후, 증발시켜 부피를 줄이고 생성된 혼합물에 물을 첨가하고 에틸 아세테이트로 추출하였다. 합한 유기상을 무수 황산나트륨상에서 건조시키고, 여과하고 진공에서 증발시켰다. 생성물을 실리카겔 컬럼 크로마토 그래피로 정제하여 에틸 (S)-2-((tert-부톡시카보닐)아미노)-3-(4-(N-히드록시카밤이미도일)페닐)프로파노에이트(2.49 g, 90%)를 흰색 고체로 수득하였다.Ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoate (2.5 g, 7.85 mmol), hydroxylamine hydrochloride (1.64 g, 23.56 mmol) and triethylamine (5.48 mL, 39.26 mmol) was dissolved in ethanol (20 mL) and stirred under reflux for 2 hours. After the reaction mixture was cooled to room temperature, the volume was reduced by evaporation, water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The product was purified by silica gel column chromatography with ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(N-hydroxycarbamiimidoyl)phenyl)propanoate (2.49 g , 90%) as a white solid.
단계 1-4: 메틸 4'-히드록시-6-메톡시바이페닐-3-카르복실레이트의 제조Step 1-4: Preparation of methyl 4'-hydroxy-6-methoxybiphenyl-3-carboxylate
Figure PCTKR2022000339-appb-img-000017
Figure PCTKR2022000339-appb-img-000017
20 mL의 1,4-다이옥산에 메틸 3-브로모-4-메톡시벤조에이트(3.9g, 15.91 mmol), (4-히드록시페닐)보론산(2.41 g, 17.51 mmol), 테트라키스(트리페닐포스핀)팔라듐(0)(919.49 mg, 0.80 mmol)을 넣은 용액에 2M 탄산 칼륨 용액(6.60 g, 47.74 mmol)을 적가한 후, 100℃에서 2시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시킨 후, 혼합물을 에틸 아세테이트와 물로 추출하였다. 상기 추출물의 혼합된 유기층을 염수로 세척하고 황산 나트륨으로 건조시킨 후 농축하였다. 상기 농축한 물질을 컬럼 크로마토 그래피로 정제하여 메틸 4'-히드록시-6-메톡시바이페닐-3-카르복실레이트(2.875 g, 70%)를 흰색 고체로 수득하였다.Methyl 3-bromo-4-methoxybenzoate (3.9 g, 15.91 mmol), (4-hydroxyphenyl)boronic acid (2.41 g, 17.51 mmol), tetrakis(tri 2M potassium carbonate solution (6.60 g, 47.74 mmol) was added dropwise to a solution of phenylphosphine) palladium (0) (919.49 mg, 0.80 mmol), followed by stirring at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, the mixture was extracted with ethyl acetate and water. The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography to obtain methyl 4'-hydroxy-6-methoxybiphenyl-3-carboxylate (2.875 g, 70%) as a white solid.
단계 1-5: 4'-히드록시-6-메톡시바이페닐-3-카르복실산의 제조Step 1-5: Preparation of 4'-hydroxy-6-methoxybiphenyl-3-carboxylic acid
Figure PCTKR2022000339-appb-img-000018
Figure PCTKR2022000339-appb-img-000018
20 mL의 THF에 메틸 4'-히드록시-6-메톡시바이페닐-3-카르복실레이트(2.88 g, 11.13 mmol)을 넣은 용액에 2M 수산화나트륨 용액을 적가하였다. 반응 혼합물을 상온에서 16시간 동안 교반하였다. 반응이 끝난 상기 혼합물을 진공 하에 THF를 제거하고, 1 N 농도의 염산으로 pH 2가 되도록 산성화시켰다. 그 후, 상기 혼합물에 추가적으로 50 mL의 물을 넣어 주고, 에틸 아세테이트(50 mL)로 3회 추출하였다. 상기 추출물의 혼합된 유기층을 염수로 세척하고 황산나트륨으로 건조시킨 후 농축하였다. 상기 농축한 물질을 컬럼 크로마토그래피로 정제하여 4'-히드록시-6-메톡시바이페닐-3-카르복실산을 백색 고체(1.83g, 67%)로 얻었다.To a solution of methyl 4'-hydroxy-6-methoxybiphenyl-3-carboxylate (2.88 g, 11.13 mmol) in 20 mL of THF, 2M sodium hydroxide solution was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. After the reaction, THF was removed from the mixture under vacuum, and acidified to pH 2 with 1 N hydrochloric acid. Then, additionally 50 mL of water was added to the mixture, and the mixture was extracted three times with ethyl acetate (50 mL). The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography to obtain 4'-hydroxy-6-methoxybiphenyl-3-carboxylic acid as a white solid (1.83 g, 67%).
단계 1-6: 4'-아세톡시-6-메톡시바이페닐-3-카르복실산의 제조Step 1-6: Preparation of 4'-acetoxy-6-methoxybiphenyl-3-carboxylic acid
Figure PCTKR2022000339-appb-img-000019
Figure PCTKR2022000339-appb-img-000019
4'-히드록시-6-메톡시바이페닐-3-카르복실산(1.83 g, 7.49 mmol) 및 피리딘(4.83 mL, 59.94 mmol)을 디클로로메탄(20 mL)에 용해시킨 혼합물을 0℃로 냉각시키고, 아세틸 클로라이드(3.73 mL, 52.45 mmol)를 적가하였다. 반응 혼합물을 실온에 도달하도록 허용하고 18시간 동안 교반하였다. 반응 완료 후 디클로로메탄과 물로 추출하였다. 상기 추출물의 혼합된 유기층을 염수로 세척하고 황산 나트륨으로 건조시킨 후 농축하였다. 상기 농축한 물질을 컬럼 크로마토 그래피로 정제하여 4'-아세톡시-6-메톡시바이페닐-3-카르복실산을 백색 고체로 수득하였다(1.185g, 55%).A mixture of 4'-hydroxy-6-methoxybiphenyl-3-carboxylic acid (1.83 g, 7.49 mmol) and pyridine (4.83 mL, 59.94 mmol) in dichloromethane (20 mL) was cooled to 0 °C. and acetyl chloride (3.73 mL, 52.45 mmol) was added dropwise. The reaction mixture was allowed to reach room temperature and stirred for 18 h. After completion of the reaction, the mixture was extracted with dichloromethane and water. The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography to obtain 4'-acetoxy-6-methoxybiphenyl-3-carboxylic acid as a white solid (1.185 g, 55%).
단계 1-7: (S)-에틸 3-(4-(N'-(4'-아세톡시-6-메톡시바이페닐카보닐옥시)카밤이미도일)페닐)-2-(tert-부톡시카보닐아미노)프로파노에이트의 제조Step 1-7: (S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamimidoyl)phenyl)-2-(tert-butoxy Preparation of carbonylamino) propanoate
Figure PCTKR2022000339-appb-img-000020
Figure PCTKR2022000339-appb-img-000020
4'-아세톡시-6-메톡시바이페닐-3-카르복실산(1.185 g, 4.139 mmol), (S)-에틸 2-(tert-부톡시카보닐아미노)-3-(4-(N'-히드록시카밤이미도일)페닐)프로파노에이트(1.75 g, 4.97 mmol), 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 염산염(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDCI, 1.98 g, 10.35 mmol), 히드록시벤조트리아졸 수화물(hydroxybenzotriazole; HOBt, 950.78 mg, 6.21 mmol) 및 N,N-디이소프로필에틸아민(N,N-diisopropylethylamine; DIPEA, 2.50 mL, 14.49 mmol)을 디클로로메탄(20 mL)에 용해시켜 상온에서 18시간 동안 교반하였다. 반응이 끝난 상기 혼합물을 물로 희석하고 디클로로메탄으로 추출하였다. 상기 추출물의 혼합된 유기층을 염수로 세척하고 황산나트륨으로 건조시킨 후 농축하였다. 상기 농축한 물질을 컬럼 크로마토그래피로 정제하여 (S)-에틸 3-(4-(N'-(4'-아세톡시-6-메톡시바이페닐카보닐옥시)카밤이미도일)페닐)-2-(tert-부톡시카보닐아미노)프로파노에이트(2.45 g, 96%)를 흰색 고체로 수득하였다.4′-acetoxy-6-methoxybiphenyl-3-carboxylic acid (1.185 g, 4.139 mmol), (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(4-(N) '-Hydroxycarbamimidoyl) phenyl) propanoate (1.75 g, 4.97 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; EDCI, 1.98 g, 10.35 mmol), hydroxybenzotriazole hydrate (HOBt, 950.78 mg, 6.21 mmol) and N,N-diisopropylethylamine (N,N-diisopropylethylamine; DIPEA, 2.50 mL, 14.49 mmol) was dissolved in dichloromethane (20 mL) and stirred at room temperature for 18 hours. After the reaction, the mixture was diluted with water and extracted with dichloromethane. The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography (S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamiimidoyl)phenyl)-2 -(tert-butoxycarbonylamino)propanoate (2.45 g, 96%) was obtained as a white solid.
단계 1-8: (S)-에틸 3-(4-(N'-(4'-아세톡시-6-메톡시바이페닐카보닐옥시)카밤이미도일)페닐)-2-(tert-부톡시카보닐아미노)프로파노에이트의 제조Step 1-8: (S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamimidoyl)phenyl)-2-(tert-butoxy Preparation of carbonylamino) propanoate
Figure PCTKR2022000339-appb-img-000021
Figure PCTKR2022000339-appb-img-000021
(S)-에틸 3-(4-(N'-(4'-아세톡시-6-메톡시바이페닐카보닐옥시)카밤이미도일)페닐)-2-(tert-부톡시카보닐아미노)프로파노에이트(2.45 g, 3.96 mmol)를 1,4-다이옥산(10 mL)에 용해시키고 반응 혼합물을 18시간 동안 환류시켰다. 반응 혼합물을 상온으로 냉각 한 후 잔류물을 에틸 아세테이트와 물로 추출하고 무수 황산나트륨으로 건조시켰다. 반응 혼합물을 컬럼 크로마토 그래피로 정제하여 (S)-에틸 3-(4-(N'-(4'-아세톡시-6-메톡시바이페닐카보닐옥시)카밤이미도일)페닐)-2-(tert-부톡시카보닐아미노)프로파노에이트(1.94g, 78%)를 흰색 고체로 수득하였다.(S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamimidoyl)phenyl)-2-(tert-butoxycarbonylamino)prop Panoate (2.45 g, 3.96 mmol) was dissolved in 1,4-dioxane (10 mL) and the reaction mixture was refluxed for 18 h. After the reaction mixture was cooled to room temperature, the residue was extracted with ethyl acetate and water, and dried over anhydrous sodium sulfate. The reaction mixture was purified by column chromatography (S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamimidoyl)phenyl)-2-( tert-butoxycarbonylamino)propanoate (1.94 g, 78%) was obtained as a white solid.
