WO2018062978A1 - 신규 헤테로아릴 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 약학적으로 허용가능한 염, 및 이를 유효성분으로 함유하는 항바이러스용 조성물 - Google Patents
신규 헤테로아릴 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 약학적으로 허용가능한 염, 및 이를 유효성분으로 함유하는 항바이러스용 조성물 Download PDFInfo
- Publication number
- WO2018062978A1 WO2018062978A1 PCT/KR2017/011091 KR2017011091W WO2018062978A1 WO 2018062978 A1 WO2018062978 A1 WO 2018062978A1 KR 2017011091 W KR2017011091 W KR 2017011091W WO 2018062978 A1 WO2018062978 A1 WO 2018062978A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- oxadiazole
- bromobenzyl
- methyl
- chloro
- bromo
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 77
- -1 heteroaryl compound Chemical class 0.000 title claims abstract description 50
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- 125000000217 alkyl group Chemical group 0.000 claims description 36
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- 238000000034 method Methods 0.000 claims description 29
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- 125000003545 alkoxy group Chemical group 0.000 claims description 6
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- OHJHLJGLCHGPDD-UHFFFAOYSA-N 2-[(4-bromophenyl)methyl]-5-[2-(2-cyclohexylphenyl)ethenyl]-1,3,4-oxadiazole Chemical compound BrC1=CC=C(CC=2OC(=NN=2)C=CC2=C(C=CC=C2)C2CCCCC2)C=C1 OHJHLJGLCHGPDD-UHFFFAOYSA-N 0.000 claims description 4
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- BRZFFFQTPFNQLU-SOFGYWHQSA-N 2-[(E)-2-(2-chloro-4-fluorophenyl)ethenyl]-5-(2H-indazol-3-ylmethyl)-1,3,4-oxadiazole Chemical compound N1N=C(C2=CC=CC=C12)CC=1OC(=NN=1)\C=C\C1=C(C=C(C=C1)F)Cl BRZFFFQTPFNQLU-SOFGYWHQSA-N 0.000 claims description 4
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
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- 230000002401 inhibitory effect Effects 0.000 claims description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical group C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
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- 238000010298 pulverizing process Methods 0.000 claims description 4
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- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- IWUOZTYSMRPANH-UHFFFAOYSA-N (3-chloro-4-fluorophenyl)-[5-(2,6-dimethylanilino)-1,3,4-oxadiazol-2-yl]methanol Chemical compound ClC=1C=C(C=CC=1F)C(O)C=1OC(=NN=1)NC1=C(C=CC=C1C)C IWUOZTYSMRPANH-UHFFFAOYSA-N 0.000 claims description 2
- PTRBYPSEQQXBHR-UHFFFAOYSA-N (3-chloro-4-fluorophenyl)-[5-(2,6-dimethylanilino)-1,3,4-oxadiazol-2-yl]methanone Chemical compound ClC=1C=C(C=CC=1F)C(=O)C=1OC(=NN=1)NC1=C(C=CC=C1C)C PTRBYPSEQQXBHR-UHFFFAOYSA-N 0.000 claims description 2
- NZGPDNBLCUIVND-UHFFFAOYSA-N (4-bromo-3,5-dimethylpyrazol-1-yl)-[2-[(2-methylphenyl)methylsulfanyl]-1,3-oxazol-5-yl]methanone Chemical compound BrC=1C(=NN(C=1C)C(=O)C1=CN=C(O1)SCC1=C(C=CC=C1)C)C NZGPDNBLCUIVND-UHFFFAOYSA-N 0.000 claims description 2
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- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical group C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 2
- YLWIPJCZQQSRSW-UHFFFAOYSA-N 1-[2-[[5-[(4-bromo-3,5-dimethylpyrazol-1-yl)methyl]-1,3,4-oxadiazol-2-yl]sulfanylmethyl]phenyl]ethanone Chemical compound BrC=1C(=NN(C=1C)CC1=NN=C(O1)SCC1=C(C=CC=C1)C(C)=O)C YLWIPJCZQQSRSW-UHFFFAOYSA-N 0.000 claims description 2
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- MPUIMAPJRNEWEM-UHFFFAOYSA-N 2-(1-benzofuran-2-yl)-5-[(4-bromophenyl)methyl]-1,3,4-oxadiazole Chemical compound O1C(=CC2=C1C=CC=C2)C=1OC(=NN=1)CC1=CC=C(C=C1)Br MPUIMAPJRNEWEM-UHFFFAOYSA-N 0.000 claims description 2
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Images
Classifications
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
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- C07—ORGANIC CHEMISTRY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
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- C07D413/06—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 only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
Definitions
- the present invention relates to a novel heteroaryl compound, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, and an antiviral composition containing the same as an active ingredient.
- Influenza viruses are one of the most common viruses in the world, affecting both humans and livestock. Influenza virus is a highly contagious virus that causes acute respiratory disease, causing mass infections or pandemic all over the world, causing severe respiratory symptoms in children, the elderly and patients with cardiopulmonary disease. These influenza viruses belong to the orthomyxovirus taxonomically and there are three types of A, B and C, and in particular, the epidemic types are A and B.
- Influenza viruses are RNA enveloped viruses having a particle size of about 125 nm in diameter. Influenza viruses basically consist of an internal nucleocapsid or core of ribonucleic acid (RNA) bound to a nucleoprotein surrounded by a viral envelope having a lipid bilayer structure and an outer glycoprotein.
- the inner layer of the viral envelope consists mainly of matrix proteins, and the outer layer consists mostly of host-derived lipid material.
- Hemagglutinin is a trimer that consists of the head and the stem, the head of which is involved in most antigenic mutations and binds to the terminal sialic acid residues on the surface of the host cell to remove the virus. It attaches and enables a virus to infiltrate a host cell sequentially (nonpatent literature 2).
- Neuraminidase is a mushroom-shaped tetramer with a head and stem shape, with active sites on the top surface of the head, and the virus cloned and propagated in infected cells and the oligosaccharide part of the cell surface.
- the cleavage of alpha-ketosidic bonds, linking neuraminic acid residues, plays an important role in the release of viruses out of host cells and into respiratory mucosal cells.
- the surface antigens of the virus cause mutations in the same subtype, with new antigenic variants appearing each year.
- the avian influenza virus which has been a problem until recently, is infected with various kinds of birds such as chickens, turkeys, ducks, and wild birds, and more than 80% of chickens die due to rapid spread. It is a virus disease that causes the greatest damage and threat to the poultry industry, and its ramifications are not limited to the poultry industry, but are reported to cause disease in humans due to infections to the human body.
- influenza viruses have caused illnesses in humans.
- the three pandemic of the 20th century the Spanish flu (H1N1), about 30 million people, the Asian flu (H2N2), about 1 million people, and the Hong Kong flu ( H3N2) has reported about one million deaths.
- the 21st century there were 385 infections and 243 deaths from 2003 to 2008, and the recent influenza in April 2009 has already officially declared Fendermic at the WHO, and 260,000 infected patients worldwide.
- the number of deaths caused by infections exceeded 1000 in 20 countries, and a nun who had volunteered in Mexico in Korea was the first confirmed patient on May 2, 2009, and announced on September 16, 2009. More than 10,000 cases were infected, 8 were severely hospitalized, and 12 died of chronic or acute complications.
- M2 inhibitors which act as antiviral agents by blocking the ion channel of M2 protein, which is a cell membrane protein essential for virus propagation, prevent the virus from uncoating. It has been reported to be effective and tolerate viruses for 40 years of use, with serious side effects in the nervous system and stomach.
- Zanamivir and Oseltamivir are inhibitors of neuraminidase, which play an important role in the propagation of the virus and have a low frequency of resistance and are reliably present in both influenza A and B influenza viruses. Has been reported for the treatment of viral infections by new drugs.
- zanamivir has a high antiviral effect but low bioavailability and fast kidney discharge, and oseltamir has serious side effects of vomiting.
- Antiviral agents developed to date have serious side effects and require much attention for their application.
- the development of a vaccine has a problem that the effect is low if the virus of the virus and the type of the epidemic does not match, there is an increasing need for the development of a new influenza virus agent excellent in the inhibitory effect and excellent in stability.
- the present inventors while studying a compound having antiviral activity against influenza virus, identified a novel heteroaryl compound exhibiting excellent antiviral activity against influenza virus and completed the present invention.
- Another object of the present invention is to provide an antiviral pharmaceutical composition containing the novel compound, its enantiomer, diastereomer, or pharmaceutically acceptable salt as an active ingredient.
- Still another object of the present invention is to provide a nutraceutical composition for an antiviral containing a novel compound, its enantiomer, diastereomer, or food acceptable salt as an active ingredient.
- Another object of the present invention is to provide a virus disinfecting or cleaning composition containing a novel compound, an enantiomer or diastereomer thereof as an active ingredient.
- the present invention provides a compound represented by the following formula (1) or (2), an enantiomer, diastereomer or pharmaceutically acceptable salt thereof:
- the present invention provides a compound represented by the following formula 1a, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof:
- the present invention also provides a method for producing a novel compound represented by Formula 1 or Formula 2.
- the present invention provides a pharmaceutical composition for an antiviral containing a compound represented by Formula 1 or Formula 2, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention also provides an anti-viral health functional food composition containing the novel compound represented by Formula 1 or Formula 2, its enantiomer, diastereomer or food acceptable salt thereof as an active ingredient.
- the present invention provides a virus disinfecting or cleaning composition containing the compound represented by Formula 1 or Formula 2, an enantiomer or diastereomer thereof as an active ingredient.
- the virus may be an influenza virus.
- influenza virus may be influenza A virus or influenza B virus.
- influenza virus may be A / California / 07/2009 (H1N1), A / Perth / 16/2009 (H3N2) or B / Florida / 04/2006.
- the composition may be used for the prevention or treatment of diseases caused by viral infection.
- the disease caused by the virus infection is one influenza virus infection selected from the group consisting of flu, cold, sore throat, bronchitis, pneumonia, bird flu, swine flu and goat flu. May be due to a disease.
- novel compounds represented by Formula 1 or Formula 2 according to the present invention are not only excellent in antiviral activity against influenza virus, but also have low cytotoxicity and thus have fewer side effects on the human body, and thus contain a pharmaceutical composition as an active ingredient. Can be usefully used for the prevention or treatment of diseases caused by influenza virus infection.
- Figure 1a shows a phenotypic-based assay for measuring influenza infection.
- Figure 1b shows the results of evaluating the antiviral activity of Oseltamivir, T-705, and Nucleozin using a phenotype-based assay for measuring influenza infection.
- the antiviral agents developed to date have serious side effects and require much attention for their application.
- the development of a vaccine has a problem that the effect is low if the virus of the virus and the type of the epidemic does not match, there is an increasing need for the development of a new influenza virus agent excellent in the inhibitory effect and excellent in stability.
- a novel heteroaryl compound exhibiting excellent antiviral activity against influenza virus is identified, and the new compound, its enantiomer, diastereomer, pharmaceutically acceptable salt or food acceptable salt; And by providing an anti-viral composition containing this as an active ingredient, the solution for the above-mentioned problem was sought.
- the present invention provides a compound represented by the following formula (1) or (2), an enantiomer or diastereomer thereof:
- X 1 is O, S or -N (CH 2 CH 3 )-,
- X 2 and X 3 are each independently N or CH,
- R c is benzene
- R 1 is ; Unsubstituted or substituted, halogen, straight or branched chain type C 1- 4 alkyl, C 3-6 cycloalkyl, -OCF 3, -CF 3, -CHF 2, -OH, phenoxy, phenyl, C 1- 4 alkoxy, - Benzene substituted with one or more selected from the group consisting of CN, -NH 2 , and -N (CH 3 ) 2 ; ; ; Pyridine unsubstituted or substituted with halogen; Unsubstituted or substituted by C 1- 4 alkoxy naphthalene; Benzotriazole; Unsubstituted or substituted, C 1- 4 alkyl, C 1- 4 the quinoline or isopropyl substituted by alkoxy or halogen quinoline; Unsubstituted or C 1- 4 indazol-substituted with alkyl; C 3-6 cycloalkyl; Benzothiophen
- R a is halogen; Straight or branched chain type C 1- 4 alkyl; OCF 3 ; CF 3 ; Or unsubstituted benzene,
- R c is benzene
- n is an integer ranging from 0 to 3
- R 2 is H; ; ; ; C 1- 4 alkyl; Naphthalene unsubstituted or substituted with halogen; ; ; Benzofuran unsubstituted or substituted with halogen; Benzodioxol unsubstituted or substituted with halogen; Quinoline or isoquinoline, unsubstituted or substituted with halogen; Unsubstituted or substituted, straight-chain or branched C 1- 4 form a pyrazole substituted with alkyl or halogen; C 1- 4 alkyl substituted by an indole; Or imidazopyridine,
- R c is an unsubstituted or a halogen-substituted benzene, C 1- 4 alkyl or halogen,
- n is an integer ranging from 0 to 2.
- R 1 is ; Unsubstituted or substituted, halogen, C 1- 4 alkyl, OCF 3, and substituted benzene with at least one member selected from the group consisting of CF 3; ; ; or ego,
- R is a C 1- 4 alkyl; halogen; Or unsubstituted benzene,
- R c is benzene
- n is an integer ranging from 0 to 3
- R 2 is ; ; ; Or a C 1- 4 alkyl
- R c is benzene
- n is an integer ranging from 0 to 2.
- the compound represented by Formula 1 or Formula 2 is as follows:
- the compound of Formula 1 or Formula 2 may be selected from below.
- the novel compounds represented by Formula 1 or Formula 2 according to the present invention can be used in the form of pharmaceutically acceptable salts.
- acid addition salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful.
- Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanediodes. Obtained from non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids.
- Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
- the acid addition salt according to the present invention is dissolved in a conventional method, for example, a compound of Formula 1 or Formula 2 in an excess of aqueous acid solution, and the salt is a water miscible organic solvent such as methanol, ethanol, It can be prepared by precipitation with acetone or acetonitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture followed by drying, or by suction filtration of the precipitated salt.
- a water miscible organic solvent such as methanol, ethanol
- Bases can also be used to make pharmaceutically acceptable metal salts.
- Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate.
- the metal salt it is pharmaceutically suitable to prepare lithium, sodium, potassium or calcium salt.
- Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
- amino acids can be used to make pharmaceutically acceptable salts.
- an amino acid salt it is pharmaceutically suitable to manufacture natural amino acids, such as glycine, alanine, phenylalanine, valine, lysine, glutamic acid, for example.
- novel compounds of the present invention may be prepared by the reaction scheme of any one of the following schemes 1 to 21, but is not limited thereto, and may be prepared by a preparation method commonly used in the art, in addition to the following preparation methods.
- novel compounds represented by Formula 1 according to the present invention can be prepared as shown in Scheme 1 below.
- novel compounds represented by Formula 1 according to the present invention can be prepared as shown in Scheme 2 below.
- novel compounds represented by Formula 1 according to the present invention can be prepared as shown in Scheme 3 below.
- novel compounds represented by Formula 1 according to the present invention can be prepared as shown in Scheme 4 below.
- novel compounds represented by Formula 1 according to the present invention can be prepared as shown in Scheme 5 below.
- novel compounds represented by Formula 1 according to the present invention can be prepared as shown in Scheme 6 below.
- novel compounds represented by Formula 1 according to the present invention can be prepared as shown in Scheme 7 below.
- novel compounds represented by Formula 1 according to the present invention can be prepared as shown in Scheme 8 below.
- novel compounds represented by Formula 1 according to the present invention can be prepared as shown in Scheme 9 below.
- novel compounds represented by Formula 1 according to the present invention can be prepared as shown in Scheme 10 below.
- novel compounds represented by Formula 1 according to the present invention can be prepared as shown in Scheme 11 below.
- a compound may be prepared as in Scheme 20 below.
- the present invention provides a pharmaceutical composition for an antiviral containing a compound represented by the following formula (1) or (2), an enantiomer, diastereomer or pharmaceutically acceptable salt thereof as an active ingredient:
- the virus may be an influenza virus, preferably may be influenza A virus or influenza B virus. More preferably, the influenza virus may be A / California / 07/2009 (H1N1), A / Perth / 16/2009 (H3N2) or B / Florida / 04/2006.
- diseases caused by the viral infection may include, for example, diseases caused by influenza virus infections such as flu, cold, sore throat, bronchitis, pneumonia, bird flu, swine flu, and goat flu. It is not limited to this.
- the antiviral activity against influenza A virus and influenza B virus against the novel compounds represented by Formula 1 or Formula 2 according to the present invention was evaluated. As a result, it was confirmed that the compound of Formula 1 or Formula 2 according to the present invention has excellent antiviral activity against influenza virus, and at the same time, low toxicity to cells.
- the compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. Are manufactured.
- Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.
- Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
- non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
- base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
- the effective dosage of the compound represented by Formula 1 or Formula 2 according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally about 0.001-1-1.
- it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals according to the judgment of the doctor or pharmacist. Multiple doses may be administered.
- the present invention provides a health functional food composition for preventing or ameliorating a disease caused by a viral infection containing the compound represented by Formula 1 or Formula 2 or a food acceptable salt thereof as an active ingredient.
- the compound of Formula 1 or Formula 2 and its antiviral activity which are included as an active ingredient in the health functional food composition of the present invention, are the same as described above in the pharmaceutical composition, and thus description thereof is omitted.
- the health functional food composition according to the present invention may be added to health functional foods such as foods and beverages for the purpose of preventing or improving diseases caused by pathogenic bacteria.
- Examples of foods to which the above-mentioned substances may be added include dairy products, various soups, drinks, meat, sausages, breads, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, and the like includes all the health functional foods in the conventional sense.
- the dietary supplement composition containing the compound of formula 1 or formula 2 according to the present invention or a food-acceptable salt thereof as an active ingredient may be added as it is or used with other foods or food ingredients, Can be used accordingly.
- the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
- the amount of the composition in the dietary supplement may be added at 0.1 to 90 parts by weight of the total food weight.
- the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
- the nutraceutical composition of the present invention is not particularly limited to other ingredients except for containing the compound as essential ingredients in the indicated ratios, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
- natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
- natural flavoring agents such as, tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
- the proportion of natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g, per 100 dietary food compositions of the present invention.
- the dietary supplement composition containing the compound of Formula 1 or Formula 2 of the present invention or a food-acceptable salt thereof as an active ingredient includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors, and natural flavoring agents. Flavors, coloring and neutralizing agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonated drinks Carbonating agent and the like.
- the health functional food composition of the present invention may contain a flesh for preparing natural fruit juice and fruit juice beverage and vegetable beverage.
- the ratio of such additives is not so important but is selected from the range of 0.1 to about 20 parts by weight per 100 parts by weight of the nutraceutical composition containing the compound of formula 1 or formula 2 of the present invention or a food acceptable salt thereof as an active ingredient. It is common to be.
- the present invention also provides a virus disinfecting or cleaning composition containing the compound represented by Formula 1 or Formula 2 as an active ingredient.
- the disinfecting or cleaning composition according to the present invention may be used as a dish detergent, laundry detergent, vegetable or vegetable cleaner, hand cleaner, or the like, but is not limited thereto.
- Disinfectant or cleaning compositions of the present invention may comprise one or more surfactants.
- the surfactant may be anionic, non-ionic, cationic, amphoteric or zwitter ionic type, or mixtures thereof.
- anionic surfactants include linear alkylbenzene sulfonates (LAS), alkyl sulfates (AS), alpha olefin sulfonates (AOS), alcohol ethoxy sulfates (AES) or alkali metal salts of natural fatty acids.
- non-ionic surfactants include alkyl polyethylene glycol ethers, nonylphenol polyethylene glycol ethers, fatty acid esters of sucrose and glucose, or esters of polyethoxylated alkyl glucosides.
- composition of the present invention depending on the application, abrasives, bleaches, surface active agents, preservatives, metal blockers, stain-reposition inhibitors, perfumes, stabilizers of enzymes and bleaches, formulation aids, optical brighteners, foam boosters, chelates It may further comprise other detergent ingredients known in the art such as agents, fillers, fabric softeners and the like. Disinfectant or cleaning compositions of the present invention may be formulated in any convenient form, such as powders, solutions, and the like.
- Influenza infection is also built phenotype-based assay (phenotypic-based assay) for measurement
- influenza virus expressing NS1A-GFP fusion protein (rA / Puerto Rico / 8/34 / NS1-GFP (H1N1))
- NS1A-GFP fusion protein (rA / Puerto Rico / 8/34 / NS1-GFP (H1N1))
- Manicassamy B Manicassamy S, Belicha-Villanueva A, Pisanelli G, Pulendran B, Garcia- Sastre A. (2010) Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus.Proc Natl Acad Sci USA 107 (25): 11531-11536).
- phenotypic-based assay was constructed.
