WO2015034271A1 - Novel antifungal pyridinylhydrazide derivatives - Google Patents

Novel antifungal pyridinylhydrazide derivatives Download PDF

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Publication number
WO2015034271A1
WO2015034271A1 PCT/KR2014/008287 KR2014008287W WO2015034271A1 WO 2015034271 A1 WO2015034271 A1 WO 2015034271A1 KR 2014008287 W KR2014008287 W KR 2014008287W WO 2015034271 A1 WO2015034271 A1 WO 2015034271A1
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Prior art keywords
fluoro
methoxypyridin
carbohydrazide
fluoropyridin
biphenyl
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PCT/KR2014/008287
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French (fr)
Inventor
Joon Seok Park
Youn Jung Yoon
Chang Min Park
Yun Soo Na
Min Jae Cho
Ho Bin Lee
Mi Ryeong Han
Yeon Jung Park
Ji Duck Kim
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Daewoong Pharmaceutical Co., Ltd.
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Publication of WO2015034271A1 publication Critical patent/WO2015034271A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C07D213/77—Hydrazine radicals
    • 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
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • 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
    • 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
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—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 chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates, in general, to a novel pyridinylhydrazide derivative with excellent antifungal activities, a method for preparing the same, an antifungal composition containing the same, and its use for the prevention or 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 antifungals, amphotericin B or azole antifungals such as fluconazole, itraconazole, voriconazole, posaconazole, etc.
  • polyene antifungals amphotericin B or azole antifungals such as fluconazole, itraconazole, voriconazole, posaconazole, etc.
  • azole-resistant bacteria has become a problem.
  • cyclic hexapeptide type echinocandins from natural products caspofungin, micafungin, and anidulafungin
  • 1,3- ⁇ -glucan synthase inhibitors 1,3- ⁇ -glucan synthase inhibitors.
  • 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 rapid and strong actions. Amphotericin B and echinocandins as fungicidal agents are known to be effective for the treatment of systemic mycoses. However, these fungicidal agents have only a limited use as they can be used in the form of injection only, and thus there is an unmet need for the development of a fungicidal agent for oral administration.
  • an objective of the present invention is to provide a novel pyridinylhydrazide derivative with an excellent antifungal activity, and a pharmaceutically acceptable salt thereof.
  • Another objective of the present invention is to provide a method for preparing the above compound.
  • a further objective of the present invention is to provide a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof.
  • a further objective of the present invention is to provide a pharmaceutical composition for treating or preventing fungal infections comprising the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a further objective of the present invention is to provide a method for treating or preventing fungal infections in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound represented by Chemical Formula 1 below, or a pharmaceutically acceptable salt thereof:
  • R 1 is H; or halogen
  • R 2 is halogen; or C 1 -4 alkoxy, and
  • R 3 is 1,3-benzodioxolyl; 2,3-dihydrobenzo[1,4]dioxinyl; biphenyl; naphthyl; isoquinolinyl; phenyl; pyridinyl; pyrimidinyl; tetrazolo[1,5-a]pyridinyl; pyridazinyl; dibenzofuranyl; or fluorenyl, wherein R 3 is unsubstituted; or substituted with one to three substituents selected from the group consisting of halogen; C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; nitro; dimethylamino; thiazolyl; pyrazolyl unsubstituted or substituted with one or two C 1-4 alkyl groups; tetrazolyl; phenyl unsubstituted or substituted with one or two of the same or different groups selected from C 1 -4
  • R 1 is H; or fluoro.
  • R 2 is fluoro; or methoxy.
  • R 1 is fluoro
  • R 2 is methoxy
  • R 1 is H
  • R 2 is fluoro
  • R 3 is unsubstituted benzo[1,3]dioxolyl; 2,3-dihydrobenzo[b][1,4]dioxinyl; isoquinolinyl; tetrazolo[1,5-a]pyridinyl; pyridazinyl; or fluorenyl.
  • R 3 is biphenyl, wherein the biphenyl is unsubstituted or substituted with one to three of the same or different groups selected from halogen, hydroxy, methoxy, methyl, and .
  • R 3 is naphthyl, wherein the naphthyl is unsubstituted or substituted with one or two of the same or different groups selected from methoxy and dimethylamino.
  • R 3 is phenyl, wherein the phenyl is unsubstituted or substituted with one to three of the same or different groups selected from halogen, methyl, trifluoromethyl, cyano, methoxy, nitro, dimethylamino, thiazolyl, pyrazolyl, tetrazolyl, phenoxy, pyrrolyl, benzoyl, hydroxy(phenyl)methyl, benzyloxy, and hydroxydiphenylmethyl.
  • R 3 is pyridinyl, wherein the pyridinyl is unsubstituted or substituted with one to three of the same or different groups selected from methoxy; fluoro; methyl; and phenyl unsubstituted or substituted with halogen, trifluoromethyl or cyano.
  • R 3 is pyridinyl, wherein the pyridinyl is substituted with halophenyl; halophenyl and methoxy; (trifluoromethyl)phenyl and methoxy; or cyanophenyl and methoxy.
  • R 3 is pyrimidinyl, wherein the pyrimidinyl is unsubstituted or substituted with one or two of the same or different groups selected from piperidinyl; methyl; phenyl unsubstituted or substituted with halogen; and methoxy.
  • R 3 is dibenzofuranyl, wherein the dibenzofuranyl is unsubstituted or substituted with hydroxy.
  • 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 inorganic acids such as hydrochloric acid and nitric acid; sulfonic acid such as methanesulfonic acid; or an acid addition salt formed by 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 comprising a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition for treating or preventing fungal infections comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for treating or preventing fungal infections in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
  • 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 for treating or preventing fungal infections 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 pharmaceutical composition may include a pharmaceutically acceptable carrier or vehicle as well.
  • the pharmaceutical 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 pharmaceutical 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, tragacanth, methylcellulose, sodium carboxymethyl cellulose or polyvinyl pyrrolidone, 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
  • the dose of the active ingredient including the compound of the present invention may vary depending on various factors such as the subject to be treated, severity of diseases, routes of administration, sex, and physician's prescription, and the effective dose may be easily 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 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.
  • the present invention provides a method for preparing a compound represented by Chemical Formula 1, the method comprising:
  • R 1 , R 2 , and R 3 are the same as defined above.
  • R 1 , R 2 , and R 3 are the same as defined above, and each reaction is preferably performed in a reaction solvent.
  • the compounds represented by Chemical Formula 2 and Chemical Formula 6, being known compounds, can be manufactured by conventional methods, and may be commercially available.
  • the reaction solvent is a polar organic solvent, and more preferably, a polar solvent such as tert -butanol, acetonitrile, dioxane or tetrahydrofuran.
  • a compound represented by Chemical Formula 4 may be prepared in the form of a hydrazide derivative by reacting a compound represented by Chemical Formula 3 with hydroxylamine in the presence of a base.
  • the hydroxylamine is activated in the presence of a base.
  • the reaction solvent to be used is a polar organic solvent, and more preferably, a polar solvent such as dimethylformamide, dioxane or tetrahydrofuran.
  • the base to be used in the present invention may be a conventional inorganic base or organic base, for example, an inorganic base such as sodium hydride (NaH) or sodium methoxide (MeONa), or a conventional organic base such as triethylamine or n-butyl lithium.
  • an inorganic base such as sodium hydride (NaH) or sodium methoxide (MeONa)
  • a conventional organic base such as triethylamine or n-butyl lithium.
  • a compound represented by Chemical Formula 5 may be prepared by reacting a compound represented by Chemical Formula 4 with an acid to remove a protecting group.
  • the acid is preferably hydrochloric acid (HCl).
  • the prepared compound of Chemical Formula 5 is present in the form of a salt with 2 equivalents of HCl.
  • a compound represented by Chemical Formula 1 of the present invention may be finally prepared by reacting a compound represented by Chemical Formula 5 with a compound represented by Chemical Formula 6.
  • the compound represented by Chemical Formula 1 may be prepared at a reaction temperature of from 0°C to 50°C, more preferably from 50°C to room temperature and under stirring condition for from 30 minutes to 24 hours.
  • the present invention provides a compound represented by Chemical Formula 5 below, an intermediate for preparing a pyridinylhydrazide derivative of the present invention.
  • R 1 and R 2 are the same as defined above.
  • the present invention provides a method for preparing a compound represented by Chemical Formula 1 above (a compound represented by Chemical Formula 1, wherein R 1 is H, and R 2 is F), as shown in Reaction Scheme 2 below.
  • R 3 is the same as defined above, and the above reaction is preferably performed in a reaction solvent, more specifically, in a polar organic solvent such as methanol, ethanol, acetonitrile, dimethoxyethane, dimethylformamide, dimethylsulfoxide, or tetrahydrofuran.
  • a reaction solvent more specifically, in a polar organic solvent such as methanol, ethanol, acetonitrile, dimethoxyethane, dimethylformamide, dimethylsulfoxide, or tetrahydrofuran.
  • a compound represented by Chemical Formula 1 (wherein R 1 is H, and R 2 is F) may be prepared by reacting a compound represented by Chemical Formula 6 with a compound represented by Chemical Formula 7.
  • the carboxylic acid of Chemical Formula 6 may be used in the form of a methyl or ethyl carboxylate or acyl chloride, according to a conventional method.
  • a compound represented by Chemical Formula 1 (wherein R 1 is H, and R 2 is F) may be prepared at a reaction temperature of from 0°C to 50°C, more preferably from 50°C to room temperature and under stirring condition for from 30 minutes to 24 hours.
  • the novel antifungal pyridinylhydrazide 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 pyridinylhydrazide derivative of the present invention is advantageous in that it can be orally administered unlike other fungicidal agents.
  • Step 1 Preparation of t - butyl (5- fluoro -6- methoxypyridin -3- yl ) carbamate
  • Step 2 Preparation of t- butyl 1-(5- fluoro -6- methoxypyridin -3- yl ) hydrazine -1- carboxylate
  • N,N -dimethylformamide (21 ml, 1.0 M) was added to 60% NaH (1.8 g, 51.6 mmol), and maintained under the nitrogen condition.
  • the t-butyl (5-fluoro-methoxypyridin-3-yl) carbamate (5 g, 20.6 mmol) obtained in Step 1 was dissolved in N,N -dimethylformamide (3 ml, minimum amount), and added dropwise to the previously prepared mixed solution, and stirred. After 30 minutes, P,P -diphenylphosphinic amide (8.7 g, 37.1 mmol) was added thereto at once, N,N -dimethylformamide (21 ml) was further added thereto, and the mixed solution was stirred.
  • Step 3 Preparation of 5- fluoro -6- methoxy - pyridin -3- yl hydrazine hydrochloride
  • Step 4 Preparation of N ' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
  • Example 58 Preparation of 4'- chloro -6- fluoro -N'-(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
  • Example 80 Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl ) tetrazolo [1,5-a] pyridine -6- carbohydrazide
  • 2-fluoro-5-hydrazinylpyridine (17.4 mg, 0.08 mmol) and benzoic acid (9.8 mg, 0.08 mmol) were dissolved in 1 ml of N,N -dimethylformamide.
  • HBTU (45.4 mg, 0.12 mmol) and DIPEA (34.8 ⁇ l, 0.2 mmol) were added thereto at room temperature, and the reactants were stirred at room temperature for 6 hours. Upon completion of the reaction, the solvent was removed, and the resultant was diluted with ethylacetate, and washed with saturated sodium chloride.