단계 1-9: (S)-2-(tert-부톡시카보닐아미노)-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산의 제조Step 1-9: (S)-2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1, Preparation of 2,4-oxadiazol-3-yl)phenyl)propanoic acid
Figure PCTKR2022000339-appb-img-000022
Figure PCTKR2022000339-appb-img-000022
50 mL의 THF/ 물(3:1)에 (S)-에틸 3-(4-(N'-(4'-아세톡시-6-메톡시바이페닐카보닐옥시)카밤이미도일)페닐)-2-(tert-부톡시카보닐아미노)프로파노에이트(1.94 g, 3.23 mmol)를 넣은 용액에 수산화나트륨(50.27 ㎎, 1.26 mmol) 수용액을 첨가하였다. 상기 혼합물을 주위 온도에서 24시간 동안 애시드 하이드로클로라이드 교반시켰다. 반응이 끝난 상기 혼합물을 진공 하에 THF를 제거하고, 1 N 농도의 염산으로 pH 4가 되도록 산성화시켰다. 상기 혼합물에 물로 희석하고 에틸 아세테이트로 추출하였다. 상기 추출물의 혼합된 유기층을 염수로 세척하고 황산나트륨으로 건조시킨 후 농축하였다. 상기 농축한 물질을 컬럼 크로마토그래피로 정제하여 (S)-2-(tert-부톡시카보닐아미노)-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산(1.58 g, 92%)을 흰색 고체로 수득하였다.(S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamimidoyl)phenyl)- in 50 mL of THF/water (3:1) To a solution of 2-(tert-butoxycarbonylamino)propanoate (1.94 g, 3.23 mmol), an aqueous solution of sodium hydroxide (50.27 mg, 1.26 mmol) was added. The mixture was stirred with acid hydrochloride at ambient temperature for 24 hours. After the reaction, THF was removed from the mixture under vacuum, and acidified to pH 4 with 1 N hydrochloric acid. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography (S)-2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3) -yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (1.58 g, 92%) was obtained as a white solid.
단계 1-10: (S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염의 제조Step 1-10: (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole- Preparation of 3-yl)phenyl)propanoic acid hydrochloride
Figure PCTKR2022000339-appb-img-000023
Figure PCTKR2022000339-appb-img-000023
10 mL의 아세트산 에틸에 (S)-2-(tert-부톡시카보닐아미노)-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산(600 mg, 1.13 mmol)을 넣은 용액에 5 mL의 4.0 M HCl in 1,4-다이옥산 용액을 적가하였다. 그 후, 상기 혼합물을 12시간 동안 교반시켰다. 반응이 끝난 상기 혼합물을 최소 부피로 농축시키고 농축물을 여과 수집하여 (S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(510 mg, 97%)을 백색 고체로 수득하였다.(S)-2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1 in 10 mL of ethyl acetate To a solution in which ,2,4-oxadiazol-3-yl)phenyl)propanoic acid (600 mg, 1.13 mmol) was added, 5 mL of 4.0 M HCl in 1,4-dioxane solution was added dropwise. After that, the mixture was stirred for 12 hours. After the reaction was completed, the mixture was concentrated to a minimum volume and the concentrate was collected by filtration (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl) )-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride (510 mg, 97%) was obtained as a white solid.
제조예 2: (S)-에틸 2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로파노에이트 염산염의 제조Preparation 2: (S)-ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole- Preparation of 3-yl)phenyl)propanoate hydrochloride
단계 2-1: (S)-에틸 2-(tert-부톡시카보닐아미노)-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로파노에이트의 제조Step 2-1: (S)-Ethyl 2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1 Preparation of ,2,4-oxadiazol-3-yl)phenyl)propanoate
Figure PCTKR2022000339-appb-img-000024
Figure PCTKR2022000339-appb-img-000024
(S)-에틸 3-(4-(5-(4'-아세톡시-6-메톡시-바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)-2-((tert-부톡시카보닐)아미노)프로파노에이트(130 mg, 0.22 mmol) 및 탄산수소나트륨(181.51 mg, 2.16 mmol)를 에탄올(5 mL)에 용해시켜 상온에서 18시간 동안 교반하였다. 반응이 끝난 상기 혼합물을 물로 희석하고 에틸아세테이트로 추출하였다. 상기 추출물의 혼합된 유기층을 염수로 세척하고 황산나트륨으로 건조시킨 후 농축하였다. 상기 농축한 물질을 컬럼 크로마토그래피로 정제하여 (S)-에틸 2-(tert-부톡시카보닐아미노)-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로파노에이트(100 mg, 83%)를 흰색 고체로 수득했다.(S)-ethyl 3-(4-(5-(4'-acetoxy-6-methoxy-biphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)- 2-((tert-butoxycarbonyl)amino)propanoate (130 mg, 0.22 mmol) and sodium hydrogen carbonate (181.51 mg, 2.16 mmol) were dissolved in ethanol (5 mL) and stirred at room temperature for 18 hours. . After the reaction, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-) 3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate (100 mg, 83%) was obtained as a white solid.
단계 2-2: (S)-에틸 2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로파노에이트 염산염의 제조Step 2-2: (S)-Ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole Preparation of -3-yl)phenyl)propanoate hydrochloride
Figure PCTKR2022000339-appb-img-000025
Figure PCTKR2022000339-appb-img-000025
5 mL의 아세트산 에틸에 (S)-에틸 2-(tert-부톡시카보닐아미노)-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로파노에이트(100 mg, 0.18 mmol)를 넣은 용액에 5 mL의 4.0 M HCl in 1,4-다이옥산 용액을 적가하였다. 그 후, 상기 혼합물을 12시간 동안 교반시켰다. 반응이 끝난 상기 혼합물을 최소 부피로 농축시키고 농축물을 여과 수집하여 (S)-에틸 2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로파노에이트 염산염(83 mg, 94%)을 백색 고체로 수득하였다.(S)-ethyl 2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)- in 5 mL of ethyl acetate To a solution in which 1,2,4-oxadiazol-3-yl)phenyl)propanoate (100 mg, 0.18 mmol) was added, 5 mL of 4.0 M HCl in 1,4-dioxane solution was added dropwise. After that, the mixture was stirred for 12 hours. After the reaction, the mixture was concentrated to a minimum volume, and the concentrate was collected by filtration, (S)-ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3- yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate hydrochloride (83 mg, 94%) was obtained as a white solid.
제조예 3: (S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판아미드 염산염의 제조Preparation 3: (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole-3 Preparation of -yl)phenyl)propanamide hydrochloride
단계 3-1: (S)-tert-부틸 1-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)-1-옥소프로판-2-일카바메이트의 제조Step 3-1: (S)-tert-Butyl 1-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxa Preparation of diazol-3-yl)phenyl)-1-oxopropan-2-ylcarbamate
Figure PCTKR2022000339-appb-img-000026
Figure PCTKR2022000339-appb-img-000026
(S)-2-((tert-부톡시카보닐)아미노)-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산(250 mg, 0.47 mmol), EDCI(270.47 mg, 1.411 mmol) 및 HOBt(144.04 mg, 0.94 mmol)를 THF(5 mL)에 용해시켜 상온에서 교반하였다. 0.5시간 후, 수산화 암모늄(80.09 mg, 4.703 mmol)을 적가하고 반응 혼합물을 상온에서 18시간 동안 교반하였다. 반응이 끝난 용매를 진공에서 제거하고 상기 혼합물을 물로 희석하고 에틸아세테이트로 추출하였다. 상기 추출물의 혼합된 유기층을 염수로 세척하고 황산나트륨으로 건조시킨 후 농축하였다. 상기 농축한 물질을 컬럼 크로마토그래피로 정제하여 (S)-tert-부틸 1-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)-1-옥소프로판-2-일카바메이트(87 mg, 35%)를 백색 고체로 수득하였다.(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4 -oxadiazol-3-yl)phenyl)propanoic acid (250 mg, 0.47 mmol), EDCI (270.47 mg, 1.411 mmol) and HOBt (144.04 mg, 0.94 mmol) were dissolved in THF (5 mL) and stirred at room temperature. After 0.5 h, ammonium hydroxide (80.09 mg, 4.703 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. After the reaction was completed, the solvent was removed in vacuo, and the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography (S)-tert-butyl 1-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1 ,2,4-oxadiazol-3-yl)phenyl)-1-oxopropan-2-ylcarbamate (87 mg, 35%) was obtained as a white solid.
단계 3-2: (S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판아미드 염산염의 제조Step 3-2: (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole- Preparation of 3-yl)phenyl)propanamide hydrochloride
Figure PCTKR2022000339-appb-img-000027
Figure PCTKR2022000339-appb-img-000027
5 mL의 아세트산 에틸에 (S)-tert-부틸 1-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)-1-옥소프로판-2-일카바메이트(87 mg, 0.16 mmol)를 넣은 용액에 5 mL의 4.0 M HCl in 1,4-다이옥산 용액을 적가하였다. 그 후, 상기 혼합물을 12시간 동안 교반시켰다. 반응이 끝난 상기 혼합물을 최소 부피로 농축시키고 농축물을 여과 수집하여 (S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판아미드 염산염(68 mg, 89%)을 백색 고체로 수득하였다.(S)-tert-Butyl 1-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4- in 5 mL of ethyl acetate To a solution in which oxadiazol-3-yl)phenyl)-1-oxopropan-2-ylcarbamate (87 mg, 0.16 mmol) was added, 5 mL of 4.0 M HCl in 1,4-dioxane solution was added dropwise. After that, the mixture was stirred for 12 hours. After the reaction was completed, the mixture was concentrated to a minimum volume and the concentrate was collected by filtration (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl) )-1,2,4-oxadiazol-3-yl)phenyl)propanamide hydrochloride (68 mg, 89%) was obtained as a white solid.
상기 제조예 1 내지 3과 유사한 방법으로 총 43종 화합물(실시예 1 내지 43)을 제조하였으며, 합성된 화합물의 화학구조식 및 화합물명을 하기 표 1에 나타내었다.A total of 43 compounds (Examples 1 to 43) were prepared in a manner similar to Preparation Examples 1 to 3, and the chemical structural formulas and compound names of the synthesized compounds are shown in Table 1 below.