- MDCK cells were plated in 384-well plates and infected with influenza virus expressing NS1-GFP fusion proteins and incubated for 37 to 24 hours. 24 hours after infection, images were obtained for NS1A-GFP (green) and nucleus (blue) using confocal microscopy (ImageXpress ® , Molecular Devices, Sunnyvale, CA, USA) and the image was developed in-house. Analyzed by software. Influenza virus infection and cytotoxicity were calculated by measuring the number of GFP positive and negative cells. Known inhibitors Oseltamivir, T-705 and Nucleozin ((De Clercq E1. (2006) Antiviral agents active against influenza A viruses.Nat Rev Drug Discov.
- Phenotype-based assays for measuring influenza infection levels constructed in this example were found to be useful for evaluating antiviral activity as shown in FIG. 1.
- MDCK cells were plated in 384-well plates, treated with compound diluted at 10 uM concentration and infected with influenza virus expressing NS1-GFP fusion protein for 37 to 24 hours. Incubated. The influenza virus infection and cytotoxicity was calculated by the infection after 24 hours, using a confocal microscope (ImageXpress ®, Molecular Devices, Sunnyvale, CA, USA) measures the number of GFP-positive cells and negative cells. The obtained image was analyzed by in-house development software. Influenza virus infection inhibition rates were calculated using EC 100 of 1% DMSO-treated cells and Nucleozin-treated cells, a known influenza infection inhibitor, and were set to 0% and 100% inhibition rates, respectively. Antiviral activity of the compounds was assessed by dose-response curve (DRC) analysis, and EC 50 and CC 50 values were calculated using Prism, version 5.0c software (GraphPad Software, Inc., La Jolla, CA, USA). .
- DRC dose-response curve
- Hits were selected for compounds with> 90% HCV infection inhibition and> 70% cell viability, which were reconfirmed by the 10-point concentration-based drug assay.
- three types of seasonal influenza viruses A / Perth / 16/09 (H3N2), A / California / 7/09 (H1N1), B / Florida / 4/06
- Drug efficacy evaluation by concentration was performed.
- a neuraminidase assay was performed to select compounds having different drug mechanisms from neuraminidase inhibitors, the most widely used anti-influenza drugs.
- THO thiooxadiazole
- the present inventors synthesized a compound including the THO scaffold selected in Example 2 and various derivatives thereof, and used Scheme 1 as follows.
- Substance A4 (119 mg, 0.26 mmol) dissolved in MeOH (15 mL) was suspended in a mixture of oxone (803 mg, 1.31 mmol) and water (15 mL). The reaction mixture was stirred at 25 ° C. for about 16 hours. After the reaction was completed, the solvent was dried in vacuo . The reaction mixture was extracted with EtOAc and washed with water. The organic layer was dried over anhydrous MgSO 4 and then evaporated in vacuo . Preferred product A5 of a white solid was obtained by column chromatography (EtOAc / Hexane, 1: 3).
- Substance A3 (50 mg, 0.19 mmol) dissolved in anhydrous DMF (1 mL) 1-iodo-2-methylbenzene (0.029 mL, 0.22 mmol), 1,10-phenanthroline (44 mg, 0.24 mmol) , CuI (2 mg, 0.01 mmol) and K 2 CO 3 (33 mg, 0.24 mmol) were added and stirred at 120 ° C. for 8 hours. After the reaction was completed, the reaction mixture was extracted with EtOAc and washed with water. The organic layer was dried over anhydrous MgSO 4 and then evaporated in vacuo . Preferred product D1 of a yellow solid was obtained by column chromatography (EtOAc / Hexane, 1: 5).
- Substance E2 (62 mg, 0.20 mmol) was dissolved in anhydrous MC (4 mL). Oxalyl chloride (0.026 mL, 0.24 mmol) and 1 drop of DMF were added to the reaction mixture at 0 ° C. The resulting mixture was stirred at 25 ° C. for 2 hours and then the solvent was evaporated in vacuo to give the desired product E3 of a yellow oil.
- Substance F2 (84 mg, 0.36 mmol) dissolved in anhydrous EtOH (1 mL) was added to AcOH (0.3 mL) and 4-bromoaniline (62 mg, 0.36 mmol) dissolved in EtOH (2 mL). The reaction mixture was stirred at 80 o C for 12 h. After the reaction was completed, EtOH was evaporated in vacuo to prepare orange oil F3.
- the target compound T2 was synthesized according to the synthesis procedure for I1 .
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Abstract
본 발명은 신규 헤테로아릴 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 약학적으로 허용가능한 염, 및 이를 유효성분으로 함유하는 항바이러스용 조성물에 관한 것이다. 본 발명에 따른 화학식 1 또는 화학식 2로 표시되는 신규한 화합물은 인플루엔자 바이러스에 대한 항바이러스 활성이 현저히 우수할 뿐만 아니라, 세포독성이 낮아 인체에 부작용이 적으므로, 이를 유효성분으로 함유하는 약학적 조성물은 인플루엔자 바이러스 감염에 의해 발병되는 질환의 예방 또는 치료에 유용하게 사용할 수 있다.
Description
본 출원은 2016년 9월 30일 출원된 대한민국출원 제10-2016-0126997호에 기초한 우선권을 주장하며, 해당 출원의 명세서 및 도면에 개시된 모든 내용은 본 출원에 원용된다.
본 발명은 신규 헤테로아릴 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 약학적으로 허용가능한 염, 및 이를 유효성분으로 함유하는 항바이러스용 조성물에 관한 것이다.
인플루엔자 바이러스는 사람 및 가축 둘 모두에 영향을 주는, 세계적으로 가장 흔하게 존재하는 바이러스 중 하나이다. 인플루엔자 바이러스는 급성 호흡기 질환을 일으키는 전염성이 매우 강한 바이러스로 온 세계에 집단감염이나 대유행을 야기하여 소아, 고령자, 심폐질환 환자에게 심각한 호흡기 증상을 유발한다. 이러한 인플루엔자 바이러스는 분류학적으로 오르토믹소바이러스(Orthomyxovirus)에 속하며 A, B 및 C의 3가지 형이 있고, 특히 유행적으로 확산되는 형은 A 및 B형이다.
인플루엔자 바이러스는 직경이 약 125 nm인 입자 크기를 갖는 RNA 외피(enveloped) 바이러스이다. 인플루엔자 바이러스는 기본적으로 지질 이층 구조 및 외부 당단백질을 갖는 바이러스 외피에 의해 둘러싸인 핵단백질과 결합된 리보핵산(RNA)의 내부 뉴클레오캡시드 또는 코어로 구성된다. 바이러스 외피의 내층은 주로 기질 단백질로 구성되며, 외층은 대부분 숙주 유래된 지질 물질로 구성된다.
이들 바이러스 표면에는 당단백질인 적혈구 응집소(hamagglutinin, HA)와 뉴라미니데이즈(neuraminidase, NA)라는 두 종류의 표면 항원이 존재하고 내부에는 8개의 분절된 RNA가 존재한다. 헤마글루티닌(hamagglutinin)은 머리와 줄기로 구성되어져 있는 트라이머(trimer) 형태이고, 이중 머리 부분은 대부분의 항원변이와 관련되어 있으며 숙주세포의 표면에 있는 말단 시알산 잔기와 결합하여 바이러스를 부착시키고, 순차적으로 바이러스가 숙주세포로 침투하는 것을 가능하게 한다(비특허문헌 2). 뉴라미니데이즈(neuraminidase)는 머리와 줄기형태를 가지는 버섯모양의 테트라머(tetramer)로 머리상단 표면에 활성자리가 있으며 감염된 세포 내에서 복제 및 증식된 바이러스가 세포표면의 올리고사카라이드 부분과 말단 뉴라민산(neuraminic acid) 잔기를 연결해주는 알파-케토사이딕 본드(ketosidic bond)를 절단하여 바이러스를 숙주 세포 밖으로 배출하여 호흡기 점막세포로 침투하는데 중요한 역할을 한다.
바이러스의 표면 항원들은 동일한 아형에서 변이를 일으키고, 매년 새로운 항원 변이주가 출현한다. 특히 인플루엔자 바이러스 중 최근까지 문제가 되고 있는 조류 인플루엔자 바이러스는 대변이가 일어나 닭, 칠면조, 오리 및 야생조류 등 여러 종류의 조류를 감염시키며 빠른 전파로 인해 닭이 감염되면 80% 이상이 폐사함으로 전 세계적으로 양계산업에 가장 큰 피해와 위협을 주는 바이러스 질환이며, 그 파급효과는 양계산업에만 한정되어 있지 않고 인체에 대한 감염으로 인하여 사람에게 질병을 일으키는 것으로 보고되고 있다. 현재까지 이러한 인플루엔자 바이러스가 사람에게 질환을 일으킨 경우를 구체적으로 살펴보면, 20세기 세 차례의 독감 대유행, 즉 스페인독감(H1N1)으로 약 3천만 명, 아시아독감(H2N2)으로 약 백만 명, 홍콩독감(H3N2)으로 백만 명 정도가 사망한 것으로 보고되고 있다. 21세기에 접어들어 2003년부터 2008년까지는 385명이 감염되어 243명이 사망에 이르렀고, 최근 2009년 4월에 발생한 신종 플루는 이미 WHO에서 공식적으로 펜더믹을 선포하였고, 세계적으로는 감염환자가 260,000명을 넘어섰으며, 감염에 의해 죽은 사망자는 20여 개국에서 1000명을 넘어섰고, 우리나라에서도 멕시코 자원봉사를 다녀온 수녀가 2009년 5월 2일 첫 확진 환자로 판명되었으며, 2009년 9월 16일 발표를 기준으로 약 1만 명 이상이 감염되었고, 8명은 중증으로 입원 치료를 받고 있으며, 12명이 지병 합병증 또는 급성 합병증으로 사망하였다.
이러한 바이러스의 감염을 예방하고 치료하기 위한 방법으로 상피세포로의 흡착 저해, 세포로의 침입 저해, 유전자의 전사 및 복제의 저해, 단백질 합성의 저해, 세포로부터 방출의 억제 등을 생각할 수 있으며, 이들 각각은 항바이러스의 표적이 되고 있다.
종래부터 인플루엔자 바이러스에 의해 야기되는 질환을 치료하기 위해서 아만타딘(Amatadine), 리만타딘(Rimatadine), 자나미비(Zanamivir), 오셀타미비르(Oseltamivir) 등 4가지 물질이 미국식품의약품 안전청(FDA)으로부터 승인받아 사용되고 있다. 그러나 바이러스 증식에 필수적인 세포막 단백질인 M2 단백질의 이온채널을 차단하여 바이러스의 탈외피(uncoating)를 방해함으로써 항바이러스 작용을 하는 M2 억제제인 아만타딘(Amatadine), 리만타딘(Rimatadine)은 인플루엔자 바이러스 A형에만 효과가 있으며 40년 동안 사용되는 동안 내성을 가진 바이러스가 발생되고 신경계 및 위장에 심각한 부작용이 나타나는 것으로 보고되고 있다. 1999년 이후에는 바이러스의 증식에 중요한 역할을 하고 내성 발생 빈도가 적으며, A형 및 B형 인플루엔자 바이러스 모두에 안정적으로 존재하는 뉴라미니데이즈의 저해제인 자나미비르(Zanamivir), 오셀타미비르(Oseltamivir)와 같은 신약에 의한 바이러스 감염 치료에 대한 보고되고 있다.
그러나, 자나미비르의 경우에는 높은 항바이러스 효과를 가지고 있지만 낮은 생체이용율과 빠른 신장에서의 배출의 단점을 가지고 있으며, 오셀타미르는 심각한 구토증세가 나타나는 부작용이 있다.
현재까지 개발된 항바이러스제들은 심각한 부작용을 나타내고 있으며 그 응용에 대한 많은 주의가 필요하다. 또한, 백신의 개발은 유행하는 바이러스의 형과 백신의 바이러스가 맞지 않으면 효과가 낮은 문제점이 있기 때문에 감염 억제 효과가 뛰어나고 안정성이 우수한 새로운 인플루엔자 바이러스제의 개발의 필요성이 증가하고 있다.
이에, 본 발명자들은 인플루엔자 바이러스에 대한 항바이러스 활성을 갖는 화합물을 연구하던 중, 인플루엔자 바이러스에 대하여 우수한 항바이러스 활성을 나타내는 신규 헤테로아릴 화합물을 확인하고 본 발명을 완성하였다.
본 발명의 목적은 인플루엔자 바이러스에 대한 항바이러스 활성을 나타내는 신규한 화합물, 이의 거울상 이성질체, 부분 입체 이성질체, 또는 약학적으로 허용가능한 염을 제공하는데 있다.
본 발명의 다른 목적은 상기 신규 화합물, 이의 거울상 이성질체, 부분 입체 이성질체, 또는 약학적으로 허용가능한 염을 유효성분으로 함유하는 항바이러스용 약학적 조성물을 제공하는 것이다.
본 발명의 또 다른 목적은 신규 화합물, 이의 거울상 이성질체, 부분 입체 이성질체, 또는 식품학적으로 허용가능한 염을 유효성분으로 함유하는 항바이러스용 건강기능식품 조성물을 제공하는 것이다.
본 발명의 다른 목적은 신규한 화합물, 이의 거울상 이성질체 또는 부분 입체 이성질체를 유효성분으로 함유하는 바이러스 소독용 또는 세정용 조성물을 제공하는 것이다.
본 발명의 또 다른 목적은 신규한 화합물, 이의 거울상 이성질체 또는 부분 입체 이성질체를 유효성분으로 사용하여, 인플루엔자 바이러스를 억제하는 방법을 제공하는 것이다.
상술한 과제를 해결하기 위해, 본 발명은 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 약학적으로 허용가능한 염을 제공한다:
[화학식 1]
[화학식 2]
상기 화학식 1 또는 화학식 2에 있어서, X1, X2, X3, Y, Z, R1 및 R2는 본 명세서에서 정의한 바와 같다.
본 발명의 바람직한 일실시예에 따르면, 본 발명은 하기 화학식 1a로 표시되는 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 약학적으로 허용가능한 염을 제공한다:
[화학식 1a]
상기 화학식 1a에 있어서, Y, Z, R1 및 R2는 본 명세서에서 정의한 바와 같다.
본 발명은 또한, 상기 화학식 1 또는 화학식 2로 표시되는 신규 화합물의 제조방법을 제공한다.
나아가, 본 발명은 상기 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 약학적으로 허용가능한 염을 유효성분으로 함유하는 항바이러스용 약학적 조성물을 제공한다.
또한, 본 발명은 상기 화학식 1 또는 화학식 2로 표시되는 신규한 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 함유하는 항바이러스용 건강기능식품 조성물을 제공한다.
나아가, 본 발명은 상기 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 거울상 이성질체 또는 부분 입체 이성질체를 유효성분으로 함유하는 바이러스 소독용 또는 세정용 조성물을 제공한다.
본 발명의 바람직한 일실시예에 따르면, 상기 바이러스는 인플루엔자 바이러스일 수 있다.
본 발명의 바람직한 다른 일실시예에 따르면, 상기 인플루엔자 바이러스는 A형 인플루엔자 바이러스 또는 B형 인플루엔자 바이러스일 수 있다.
본 발명의 바람직한 또 다른 일실시예에 따르면, 상기 인플루엔자 바이러스는 A/California/07/2009 (H1N1), A/Perth/16/2009 (H3N2) 또는 B/Florida/04/2006일 수 있다.
본 발명의 바람직한 다른 일실시예에 따르면, 상기 조성물은 바이러스 감염으로 인한 질환의 예방 또는 치료에 사용될 수 있다.
본 발명의 바람직한 또 다른 일실시예에 따르면, 상기 바이러스 감염으로 인한 질환은 독감, 감기, 인후염, 기관지염, 폐렴, 조류독감, 돼지독감 및 염소독감으로 이루어진 군에서 선택되는 1종의 인플루엔자 바이러스 감염으로 인한 질환일 수 있다.
본 발명에 따른 화학식 1 또는 화학식 2로 표시되는 신규한 화합물은 인플루엔자 바이러스에 대한 항바이러스 활성이 현저히 우수할 뿐만 아니라, 세포독성이 낮아 인체에 부작용이 적으므로, 이를 유효성분으로 함유하는 약학적 조성물은 인플루엔자 바이러스 감염에 의해 발병되는 질환의 예방 또는 치료에 유용하게 사용할 수 있다.
도 1a은 인플루엔자 감염도 측정을 위한 표현형 기반 어세이(phenotypic-based assay)를 나타낸 것이다.
도 1b는 인플루엔자 감염도 측정을 위한 표현형 기반 어세이를 이용하여 Oseltamivir, T-705, 그리고 Nucleozin의 항바이러스 활성을 평가한 결과를 나타낸 것이다.
이하, 본 발명을 보다 상세하게 설명한다.
상술한 바와 같이, 현재까지 개발된 항바이러스제들은 심각한 부작용을 나타내고 있으며 그 응용에 대한 많은 주의가 필요하다. 또한, 백신의 개발은 유행하는 바이러스의 형과 백신의 바이러스가 맞지 않으면 효과가 낮은 문제점이 있기 때문에 감염 억제 효과가 뛰어나고 안정성이 우수한 새로운 인플루엔자 바이러스제의 개발의 필요성이 증가하고 있다.
이에 본 발명에서는, 인플루엔자 바이러스에 대하여 우수한 항바이러스 활성을 나타내는 신규 헤테로아릴 화합물을 확인하고, 상기 신규 화합물, 이의 거울상 이성질체, 부분 입체 이성질체, 약학적으로 허용가능한 염 또는 식품학적으로 허용가능한 염; 및 이를 유효성분으로 함유하는 항바이러스용 조성물을 제공함으로써 상술한 문제의 해결방안을 모색하였다.
본 발명은 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 거울상 이성질체 또는 부분 입체 이성질체를 제공한다:
[화학식 1]
또는
[화학식 2]
상기 식에서,
X1은 O, S 또는 -N(CH2CH3)- 이고,
X2 및 X3는 각각 독립적으로 N 또는 CH 이며,
Y는 존재하지 않거나; -CH2-; -CH2NH-; -C(=O)-; -CH2CH2-; -NH-; -NHC(=O)-; -C(=O)NH-; -CH(CH3)-; -CF2-; -CH(OCH3)-; -CH2O-; -N(CH3)-; 또는 -CH2NHC(=O)- 이고,
Z는 존재하지 않거나, -CH2S-; -CH2S(=O)-; -CH2NH-; -CH(Rc)S-; -CH2CH2S-; -CH2N(CH3)-; ; -CH=CH-; -S-; -CH2-; -O-; -CH2S(=O)2-; -C(=O)-; -SCH2-; -CH2CH2-; -CH(OH)-; -CH(CH3)CH2-; -OCH2-; -C(=O)CH2S-; -C(=O)-NH-; -CH=C(CH3)-; -CH2-사이클로프로필-; -NH-S(=O)2-; -S(=O)2-NH-; -NH-C(=O)-이며,
Rc는 벤젠이고,
R1은 ; 비치환되거나, 할로겐, 직쇄 또는 분쇄형 C1-
4알킬, C3-6 사이클로알킬, -OCF3, -CF3, -CHF2, -OH, 페녹시, 페닐, C1-
4알콕시, -CN, -NH2, 및 -N(CH3)2로 이루어진 군에서 선택한 1종 이상으로 치환된 벤젠;; ; ; 비치환되거나 할로겐으로 치환된 피리딘; 비치환되거나 C1-
4알콕시로 치환된 나프탈렌; 벤조트리아졸; 비치환되거나, C1-
4알킬, C1-
4알콕시 또는 할로겐으로 치환된 퀴놀린 또는 이소퀴놀린; 비치환되거나 C1-
4알킬로 치환된 인다졸; C3-6 사이클로알킬; 벤조티오펜; 벤조퓨란; 비치환되거나 C1-
4알킬로 치환된 인돌; 또는 티오펜이며,
Ra는 할로겐; 직쇄 또는 분쇄형 C1-
4알킬; OCF3; CF3; 또는 비치환된 벤젠이고,
Rc는 벤젠이며,
n은 0 내지 3 범위의 정수이고,
R2는 H;
; ; ; ; C1-
4알킬; 비치환되거나 또는 할로겐으로 치환된 나프탈렌; ; ; ; 비치환되거나 또는 할로겐으로 치환된 벤조퓨란; 비치환되거나 또는 할로겐으로 치환된 벤조디옥솔; 비치환되거나 또는 할로겐으로 치환된 퀴놀린 또는 이소퀴놀린; 비치환되거나, 직쇄형 또는 분쇄형 C1-
4알킬 또는 할로겐으로 치환된 피라졸; C1-
4알킬로 치환된 인돌; 또는 이미다조피리딘이며,
Rb는 비치환되거나, 직쇄 C1-
4알킬 및 할로겐으로 이루어진 군에서 선택한 1종 이상으로 치환된 벤젠; 직쇄 C1-
4알킬; 분쇄형 C3-
5알킬; -OCH3; N, O 또는 S를 포함하는 5원자 또는 6원자 헤테로아릴; 탄소수 5 내지 7의 사이클로알킬; -C(=O)CH3; -ORc; -C(=O)OCH3; CH2RC; -CH2RC; -CF3; -OCF3; -OH; -N(CH3)2; -C(=O)-OH; 피롤리딘; 피페리딘; 피롤; 퓨란; 티오펜; 모폴린; 모폴린으로 치환된 C1-
4알콕시; -NRdRe (여기서 Rd는 H 또는 메틸이고, Re는 -CH2CH2OCH3 또는 -CH2CH2Ph임); 또는 할로겐이고,
Rc는 비치환되거나 할로겐으로 치환된 벤젠, C1-
4알킬 또는 할로겐이며,
m은 0 내지 2 범위의 정수이다.
