WO2015069011A1 - Nouveau composé, procédé de préparation de celui-ci, et composition antifongique le comprenant - Google Patents

Nouveau composé, procédé de préparation de celui-ci, et composition antifongique le comprenant Download PDF

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WO2015069011A1
WO2015069011A1 PCT/KR2014/010551 KR2014010551W WO2015069011A1 WO 2015069011 A1 WO2015069011 A1 WO 2015069011A1 KR 2014010551 W KR2014010551 W KR 2014010551W WO 2015069011 A1 WO2015069011 A1 WO 2015069011A1
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carbohydrazide
fluoro
fluoropyridin
methoxypyridin
phenyl
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PCT/KR2014/010551
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English (en)
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Joon Seok Park
Youn Jung Yoon
Chang Min Park
Yun Soo Na
Min Jae Cho
Ho Bin Lee
Yeon Jung Park
Ji Duck Kim
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Daewoong Pharmaceutical Co., Ltd.
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Publication of WO2015069011A1 publication Critical patent/WO2015069011A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D417/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to a novel compound with excellent antifungal activities, an antifungal composition containing the same, and an use of the composition for the prevention and treatment of fungal infectious diseases.
  • antifungal agents available at present is much less than that of antibiotics used for the treatment of bacterial infections.
  • examples of the antifungal agents developed so far include polyene amphotericin B or fluconazole, itraconazole, voriconazole, posaconazole, etc., of azole class.
  • polyene amphotericin B or fluconazole polyene amphotericin B or fluconazole
  • itraconazole voriconazole
  • posaconazole etc.
  • the appearance of azole-resistance bacteria has become a problem.
  • cyclic hexapeptide type echinocandins from natural products caspofungin, micafungin, and anidulafungin
  • the antifungal agents may be classified into fungistatics and fungicides depending on the effects of their actions. Generally, fungicidal agents have a high clinical value due to their prompt and strong actions. Amphotericin B and echinocandins are known to be effective for the treatment of systemic mycosis. However, these fungicidal agents have only a limited use as injections are not applicable to patients with various types of infections.
  • the inventors of the present invention while endeavoring to find a compound useful as an antifungal agent, have found that the novel compound represented by Chemical Formula 1 as described in the specification of the present invention has an excellent antifungal effect, thereby completing the present invention.
  • It is a further objective of the present invention to provide a method for the prevention or treatment of fungal infectious diseases comprising administering an effective amount of the above compound of the present invention or a pharmaceutically acceptable salt thereof to a subject with fungal infectious diseases or a subject suspected of having the same.
  • the novel antifungal oxodihydropyridine carbohydrazide derivative of the present invention has excellent antifungal and fungicidal activities, and thus will be useful for the prevention and treatment of various fungal infections such as Candida spp ., Aspergillus spp ., Cryptococcus neoformans and Trichophyton spp . Additionally, the oxodihydropyridine carbohydrazide derivative of the present invention is advantageous in that it can be orally administered unlike other fungicidal agents.
  • the present invention provides a compound represented by Chemical Formula 1 below, or a pharmaceutically acceptable salt thereof.
  • A is 5-11 membered heteroaryl with one to three heteroatoms each independently selected from the group consisting of N, O and S,
  • R 1 is hydrogen or halogen
  • R 2 is halogen or C 1-4 alkoxy
  • R 3 is hydrogen, 3-methylthien-2-ylcarbonyl or t-butoxycarbonyl
  • R 4 is hydrogen, R 5 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, halogen or benzyl; or R 4 and R 5 are attached together to form C 2-4 alkylene,
  • R 6 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-6 cycloalkyl, halogen, nitro, amino, NH(t-butoxycarbonyl), NH(C 1-4 alkyl), phenyl, pyridinyl, pyrrolyl or thiazolyl,
  • phenyl, the pyridinyl, the pyrrolyl or the thiazolyl is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, halogen, cyano and phenyl.
  • R 5 and R 6 respectively represent a substituent substituted to A.
  • A is benzo[b]thienyl, benzofuro[3,2-b]pyrrolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl or triazolyl.