실시예Example 화학구조식chemical structural formula 화합물명compound name
1One
Figure PCTKR2022000339-appb-img-000028
Figure PCTKR2022000339-appb-img-000028
 		(S)-2-아미노-3-(4-(5-페닐-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
22
Figure PCTKR2022000339-appb-img-000029
Figure PCTKR2022000339-appb-img-000029
 		(S)-2-아미노-3-(4-(5-(4-메톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
33
Figure PCTKR2022000339-appb-img-000030
Figure PCTKR2022000339-appb-img-000030
 		(S)-2-아미노-3-(4-(5-(3-메톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
44
Figure PCTKR2022000339-appb-img-000031
Figure PCTKR2022000339-appb-img-000031
 		(S)-2-아미노-3-(4-(5-(4-히드록시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
55
Figure PCTKR2022000339-appb-img-000032
Figure PCTKR2022000339-appb-img-000032
 		(S)-2-아미노-3-(4-(5-(4-에톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
66
Figure PCTKR2022000339-appb-img-000033
Figure PCTKR2022000339-appb-img-000033
 		(S)-2-아미노-3-(4-(5-(3,4-디메톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
77
Figure PCTKR2022000339-appb-img-000034
Figure PCTKR2022000339-appb-img-000034
 		(S)-2-아미노-3-(4-(5-(4-플루오로페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
88
Figure PCTKR2022000339-appb-img-000035
Figure PCTKR2022000339-appb-img-000035
 		(S)-2-아미노-3-(4-(5-(4-브로모페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
99
Figure PCTKR2022000339-appb-img-000036
Figure PCTKR2022000339-appb-img-000036
 		(S)-2-아미노-3-(4-(5-(4-아이오도페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-iodophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
1010
Figure PCTKR2022000339-appb-img-000037
Figure PCTKR2022000339-appb-img-000037
 		(S)-2-아미노-3-(4-(5-(4-(트리플루오로메틸)페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
1111
Figure PCTKR2022000339-appb-img-000038
Figure PCTKR2022000339-appb-img-000038
 		(S)-2-아미노-3-(4-(5-(4-(트리플루오로메톡시)페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
1212
Figure PCTKR2022000339-appb-img-000039
Figure PCTKR2022000339-appb-img-000039
 		(S)-2-아미노-3-(4-(5-(4-시아노페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
1313
Figure PCTKR2022000339-appb-img-000040
Figure PCTKR2022000339-appb-img-000040
 		(S)-3-(4-(5-(4-아세틸페닐)-1,2,4-옥사디아졸-3-일)페닐)-2-아미노프로판산 염산염(S)-3-(4-(5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid hydrochloride
1414
Figure PCTKR2022000339-appb-img-000041
Figure PCTKR2022000339-appb-img-000041
 		(S)-2-아미노-3-(4-(5-(4-니트로페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
1515
Figure PCTKR2022000339-appb-img-000042
Figure PCTKR2022000339-appb-img-000042
 		(S)-2-아미노-3-(4-(5-(4-메톡시-3-니트로페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-methoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
1616
Figure PCTKR2022000339-appb-img-000043
Figure PCTKR2022000339-appb-img-000043
 		(S)-2-아미노-3-(4-(5-(4-메톡시벤질)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
1717
Figure PCTKR2022000339-appb-img-000044
Figure PCTKR2022000339-appb-img-000044
 		(S)-2-아미노-3-(4-(5-(3-브로모-4-메톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(3-bromo-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
1818
Figure PCTKR2022000339-appb-img-000045
Figure PCTKR2022000339-appb-img-000045
 		(S)-2-아미노-3-(4-(5-(6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
1919
Figure PCTKR2022000339-appb-img-000046
Figure PCTKR2022000339-appb-img-000046
 		(S)-2-아미노-3-(4-(5-(4',6-디메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4′,6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
2020
Figure PCTKR2022000339-appb-img-000047
Figure PCTKR2022000339-appb-img-000047
 		(S)-2-아미노-3-(4-(5-(4'-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4'-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
2121
Figure PCTKR2022000339-appb-img-000048
Figure PCTKR2022000339-appb-img-000048
 		(S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid hydrochloride
2222
Figure PCTKR2022000339-appb-img-000049
Figure PCTKR2022000339-appb-img-000049
 		(S)-2-아미노-3-(4-(5-(4',6-디메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판아미드 염산염(S)-2-amino-3-(4-(5-(4′,6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide hydrochloride
2323
Figure PCTKR2022000339-appb-img-000050
Figure PCTKR2022000339-appb-img-000050
 		(S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판아미드 염산염(S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanamide hydrochloride
2424
Figure PCTKR2022000339-appb-img-000051
Figure PCTKR2022000339-appb-img-000051
 		(S)-에틸 2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로파노에이트 염산염(S)-ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl) Phenyl)propanoate hydrochloride
2525
Figure PCTKR2022000339-appb-img-000052
Figure PCTKR2022000339-appb-img-000052
 		(S)-2-아미노-3-(4-(5-(3',6-디메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(3′,6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
2626
Figure PCTKR2022000339-appb-img-000053
Figure PCTKR2022000339-appb-img-000053
 		(S)-2-아미노-3-(4-(5-(3'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(3'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid hydrochloride
2727
Figure PCTKR2022000339-appb-img-000054
Figure PCTKR2022000339-appb-img-000054
 		(S)-2-아미노-3-(4-(5-(2',6-디메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(2′,6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
2828
Figure PCTKR2022000339-appb-img-000055
Figure PCTKR2022000339-appb-img-000055
 		(S)-2-아미노-3-(4-(5-(2'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(2'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid hydrochloride
2929
Figure PCTKR2022000339-appb-img-000056
Figure PCTKR2022000339-appb-img-000056
 		(S)-2-아미노-3-(4-(5-(5-메톡시바이페닐-2-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
3030
Figure PCTKR2022000339-appb-img-000057
Figure PCTKR2022000339-appb-img-000057
 		(S)-2-아미노-3-(4-(5-(4',5-디메톡시바이페닐-2-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4′,5-dimethoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
3131
Figure PCTKR2022000339-appb-img-000058
Figure PCTKR2022000339-appb-img-000058
 		(S)-2-아미노-3-(4-(5-(4'-히드록시-5-메톡시바이페닐-2-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4'-hydroxy-5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid hydrochloride
3232
Figure PCTKR2022000339-appb-img-000059
Figure PCTKR2022000339-appb-img-000059
 		(S)-3-(4-(5-(1H-인돌-6-일)-1,2,4-옥사디아졸-3-일)페닐)-2-아미노프로판산 염산염(S)-3-(4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid hydrochloride
3333
Figure PCTKR2022000339-appb-img-000060
Figure PCTKR2022000339-appb-img-000060
 		(S)-3-(4-(5-(1H-인다졸-6-일)-1,2,4-옥사디아졸-3-일)페닐)-2-아미노프로판산 염산염(S)-3-(4-(5-(1H-indazol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid hydrochloride
3434
Figure PCTKR2022000339-appb-img-000061
Figure PCTKR2022000339-appb-img-000061
 		(S)-2-아미노-3-(4-(5-(2,3-디하이드로벤조[b][1,4]디옥신-6-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,4-oxadiazole- 3-yl)phenyl)propanoic acid hydrochloride
3535
Figure PCTKR2022000339-appb-img-000062
Figure PCTKR2022000339-appb-img-000062
 		(S)-2-아미노-3-(4-(5-(벤조[d][1,3]디옥솔-5-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid hydrochloride
3636
Figure PCTKR2022000339-appb-img-000063
Figure PCTKR2022000339-appb-img-000063
 		(S)-2-아미노-3-(4-(5-(디벤조[b,d]퓨란-2-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(dibenzo[b,d]furan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
3737
Figure PCTKR2022000339-appb-img-000064
Figure PCTKR2022000339-appb-img-000064
 		(S)-2-아미노-3-(4-(5-(4-(디메틸아미노)페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-(dimethylamino)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
3838
Figure PCTKR2022000339-appb-img-000065
Figure PCTKR2022000339-appb-img-000065
 		(S)-2-아미노-3-(4-(5-(4-벤질페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
3939
Figure PCTKR2022000339-appb-img-000066
Figure PCTKR2022000339-appb-img-000066
 		(S)-2-아미노-3-(4-(5-(4-(벤질옥시)페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
4040
Figure PCTKR2022000339-appb-img-000067
Figure PCTKR2022000339-appb-img-000067
 		(S)-3-(4-(5-(4-아세트아미도페닐)-1,2,4-옥사디아졸-3-일)페닐)-2-아미노프로판산 염산염(S)-3-(4-(5-(4-acetamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid hydrochloride
4141
Figure PCTKR2022000339-appb-img-000068
Figure PCTKR2022000339-appb-img-000068
 		(S)-2-아미노-3-(4-(5-(4-벤즈아미도페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산 염산염(S)-2-amino-3-(4-(5-(4-benzamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride
4242
Figure PCTKR2022000339-appb-img-000069
Figure PCTKR2022000339-appb-img-000069
 		(S)-2-아미노-N-히드록시-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판아미드 염산염(S)-2-amino-N-hydroxy-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole- 3-yl)phenyl)propanamide hydrochloride
4343
Figure PCTKR2022000339-appb-img-000070
Figure PCTKR2022000339-appb-img-000070
 		(S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)-N-(2-히드록시에톡시)프로판아미드 염산염(S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl )-N-(2-hydroxyethoxy)propanamide hydrochloride
실험예 1: 합성된 화합물의 동정Experimental Example 1: Identification of the synthesized compound
상기 제조예를 통해 합성된 실시예 1 내지 43의 화합물을 핵자기공명분광분석기(nuclear magnetic resonance; NMR) 또는 LC-MS(liquid chromatography-mass spectrometry)로 분석하여 동정하였다. 각 화합물에 대해 측정된 결과를 하기 표 2에 나타내었다.The compounds of Examples 1 to 43 synthesized through Preparation Examples were identified by analysis by nuclear magnetic resonance (NMR) or liquid chromatography-mass spectrometry (LC-MS). The results measured for each compound are shown in Table 2 below.