바람직하게는, 하기 화학식 1a로 표시되는 화합물, 이의 거울상 이성질체 또는 부분입체 이성질체를 제공한다:
[화학식 1a]
상기 식에서,
Y는 존재하지 않거나; -CH2-; -CH2NH-; -C(=O)-; -CH2CH2-; -NH-; -CH2O-; -N(CH3)-; -CH(CH3)-; -CF2-; 또는 -CH(OCH3)- 이고,
Z는 -CH2S-; -CH2S(=O)-; -CH(Rc)S-; -CH2CH2S-; -S-; CH2S(=O)2-; 또는 -SCH2- 이며,
Ra는 C1-
4알킬; 할로겐; 또는 비치환된 벤젠이며,
Rc는 벤젠이고,
n은 0 내지 3 범위의 정수이며,
Rb는 비치환되거나, 직쇄 C1-
4알킬 및 할로겐으로 이루어진 군에서 선택한 1종 이상으로 치환된 벤젠; 직쇄 C1-
4알킬; 분쇄형 C3-
5알킬; OCH3; N, O 또는 S를 포함하는 5원자 또는 6원자 헤테로아릴; 탄소수 5 내지 7의 사이클로알킬; C(=O)CH3; ORc; C(=O)OCH3; CH2RC; 또는 할로겐이며,
Rc는 벤젠이고,
m은 0 내지 2 범위의 정수이다.
바람직하게는, 상기 화학식 1 또는 화학식 2로 표시되는 화합물은 다음과 같다:
상기 화학식 1 또는 화학식 2의 화합물은 하기에서 선택되는 것일 수 있다.
1
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
2
2-(([1,1'-biphenyl]-4-ylmethyl)thio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
3
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-bromo-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
4
2-((1H-pyrazol-1-yl)methyl)-5-(([1,1'-biphenyl]-2-ylmethyl)thio)-1,3,4-oxadiazole
5
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
6
2-(([1,1'-biphenyl]-3-ylmethyl)thio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
7
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
8
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((naphthalen-1-ylmethyl)thio)-1,3,4-oxadiazole
9
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-methylbenzyl)thio)-1,3,4-oxadiazole
10
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-methoxybenzyl)thio)-1,3,4-oxadiazole
11
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((3-bromo-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
12
2-(([1,1'-biphenyl]-2-ylmethyl)sulfinyl)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
13
1-([1,1'-biphenyl]-2-yl)-2-((5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-on
14
2-(benzylthio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
15
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-(pyridin-4-yl)benzyl)thio)-1,3,4-oxadiazole
16
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(((3-phenylpyridin-4-yl)methyl)thio)-1,3,4-oxadiazole
17
N-([1,1'-biphenyl]-2-ylmethyl)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazol-2-amine
18
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-benzyl-1,3,4-oxadiazole
19
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-(pyridin-3-yl)benzyl)thio)-1,3,4-oxadiazole
20
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-(pyridin-4-yl)benzyl)thio)-1,3,4-oxadiazole
21
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(((3-phenylpyridin-4-yl)methyl)thio)-1,3,4-oxadiazole
22
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(4-bromobenzyl)-1,3,4-oxadiazole
23
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-isopropylbenzyl)thio)-1,3,4-oxadiazole
24
3-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-4-ethyl-4H-1,2,4-triazole
25
2-(benzhydrylthio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
26
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-methylphenethyl)thio)-1,3,4-oxadiazole
27
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(pyridin-2-ylmethyl)-1,3,4-oxadiazole
28
1-(2-(((5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)thio)methyl)phenyl)ethan-1-one
29
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-phenoxybenzyl)thio)-1,3,4-oxadiazole
30
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-phenyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
31
2-((2-(1H-pyrrol-1-yl)benzyl)thio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
32
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(((4'-methyl-[1,1'-biphenyl]-2-yl)methyl)thio)-1,3,4-oxadiazole
33
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)thio)-1,3,4-oxadiazole
34
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-(furan-3-yl)benzyl)thio)-1,3,4-oxadiazole
35
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-(thiophen-3-yl)benzyl)thio)-1,3,4-oxadiazole
36
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(1-phenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazole
37
methyl 2-(((5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)thio)methyl)benzoate
38
2-((2-benzylbenzyl)thio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
39
2-(([1,1'-biphenyl]-3-ylmethyl)thio)-5-((4-phenyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
40
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2,6-dimethylbenzyl)thio)-1,3,4-oxadiazole
41
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-1,3,4-oxadiazole
42
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(4-bromophenyl)-1,3,4-oxadiazole
43
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-phenyl-1,3,4-oxadiazole
44
N-([1,1'-biphenyl]-2-ylmethyl)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methyl-1,3,4-oxadiazol-2-amine
45
N-([1,1'-biphenyl]-2-ylmethyl)-N-(5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)acetamide
46
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(3-chlorobenzyl)-1,3,4-oxadiazole
47
N-((5-(([1,1'-biphenyl]-2-ylmethyl)thio)-1,3,4-oxadiazol-2-yl)methyl)-4-bromoaniline
48
(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)(5-((2-methylbenzyl)thio)furan-2-yl)methanone
49
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(2-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazole
50
(E)-2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
51
N-((5-(([1,1'-biphenyl]-2-ylmethyl)thio)-1,3,4-oxadiazol-2-yl)methyl)-4-bromobenzamide
52
5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-(4-bromophenyl)-1,3,4-oxadiazol-2-amine
53
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(o-tolylthio)-1,3,4-oxadiazole
54
2-(2-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-5-(o-tolylthio)-1,3,4-oxadiazole
55
(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)(2-((2-methylbenzyl)thio)oxazol-5-yl)methanone
56
(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)(5-((2-isopropylphenyl)thio)furan-2-yl)methanone
57
(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)(5-(2-isopropylphenoxy)furan-2-yl)methanone
58
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-bromophenoxy)methyl)-1,3,4-oxadiazole
59
2-(([1,1'-biphenyl]-2-ylmethyl)sulfinyl)-5-(4-bromobenzyl)-1,3,4-oxadiazole
60
2-(([1,1'-biphenyl]-2-ylmethyl)sulfonyl)-5-(4-bromobenzyl)-1,3,4-oxadiazole
61
5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-(4-bromo-2,6-dimethylphenyl)-1,3,4-oxadiazol-2-amine
62
5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-(4-bromo-3-methylphenyl)-1,3,4-oxadiazol-2-amine
63
5-(([1,1'-biphenyl]-2-ylmethyl)sulfinyl)-N-(4-bromophenyl)-1,3,4-oxadiazol-2-amine
64
(5-(4-bromobenzyl)-1,3,4-oxadiazol-2-yl)(phenyl)methanone
65
5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-(4-bromophenyl)-N-methyl-1,3,4-oxadiazol-2-amine
66
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(((2-isopropylphenyl)thio)methyl)-1,3,4-oxadiazole
67
2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazole
68
5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-(3,5-dimethylphenyl)-1,3,4-oxadiazol-2-amine
69
[1,1'-biphenyl]-3-yl(5-(4-bromobenzyl)-1,3,4-oxadiazol-2-yl)methanone
70
[1,1'-biphenyl]-3-yl(5-(4-bromobenzyl)-1,3,4-oxadiazol-2-yl)methanol
71
5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-phenyl-1,3,4-oxadiazol-2-amine
72
5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-(4-bromophenyl)-1,3,4-oxadiazole-2-carboxamide
73
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(1-phenylethyl)-1,3,4-oxadiazole
74
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-bromophenyl)difluoromethyl)-1,3,4-oxadiazole
75
4-bromo-N-((5-((2-methylbenzyl)thio)furan-2-yl)methyl)aniline
76
(5-((2,6-dimethylphenyl)amino)-1,3,4-oxadiazol-2-yl)(phenyl)methanone
77
(5-((2,6-dimethylphenyl)amino)-1,3,4-oxadiazol-2-yl)(phenyl)methanol
78
(3-chloro-4-fluorophenyl)(5-((2,6-dimethylphenyl)amino)-1,3,4-oxadiazol-2-yl)methanone
79
(3-chloro-4-fluorophenyl)(5-((2,6-dimethylphenyl)amino)-1,3,4-oxadiazol-2-yl)methanol
80
2-benzyl-5-(methylthio)-1,3,4-oxadiazole
81
(E)-2-(2-isopropylstyryl)-5-(4-(trifluoromethoxy)benzyl)-1,3,4-oxadiazole
82
(E)-2-(4-bromobenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
83
(E)-N-(4-bromophenyl)-5-(2-bromostyryl)-1,3,4-oxadiazol-2-amine
84
N-(4-bromophenyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazol-2-amine
85
N-(2,6-dimethylphenyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazol-2-amine
86
(E)-2-(4-bromobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
87
(E)-N-(4-bromophenyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol-2-amine
88
(E)-N-(4-bromo-3-fluorophenyl)-5-(2-bromostyryl)-1,3,4-oxadiazol-2-amine
89
N-(4-bromophenyl)-5-(2-methylphenethyl)-1,3,4-oxadiazol-2-amine
90
N-(4-bromo-3-methylphenyl)-5-(2-methylphenethyl)-1,3,4-oxadiazol-2-amine
91
N-(4-bromo-3-fluorophenyl)-5-(2-methylphenethyl)-1,3,4-oxadiazol-2-amine
92
2-(4-bromobenzyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazole
93
2-(2-isopropylphenethyl)-5-(4-(trifluoromethoxy)benzyl)-1,3,4-oxadiazole
94
2-(3,5-dimethylbenzyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazole
95
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(3-chlorobenzyl)-1,3,4-oxadiazole
96
2-(([1,1'-biphenyl]-2-ylmethyl)sulfonyl)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole
97
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(methoxy(phenyl)methyl)-1,3,4-oxadiazole
98
2-(4-bromobenzyl)-5-(naphthalen-2-yl)-1,3,4-oxadiazole
99
4-bromo-N-((2-((2-methylbenzyl)thio)oxazol-5-yl)methyl)aniline
100
2-(4-bromobenzyl)-5-(naphthalen-1-ylmethyl)-1,3,4-oxadiazole
101
2-(3-bromobenzyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazole
102
2-(3-chlorobenzyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazole
103
2-(4-bromobenzyl)-5-(2-methylphenethyl)-1,3,4-oxadiazole
104
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(3-bromobenzyl)-1,3,4-oxadiazole
105
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(3,5-dimethylbenzyl)-1,3,4-oxadiazole
106
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(4-(trifluoromethoxy)benzyl)-1,3,4-oxadiazole
107
2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(4-isopropylbenzyl)-1,3,4-oxadiazole
108
2-(3-chloro-4-fluorobenzyl)-5-(2-methylphenethyl)-1,3,4-oxadiazole
109
2-(4-bromobenzyl)-5-((1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-1,3,4-oxadiazole
110
2-(4-bromobenzyl)-5-(2-(o-tolyl)propyl)-1,3,4-oxadiazole
111
2-(4-bromobenzyl)-5-(2-cyclohexylstyryl)-1,3,4-oxadiazole
112
2-(4-bromobenzyl)-5-(2-cyclohexylstyryl)-1,3,4-oxadiazole
113
2-(3,5-dimethylbenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
114
2-benzyl-5-((2-isopropylphenoxy)methyl)-1,3,4-oxadiazole
115
2-(4-bromobenzyl)-5-((2-isopropylphenoxy)methyl)-1,3,4-oxadiazole
116
(E)-N-(4-bromophenyl)-5-(2-cyclohexylstyryl)-1,3,4-oxadiazol-2-amine
117
(E)-N-(4-bromophenyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazol-2-amine
118
5-(2-([1,1'-biphenyl]-2-yl)ethyl)-N-(4-bromophenyl)-1,3,4-oxadiazol-2-amine
119
2-(2-([1,1'-biphenyl]-2-yl)ethyl)-5-(4-bromobenzyl)-1,3,4-oxadiazole
120
(E)-N-(4-bromophenyl)-5-(2-methoxystyryl)-1,3,4-oxadiazol-2-amine
121
(E)-N-(4-bromophenyl)-5-(2-(quinolin-5-yl)vinyl)-1,3,4-oxadiazol-2-amine
122
N-(3-chloro-4-fluorophenyl)-5-(2-methylphenethyl)-1,3,4-oxadiazol-2-amine
123
5-(2-methylphenethyl)-N-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-amine
124
(E)-5-(2-([1,1'-biphenyl]-2-yl)vinyl)-N-(4-bromophenyl)-1,3,4-oxadiazol-2-amine
125
(E)-N-(4-bromophenyl)-5-(2-phenoxystyryl)-1,3,4-oxadiazol-2-amine
126
(E)-2-(2-([1,1'-biphenyl]-2-yl)vinyl)-5-(4-bromobenzyl)-1,3,4-oxadiazole
127
(E)-2-(4-bromobenzyl)-5-(2-phenoxystyryl)-1,3,4-oxadiazole
128
(E)-2-(4-bromobenzyl)-5-(2-bromostyryl)-1,3,4-oxadiazole
129
2-(4-bromobenzyl)-5-(1-(2-methylbenzyl)cyclopropyl)-1,3,4-oxadiazole
130
2-(3-bromobenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
131
2-(3-chloro-4-fluorobenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
132
2-(2-isopropylstyryl)-5-(naphthalen-1-ylmethyl)-1,3,4-oxadiazole
133
2-(4-isopropylbenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
134
2-(4-bromobenzyl)-5-(2,6-dimethylstyryl)-1,3,4-oxadiazole
135
2-(4-bromobenzyl)-5-(2,6-dimethylphenethyl)-1,3,4-oxadiazole
136
2-([1,1'-biphenyl]-4-ylmethyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
137
2-(4-bromobenzyl)-5-(1-(o-tolyl)propan-2-yl)-1,3,4-oxadiazole
138
2-(4-bromobenzyl)-5-(1-(o-tolyl)prop-1-en-2-yl)-1,3,4-oxadiazole
139
2-([1,1'-biphenyl]-4-ylmethyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
140
2-(4-bromobenzyl)-5-(1-(o-tolyl)propan-2-yl)-1,3,4-oxadiazole
141
2-(4-bromobenzyl)-5-(1-(o-tolyl)prop-1-en-2-yl)-1,3,4-oxadiazole
142
2-([1,1'-biphenyl]-4-ylmethyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
143
2-(4-bromobenzyl)-5-(1-(o-tolyl)propan-2-yl)-1,3,4-oxadiazole
144
2-(4-bromobenzyl)-5-(1-(o-tolyl)prop-1-en-2-yl)-1,3,4-oxadiazole
145
2-(3-bromo-4-methylbenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
146
2-(3,4-dimethylbenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
147
2-(2-isopropylstyryl)-5-(1-phenylethyl)-1,3,4-oxadiazole
148
2-(1-(4-isobutylphenyl)ethyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
149
2-(4-bromobenzyl)-5-(3,4-dichlorostyryl)-1,3,4-oxadiazole
150
2-(4-bromobenzyl)-5-(2,3-dimethylstyryl)-1,3,4-oxadiazole
151
2-(4-bromobenzyl)-5-(3-isopropylstyryl)-1,3,4-oxadiazole
152
2-(4-bromobenzyl)-5-(2-chloro-3-(trifluoromethyl)styryl)-1,3,4-oxadiazole
153
2-(4-bromobenzyl)-5-(2-(4'-chloro-[1,1'-biphenyl]-2-yl)vinyl)-1,3,4-oxadiazole
154
2-(4-bromobenzyl)-5-(4-isopropylstyryl)-1,3,4-oxadiazole
155
2-(4-bromobenzyl)-5-(2-(4-fluorophenoxy)styryl)-1,3,4-oxadiazole
156
2-(benzofuran-2-yl)-5-(4-bromobenzyl)-1,3,4-oxadiazole
157
2-(4-bromobenzyl)-5-(5-chlorobenzofuran-2-yl)-1,3,4-oxadiazole
158
(E)-2-benzyl-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
159
(E)-2-(3-chloro-4-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
160
(E)-N-(4-bromo-3-fluorophenyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol-2-amine
161
(E)-N-(4-bromo-3-fluorophenyl)-5-(2-chloro-4-fluorostyryl)-N-methyl-1,3,4-oxadiazol-2-amine
162
2-(4-bromobenzyl)-5-(2-(6-chlorobenzo[d][1,3]dioxol-5-yl)vinyl)-1,3,4-oxadiazole
163
2-(4-bromobenzyl)-5-(2-methoxystyryl)-1,3,4-oxadiazole
164
2-(4-bromo-3-fluorobenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
165
2-(4-bromobenzyl)-5-styryl-1,3,4-oxadiazole
166
2-(4-bromobenzyl)-5-(2-chlorostyryl)-1,3,4-oxadiazole
167
2-(4-bromobenzyl)-5-(3-chlorostyryl)-1,3,4-oxadiazole
168
2-(4-bromobenzyl)-5-(2,6-dichlorostyryl)-1,3,4-oxadiazole
169
2-(4-bromo-2-fluorobenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
170
2-(4-bromobenzyl)-5-(2-methylstyryl)-1,3,4-oxadiazole
171
2-(4-bromobenzyl)-5-(4-chlorostyryl)-1,3,4-oxadiazole
172
2-(4-bromo-3-methylbenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
173
2-(2-fluoro-5-methylbenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole
174
(E)-3-(4-bromobenzyl)-5-styryl-1,2,4-oxadiazole
175
(E)-3-(4-bromobenzyl)-5-(2-isopropylstyryl)-1,2,4-oxadiazole
176
(E)-2-(4-bromo-3-methylbenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
177
(E)-2-(2-chloro-4-fluorostyryl)-5-(2-fluoro-5-methylbenzyl)-1,3,4-oxadiazole
178
(E)-2-(3-bromobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
179
(E)-2-(2-chloro-4-fluorostyryl)-5-(3-chlorobenzyl)-1,3,4-oxadiazole
180
(E)-2-(2-chloro-4-fluorostyryl)-5-((6-chloropyridin-3-yl)methyl)-1,3,4-oxadiazole
181
(E)-2-(3-bromo-4-methylbenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
182
(E)-2-(2-chloro-4-fluorostyryl)-5-(3-isopropylbenzyl)-1,3,4-oxadiazole
183
(E)-5-(4-bromobenzyl)-3-styryl-1,2,4-oxadiazole
184
(E)-2-(4-bromo-3-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
185
(E)-2-(2-chloro-4-fluorostyryl)-5-(naphthalen-1-ylmethyl)-1,3,4-oxadiazole
186
2-(3-bromobenzyl)-5-(4-fluoro-2-methylstyryl)-1,3,4-oxadiazole
187
2-(3-chlorobenzyl)-5-(2-fluorostyryl)-1,3,4-oxadiazole
188
2-(3-bromobenzyl)-5-(4-fluorostyryl)-1,3,4-oxadiazole
189