  • A is benzo[b]thien-3-yl, benzofuro[3,2-b]pyrrol-2-yl, imidazol-2-yl, indol-2-yl, indol-3-yl, isoxazol-3-yl, isoxazol-5-yl, oxazol-4-yl, oxazol-5-yl, pyrazole-5-yl, pyrrol-2-yl, thiazol-2-yl, thiazol-3-yl, thiazol-5-yl, thien-2-yl, thien-3-yl, 1,2,3-triazol-4-yl or 1,2,4-triazol-5-yl.
  • R 1 is hydrogen, R 2 is fluoro; or R 1 is fluoro, R 2 is methoxy.
  • R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloro or benzyl.
  • R 6 is hydrogen, methyl, methoxy, difluoromethyl, cyclopropyl, fluoro, chloro, nitro, amino, NH(t-butoxycarbonyl), ethylamino, phenyl, pyridinyl, pyrrolyl or thiazolyl,
  • phenyl, the pyridinyl, the pyrrolyl or the thiazolyl is unsubstituted or substituted with one or two substituents selected from the group consisting of methyl, t-butyl, trifluoromethyl, fluoro, chloro, cyano and phenyl.
  • R 6 is phenyl unsubstituted or substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, halogen, cyano and phenyl; unsubstituted pyridinyl; pyrrolyl substituted with C 1-4 alkyl; or thiazolyl substituted with C 1-4 alkyl.
  • A is indolyl
  • R 5 is hydrogen or C 1-4 alkyl
  • R 6 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy or halogen.
  • A is isoxazolyl
  • R 5 is hydrogen
  • R 6 is C 1-4 alkyl or phenyl
  • phenyl is unsubstituted or substituted with halogen.
  • A is oxazolyl
  • R 5 is hydrogen or C 1-4 alkyl
  • R 6 is C 1-4 alkyl or phenyl
  • phenyl is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of C 1-4 haloalkyl, halogen and phenyl.
  • A is pyrazolyl
  • R 4 is hydrogen, R 5 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl or benzyl; or R 4 and R 5 are attached together to form C 2-4 alkylene, and
  • R 6 is C 1-4 alkyl, C 3-6 cycloalkyl, nitro, phenyl, pyridinyl or pyrrolyl,
  • phenyl, the pyridinyl or the pyrrolyl is unsubstituted or substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, halogen and cyano.
  • A is thiazolyl
  • R 5 is hydrogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R 6 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-6 cycloalkyl, halogen, amino, NH(t-butoxycarbonyl), NH(C 1-4 alkyl) or phenyl,
  • phenyl is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of C 1-4 haloalkyl, halogen and cyano.
  • A is thienyl
  • R 5 is hydrogen or halogen
  • R 6 is hydrogen, C 1-4 alkyl, halogen or phenyl
  • phenyl is unsubstituted or substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, halogen and cyano.
  • A is triazolyl
  • R 5 is C 1-4 alkyl
  • R 6 is phenyl
  • the present invention provides a method for manufacturing a compound represented by Chemical Formula 1 above.
  • the compound represented by Chemical Formula 1 above may be manufactured by a method shown in Reaction Scheme 1 below.
  • R 1 , R 2 , R 3 and R 6 are the same as defined above, and R 5 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, halogen or benzyl.
  • the reaction shown above is a reaction to form an amide bond by reacting an amine group in a compound represented by Chemical Formula 2 with a carboxyl group in a compound represented by Chemical Formula 3, which may be carried out under a conventional amide bond-forming reaction condition.
  • the carboxylic acid of Chemical Formula 2 may be used after converting into methyl carboxylate, ethyl carboxylate or chloroacyl group according to a conventional method.
  • the reaction may be carried out at a temperature from 0°C to 50°C, preferably from room temperature to 50°C, and stirred for from 30 minutes to 24 hours.
  • Step 1 above is a reaction to form an amide bond by reacting an amine group in a compound represented by Chemical Formula 4 with a carboxylic group in a compound represented by Chemical Formula 5, which may be carried out under a conventional amide bond-forming reaction condition.
  • the carboxylic acid of Chemical Formula 5 may be used after converting into methyl carboxylate, ethyl carboxylate or chloroacyl group according to a conventional method.
  • the reaction may be carried out at a temperature from 0°C to 50°C, preferably from room temperature to 50°C, and stirred for from 30 minutes to 24 hours.
  • Step 2 above is a reaction to react a compound represented by Chemical Formula 6 with a compound represented by Chemical Formula 7 thereby allowing R 4 and R 5 to be attached together to have a structure of forming C 2-4 alkylene.