실시예Example LCMS 또는 NMRLCMS or NMR
1One 1H NMR (400 MHz, DMSO-d 6) δ 8.48 (s, 3H), 8.20 (d, J = 7.3 Hz, 2H), 8.06 (d, J = 7.9 Hz, 2H), 7.77-7.66 (m, 3H), 7.52 (d, J = 8.2 Hz, 2H), 4.24 (t, J = 6.3 Hz, 1H), 3.24 (d, J = 6.1 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.48 (s, 3H), 8.20 (d, J = 7.3 Hz, 2H), 8.06 (d, J = 7.9 Hz, 2H), 7.77-7.66 (m, 3H), 7.52 (d, J = 8.2 Hz, 2H), 4.24 (t, J = 6.3 Hz, 1H), 3.24 (d, J = 6.1 Hz, 2H)
22 1H NMR (400 MHz, DMSO-d 6) δ 8.45 (s, 3H), 8.14 (d, J = 8.9 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 9.2 Hz, 2H), 4.24 (t, J = 6.3 Hz, 1H), 3.89 (s, 3H), 3.22 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.45 (s, 3H), 8.14 (d, J = 8.9 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 9.2 Hz, 2H), 4.24 (t, J = 6.3 Hz, 1H), 3.89 (s, 3H), 3.22 (d, J = 6.4 Hz, 2H)
33 1H NMR (400 MHz, DMSO-d 6) δ 8.47 (s, 3H), 8.06 (d, J = 8.2 Hz, 2H), 7.77 (dt, J = 7.7, 1.1 Hz, 1H), 7.66 (q, J = 1.3 Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.32 (ddd, J = 8.3, 2.7, 0.8 Hz, 1H), 4.22 (t, J = 6.6 Hz, 1H), 3.89 (s, 3H), 3.23 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.47 (s, 3H), 8.06 (d, J = 8.2 Hz, 2H), 7.77 (dt, J = 7.7, 1.1 Hz, 1H), 7.66 (q, J = 1.3 Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.32 (ddd, J = 8.3, 2.7, 0.8 Hz, 1H), 4.22 ( t, J = 6.6 Hz, 1H), 3.89 (s, 3H), 3.23 (d, J = 6.4 Hz, 2H)
44 1H NMR (400 MHz, DMSO-d 6) δ 10.69 (s, 1H), 8.47 (s, 3H), 8.02 (d, J = 8.7 Hz, 4H), 7.50 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 4.20 (t, J = 5.5 Hz, 1H), 3.22 (d, J = 5.5 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.69 (s, 1H), 8.47 (s, 3H), 8.02 (d, J = 8.7 Hz, 4H), 7.50 (d, J = 7.8 Hz, 2H) , 7.02 (d, J = 8.7 Hz, 2H), 4.20 (t, J = 5.5 Hz, 1H), 3.22 (d, J = 5.5 Hz, 2H)
55 1H NMR (400 MHz, DMSO-d 6) δ 8.46 (s, 3H), 8.12 (d, J = 8.5 Hz, 2H), 8.04 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 4.22 (t, J = 5.3 Hz, 1H), 4.16 (q, J = 6.9 Hz, 2H), 3.23 (d, J = 5.8 Hz, 2H), 1.37 (t, J = 6.9 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.46 (s, 3H), 8.12 (d, J = 8.5 Hz, 2H), 8.04 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 4.22 (t, J = 5.3 Hz, 1H), 4.16 (q, J = 6.9 Hz, 2H), 3.23 (d, J = 5.8 Hz) , 2H), 1.37 (t, J = 6.9 Hz, 3H)
66 1H NMR (400 MHz, DMSO-d 6) δ 8.48 (s, 3H), 8.05 (d, J = 8.2 Hz, 2H), 7.80 (dd, J = 8.5, 2.1 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 1H), 4.22 (t, J = 6.4 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.23 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.48 (s, 3H), 8.05 (d, J = 8.2 Hz, 2H), 7.80 (dd, J = 8.5, 2.1 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 1H), 4.22 (t, J = 6.4 Hz, 1H), 3.90 (s, 3H) , 3.89 (s, 3H), 3.23 (d, J = 6.4 Hz, 2H)
77 1H NMR (400 MHz, DMSO-d 6) δ 8.46 (s, 3H), 8.24-8.29 (m, 2H), 8.05 (d, J = 8.5 Hz, 2H), 7.51-7.56 (m, 4H), 4.24 (t, J = 6.5 Hz, 1H), 3.23 (d, J = 6.6 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.46 (s, 3H), 8.24-8.29 (m, 2H), 8.05 (d, J = 8.5 Hz, 2H), 7.51-7.56 (m, 4H), 4.24 (t, J = 6.5 Hz, 1H), 3.23 (d, J = 6.6 Hz, 2H)
88 1H NMR (400 MHz, DMSO-d 6) δ 8.48 (s, 2H), 8.12 (dt, J = 8.9, 2.1 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 7.89 (dt, J = 9.0, 2.1 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 4.23 (t, J = 6.6 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.48 (s, 2H), 8.12 (dt, J = 8.9, 2.1 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 7.89 (dt, J = 9.0, 2.1 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 4.23 (t, J = 6.6 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H)
99 1H NMR (400 MHz, DMSO-d 6) δ 8.43 (s, 3H), 8.06 (t, J = 7.6 Hz, 4H), 7.94 (d, J = 6.9 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H), 4.24 (t, J = 5.9 Hz, 1H), 3.22 (d, J = 5.7 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.43 (s, 3H), 8.06 (t, J = 7.6 Hz, 4H), 7.94 (d, J = 6.9 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H), 4.24 (t, J = 5.9 Hz, 1H), 3.22 (d, J = 5.7 Hz, 2H)
1010 1H NMR (400 MHz, DMSO-d 6) δ 8.48 (s, 3H), 8.40 (d, J = 8.2 Hz, 2H), 8.06 (t, J = 7.9 Hz, 4H), 7.53 (d, J = 8.2 Hz, 2H), 4.24 (t, J = 6.6 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.48 (s, 3H), 8.40 (d, J = 8.2 Hz, 2H), 8.06 (t, J = 7.9 Hz, 4H), 7.53 (d, J = 8.2 Hz, 2H), 4.24 (t, J = 6.6 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H)
1111 1H NMR (400 MHz, DMSO-d 6) δ 8.48 (s, 3H), 8.33 (dt, J = 9.6, 2.4 Hz, 2H), 8.06 (d, J = 8.5 Hz, 2H), 7.67 (dd, J = 9.2, 0.9 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 4.24 (t, J = 6.6 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.48 (s, 3H), 8.33 (dt, J = 9.6, 2.4 Hz, 2H), 8.06 (d, J = 8.5 Hz, 2H), 7.67 (dd, J = 9.2, 0.9 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 4.24 (t, J = 6.6 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H)
1212 1H NMR (400 MHz, DMSO-d 6) δ 8.46 (s, 3H), 8.26 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 4.21 (t, J = 6.1 Hz, 1H), 3.23 (d, J = 6.1 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.46 (s, 3H), 8.26 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 4.21 (t, J = 6.1 Hz, 1H), 3.23 (d, J = 6.1 Hz, 2H)
1313 1H NMR (400 MHz, DMSO-d 6) δ 8.46 (s, 3H), 8.26 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 4.21 (t, J = 6.1 Hz, 1H), 3.23 (d, J = 6.1 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.46 (s, 3H), 8.26 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 4.21 (t, J = 6.1 Hz, 1H), 3.23 (d, J = 6.1 Hz, 2H)
1414 1H NMR (400 MHz, DMSO-d 6) δ 8.54 (s, 23H), 8.49 (dd, J = 6.9, 2.3 Hz, 2H), 8.44 (dd, J = 6.9, 2.3 Hz, 2H), 8.07 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 4.24 (t, J = 6.3 Hz, 1H), 3.25 (d, J = 6.5 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 23H), 8.49 (dd, J = 6.9, 2.3 Hz, 2H), 8.44 (dd, J = 6.9, 2.3 Hz, 2H), 8.07 ( d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 4.24 (t, J = 6.3 Hz, 1H), 3.25 (d, J = 6.5 Hz, 2H)
1515 1H NMR (400 MHz, DMSO-d 6) δ 13.99 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.47 (s, 3H), 8.44 (dd, J = 8.9, 2.1 Hz, 2H), 8.06 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 4.25 (t, J = 6.4 Hz, 1H), 4.06 (s, 3H), 3.23 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.99 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.47 (s, 3H), 8.44 (dd, J = 8.9, 2.1 Hz, 2H), 8.06 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 4.25 (t, J = 6.4 Hz, 1H) , 4.06 (s, 3H), 3.23 (d, J = 6.4 Hz, 2H)
1616 1H NMR (400 MHz, DMSO-d 6) δ 8.42 (s, 3H), 7.93 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.31 (dt, J = 9.5, 2.5 Hz, 2H), 6.93 (dt, J = 9.5, 2.5 Hz, 2H), 4.36 (s, 2H), 4.20 (t, J = 6.4 Hz, 1H), 3.74 (s, 3H), 3.20 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.42 (s, 3H), 7.93 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.31 (dt, J = 9.5, 2.5 Hz, 2H), 6.93 (dt, J = 9.5, 2.5 Hz, 2H), 4.36 (s, 2H), 4.20 (t, J = 6.4 Hz, 1H), 3.74 (s, 3H), 3.20 ( d, J = 6.4 Hz, 2H)
1717 1H NMR (400 MHz, DMSO-d 6) δ 8.47 (s, 3H), 8.33 (d, J = 2.1 Hz, 1H), 8.19 (dd, J = 8.9, 2.1 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.9 Hz, 1H), 4.24 (t, J = 6.4 Hz, 1H), 3.99 (s, 3H), 3.23 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.47 (s, 3H), 8.33 (d, J = 2.1 Hz, 1H), 8.19 (dd, J = 8.9, 2.1 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.9 Hz, 1H), 4.24 (t, J = 6.4 Hz, 1H), 3.99 (s, 3H) , 3.23 (d, J = 6.4 Hz, 2H)
1818 1H NMR (400 MHz, DMSO-d 6) δ 8.43 (s, 3H), 8.19 (dd, J = 8.5, 2.1 Hz, 1H), 8.03-8.06 (m, 3H), 7.55 (d, J = 7.0 Hz, 2H), 7.46-7.51(m, 4H), 7.39-7.42 (m, 2H), 4.23 (t, J = 6.3 Hz, 1H), 3.90 (s, 3H), 3.22 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.43 (s, 3H), 8.19 (dd, J = 8.5, 2.1 Hz, 1H), 8.03-8.06 (m, 3H), 7.55 (d, J = 7.0) Hz, 2H), 7.46-7.51 (m, 4H), 7.39-7.42 (m, 2H), 4.23 (t, J = 6.3 Hz, 1H), 3.90 (s, 3H), 3.22 (d, J = 6.4 Hz) , 2H)