2-(3-bromobenzyl)-5-(2,4-difluorostyryl)-1,3,4-oxadiazole
190
2-(3-bromobenzyl)-5-(4-chloro-2-fluorostyryl)-1,3,4-oxadiazole
191
2-(3-bromobenzyl)-5-(3,4-difluorostyryl)-1,3,4-oxadiazole
192
2-(3-bromobenzyl)-5-(2,4-dichlorostyryl)-1,3,4-oxadiazole
193
2-(3-bromobenzyl)-5-(2-chloro-5-fluorostyryl)-1,3,4-oxadiazole
194
2-(3-bromobenzyl)-5-(2-chloro-3-fluorostyryl)-1,3,4-oxadiazole
195
2-(3-bromobenzyl)-5-(2-chloro-4-methylstyryl)-1,3,4-oxadiazole
196
2-benzyl-5-(2-isopropylstyryl)-1,3,4-oxadiazole
197
2-(4-bromobenzyl)-5-(2-(naphthalen-1-yl)vinyl)-1,3,4-oxadiazole
198
2-(3-bromobenzyl)-5-(2-methyl-4-(trifluoromethyl)styryl)-1,3,4-oxadiazole
199
2-(3-bromobenzyl)-5-(2-chloro-5-(trifluoromethyl)styryl)-1,3,4-oxadiazole
200
2-(3-bromobenzyl)-5-(2,4-dimethylstyryl)-1,3,4-oxadiazole
201
(E)-3-((5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol-2-yl)methyl)phenol
202
(E)-2-(2-chloro-4-fluorostyryl)-5-(3-methoxybenzyl)-1,3,4-oxadiazole
203
(E)-2-(2-chloro-4-fluorostyryl)-5-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-1,3,4-oxadiazole
204
E)-2-(3-bromobenzyl)-5-(2-(2-methylpyridin-3-yl)vinyl)-1,3,4-oxadiazole
205
(E)-2-((5-bromopyridin-3-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
206
(E)-2-(2-chloro-4-fluorostyryl)-5-((4-chloropyridin-2-yl)methyl)-1,3,4-oxadiazole
207
2-(3-bromo-4-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
208
2-(2-chloro-4-fluorostyryl)-5-(3,4-dichlorobenzyl)-1,3,4-oxadiazole
209
2-(2-(5-(4-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)phenol
210
2-(3-bromobenzyl)-5-(2-methoxystyryl)-1,3,4-oxadiazole
211
2-(2-chloro-4-fluorostyryl)-5-(3-methylbenzyl)-1,3,4-oxadiazole
212
2-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol
213
2-(2-chloro-4-fluorostyryl)-5-((1-methyl-1H-indol-3-yl)methyl)-1,3,4-oxadiazole
214
(E)-2-(2-chloro-4-fluorostyryl)-5-((1-methyl-1H-indazol-3-yl)methyl)-1,3,4-oxadiazole
215
2-(2-bromo-4-fluorostyryl)-5-(3-bromobenzyl)-1,3,4-oxadiazole
216
2-(3-bromobenzyl)-5-(2-(3-methylpyridin-4-yl)vinyl)-1,3,4-oxadiazole
217
3-((5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol-2-yl)methyl)-N,N-dimethylaniline
218
2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)phenol
219
2-(2-chloro-4-fluorostyryl)-5-((6-chloropyridin-2-yl)methyl)-1,3,4-oxadiazole
220
2-(3-bromobenzyl)-5-(2-ethylstyryl)-1,3,4-oxadiazole
221
2-(2-chloro-4-fluorostyryl)-5-(2,3-dimethylbenzyl)-1,3,4-oxadiazole
222
2-(2-bromobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
223
2-(3-bromophenethyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
224
2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)-N,N-dimethylaniline
225
2-(3-bromobenzyl)-5-(2-(2-chloropyridin-3-yl)vinyl)-1,3,4-oxadiazole
226
2-(2-chloro-4-fluorostyryl)-5-(3-fluorobenzyl)-1,3,4-oxadiazole
227
(E)-2-(2-chloro-4-fluorostyryl)-5-(3,5-dibromobenzyl)-1,3,4-oxadiazole
228
(E)-2-(2-chloro-4-fluorostyryl)-5-(naphthalen-2-ylmethyl)-1,3,4-oxadiazole
229
(E)-2-(3-bromo-4-methoxybenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
230
(E)-2-bromo-4-((5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol-2-yl)methyl)phenol
231
(E)-2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)-5-fluoro-N,N-dimethylaniline
232
(E)-2-(3-bromobenzyl)-5-(4-fluoro-2-(pyrrolidin-1-yl)styryl)-1,3,4-oxadiazole
233
(E)-2-(3-bromobenzyl)-5-(2,4,6-trifluorostyryl)-1,3,4-oxadiazole
234
(E)-3-((5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol-2-yl)methyl)benzonitrile
235
(E)-2-(2-chloro-4-fluorostyryl)-5-(3-(trifluoromethoxy)benzyl)-1,3,4-oxadiazole
236
2-(2-chloro-4-fluorostyryl)-5-(quinolin-8-ylmethyl)-1,3,4-oxadiazole
237
2-(2-chloro-4-fluorostyryl)-5-(isoquinolin-1-ylmethyl)-1,3,4-oxadiazole
238
2-(2-chloro-4-fluorostyryl)-5-(isoquinolin-4-ylmethyl)-1,3,4-oxadiazole
239
2-(3-bromobenzyl)-5-(2-(5-fluoropyridin-2-yl)vinyl)-1,3,4-oxadiazole
240
2-((6-bromopyridin-3-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
241
2-((6-bromopyridin-3-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
242
methyl-2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)benzoate
243
2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)benzoic acid
244
5-(3-bromobenzyl)-N-(2-chloro-4-fluorophenyl)-1,3,4-oxadiazole-2-carboxamide
245
2-(3-bromobenzyl)-5-(2-chloro-4,6-difluorostyryl)-1,3,4-oxadiazole
246
N-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)-2-chloro-4-fluorobenzenesulfonamide
247
(E)-2-(2-chloro-4-fluorostyryl)-5-(3-(trifluoromethyl)benzyl)-1,3,4-oxadiazole
248
(E)-2-(3-bromobenzyl)-5-(2-(1-isopropyl-1H-pyrazol-5-yl)vinyl)-1,3,4-oxadiazole
249
(E)-2-((1H-indazol-3-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
250
(E)-2-(2-chloro-4-fluorostyryl)-5-(cyclohexylmethyl)-1,3,4-oxadiazole
251
(E)-2-(benzo[b]thiophen-3-ylmethyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
252
(E)-2-(3-bromobenzyl)-5-(4-fluoro-2-(piperidin-1-yl)styryl)-1,3,4-oxadiazole
253
N-(3-bromophenyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole-2-carboxamide
254
(E)-2-(3-bromobenzyl)-5-(2-(4-chloro-1-isopropyl-1H-pyrazol-3-yl)vinyl)-1,3,4-oxadiazole
255
2-(2-chloro-4-fluorostyryl)-5-(3-fluoro-5-methylbenzyl)-1,3,4-oxadiazole
256
2-(3-bromobenzyl)-5-(2-(trifluoromethoxy)styryl)-1,3,4-oxadiazole
257
2-(3-bromobenzyl)-5-(2-(3-chloro-5-fluoropyridin-2-yl)vinyl)-1,3,4-oxadiazole
258
2-(5-bromo-2-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
259
(E)-2-(3-bromobenzyl)-5-(2-(1-isopropyl-1H-imidazol-2-yl)vinyl)-1,3,4-oxadiazole
260
(E)-2-(3-bromobenzyl)-5-(2,6-dichloro-4-fluorostyryl)-1,3,4-oxadiazole
261
(E)-2-(2-chloro-4-fluorostyryl)-5-((1-isopropyl-1H-indazol-3-yl)methyl)-1,3,4-oxadiazole
262
2-(3-bromo-4-methylbenzyl)-5-(2,4-difluorostyryl)-1,3,4-oxadiazole
263
2-(3-bromo-4-fluorobenzyl)-5-(2,4-difluorostyryl)-1,3,4-oxadiazole
264
2-(3-bromobenzyl)-5-(4-fluoro-2-(trifluoromethyl)styryl)-1,3,4-oxadiazole
265
2-(2-bromo-4-fluorostyryl)-5-(3-bromo-4-methylbenzyl)-1,3,4-oxadiazole
266
2-(3-bromo-4-fluorobenzyl)-5-(2-bromo-4-fluorostyryl)-1,3,4-oxadiazole
267
2-(2-chloro-4-fluorostyryl)-5-(3-cyclopropylbenzyl)-1,3,4-oxadiazole
268
(E)-2-(2-(5-(3-Bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)-5-fluoro-N-(2-methoxyethyl)-N-methylaniline
269
(E)-2-(3-bromobenzyl)-5-(4-fluoro-2-(furan-3-yl)styryl)-1,3,4-oxadiazole
270
(E)-2-(3-bromobenzyl)-5-(4-fluoro-2-(thiophen-3-yl)styryl)-1,3,4-oxadiazole
271
(E)-4-(2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)-5-fluorophenyl)morpholine
272
(E)-2-(benzofuran-3-ylmethyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
273
(E)-2-(3-bromobenzyl)-5-(4-fluoro-2-isopropylstyryl)-1,3,4-oxadiazole
274
(E)-2-(2-(1H-pyrrol-1-yl)styryl)-5-(3-bromobenzyl)-1,3,4-oxadiazole
275
2-(3-bromobenzyl)-5-(2-chloro-4-fluorophenethyl)-1,3,4-oxadiazole
276
(E)-2-(3-bromobenzyl)-5-(2-(naphthalen-1-yl)vinyl)-1,3,4-oxadiazole
277
(E)-2-(3-bromobenzyl)-5-(2-(4-fluoronaphthalen-1-yl)vinyl)-1,3,4-oxadiazole
278
(E)-2-((1H-indazol-3-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
279
(E)-2-(2-chloro-4-fluorostyryl)-5-((2-methyl-1H-indol-1-yl)methyl)-1,3,4-oxadiazole
280
2-(3-bromobenzyl)-5-(2,3-difluorostyryl)-1,3,4-oxadiazole
281
2-(3-bromobenzyl)-5-(2-(trifluoromethyl)styryl)-1,3,4-oxadiazole
282
2-(5-bromo-2-methylbenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
283
2-((4-bromopyridin-2-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
284
2-(3-bromobenzyl)-5-(2-(3,5-difluoropyridin-2-yl)vinyl)-1,3,4-oxadiazole
285
2-(3-bromo-4-methylbenzyl)-5-(2-chloro-4-fluorophenethyl)-1,3,4-oxadiazole
286
(E)-2-(2-chloro-4-fluorostyryl)-5-(thiophen-3-ylmethyl)-1,3,4-oxadiazole
287
(E)-2-(3-bromobenzyl)-5-(2-(naphthalen-2-yl)vinyl)-1,3,4-oxadiazole
288
(E)-2-(3-bromobenzyl)-5-(2,3-dimethylstyryl)-1,3,4-oxadiazole
289
(E)-2-(3-bromobenzyl)-5-(2-(quinolin-5-yl)vinyl)-1,3,4-oxadiazole
290
2-(2-bromo-4,6-difluorostyryl)-5-(3-bromobenzyl)-1,3,4-oxadiazole
291
2-(3-chloro-2-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
292
2-(3-bromo-5-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
293
2-(3-bromo-2-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
294
2-(3-bromo-2-methylbenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole
295
2-(2-chloro-4-fluorostyryl)-5-((2-methylquinolin-8-yl)methyl)-1,3,4-oxadiazole
296
2-(2-chloro-4-fluorostyryl)-5-((3-chloroisoquinolin-1-yl)methyl)-1,3,4-oxadiazole
297
2-(2-chloro-4-fluorostyryl)-5-((3-methoxyisoquinolin-1-yl)methyl)-1,3,4-oxadiazole
298
2-(2-chloro-4-fluorostyryl)-5-((7-methoxynaphthalen-1-yl)methyl)-1,3,4-oxadiazole
299
2-(2-chloro-4-fluorostyryl)-5-(3-(difluoromethyl)benzyl)-1,3,4-oxadiazole
300
2-(2-chloro-4-fluorostyryl)-5-(3-chloro-4-methylbenzyl)-1,3,4-oxadiazole
301
(E)-2-(3-bromobenzyl)-5-(2-(quinolin-8-yl)vinyl)-1,3,4-oxadiazole
302
(E)-4-(2-(2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)-5-fluorophenoxy)ethyl)morpholine
303
(E)-2-(3-bromobenzyl)-5-(2-(isoquinolin-5-yl)vinyl)-1,3,4-oxadiazole
304
(E)-2-(3-bromobenzyl)-5-(2-(1-methyl-1H-indol-3-yl)vinyl)-1,3,4-oxadiazole
305
2-(2-(5-(3-bromo-4-methylbenzyl)-1,3,4-oxadiazol-2-yl)vinyl)-5-fluoro-N-methyl-N-phenethylaniline
306
(E)-2-(3-bromobenzyl)-5-(2-(imidazo[1,2-a]pyridin-3-yl)vinyl)-1,3,4-oxadiazole
307
(E)-2-(3-bromobenzyl)-5-(2-(1-methyl-1H-indol-4-yl)vinyl)-1,3,4-oxadiazole
본 발명에 따른 화학식 1 또는 화학식 2로 표시되는 신규한 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있다. 상기 염으로는 약학적으로 또는 생리학적으로 허용되는 다양한 유기산 또는 무기산에 의해 형성된 산부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요오드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 다이카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피온산, 옥살산, 말론산, 숙신산, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디온산, 벤조산, 클로로벤조산, 메틸벤조산, 디니트로 벤조산, 하이드록시벤조에이트, 메톡시벤조산, 프탈산, 테레프탈레이트, 벤젠설폰산, 톨루엔설폰산, 클로로벤젠설폰산, 크실렌설폰산, 페닐아세트산, 페닐프로피온산, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트, 트라이플루오로아세트산 등을 사용하여 제조할 수 있다.
이때, 본 발명에 따른 상기 산 부가염은 통상의 방법, 예를 들면, 화학식 1 또는 화학식 2의 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나, 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면, 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 리튬, 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예를 들면, 질산은)과 반응시켜 얻는다.
나아가, 아미노산을 사용하여 약학적으로 허용 가능한 염을 만들 수 있다. 아미노산염으로는 예를 들면, 글라이신, 알라닌, 페닐알라닌, 발린, 라이신, 글루타믹산 등의 천연 아미노산을 제조하는 것이 제약상 적합하다.
이하, 본 발명에 따른 화학식 1 또는 화학식 2로 표시되는 신규한 화합물의 제조방법을 상세히 설명한다.
본 발명의 신규 화합물은 대표적으로 하기 반응식 1 내지 21 중 어느 하나의 반응식으로 제조될 수 있으나, 이에 한정되지 않으며, 하기 제조방법 외에도 당분야에서 통상적으로 사용되고 있는 제조방법에 의해 제조될 수 있다.
제법 1
본 발명에 따른 화학식 1로 표시되는 신규한 화합물은 하기 반응식 1에 나타낸 바와 같이 제조될 수 있다.
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제법 2
본 발명에 따른 화학식 1로 표시되는 신규한 화합물은 하기 반응식 2에 나타낸 바와 같이 제조될 수 있다.
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제법 3
본 발명에 따른 화학식 1로 표시되는 신규한 화합물은 하기 반응식 3에 나타낸 바와 같이 제조될 수 있다.
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제법 4
본 발명에 따른 화학식 1로 표시되는 신규한 화합물은 하기 반응식 4에 나타낸 바와 같이 제조될 수 있다.
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제법 5
본 발명에 따른 화학식 1로 표시되는 신규한 화합물은 하기 반응식 5에 나타낸 바와 같이 제조될 수 있다.
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제법 6
본 발명에 따른 화학식 1로 표시되는 신규한 화합물은 하기 반응식 6에 나타낸 바와 같이 제조될 수 있다.
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제법 7
본 발명에 따른 화학식 1로 표시되는 신규한 화합물은 하기 반응식 7에 나타낸 바와 같이 제조될 수 있다.
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제법 8
본 발명에 따른 화학식 1로 표시되는 신규한 화합물은 하기 반응식 8에 나타낸 바와 같이 제조될 수 있다.
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제법 9
본 발명에 따른 화학식 1로 표시되는 신규한 화합물은 하기 반응식 9에 나타낸 바와 같이 제조될 수 있다.
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제법 10
본 발명에 따른 화학식 1로 표시되는 신규한 화합물은 하기 반응식 10에 나타낸 바와 같이 제조될 수 있다.
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제법 11
본 발명에 따른 화학식 1로 표시되는 신규한 화합물은 하기 반응식 11에 나타낸 바와 같이 제조될 수 있다.
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제법 12
본 발명에 따른 화학식 2로 표시되는 신규한 화합물은 하기 반응식 12에 나타낸 바와 같이 제조될 수 있다.
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제법 13
본 발명에 있어서 하기 반응식 13과 같이 화합물을 제조할 수 있다.
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제법 14
본 발명에 있어서 하기 반응식 14와 같이 화합물을 제조할 수 있다.
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제법 15
본 발명에 있어서 하기 반응식 15와 같이 화합물을 제조할 수 있다.
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제법 16
본 발명에 있어서 하기 반응식 16와 같이 화합물을 제조할 수 있다.
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제법 17
본 발명에 있어서 하기 반응식 17와 같이 화합물을 제조할 수 있다.
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제법 18
본 발명에 있어서 하기 반응식 18과 같이 화합물을 제조할 수 있다.
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제법 19
본 발명에 있어서 하기 반응식 19와 같이 화합물을 제조할 수 있다.
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제법 20
본 발명에 있어서 하기 반응식 20과 같이 화합물을 제조할 수 있다.
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제법 21
본 발명에 있어서 하기 반응식 21과 같이 화합물을 제조할 수 있다.
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나아가, 본 발명은 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 약학적으로 허용가능한 염을 유효성분으로 함유하는 항바이러스용 약학적 조성물을 제공한다:
[화학식 1]
[화학식 2]
상기 화학식 1 또는 화학식 2에 있어서, X1, X2, X3, Y, Z, R1 및 R2는 본 명세서에서 정의한 바와 같다.
본 발명의 조성물에 있어서, 상기 바이러스는 인플루엔자 바이러스일 수 있으며, 바람직하게는 A형 인플루엔자 바이러스 또는 B형 인플루엔자 바이러스일 수 있다. 보다 바람직하게는 상기 인플루엔자 바이러스는 A/California/07/2009 (H1N1), A/Perth/16/2009 (H3N2) 또는 B/Florida/04/2006일 수 있다.
본 발명의 조성물에 있어서, 상기 바이러스 감염으로 인한 질환으로는 예를 들어, 독감, 감기, 인후염, 기관지염, 폐렴, 조류독감, 돼지독감, 염소독감 등의 인플루엔자 바이러스 감염으로 인한 질환을 들 수 있으나, 이에 제한되는 것은 아니다.
본 발명에 따른 화학식 1 또는 화학식 2로 표시되는 신규 화합물에 대한 A형 인플루엔자 바이러스 및 B형 인플루엔자 바이러스에 대한 항바이러스 활성을 평가하였다. 그 결과, 본 발명에 따른 화학식 1 또는 화학식 2의 화합물은 인플루엔자 바이러스에 대한 항바이러스 활성이 우수한 것으로 확인되었으며, 동시에 세포에 대한 독성이 낮은 것으로 나타났다.
본 발명의 화합물은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있으며, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다.
경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose) 또는 락토오스(lactose) 또는 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용 액제, 유제 또는 시럽제 등이 해당 되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁 용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.
또한, 본 발명에 따른 화학식 1 또는 화학식 2로 표시되는 화합물의 인체에 대한 효과적인 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 일반적으로 약 0.001-100 mg/kg/일이며, 바람직하게는 0.01-35 mg/kg/일이다. 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.07-7000 mg/일이며, 바람직하게는 0.7-2500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.
나아가, 본 발명은 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 함유하는 바이러스 감염으로 인한 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.
본 발명의 건강기능식품 조성물에 유효성분으로 포함되는 상기 화학식 1 또는 화학식 2의 화합물 및 이의 항바이러스 활성은 앞서 약학적 조성물에서 설명한 바와 동일하므로, 그 기재를 생략한다.
본 발명에 따른 건강기능식품 조성물은 병원성 세균에 의하여 발병하는 질환의 예방 또는 개선을 목적으로 식품, 음료 등의 건강기능식품에 첨가할 수 있다.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.
본 발명에 따른 화학식 1 또는 화학식 2의 화합물 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 함유하는 건강기능식품 조성물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강기능식품 중의 상기 조성물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.
본 발명의 건강기능식품 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트라이톨 등의 당알코올이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강기능성 식품 조성물 100 당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.
상기 외에 본 발명의 화학식 1 또는 화학식 2의 화합물 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 함유하는 건강기능식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 건강기능식품 조성물은 천연 과일쥬스 및 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 화학식 1 또는 화학식 2의 화합물 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 함유하는 건강기능식품 조성물 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.
또한, 본 발명은 상기 화학식 1 또는 화학식 2로 표시되는 화합물을 유효성분으로 함유하는 바이러스 소독용 또는 세정용 조성물을 제공한다.
본 발명의 소독용 또는 세정용 조성물에 유효성분으로 포함되는 화학식 1 또는 화학식 2의 화합물 및 이의 항바이러스 활성 또한 앞서 약학적 조성물에서 설명한 바와 동일하므로, 그 기재를 생략한다.
본 발명에 따른 상기 소독용 또는 세정용 조성물은 주방세제, 세탁세제, 야채 또는 채소 세척제, 손 세정제 등의 용도로 사용될 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 소독용 또는 세정용 조성물은 하나 이상의 계면활성제를 포함할 수 있다. 상기 계면활성제는 음이온성, 비-이온성, 양이온성, 양쪽성 또는 양이온성형태(zwitter ionic type), 또는 이것들의 혼합물일 수 있다.
음이온성 계면활성제의 대표적인 예로는 선형 알킬벤젠술폰산염(LAS), 알킬황산염(AS), 알파올레핀술폰산염(AOS), 알코올에톡시황산염(AES) 또는 천연지방산의 알칼리금속염을 들 수 있다. 비-이온성 계면활성제의 예로는 알킬폴리에틸렌글리콜에테르, 노닐페놀 폴리에틸렌글리콜 에테르, 수크로스와 글루코스의 지방산에스테르, 또는 폴리에톡실화 알킬글루코시드의 에스테르를 들 수 있다.