  • the reaction above is preferably performed in a basic condition.
  • the base to be used in the present invention may include a conventional inorganic base, for example, sodium hydroxide (NaOH), potassium hydroxide (KOH), potassium carbonate (K 2 CO 3 ), sodium hydride (NaH), etc.
  • the solvent to be used in the reaction is a polar organic solvent, and more preferably a polar solvent such as dimethylformamide.
  • Step 3 above is a reaction to remove a protection group from a compound represented by Chemical Formula 8, by which a compound represented by Chemical Formula 1 can be prepared.
  • the removal of a protection group may be performed using an acidic solution, for example, hydrochloric acid solution.
  • the compound represented by Chemical Formula 1 of the present invention may be provided in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid.
  • the salts to be used in the present invention may include inorganic or organic salts known in the art of antifungal agents, and they may be manufactured by a known method.
  • the salts are acid addition salts formed by inorganic acids such as hydrochloric acid and nitric acid; sulfonic acid such as methanesulfonic acid; or an organic carbonic acid such as oxalic acid.
  • the compound represented by Chemical Formula 1 of the present invention may include a hydrate and a solvate that can be manufactured therefrom.
  • the present invention provides a pharmaceutical composition, a pharmaceutical composition for the prevention or treatment of fungal infectious diseases, and an antifungal composition comprising a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient, respectively.
  • the compound represented by Chemical Formula 1 may be useful for the prevention and treatment of various types fungal infections such as infections by Candida spp ., Aspergillus spp ., Cryptococcus neoformans and Trichophyton spp .
  • the present invention provides a pharmaceutical composition, a pharmaceutical composition for the prevention or treatment of fungal infectious diseases, and an antifungal composition comprising a compound selected from the group consisting of a compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof, and a solvate thereof, as an active ingredient.
  • the antifungal composition may include a pharmaceutically acceptable carrier or vehicle as well.
  • the antifungal composition of the present invention may be formulated into various types via a conventional method in the art by mixing the compound of the present invention with a pharmaceutically acceptable inert carrier or vehicle suitable for oral or parenteral, or topical administration.
  • the antifungal composition of the present invention has a fungicidal activity and may be orally administered.
  • Examples of the preparations for oral administration may include tablets, capsules, etc., which may include, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose or glycine, etc.), a lubricant (e.g., silica, talc, stearic acid and magnesium stearate or calcium stearate, or polyethylene glycol, etc.) or a binder (e.g., magnesium aluminum silicate, starch paste, gelatin, tracacanth, methylcellulose, sodium carboxymethyl cellulose or polyvinyl pyrrolidine, etc.), and may further include starch, agar, a disintegrating agent such as alginic acid or sodium alginate, an azeotropic mixture, an absorbent, a coloring agent, a flavoring agent, a sweetener, etc., as necessary.
  • a diluent e.g
  • the present invention provides a method for the prevention or treatment of fungal infectious diseases comprising administering a composition comprising a compound represented by Chemical Formula 1 above or a pharmaceutically acceptable salt thereof as an active ingredient to a subject with a fungal infectious disease or a subject suspected of having the same.
  • the above subject refers to all animals including humans with a fungal infectious disease or a potential of having the same.
  • the above compound may be administered in the form of a pharmaceutical composition, orally or parenterally. Additionally, the preferred dosage of the compound of the present invention may vary depending on various factors such as health status, body weight, and severity of disease(s) of a subject, drug types, administration routes and duration, and may be appropriately determined by one of ordinary skill in the art.
  • the compound of the present invention may be administered for the treatment of mammals including humans with fungal infections or with a potential having the same in the amount of from 0.05 mg/kg/day to 200 mg/kg/day, more preferably from 0.05 mg/kg/day to 100 mg/kg/day, orally or via an injection.
  • administration refers to introduction of a compound or composition of the present invention into a subject in a suitable manner. Any administration route may be taken orally or via various parenteral routes, as long as it allows the composition to reach a target tissue in the body, in particular, oral, rectal, local, intravenous, intraperitoneal, intramuscular, intraarterial, transdermal, intranasal, inhalative or intravascular routes via a conventional method.
  • the present invention provides a method for manufacturing a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of a composition comprising a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of fungal infectious diseases.