  • Example 85 The title compound (15.6 mg, yield 71%) was obtained in the same manner as in Example 85 except that 4-cyano-3-fluorobenzoic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (16.7 mg, yield 79%) was obtained in the same manner as in Example 85 except that 4-fluoro-3-methylbenzoic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (19.1 mg, yield 76%) was obtained in the same manner as in Example 85 except that 4-methyl-3-(trifluoromethyl)benzoic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (18.0 mg, yield 82%) was obtained in the same manner as in Example 85 except that 3-cyano-4-fluorobenzoic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (14.9 mg, yield 61%) was obtained in the same manner as in Example 85 except that 3-(dimethylamino)-4-methoxybenzoic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (11.8 mg, yield 63%) was obtained in the same manner as in Example 85 except that pyrimidine-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (12.5 mg, yield 67%) was obtained in the same manner as in Example 85 except that pyrimidine-2-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (12.1 mg, yield 65%) was obtained in the same manner as in Example 85 except that pyrimidine-5-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (11.2 mg, yield 60%) was obtained in the same manner as in Example 85 except that pyridazine-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (18.9 mg, yield 69%) was obtained in the same manner as in Example 85 except that 4'-chloro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (15.7 mg, yield 57%) was obtained in the same manner as in Example 85 except that 5-(4-chlorophenyl)nicotinic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (15.7 mg, yield 57%) was obtained in the same manner as in Example 85 except that 6-phenylpyrimidine-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 102 Preparation of 6-(4- fluorophenyl )- N' -(6- fluoropyridin -3- yl ) pyrimidine -4- carbohydrazide
  • Example 85 The title compound (17.6 mg, yield 67%) was obtained in the same manner as in Example 85 except that 6-(4-fluorophenyl)pyrimidine-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 104 Preparation of 4'- chloro -6- fluoro - N '-(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
  • Example 85 The title compound (17.0 mg, yield 59%) was obtained in the same manner as in Example 85 except that 4'-chloro-6-fluoro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 105 Preparation of 6- chloro - N ' -(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
  • Example 106 Preparation of 5-(4- fluorophenyl )- N ' -(6- fluoropyridin -3- yl )-6- methoxynicotinohydrazide
  • Example 85 The title compound (19.7 mg, yield 66%) was obtained in the same manner as in Example 85 except that 5-(4-chlorophenyl)-6-methoxynicotinic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (16.7 mg, yield 68%) was obtained in the same manner as in Example 85 except that [1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 112 Preparation of 4'- fluoro - N '-(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-4- carbohydrazide
  • Example 85 The title compound (17.7 mg, yield 68%) was obtained in the same manner as in Example 85 except that 4'-fluoro-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (18.1 mg, yield 66%) was obtained in the same manner as in Example 85 except that 4'-chloro-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (15.9 mg, yield 61%) was obtained in the same manner as in Example 85 except that 2-fluoro-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (15.2 mg, yield 59%) was obtained in the same manner as in Example 85 except that 2-methyl-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (18.4 mg, yield 71%) was obtained in the same manner as in Example 85 except that 4-phenoxybenzoic acid was used instead of benzoic acid in Example 85.
  • Example 1 50 mg of the compound prepared in Example 1, was granulated, in combination with 20 mg of magnesium stearate, using 35 mg of soluble starch and dried. The granules were then mixed with 65 mg of lactose and 30 mg of corn starch using a mechanical shaker and a mixer for 30 minutes. The resulting mixture was compressed and formulated into tablets.
  • 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.
  • the prepared strain dilutions were diluted in RPMI (Roswell park memorial institute) 1640 medium at a 1:10 ratio, and the resultant was diluted again at a 1:100 ratio to prepare inoculums having a cell density of from 1.0 x 10 3 to 5.0 x 10 3 CFU/ml.
  • Aspergillus fumigatus to the cultured Sabouraud dextrose agar was added 1 mL of 0.2% Tween 20 diluted with 0.85% sterile saline solution, and then the plate was shaken to detach conidiums 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 such as medium.
  • strain dilutions were prepared with a cell density of from 0.4 x 10 6 to 5.0 x 10 6 CFU/ml using a hemocytometer.
  • the thus prepared strain dilutions were diluted in RPMI 1640 medium at a 1:100 ratio to obtain inoculums 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 Alamar blue color developing reagent. All experiments were repeated twice for each concentration, and the results of antifungal activities (MIC 80 and MIC 50 ⁇ g/ml) are shown in Tables 1 to 3.
  • Example No. Candida albicans MIC 80 Aspergillus fumigatus MIC 50 1 0.03 0.4 21 0.07 - 2 0.03 - 22 0.12 - 3 0.03 - 23 0.04 0.3 4 0.03 - 24 0.03 0.6 5 0.03 - 25 0.04 0.3 6 0.03 - 26 0.08 1.3 7 0.03 - 27 ⁇ 0.01 - 8 0.03 - 28 0.06 1.0 9 0.03 - 29 0.06 - 10 0.03 - 30 0.03 0.5 11 0.03 - 31 0.03 0.5 12 0.03 - 32 0.03 - 13 0.06 - 33 0.04 - 14 0.03 - 34 0.06 - 15 0.06 - 35 0.07 - 16 0.03 - 36 0.03 - 17 0.06 - 37 0.25 - 18 0.06 - 38 0.04 - 19 0.03 - 39 0.03 - 20
  • Example No. Candida albicans MIC 80 Aspergillus fumigatus MIC 50 41 0.04 - 61 0.07 - 42 0.12 - 62 0.06 - 43 0.05 0.4 63 0.29 - 44 0.02 - 64 0.01 0.2 45 0.04 - 65 ⁇ 0.01 0.3 46 0.03 - 66 0.02 0.3 47 0.26 0.5 67 0.04 0.7 48 ⁇ 0.01 0.6 68 0.04 0.6 49 0.02 - 69 0.53 1.1 50 ⁇ 0.01 0.3 70 0.02 1.1 51 ⁇ 0.01 0.3 71 ⁇ 0.01 - 52 ⁇ 0.01 0.6 72 0.02 0.3 53 ⁇ 0.01 - 73 0.03 - 54 0.04 - 74 0.03 0.3 55 ⁇ 0.01 0.3 75 0.02 0.6 56 ⁇ 0.01 0.3 76 0.03 0.3 57 ⁇
  • Example No. Candida albicans MIC 80 Aspergillus fumigatus MIC 50 81 0.15 - 106 0.14 0.6 82 0.07 - 107 0.04 0.6 83 ⁇ 0.01 - 108 0.04 0.6 84 ⁇ 0.01 - 109 0.07 0.6 85 0.05 0.4 110 0.07 0.5 86 0.11 0.9 111 0.06 1.0 87 0.01 0.01 112 0.13 1.0 88 0.12 1.0 113 0.27 1.1 89 0.11 - 114 0.13 0.5 90 0.06 - 115 0.06 - 91 0.09 - 116 0.12 0.5 92 0.09 - 117 0.13 1.1 93 0.09 - 118 0.12 0.5 94 0.18 - 119 0.06 - 95 0.06 0.9 120 0.13 0.5 96 0.06 1.0 121 0.13 0.5 97
  • the compounds of the present invention have exhibited significantly excellent antifungal effects compared to the traditional antifungal agents such as caspofungin and fluconazole.
  • Test Example 2 In vitro fungicidal activity test (Minimum Fungicidal Concentration, MFC )
  • the evaluations of the fungicidal activity of Candida albicans were performed using the test plate already completed of antifungal activity, from the highest concentration of a given sample to the concentration right next to the concentration determined to be MIC. Test solutions at each concentration were pipetted about 5 times, all were collected (about a total of 225 ⁇ L), and added into a 12-well Sabouraud dextrose agar plate. The test plate was cultured at 35°C for 48 hours, and the minimum concentration at which no fungal growth was observed with the naked eye. The result of fungicidal activity (MFC ⁇ g/mL) is shown in Table 4.
  • the compounds of the present invention have exhibited a significantly excellent fungicidal effect over the traditional fungicides such as caspofungin and fluconazole.

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Abstract

The present invention relates to novel pyridinylhydrazide derivatives and a method for manufacturing the same. The pyridinylhydrazide derivatives of the present invention have excellent antifungal and fungicidal activities, and thus will be useful for the prevention and treatment of various fungal infections. Additionally, the pyridinylhydrazide derivatives of the present invention, unlike other fungicidal preparations, can be orally administered.

Description

NOVEL ANTIFUNGAL PYRIDINYLHYDRAZIDE DERIVATIVES
The present invention relates, in general, to a novel pyridinylhydrazide derivative with excellent antifungal activities, a method for preparing the same, an antifungal composition containing the same, and its use for the prevention or treatment of fungal infectious diseases.
Recently, there have been a growing number of reports on serious fungal infections in immuno-compromised patients such as cancer patients undergoing chemotherapy, organ transplant recipients, AIDS patients, etc. Most of the fungal infections are known to be caused by opportunistic pathogens such as Candida spp., Aspergillus spp. and Cryptococcus neoformans. Accordingly, for the future aged society, development of medical countermeasures for emerging infectious diseases caused by pathogens including resistant bacteria will become one of the important issues.
The number of 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 antifungals, amphotericin B or azole antifungals such as fluconazole, itraconazole, voriconazole, posaconazole, etc. However, the appearance of azole-resistant bacteria has become a problem. Recently, cyclic hexapeptide type echinocandins from natural products (caspofungin, micafungin, and anidulafungin) have been developed as a new class of antifungals, 1,3-β-glucan synthase inhibitors.
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 rapid and strong actions. Amphotericin B and echinocandins as fungicidal agents are known to be effective for the treatment of systemic mycoses. However, these fungicidal agents have only a limited use as they can be used in the form of injection only, and thus there is an unmet need for the development of a fungicidal agent for oral administration.
Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an objective of the present invention is to provide a novel pyridinylhydrazide derivative with an excellent antifungal activity, and a pharmaceutically acceptable salt thereof.
Another objective of the present invention is to provide a method for preparing the above compound.
A further objective of the present invention is to provide a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof.
A further objective of the present invention is to provide a pharmaceutical composition for treating or preventing fungal infections comprising the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
A further objective of the present invention is to provide a method for treating or preventing fungal infections in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof.
In order to accomplish the above objectives, the present invention provides a compound represented by Chemical Formula 1 below, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
Figure PCTKR2014008287-appb-I000001
wherein, in Chemical Formula 1,
R1 is H; or halogen,
R2 is halogen; or C1 -4 alkoxy, and
R3 is 1,3-benzodioxolyl; 2,3-dihydrobenzo[1,4]dioxinyl; biphenyl; naphthyl; isoquinolinyl; phenyl; pyridinyl; pyrimidinyl; tetrazolo[1,5-a]pyridinyl; pyridazinyl; dibenzofuranyl; or fluorenyl, wherein R3 is unsubstituted; or substituted with one to three substituents selected from the group consisting of halogen; C1-4 alkyl; C1-4 haloalkyl; cyano; C1-4 alkoxy; nitro; dimethylamino; thiazolyl; pyrazolyl unsubstituted or substituted with one or two C1-4 alkyl groups; tetrazolyl; phenyl unsubstituted or substituted with one or two of the same or different groups selected from C1 -4 alkyl, halogen, C1 -4 haloalkyl andcyano; phenoxy; pyrrolyl; piperidinyl; hydroxy; benzoyl; hydroxy(phenyl)methyl; benzyloxy; hydroxydiphenylmethyl; and
Figure PCTKR2014008287-appb-I000002
.
Preferably, R1 is H; or fluoro.
In a preferred embodiment, R2 is fluoro; or methoxy.
In a further preferred embodiment, R1 is fluoro, R2 is methoxy; or R1 is H, R2 is fluoro.
In another preferred embodiment, R3 is unsubstituted benzo[1,3]dioxolyl; 2,3-dihydrobenzo[b][1,4]dioxinyl; isoquinolinyl; tetrazolo[1,5-a]pyridinyl; pyridazinyl; or fluorenyl.
In a further preferred embodiment, R3 is biphenyl, wherein the biphenyl is unsubstituted or substituted with one to three of the same or different groups selected from halogen, hydroxy, methoxy, methyl, and
Figure PCTKR2014008287-appb-I000003
.
In a further preferred embodiment, R3 is naphthyl, wherein the naphthyl is unsubstituted or substituted with one or two of the same or different groups selected from methoxy and dimethylamino.