또한, 본 발명의 상기 조성물은 용도에 맞추어 연마제, 표백제, 표면활성제, 부식방지제, 금속봉쇄제, 얼룩-재침착 방지제, 향수, 효소 및 표백제의 안정화제, 제형 보조제, 광증백제, 거품부스터, 킬레이트화제, 충전제, 직물연화제 등과 같은 당업계에서 공지된 다른 세제 성분들을 추가로 포함할 수 있다. 본 발명의 소독용 또는 세정용 조성물은 분제, 액제 등의 임의의 편리한 형태로 제형화될 수 있다.
이하, 본 발명을 실시예에 의하여 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 이에 한정되는 것은 아니다.
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인플루엔자 감염도 측정을 위한 표현형 기반 어세이 (phenotypic-based assay) 구축
본 발명자들은 NS1A-GFP 융합 단백질을 발현하는 인플루엔자 바이러스 (rA/Puerto Rico/8/34/NS1-GFP (H1N1)) (Manicassamy B, Manicassamy S, Belicha-Villanueva A, Pisanelli G, Pulendran B, Garcia-Sastre A. (2010) Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus. Proc Natl Acad Sci U S A 107(25):11531-11536)를 이용하여 인플루엔자 감염도를 측정하는 표현형 기반 어세이(phenotypic-based assay)를 구축하였다.
MDCK 세포를 384-웰 플레이트에 평판하였고 NS1-GFP 융합 단백질을 발현하는 인플루엔자 바이러스로 감염하고 37에서 24 시간 동안 배양하였다. 감염 24 시간 후에, 공초점 현미경(ImageXpress®, Molecular Devices, Sunnyvale, CA, USA) 을 사용하여 NS1A-GFP (녹색) 및 세포핵 (파란색)에 대한 이미지를 획득하였고 이미지는 내부(in-house) 개발 소프트웨어로 분석되었다. GFP 양성 세포와 음성 세포의 수를 측정함으로써 인플루엔자 바이러스 감염률과 세포독성이 계산되었다. 표현형 기반 어세이를 이용한 감염도 측정 평가를 위해 이미 알려진 억제제인 Oseltamivir, T-705 그리고 Nucleozin ((De Clercq E1. (2006) Antiviral agents active against influenza A viruses. Nat Rev Drug Discov. 5(12):1015-25)을 각각 NS1A-GFP 바이러스와 함께 37에서 24 시간 동안 배양 후 항 바이러스 활성을 평가하였다. 농도별 약물 효능 평가 (DRC; dose-response curve)를 통해 각 억제제의 EC50 및 CC50 값을 프리즘, 버전 5.0c 소프트웨어 (GraphPad Software, Inc., La Jolla, CA, USA)를 사용하여 계산하였다.
본 실시예에서 구축된 인플루엔자 감염도 측정을 위한 표현형 기반 어세이는 도 1에 나타난 바와 같이 항바이러스 활성을 평가하는데 유용함을 확인하였다.
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항인플루엔자
효능을 가진 신규 화합물
스캐폴드
(scaffold) 동정
본 발명자들은 NS1A-GFP 융합 단백질을 발현하는 인플루엔자 바이러스 (rA/Puerto Rico/8/34/NS1-GFP (H1N1))와 약 110,000개의 화합물로 구성된 한국파스퇴르연구소 내부 화합물 라이브러리를 이용하여 항 인플루엔자 효능을 가지는 새로운 화합물 스캐폴드를 동정하였다.
화합물들의 항바이러스 활성을 테스트하기 위해, MDCK 세포를 384-웰 플레이트에 평판하였고, 10 uM 농도로 희석시킨 화합물을 처리하고 NS1-GFP 융합 단백질을 발현하는 인플루엔자 바이러스로 감염한후 37에서 24 시간 동안 배양하였다. 감염 24 시간 후에, 공초점 현미경(ImageXpress®, Molecular Devices, Sunnyvale, CA, USA) 을 사용하여 GFP 양성 세포와 음성 세포의 수를 측정함으로써 인플루엔자 바이러스 감염률과 세포독성이 계산되었다. 수득된 이미지는 내부(in-house) 개발 소프트웨어로 분석되었다. 인플루엔자 바이러스 감염 억제 비율은 1% DMSO-처리 세포와 이미 알려진 인플루엔자 감염 억제제인 Nucleozin 처리 세포의 EC100 을 이용하여 계산하였고, 각각 0% 와 100% 억제율로 설정하였다. 화합물의 항바이러스 활성은 DRC (dose-response curve) 분석으로 평가되었고, EC50 및 CC50 값은 프리즘, 버전 5.0c 소프트웨어 (GraphPad Software, Inc., La Jolla, CA, USA)를 사용하여 계산하였다.
히트(hits)는 >90% HCV 감염 억제 및 >70% 세포 생존율을 보인 화합물들이 선정되었으며 이 화합물들은 다시 10-포인트 농도별 약효 분석을 통해 항 바이러스 효과가 재확인되었다. 범용 인플루엔자 바이러스 저해제로서의 가능성을 평가하기 위해서 세 가지 종류의 계절성 인플루엔자 바이러스 (A/Perth/16/09(H3N2), A/California/7/09(H1N1), B/Florida/4/06)에 대한 농도별 약효 효능 평가를 실시하였다. 그리고 현재 가장 널리 사용되고 있는 항 인플루엔자 약물인 뉴라미니데이즈 저해제와는 다른 약물기전을 가지고 있는 화합물을 선별하기 위해서 뉴라미니데이즈 어세이를 실시하였다. 상기와 같은 과정을 통해 티오옥사디아졸 (Thio oxadiazole, THO) 스캐폴드가 선정되었다.
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반응식 1을 이용한 본 발명의 화학식 1로 표시되는 화합물의 제법
본 발명자들은 상기 실시예 2에서 선정된 THO 스캐폴드를 포함하는 화합물 및 이의 다양한 유도체를 합성하였으며, 하기와 같은 반응식 1을 이용하였다.
[반응식 1]
A1 합성의 일반적인 방법
4-브로모-3,5-디메틸-1H-피라졸 (1 g, 5.71 mmol)과 K2CO3 (1.58 g, 11.43 mmol)를 무수 DMF (8 mL)에 용해시켰다. 에틸 브로모아세테이트 (1.25 mL, 11.43 mmol)를 반응 혼합물에 첨가하고 90 oC에서 8시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시킨 다음 물에 붓고, EtOAc로 추출하였으며, 물로 세척하고, MgSO4로 건조시켰다. 반응 혼합물을 농축하여 원료 고체(crude solid)를 형성하였다. 이를 헥산(hexane)으로 세척하여 갈색 고체의 바람직한 생산물 A1을 제조하였다.
A2 합성의 일반적인 방법
물질 A1 (747 mg, 2.86 mmol)을 무수 EtOH (10 mL)에 용해시켰다. 하이드라진 모노하이드레이트 (0.90 mL, 28.61 mmol)를 반응 혼합물에 첨가하고 90 oC에서 16시간 동안 교반하였다. 반응 혼합물을 진공에서 건조시키고 이에 따라 형성된 고체를 여과시켜 흰색 고체의 바람직한 생산물 A2를 제조하였다.
A3 합성의 일반적인 방법
물질 A2 (500 mg, 2.02 mmol)와 1N KOH (2.02 mL, 2.02 mmol)를 MeOH (6 mL)에 용해시켰다. CS2 (0.30 mL, 5.06 mmol)를 반응 혼합물에 첨가하고 90 oC에서 8시간 동안 교반하였다. 반응 혼합물을 농축한 다음 여기에 물을 붓고 1N HCl(aq.)를 이용하여 pH 6으로 조정하였다. 형성된 고체를 여과시키고 물로 세척한 다음 건조기(oven)에서 60 oC로 건조시켜 베이지색 고체의 바람직한 생산물 A3를 제조하였다.
A4 합성의 일반적인 방법
물질 A3 (35 mg, 0.12 mmol), DIPEA (0.021 mL, 0.12 mmol) 및 2-(브로모메틸)-1,1'-비페닐 (33 mg, 0.13 mmol)을 무수 DMF (1 mL)에 용해시켰다. 반응 혼합물을 25 oC에서 약 16시간 동안 교반한 다음 EtOAc에 희서시키고 NH4Cl(aq.) 용액과 물로 세척하였다. 유기층을 무수 MgSO4로 건조시킨 다음 진공에서(in
vacuo) 증발시켰다. 무색 오일의 바람직한 생산물 A4를 컬럼 크로마토그래피 (EtOAc/Hexane, 1:1)로 수득하였다.
A5 합성의 일반적인 방법
MeOH (15 mL)에 용해한 물질 A4 (119 mg, 0.26 mmol) 를 옥손 (803 mg, 1.31 mmol)과 물 (15 mL)의 혼합물에 현탁시켰다. 반응 혼합물을 25 oC에서 약 16시간 동안 교반하였다. 반응이 완료된 후, 진공에서(in
vacuo) 용매를 건조시켰다. 반응 혼합물을 EtOAc로 추출하고 물로 세척하였다. 유기층을 무수 MgSO4로 건조시킨 다음 진공에서(in
vacuo) 증발시켰다. 흰색 고체의 바람직한 생산물 A5를 컬럼 크로마토그래피 (EtOAc/Hexane, 1:3)로 수득하였다.
A6 합성의 일반적인 방법
AcOH (2 mL)에 용해된 물질 A4 (41 mg, 0.09mmol)의 용액을 H2O (0.4 mL)에 용해된 5% KMnO4 (19 mg, 0.12 mmol)에 현탁시켰다. 반응 혼합물을 25 oC에서 약 12시간 동안 교반하였다. 반응이 완료된 후, 40% 농도(strength)의 소듐 하이드로겐 설파이트 수용액을 혼합물이 탁색될 때 까지 첨가하였고, 이후 H2O를 첨가하였다. 반응 혼합물을 EtOAc로 추출하고 물로 세척하였다. 유기층을 무수 MgSO4로 건조시킨 다음 진공에서(in
vacuo) 증발시켰다. 흰색 고체의 바람직한 생산물 A6를 컬럼 크로마토그래피 (EtOAc/Hexane, 1:3)로 수득하였다.
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반응식 2를 이용한 본 발명의 화학식 1로 표시되는 화합물의 제법
[반응식 2]
B1 합성의 일반적인 방법
물질 A2 (200 mg, 0.81 mmol)를 무수 EtOH (4 mL)에 용해시켰다. 이소티오시아나토에탄 (0.071 mL, 0.81 mmol)을 반응 혼합물에 첨가하고 100 oC에서 약 3시간 동안 교반하였다. 반응 혼합물을 0 oC로 냉각시킨 다음 형성된 고체를 여과시키고 EtOH로 세척하여 흰색 고체의 바람직한 생산물 B1을 제조하였다.
B2 합성의 일반적인 방법
MeOH (3 mL)에 용해된 물질 B1 (228 mg, 0.68 mmol)의 용액에 메탄올(methanolic) 1N KOH (2.73 mL, 1.00 mmol)를 첨가하고 100 oC에서 8시간 동안 교반하였다. 반응 혼합물을 0 oC로 냉각시키고 1N HCl(aq.)을 이용하여 pH 2로 조절하였다. 형성된 고체를 여과시키고 물로 세척한 다음 건조기(oven)에서 60 oC로 건조사여 흰색 고체의 바람직한 생산물 B2를 제조하였다.
B3 합성의 일반적인 방법
물질 B2 (50 mg, 0.16 mmol), DIPEA (0.028 mL, 0.16 mmol) 및 2-(브로모메틸)-1,1'-비페닐 (32 mg, 0.17 mmol)을 무수 DMF (2 mL)에 용해시켰다. 반응 혼합물을 25 oC에서 16시간 동안 교반시키고, EtOAc에 희석시킨 다음 NH4Cl(aq.) 용액 및 물로 세척하였다. 유기층을 무수 MgSO4로 건조시킨 다음 진공에서(in
vacuo) 증발시켰다. 흰색 고체의 바람직한 생산물 B3를 컬럼 크로마토그래피 (EtOAc/Hexane, 1:1)로 수득하였다.
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반응식 3을 이용한 화학식 1로 표시되는 화합물의 제법
[반응식 3]
C1 합성의 일반적인 방법
물질 A2 (405 mg, 1.55 mmol)를 무수 EtOH (6 mL)에 용해시켰다. 2-(이소티오시아나토메틸)-1,1'-비페닐 (349 mg, 1.55 mmol)을 반응 혼합물에 첨가하고 95 oC에서 6시간 동안 교반하였다. 반응 혼합물을 0 oC로 냉각시킨 다음 형성된 고체를 여과시키고 EtOH로 세척하여 흰색 고체의 바람직한 생산물 C1을 제조하였다.
C2 합성의 일반적인 방법
물질 C1 (200 mg, 0.40 mmol)을 0 oC의 H2SO4 (2 mL)에 용해시키고 동일한 온도에서 2시간 동안 교반하였다. 얼음물을 반응 혼합물에 부은 후 형성된 고체를 여과시키고 물로 세척하였다. 결과적으로 형성된 고체를 MC에 용해시키고 유기층을 무수 MgSO4로 건조시킨 다음 진공에서(in vacuum)에서 증발시켰다. 흰색 고체의 바람직한 생산물 C2를 컬럼 크로마토그래피 (EtOAc/Hexane, 1:1)로 수득하였다.
C3 합성의 일반적인 방법
물질 C2 (21 mg, 0.05 mmol), TEA (0.010 mL, 0.07 mmol) 및 아이오도메테인 (0.006 mL, 0.10 mmol)을 무수 DMF (1 mL)에 용해시켰다. 반응 혼합물을 70 oC에서 3시간 동안 교반한 다음 EtOAc에 희석시키고 NaHCO3(aq.) 용액 및 물로 세척하였다. 유기층을 무수 MgSO4로 건조시킨 다음 진공에서(in
vacuo) 증발시켰다. 노란색 오일의 바람직한 생성물 C3를 컬럼 크로마토그래피 (EtOAc/Hexane, 1:1)로 수득하였다.
C4 합성의 일반적인 방법
톨루엔 (2 mL)에 용해된 TEA (0.010 mL, 0.07 mmol) 및 물질 C2 (21 mg, 0.05 mmol)의 용액에 무수 아세트산 (0.014 mL, 0.14 mmol)을 첨가하고 50 oC에서 2시간 동안 교반하였다. 반응 혼합물을 EtOAc에 희석시키고 NaHCO3(aq.) 및 물로 세척하였다. 유기층을 무수 MgSO4로 건조시킨 다음 진공에서(in
vacuo) 증발시켰다. 노란색 오일의 바람직한 생산물 C4를 컬럼 크로마토그래피 (EtOAc/Hexane, 1:1)로 수득하였다.
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반응식 4를 이용한 본 발명의 화학식 1로 표시되는 화합물의 제법
[반응식 4]
D1 합성의 일반적인 방법
물질 A3 (50 mg, 0.19 mmol)을 무수 DMF (1 mL)에 용해된 1-아이오도-2-메틸벤젠 (0.029 mL, 0.22 mmol), 1,10-페난트롤린 (44 mg, 0.24 mmol), CuI (2 mg, 0.01 mmol) 및 K2CO3 (33 mg, 0.24 mmol)에 첨가한 후 120 oC에서 8시간 동안 교반하였다. 반응이 완료된 후, 반응 혼합물을 EtOAc로 추출하고 물로 세척하였다. 유기층을 무수 MgSO4로 건조시킨 다음 진공에서(in
vacuo) 증발시켰다. 노란색 고체의 바람직한 생산물 D1을 컬럼 크로마토그래피 (EtOAc/Hexane, 1:5)로 수득하였다.
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반응식 5를 이용한 본 발명의 화학식 1로 표시되는 화합물의 제법
[반응식 5]
E1 합성의 일반적인 방법
오일에 용해된 60% NaH (31 mg, 0.78 mmol)를, 무수 DMF (2 mL)에 용해된 o-톨릴메테인티올 (54 mg, 0.39 mmol) 용액에 0 oC에서 첨가한 다음 용액을 실온에 두었다. 메틸 5-니트로푸란-2-카르복실레이트 (67 mg, 0.39 mmol)를 반응 혼합물에 첨가하고 70 oC에서 3시간 동안 교반하였다. 결과적으로 형성된 혼합물을 실온으로 냉각시키고, 물로 식힌 다음 EtOAc로 추출하고 NaHCO3(aq.) 용액으로 세척하였다. 유기층을 무수 MgSO4로 건조시킨 다음 진공에서(in
vacuo) 증발시켰다. 무색 오일의 바람직한 생산물 E1을 컬럼 크로마토그래피 (EtOAc/Hexane, 1:10)로 수득하였다.
E2 합성의 일반적인 방법
THF/EtOH/H2O(1:1:1, v/v) (2 mL)에 용해된 물질 E1 (69mg, 0.26 mmol) 용액에 LiOH (12 mg, 0.29 mmol)를 첨가하고 25 oC에서 16시간 동안 교반하였다. 반응이 완료된 후, 용매를 증발시켰다. 반응 혼합물을 EtOAc와 물에 희석시킨 다음 용액을 1N HCl(aq.)로 산성화 하였다. 용액을 EtOAc로 추출하고, 물로 세척하였다. 유기층을 무수 MgSO4로 건조시킨 다음 진공에서(in
vacuo) 증발시켜 흰색 고체의 바람직한 생산물 E2를 제조하였다.
E3 합성의 일반적인 방법
물질 E2 (62 mg, 0.20 mmol)를 무수 MC (4 mL)에 용해하였다. 옥살릴 클로라이드 (0.026 mL, 0.24 mmol)와 DMF 1방울을 0 oC에서 반응 혼합물에 첨가하였다. 결과적으로 형성된 혼합물을 25 oC에서 2시간 동안 교반한 다음 용매를 진공에서(in vacuo) 증발시켜 노란색 오일의 바람직한 생산물 E3를 제조하였다.
E3 합성의 일반적인 방법
톨루엔 (2 mL)에 용해된 물질 E3 (96 mg, 0.36 mmol) 용액에 TEA (0.10 mL, 0.72 mmol)와 4-브로모-3,5-디메틸-1H-피라졸 (63 mg, 0.36 mmol)을 첨가하였다. 반응 혼합물을 25 oC에서 12시간 동안 교반하였다. 반응이 완료된 후, 용매를 진공에서(in
vacuo) 증발시켰다. 반응 혼합물을 EtOAc와 물에 희석시킨 다음 용액을 EtOAc로 추출하였다. 유기층을 물로 세척하고, 무수 MgSO4로 건조시킨 다음 진공에서 증발시켰다(in
vacuo). 이에 따라 형성된 고체를 MC로 세척하여 노란색 고체의 바람직한 생성물 E4를 제조하였다.
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반응식 6을 이용한 화학식 1로 표시되는 화합물의 제법
[반응식 6]
F1 합성의 일반적인 방법
N2 (g) 조건 하에, 0 oC에서 1N LiAlH4 (0.66 mL, 0.66 mmol)를 무수 THF (10 mL)에 용해된 물질 E1 (157 mg, 0.60 mmol) 용액에 첨가하고 동일한 온도에서 3시간 동안 교반하였다. 반응이 완료된 후, 반응물을 0 oC의 얼음물을 첨가하여 식혔다. 반응 혼합물을 EtOAc로 추출하고 진공에서(in
vacuo) 증발시켰다. 무색 오일의 바람직한 생성물 F2를 컬럼 크로마토그래피 (EtOAc/Hexane, 1:5)로 수득하였다.
F2 합성의 일반적인 방법
무수 MC (10 mL)에 용해된 물질 F1 (122 mg, 0.52 mmol) 용액에 MnO2 (455 mg, 5.23 mmol)를 첨가하고, N2 (g) 조건 하에 25 oC에서 4일 동안 교반하였다. 반응이 완료된 후, 잔여물을 셀라이트 패드(celite pad)를 통해 여과시키고 진공에서(in
vacuo) 증발시켜 노란색 오일의 F2를 제조하였다.
F3 합성의 일반적인 방법
무수 EtOH (1 mL)에 용해된 물질 F2 (84 mg, 0.36 mmol)를 EtOH (2 mL)에 용해된 AcOH (0.3 mL)과 4-브로모아닐린 (62 mg, 0.36 mmol)에 첨가하였다. 반응 혼합물을 80 oC에서 12시간 동안 교반하였다. 반응이 완료된 후, 진공에서(in
vacuo) EtOH을 증발시켜 오렌지색 오일의 F3를 제조하였다.
F4 합성의 일반적인 방법
N2 (g) 조건 하에, 25 oC에서 NaBH4 (4 mg, 0.11 mmol)를 무수 EtOH (1 mL)에 용해된 물질 F3 (30 mg, 0.08 mmol) 용액에 첨가하고 85 oC에서 12시간 동안 교반하였다. 반응이 완료된 후, 반응물을 0 oC의 물로 식혔다. 반응 혼합물을 EtOAc로 추출하고 진공에서(in
vacuo) 증발시켰다. 노란색 오일의 바람직한 생성물 F4를 컬럼 크로마토그래피 (EtOAc/Hexane, 1:6)로 수득하였다.