1919 1H NMR (400 MHz, DMSO-d 6) δ 8.46 (s, 3H), 8.15 (dd, J = 8.8, 2.3 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 2.3 Hz, 1H), 7.48-7.51 (m, 4H), 7.37 (d, J = 9.2 Hz, 1H), 7.03 (dt, J = 9.4, 2.6 Hz, 2H), 4.23 (t, J = 6.5 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.22 (d, J = 6.5 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.46 (s, 3H), 8.15 (dd, J = 8.8, 2.3 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 2.3 Hz, 1H), 7.48-7.51 (m, 4H), 7.37 (d, J = 9.2 Hz, 1H), 7.03 (dt, J = 9.4, 2.6 Hz, 2H), 4.23 (t, J = 6.5) Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.22 (d, J = 6.5 Hz, 2H)
2020 1H NMR (400 MHz, DMSO-d 6) δ 8.45 (s, 3H), 8.35 (t, J = 1.7 Hz, 1H), 8.12 (dt, J = 8.1, 1.3 Hz, 1H), 8.09 (d, J = 8.4 Hz, 2H), 8.00 (dq, J = 7.9, 1.0 Hz, 1H), 7.71-7.76 (m, 3H), 7.53 (d, J = 8.0 Hz, 2H), 7.09 (dt, J = 9.5, 2.5 Hz, 2H), 4.24 (t, J = 6.3 Hz, 1H), 3.23 (d, J = 6.5 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.45 (s, 3H), 8.35 (t, J = 1.7 Hz, 1H), 8.12 (dt, J = 8.1, 1.3 Hz, 1H), 8.09 (d, J = 8.4 Hz, 2H), 8.00 (dq, J = 7.9, 1.0 Hz, 1H), 7.71-7.76 (m, 3H), 7.53 (d, J = 8.0 Hz, 2H), 7.09 (dt, J = 9.5) , 2.5 Hz, 2H), 4.24 (t, J = 6.3 Hz, 1H), 3.23 (d, J = 6.5 Hz, 2H)
2121 1H NMR (400 MHz, DMSO-d 6) δ 9.62 (s, 1H), 8.44 (s, 3H), 8.12 (dd, J = 8.5, 2.1 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.38 (dt, J = 9.2, 2.3 Hz, 2H), 7.35 (d, J = 8.9 Hz, 1H), 6.86 (dt, J = 9.2, 2.3 Hz, 2H), 4.23 (t, J = 6.4 Hz, 1H), 3.89 (s, 3H), 3.22 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.62 (s, 1H), 8.44 (s, 3H), 8.12 (dd, J = 8.5, 2.1 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.38 (dt, J = 9.2, 2.3 Hz, 2H), 7.35 (d, J = 8.9 Hz, 1H), 6.86 (dt, J = 9.2, 2.3 Hz, 2H), 4.23 (t, J = 6.4 Hz, 1H), 3.89 (s, 3H), 3.22 (d, J = 6.4 Hz, 2H)
2222 LCMS [M+H] 445.18LCMS [M+H] 445.18
2323 1H NMR (400 MHz, DMSO-d 6) δ 9.64 (s, 1H), 8.23 (s, 3H), 8.13 (dd, J = 8.5, 2.3 Hz, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 2.3 Hz, 1H), 7.97 (s, 1H), 7.60 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.38 (dt, J = 8.4, 2.8 Hz, 2H), 7.35 (d, J = 8.7 Hz, 1H), 6.86 (dt, J = 8.4, 2.8 Hz, 2H), 4.02 (t, J = 6.9 Hz, 1H), 3.89 (s, 3H), 3.20 (dd, J = 13.7, 6.0 Hz, 1H), 3.10 (dd, J = 13.9, 7.4 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.64 (s, 1H), 8.23 (s, 3H), 8.13 (dd, J = 8.5, 2.3 Hz, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 2.3 Hz, 1H), 7.97 (s, 1H), 7.60 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.38 (dt, J = 8.4, 2.8) Hz, 2H), 7.35 (d, J = 8.7 Hz, 1H), 6.86 (dt, J = 8.4, 2.8 Hz, 2H), 4.02 (t, J = 6.9 Hz, 1H), 3.89 (s, 3H), 3.20 (dd, J = 13.7, 6.0 Hz, 1H), 3.10 (dd, J = 13.9, 7.4 Hz, 1H)
2424 1H NMR (400 MHz, DMSO-d 6) δ 9.62 (s, 1H), 8.59 (s, 3H), 8.13 (dd, J = 8.8, 2.3 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.37-7.40 (dt, J = 8.4, 3.2 Hz, 2H), 7.35 (d, J = 9.2 Hz, 1H), 6.86 (dt, J = 8.4, 3.2 Hz, 2H), 4.34 (t, J = 6.7 Hz, 1H), 4.10-4.20 (m, 2H), 3.90 (s, 3H), 3.28 (dd, J = 13.9, 5.9 Hz, 1H), 3.17 (dd, J = 13.9, 7.8 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.62 (s, 1H), 8.59 (s, 3H), 8.13 (dd, J = 8.8, 2.3 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.37-7.40 (dt, J = 8.4, 3.2 Hz, 2H), 7.35 (d, J = 9.2) Hz, 1H), 6.86 (dt, J = 8.4, 3.2 Hz, 2H), 4.34 (t, J = 6.7 Hz, 1H), 4.10-4.20 (m, 2H), 3.90 (s, 3H), 3.28 (dd , J = 13.9, 5.9 Hz, 1H), 3.17 (dd, J = 13.9, 7.8 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H)
2525 1H NMR (400 MHz, DMSO-d 6) δ 8.45 (s, 3H), 8.19 (dd, J = 8.7, 2.3 Hz, 1H), 8.03-8.06 (m, 3H), 7.50 (d, J = 8.2 Hz, 2H), 7.37-7.40 (m, 2H), 7.09-7.11 (m, 2H), 6.98 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H), 4.23 (t, J = 6.4 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.22 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.45 (s, 3H), 8.19 (dd, J = 8.7, 2.3 Hz, 1H), 8.03-8.06 (m, 3H), 7.50 (d, J = 8.2) Hz, 2H), 7.37-7.40 (m, 2H), 7.09-7.11 (m, 2H), 6.98 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H), 4.23 (t, J = 6.4 Hz, 1H) , 3.90 (s, 3H), 3.80 (s, 3H), 3.22 (d, J = 6.4 Hz, 2H)
2626 1H NMR (400 MHz, DMSO-d 6) δ 9.56 (s, 1H), 8.17 (s, 2H), 8.16 (dd, J = 8.7, 1.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 2H), 7.99 (d, J = 1.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.7 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 6.94-6.95 (m, J = 2.1 Hz, 2H), 6.80 (dd, J = 8.0, 2.1 Hz, 1H), 4.11 (t, J = 5.5 Hz, 1H), 3.90 (s, 3H), 3.22 (dd, J = 14.7, 6.4 Hz, 1H), 3.16 (dd, J = J = 14.7, 6.4 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.56 (s, 1H), 8.17 (s, 2H), 8.16 (dd, J = 8.7, 1.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 2H), 7.99 (d, J = 1.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.7 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H) , 6.94-6.95 (m, J = 2.1 Hz, 2H), 6.80 (dd, J = 8.0, 2.1 Hz, 1H), 4.11 (t, J = 5.5 Hz, 1H), 3.90 (s, 3H), 3.22 ( dd, J = 14.7, 6.4 Hz, 1H), 3.16 (dd, J = J = 14.7, 6.4 Hz, 1H)
2727 1H NMR (400 MHz, DMSO-d 6) δ 8.40 (s, 3H), 8.18 (dd, J = 8.7, 2.3 Hz, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.37-7.42 (m, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.22 (dd, J = 7.5, 1.7 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.03 (td, J = 7.5, 0.9 Hz, 1H), 4.23 (t, J = 6.4 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.16-3.25 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.40 (s, 3H), 8.18 (dd, J = 8.7, 2.3 Hz, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.37-7.42 (m, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.22 (dd, J = 7.5, 1.7) Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.03 (td, J = 7.5, 0.9 Hz, 1H), 4.23 (t, J = 6.4 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.16-3.25 (m, 2H)
2828 1H NMR (400 MHz, DMSO-d 6) δ 9.46 (s, 1H), 8.35 (s, 2H), 8.14 (dd, J = 8.7, 2.3 Hz, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.94 (d, J = 2.3 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.7 Hz, 1H), 7.20 (td, J = 7.8, 1.5 Hz, 1H), 7.16 (dd, J = 7.6, 1.6 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.85 (td, J = 7.4, 1.1 Hz, 1H), 4.08 (t, J = 6.2 Hz, 1H), 3.84 (s, 3H), 3.23 (dd, J = 14.2, 6.0 Hz, 1H), 3.16 (dd, J = 14.2, 6.0 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.46 (s, 1H), 8.35 (s, 2H), 8.14 (dd, J = 8.7, 2.3 Hz, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.94 (d, J = 2.3 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.7 Hz, 1H), 7.20 (td, J = 7.8, 1.5 Hz, 1H), 7.16 (dd, J = 7.6, 1.6 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.85 (td, J = 7.4, 1.1 Hz, 1H), 4.08 (t, J = 6.2) Hz, 1H), 3.84 (s, 3H), 3.23 (dd, J = 14.2, 6.0 Hz, 1H), 3.16 (dd, J = 14.2, 6.0 Hz, 1H)
2929 1H NMR (400 MHz, DMSO-d 6) δ 8.44 (s, 3H), 8.07 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.39-7.43 (m, 3H), 7.30-7.33 (m, 2H), 7.21 (dd, J = 8.9, 2.7 Hz, 1H), 7.05 (d, J = 2.7 Hz, 1H), 4.14 (t, J = 6.0 Hz, 1H), 3.92 (s, 3H), 3.15-3.23 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.44 (s, 3H), 8.07 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.39-7.43 (m, 3H), 7.30-7.33 (m, 2H), 7.21 (dd, J = 8.9, 2.7 Hz, 1H), 7.05 (d, J = 2.7 Hz, 1H), 4.14 (t, J = 6.0 Hz, 1H), 3.92 (s, 3H), 3.15-3.23 (m, 2H)
3030 1H NMR (400 MHz, DMSO-d 6) δ 8.38 (s, 3H), 8.03 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.23 (dt, J = 9.4, 2.5 Hz, 2H), 7.17 (dd, J = 8.7, 2.6 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.97 (dt, J = 9.5, 2.6 Hz, 2H), 4.17 (t, J = 6.4 Hz, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.15-3.24 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.38 (s, 3H), 8.03 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.23 (dt, J = 9.4, 2.5 Hz, 2H), 7.17 (dd, J = 8.7, 2.6 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.97 (dt, J = 9.5, 2.6 Hz, 2H), 4.17 (t, J = 6.4 Hz, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.15-3.24 (m, 2H)