In still a further preferred embodiment, R3 is phenyl, wherein the phenyl is unsubstituted or substituted with one to three of the same or different groups selected from halogen, methyl, trifluoromethyl, cyano, methoxy, nitro, dimethylamino, thiazolyl, pyrazolyl, tetrazolyl, phenoxy, pyrrolyl, benzoyl, hydroxy(phenyl)methyl, benzyloxy, and hydroxydiphenylmethyl.
In still a further preferred embodiment, R3 is pyridinyl, wherein the pyridinyl is unsubstituted or substituted with one to three of the same or different groups selected from methoxy; fluoro; methyl; and phenyl unsubstituted or substituted with halogen, trifluoromethyl or cyano.
In still a further preferred embodiment, R3 is pyridinyl, wherein the pyridinyl is substituted with halophenyl; halophenyl and methoxy; (trifluoromethyl)phenyl and methoxy; or cyanophenyl and methoxy.
In still a further preferred embodiment, R3 is pyrimidinyl, wherein the pyrimidinyl is unsubstituted or substituted with one or two of the same or different groups selected from piperidinyl; methyl; phenyl unsubstituted or substituted with halogen; and methoxy.
In still a further preferred embodiment, R3 is dibenzofuranyl, wherein the dibenzofuranyl is unsubstituted or substituted with hydroxy.
Examples of the preferred compounds according to the present invention are as follows:
1) N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
2) 3-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
3) 4-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
4) 3-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
5) 4-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
6) 3-bromo-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
7) 4-bromo-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
8) N'-(5-fluoro-6-methoxypyridin-3-yl)-3-methylbenzohydrazide,
9) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-methylbenzohydrazide,
10) N'-(5-fluoro-6-methoxypyridin-3-yl)-3-(trifluoromethyl)benzohydrazide,
11) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-(trifluoromethyl)benzohydrazide,
12) 3-cyano-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
13) 4-cyano-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
14) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-methoxybenzohydrazide,
15) 6-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)nicotinohydrazide,
16) 6-bromo-N'-(5-fluoro-6-methoxypyridin-3-yl)nicotinohydrazide,
17) N'-(5-fluoro-6-methoxypyridin-3-yl)-6-(trifluoromethyl)nicotinohydrazide,
18) 6-cyano-N'-(5-fluoro-6-methoxypyridin-3-yl)nicotinohydrazide,
19) N'-(5-fluoro-6-methoxypyridin-3-yl)-2-methoxynicotinohydrazide,
20) N'-(5-fluoro-6-methoxypyridin-3-yl)-2-methoxypyrimidine-4-carbohydrazide,
21) 4-bromo-3-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
22) 4-cyano-3-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
23) 4-bromo-3-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
24) 3-bromo-4-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
25) 3-bromo-4-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
26) 3-bromo-N'-(5-fluoro-6-methoxypyridin-3-yl)-4-(trifluoromethyl)benzohydrazide,
27) 4-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-3-methylbenzohydrazide,
28) 4-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)-3-methylbenzohydrazide,
29) N'-(5-fluoro-6-methoxypyridin-3-yl)-3-methyl-4-nitrobenzohydrazide,
30) 4-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-3-(trifluoromethyl)benzohydrazide,
31) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzohydrazide,
32) N'-(5-fluoro-6-methoxypyridin-3-yl)-2,3-dimethoxybenzohydrazide,
33) 5-bromo-N'-(5-fluoro-6-methoxypyridin-3-yl)-2-methoxybenzohydrazide,
34) 4-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-3-nitrobenzohydrazide,
35) 3-(dimethylamino)-N'-(5-fluoro-6-methoxypyridin-3-yl)-4-methoxybenzohydrazide,
36) N'-(5-fluoro-6-methoxypyridin-3-yl)benzo[d][1,3]dioxole-5-carbohydrazide,
37) N'-(5-fluoro-6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide,
38) 6-bromo-5-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)picolinohydrazide,
39) 5-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-6-methylnicotinohydrazide,
40) 5-bromo-6-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)nicotinohydrazide,
41) 5-bromo-6-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)nicotinohydrazide,
42) 2-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)-6-methylisonicotinohydrazide,
43) N'-(5-fluoro-6-methoxypyridin-3-yl)pyrimidine-5-carbohydrazide,
44) 5-bromo-2,4-dichloro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
45) 5-bromo-2,4-difluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
46) N'-(5-fluoro-6-methoxypyridin-3-yl)-3,5-dimethoxy-4-methylbenzohydrazide,
47) N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
48) 3'-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
49) 2'-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
50) 4'-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
51) 2'-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
52) 3'-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
53) 4'-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
54) N'-(5-fluoro-6-methoxypyridin-3-yl)-2'-methoxy-[1,1-biphenyl]-3-carbohydrazide,
55) N'-(5-fluoro-6-methoxypyridin-3-yl)-3'-methoxy-[1,1-biphenyl]-3-carbohydrazide,
56) N'-(5-fluoro-6-methoxypyridin-3-yl)-4'-methoxy-[1,1-biphenyl]-3-carbohydrazide,
57) 6-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
58) 4'-chloro-6-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
59) 6-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
60) N'-(5-fluoro-6-methoxypyridin-3-yl)-3-(thiazole-2-yl)benzohydrazide,
61) 3-(3,5-dimethyl-1H-pyrazol-1-yl)-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
62) N'-(5-fluoro-6-methoxypyridin-3-yl)-3-(1H-tetrazol-1-yl)benzohydrazide,
63) 6-(4-chlorophenyl)-N'-(5-fluoro-6-methoxypyridin-3-yl)picolinohydrazide,
64) N'-(5-fluoro-6-methoxypyridin-3-yl)-5-(4-fluorophenyl)-6-methoxynicotinohydrazide,
65) 5-(4-chlorophenyl)-N'-(5-fluoro-6-methoxypyridin-3-yl)nicotinohydrazide,
66) 5-(4-chlorophenyl)-N'-(5-fluoro-6-methoxypyridin-3-yl)-6-methoxynicotinohydrazide,
67) N'-(5-fluoro-6-methoxypyridin-3-yl)-6-methoxy-5-(4-(trifluoromethyl)phenyl)nicotinohydrazide,
68) 5-(4-cyanophenyl)-N'-(5-fluoro-6-methoxypyridin-3-yl)-6-methoxynicotinohydrazide,
69) N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-4-carbohydrazide,
70) 2-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-4-carbohydrazide,
71) N'-(5-fluoro-6-methoxypyridin-3-yl)-2-methyl-[1,1-biphenyl]-4-carbohydrazide,
72) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-phenoxybenzohydrazide,
73) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-(1H-pyrrole-1-yl)benzohydrazide,
74) N'-(5-fluoro-6-methoxypyridin-3-yl)-2-phenylpyrimidine-5-carbohydrazide,
75) 2-(4-chlorophenyl)-N'-(5-fluoro-6-methoxypyridin-3-yl)pyrimidine-5-carbohydrazide,
76) N'-(5-fluoro-6-methoxypyridin-3-yl)-2-(piperidin-1-yl)pyrimidine-5-carbohydrazide,
77) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-2-phenylpyrimidine-5-carbohydrazide,
78) N'-(5-fluoro-6-methoxypyridin-3-yl)-2-naphthohydrazide,
79) N'-(5-fluoro-6-methoxypyridin-3-yl)isoquinoline-4-carbohydrazide,
80) N'-(5-fluoro-6-methoxypyridin-3-yl)tetrazolo[1,5-a]pyridine-6-carbohydrazide,
81) N'-(5-fluoro-6-methoxypyridin-3-yl)-4,7-dimethoxy-1-naphthohydrazide,
82) 4-(dimethylamino)-N'-(5-fluoro-6-methoxypyridin-3-yl)-1-naphthohydrazide,
83) N'3,N'3'-bis(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3,3'-dicarbohydrazide,
84) N'3,N'4'-bis(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3,4'-dicarbohydrazide,
85) N'-(6-fluoropyridin-3-yl)benzohydrazide,
86) 4-cyano-3-fluoro-N'-(6-fluoropyridin-3-yl)benzohydrazide,
87) 4-fluoro-N'-(6-fluoropyridin-3-yl)-3-methylbenzohydrazide,
88) N'-(6-fluoropyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzohydrazide,
89) 3-cyano-4-fluoro-N'-(6-fluoropyridin-3-yl)benzohydrazide,
90) 3-(dimethylamino)-N'-(6-fluoropyridin-3-yl)-4-methoxybenzohydrazide,
91) N'-(6-fluoropyridin-3-yl)pyrimidine-4-carbohydrazide,
92) N'-(6-fluoropyridin-3-yl)pyrimidine-2-carbohydrazide,
93) N'-(6-fluoropyridin-3-yl)pyrimidine-5-carbohydrazide,
94) N'-(6-fluoropyridin-3-yl)pyridazine-4-carbohydrazide,
95) N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
96) 4'-fluoro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
97) 4'-chloro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
98) 2',4'-difluoro-N'-(6-fluoropyridin-3-yl)-4-hydroxy-[1,1-biphenyl]-3-carbohydrazide
99) 6-(4-chlorophenyl)-N'-(6-fluoropyridin-3-yl)picolinohydrazide,
100) 5-(4-chlorophenyl)-N'-(6-fluoropyridin-3-yl)nicotinohydrazide,
101) N'-(6-fluoropyridin-3-yl)-6-phenylpyrimidine-4-carbohydrazide,
102) 6-(4-fluorophenyl)-N'-(6-fluoropyridin-3-yl)pyrimidine-4-carbohydrazide,
103) 6-fluoro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
104) 4'-chloro-6-fluoro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
105) 6-chloro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
106) 5-(4-fluorophenyl)-N'-(6-fluoropyridin-3-yl)-6-methoxynicotinohydrazide,
107) 5-(4-chlorophenyl)-N'-(6-fluoropyridin-3-yl)-6-methoxynicotinohydrazide,
108) N'-(6-fluoropyridin-3-yl)-6-methoxy-5-(4-(trifluoromethyl)phenyl)nicotinohydrazide,
109) 5-(4-cyanophenyl)-N'-(6-fluoropyridin-3-yl)-6-methoxynicotinohydrazide,
110) 3-benzoyl-N'-(6-fluoropyridin-3-yl)benzohydrazide,
111) N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-4-carbohydrazide,
112) 4'-fluoro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-4-carbohydrazide,
113) 4'-chloro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-4-carbohydrazide,
114) 2-fluoro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-4-carbohydrazide,
115) N'-(6-fluoropyridin-3-yl)-2-methyl-[1,1-biphenyl]-4-carbohydrazide,
116) N'-(6-fluoropyridin-3-yl)-2-phenylpyrimidine-5-carbohydrazide,
117) 2-(4-chlorophenyl)-N'-(6-fluoropyridin-3-yl)pyrimidine-5-carbohydrazide,
118) N'-(6-fluoropyridin-3-yl)-2-(piperidin-1-yl)pyrimidine-5-carbohydrazide,
119) N'-(6-fluoropyridin-3-yl)-4-methyl-2-phenylpyrimidine-5-carbohydrazide,
120) 4-benzoyl-N'-(6-fluoropyridin-3-yl)benzohydrazide,
121) N'-(6-fluoropyridin-3-yl)-4-(hydroxy(phenyl)methyl)benzohydrazide,
122) N'-(6-fluoropyridin-3-yl)-4-phenoxybenzohydrazide,
123) 4-(benzyloxy)-N'-(6-fluoropyridin-3-yl)benzohydrazide,
124) N'-(6-fluoropyridin-3-yl)-4-(hydroxydiphenylmethyl)benzohydrazide,
125) N'-(6-fluoropyridin-3-yl)-1-naphthohydrazide,
126) N'-(6-fluoropyridin-3-yl)-2-naphthohydrazide,
127) N'-(6-fluoropyridin-3-yl)-2-hydroxydibenzo[b,d]furan-3-carbohydrazide,
128) N'-(6-fluoropyridin-3-yl)-9H-fluorene-2-carbohydrazide, and
129) N'-(6-fluoropyridin-3-yl)-9H-fluorene-3-carbohydrazide.