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반응식 7을 이용한 본 발명의 화학식 1로 표시되는 화합물의 제법
[반응식 7]
G1 합성의 일반적인 방법
무수 MeCN (4 mL)에 용해된 o-톨릴메테인티올 (128 mg, 0.93 mmol) 용액에 K2CO3 (214 mg, 1.55 mmol)와 메틸 2-클로로옥사졸-5-카르복실레이트 (100 mg, 0.62 mmol)를 첨가하고 결과적으로 형성된 혼합물을 80 oC에서 2시간 동안 교반하였다. 혼합물을 실온으로 냉각시키고, EtOAc로 추출한 다음 NaHCO3(aq.)로 세척하였다. 유기층을 무수 MgSO4로 건조시킨 다음 진공에서(in
vacuo) 증발시켰다. 무색 오일의 바람직한 생성물 G1을 컬럼 크로마토그래피 (EtOAc/Hexane, 1:10)로 수득하였다.
G2 합성의 일반적인 방법
N2 (g) 조건 하에, 0 oC 에서 LiAlH4 (0.56 mL, 0.56 mmol)를 무수 THF (10 mL)에 용해된 물질 G1 (135 mg, 0.51 mmol) 용액에 첨가하고 혼합물을 3시간 동안 교반하였다. 반응이 완료된 후, 반응물을 차가운 물로 식혔다. 반응 혼합물을 EtOAc로 추출하고 유기층을 증발시켰다. 무색 오일의 바람직한 생성물 G2를 컬럼 크로마토그래피 (EtOAc/Hexane, 1:5)로 수득하였다.
G3 합성의 일반적인 방법
무수 MC (10 mL)에 용해된 물질 G2 (124 mg, 0.53 mmol) 용액에 MnO2 (458 mg, 5.27 mmol)를 첨가하고 N2 (g) 조건 하에, 25 oC에서 4일 동안 교반하였다. 반응이 완료된 후, 반응 잔여물을 셀라이트 패드를 통해 여과시키고 진공에서(in vacuo) 증발시켜 노란색 오일의 G2를 제조하였다.
G4 합성의 일반적인 방법
무수 EtOH (1 mL)에 용해된 물질 G3 (73 mg, 0.31 mmol)를 EtOH (2 mL)에 용해된 AcOH (0.2 mL)와 4-브로모아닐린 (54 mg, 0.31 mmol)에 첨가하였다. 반응 혼합물을 80 oC에서 12시간 동안 교반하였다. 반응이 완료된 후, EtOH을 진공에서(in vacuo) 증발시켜 노란색 오일의 G4를 제조하였다.
G5 합성의 일반적인 방법
무수 EtOH (1 mL)에 용해된 물질 G4 (22 mg, 0.06 mmol) 용액에 NaBH4 (3 mg, 0.09 mmol)를 첨가하고 혼합물을 85 oC에서 12시간 동안 교반하였다. 반응이 완료된 후, 반응물을 차가운 물로 식혔다. 반응 혼합물을 EtOAc로 추출하고 진공에서(in
vacuo) 증발시켰다. 노란색 오일의 바람직한 생성물 G5를 컬럼 크로마토그래피 (EtOAc/Hexane, 1:4)로 수득하였다.
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반응식 8을 이용한 본 발명의 화학식 1로 표시되는 화합물의 제법
[반응식 8]
H1 합성의 일반적인 방법
THF (15 mL)에 용해된 4-브로모-아닐린 (1 g, 5.71 mmol) 용액에 DIPEA (1.58 g, 11.43 mmol)를 첨가하고 혼합물을 30분 동안 교반하였다. 그 다음, 혼합물을 냉각시키고 얼음 배스(ice-bath)에서 에틸 클로로포름산염 (1 g, 5.71 mmol)을 반응 혼합물에 첨가하였다. 3시간 후, 반응 혼합물을 EtOAc로 추출하고 NaHCO3(aq.)와 물로 세척하였다. 유기층을 MgSO4로 건조시키고 진공에서(in
vacuo) 증발시켰다. 무색 오일의 바람직한 생성물 H1을 컬럼 크로마토그래피 (EtOAc/Hexane, 1:10)로 수득하였다.
H2 합성의 일반적인 방법
하이드라진 모노하이드레이트 (0.404 mL, 12.86 mmol)를 무수 EtOH (10 mL)에 용해된 H1 (350 mg, 1.29 mmol)의 교반 용액에 첨가하고 90 oC에서 3시간 동안 교반하였다. 반응 혼합물을 진공에서(in
vacuo) 증발시키고 형성된 고체를 여과시키고 건조하여 흰색 고체의 바람직한 생성물 H2를 제조하였다.
H3 합성의 일반적인 방법
MeOH (6 mL)에 용해된 1N KOH (1.17 mL, 1.00 mmol)와 H2 (302 mg, 1.17 mmol)의 혼합물에 CS2 (0.16 mL, 2.69mmol)를 첨가하고 결과적으로 형성된 혼합물을 80 oC에서 12시간 동안 교반하였다. 반응이 완료된 후, 혼합물을 농축하고 물에 부은 후 1N HCl(aq.)을 이용하여 pH 6으로 조절하였다. 형성된 고체를 여과시키고 물로 세척한 후 건조시켜 아이보리색 고체의 바람직한 생성물 H3를 제조하였다.
H4 합성의 일반적인 방법
물질 H3 (60 mg, 0.20 mmol), DIPEA (0.035 mL, 0.22 mmol) 및 2-(브로모메틸)-1,1'-비페닐 (0.040 mL, 0.22 mmol)을 무수 DMF (2 mL)에 용해시켰다. 반응 혼합물을 25 oC에서 약 16시간 동안 교반한 다음 EtOAc에 희석시키고 NH4Cl(aq.)과 물로 세척하였다. 유기층을 무수 MgSO4로 건조시킨 다음 진공에서(in
vacuo) 증발시켰다. 흰색 고체의 바람직한 생성물 H4를 컬럼 크로마토그래피 (10% EtOAc in hexane/MC, 2:1)로 수득하였다.
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반응식 9를 이용한 본 발명의 화학식 1로 표시되는 화합물의 제법
[반응식 9]
I1 합성의 일반적인 방법
촉매, 피페리딘 (0.3 mmol), 알데하이드 (1 mmol) 및 말론산 (1 mmol)을 피리딘 (2 mL)에 현탁시키고, 용액을 100 oC에서 4시간 동안 교반하였다. 이후, 반응 혼합물을 0 oC로 냉각하고 이어서 HCl 용액 (conc., 5 mL)으로 산성화 시켰다. 결과적으로 생성된 고체를 여과시키고 건조하여 I1를 제조하였다 (95 %).
I2 합성의 일반적인 방법
(E)-3-(2-클로로-4-플루오로페닐)아크릴산 I1 (1 mmol)과 2-(4-브로모페닐)아세토하이드라지드 (1 mmol)를 POCl3 (2 mL)에 현탁시키고 혼합물을 밤새 100
oC로 가열하였다. 반응이 완료된 후, 용매를 증발시키고 잔여물을 2N NaOH로 식혔다. 혼합물을 EtOAc로 추출하고 물로 세척하였다. 유기층을 MgSO4로 건조시키고 농축하였다. 원료 잔여물을(crude residue)을 컬럼 크로마토그래피 (n-hexane : ethyl acetate = 5 : 1 )로 정제하여 옅은 노란색 고체의 I2를 제조하였다 (85%).
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반응식 10을 이용한 본 발명의 화학식 1로 표시되는 화합물의 제법
[반응식 10]
J 합성의 일반적인 방법
MeOH/THF ( 5 : 1 = 5 mL : 1mL)에 용해된 [1,1'-비페닐]-3-일(5-(4-브로모벤질)-1,3,4-옥사디아졸-2-일)메탄온 (1 mmol)의 교반 용액에 NaBH4 (2 mmol)를 첨가하고 혼합물을 1시간 동안 실온에서 교반하였다. 반응이 완료된 후, 반응 혼합물을 H2O로 식히고 디클로로메테인으로 추출하였다. 유기층을 MgSO4로 건조시키고 감소된 압력에서 농축하였다. 원료 잔여물(crude residue)을 컬럼 크로마토그래피(n-hexane : ethyl acetate = 3 : 1 )로 정제하여 흰색 고체의 J를 제조하였다 (70%).
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반응식 11을 이용한 본 발명의 화학식 1로 표시되는 화합물의 제법
[반응식 11]
K 합성의 일반적인 방법
아세토니트릴(10 mL)에 용해된 5-(([1,1'-비페닐]-2-일메틸)티오)-N-(4-브로모페닐)-1,3,4-옥사디아졸-2-아민 (1 mmol), K2CO3 (5 mmol), tBu4NBr (1 mmol) 및 디메틸 설페이트 (1 mmol)의 혼합물을 2시간 동안 환류시켰다. 반응이 완료된 후, 반응 혼합물을 디클로로메테인으로 추출하고 유기층을 MgSO4로 건조시킨 다음 감소된 압력에서 농축하였다. 원료 잔여물(crude residue)을 컬럼 크로마토그래피 (n-hexane : ethyl acetate = 3 : 1 )로 정제하여 무색 오일의 K를 제조하였다 (60%).
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반응식 12를 이용한 화합물의 제법
L1 합성 절차
EtOH (5 mL) 중의 시나몬니트릴 (1.0 mmol), 하이드록실아민 (3.0 mmol) 및 K2CO3 (3.0 mmol) 혼합물을 4시간 동안 환류하였다. 반응 완결 후, 혼합물을 증발시키고 EtOAc로 추출하였다. MgSO4 상에서 유기층을 건조시키고 감압 하 농축하였다. 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:에틸 아세테이트 = 1:1 비율) 백색 고체로서 L1을 얻었다(60%).
L2 합성 절차
DMF (3 mL) 중의 (Z)-N'-하이드록시 신남이미드아미드(hydroxycinnamimidamide) (1.0 mmol), 2-(4-브르모페닐)아세트산 (1.2 mmol), 1-에틸-3-(3-디메틸아미노프로필)카르보디이미드 (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (1.5 mmol) 및 1-하이드록시벤조트리아졸 하이드레이트 (1-hydroxybenzotriazole hydrate) (0.5 mmol) 혼합물을 50 ℃에서 밤새 가열하였다. 반응 완결 후, 반응 혼합물을 EtOAc로 추출하였다. MgSO4 상에서 유기 층을 건조시키고, 감압 하 농축하였다. 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:에틸 아세테이트 = 2:1 비율) 담황색 고체로서 L2를 얻었다(80%).
L3 합성 절차
DMF (3 mL) 중의 2-(4-브로모페닐)-N-((1E,2E)-1-(하이드록시이미노)-3-페닐알릴)아세트아미드 (1.0 mmol)를 130 ℃에서 밤새 가열하였다. 반응 완결 후, 혼합물을 에틸 아세테이트로 추출하였다. MgSO4 상에서 유기층을 건조시키고 감압 하 농축하였다. 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:에틸 아세테이트 = 10:1 비율) 백색 고체로서 L3을 얻었다(50%).
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반응식 13을 이용한 화합물의 제법
M 1 합성 절차
EtOH (5 mL) 중의 2-(4-브로모페닐)아세토니트릴 (1.0 mmol), 하이드록실아민 (3.0 mmol) 및 K2CO3 (3.0 mmol) 혼합물을 4시간 동안 환류하였다. 반응 완결 후, 혼합물을 증발시키고 에틸아세테이트로 추출하였다. MgSO4 상에서 유기층을 건조시키고 감압 하 농축하였다. 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:에틸 아세테이트 = 1:1 비율) 백색 고체로서 M1을 얻었다(60%).
M 2 합성 절차
DMF (3 mL) 중의 (Z)-2-(4-브로모페닐)-N'-하이드록시아세트이미드아미드 (1.0 mmol), 신남산(cinnamic acid) (1.2 mmol), 1-에틸-3-(3-디메틸아미노프로필)카르보디이미드 (1.5 mmol) 및 1-하이드록시벤조트리아졸 하이드레이트 (0.5 mmol) 혼합물을 50 ℃에서 밤새 가열하였다. 반응 완결 후, 혼합물을 에틸 아세테이트로 추출하였다. MgSO4 상에서 유기층을 건조시키고 감압 하 농축하였다. 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:에틸 아세테이트 = 1:1 비율) 담황색 고체로서 M2를 얻었다(80%).
M 3 합성 절차
DMF (3 mL) 중의 N-((E)-2-(4-브로모페닐)-1-(하이드록시이미노)에틸)신남아미드 (1.0 mmol)를 130 ℃에서 밤새 가열하였다. 반응 완결 후, 반응 혼합물을 에틸 아세테이트로 추출하였다. MgSO4 상에서 유기층을 건조시키고 감압 하 농축하였다. 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:에틸 아세테이트 = 10:1 비율) 백색 고체로서 M3을 얻었다(50%).
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반응식 14를 이용한 화합물의 제법
N 1 합성 절차
POCl3 (2 mL) 중의 2-(4-브로모-3,5-디메틸-1H-피라졸-1-일)아세토하이드라자이드 (0.61 mmol) 및 2-클로로아세트산 (1.21 mmol) 혼합물을 100 ℃에서 밤새 가열하였다. 냉각 후 반응 혼합물을 얼음에 붓고 메틸렌 클로라이드로 추출하였다(3회). MgSO4 상에서 유기층을 건조시키고 진공에서 농축하여 백색 고체로서 크루드 산물을 얻었다.
N 2 합성 절차
얼음 욕조에서 NaH (파라핀 내 60% 분산물, 0.24 mmol)를, DMF (3 mL) 중의 2-이소프로필 벤젠티올 (0.19 mmol) 교반된 용액에 첨가하였다. 10분 후에, DMF (2 mL) 중의 N1 (0.16 mmol) 용액을 반응 혼합물에 첨가하고, 실온에서 반응하도록 두었다. 밤이 경과한 후, 물로 반응을 종결시키고 혼합물을 EtOAc로 추출하였다(2회). 유기층을 염수로 세척하고, MgSO4 상에서 건조시키고, 진공에서 농축하였다. 플래시 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:EtOAc = 3:1 비율) 백색 고체로서 타겟 화합물을 얻었다.
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반응식 15를 이용한 화합물의 제법
O1 합성 절차
EtOH (5mL) 중의 2-(3-브로모페닐)아세토하이드라자이드 (1.25 mmol) 및 시아노겐 브로마이드(cyanogen bromide) (1.88 mmol) 혼합물을 실온에서 5일간 교반하였다. 불용성 고체를 걸러내고 얻어진 여과액을 진공에서 농축하여 크루드 타겟 화합물을 얻었다.
O2 합성 절차
메틸렌 클로라이드 (2 mL) 중의 O1 (0.26 mmol) 및 트리메틸아민 (0.34 mmol) 교반된 용액에 2-클로로-4-플루오로벤젠설포닐 클로라이드(0.23 mmol)를 첨가하고, 혼합물을 실온에서 2시간 동안 교반하였다. 플래시 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:EtOAc = 3:1 비율) 백색 고체로서 타겟 화합물을 얻었다.
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반응식 16을 이용한 화합물의 제법
P1 합성 절차
톨루엔 (5mL) 중의 2-브로모-4-플루오로벤즈알데하이드 (1.48 mmol), Pd2(dba)3 (0.14 mmol), BINAP (0.29 mmol) 및 CsCO3 (2.22 mmol)의 교반된 용액에 2-메톡시-N-메틸에탄-1-아민 (1.78 mmol)을 첨가하였다. 혼합물을 100 ℃에서 가열하고 밤새 교반하였다. 불용성 고체를 걸러내고, EtOAC로 여과액을 희석하였다. 물과 염수로 유기 용액을 세척하고 진공에서 농축하였다. 플래시 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:EtOAc = 9:1 비율) 황색 오일로서 타겟 화합물을 얻었다(68%).
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반응식 17을 이용한 화합물의 제법
Q1 합성 절차
디클로로메탄 (18 mL) 중의 [2-(1H-피롤-1-일)페닐]메탄올 (1.44 mmol) 용액에 MnO2
(7.22 mmol)를 첨가하고, 혼합물을 실온에서 16시간 동안 교반하였다. 불용성 잔여물을 걸러내고, 여과액을 농축하여 황색 오일로서 크루드 타겟 화합물을 얻었다(89%).
Q2 합성 절차
CH3CN (8 mL) 중의 A1 (1.29 mmol), LiCl (1.75 mmol) 용액에 트리에틸 포스포노아세테이트 (1.75 mmol) 및 DBU (1.45 mmol)를 첨가하고, 혼합물을 실온에서 교반하였다. 4시간 후에, 유기 용매를 제거하고 얻어진 잔여물을 EtOAc에 용해하였다. 염수로 유기 용액을 세척하고 MgSO4 상에서 건조시키고 농축하여, 황색 오일로서의 크루드 타겟 화합물을 얻었다(94%).
Q3 합성 절차
THF: EtOH: H2O (1:1:1, 6mL) 중의 A2 (1.20 mmol) 용액에 LiOH (6.01 mmol)를 첨가하였다. 혼합물을 실온에서 16시간 동안 교반하였다. 유기 용매를 제거하고 얻어진 수용액을 2N HCl (aq.)를 사용하여 산성화하였다. 얻어진 침전물을 여과하고, 물 및 n-헥산으로 세척하고, 감압 하 건조하였다. 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:EtOAc = 1:1 비율) 담황색 고체로서 타겟 화합물을 얻었다.
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반응식 18을 이용한 화합물의 제법
R1 합성 절차
DMF (5 mL) 중의 2-이소프로필페놀 (1.0 g, 7.34 mmol) 및 K2CO3 (3.04 g, 22.03 mmol) 용액에 에틸 2-클로로아세테이트 (1.08 g, 8.81 mmol)를 첨가하고, 그 다음 혼합물을 25 ℃에서 24시간 동안 교반하였다. 반응 완결 후, EtOAc 중에 반응 혼합물을 희석하고, 물 및 sat. NaHCO3(aq.)를 사용하여 세척하였다. 무수 MgSO4 상에서 유기층을 건조시키고 진공에서 농축하였다. 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 황색 오일로서 타겟 화합물을 얻었다.
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반응식 19를 이용한 화합물의 제법
S1 합성 절차
톨루엔 (3 mL) 중의 2-브로모-4-플루오로벤즈알데하이드 (1.97 mmol) 용액에, Pd2(dba)3 (0.20 mmol), 2,2'-비스(디페니포스피노)-1,1'-비나프틸) (0.39 mmol), Cs2CO3 (2.96 mmol) 및 모폴린 (2.36 mmol)을 첨가하였다. 반응 혼합물을 90 ℃까지 24시간 동안 가열하였다. 불용성 고체를 걸러내고, 여과액을 진공에서 농축하였다. 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:EtOAc = 5:1 비율) 황색 오일로서 타겟 화합물을 얻었다.
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반응식 20을 이용한 화합물의 제법
T1 합성 절차
DME (3 mL) 중의 2-브로모-4-플루오로벤즈알데하이드 (2.46 mmol), Pd(dppf)Cl2 (0.25 mmol), 퓨란-3-일-보론산 (2.71 mmol) 용액에, Na2CO3 (4.93 mmol, 1mL) 수용액을 첨가하였다. 반응 혼합물을 80 ℃까지 24시간 동안 가열하였다. 반응 용매를 제거하고 얻어진 잔여물을 CH2Cl2 중에 용해시켰다. 유기 층을 물로 세척하고 무수 MgSO4 상에서 건조시키고 진공에서 증발시켰다. 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:EtOAc = 1:5 비율) 타겟 화합물을 얻었다.
T2 합성 절차
유사한 방법으로 I1의 합성 절차에 따라 타겟 화합물 T2를 합성하였다.
T3 합성 절차
DMF (10 mL) 중의 T3 (1.1 mmol), 2-(3-브로모페닐)아세토하이드라자이드 (1.0 mmol) 및 EDC (1.5 mmol) 혼합물을 실온에서 밤새 교반하였다. 반응 완결 후, 용매를 제거하였다. 얻어진 잔여물을 물 및 디에틸 에테르로 세척하여 크루드 타겟 화합물을 얻었다.
T4 합성 절차
CH2Cl2 중의 (E)-N'-(2-(3-브로모페닐)아세틸)-3-(4-플루오로-2-(퓨란-3-일)페닐) 아크릴로하이드라자이드 (0.41 mmol) 및 p-TsCl (0.41 mmol) 용액에 Et3N (1.22 mmol)을 첨가하고, 반응 혼합물을 실온에서 교반하였다. 밤이 지난 후, 불용성 고체를 걸러내고 여과액을 진공에서 농축하였다. 컬럼 크로마토그래피로 얻어진 크루드 잔여물을 정제하여 (n-헥산:EtOAc = 3:1 비율) 황색 고체로서 타겟 화합물을 얻었다.