3131 1H NMR (400 MHz, DMSO-d 6) δ 9.70 (s, 1H), 8.42 (s, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.13 (dd, J = 8.7, 2.7 Hz, 1H), 7.09 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 2.3 Hz, 1H), 6.77 (d, J = 8.2 Hz, 2H), 3.89 (s, 3H), 3.86 (t, J = 6.1 Hz, 1H), 3.21 (dd, J = 14.7, 5.0 Hz, 1H), 3.08 (dd, J = 14.7, 5.0 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.70 (s, 1H), 8.42 (s, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H) , 7.45 (d, J = 8.2 Hz, 2H), 7.13 (dd, J = 8.7, 2.7 Hz, 1H), 7.09 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 2.3 Hz, 1H) , 6.77 (d, J = 8.2 Hz, 2H), 3.89 (s, 3H), 3.86 (t, J = 6.1 Hz, 1H), 3.21 (dd, J = 14.7, 5.0 Hz, 1H), 3.08 (dd, J = 14.7, 5.0 Hz, 1H)
3232 1H NMR (400 MHz, DMSO-d 6) δ 13.92 (s, 1H), 11.72 (s, 1H), 8.49 (s, 3H), 8.47 (d, J = 1.5 Hz, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.91 (dd, J = 8.5, 1.8 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.55 (t, J = 2.7 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 6.68 (t, J = 2.1 Hz, 1H), 4.26 (t, J = 5.2 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.92 (s, 1H), 11.72 (s, 1H), 8.49 (s, 3H), 8.47 (d, J = 1.5 Hz, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.91 (dd, J = 8.5, 1.8 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.55 (t, J = 2.7 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 6.68 (t, J = 2.1 Hz, 1H), 4.26 (t, J = 5.2 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H)
3333 1H NMR (400 MHz, DMSO-d 6) δ 8.73 (s, 1H), 8.47 (s, 3H), 8.35 (s, 1H), 8.13 (dd, J = 8.9, 0.6 Hz, 1H), 8.08 (d, J = 8.2 Hz, 2H), 7.81 (dd, J = 8.9, 0.6 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 4.27 (q, J = 5.4 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.73 (s, 1H), 8.47 (s, 3H), 8.35 (s, 1H), 8.13 (dd, J = 8.9, 0.6 Hz, 1H), 8.08 ( d, J = 8.2 Hz, 2H), 7.81 (dd, J = 8.9, 0.6 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 4.27 (q, J = 5.4 Hz, 1H), 3.24 ( d, J = 6.4 Hz, 2H)
3434 1H NMR (400 MHz, DMSO-d 6) δ 8.43 (s, 3H), 8.03 (d, J = 8.2 Hz, 2H), 7.68 (dd, J = 8.5, 2.1 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.5 Hz, 1H), 4.34-4.38 (m, 4H), 4.23 (t, J = 6.4 Hz, 1H), 3.16-3.26 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.43 (s, 3H), 8.03 (d, J = 8.2 Hz, 2H), 7.68 (dd, J = 8.5, 2.1 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.5 Hz, 1H), 4.34-4.38 (m, 4H), 4.23 (t, J = 6.4 Hz, 1H), 3.16-3.26 (m, 2H)
3535 1H NMR (400 MHz, DMSO-d 6) δ 8.47 (s, 3H), 8.03 (d, J = 8.4 Hz, 2H), 7.78 (dd, J = 8.2, 1.7 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 1H), 6.21 (s, 2H), 4.23 (t, J = 6.5 Hz, 1H), 3.22 (d, J = 6.5 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.47 (s, 3H), 8.03 (d, J = 8.4 Hz, 2H), 7.78 (dd, J = 8.2, 1.7 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 1H), 6.21 (s, 2H), 4.23 (t, J = 6.5 Hz, 1H) , 3.22 (d, J = 6.5 Hz, 2H)
3636 1H NMR (400 MHz, DMSO-d 6) δ 9.06 (d, J = 1.5 Hz, 1H), 8.49 (s, 3H), 8.41 (d, J = 7.3 Hz, 1H), 8.35 (dd, J = 8.7, 2.0 Hz, 1H), 8.10 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.63 (td, J = 7.8, 1.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.48-7.52 (m, 1H), 4.25 (t, J = 6.4 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.06 (d, J = 1.5 Hz, 1H), 8.49 (s, 3H), 8.41 (d, J = 7.3 Hz, 1H), 8.35 (dd, J = 8.7, 2.0 Hz, 1H), 8.10 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.63 (td, J = 7.8, 1.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.48-7.52 (m, 1H), 4.25 (t, J = 6.4 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H)
3737 1H-NMR (400 MHz, DMSO-d 6) δ 8.02 (d, J = 8.2 Hz, 2H), 7.96 (dt, J = 9.7, 2.4 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 6.87 (dt, J = 9.8, 2.3 Hz, 2H), 4.23 (q, J = 5.5 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H), 3.05 (s, 6H) 1 H-NMR (400 MHz, DMSO- d 6 ) δ 8.02 (d, J = 8.2 Hz, 2H), 7.96 (dt, J = 9.7, 2.4 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H) ), 6.87 (dt, J = 9.8, 2.3 Hz, 2H), 4.23 (q, J = 5.5 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H), 3.05 (s, 6H)
3838 1H-NMR (400 MHz, DMSO-d 6) δ 8.47 (s, 2H), 8.11 (dd, J = 6.6, 1.7 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.52 (dd, J = 8.4, 6.6 Hz, 4H), 7.34-7.27 (m, 4H), 7.24-7.19 (m, 1H), 4.24 (t, J = 6.4 Hz, 1H), 4.08 (s, 2H), 3.23 (d, J = 6.4 Hz, 2H) 1 H-NMR (400 MHz, DMSO- d 6 ) δ 8.47 (s, 2H), 8.11 (dd, J = 6.6, 1.7 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.52 (dd , J = 8.4, 6.6 Hz, 4H), 7.34-7.27 (m, 4H), 7.24-7.19 (m, 1H), 4.24 (t, J = 6.4 Hz, 1H), 4.08 (s, 2H), 3.23 ( d, J = 6.4 Hz, 2H)
3939 1H-NMR (400 MHz, DMSO-d 6) δ 8.45 (s, 2H), 8.14 (dt, J = 9.6, 2.4 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.52-7.48 (m, 4H), 7.44-7.40 (m, 2H), 7.38-7.34 (m, 1H), 7.29 (dt, J = 9.6, 2.4 Hz, 2H), 5.25 (s, 2H), 4.24 (t, J = 6.6 Hz, 1H), 3.22 (d, J = 6.4 Hz, 2H) 1 H-NMR (400 MHz, DMSO- d 6 ) δ 8.45 (s, 2H), 8.14 (dt, J = 9.6, 2.4 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.52-7.48 (m, 4H), 7.44-7.40 (m, 2H), 7.38-7.34 (m, 1H), 7.29 (dt, J = 9.6, 2.4 Hz, 2H), 5.25 (s, 2H), 4.24 (t, J) = 6.6 Hz, 1H), 3.22 (d, J = 6.4 Hz, 2H)
4040 1H-NMR (400 MHz, DMSO-d 6) δ10.52 (s, 1H), 8.45 (s, 3H), 8.13 (dd, J = 7.0, 1.8 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.25 (t, J = 6.4 Hz, 1H), 3.23 (d, J = 6.7 Hz, 2H), 2.12 (s, 3H) 1 H-NMR (400 MHz, DMSO- d 6 ) δ10.52 (s, 1H), 8.45 (s, 3H), 8.13 (dd, J = 7.0, 1.8 Hz, 2H), 8.04 (d, J = 8.2) Hz, 2H), 7.88 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.25 (t, J = 6.4 Hz, 1H), 3.23 (d, J = 6.7 Hz, 2H), 2.12 (s, 3H)
4141 1H-NMR (400 MHz, DMSO-d 6) δ 10.71 (s, 1H), 8.40 (s, 2H), 8.19 (d, J = 8.9 Hz, 2H), 8.12-8.10 (m, 2H), 8.05 (d, J = 8.2 Hz, 2H), 8.00-7.98 (m, 2H), 7.65-7.61 (m, 1H), 7.58-7.54 (m, 2H), 7.51 (d, J = 8.5 Hz, 2H), 4.24 (t, J = 6.6 Hz, 1H), 3.21 (d, J = 4.9 Hz, 2H) 1 H-NMR (400 MHz, DMSO- d 6 ) δ 10.71 (s, 1H), 8.40 (s, 2H), 8.19 (d, J = 8.9 Hz, 2H), 8.12-8.10 (m, 2H), 8.05 (d, J = 8.2 Hz, 2H), 8.00-7.98 (m, 2H), 7.65-7.61 (m, 1H), 7.58-7.54 (m, 2H), 7.51 (d, J = 8.5 Hz, 2H), 4.24 (t, J = 6.6 Hz, 1H), 3.21 (d, J = 4.9 Hz, 2H)
4242 1H-NMR (400 MHz, DMSO-d 6) δ 11.05 (s, 1H), 9.63 (s, 1H), 9.27 (s, 1H), 8.36 (s, 2H), 8.13 (dd, J = 8.5, 2.1 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.39-7.34 (m, 4H), 6.86 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 3.82 (t, J = 6.9 Hz, 1H), 3.10 (d, J = 6.4 Hz, 2H) 1 H-NMR (400 MHz, DMSO- d 6 ) δ 11.05 (s, 1H), 9.63 (s, 1H), 9.27 (s, 1H), 8.36 (s, 2H), 8.13 (dd, J = 8.5, 2.1 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.39-7.34 (m, 4H) , 6.86 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 3.82 (t, J = 6.9 Hz, 1H), 3.10 (d, J = 6.4 Hz, 2H)
4343 LCMS [M+H] 491.19LCMS [M+H] 491.19
실험예 2: 트립토판 수산화효소 활성 저해 효과Experimental Example 2: Inhibitory effect of tryptophan hydroxylase activity
상기 제조예를 통해 합성된 실시예 1 내지 43의 화합물의 트립토판 수산화효소(tryptophan hydroxylase) 활성 저해 효과를 확인하기 위하여, TPH1(TRYPTOPHAN HYDROXYLASE 1) Inhibitor Screening Assay Kit(BPS Bioscience, Catalog # 72053)를 사용하여 테스트하였다. 상기 TPH1 Inhibitor Screening Assay Kit는 제조사의 매뉴얼에 따라 사용하였으며, 그 결과를 하기 표 3에 나타내었다.In order to confirm the tryptophan hydroxylase activity inhibitory effect of the compounds of Examples 1 to 43 synthesized through the above preparation examples, TPH1 (TRYPTOPHAN HYDROXYLASE 1) Inhibitor Screening Assay Kit (BPS Bioscience, Catalog # 72053) was used. and tested. The TPH1 Inhibitor Screening Assay Kit was used according to the manufacturer's manual, and the results are shown in Table 3 below.