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. Examples of 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. Examples of the salts are inorganic acids such as hydrochloric acid and nitric acid; sulfonic acid such as methanesulfonic acid; or an acid addition salt formed by an organic carbonic acid such as oxalic acid.
Additionally, the compound represented by Chemical Formula 1 of the present invention may include a hydrate and a solvate that can be manufactured therefrom.
Additionally, the present invention provides a pharmaceutical composition comprising a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof.
Further, the present invention provides a pharmaceutical composition for treating or preventing fungal infections comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
Further, the present invention provides a method for treating or preventing fungal infections in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
Because the compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof, and a solvate thereof have an excellent fungicidal activity along with an excellent antifungal activity, they 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.
Accordingly, the present invention provides a pharmaceutical composition for treating or preventing fungal infections 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.
In particular, the pharmaceutical composition may include a pharmaceutically acceptable carrier or vehicle as well.
The pharmaceutical 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. In particular, the pharmaceutical 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, tragacanth, methylcellulose, sodium carboxymethyl cellulose or polyvinyl pyrrolidone, 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.
Additionally, the dose of the active ingredient including the compound of the present invention may vary depending on various factors such as the subject to be treated, severity of diseases, routes of administration, sex, and physician's prescription, and the effective dose may be easily determined by one of ordinary skill in the art. Preferably, the compound of the present invention may be administered for the treatment of mammals including humans with fungal infections 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.
Additionally, the present invention provides a method for preparing a compound represented by Chemical Formula 1, the method comprising:
reacting a compound represented by Chemical Formula 2 below with tert-butyl carbamate(=Boc) to obtain a compound represented by Chemical Formula 3 below;
reacting a compound represented by Chemical Formula 3 below with hydroxylamine in the presence of a base to obtain a compound represented by Chemical Formula 4 below;
reacting a compound represented by Chemical Formula 4 below with an acid to remove a protecting group, thereby obtaining a compound represented by Chemical Formula 5 below; and
reacting a compound represented by Chemical Formula 5 below with a compound represented by Chemical Formula 6 below to obtain a compound represented by Chemical Formula 1 below,
[Chemical Formula 1]
Figure PCTKR2014008287-appb-I000004
[Chemical Formula 2]
Figure PCTKR2014008287-appb-I000005
[Chemical Formula 3]
Figure PCTKR2014008287-appb-I000006
[Chemical Formula 4]
Figure PCTKR2014008287-appb-I000007
[Chemical Formula 5]
Figure PCTKR2014008287-appb-I000008
[Chemical Formula 6]
Figure PCTKR2014008287-appb-I000009
wherein, in above Chemical Formulas, R1, R2, and R3 are the same as defined above.
The method of the present invention is schematically illustrated in Reaction Scheme 1 below.
[Reaction Scheme 1]
Figure PCTKR2014008287-appb-I000010
In Reaction Scheme 1, R1, R2, and R3 are the same as defined above, and each reaction is preferably performed in a reaction solvent.
The compounds represented by Chemical Formula 2 and Chemical Formula 6, being known compounds, can be manufactured by conventional methods, and may be commercially available.
In Reaction Scheme 1, a compound represented by Chemical Formula 3 may be prepared from a compound represented by Chemical Formula 2 by a conventionally known tert-butyl carbamate(=Boc) protection reaction. Preferably, the reaction solvent is a polar organic solvent, and more preferably, a polar solvent such as tert-butanol, acetonitrile, dioxane or tetrahydrofuran.
In Reaction Scheme 1, a compound represented by Chemical Formula 4 may be prepared in the form of a hydrazide derivative by reacting a compound represented by Chemical Formula 3 with hydroxylamine in the presence of a base. Here, the hydroxylamine is activated in the presence of a base. Preferably, the reaction solvent to be used is a polar organic solvent, and more preferably, a polar solvent such as dimethylformamide, dioxane or tetrahydrofuran.
Additionally, the base to be used in the present invention may be a conventional inorganic base or organic base, for example, an inorganic base such as sodium hydride (NaH) or sodium methoxide (MeONa), or a conventional organic base such as triethylamine or n-butyl lithium.
In Reaction Scheme 1 above, a compound represented by Chemical Formula 5 may be prepared by reacting a compound represented by Chemical Formula 4 with an acid to remove a protecting group. The acid is preferably hydrochloric acid (HCl). The prepared compound of Chemical Formula 5 is present in the form of a salt with 2 equivalents of HCl.
In Reaction Scheme 1 above, a compound represented by Chemical Formula 1 of the present invention may be finally prepared by reacting a compound represented by Chemical Formula 5 with a compound represented by Chemical Formula 6. In particular, the compound represented by Chemical Formula 1 may be prepared at a reaction temperature of from 0℃ to 50℃, more preferably from 50℃ to room temperature and under stirring condition for from 30 minutes to 24 hours.
Additionally, the present invention provides a compound represented by Chemical Formula 5 below, an intermediate for preparing a pyridinylhydrazide derivative of the present invention.
[Chemical Formula 5]
Figure PCTKR2014008287-appb-I000011
In the above formula, R1 and R2 are the same as defined above.
Additionally, the present invention provides a method for preparing a compound represented by Chemical Formula 1 above (a compound represented by Chemical Formula 1, wherein R1 is H, and R2 is F), as shown in Reaction Scheme 2 below.
[Reaction Scheme 2]
Figure PCTKR2014008287-appb-I000012
In Reaction Scheme 2 above, R3 is the same as defined above, and the above reaction is preferably performed in a reaction solvent, more specifically, in a polar organic solvent such as methanol, ethanol, acetonitrile, dimethoxyethane, dimethylformamide, dimethylsulfoxide, or tetrahydrofuran.
In Reaction Scheme 2 above, a compound represented by Chemical Formula 1 (wherein R1 is H, and R2 is F) may be prepared by reacting a compound represented by Chemical Formula 6 with a compound represented by Chemical Formula 7. In addition, the carboxylic acid of Chemical Formula 6 may be used in the form of a methyl or ethyl carboxylate or acyl chloride, according to a conventional method. In particular, a compound represented by Chemical Formula 1 (wherein R1 is H, and R2 is F) may be prepared at a reaction temperature of from 0℃ to 50℃, more preferably from 50℃ to room temperature and under stirring condition for from 30 minutes to 24 hours.
The novel antifungal pyridinylhydrazide 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 pyridinylhydrazide derivative of the present invention is advantageous in that it can be orally administered unlike other fungicidal agents.
Hereinafter, preferred examples are provided to allow for a clearer understanding of the present invention. However, the following examples are merely presented to exemplify the present invention, and the scope of the present invention is not limited thereto.
Example 1: Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
Step 1: Preparation of t - butyl (5- fluoro -6- methoxypyridin -3- yl ) carbamate
5-fluoro-6-methoxy-pyridin-3-ylamine (10 g, 70.3 mmol) was dissolved in t-butanol (7.04 ml, 10 M), and then di-t-butyl dicarbonate (42 ml, 182.8 mmol) was added dropwise, and stirred at 40 - 50℃ for 15 hours. Upon completion of the reaction, the resultant was cooled to room temperature, and purified via column chromatography(developing solvent, ethylacetate:hexane = 1:4) to afford the title compound (16g, yield 94%).
Step 2: Preparation of t- butyl 1-(5- fluoro -6- methoxypyridin -3- yl ) hydrazine -1- carboxylate
N,N-dimethylformamide (21 ml, 1.0 M) was added to 60% NaH (1.8 g, 51.6 mmol), and maintained under the nitrogen condition. The t-butyl (5-fluoro-methoxypyridin-3-yl) carbamate (5 g, 20.6 mmol) obtained in Step 1 was dissolved in N,N-dimethylformamide (3 ml, minimum amount), and added dropwise to the previously prepared mixed solution, and stirred. After 30 minutes, P,P-diphenylphosphinic amide (8.7 g, 37.1 mmol) was added thereto at once, N,N-dimethylformamide (21 ml) was further added thereto, and the mixed solution was stirred. After stirring for 1 hour, the reaction was stopped with water, and the resultant was extracted with ethyl acetate, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified via column chromatography (developing solvent, ethylacetate:hexane = 1:4) to afford the title compound (3.6g, yield 68%).
Step 3: Preparation of 5- fluoro -6- methoxy - pyridin -3- yl hydrazine hydrochloride
The t-butyl 1-(5-fluoro-6-methoxypyridin-3-yl)hydrazine-1-carboxylate (6.2 g, 24.1 mmol) obtained in Step 2 was completely dissolved in 4N HCl (31 ml, 1ml/200mg) and then methanol (9.3 ml, volume of 4N HCl*0.3) was slowly added. Upon formation of crystals, the resultant was stirred for 1 hour, filtered, and washed with tetrahydrofuran (31 ml) to afford the title compound (4.7g, yield 86%).
Step 4: Preparation of N ' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The 5-fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride (20 mg, 0.08 mmol) obtained in Step 3 and the benzoic acid (9.8 mg, 0.08 mmol) were dissolved in 1 ml of N,N-dimethylformamide. HBTU (45.4 mg, 0.12 mmol) and DIPEA (34.8 ㎕, 0.2 mmol) were added thereto at room temperature, and the reactants were stirred at room temperature for 6 hours. Upon completion of the reaction, the solvent was removed, and the resultant was diluted with ethylacetate, and washed with saturated sodium chloride. The organic layer was collected, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified via column chromatography (developing solvent, ethylacetate:hexane = 1:1) to afford the title compound (18.2 mg, yield 80%).