  • 2-fluoro-5-hydrazinylpyridine (17.4 mg, 0.08 mmol) and 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid (16.7 mg, 0.08 mmol) were dissolved in 1 mL of N,N-dimethylformamide.
  • the resultant was added with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (45.4 mg, 0.12 mmol) and diisopropylethylamine (34.8 ⁇ L, 0.2 mmol) at room temperature, and stirred at room temperature for 6 hours.
  • a title compound (9.7 mg, yield 51%) was obtained in the same manner as in Example 1 except that thiophene-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (11.5 mg, yield 57%) was obtained in the same manner as in Example 1 except that 3-methylthiophene-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (11.1 mg, yield 55%) was obtained in the same manner as in Example 1 except that 4-methylthiophene-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (17.7 mg, yield 59%) was obtained in the same manner as in Example 1 except that 3-methylthiophene-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (10.3 mg, yield 42%) was obtained in the same manner as in Example 1 except that 2,5-dichlorothiophene-3-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (13.4 mg, yield 50%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2,5-dichlorothiophene-3-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.0 mg, yield 56%) was obtained in the same manner as in Example 1 except that 5-phenylthiophene-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.0 mg, yield 51%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-phenylthiophene-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (15.1 mg, yield 57%) was obtained in the same manner as in Example 1 except that 5-(4-fluorophenyl)thiophene-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (15.9 mg, yield 55%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-(4-fluorophenyl)thiophene-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (16.6 mg, yield 55%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-(4-chlorophenyl)thiophene-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (17.4 mg, yield 59%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-(4-cyanophenyl)thiophene-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (16.8 mg, yield 51%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-(4-(trifluoromethyl)phenyl)thiophene-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (18.9 mg, yield 59%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-(4-(t-butyl)phenyl)thiophene-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (10.4 mg, yield 49%) was obtained in the same manner as in Example 1 except that 5-nitro-1H-pyrazole-3-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (11.0 mg, yield 47%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 3-cyclopropyl-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (13.3 mg, yield 56%) was obtained in the same manner as in Example 1 except that 3-phenyl-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (12.9 mg, yield 51%) was obtained in the same manner as in Example 1 except that 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (15.1 mg, yield 57%) was obtained in the same manner as in Example 1 except that 3-(4-chlorophenyl)-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (16.1 mg, yield 55%) was obtained in the same manner as in Example 1 except that 3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (16.2 mg, yield 63%) was obtained in the same manner as in Example 1 except that 3-(4-cyanophenyl)-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (12.3 mg, yield 51%) was obtained in the same manner as in Example 1 except that 3-(1-methyl-1H-pyrrol-2-yl)-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.6 mg, yield 61%) was obtained in the same manner as in Example 1 except that 3-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (19.1 mg, yield 56%) was obtained in the same manner as in Example 1 except that t-butyl 1-(5-fluoro-6-methoxypyridin-3-yl)hydrazine-1-carboxylate prepared in Step 2 was used instead of 2-fluoro-5-hydrazinylpyridine, and 3-phenyl-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (13.4 mg, yield 51%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 3-phenyl-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (15.7 mg, yield 57%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (15.9 mg, yield 55%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 3-(4-chlorophenyl)-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.9 mg, yield 47%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (11.8 mg, yield 42%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 3-(4-cyanophenyl)-1H-pyrazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (13.7 mg, yield 52%) was obtained in the same manner as in Example 31 except that 5-(4-fluorophenyl)-1H-pyrazole-3-carboxylate was used in Step 1 instead of 5-phenyl-1H-pyrazole-3-carboxylate.
  • a title compound (11.7 mg, yield 47%) was obtained in the same manner as in Example 31 except that 3-phenyl-1H-pyrazole-5-carboxylate was used in Step 1 instead of 5-phenyl-1H-pyrazole-3-carboxylate.
  • a title compound (11.5 mg, yield 42%) was obtained in the same manner as in Example 31 except that 3-phenyl-1H-pyrazole-5-carboxylate was used in Step 1 instead of 5-phenyl-1H-pyrazole-3-carboxylate, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (16.1 mg, yield 56%) was obtained in the same manner as in Example 31 except that 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate was used in Step 1 instead of 5-phenyl-1H-pyrazole-3-carboxylate, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (15.2 mg, yield 51%) was obtained in the same manner as in Example 31 except that 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and ethyl iodide was used instead of iodomethane in Step 1, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (14.8 mg, yield 57%) was obtained in the same manner as in Example 31 except that 3-phenyl-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and ethyl iodide was used instead of iodomethane in Step 1.