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반응식 21을 이용한 화합물의 제법
U1 합성 절차
1,4-디옥산 (3 mL) 중의 2,4-디플루오로벤즈알데하이드 (3.52 mmol) 및 t-BuOK (4.22 mmol) 용액에 2-모폴리노에탄-1-올 (4.22 mmol)을 첨가하고, 반응 혼합물을 25 oC에서 24시간 동안 교반하였다. 반응 완결 후, EtOAc로 혼합물을 희석시키고, 물로 세척하였다. 무수 MgSO4 상에서 유기층을 건조시키고 진공에서 농축하였다. 컬럼 크로마토그래피로 크루드 잔여물을 정제하여 (n-헥산:EtOAc = 3:1 비율) 황색 오일로서 타겟 화합물을 얻었다.
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본 발명에 따른 화학식 1 또는 화학식 2의 신규 화합물 제조 및 항바이러스 활성 평가
상기 실시예 1 내지 23의 대표적인 제조방법을 이용하여, 본 발명의 화학식 1 또는 2로 표시되는 화합물 307종을 제조하였으며(표 1 내지 31), 제조된 화합물의 항인플루엔자 바이러스 활성과 세포독성을 평가하였다(표 32 내지 62).
상기 표 32 내지 62에 나타난 바와 같이, 본 발명에 따른 화학식 1 또는 화학식 2의 신규 화합물은 A형 인플루엔자 바이러스 및 B형 인플루엔자 바이러스에 대하여 항바이러스 활성이 우수한 것을 알 수 있으며, 세포독성이 낮은 것을 알 수 있다.
따라서, 본 발명의 화학식 1 또는 화학식 2의 신규 화합물은 인플루엔자 바이러스 감염에 의해 발병되는 질환의 예방 또는 치료에 유용하게 사용할 수 있다.
Claims (20)
- 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 약학적으로 허용가능한 염:[화학식 1][화학식 2]상기 식에서,X1은 O, S 또는 -N(CH2CH3)-이고,X2 및 X3는 각각 독립적으로 N 또는 CH 이며,Y는 존재하지 않거나; -CH2-; -CH2NH-; -C(=O)-; -CH2CH2-; -NH-; -NHC(=O)-; -C(=O)NH-; -CH(CH3)-; -CF2-; -CH(OCH3)-; -CH2O-; -N(CH3)-; 또는 -CH2NHC(=O)- 이고,Z는 존재하지 않거나, -CH2S-; -CH2S(=O)-; -CH2NH-; -CH(Rc)S-; -CH2CH2S-; -CH2N(CH3)-; ; -CH=CH-; -S-; -CH2-; -O-; -CH2S(=O)2-; -C(=O)-; -SCH2-; -CH2CH2-; -CH(OH)-; -CH(CH3)CH2-; -OCH2-; -C(=O)CH2S-; -C(=O)-NH-; -CH=C(CH3)-; -CH2-사이클로프로필-; -NH-S(=O)2-; -S(=O)2-NH-; 또는 -NH-C(=O)-이며,Rc는 벤젠이고,R1은 ; 비치환되거나, 할로겐, 직쇄 또는 분쇄형 C1- 4알킬, C3-6 사이클로알킬, -OCF3, -CF3, -CHF2, -OH, 페녹시, 페닐, C1- 4알콕시, -CN, -NH2, 및 -N(CH3)2로 이루어진 군에서 선택한 1종 이상으로 치환된 벤젠; ; ; ; 비치환되거나 할로겐으로 치환된 피리딘; 비치환되거나 C1- 4알콕시로 치환된 나프탈렌; 벤조트리아졸; 비치환되거나, C1- 4알킬, C1- 4알콕시 또는 할로겐으로 치환된 퀴놀린 또는 이소퀴놀린; 비치환되거나 C1- 4알킬로 치환된 인다졸; C3-6 사이클로알킬; 벤조티오펜; 벤조퓨란; 비치환되거나 C1- 4알킬로 치환된 인돌; 또는 티오펜이며,Ra는 할로겐; 직쇄 또는 분쇄형 C1- 4알킬; OCF3; CF3; 또는 비치환된 벤젠이고,Rc는 벤젠이며,n은 0 내지 3 범위의 정수이고,R2는 H; ; ; ; ; C1- 4알킬; 비치환되거나 또는 할로겐으로 치환된 나프탈렌; ; ; ; 비치환되거나 또는 할로겐으로 치환된 벤조퓨란; 비치환되거나 또는 할로겐으로 치환된 벤조디옥솔; 비치환되거나 또는 할로겐으로 치환된 퀴놀린 또는 이소퀴놀린; 비치환되거나, 직쇄형 또는 분쇄형 C1- 4알킬 또는 할로겐으로 치환된 피라졸; C1- 4알킬로 치환된 인돌; 또는 이미다조피리딘이며,Rb는 비치환되거나, 직쇄 C1- 4알킬 및 할로겐으로 이루어진 군에서 선택한 1종 이상으로 치환된 벤젠; 직쇄 C1- 4알킬; 분쇄형 C3- 5알킬; -OCH3; N, O 또는 S를 포함하는 5원자 또는 6원자 헤테로아릴; 탄소수 5 내지 7의 사이클로알킬; -C(=O)CH3; -ORc; -C(=O)OCH3; -CH2RC; -CF3; -OCF3; -OH; -N(CH3)2; -C(=O)-OH; 피롤리딘; 피페리딘; 피롤; 퓨란; 티오펜; 모폴린; 모폴린으로 치환된 C1- 4알콕시; -NRdRe (여기서 Rd는 H 또는 메틸이고, Re는 -CH2CH2OCH3 또는 -CH2CH2Ph임); 또는 할로겐이고,Rc는 비치환되거나 할로겐으로 치환된 벤젠, C1- 4알킬 또는 할로겐이며,m은 0 내지 2 범위의 정수이다.
- 제1항에 있어서, 하기 화학식 1a로 표시되는 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 약학적으로 허용가능한 염:[화학식 1a]상기 식에서,Y는 존재하지 않거나; -CH2-; -CH2NH-; -C(=O)-; -CH2CH2-; -NH-; -CH2O-; -N(CH3)-; -CH(CH3)-; -CF2-; 또는 -CH(OCH3)- 이고,Z는 -CH2S-; -CH2S(=O)-; -CH(Rc)S-; -CH2CH2S-; -S-; CH2S(=O)2-; 또는 -SCH2- 이며,Ra는 C1- 4알킬; 할로겐; 또는 비치환된 벤젠이며,Rc는 벤젠이고,n은 0 내지 3 범위의 정수이며,Rb는 비치환되거나, 직쇄 C1- 4알킬 및 할로겐으로 이루어진 군에서 선택한 1종 이상으로 치환된 벤젠; 직쇄 C1- 4알킬; 분쇄형 C3- 5알킬; OCH3; N, O 또는 S를 포함하는 5원자 또는 6원자 헤테로아릴; 탄소수 5 내지 7의 사이클로알킬; C(=O)CH3; ORc; C(=O)OCH3; CH2RC; 또는 할로겐이며,Rc는 벤젠이고,m은 0 내지 2 범위의 정수이다.
- 제1항에 있어서, 상기 화학식 1 또는 화학식 2의 화합물은 하기 표 63에서 선택한 1종인 것을 특징으로 하는 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 약학적으로 허용가능한 염.
cpd # IUPAC name 1 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 2 2-(([1,1'-biphenyl]-4-ylmethyl)thio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 3 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-bromo-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 4 2-((1H-pyrazol-1-yl)methyl)-5-(([1,1'-biphenyl]-2-ylmethyl)thio)-1,3,4-oxadiazole 5 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 6 2-(([1,1'-biphenyl]-3-ylmethyl)thio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 7 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 8 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((naphthalen-1-ylmethyl)thio)-1,3,4-oxadiazole 9 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-methylbenzyl)thio)-1,3,4-oxadiazole 10 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-methoxybenzyl)thio)-1,3,4-oxadiazole 11 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((3-bromo-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 12 2-(([1,1'-biphenyl]-2-ylmethyl)sulfinyl)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 13 1-([1,1'-biphenyl]-2-yl)-2-((5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-on 14 2-(benzylthio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 15 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-(pyridin-4-yl)benzyl)thio)-1,3,4-oxadiazole 16 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(((3-phenylpyridin-4-yl)methyl)thio)-1,3,4-oxadiazole 17 N-([1,1'-biphenyl]-2-ylmethyl)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazol-2-amine 18 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-benzyl-1,3,4-oxadiazole 19 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-(pyridin-3-yl)benzyl)thio)-1,3,4-oxadiazole 20 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-(pyridin-4-yl)benzyl)thio)-1,3,4-oxadiazole 21 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(((3-phenylpyridin-4-yl)methyl)thio)-1,3,4-oxadiazole 22 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(4-bromobenzyl)-1,3,4-oxadiazole 23 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-isopropylbenzyl)thio)-1,3,4-oxadiazole 24 3-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-4-ethyl-4H-1,2,4-triazole 25 2-(benzhydrylthio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 26 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-methylphenethyl)thio)-1,3,4-oxadiazole 27 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(pyridin-2-ylmethyl)-1,3,4-oxadiazole 28 1-(2-(((5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)thio)methyl)phenyl)ethan-1-one 29 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-phenoxybenzyl)thio)-1,3,4-oxadiazole 30 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-phenyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 31 2-((2-(1H-pyrrol-1-yl)benzyl)thio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 32 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(((4'-methyl-[1,1'-biphenyl]-2-yl)methyl)thio)-1,3,4-oxadiazole 33 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)thio)-1,3,4-oxadiazole 34 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-(furan-3-yl)benzyl)thio)-1,3,4-oxadiazole 35 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2-(thiophen-3-yl)benzyl)thio)-1,3,4-oxadiazole 36 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(1-phenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazole 37 methyl 2-(((5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)thio)methyl)benzoate 38 2-((2-benzylbenzyl)thio)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 39 2-(([1,1'-biphenyl]-3-ylmethyl)thio)-5-((4-phenyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 40 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-((2,6-dimethylbenzyl)thio)-1,3,4-oxadiazole 41 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-1,3,4-oxadiazole 42 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(4-bromophenyl)-1,3,4-oxadiazole 43 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-phenyl-1,3,4-oxadiazole 44 N-([1,1'-biphenyl]-2-ylmethyl)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methyl-1,3,4-oxadiazol-2-amine 45 N-([1,1'-biphenyl]-2-ylmethyl)-N-(5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)acetamide 46 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(3-chlorobenzyl)-1,3,4-oxadiazole 47 N-((5-(([1,1'-biphenyl]-2-ylmethyl)thio)-1,3,4-oxadiazol-2-yl)methyl)-4-bromoaniline 48 (4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)(5-((2-methylbenzyl)thio)furan-2-yl)methanone 49 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(2-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazole 50 (E)-2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 51 N-((5-(([1,1'-biphenyl]-2-ylmethyl)thio)-1,3,4-oxadiazol-2-yl)methyl)-4-bromobenzamide 52 5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-(4-bromophenyl)-1,3,4-oxadiazol-2-amine 53 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(o-tolylthio)-1,3,4-oxadiazole 54 2-(2-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-5-(o-tolylthio)-1,3,4-oxadiazole 55 (4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)(2-((2-methylbenzyl)thio)oxazol-5-yl)methanone 56 (4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)(5-((2-isopropylphenyl)thio)furan-2-yl)methanone 57 (4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)(5-(2-isopropylphenoxy)furan-2-yl)methanone 58 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-bromophenoxy)methyl)-1,3,4-oxadiazole 59 2-(([1,1'-biphenyl]-2-ylmethyl)sulfinyl)-5-(4-bromobenzyl)-1,3,4-oxadiazole 60 2-(([1,1'-biphenyl]-2-ylmethyl)sulfonyl)-5-(4-bromobenzyl)-1,3,4-oxadiazole 61 5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-(4-bromo-2,6-dimethylphenyl)-1,3,4-oxadiazol-2-amine 62 5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-(4-bromo-3-methylphenyl)-1,3,4-oxadiazol-2-amine 63 5-(([1,1'-biphenyl]-2-ylmethyl)sulfinyl)-N-(4-bromophenyl)-1,3,4-oxadiazol-2-amine 64 (5-(4-bromobenzyl)-1,3,4-oxadiazol-2-yl)(phenyl)methanone 65 5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-(4-bromophenyl)-N-methyl-1,3,4-oxadiazol-2-amine 66 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(((2-isopropylphenyl)thio)methyl)-1,3,4-oxadiazole 67 2-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazole 68 5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-(3,5-dimethylphenyl)-1,3,4-oxadiazol-2-amine 69 [1,1'-biphenyl]-3-yl(5-(4-bromobenzyl)-1,3,4-oxadiazol-2-yl)methanone 70 [1,1'-biphenyl]-3-yl(5-(4-bromobenzyl)-1,3,4-oxadiazol-2-yl)methanol 71 5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-phenyl-1,3,4-oxadiazol-2-amine 72 5-(([1,1'-biphenyl]-2-ylmethyl)thio)-N-(4-bromophenyl)-1,3,4-oxadiazole-2-carboxamide 73 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(1-phenylethyl)-1,3,4-oxadiazole 74 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-((4-bromophenyl)difluoromethyl)-1,3,4-oxadiazole 75 4-bromo-N-((5-((2-methylbenzyl)thio)furan-2-yl)methyl)aniline 76 (5-((2,6-dimethylphenyl)amino)-1,3,4-oxadiazol-2-yl)(phenyl)methanone 77 (5-((2,6-dimethylphenyl)amino)-1,3,4-oxadiazol-2-yl)(phenyl)methanol 78 (3-chloro-4-fluorophenyl)(5-((2,6-dimethylphenyl)amino)-1,3,4-oxadiazol-2-yl)methanone 79 (3-chloro-4-fluorophenyl)(5-((2,6-dimethylphenyl)amino)-1,3,4-oxadiazol-2-yl)methanol 80 2-benzyl-5-(methylthio)-1,3,4-oxadiazole 81 (E)-2-(2-isopropylstyryl)-5-(4-(trifluoromethoxy)benzyl)-1,3,4-oxadiazole 82 (E)-2-(4-bromobenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 83 (E)-N-(4-bromophenyl)-5-(2-bromostyryl)-1,3,4-oxadiazol-2-amine 84 N-(4-bromophenyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazol-2-amine 85 N-(2,6-dimethylphenyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazol-2-amine 86 (E)-2-(4-bromobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 87 (E)-N-(4-bromophenyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol-2-amine 88 (E)-N-(4-bromo-3-fluorophenyl)-5-(2-bromostyryl)-1,3,4-oxadiazol-2-amine 89 N-(4-bromophenyl)-5-(2-methylphenethyl)-1,3,4-oxadiazol-2-amine 90 N-(4-bromo-3-methylphenyl)-5-(2-methylphenethyl)-1,3,4-oxadiazol-2-amine 91 N-(4-bromo-3-fluorophenyl)-5-(2-methylphenethyl)-1,3,4-oxadiazol-2-amine 92 2-(4-bromobenzyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazole 93 2-(2-isopropylphenethyl)-5-(4-(trifluoromethoxy)benzyl)-1,3,4-oxadiazole 94 2-(3,5-dimethylbenzyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazole 95 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(3-chlorobenzyl)-1,3,4-oxadiazole 96 2-(([1,1'-biphenyl]-2-ylmethyl)sulfonyl)-5-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1,3,4-oxadiazole 97 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(methoxy(phenyl)methyl)-1,3,4-oxadiazole 98 2-(4-bromobenzyl)-5-(naphthalen-2-yl)-1,3,4-oxadiazole 99 4-bromo-N-((2-((2-methylbenzyl)thio)oxazol-5-yl)methyl)aniline 100 2-(4-bromobenzyl)-5-(naphthalen-1-ylmethyl)-1,3,4-oxadiazole 101 2-(3-bromobenzyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazole 102 2-(3-chlorobenzyl)-5-(2-isopropylphenethyl)-1,3,4-oxadiazole 103 2-(4-bromobenzyl)-5-(2-methylphenethyl)-1,3,4-oxadiazole 104 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(3-bromobenzyl)-1,3,4-oxadiazole 105 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(3,5-dimethylbenzyl)-1,3,4-oxadiazole 106 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(4-(trifluoromethoxy)benzyl)-1,3,4-oxadiazole 107 2-(([1,1'-biphenyl]-2-ylmethyl)thio)-5-(4-isopropylbenzyl)-1,3,4-oxadiazole 108 2-(3-chloro-4-fluorobenzyl)-5-(2-methylphenethyl)-1,3,4-oxadiazole 109 2-(4-bromobenzyl)-5-((1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-1,3,4-oxadiazole 110 2-(4-bromobenzyl)-5-(2-(o-tolyl)propyl)-1,3,4-oxadiazole 111 2-(4-bromobenzyl)-5-(2-cyclohexylstyryl)-1,3,4-oxadiazole 112 2-(4-bromobenzyl)-5-(2-cyclohexylstyryl)-1,3,4-oxadiazole 113 2-(3,5-dimethylbenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 114 2-benzyl-5-((2-isopropylphenoxy)methyl)-1,3,4-oxadiazole 115 2-(4-bromobenzyl)-5-((2-isopropylphenoxy)methyl)-1,3,4-oxadiazole 116 (E)-N-(4-bromophenyl)-5-(2-cyclohexylstyryl)-1,3,4-oxadiazol-2-amine 117 (E)-N-(4-bromophenyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazol-2-amine 118 5-(2-([1,1'-biphenyl]-2-yl)ethyl)-N-(4-bromophenyl)-1,3,4-oxadiazol-2-amine 119 2-(2-([1,1'-biphenyl]-2-yl)ethyl)-5-(4-bromobenzyl)-1,3,4-oxadiazole 120 (E)-N-(4-bromophenyl)-5-(2-methoxystyryl)-1,3,4-oxadiazol-2-amine 121 (E)-N-(4-bromophenyl)-5-(2-(quinolin-5-yl)vinyl)-1,3,4-oxadiazol-2-amine 122 N-(3-chloro-4-fluorophenyl)-5-(2-methylphenethyl)-1,3,4-oxadiazol-2-amine 123 5-(2-methylphenethyl)-N-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-amine 124 (E)-5-(2-([1,1'-biphenyl]-2-yl)vinyl)-N-(4-bromophenyl)-1,3,4-oxadiazol-2-amine 125 (E)-N-(4-bromophenyl)-5-(2-phenoxystyryl)-1,3,4-oxadiazol-2-amine 126 (E)-2-(2-([1,1'-biphenyl]-2-yl)vinyl)-5-(4-bromobenzyl)-1,3,4-oxadiazole 127 (E)-2-(4-bromobenzyl)-5-(2-phenoxystyryl)-1,3,4-oxadiazole 128 (E)-2-(4-bromobenzyl)-5-(2-bromostyryl)-1,3,4-oxadiazole 129 2-(4-bromobenzyl)-5-(1-(2-methylbenzyl)cyclopropyl)-1,3,4-oxadiazole 130 2-(3-bromobenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 131 2-(3-chloro-4-fluorobenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 132 2-(2-isopropylstyryl)-5-(naphthalen-1-ylmethyl)-1,3,4-oxadiazole 133 2-(4-isopropylbenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 134 2-(4-bromobenzyl)-5-(2,6-dimethylstyryl)-1,3,4-oxadiazole 135 2-(4-bromobenzyl)-5-(2,6-dimethylphenethyl)-1,3,4-oxadiazole 136 2-([1,1'-biphenyl]-4-ylmethyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 137 2-(4-bromobenzyl)-5-(1-(o-tolyl)propan-2-yl)-1,3,4-oxadiazole 138 2-(4-bromobenzyl)-5-(1-(o-tolyl)prop-1-en-2-yl)-1,3,4-oxadiazole 