1H-NMR (500MHz, DMSO-d6): 10.44(s,1H), 8.00(s,1H), 7.88(d,2H) 7.47-7.58(m,4H), 7.13(dd,1H), 3.82(s,3H)
Example 2 : Preparation of 3-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide
The title compound (15.8 mg , yield 65%) was obtained in the same manner as in Example 1 except that 3-fluorobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.71(d,1H), 7.61(d,1H), 7.54(m,2H), 7.34(t,1H), 7.10(d,1H), 3.91(s,3H)
Example 3 : Preparation of 4- fluoro - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (18.2 mg, yield 75%) was obtained in the same manner as in Example 1 except that 4-fluorobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, DMSO-d6): 8.11(s,1H), 7.96(d,2H), 7.51(s,1H), 7.39(d,2H), 3.84(s,3H)
Example 4 : Preparation of 3- chloro - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (15.7 mg, yield 61%) was obtained in the same manner as in Example 1 except that 3-chlorobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.89(s,1H), 7.81(d,1H), 7.60(d,1H), 7.55(s,1H), 7.50(t,1H), 7.11(d,1H), 3.91(s,3H)
Example 5 : Preparation of 4- chloro - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (20.3 mg, yield 79%) was obtained in the same manner as in Example 1 except that 4-chlorobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, DMSO-d6): 8.04(s,1H), 7.92(d,2H), 7.59(d,2H), 7.54(s,1H), 3.84(s,3H)
Example 6 : Preparation of 3- bromo - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (21.3 mg, yield 72%) was obtained in the same manner as in Example 1 except that 3-bromobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.04(s,1H), 7.85(d,1H), 7.75(d,1H), 7.55(s,1H), 7.43(t,1H), 7.10(d,1H), 3.91(s,3H)
Example 7 : Preparation of 4- bromo - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (22.5 mg, yield 76%) was obtained in the same manner as in Example 1 except that 4-bromobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, DMSO-d6): 7.88(d,2H), 7.80(s,1H), 7.74(s,1H), 7.71(d,2H), 3.84(s,3H)
Example 8 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-3- methylbenzohydrazide
The title compound (15.1 mg, yield 63%) was obtained in the same manner as in Example 1 except that 3-methylbenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.70(s,1H), 7.66(d,1H), 7.55(s,1H), 7.40(m,2H), 7.10(d,1H), 3.91(s,3H)
Example 9 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-4- methylbenzohydrazide
The title compound (17.7 mg, yield 74%) was obtained in the same manner as in Example 1 except that 4-methylbenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.78(d,2H), 7.55(s,1H), 7.32(d,2H), 7.10 (d,1H), 3.90(s,3H), 2.41(s,3H)
Example 10 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-3-( trifluoromethyl ) benzohydrazide
The title compound (17.2 mg, yield 60%) was obtained in the same manner as in Example 1 except that 3-(trifluoromethyl)benzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.20(s,1H), 8.15(d,1H), 7.90(d,1H), 7.72(t,1H), 7.56(s,1H), 7.13(d,1H), 3.91(s,3H)
Example 11 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-4-( trifluoromethyl ) benzohydrazide
The title compound (21.5 mg, yield 75%) was obtained in the same manner as in Example 1 except that 4-(trifluoromethyl)benzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, DMSO-d6): 8.12(s,1H), 7.90(d,2H), 7.58(s,1H), 7.11(d,2H), 3.85(s,3H)
Example 12 : Preparation of 3- cyano - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (15.2 mg, yield 61%) was obtained in the same manner as in Example 1 except that 3-cyanobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.23(s,1H), 8.17(d,1H), 7.95(d,1H), 7.70(t,1H), 7.56(s,1H), 7.13(d,1H), 3.91(s,3H)
Example 13 : Preparation of 4- Cyano - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (17.2 mg, yield 69%) was obtained in the same manner as in Example 1 except that 4-cyanobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, DMSO-d6): 8.10(s,1H), 8.06(d,2H), 8.01(d,2H), 7.56(s,1H), 3.84(s,3H)
Example 14 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-4- methoxybenzohydrazide
The title compound (19.8 mg, yield 78%) was obtained in the same manner as in Example 1 except that 4-methoxybenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, DMSO-d6): 8.01(s,1H), 7.88(d,2H), 7.54(s,1H), 7.04(d,2H), 3.84(s,3H), 3.82(s,3H)
Example 15 : Preparation of 6- chloro - N' -(5- fluoro -6- methoxypyridin -3- yl ) nicotinohydrazide
The title compound (16.8 mg, yield 65%) was obtained in the same manner as in Example 1 except that 6-chloronicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, DMSO-d6): 8.31(s,1H), 8.12(s,1H), 7.71(s,1H), 7.58(s,1H), 7.25(s,1H), 3.85(s,3H)
Example 16 : Preparation of 6- bromo - N' -(5- fluoro -6- methoxypyridin -3- yl ) nicotinohydrazide
The title compound (19.3 mg, yield 65%) was obtained in the same manner as in Example 1 except that 6-bromonicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.82(s,1H), 8.13(d,1H), 7.76(d,1H), 7.56(s,1H), 7.12(s,1H), 3.90(s,3H)
Example 17 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-6-( trifluoromethyl ) nicotinohydrazide
The title compound (19.8 mg, yield 69%) was obtained in the same manner as in Example 1 except that 6-(trifluoromethyl)nicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, DMSO-d6): 8.51(s,1H), 8.19(s,1H), 8.09(s,1H), 7.61(s,1H), 7.25(s,1H), 3.85(s,3H)
Example 18 : Preparation of 6- cyano - N' -(5- fluoro -6- methoxypyridin -3- yl ) nicotinohydrazide
The title compound (14.2 mg, yield 57%) was obtained in the same manner as in Example 1 except that 6-cyanonicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, DMSO-d6): 8.49(s,1H), 8.24(s,1H), 8.15(s,1H), 7.61(s,1H), 7.27(s,1H), 3.85(s,3H)
Example 19 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-2- methoxynicotinohydrazide
The title compound (16.0 mg, yield 63%) was obtained in the same manner as in Example 1 except that 2-methoxynicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.08(s,1H), 7.83(d,1H), 7.59(s,1H), 7.14(m,2H), 4.01(s,3H), 3.91(s,3H)
Example 20 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-2- methoxypyrimidine -4- carbohydrazide
The title compound (13.3 mg, yield 52%) was obtained in the same manner as in Example 1 except that 2-methoxypyrimidine-4-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.83(d,1H), 7.70(d,1H), 7.58(d,1H), 7.15(d,1H), 4.13(s,3H), 3.93(s,3H)
Example 21 : Preparation of 4- bromo -3- fluoro - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (24.6 mg, yield 79%) was obtained in the same manner as in Example 1 except that 4-bromo-3-fluorobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.78(t,1H), 7.73(d,1H), 7.64(d,1H), 7.55(s,1H), 7.11(d,1H), 3.91(s,3H)
Example 22 : Preparation of 4- cyano -3- fluoro - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (20.6 mg, yield 78%) was obtained in the same manner as in Example 1 except that 4-cyano-3-fluorobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.94(d,1H), 7.85(m,2H), 7.56(s,1H), 7.13(d,1H), 3.91(s,3H)
Example 23 : Preparation of 4- bromo -3- chloro - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (23.4 mg, yield 72%) was obtained in the same manner as in Example 1 except that 4-bromo-3-chlorobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.04(s,1H), 7.85(d,1H), 7.70(d,1H), 7.55(d,1H), 7.11(d,1H), 3.91(s,3H)
Example 24 : Preparation of 3- bromo -4- fluoro - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (23.0 mg, yield 74%) was obtained in the same manner as in Example 1 except that 3-bromo-4-fluorobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.21(d,1H), 7.94(m,1H), 7.57(s,1H), 7.38(d,1H), 7.12(d,1H), 3.93(s,3H)
Example 25 : Preparation of 3- bromo -4- chloro - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (24.7 mg, yield 76%) was obtained in the same manner as in Example 1 except that 3-bromo-4-chlorobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.23(s,1H), 7.87(d,1H), 7.69(d,1H), 7.57(s,1H), 7.13(d,1H), 3.93(s,3H)
Example 26 : Preparation of 3- bromo - N' -(5- fluoro -6- methoxypyridin -3- yl )-4-( trifluoromethyl ) benzohydrazide
The title compound (27.0 mg, yield 76%) was obtained in the same manner as in Example 1 except that 3-bromo-4-(trifluoromethyl)benzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.31(s,1H), 8.03(d,1H), 7.94(d,1H), 7.59(s,1H), 7.16(d,1H), 3.93(s,3H)
Example 27 : Preparation of 4- fluoro - N' -(5- fluoro -6- methoxypyridin -3- yl )-3- methylbenzohydrazide
The title compound (20.4 mg, yield 80%) was obtained in the same manner as in Example 1 except that 4-fluoro-3-methylbenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.81(d,1H), 7.74(m,1H), 7.55(d,1H), 7.16(t,1H), 7.10(dd,1H), 3.91(s,3H), 2.36(s,3H)
Example 28 : Preparation of 4- chloro - N' -(5- fluoro -6- methoxypyridin -3- yl )-3- methylbenzohydrazide
The title compound (21.8 mg, yield 81%) was obtained in the same manner as in Example 1 except that 4-chloro-3-methylbenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.84(d,1H), 7.72(t,1H), 7.58(s,1H), 7.52(t,1H), 7.11(d,1H), 3.93(s,3H), 2.47(s,3H)
Example 29 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-3- methyl -4- nitrobenzohydrazide
The title compound (17.8 mg, yield 64%) was obtained in the same manner as in Example 1 except that 3-methyl-4-nitrobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.04(d,1H), 7.93(s,1H), 7.88(d,1H), 7.57(s,1H), 7.13(d,1H), 3.91(s,3H), 2.61(s,3H)
Example 30 : Preparation of 4- fluoro - N' -(5- fluoro -6- methoxypyridin -3- yl )-3-( trifluoromethyl ) benzohydrazide
The title compound (22.6 mg, yield 75%) was obtained in the same manner as in Example 1 except that 4-fluoro-3-(trifluoromethyl)benzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.23(m,2H), 7.56(s,1H), 7.49(t,1H), 7.11(d,1H), 3.91(s,3H)
Example 31 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-4- methyl -3-( trifluoromethyl ) benzohydrazide
The title compound (23.mg, yield 77%) was obtained in the same manner as in Example 1 except that 4-methyl-3-(trifluoromethyl)benzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.19(s,1H), 8.04(d,1H), 7.57(m,2H), 7.13(d,1H), 3.93(s,3H), 2.58(s,3H)
Example 32 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-2,3- dimethoxybenzohydrazide
The title compound (14.2 mg, yield 51%) was obtained in the same manner as in Example 1 except that 2,3-dimethoxybenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.60(s,1H), 7.21(m,2H), 7.16(m,2H), 3.93(s,3H), 3.91(s,3H), 3.90(s,3H)
Example 33 : Preparation of 5- bromo - N' -(5- fluoro -6- methoxypyridin -3- yl )-2- methoxybenzohydrazide
The title compound (19.0 mg, yield 59%) was obtained in the same manner as in Example 1 except that 5-bromo-2-methoxybenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.32(d,1H), 8.20(d,1H), 7.58(s,1H), 7.12(m,2H), 4.11(s,3H), 3.91(s,3H)
Example 34 : Preparation of 4- fluoro - N' -(5- fluoro -6- methoxypyridin -3- yl )-3- nitrobenzohydrazide
The title compound (22.3 mg, yield 79%) was obtained in the same manner as in Example 1 except that 4-fluoro-3-nitrobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.68(d,1H), 8.29(d,1H), 7.60(m,2H), 7.15(d,1H), 3.93(s,3H)