  • a title compound (16.2 mg, yield 59%) was obtained in the same manner as in Example 31 except that 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and ethyl iodide was used instead of iodomethane in Step 1.
  • a title compound (14.6 mg, yield 51%) was obtained in the same manner as in Example 31 except that 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and iodopropane was used instead of iodomethane in Step 1.
  • a title compound (14.0 mg, yield 49%) was obtained in the same manner as in Example 31 except that 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and isopropyl iodide was used instead of iodomethane in Step 1.
  • a title compound (15.2 mg, yield 47%) was obtained in the same manner as in Example 31 except that 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and benzyl bromide was used instead of iodomethane in Step 1.
  • a title compound (13.9 mg, yield 56%) was obtained in the same manner as in Example 31 except that 3-methyl-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and bromobenzene was used instead of iodomethane in Step 1.
  • a title compound (15.8 mg, yield 51%) was obtained in the same manner as in Example 31 except that 3-phenyl-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and benzyl bromide was used instead of iodomethane in Step 1.
  • a title compound (17.1 mg, yield 57%) was obtained in the same manner as in Example 31 except that 3-(4-chlorophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate in Step 1, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (17.2 mg, yield 55%) was obtained in the same manner as in Example 31 except that 3-(4-chlorophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and ethyl iodide was used instead of iodomethane in Step 1, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (18.7 mg, yield 57%) was obtained in the same manner as in Example 31 except that 3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate in Step 1, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (18.6 mg, yield 55%) was obtained in the same manner as in Example 31 except that 3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and ethyl iodide was used instead of iodomethane in Step 1, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (17.3 mg, yield 59%) was obtained in the same manner as in Example 31 except that 3-(4-cyanophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate in Step 1, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (16.1 mg, yield 50%) was obtained in the same manner as in Example 31 except that 3-(4-cyanophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and ethyl iodide was used instead of iodomethane in Step 1, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (15.5 mg, yield 51%) was obtained in the same manner as in Example 31 except that 3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate in Step 1.
  • a title compound (15.3 mg, yield 57%) was obtained in the same manner as in Example 31 except that 3-(4-cyanophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate in Step 1.
  • a title compound (15.8 mg, yield 55%) was obtained in the same manner as in Example 31 except that 3-(4-chlorophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and ethyl iodide was used instead of iodomethane in Step 1.
  • a title compound (18.6 mg, yield 59%) was obtained in the same manner as in Example 31 except that 3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and ethyl iodide was used instead of iodomethane in Step 1.
  • a title compound (14.3 mg, yield 51%) was obtained in the same manner as in Example 31 except that 3-(4-cyanophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and ethyl iodide was used instead of iodomethane in Step 1.
  • a title compound (14.9 mg, yield 49%) was obtained in the same manner as in Example 31 except that 3-(4-cyanophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and ethyl iodide was used instead of iodomethane in Step 1, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (13.4 mg, yield 47%) was obtained in the same manner as in Example 31 except that 3-phenyl-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and ethyl iodide was used instead of iodomethane in Step 1, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (14.0 mg, yield 42%) was obtained in the same manner as in Example 31 except that 3-phenyl-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and benzyl bromide was used instead of iodomethane in Step 1, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (15.9 mg, yield 50%) was obtained in the same manner as in Example 31 except that 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and (2,2,2-trifluoroethyl)iodide was used instead of iodomethane in Step 1.
  • a title compound (17.8 mg, yield 52%) was obtained in the same manner as in Example 31 except that 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate, and (2,2,2-trifluoroethyl)iodide was used instead of iodomethane in Step 1, and 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3.