구체적으로, 합성한 화합물을 DMSO에 용해시킨 후 96웰 마이크로플레이트에 10 μL의 화합물을 넣고 40 μL의 TPH1 효소를 첨가하였다. 이어 50 μL의 TPH1 반응 용액을 추가한 후 마이크로플레이트는 알루미늄 호일로 차광하였다. 마이크로플레이트를 4℃ 환경에 옮기고, 조심스럽게 흔든 후 4시간 동안 배양하였다. 이후 10 μL의 quench 솔루션을 추가하고 Flexstation3 마이크로플레이트 리더에서 형광 발색 정도를 읽어 TPH1 활성을 측정하였다. 이때 들뜸(excitation) 스펙트럼은 300 nm 파장, 방출(emission) 스펙트럼은 360 nm 파장에서 측정하였다.Specifically, after dissolving the synthesized compound in DMSO, 10 μL of the compound was placed in a 96-well microplate, and 40 μL of TPH1 enzyme was added. Then, after adding 50 μL of TPH1 reaction solution, the microplate was shielded from light with aluminum foil. The microplate was transferred to a 4°C environment, shaken carefully, and incubated for 4 hours. Then, 10 μL of quench solution was added and TPH1 activity was measured by reading the degree of fluorescence in a Flexstation3 microplate reader. At this time, the excitation spectrum was measured at a wavelength of 300 nm, and the emission spectrum was measured at a wavelength of 360 nm.
실시예Example TPH1 활성도 (% inhibition at 1 μM)TPH1 activity (% inhibition at 1 μM) 실시예Example TPH1 활성도 (% inhibition at 1 μM)TPH1 activity (% inhibition at 1 μM)
1One ＜5<5 2323 ＜5<5
22 53.553.5 2424 80.780.7
33 ＜5<5 2525 90.790.7
44 ＜5<5 2626 96.796.7
55 ＜5<5 2727 98.898.8
66 67.667.6 2828 97.097.0
77 47.047.0 2929 30.130.1
88 86.386.3 3030 44.844.8
99 84.984.9 3131 43.543.5
1010 39.339.3 3232 ＜5<5
1111 ＜5<5 3333 ＜5<5
1212 6.16.1 3434 ＜5<5
1313 ＜5<5 3535 ＜5<5
1414 41.541.5 3636 12.212.2
1515 42.442.4 3737 ＜5<5
1616 ＜5<5 3838 ＜5<5
1717 38.038.0 3939 ＜5<5
1818 96.596.5 4040 ＜5<5
1919 100100 4141 ＜5<5
2020 32.232.2 4242 17.717.7
2121 100100 4343 78.778.7
2222 7.47.4
상기와 같이, 본 발명에 따른 화학식 1로 표시되는 화합물은 TPH1에 대한 저해 효과가 우수한 바, TPH1의 활성과 관련된 질환인 대사질환, 암, 소화기계 질환 또는 순환기계 질환의 예방 또는 치료에 유용하게 사용될 수 있다.As described above, the compound represented by Formula 1 according to the present invention has an excellent inhibitory effect on TPH1, so it is useful for preventing or treating metabolic diseases, cancer, digestive system diseases, or circulatory system diseases, which are diseases related to TPH1 activity. can be used
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시 예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로서 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the claims described below and their equivalents.

Claims (15)

  1. 하기 화학식 1로 표시되는 화합물, 이의 이성질체, 또는 이들의 약학적으로 허용 가능한 염:A compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2022000339-appb-img-000071
    Figure PCTKR2022000339-appb-img-000071
    상기 화학식 1에서,In Formula 1,
    n은 0 내지 2의 정수,n is an integer from 0 to 2,
    R1은 히드록시, 아미노, C1-6 알콕시, 히드록시-C1-4 알콕시, 또는 히드록시-아미노,R 1 is hydroxy, amino, C 1-6 alkoxy, hydroxy-C 1-4 alkoxy, or hydroxy-amino,
    R2 내지 R6은 각각 독립적으로 수소, 히드록시, 니트로, 시아노, 할로, C1-6 할로알킬, C1-6 알콕시, C1-6 할로알콕시, C1-4 알킬아미노, 디(C1-4 알킬)아미노, C1-4 알킬카보닐, C1-4 알킬카보닐아미노, C6-10 아릴카보닐아미노, C6-14 아릴, C6-10 아릴-C1-4 알킬, C6-10 아릴-C1-4 알콕시, C1-4 알콕시-C6-10 아릴, 또는R 2 To R 6 are each independently hydrogen, hydroxy, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-4 alkylamino, di( C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonylamino, C 6-10 arylcarbonylamino, C 6-14 aryl, C 6-10 aryl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkoxy, C 1-4 alkoxy-C 6-10 aryl, or
    R3 및 R4가 서로 연결되어 C3-14 헤테로사이클릴, 또는 C5-14 헤테로아릴을 형성하고,R 3 and R 4 are linked to each other to C 3-14 heterocyclyl, or form C 5-14 heteroaryl;
    상기 아릴, 헤테로아릴 및 헤테로사이클릴은 각각 독립적으로 비치환 또는 히드록시, 옥소, C1-4 알콕시, 또는 C1-4 할로알킬로 치환됨.wherein said aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with hydroxy, oxo, C 1-4 alkoxy, or C 1-4 haloalkyl.
  2. 제1항에 있어서,According to claim 1,
    n은 0 또는 1인 것인, 화합물, 이의 이성질체 또는 이들의 약학적으로 허용 가능한 염.n is 0 or 1, the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  3. 제1항에 있어서,According to claim 1,
    R1은 히드록시, 아미노, 에톡시, 히드록시에톡시, 또는 히드록시아미노인 것인, 화합물, 이의 이성질체 또는 이들의 약학적으로 허용 가능한 염.R 1 is hydroxy, amino, ethoxy, hydroxyethoxy, or hydroxyamino. A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  4. 제1항에 있어서,According to claim 1,
    R2는 수소, 페닐, 히드록시페닐, 또는 메톡시페닐인 것인, 화합물, 이의 이성질체 또는 이들의 약학적으로 허용 가능한 염.R 2 is hydrogen, phenyl, hydroxyphenyl, or methoxyphenyl, a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  5. 제1항에 있어서,According to claim 1,
    R3은 수소, 브로모, 니트로, 메톡시, 페닐, 히드록시페닐, 또는 메톡시페닐인 것인, 화합물, 이의 이성질체 또는 이들의 약학적으로 허용 가능한 염.R 3 is hydrogen, bromo, nitro, methoxy, phenyl, hydroxyphenyl, or methoxyphenyl, a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  6. 제1항에 있어서,According to claim 1,
    R4는 수소, 히드록시, 니트로, 시아노, 플루오로, 브로모, 아이오도, 메톡시, 에톡시, 아세틸, 메틸카보닐아미노, 페닐카보닐아미노, 페닐메톡시, 페닐메틸, 디메틸아미노, 트리플루오로메틸, 또는 트리플루오로메톡시인 것인, 화합물, 이의 이성질체 또는 이들의 약학적으로 허용 가능한 염.R 4 is hydrogen, hydroxy, nitro, cyano, fluoro, bromo, iodo, methoxy, ethoxy, acetyl, methylcarbonylamino, phenylcarbonylamino, phenylmethoxy, phenylmethyl, dimethylamino, A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is trifluoromethyl, or trifluoromethoxy.