Example 35 : Preparation of 3-( dimethylamino )- N' -(5- fluoro -6- methoxypyridin -3- yl )-4- methoxybenzohydrazide
The title compound (20.6 mg, yield 71%) was obtained in the same manner as in Example 1 except that 3-(dimethylamino)-4-methoxybenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.61(d,1H), 7.54(m,2H), 7.08(m,2H), 3.95(s,3H), 3.90(s,3H), 2.78(s,6H)
Example 36 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl ) benzo [d][1,3] dioxole -5- carbohydrazide
The title compound (13.0 mg, yield 49%) was obtained in the same manner as in Example 1 except that benzo[d][1,3]dioxole-5-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, DMSO-d6): 10.28(s,1H), 7.94(s,1H), 7.49-7.50(m,2H), 7.41(s,1H), 7.11(dd,1H), 7.00(d,1H), 6.10(s,2H), 3.82(s,3H)
Example 37 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-2,3- dihydrobenzo [b][1,4]dioxin-6- carbohydrazide
The title compound (13.0 mg, yield 47%) was obtained in the same manner as in Example 1 except that 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, DMSO-d6): 10.27(s,1H), 7.93(s,1H), 7.49(s,1H), 7.39-7.48(m,2H), 7.09(dd,1H), 6.93(d,1H), 4.27(q,4H), 3.82(s,3H)
Example 38 : Preparation of 6- bromo -5- fluoro - N' -(5- fluoro -6- methoxypyridin -3- yl ) picolinohydrazide
The title compound (17.5 mg, yield 56%) was obtained in the same manner as in Example 1 except that 6-bromo-5-fluoropicolinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.17(d,1H), 7.86(t,1H), 7.58(s,1H), 7.13(d,1H), 3.93(s,3H)
Example 39 : Preparation of 5- fluoro - N' -(5- fluoro -6- methoxypyridin -3- yl )-6- methylnicotinohydrazide
The title compound (15.9 mg, yield 62%) was obtained in the same manner as in Example 1 except that 5-fluoro-6-methylnicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.77(s,1H), 8.00(d,1H), 7.57(d,1H), 7.14(dd,1H), 3.91(s,3H), 2.58(d,3H)
Example 40 : Preparation of 5- bromo -6- fluoro - N' -(5- fluoro -6- methoxypyridin -3- yl ) nicotinohydrazide
The title compound (15.9 mg, yield 51%) was obtained in the same manner as in Example 1 except that 5-bromo-6-fluoronicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.51(s,1H), 8.46(d,1H), 7.61(s,1H), 7.16(d,1H), 3.94(s,3H)
Example 41 : Preparation of 5- bromo -6- chloro - N' -(5- fluoro -6- methoxypyridin -3- yl ) nicotinohydrazide
The title compound (18.6 mg, yield 57%) was obtained in the same manner as in Example 1 except that 5-bromo-6-chloronicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.82(s,1H), 8.56(s,1H), 7.57(s,1H), 7.15(d,1H), 3.91(s,3H)
Example 42 : Preparation of 2- chloro - N' -(5- fluoro -6- methoxypyridin -3- yl )-6- methylisonicotinohydrazide
The title compound (14.6 mg, yield 54%) was obtained in the same manner as in Example 1 except that 2-chloro-6-methylisonicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.65(s,1H), 7.63(s,1H), 7.56(s,1H), 7.12(d,1H), 3.91(s,3H), 2.58(s,3H)
Example 43 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl ) pyrimidine -5- carbohydrazide
The title compound (14.0 mg, yield 61%) was obtained in the same manner as in Example 1 except that pyrimidine-5-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 9.32(s,1H), 9.22(s,2H), 7.59(d,1H), 7.18(d,1H), 3.91(s,3H)
Example 44 : Preparation of 5- bromo -2,4- dichloro - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (19.6 mg, yield 55%) was obtained in the same manner as in Example 1 except that 5-bromo-2,4-dichlorobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.89(s,1H), 7.78(s,1H), 7.62(s,1H), 7.16(d,1H), 3.92(s,3H)
Example 45 : Preparation of 5- bromo -2,4- difluoro - N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (19.3 mg, yield 59%) was obtained in the same manner as in Example 1 except that 5-bromo-2,4-difluorobenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.03(t,1H), 7.57(s,1H), 7.32(t,1H), 7.11(t,1H), 3.91(s,3H)
Example 46 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-3,5- dimethoxy -4- methylbenzohydrazide
The title compound (18.4 mg, yield 63%) was obtained in the same manner as in Example 1 except that 3,5-dimethoxy-4-methylbenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.56(s,1H), 7.12(m,3H), 3.90(s,3H), 3.88(s,6H), 2.09(s,3H)
Example 47 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (21.1 mg, yield 72%) was obtained in the same manner as in Example 1 except that [1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.12(s,1H), 7.84(d,1H), 7.80(d,1H), 7.64(m,2H), 7.58(d,1H), 7.52(m,1H), 7.43(m,2H), 7.33(m,1H), 7.12(dd,1H), 3.88(s,3H)
Example 48 : Preparation of 3'- fluoro -N'-(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (18.8 mg, yield 61%) was obtained in the same manner as in Example 1 except that 3'-fluoro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.15(s,1H), 7.89(dd,2H), 7.60(dd,2H), 7.49(m,3H), 7.13(m,2H), 3.91(s,3H)
Example 49: Preparation of 2'- fluoro -N'-(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (18.8 mg, yield 61%) was obtained in the same manner as in Example 1 except that 2'-fluoro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.06(s,1H), 7.90(d,1H), 7.78(d,1H), 7.59(dd,2H), 7.55(t,1H), 7.41(m,1H), 7.29(t,1H), 7.22(dd,1H), 7.13(dd,1H), 3.91(s,3H)
Example 50 : Preparation of 4'- fluoro -N'-(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (19.2 mg, yield 62%) was obtained in the same manner as in Example 1 except that 4'-fluoro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.11(s,1H), 7.85(dd,2H), 7.71(dd,2H), 7.59(m,2H), 7.21(t,2H), 7.14(dd,1H), 3.91(s,3H)
Example 51 : Preparation of 2'- chloro -N'-(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (20.0 mg, yield 62%) was obtained in the same manner as in Example 1 except that 2'-chloro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.94(s,1H), 7.92(d,1H), 7.67(d,1H), 7.59(dd,2H), 7.53(d,1H), 7.39(m,3H), 7.12(dd,1H), 3.91(s,3H)
Example 52 : Preparation of 3'- chloro -N'-(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (19.7 mg, yield 61%) was obtained in the same manner as in Example 1 except that 3'-chloro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.14(s,1H), 7.91(d,1H), 7.86(d,1H), 7.73(s,1H), 7.62(dd,2H), 7.59(dd,1H), 7.47(t,1H), 7.40(d,1H), 7.14(d,1H), 3.91(s,3H)
Example 53 : Preparation of 4'- chloro - N' -(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (19.7 mg, yield 61%) was obtained in the same manner as in Example 1 except that 4'-chloro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.12(s,1H), 7.87(d,1H), 7.84(d,1H), 7.68(d,2H), 7.60-7.57(m,2H), 7.47(m,2H), 7.12(dd,1H), 3.90(s,3H)
Example 54 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-2'- methoxy -[1,1'- biphenyl ]-3- carbohydrazide
The title compound (21.7 mg, yield 68%) was obtained in the same manner as in Example 1 except that 2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.00(s,1H), 7.82(d,1H), 7.72(d,1H), 7.58(d,1H), 7.52(t,1H), 7.36(m,2H), 7.11(m,H), 7.04(t,1H), 3.91(s,3H), 3.81(s,3H)
Example 55 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-3'- methoxy -[1,1'- biphenyl ]-3- carbohydrazide
The title compound (21.4 mg, yield 67%) was obtained in the same manner as in Example 1 except that 3'-methoxy-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.13(s,1H), 7.86(t,2H), 7.59(dd,2H), 7.38(t,1H),7.25(dd,2H), 7.14(dd,1H), 6.95(dd,1H), 3.91(s,3H), 3.86(s,3H)
Example 56 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-4'- methoxy -[1,1'- biphenyl ]-3- carbohydrazide
The title compound (22.0 mg, yield 69%) was obtained in the same manner as in Example 1 except that 4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.09(s,1H), 7.81(d,2H), 7.63(d,2H), 7.59(d,1H), 7.55(t,1H), 7.13(dd,1H), 7.03(d,2H), 3.91(s,3H), 3.84(s,3H)
Example 57 : Preparation of 6- fluoro - N' -(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (19.5 mg, yield 63%) was obtained in the same manner as in Example 1 except that 6-fluoro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.01(dd,1H), 7.91-7.88(m,1H), 7.57(d,2H), 7.55(d,1H), 7.45(t,2H), 7.40-7.37(m,1H), 7.31(t,1H), 7.10(dd,1H), 3.88(s,3H)
Example 58 : Preparation of 4'- chloro -6- fluoro -N'-(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (21.7 mg, yield 64%) was obtained in the same manner as in Example 1 except that 4'-chloro-6-fluoro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.05(dd,1H), 7.95(m,1H), 7.61(d,2H), 7.57(dd,1H), 7.50(d,2H), 7.36(t,1H), 7.13(dd,1H), 3.91(s,3H)
Example 59 : Preparation of 6- chloro - N' -(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (22.6 mg, yield 70%) was obtained in the same manner as in Example 1 except that 6-chloro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.86(d,1H), 7.82(dd,1H), 7.62(d,1H), 7.53(d,1H), 7.44-7.41(m,4H), 7.41-7.38(m,1H), 7.08(dd,1H), 3.87(s,3H)
Example 60 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-3-( thiazole -2- yl ) benzohydrazide
The title compound (21.3 mg, yield 71%) was obtained in the same manner as in Example 1 except that 3-(thiazol-2-yl)benzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.46(s,1H), 8.16(d,1H), 7.95(d,1H), 7.90(d,1H), 7.63(m,2H), 7.58(d,1H), 7.13(dd,1H), 3.90(s,3H)
Example 61 : Preparation of 3-(3,5- dimethyl -1H- pyrazol -1- yl )- N' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
The title compound (13.3 mg, yield 43%) was obtained in the same manner as in Example 1 except that 3-(3,5-dimethyl-1H-pyrazol-1-yl)benzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.95(m,2H), 7.67(m,2H), 7.58(d,1H), 7.12(m,1H), 6.11(s,1H), 3.91(s,3H), 2.32(s,3H), 2.26(s,3H)
Example 62 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-3-(1H- tetrazol -1- yl ) benzohydrazide
The title compound (14.0 mg, yield 49%) was obtained in the same manner as in Example 1 except that 3-(1H-tetrazol-1-yl)benzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 9.85(s,1H), 8.41(s,1H), 8.12(m,1H), 8.07(m,1H), 7.79(m,1H), 7.59(s,1H), 7.15(dd,1H), 3.91(s,3H)
Example 63 : Preparation of 6-(4- chlorophenyl )- N' -(5- fluoro -6- methoxypyridin -3- yl ) picolinohydrazide
The title compound (15.2 mg, yield 47%) was obtained in the same manner as in Example 1 except that 6-(4-chlorophenyl)picolinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.25(d,2H), 8.13(m,1H), 8.05(d,2H), 7.59(d,1H), 7.52(d,2H), 7.14(dd,1H), 3.91(s,3H)
Example 64 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-5-(4- fluorophenyl )-6- methoxynicotinohydrazide
The title compound (14.1 mg, yield 42%) was obtained in the same manner as in Example 1 except that 5-(4-fluorophenyl)-6-methoxynicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.70(d,1H), 8.16(d,1H), 7.63(m,2H), 7.58(d,1H), 7.18(t,2H), 7.13(dd,1H), 4.03(s,3H), 3.91(s,3H)
Example 65 : Preparation of 5-(4- chlorophenyl )- N' -(5- fluoro -6- methoxypyridin -3- yl ) nicotinohydrazide
The title compound (16.2 mg, yield 50%) was obtained in the same manner as in Example 1 except that 5-(4-chlorophenyl)nicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 9.02(dd,2H), 8.53(s,1H), 7.76(d,2H), 7.61(d,1H), 7.55(d,2H), 7.18(dd,1H), 3.91(s,3H)
Example 66 : Preparation of 5-(4- chlorophenyl )- N' -(5- fluoro -6- methoxypyridin -3- yl )-6- methoxynicotinohydrazide