  • a title compound (11.5 mg, yield 61%) was obtained in the same manner as in Example 1 except that 5-methylisoxazole-3-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (17.5 mg, yield 63%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-(4-fluorophenyl)isoxazole-3-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (16.3 mg, yield 56%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and of 5-(4-chlorophenyl)isoxazole-3-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.1 mg, yield 51%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 3-(4-fluorophenyl)isoxazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (11.4 mg, yield 57%) was obtained in the same manner as in Example 1 except that 3,5-dimethyl-1H-pyrazole-4-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (9.7 mg, yield 55%) was obtained in the same manner as in Example 1 except that 1H-imidazole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.2 mg, yield 52%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-methyl-2-phenyloxazole-4-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (12.0 mg, yield 63%) was obtained in the same manner as in Example 1 except that thiazole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (13.5 mg, yield 49%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 4-phenylthiazole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (9.0 mg, yield 47%) was obtained in the same manner as in Example 1 except that thiazole-4-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (11.6 mg, yield 42%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-phenylthiazole-4-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (13.4 mg, yield 51%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-phenyloxazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.4 mg, yield 57%) was obtained in the same manner as in Example 1 except that 2-(4-fluorophenyl)oxazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.7 mg, yield 55%) was obtained in the same manner as in Example 1 except that 2-(3,4-difluorophenyl)oxazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (16.6 mg, yield 57%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-(3,4-difluorophenyl)oxazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (16.1 mg, yield 55%) was obtained in the same manner as in Example 1 except that 2-(4-(trifluoromethyl)phenyl)oxazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (18.7 mg, yield 59%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-(4-(trifluoromethyl)phenyl)oxazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (15.7 mg, yield 63%) was obtained in the same manner as in Example 1 except that 4-methyl-2-phenyloxazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (13.4 mg, yield 49%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 4-methyl-2-phenyloxazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (13.6 mg, yield 42%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-([1,1'-biphenyl]-3-yl)oxazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (10.1 mg, yield 50%) was obtained in the same manner as in Example 1 except that 4-methylthiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (16.1 mg, yield 57%) was obtained in the same manner as in Example 1 except that 2-((t-butoxycarbonyl)amino)thiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.3 mg, yield 59%) was obtained in the same manner as in Example 1 except that 4-(difluoromethyl)-2-methylthiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (9.9 mg, yield 42%) was obtained in the same manner as in Example 1 except that 2-(ethylamino)-4-methylthiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (12.6 mg, yield 52%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-chlorothiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (11.5 mg, yield 51%) was obtained in the same manner as in Example 1 except that 2-methoxy-4-methylthiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.1 mg, yield 57%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-cyclopropylthiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (16.2 mg, yield 56%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-(4-fluorophenyl)thiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (15.5 mg, yield 51%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-(4-chlorophenyl)thiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (17.4 mg, yield 57%) was obtained in the same manner as in Example 1 except that 2-(4-(trifluoromethyl)phenyl)thiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (15.2 mg, yield 55%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-phenylthiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (19.5 mg, yield 59%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-(4-(trifluoromethyl)phenyl)thiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.2 mg, yield 49%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-(3-fluorophenyl)thiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.3 mg, yield 47%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-(2,4-difluorophenyl)thiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (12.8 mg, yield 42%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-(3,4-difluorophenyl)thiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (16.0 mg, yield 51%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-(4-chlorophenyl)-4-methylthiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (16.1 mg, yield 57%) was obtained in the same manner as in Example 1 except that 2-(4-cyanophenyl)-4-methylthiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (17.4 mg, yield 55%) was obtained in the same manner as in Example 1 except that 4-methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (16.2 mg, yield 59%) was obtained in the same manner as in Example 1 except that 4-ethyl-2-phenylthiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (20.4 mg, yield 57%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 2-(4-chlorophenyl)-4-(trifluoromethyl)thiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (21.1 mg, yield 55%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 