  7. 제1항에 있어서,According to claim 1,
    R3 및 R4가 서로 연결되어 디옥솔라닐, 디옥사닐, 피라졸릴, 피롤린, 또는 벤조퓨라닐을 형성하는 것인, 화합물, 이의 이성질체 또는 이들의 약학적으로 허용 가능한 염.R 3 and R 4 are linked to each other to form dioxolanyl, dioxanyl, pyrazolyl, pyrroline, or benzofuranyl, a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  8. 제1항에 있어서,According to claim 1,
    R5 및 R6은 모두 수소인 것인, 화합물, 이의 이성질체 또는 이들의 약학적으로 허용 가능한 염.R 5 and R 6 are both hydrogen. A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  9. 제1항에 있어서,According to claim 1,
    상기 화합물은The compound is
    1. (S)-2-아미노-3-(4-(5-페닐-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),1. (S)-2-amino-3-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2-amino-3-( 4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    2. (S)-2-아미노-3-(4-(5-(4-메톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),2. (S)-2-amino-3-(4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    3. (S)-2-아미노-3-(4-(5-(3-메톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),3. (S)-2-amino-3-(4-(5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    4. (S)-2-아미노-3-(4-(5-(4-히드록시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),4. (S)-2-amino-3-(4-(5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    5. (S)-2-아미노-3-(4-(5-(4-에톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),5. (S)-2-amino-3-(4-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    6. (S)-2-아미노-3-(4-(5-(3,4-디메톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),6. (S)-2-amino-3-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S) -2-amino-3-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    7. (S)-2-아미노-3-(4-(5-(4-플루오로페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),7. (S)-2-amino-3-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    8. (S)-2-아미노-3-(4-(5-(4-브로모페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),8. (S)-2-amino-3-(4-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    9. (S)-2-아미노-3-(4-(5-(4-아이오도페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-iodophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),9. (S)-2-amino-3-(4-(5-(4-iodophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-iodophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    10. (S)-2-아미노-3-(4-(5-(4-(트리플루오로메틸)페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),10. (S)-2-amino-3-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (( S)-2-amino-3-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    11. (S)-2-아미노-3-(4-(5-(4-(트리플루오로메톡시)페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),11. (S)-2-amino-3-(4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (( S)-2-amino-3-(4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    12. (S)-2-아미노-3-(4-(5-(4-시아노페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),12. (S)-2-amino-3-(4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    13. (S)-3-(4-(5-(4-아세틸페닐)-1,2,4-옥사디아졸-3-일)페닐)-2-아미노프로판산((S)-3-(4-(5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),13. (S)-3-(4-(5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S)-3- (4-(5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),
    14. (S)-2-아미노-3-(4-(5-(4-니트로페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),14. (S)-2-amino-3-(4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2- amino-3-(4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    15. (S)-2-아미노-3-(4-(5-(4-메톡시-3-니트로페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-methoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),15. (S)-2-amino-3-(4-(5-(4-methoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (( S)-2-amino-3-(4-(5-(4-methoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    16. (S)-2-아미노-3-(4-(5-(4-메톡시벤질)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),16. (S)-2-amino-3-(4-(5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    17. (S)-2-아미노-3-(4-(5-(3-브로모-4-메톡시페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(3-bromo-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),17. (S)-2-amino-3-(4-(5-(3-bromo-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ( (S)-2-amino-3-(4-(5-(3-bromo-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    18. (S)-2-아미노-3-(4-(5-(6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),18. (S)-2-amino-3-(4-(5-(6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ( (S)-2-amino-3-(4-(5-(6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    19. (S)-2-아미노-3-(4-(5-(4',6-디메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),19. (S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    20. (S)-2-아미노-3-(4-(5-(4'-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4'-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),20. (S)-2-amino-3-(4-(5-(4'-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(4'-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    21. (S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),21. (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),
    22. (S)-2-아미노-3-(4-(5-(4',6-디메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판아미드((S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide),22. (S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanamide ((S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide),
    23. (S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판아미드((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide),23. (S)-2-Amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanamide ((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl )propanamide),
    24. (S)-에틸 2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로파노에이트((S)-ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate),24. (S)-Ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole-3- yl)phenyl)propanoate ((S)-ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3- yl)phenyl)propanoate),
    25. (S)-2-아미노-3-(4-(5-(3',6-디메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(3',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),25. (S)-2-amino-3-(4-(5-(3',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(3',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    26. (S)-2-아미노-3-(4-(5-(3'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(3'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),26. (S)-2-amino-3-(4-(5-(3'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(3'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),
    27. (S)-2-아미노-3-(4-(5-(2',6-디메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(2',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),27. (S)-2-amino-3-(4-(5-(2',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(2',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    28. (S)-2-아미노-3-(4-(5-(2'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(2'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),28. (S)-2-amino-3-(4-(5-(2'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(2'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),
    29. (S)-2-아미노-3-(4-(5-(5-메톡시바이페닐-2-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),29. (S)-2-amino-3-(4-(5-(5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ( (S)-2-amino-3-(4-(5-(5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    30. (S)-2-아미노-3-(4-(5-(4',5-디메톡시바이페닐-2-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4',5-dimethoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),30. (S)-2-amino-3-(4-(5-(4',5-dimethoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(4',5-dimethoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    31. (S)-2-아미노-3-(4-(5-(4'-히드록시-5-메톡시바이페닐-2-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4'-hydroxy-5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),31. (S)-2-amino-3-(4-(5-(4'-hydroxy-5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(4'-hydroxy-5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),
    32. (S)-3-(4-(5-(1H-인돌-6-일)-1,2,4-옥사디아졸-3-일)페닐)-2-아미노프로판산((S)-3-(4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),32. (S)-3-(4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S) -3-(4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),
    33. (S)-3-(4-(5-(1H-인다졸-6-일)-1,2,4-옥사디아졸-3-일)페닐)-2-아미노프로판산((S)-3-(4-(5-(1H-indazol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),33. (S)-3-(4-(5-(1H-indazol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S) )-3-(4-(5-(1H-indazol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),
    34. (S)-2-아미노-3-(4-(5-(2,3-디하이드로벤조[b][1,4]디옥신-6-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),34. (S)-2-amino-3-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,4-oxadia zol-3-yl)phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1, 2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    35. (S)-2-아미노-3-(4-(5-(벤조[d][1,3]디옥솔-5-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),35. (S)-2-amino-3-(4-(5-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-3-yl) Phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-3-yl) phenyl) propanoic acid),
    36. (S)-2-아미노-3-(4-(5-(디벤조[b,d]퓨란-2-일)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(dibenzo[b,d]furan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),36. (S)-2-amino-3-(4-(5-(dibenzo[b,d]furan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propane acid ((S)-2-amino-3-(4-(5-(dibenzo[b,d]furan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    37. (S)-2-아미노-3-(4-(5-(4-(디메틸아미노)페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-(dimethylamino)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),37. (S)-2-amino-3-(4-(5-(4-(dimethylamino)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S) -2-amino-3-(4-(5-(4-(dimethylamino)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    38. (S)-2-아미노-3-(4-(5-(4-벤질페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),38. (S)-2-amino-3-(4-(5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2- amino-3-(4-(5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    39. (S)-2-아미노-3-(4-(5-(4-(벤질옥시)페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),39. (S)-2-amino-3-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S) -2-amino-3-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    40. (S)-3-(4-(5-(4-아세트아미도페닐)-1,2,4-옥사디아졸-3-일)페닐)-2-아미노프로판산((S)-3-(4-(5-(4-acetamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),40. (S)-3-(4-(5-(4-acetamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S)- 3-(4-(5-(4-acetamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),
    41. (S)-2-아미노-3-(4-(5-(4-벤즈아미도페닐)-1,2,4-옥사디아졸-3-일)페닐)프로판산((S)-2-amino-3-(4-(5-(4-benzamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),41. (S)-2-amino-3-(4-(5-(4-benzamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)- 2-amino-3-(4-(5-(4-benzamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
    42. (S)-2-아미노-N-히드록시-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)프로판아미드((S)-2-amino-N-hydroxy-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide), 또는42. (S)-2-Amino-N-hydroxy-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadia zol-3-yl)phenyl)propanamide ((S)-2-amino-N-hydroxy-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2, 4-oxadiazol-3-yl)phenyl)propanamide), or
    43. (S)-2-아미노-3-(4-(5-(4'-히드록시-6-메톡시바이페닐-3-일)-1,2,4-옥사디아졸-3-일)페닐)-N-(2-히드록시에톡시)프로판아미드((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(2-hydroxyethoxy)propanamide)인 것인, 화합물, 이의 이성질체 또는 이들의 약학적으로 허용 가능한 염.43. (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)-N-(2-hydroxyethoxy)propanamide ((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1, 2,4-oxadiazol-3-yl)phenyl)-N-(2-hydroxyethoxy)propanamide), a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  10. 하기 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 합성하는 제1단계; 및A first step of synthesizing a compound represented by Formula 4 by reacting a compound represented by Formula 2 with a compound represented by Formula 3; and
    이전 단계로부터 수득한 화학식 4로 표시되는 화합물을 화학식 1로 표시되는 화합물로 전환하는 제2단계;를 포함하는, 화학식 1로 표시되는 화합물의 제조방법:A second step of converting the compound represented by Formula 4 obtained from the previous step into the compound represented by Formula 1; Method for preparing a compound represented by Formula 1, including:
    [화학식 1][Formula 1]
    Figure PCTKR2022000339-appb-img-000072
    Figure PCTKR2022000339-appb-img-000072
    [화학식 2][Formula 2]
    Figure PCTKR2022000339-appb-img-000073
    Figure PCTKR2022000339-appb-img-000073
    [화학식 3][Formula 3]
    Figure PCTKR2022000339-appb-img-000074
    Figure PCTKR2022000339-appb-img-000074
    [화학식 4][Formula 4]
    Figure PCTKR2022000339-appb-img-000075
    Figure PCTKR2022000339-appb-img-000075
    상기 화학식 1 내지 4에 있어서,In Formulas 1 to 4,
    n은 0 내지 2의 정수,n is an integer from 0 to 2,
    R1은 히드록시, 아미노, C1-6 알콕시, 히드록시-C1-4 알콕시, 또는 히드록시-아미노,R 1 is hydroxy, amino, C 1-6 alkoxy, hydroxy-C 1-4 alkoxy, or hydroxy-amino,
    R2 내지 R6은 각각 독립적으로 수소, 히드록시, 니트로, 시아노, 할로, C1-6 할로알킬, C1-6 알콕시, C1-6 할로알콕시, C1-4 알킬아미노, 디(C1-4 알킬)아미노, C1-4 알킬카보닐, C1-4 알킬카보닐아미노, C6-10 아릴카보닐아미노, C6-14 아릴, C6-10 아릴-C1-4 알킬, C6-10 아릴-C1-4 알콕시, C1-4 알콕시-C6-10 아릴, 또는R 2 To R 6 are each independently hydrogen, hydroxy, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-4 alkylamino, di( C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonylamino, C 6-10 arylcarbonylamino, C 6-14 aryl, C 6-10 aryl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkoxy, C 1-4 alkoxy-C 6-10 aryl, or
    R3 및 R4가 서로 연결되어 C3-14 헤테로사이클릴, 또는 C5-14 헤테로아릴을 형성하고,R 3 and R 4 are linked to each other to C 3-14 heterocyclyl, or form C 5-14 heteroaryl;
    R2' 내지 R6'은 각각 R2 내지 R6와 동일하거나, 이들의 전구체이며,R 2 ' to R 6 ' are each the same as R 2 to R 6 or a precursor thereof,
    상기 아릴, 헤테로아릴 및 헤테로사이클릴은 각각 독립적으로 비치환 또는 히드록시, 옥소, C1-4 알콕시, 또는 C1-4 할로알킬로 치환됨.wherein said aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with hydroxy, oxo, C 1-4 alkoxy, or C 1-4 haloalkyl.
  11. 제10항에 있어서,11. The method of claim 10,
    상기 화학식 2로 표시되는 화합물 중 R2' 내지 R6'에 아릴기를 통해 결합된 치환기를 포함하는 화합물은 R2' 내지 R6'의 보론산 유도체를 해당 치환기가 결합된 자리에 할로겐이 치환된 화학식 2의 화합물의 유도체와 반응시켜 준비하는 것인, 제조방법.Among the compounds represented by Formula 2, the compound including a substituent bonded to R 2 ' to R 6 ' through an aryl group is a boronic acid derivative of R 2 ' to R 6 ', in which a halogen is substituted at the site to which the substituent is bonded. A method for preparing by reacting with a derivative of the compound of formula (2).
  12. 제10항에 있어서,11. The method of claim 10,
    상기 화학식 3으로 표시되는 화합물은 (S)-2-아미노-3-(4-시아노페닐)프로판산으로부터 준비되는 것인, 제조방법.The compound represented by Formula 3 is prepared from (S)-2-amino-3-(4-cyanophenyl)propanoic acid.
  13. 제1항 내지 제9항 중 어느 한 항의 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 트립토판 수산화효소 저해용 조성물.A composition for inhibiting tryptophan hydroxylase, comprising the compound of any one of claims 1 to 9, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  14. 제1항 내지 제9항 중 어느 한 항의 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 대사성 질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for the prevention or treatment of metabolic diseases, comprising the compound of any one of claims 1 to 9, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  15. 제1항 내지 제9항 중 어느 한 항의 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암 질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer, comprising the compound of any one of claims 1 to 9, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
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