The title compound (18.2 mg, yield 52%) was obtained in the same manner as in Example 1 except that 5-(4-chlorophenyl)-6-methoxynicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.71(d,1H), 8.18(d,1H), 7.60(d,2H), 7.58(d,1H), 7.45(d,2H), 7.13(dd,1H), 4.04(s,3H), 3.91(s,3H)
Example 67 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-6- methoxy -5-(4-( trifluoromethyl ) phenyl ) nicotinohydrazide
The title compound (19.3 mg, yield 51%) was obtained in the same manner as in Example 1 except that 6-methoxy-5-(4-(trifluoromethyl)phenyl)nicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.75(d,1H), 8.23(d,1H), 7.82(d,2H), 7.74(d,2H), 7.58(d,1H), 7.13(dd,1H), 4.05(s,3H), 3.91(s,3H)
Example 68 : Preparation of 5-(4- cyanophenyl )- N' -(5- fluoro -6- methoxypyridin -3- yl )-6- methoxynicotinohydrazide
The title compound (20.2 mg, yield 59%) was obtained in the same manner as in Example 1 except that 5-(4-cyanophenyl)-6-methoxynicotinic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.75(d,1H), 8.23(d,1H), 7.81(d,4H), 7.58(d,1H), 7.14(dd,1H), 4.05(s,3H), 3.91(s,3H)
Example 69 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-4- carbohydrazide
The title compound (20.2 mg, yield 69%) was obtained in the same manner as in Example 1 except that [1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.97(d,2H), 7.78(d,2H), 7.69(d,2H), 7.59(d,1H), 7.48(m,2H), 7.40(m,1H), 7.13(dd,1H), 3.92(s,3H)
Example 70 : Preparation of 2- fluoro - N' -(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-4- carbohydrazide
The title compound (20.1 mg, yield 65%) was obtained in the same manner as in Example 1 except that 2-fluoro-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.79(d,1H), 7.73(d,1H), 7.60(m,4H), 7.45(m,3H), 7.12(d,1H), 3.91(s,3H)
Example 71 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-2- methyl -[1,1'- biphenyl ]-4- carbohydrazide
The title compound (18.6 mg, yield 61%) was obtained in the same manner as in Example 1 except that 2-methyl-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.82(s,1H), 7.75(d,1H), 7.59(s,2H), 7.44(m,2H), 7.34(m,4H), 7.11(d,1H), 3.91(s,3H), 2.32(s,3H)
Example 72 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-4- phenoxybenzohydrazide
The title compound (19.4 mg, yield 63%) was obtained in the same manner as in Example 1 except that 4-phenoxybenzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 7.86(d,2H), 7.53(d,1H), 7.39(t,2H), 7.18(t,1H), 7.08(d,1H), 7.05(d,2H), 7.01(d,2H), 3.88(s,3H)
Example 73 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-4-(1H- pyrrole -1- yl ) benzohydrazide
The title compound (17.0 mg, yield 60%) was obtained in the same manner as in Example 1 except that 4-(1H-pyrrol-1-yl)benzoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, DMSO-d6): 10.47(s,1H), 7.98(m,3H), 7.71(d,2H), 7.49-7.52(m,3H), 7.15(dd,1H), 6.30(s,2H), 3.82(s,3H)
Example 74 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-2- phenylpyrimidine -5- carbohydrazide
The title compound (18.0 mg, yield 61%) was obtained in the same manner as in Example 1 except that 2-phenylpyrimidine-5-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 9.27(s,2H), 8.52(d,2H), 7.61(d,1H), 7.55(m,3H), 7.19(d,1H), 3.92(s,3H)
Example 75 : Preparation of 2-(4- chlorophenyl )- N' -(5- fluoro -6- methoxypyridin -3- yl ) pyrimidine -5- carbohydrazide
The title compound (20.5 mg, yield 63%) was obtained in the same manner as in Example 1 except that 2-(4-chlorophenyl)pyrimidine-5-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 9.27(s,2H), 8.51(d,1H), 7.61(d,1H), 7.54(d,2H), 7.18(dd,1H), 3.92(s,3H)
Example 76 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-2-( piperidin -1- yl ) pyrimidine -5- carbohydrazide
The title compound (15.4 mg, yield 51%) was obtained in the same manner as in Example 1 except that 2-(piperidin-1-yl)pyrimidine-5-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.76(s,2H), 7.54(d,1H), 7.10(dd,1H), 3.89(m,7H), 1.73(t,2H), 1.63(t,4H)
Example 77 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-4- methyl -2- phenylpyrimidine -5- carbohydrazide
The title compound (18.1 mg, yield 59%) was obtained in the same manner as in Example 1 except that 4-methyl-2-phenylpyrimidine-5-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.89(s,1H), 8.48(d,2H), 7.63(d,1H), 7.52(m,3H), 7.18(dd,1H), 3.93(s,3H), 2.73(s,3H)
Example 78 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-2- naphthohydrazide
The title compound (15.2 mg, yield 56%) was obtained in the same manner as in Example 1 except that 2-naphthoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.43(s,1H), 7.97(m,2H), 7.90(m,2H), 7.58(m,3H), 7.15(dd,1H), 3.89(s,3H)
Example 79 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl ) isoquinoline -4- carbohydrazide
The title compound (13.8 mg, yield 51%) was obtained in the same manner as in Example 1 except that isoquinoline-4-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 9.37(s,1H), 8.70 (s,1H), 8.30(d,1H), 8.20(d,1H), 7.90(m,1H), 7.78(m,1H), 7.64(d,1H), 7.19(m,1H), 3.92(s,3H)
Example 80 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl ) tetrazolo [1,5-a] pyridine -6- carbohydrazide
The title compound (15.0 mg, yield 57%) was obtained in the same manner as in Example 1 except that tetrazolo[1,5-a]pyridine-6-carboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 9.69(s,1H), 8.24(d,1H), 8.19(d,1H), 7.62(s,1H), 7.20(d,1H), 3.92(s,3H)
Example 81 : Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl )-4,7- dimethoxy -1- naphthohydrazide
The title compound (17.8 mg, yield 55%) was obtained in the same manner as in Example 1 except that 4,7-dimethoxy-1-naphthoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.19(d,1H), 7.73(d,1H), 7.67(dd,1H), 7.17(m,2H), 6.85(d,1H), 4.04(s,3H). 3.93(s,3H), 3.87(s,3H)
Example 82 : Preparation of 4-( dimethylamino )- N' -(5- fluoro -6- methoxypyridin -3- yl )-1- naphthohydrazide
The title compound (18.2 mg, yield 59%) was obtained in the same manner as in Example 1 except that 4-(dimethylamino)-1-naphthoic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.26(dd,2H), 7.69(d,1H), 7.65(d,1H), 7.53(m,2H), 7.17(dd,1H), 7.11(d,1H), 3.93(s,3H), 2.95(s,6H)
Example 83 : Preparation of N'3 , N'3' -bis(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3,3'- dicarbohydrazide
The title compound (19.0 mg, yield 42%) was obtained in the same manner as in Example 1 except that [1,1'-biphenyl]-3,3'-dicarboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.22(s,1H), 8.01(d,2H), 7.94(m,2H), 7.86(d,2H), 7.64(t,1H), 7.60(t,1H), 7.14(m,1H), 3.92(s,6H)
Example 84 : Preparation of N'3 , N'4' -bis(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3,4'- dicarbohydrazide
The title compound (19.5 mg, yield 43%) was obtained in the same manner as in Example 1 except that [1,1'-biphenyl]-3,4'-dicarboxylic acid was used instead of benzoic acid in Step 4 of Example 1.
1H-NMR (500MHz, CD3OD-d4): 8.20(s,2H), 7.91(m,4H), 7.62(t,2H), 7.57(d,2H), 7.12(m,2H), 3.89(s,6H)
Example 85 : Preparation of N' -(6- fluoropyridin -3- yl ) benzohydrazide
2-fluoro-5-hydrazinylpyridine (17.4 mg, 0.08 mmol) and benzoic acid (9.8 mg, 0.08 mmol) were dissolved in 1 ml of N,N-dimethylformamide. HBTU (45.4 mg, 0.12 mmol) and DIPEA (34.8 ㎕, 0.2 mmol) were added thereto at room temperature, and the reactants were stirred at room temperature for 6 hours. Upon completion of the reaction, the solvent was removed, and the resultant was diluted with ethylacetate, and washed with saturated sodium chloride. The organic layer was collected, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified via column chromatography (developing solvent, ethylacetate:hexane = 1:1) to afford the title compound (14.1 mg, yield 76%).
1H-NMR (500MHz, CD3OD-d4): 7.92-7.88(m,2H), 7.77(s,1H), 7.64-7.62(m,1H), 7.52-7.46(m,3H), 6.94(dd,1H)
Example 86 : Preparation of 4- cyano -3- fluoro - N' -(6- fluoropyridin -3- yl ) benzohydrazide
The title compound (15.6 mg, yield 71%) was obtained in the same manner as in Example 85 except that 4-cyano-3-fluorobenzoic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 7.94-7.91(m,1H), 7.87-7.85(d,2H), 7.73(s,1H), 7.47-7.43(m,1H), 6.93(dd,1H)
Example 87 : Preparation of 4- fluoro - N ' -(6- fluoropyridin -3- yl )-3- methylbenzohydrazide
The title compound (16.7 mg, yield 79%) was obtained in the same manner as in Example 85 except that 4-fluoro-3-methylbenzoic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 7.79(s,1H), 7.69(s,1H), 7.66(d,1H), 7.57(dd,1H), 7.42-7.39(m,1H), 6.90(dd,1H), 2.44(s,3H)
Example 88 : Preparation of N ' -(6- fluoropyridin -3- yl )-4- methyl -3-( trifluoromethyl ) benzohydrazide
The title compound (19.1 mg, yield 76%) was obtained in the same manner as in Example 85 except that 4-methyl-3-(trifluoromethyl)benzoic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.20(s,1H), 8.04(d,1H), 7.74(s,1H), 7.55(d,1H), 7.45(m,1H), 6.94(m,1H), 2.57(s,3H)
Example 89 : Preparation of 3- cyano -4- fluoro - N' -(6- fluoropyridin -3- yl ) benzohydrazide
The title compound (18.0 mg, yield 82%) was obtained in the same manner as in Example 85 except that 3-cyano-4-fluorobenzoic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.30(s,1H), 8.23(m,1H), 7.72(s,1H), 7.50(m,1H), 7.43(m,1H), 6.91(m,1H)
Example 90 : Preparation of 3-( dimethylamino )- N ' -(6- fluoropyridin -3- yl )-4- methoxybenzohydrazide
The title compound (14.9 mg, yield 61%) was obtained in the same manner as in Example 85 except that 3-(dimethylamino)-4-methoxybenzoic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 7.71(s,1H), 7.60(m,1H), 7.53(d,1H), 7.41(m,1H), 7.04(d,1H), 6.91(dd,1H), 3.94(s,3H), 2.77(s,6H)
Example 91 : Preparation of N ' -(6- fluoropyridin -3- yl ) pyrimidine -4- carbohydrazide
The title compound (11.8 mg, yield 63%) was obtained in the same manner as in Example 85 except that pyrimidine-4-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, DMSO-d6): 11.04(s,1H), 9.37(s,1H), 9.10(d,1H), 8.30(d,1H), 8.01(d,1H), 7.66(s,1H), 7.34(m,1H), 6.98(m,1H)
Example 92 : Preparation of N ' -(6- fluoropyridin -3- yl ) pyrimidine -2- carbohydrazide
The title compound (12.5 mg, yield 67%) was obtained in the same manner as in Example 85 except that pyrimidine-2-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.98(d,2H), 7.76(s1H), 7.68(t,1H), 7.47(m,1H), 6.93(dd,1H)
Example 93 : Preparation of N ' -(6- fluoropyridin -3- yl ) pyrimidine -5- carbohydrazide
The title compound (12.1 mg, yield 65%) was obtained in the same manner as in Example 85 except that pyrimidine-5-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 9.33(s,1H), 9.23(s,2H), 7.78(s,1H), 7.49(m,1H), 6.94(dd,1H)
Example 94 : Preparation of N ' -(6- fluoropyridin -3- yl ) pyridazine -4- carbohydrazide
The title compound (11.2 mg, yield 60%) was obtained in the same manner as in Example 85 except that pyridazine-4-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 9.59(s,1H), 9.43(d,1H), 8.12(dd,1H), 7.78(s,1H), 7.49(m,1H), 6.95(dd,1H)
Example 95 : Preparation of N ' -(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (18.5 mg, yield 75%) was obtained in the same manner as in Example 85 except that [1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CDCl3-d): 8.05(s,1H), 7.93(s,1H), 7.82-7.79(m,2H), 7.62-7.56(m,3H), 7.49-7.47(m,2H), 7.43-7.38(m,2H), 6.84(d,1H)