4-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)thiazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.2 mg, yield 52%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (12.2 mg, yield 49%) was obtained in the same manner as in Example 1 except that 1-methyl-3-phenyl-1H-1,2,4-triazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (12.9 mg, yield 47%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 1-methyl-3-phenyl-1H-1,2,4-triazole-5-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (11.8 mg, yield 42%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 1-methyl-1H-indole-3-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (10.8 mg, yield 50%) was obtained in the same manner as in Example 1 except that 1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (11.8 mg, yield 51%) was obtained in the same manner as in Example 1 except that 6-fluoro-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (13.9 mg, yield 57%) was obtained in the same manner as in Example 1 except that 7-chloro-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (13.7 mg, yield 56%) was obtained in the same manner as in Example 1 except that 6-chloro-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (12.4 mg, yield 51%) was obtained in the same manner as in Example 1 except that 4-chloro-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (13.9 mg, yield 57%) was obtained in the same manner as in Example 1 except that 3-chloro-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (12.5 mg, yield 55%) was obtained in the same manner as in Example 1 except that 1-methyl-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (11.8 mg, yield 49%) was obtained in the same manner as in Example 1 except that 5-fluoro-1-methyl-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (11.3 mg, yield 47%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (10.7 mg, yield 42%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 6-fluoro-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (12.8 mg, yield 51%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 1-methyl-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (15.3 mg, yield 57%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 3-chloro-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.7 mg, yield 55%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 4-chloro-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (15.8 mg, yield 59%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 6-chloro-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (15.0 mg, yield 56%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 7-chloro-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (13.0 mg, yield 51%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-fluoro-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (15.3 mg, yield 57%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-chloro-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.5 mg, yield 55%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-methoxy-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (12.5 mg, yield 47%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methoxy-pyridin-3ylhydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine, and 5-fluoro-1-methyl-1H-indole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • a title compound (14.5 mg, yield 56%) was obtained in the same manner as in Example 1 except that 1-methyl-1H-benzofuro[3,2-b]pyrrole-2-carboxylic acid was used instead of 4-(2-methylthiazol-4-yl)-1H-pyrrole-2-carboxylic acid.
  • Step 2 Preparation of t-butyl (5-fluoro-6-methoxypyridin-3-yl)(4-oxo-2-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)carbamate
  • the antifungal activities of the compounds of the present invention were evaluated using Candida albicans as a yeast fungus, and Aspergillus fumigatus as a filamentous fungus.
  • Candida albicans as a yeast fungus
  • Aspergillus fumigatus as a filamentous fungus.
  • the above fungi used were all purchased from American Type Culture Collection (ATCC).
  • the strains used in the experiment were inoculated into a Sabouraud dextrose agar medium, and then cultured at 35°C for a sufficient period of time, e.g., 24 hours for Candida albicans , and about 7 days for Aspergillus fumigatus .
  • a sufficient period of time e.g. 24 hours for Candida albicans
  • Aspergillus fumigatus about 7 days for Aspergillus fumigatus .
  • As for Candida albicans about 5 to 7 single colonies were taken from the cultured medium, sufficiently suspended in 1 ml of 0.85% sterile saline solution, and adjusted to have an optical density of from 0.095 to 0.107 at 530 nm.
  • a preparation of a strain diluent was diluted in Roswell park memorial institute (RPMI) 1640 medium at a 1:10 ratio, and the resultant was diluted again at a 1:100 ratio to obtain an inoculation preparation for Candida albicans with a concentration of from 1.0 ⁇ 10 3 to 5.0 ⁇ 10 3 CFU/mL.
  • Aspergillus fumigatus the cultured Sabouraud dextrose agar was added with 1 mL of 0.2% Tween 20 diluted with 0.85% sterile saline solution, and then the plate was shaken to detach conidium from the plate. The solution collected from the plate surface was transferred into a sterile tube, and placed at room temperature for 5 minutes to sediment heavy substances.
  • the resulting supernatant was transferred into the sterile tube, sufficiently suspended for about 15 seconds, and a strain diluent was prepared with a concentration of from 0.4 ⁇ 10 6 to 5.0 ⁇ 10 6 CFU/mL using a hemocytometer.
  • the thus prepared strain diluent was diluted in RPMI 1640 medium at a 1:100 ratio to obtain an inoculation preparation for Aspergillus fumigatus .
  • Candida albicans was cultured at 35°C for 24 hours and Aspergillus fumigatus was cultured at 35°C for 48 hours, and the concentrations, at which growth is inhibited by 80% or 50% compared to a negative control group, were determined using alama blue color developing reagent. All experiments were repeated twice for each concentration, and the results of antifungal activities (MIC 80 MIC 50 ⁇ g/mL) are shown in Tables 1 to 4(In the Tables 1 to 4 below, the mark of '-' means that it did not measure.).