139 2-([1,1'-biphenyl]-4-ylmethyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 140 2-(4-bromobenzyl)-5-(1-(o-tolyl)propan-2-yl)-1,3,4-oxadiazole 141 2-(4-bromobenzyl)-5-(1-(o-tolyl)prop-1-en-2-yl)-1,3,4-oxadiazole 142 2-([1,1'-biphenyl]-4-ylmethyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 143 2-(4-bromobenzyl)-5-(1-(o-tolyl)propan-2-yl)-1,3,4-oxadiazole 144 2-(4-bromobenzyl)-5-(1-(o-tolyl)prop-1-en-2-yl)-1,3,4-oxadiazole 145 2-(3-bromo-4-methylbenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 146 2-(3,4-dimethylbenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 147 2-(2-isopropylstyryl)-5-(1-phenylethyl)-1,3,4-oxadiazole 148 2-(1-(4-isobutylphenyl)ethyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 149 2-(4-bromobenzyl)-5-(3,4-dichlorostyryl)-1,3,4-oxadiazole 150 2-(4-bromobenzyl)-5-(2,3-dimethylstyryl)-1,3,4-oxadiazole 151 2-(4-bromobenzyl)-5-(3-isopropylstyryl)-1,3,4-oxadiazole 152 2-(4-bromobenzyl)-5-(2-chloro-3-(trifluoromethyl)styryl)-1,3,4-oxadiazole 153 2-(4-bromobenzyl)-5-(2-(4'-chloro-[1,1'-biphenyl]-2-yl)vinyl)-1,3,4-oxadiazole 154 2-(4-bromobenzyl)-5-(4-isopropylstyryl)-1,3,4-oxadiazole 155 2-(4-bromobenzyl)-5-(2-(4-fluorophenoxy)styryl)-1,3,4-oxadiazole 156 2-(benzofuran-2-yl)-5-(4-bromobenzyl)-1,3,4-oxadiazole 157 2-(4-bromobenzyl)-5-(5-chlorobenzofuran-2-yl)-1,3,4-oxadiazole 158 (E)-2-benzyl-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 159 (E)-2-(3-chloro-4-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 160 (E)-N-(4-bromo-3-fluorophenyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol-2-amine 161 (E)-N-(4-bromo-3-fluorophenyl)-5-(2-chloro-4-fluorostyryl)-N-methyl-1,3,4-oxadiazol-2-amine 162 2-(4-bromobenzyl)-5-(2-(6-chlorobenzo[d][1,3]dioxol-5-yl)vinyl)-1,3,4-oxadiazole 163 2-(4-bromobenzyl)-5-(2-methoxystyryl)-1,3,4-oxadiazole 164 2-(4-bromo-3-fluorobenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 165 2-(4-bromobenzyl)-5-styryl-1,3,4-oxadiazole 166 2-(4-bromobenzyl)-5-(2-chlorostyryl)-1,3,4-oxadiazole 167 2-(4-bromobenzyl)-5-(3-chlorostyryl)-1,3,4-oxadiazole 168 2-(4-bromobenzyl)-5-(2,6-dichlorostyryl)-1,3,4-oxadiazole 169 2-(4-bromo-2-fluorobenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 170 2-(4-bromobenzyl)-5-(2-methylstyryl)-1,3,4-oxadiazole 171 2-(4-bromobenzyl)-5-(4-chlorostyryl)-1,3,4-oxadiazole 172 2-(4-bromo-3-methylbenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 173 2-(2-fluoro-5-methylbenzyl)-5-(2-isopropylstyryl)-1,3,4-oxadiazole 174 (E)-3-(4-bromobenzyl)-5-styryl-1,2,4-oxadiazole 175 (E)-3-(4-bromobenzyl)-5-(2-isopropylstyryl)-1,2,4-oxadiazole 176 (E)-2-(4-bromo-3-methylbenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 177 (E)-2-(2-chloro-4-fluorostyryl)-5-(2-fluoro-5-methylbenzyl)-1,3,4-oxadiazole 178 (E)-2-(3-bromobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 179 (E)-2-(2-chloro-4-fluorostyryl)-5-(3-chlorobenzyl)-1,3,4-oxadiazole 180 (E)-2-(2-chloro-4-fluorostyryl)-5-((6-chloropyridin-3-yl)methyl)-1,3,4-oxadiazole 181 (E)-2-(3-bromo-4-methylbenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 182 (E)-2-(2-chloro-4-fluorostyryl)-5-(3-isopropylbenzyl)-1,3,4-oxadiazole 183 (E)-5-(4-bromobenzyl)-3-styryl-1,2,4-oxadiazole 184 (E)-2-(4-bromo-3-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 185 (E)-2-(2-chloro-4-fluorostyryl)-5-(naphthalen-1-ylmethyl)-1,3,4-oxadiazole 186 2-(3-bromobenzyl)-5-(4-fluoro-2-methylstyryl)-1,3,4-oxadiazole 187 2-(3-chlorobenzyl)-5-(2-fluorostyryl)-1,3,4-oxadiazole 188 2-(3-bromobenzyl)-5-(4-fluorostyryl)-1,3,4-oxadiazole 189 2-(3-bromobenzyl)-5-(2,4-difluorostyryl)-1,3,4-oxadiazole 190 2-(3-bromobenzyl)-5-(4-chloro-2-fluorostyryl)-1,3,4-oxadiazole 191 2-(3-bromobenzyl)-5-(3,4-difluorostyryl)-1,3,4-oxadiazole 192 2-(3-bromobenzyl)-5-(2,4-dichlorostyryl)-1,3,4-oxadiazole 193 2-(3-bromobenzyl)-5-(2-chloro-5-fluorostyryl)-1,3,4-oxadiazole 194 2-(3-bromobenzyl)-5-(2-chloro-3-fluorostyryl)-1,3,4-oxadiazole 195 2-(3-bromobenzyl)-5-(2-chloro-4-methylstyryl)-1,3,4-oxadiazole 196 2-benzyl-5-(2-isopropylstyryl)-1,3,4-oxadiazole 197 2-(4-bromobenzyl)-5-(2-(naphthalen-1-yl)vinyl)-1,3,4-oxadiazole 198 2-(3-bromobenzyl)-5-(2-methyl-4-(trifluoromethyl)styryl)-1,3,4-oxadiazole 199 2-(3-bromobenzyl)-5-(2-chloro-5-(trifluoromethyl)styryl)-1,3,4-oxadiazole 200 2-(3-bromobenzyl)-5-(2,4-dimethylstyryl)-1,3,4-oxadiazole 201 (E)-3-((5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol-2-yl)methyl)phenol 202 (E)-2-(2-chloro-4-fluorostyryl)-5-(3-methoxybenzyl)-1,3,4-oxadiazole 203 (E)-2-(2-chloro-4-fluorostyryl)-5-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-1,3,4-oxadiazole 204 E)-2-(3-bromobenzyl)-5-(2-(2-methylpyridin-3-yl)vinyl)-1,3,4-oxadiazole 205 (E)-2-((5-bromopyridin-3-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 206 (E)-2-(2-chloro-4-fluorostyryl)-5-((4-chloropyridin-2-yl)methyl)-1,3,4-oxadiazole 207 2-(3-bromo-4-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 208 2-(2-chloro-4-fluorostyryl)-5-(3,4-dichlorobenzyl)-1,3,4-oxadiazole 209 2-(2-(5-(4-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)phenol 210 2-(3-bromobenzyl)-5-(2-methoxystyryl)-1,3,4-oxadiazole 211 2-(2-chloro-4-fluorostyryl)-5-(3-methylbenzyl)-1,3,4-oxadiazole 212 2-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol 213 2-(2-chloro-4-fluorostyryl)-5-((1-methyl-1H-indol-3-yl)methyl)-1,3,4-oxadiazole 214 (E)-2-(2-chloro-4-fluorostyryl)-5-((1-methyl-1H-indazol-3-yl)methyl)-1,3,4-oxadiazole 215 2-(2-bromo-4-fluorostyryl)-5-(3-bromobenzyl)-1,3,4-oxadiazole 216 2-(3-bromobenzyl)-5-(2-(3-methylpyridin-4-yl)vinyl)-1,3,4-oxadiazole 217 3-((5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol-2-yl)methyl)-N,N-dimethylaniline 218 2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)phenol 219 2-(2-chloro-4-fluorostyryl)-5-((6-chloropyridin-2-yl)methyl)-1,3,4-oxadiazole 220 2-(3-bromobenzyl)-5-(2-ethylstyryl)-1,3,4-oxadiazole 221 2-(2-chloro-4-fluorostyryl)-5-(2,3-dimethylbenzyl)-1,3,4-oxadiazole 222 2-(2-bromobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 223 2-(3-bromophenethyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 224 2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)-N,N-dimethylaniline 225 2-(3-bromobenzyl)-5-(2-(2-chloropyridin-3-yl)vinyl)-1,3,4-oxadiazole 226 2-(2-chloro-4-fluorostyryl)-5-(3-fluorobenzyl)-1,3,4-oxadiazole 227 (E)-2-(2-chloro-4-fluorostyryl)-5-(3,5-dibromobenzyl)-1,3,4-oxadiazole 228 (E)-2-(2-chloro-4-fluorostyryl)-5-(naphthalen-2-ylmethyl)-1,3,4-oxadiazole 229 (E)-2-(3-bromo-4-methoxybenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 230 (E)-2-bromo-4-((5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol-2-yl)methyl)phenol 231 (E)-2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)-5-fluoro-N,N-dimethylaniline 232 (E)-2-(3-bromobenzyl)-5-(4-fluoro-2-(pyrrolidin-1-yl)styryl)-1,3,4-oxadiazole 233 (E)-2-(3-bromobenzyl)-5-(2,4,6-trifluorostyryl)-1,3,4-oxadiazole 234 (E)-3-((5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazol-2-yl)methyl)benzonitrile 235 (E)-2-(2-chloro-4-fluorostyryl)-5-(3-(trifluoromethoxy)benzyl)-1,3,4-oxadiazole 236 2-(2-chloro-4-fluorostyryl)-5-(quinolin-8-ylmethyl)-1,3,4-oxadiazole 237 2-(2-chloro-4-fluorostyryl)-5-(isoquinolin-1-ylmethyl)-1,3,4-oxadiazole 238 2-(2-chloro-4-fluorostyryl)-5-(isoquinolin-4-ylmethyl)-1,3,4-oxadiazole 239 2-(3-bromobenzyl)-5-(2-(5-fluoropyridin-2-yl)vinyl)-1,3,4-oxadiazole 240 2-((6-bromopyridin-3-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 241 2-((6-bromopyridin-3-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 242 methyl-2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)benzoate 243 2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)benzoic acid 244 5-(3-bromobenzyl)-N-(2-chloro-4-fluorophenyl)-1,3,4-oxadiazole-2-carboxamide 245 2-(3-bromobenzyl)-5-(2-chloro-4,6-difluorostyryl)-1,3,4-oxadiazole 246 N-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)-2-chloro-4-fluorobenzenesulfonamide 247 (E)-2-(2-chloro-4-fluorostyryl)-5-(3-(trifluoromethyl)benzyl)-1,3,4-oxadiazole 248 (E)-2-(3-bromobenzyl)-5-(2-(1-isopropyl-1H-pyrazol-5-yl)vinyl)-1,3,4-oxadiazole 249 (E)-2-((1H-indazol-3-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 250 (E)-2-(2-chloro-4-fluorostyryl)-5-(cyclohexylmethyl)-1,3,4-oxadiazole 251 (E)-2-(benzo[b]thiophen-3-ylmethyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 252 (E)-2-(3-bromobenzyl)-5-(4-fluoro-2-(piperidin-1-yl)styryl)-1,3,4-oxadiazole 253 N-(3-bromophenyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole-2-carboxamide 254 (E)-2-(3-bromobenzyl)-5-(2-(4-chloro-1-isopropyl-1H-pyrazol-3-yl)vinyl)-1,3,4-oxadiazole 255 2-(2-chloro-4-fluorostyryl)-5-(3-fluoro-5-methylbenzyl)-1,3,4-oxadiazole 256 2-(3-bromobenzyl)-5-(2-(trifluoromethoxy)styryl)-1,3,4-oxadiazole 257 2-(3-bromobenzyl)-5-(2-(3-chloro-5-fluoropyridin-2-yl)vinyl)-1,3,4-oxadiazole 258 2-(5-bromo-2-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 259 (E)-2-(3-bromobenzyl)-5-(2-(1-isopropyl-1H-imidazol-2-yl)vinyl)-1,3,4-oxadiazole 260 (E)-2-(3-bromobenzyl)-5-(2,6-dichloro-4-fluorostyryl)-1,3,4-oxadiazole 261 (E)-2-(2-chloro-4-fluorostyryl)-5-((1-isopropyl-1H-indazol-3-yl)methyl)-1,3,4-oxadiazole 262 2-(3-bromo-4-methylbenzyl)-5-(2,4-difluorostyryl)-1,3,4-oxadiazole 263 2-(3-bromo-4-fluorobenzyl)-5-(2,4-difluorostyryl)-1,3,4-oxadiazole 264 2-(3-bromobenzyl)-5-(4-fluoro-2-(trifluoromethyl)styryl)-1,3,4-oxadiazole 265 2-(2-bromo-4-fluorostyryl)-5-(3-bromo-4-methylbenzyl)-1,3,4-oxadiazole 266 2-(3-bromo-4-fluorobenzyl)-5-(2-bromo-4-fluorostyryl)-1,3,4-oxadiazole 267 2-(2-chloro-4-fluorostyryl)-5-(3-cyclopropylbenzyl)-1,3,4-oxadiazole 268 (E)-2-(2-(5-(3-Bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)-5-fluoro-N-(2-methoxyethyl)-N-methylaniline 269 (E)-2-(3-bromobenzyl)-5-(4-fluoro-2-(furan-3-yl)styryl)-1,3,4-oxadiazole 270 (E)-2-(3-bromobenzyl)-5-(4-fluoro-2-(thiophen-3-yl)styryl)-1,3,4-oxadiazole 271 (E)-4-(2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)-5-fluorophenyl)morpholine 272 (E)-2-(benzofuran-3-ylmethyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 273 (E)-2-(3-bromobenzyl)-5-(4-fluoro-2-isopropylstyryl)-1,3,4-oxadiazole 274 (E)-2-(2-(1H-pyrrol-1-yl)styryl)-5-(3-bromobenzyl)-1,3,4-oxadiazole 275 2-(3-bromobenzyl)-5-(2-chloro-4-fluorophenethyl)-1,3,4-oxadiazole 276 (E)-2-(3-bromobenzyl)-5-(2-(naphthalen-1-yl)vinyl)-1,3,4-oxadiazole 277 (E)-2-(3-bromobenzyl)-5-(2-(4-fluoronaphthalen-1-yl)vinyl)-1,3,4-oxadiazole 278 (E)-2-((1H-indazol-3-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 279 (E)-2-(2-chloro-4-fluorostyryl)-5-((2-methyl-1H-indol-1-yl)methyl)-1,3,4-oxadiazole 280 2-(3-bromobenzyl)-5-(2,3-difluorostyryl)-1,3,4-oxadiazole 281 2-(3-bromobenzyl)-5-(2-(trifluoromethyl)styryl)-1,3,4-oxadiazole 282 2-(5-bromo-2-methylbenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 283 2-((4-bromopyridin-2-yl)methyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 284 2-(3-bromobenzyl)-5-(2-(3,5-difluoropyridin-2-yl)vinyl)-1,3,4-oxadiazole 285 2-(3-bromo-4-methylbenzyl)-5-(2-chloro-4-fluorophenethyl)-1,3,4-oxadiazole 286 (E)-2-(2-chloro-4-fluorostyryl)-5-(thiophen-3-ylmethyl)-1,3,4-oxadiazole 287 (E)-2-(3-bromobenzyl)-5-(2-(naphthalen-2-yl)vinyl)-1,3,4-oxadiazole 288 (E)-2-(3-bromobenzyl)-5-(2,3-dimethylstyryl)-1,3,4-oxadiazole 289 (E)-2-(3-bromobenzyl)-5-(2-(quinolin-5-yl)vinyl)-1,3,4-oxadiazole 290 2-(2-bromo-4,6-difluorostyryl)-5-(3-bromobenzyl)-1,3,4-oxadiazole 291 2-(3-chloro-2-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 292 2-(3-bromo-5-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 293 2-(3-bromo-2-fluorobenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 294 2-(3-bromo-2-methylbenzyl)-5-(2-chloro-4-fluorostyryl)-1,3,4-oxadiazole 295 2-(2-chloro-4-fluorostyryl)-5-((2-methylquinolin-8-yl)methyl)-1,3,4-oxadiazole 296 2-(2-chloro-4-fluorostyryl)-5-((3-chloroisoquinolin-1-yl)methyl)-1,3,4-oxadiazole 297 2-(2-chloro-4-fluorostyryl)-5-((3-methoxyisoquinolin-1-yl)methyl)-1,3,4-oxadiazole 298 2-(2-chloro-4-fluorostyryl)-5-((7-methoxynaphthalen-1-yl)methyl)-1,3,4-oxadiazole 299 2-(2-chloro-4-fluorostyryl)-5-(3-(difluoromethyl)benzyl)-1,3,4-oxadiazole 300 2-(2-chloro-4-fluorostyryl)-5-(3-chloro-4-methylbenzyl)-1,3,4-oxadiazole 301 (E)-2-(3-bromobenzyl)-5-(2-(quinolin-8-yl)vinyl)-1,3,4-oxadiazole 302 (E)-4-(2-(2-(2-(5-(3-bromobenzyl)-1,3,4-oxadiazol-2-yl)vinyl)-5-fluorophenoxy)ethyl)morpholine 303 (E)-2-(3-bromobenzyl)-5-(2-(isoquinolin-5-yl)vinyl)-1,3,4-oxadiazole 304 (E)-2-(3-bromobenzyl)-5-(2-(1-methyl-1H-indol-3-yl)vinyl)-1,3,4-oxadiazole 305 2-(2-(5-(3-bromo-4-methylbenzyl)-1,3,4-oxadiazol-2-yl)vinyl)-5-fluoro-N-methyl-N-phenethylaniline 306 (E)-2-(3-bromobenzyl)-5-(2-(imidazo[1,2-a]pyridin-3-yl)vinyl)-1,3,4-oxadiazole 307 (E)-2-(3-bromobenzyl)-5-(2-(1-methyl-1H-indol-4-yl)vinyl)-1,3,4-oxadiazole - 제1항의 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 약학적으로 허용가능한 염을 유효성분으로 함유하는 항바이러스용 약학적 조성물.
- 제4항에 있어서, 상기 바이러스는 인플루엔자 바이러스인 것을 특징으로 하는 약학적 조성물.
- 제5항에 있어서, 상기 인플루엔자 바이러스는 A형 인플루엔자 바이러스 또는 B형 인플루엔자 바이러스인 것을 특징으로 하는 약학적 조성물.
- 제6항에 있어서, 상기 인플루엔자 바이러스는 A/California/07/2009 (H1N1), A/Perth/16/2009 (H3N2) 또는 B/Florida/04/2006인 것을 특징으로 하는 약학적 조성물.
- 제4항에 있어서, 상기 조성물은 바이러스 감염으로 인한 질환의 예방 또는 치료에 사용되는 것을 특징으로 하는 약학적 조성물.
- 제8항에 있어서, 상기 바이러스 감염으로 인한 질환은 독감, 감기, 인후염, 기관지염, 폐렴, 조류독감, 돼지독감 및 염소독감으로 이루어진 군에서 선택되는 1종의 인플루엔자 바이러스 감염으로 인한 질환인 것을 특징으로 하는 약학적 조성물.
- 제1항의 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 거울상 이성질체, 부분 입체 이성질체 또는 식품학적으로 허용가능한 염을 유효성분으로 함유하는 바이러스 감염으로 인한 질환의 예방 또는 개선용 건강기능식품 조성물.
- 제10항에 있어서, 상기 바이러스는 인플루엔자 바이러스인 것을 특징으로 하는 건강기능식품 조성물.
- 제11항에 있어서, 상기 인플루엔자 바이러스는 A형 인플루엔자 바이러스 또는 B형 인플루엔자 바이러스인 것을 특징으로 하는 건강기능식품 조성물.
- 제12항에 있어서, 상기 인플루엔자 바이러스는 A/California/07/2009 (H1N1), A/Perth/16/2009 (H3N2) 또는 B/Florida/04/2006인 것을 특징으로 하는 건강기능식품 조성물.
- 제10항에 있어서, 상기 바이러스 감염으로 인한 질환은 독감, 감기, 인후염, 기관지염, 폐렴, 조류독감, 돼지독감 및 염소독감으로 이루어진 군에서 선택되는 1종의 인플루엔자 바이러스 감염으로 인한 질환인 것을 특징으로 하는 건강기능식품 조성물.
- 제1항의 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 거울상 이성질체 또는 부분 입체 이성질체를 유효성분으로 함유하는 바이러스 소독용 또는 세정용 조성물.
- 제15항에 있어서, 상기 바이러스는 인플루엔자 바이러스인 것을 특징으로 하는 소독용 또는 세정용 조성물.
- 제16항에 있어서, 상기 인플루엔자 바이러스는 A형 인플루엔자 바이러스 또는 B형 인플루엔자 바이러스인 것을 특징으로 하는 소독용 또는 세정용 조성물.
- 제17항에 있어서, 상기 인플루엔자 바이러스는 A/California/07/2009 (H1N1), A/Perth/16/2009 (H3N2) 또는 B/Florida/04/2006인 것을 특징으로 하는 소독용 또는 세정용 조성물.
- 제1항의 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 거울상 이성질체 또는 부분 입체 이성질체를 유효성분으로 사용하여, 인플루엔자 바이러스를 억제하는 방법.
- 제1항의 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 거울상 이성질체 또는 부분 입체 이성질체를 유효성분으로 사용하여, 인플루엔자 바이러스 감염에 의해 발병되는 질환을 예방 또는 치료하는 방법.
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US11091447B2 (en) | 2020-01-03 | 2021-08-17 | Berg Llc | UBE2K modulators and methods for their use |
US11884682B2 (en) * | 2020-06-23 | 2024-01-30 | Nanjing Immunophage Biotech Co., Ltd. | Compounds and their uses as MIF inhibitors |
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