  • Example No. Candida albicans MIC 80 Aspergillusfumigatus MIC 50 1 0.2 - 21 0.14 - 2 0.1 - 22 0.13 - 3 0.2 - 23 0.12 - 4 0.1 - 24 0.12 - 5 1.2 - 25 0.14 - 6 0.1 0.5 26 ⁇ 0.01 - 7 0.1 - 27 0.03 - 8 0.1 0.5 28 0.02 0.3 9 0.01 - 29 0.02 0.6 10 0.1 - 30 0.03 - 11 0.02 - 31 0.1 - 12 0.02 1.2 32 0.1 1.0 13 0.01 0.6 33 0.1 0.5 14 0.04 1.3 34 0.07 - 15 0.16 1.2 35 0.04 1.1 16 0.1 - 36 0.02 0.6 17 0.03 - 37 0.1 - 18 0.1 - 38 0.1 - 19 0.06 - 39 0.1 0.5 20 0.13 - 40 0.1 0.6
  • Example No. Candida albicans MIC 80 Aspergillusfumigatus MIC 50 41 0.1 0.6 61 ⁇ 0.01 0.3 42 0.04 1.3 62 0.1 - 43 0.1 - 63 0.07 - 44 0.1 1.2 64 0.14 - 45 0.04 0.6 65 0.14 - 46 ⁇ 0.01 0.6 66 0.8 - 47 0.04 - 67 0.2 - 48 0.02 0.3 68 0.1 - 49 0.04 0.6 69 0.1 - 50 ⁇ 0.01 - 70 0.02 0.3 51 0.07 - 71 0.1 - 52 0.07 - 72 0.03 - 53 0.26 - 73 0.1 - 54 0.07 - 74 0.1 - 55 0.01 - 75 0.03 0.5 56 0.07 - 76 0.1 - 57 0.07 - 77 0.13 - 58 0.03 - 78 0.04 - 59 ⁇

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Abstract

L'invention porte sur un composé ayant une excellente activité antifongique, sur une composition le contenant, et sur son utilisation pour la prévention et le traitement de maladies infectieuses fongiques.
PCT/KR2014/010551 2013-11-05 2014-11-05 Nouveau composé, procédé de préparation de celui-ci, et composition antifongique le comprenant WO2015069011A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104926738A (zh) * 2015-06-08 2015-09-23 南京农业大学 一类1,2,3-***-4-酰肼衍生物在制备农用杀菌剂中的应用

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010078906A2 (fr) * 2008-12-18 2010-07-15 Bayer Cropscience Ag Hydrazides, procédé permettant leur préparation et leur utilisation en tant qu'herbicides et insecticides
WO2012046050A1 (fr) * 2010-10-07 2012-04-12 Astrazeneca Ab Nouvelles combinaisons

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150027922A (ko) * 2013-09-04 2015-03-13 주식회사 대웅제약 신규한 항진균성 피리디닐하이드라자이드 유도체
KR102076820B1 (ko) * 2013-10-21 2020-02-13 주식회사 대웅테라퓨틱스 신규한 항진균성 옥소다이하이드로피리딘카보하이드라자이드 유도체

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010078906A2 (fr) * 2008-12-18 2010-07-15 Bayer Cropscience Ag Hydrazides, procédé permettant leur préparation et leur utilisation en tant qu'herbicides et insecticides
WO2012046050A1 (fr) * 2010-10-07 2012-04-12 Astrazeneca Ab Nouvelles combinaisons

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
0. V. SURIKOVA ET AL.: "Synthesis and antifungal activity of 2-(3,3- dimethyl-1,2,3,4-tetrahydroquinolin-1-idene)-2-oxopropanoic acid amides and hydrazides", PHARMACEUTICAL CHEMISTRY JOURNAL, vol. 44, no. 2, 2010, pages 58 - 60 *
T. CHANDRASEKHAR ET AL.: "Synthesis and biological evaluation of some new aryl acid N'-(1H-indazole-3-carbonyl)-hydrazide derivatives", J. CHEMICAL PHARMACEUTICAL RES., vol. 4, no. 5, 2012, pages 2795 - 2802 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104926738A (zh) * 2015-06-08 2015-09-23 南京农业大学 一类1,2,3-***-4-酰肼衍生物在制备农用杀菌剂中的应用
CN104926738B (zh) * 2015-06-08 2017-05-24 南京农业大学 一类1,2,3‑***‑4‑酰肼衍生物在制备农用杀菌剂中的应用

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