Example 96 : Preparation of 4'- fluoro - N '-(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (18.8 mg, yield 72%) was obtained in the same manner as in Example 85 except that 4'-fluoro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.12(s,1H), 7.87(d,1H), 7.83(d,1H), 7.75(s,1H), 7.72-7.70(m,2H), 7.58(t,1H), 7.48-7.45(m,1H), 7.21(t,2H), 6.93(dd,1H)
Example 97 : Preparation of 4'- chloro - N '-(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (18.9 mg, yield 69%) was obtained in the same manner as in Example 85 except that 4'-chloro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.11(s,1H), 7.86(d,1H), 7.82(d,1H), 7.72(s,1H), 7.66(d,2H), 7.57(t,1H), 7.46-7.42(m,3H), 6.91(dd,1H)
Example 98 : Preparation of 2',4'- difluoro - N ' -(6- fluoropyridin -3- yl )-4- hydroxy -[1,1'- biphenyl ]-3- carbohydrazide
The title compound (15.8 mg, yield 55%) was obtained in the same manner as in Example 85 except that 2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.07(s,1H), 8.01(d,1H), 7.76(s,1H), 7.53(m,3H), 7.47(m,1H), 7.36(t,1H), 6.93(dd,1H)
Example 99 : Preparation of 6-(4- chlorophenyl )- N' -(6- fluoropyridin -3- yl ) picolinohydrazide
The title compound (14.6 mg, yield 53%) was obtained in the same manner as in Example 85 except that 6-(4-chlorophenyl)picolinic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.26(d,2H), 8.13(m,1H), 8.07(d,2H), 7.76(s,1H), 7.51(d,2H), 7.47(m,1H), 6.93(dd,1H)
Example 100 : Preparation of 5-(4- chlorophenyl )- N ' -(6- fluoropyridin -3- yl ) nicotinohydrazide
The title compound (15.7 mg, yield 57%) was obtained in the same manner as in Example 85 except that 5-(4-chlorophenyl)nicotinic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 9.03(d,2H), 8.54(s,1H), 7.77(t,3H), 7.55(d,2H), 7.50(m,1H), 6.95(dd,1H)
Example 101 : Preparation of N ' -(6- fluoropyridin -3- yl )-6- phenylpyrimidine -4- carbohydrazide
The title compound (15.7 mg, yield 57%) was obtained in the same manner as in Example 85 except that 6-phenylpyrimidine-4-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 9.03(d,2H), 8.54(s,1H), 7.77(t,3H), 7.55(d,2H), 7.50(m,1H), 6.95(dd,1H)
Example 102 : Preparation of 6-(4- fluorophenyl )- N' -(6- fluoropyridin -3- yl ) pyrimidine -4- carbohydrazide
The title compound (17.6 mg, yield 67%) was obtained in the same manner as in Example 85 except that 6-(4-fluorophenyl)pyrimidine-4-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 9.31(s,1H), 8.52(s,1H), 8.33(dd,2H), 7.76(s1H), 7.47(m,1H), 7.30(t,2H), 6.94(dd,1H)
Example 103 : Preparation of 6- fluoro - N ' -(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (15.6 mg, yield 60%) was obtained in the same manner as in Example 85 except that 6-fluoro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.06(m,1H), 7.93(m,1H), 7.75(d,1H), 7.60(d,2H), 7.45(m,H), 7.35(t,1H), 6.93(dd,1H)
Example 104 : Preparation of 4'- chloro -6- fluoro - N '-(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (17.0 mg, yield 59%) was obtained in the same manner as in Example 85 except that 4'-chloro-6-fluoro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.05(dd,1H), 7.95(m,1H), 7.74(s,1H), 7.61(d,2H), 7.50(d,2H), 7.45(m,1H), 7.36(t,1H), 6.93(dd,1H)
Example 105 : Preparation of 6- chloro - N ' -(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
The title compound (12.9 mg, yield 47%) was obtained in the same manner as in Example 85 except that 6-chloro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 7.91(d,1H), 7.87(dd,1H), 7.74(s,1H), 7.66(d,1H), 7.49-7.45(m,4H), 7.45-7.42(m,2H), 6.94(dd,1H)
Example 106 : Preparation of 5-(4- fluorophenyl )- N ' -(6- fluoropyridin -3- yl )-6- methoxynicotinohydrazide
The title compound (20.0 mg, yield 70%) was obtained in the same manner as in Example 85 except that 5-(4-fluorophenyl)-6-methoxynicotinic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.70(d,1H), 8.16(d,1H), 7.75(s,1H), 7.63(m,2H), 7.17(m,3H), 6.93(m,1H), 4.02(s,3H)
Example 107 : Preparation of 5-(4- chlorophenyl )- N' -(6- fluoropyridin -3- yl )-6- methoxynicotinohydrazide
The title compound (19.7 mg, yield 66%) was obtained in the same manner as in Example 85 except that 5-(4-chlorophenyl)-6-methoxynicotinic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.71(d,1H), 8.17(d,1H), 7.75(s,1H), 7.59(d,2H), 7.44(m,3H), 6.93(m,1H), 4.05(s,3H)
Example 108 : Preparation of N ' -(6- fluoropyridin -3- yl )-6- methoxy -5-(4-( trifluoromethyl ) phenyl ) nicotinohydrazide
The title compound (19.5 mg, yield 60%) was obtained in the same manner as in Example 85 except that 6-methoxy-5-(4-(trifluoromethyl)phenyl)nicotinic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.76(d,1H), 8.24(d,1H), 7.80(d,2H), 7.75(d,3H), 7.47(m,1H), 6.94(m,1H), 4.03(s,3H)
Example 109 : Preparation of 5-(4- cyanophenyl )- N ' -(6- fluoropyridine -3- yl )-6- methoxynicotinohydrazide
The title compound (14.3 mg, yield 49%) was obtained in the same manner as in Example 85 except that 5-(4-cyanophenyl)-6-methoxynicotinic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.76(d,1H), 8.24(d,H), 7.82(s,4H), 7.75(s,1H), 7.47(m,1H), 6.93(dd,1H), 4.04(s,3H)
Example 110 : Preparation of 3- benzoyl - N ' -(6- fluoropyridin -3- yl ) benzohydrazide
The title compound (14.8 mg, yield 55%) was obtained in the same manner as in Example 85 except that 3-benzoylbenzoic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.29(s,1H), 8.14(d,1H), 7.95(d,1H), 7.78(d,2H), 7.73(s,1H), 7.65(m,2H), 7.53(m,2H), 7.43(m,1H), 6.90(dd,1H)
Example 111 : Preparation of N ' -(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-4- carbohydrazide
The title compound (16.7 mg, yield 68%) was obtained in the same manner as in Example 85 except that [1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CDCl3-d): 8.36(s,1H), 8.18(s,1H), 7.93(d,2H), 7.70(d,2H), 7.62(d,2H), 7.49-7.47(m,2H), 7.42-7.39(m,1H), 7.19-7.17(m,1H)
Example 112 : Preparation of 4'- fluoro - N '-(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-4- carbohydrazide
The title compound (17.7 mg, yield 68%) was obtained in the same manner as in Example 85 except that 4'-fluoro-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 7.96(d,2H), 7.73(m,3H), 7.70(m,2H), 7.45(m,1H), 7.20(t,2H), 6.93(dd,1H)
Example 113 : Preparation of 4'- chloro - N '-(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-4- carbohydrazide
The title compound (18.1 mg, yield 66%) was obtained in the same manner as in Example 85 except that 4'-chloro-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.00(d,2H), 7.79(d,2H), 7.76(s,1H), 7.70(d,2H), 7.50(d,2H), 7.48-7.46(m,1H), 6.96(dd,1H)
Example 114 : Preparation of 2- fluoro - N ' -(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-4- carbohydrazide
The title compound (15.9 mg, yield 61%) was obtained in the same manner as in Example 85 except that 2-fluoro-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 7.79(d,1H), 7.72(m,2H), 7.61(t,1H), 7.57(m,2H), 7.43(m,4H), 6.93(m,1H)
Example 115 : Preparation of N ' -(6- fluoropyridin -3- yl )-2- methyl -[1,1'- biphenyl ]-4- carbohydrazide
The title compound (15.2 mg, yield 59%) was obtained in the same manner as in Example 85 except that 2-methyl-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.01(s,1H), 7.76(s,1H), 7.60(m,1H), 7.51(m,1H), 7.46(m,1H), 7.05(m,3H), 6.93(dd,1H)
Example 116 : Preparation of N ' -(6- fluoropyridin -3- yl )-2- phenylpyrimidine -5- carbohydrazide
The title compound (10.9 mg, yield 44%) was obtained in the same manner as in Example 85 except that 2-phenylpyrimidine-5-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 9.28(s,2H), 8.52(d,2H), 7.79(s,1H), 7.53(m,4H), 6.96(dd,1H)
Example 117 : Preparation of 2-(4- chlorophenyl )- N ' -(6- fluoropyridin -3- yl ) pyrimidine -5- carbohydrazide
The title compound (12.7 mg, yield 46%) was obtained in the same manner as in Example 85 except that 2-(4-chlorophenyl)pyrimidine-5-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 9.28(s,2H), 8.51(d,2H), 7.79(s,1H), 7.54(d,2H), 7.50(m,1H), 6.95(d,1H)
Example 118 : Preparation of N ' -(6- fluoropyridin -3- yl )-2-( piperidin -1- yl ) pyrimidine -5- carbohydrazide
The title compound (10.6 mg, yield 42%) was obtained in the same manner as in Example 85 except that 2-(piperidin-1-yl)pyrimidine-5-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.77(s,2H), 7.72(s,1H), 7.43(m,1H), 6.93(dd,1H), 3.90(t,4H), 1.73(t,2H), 1.63(dd,4H)
Example 119 : Preparation of N ' -(6- fluoropyridin -3- yl )-4- methyl -2- phenylpyrimidine -5- carbohydrazide
The title compound (11.1 mg, yield 43%) was obtained in the same manner as in Example 85 except that 4-methyl-2-phenylpyrimidine-5-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.91(s,1H), 8.48(d,2H), 7.80(s,1H), 7.52(m,4H), 6.98(dd,1H), 2.73(s,3H)
Example 120 : Preparation of 4- benzoyl - N ' -(6- fluoropyridin -3- yl ) benzohydrazide
The title compound (14.0 mg, yield 52%) was obtained in the same manner as in Example 85 except that 4-benzoylbenzoic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.14(d,2H), 7.85(d,2H), 7.79(m,3H), 7.65(m,1H), 7.53(m,2H), 7.46(m,1H), 6.93(dd,1H)
Example 121 : Preparation of N ' -(6- fluoropyridin -3- yl )-4-(hydroxy( phenyl )methyl) benzohydrazide
The title compound (14.3 mg, yield 53%) was obtained in the same manner as in Example 85 except that 4-(hydroxy(phenyl)methyl)benzoic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 7.85(d,2H), 7.72(s,1H), 7.53(d,2H), 7.42(m,1H), 7.37(d,2H), 7.32(t,2H), 7.24(t,1H), 6.92(dd,1H), 4.09(q,1H)
Example 122 : Preparation of N ' -(6- fluoropyridin -3- yl )-4- phenoxybenzohydrazide
The title compound (18.4 mg, yield 71%) was obtained in the same manner as in Example 85 except that 4-phenoxybenzoic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CDCl3-d): 7.82-7.79(m,2H), 7.42-7.36(m,3H), 7.23-7.20(m,2H), 7.08-7.04(m,3H), 6.85-6.83(m,1H), 6.30(s,1H)
Example 123 : Preparation of 4-( benzyloxy )- N ' -(6- fluoropyridin -3- yl ) benzohydrazide
The title compound (20.3 mg, yield 75%) was obtained in the same manner as in Example 85 except that 4-(benzyloxy)benzoic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 7.86(d,2H), 7.71(s,1H), 7.42(m,5H), 7.35(m,1H), 7.10(d,2H), 6.91(dd,1H), 5.17(s,2H)
Example 124 : Preparation of N ' -(6- fluoropyridin -3- yl )-4-( hydroxydiphenylmethyl ) benzohydrazide
The title compound (19.9 mg, yield 60%) was obtained in the same manner as in Example 85 except that 4-(hydroxydiphenylmethyl)benzoic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 7.83(d,2H), 7.73(s,1H), 7.44(m,3H), 7.2(m,10H), 6.91(dd,1H)
Example 125 : Preparation of N ' -(6- fluoropyridin -3- yl )-1- naphthohydrazide
The title compound (11.0 mg, yield 49%) was obtained in the same manner as in Example 85 except that 1-naphthonic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.27(d,1H), 8.08(d,1H), 7.99(d,1H), 7.87(s,1H), 7.82(d,1H), 7.63-7.56(m,4H), 7.02(dd,1H)
Example 126 : Preparation of N ' -(6- fluoropyridin -3- yl )-2- naphthohydrazide
The title compound (10.8 mg, yield 48%) was obtained in the same manner as in Example 85 except that 2-naphthonic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.46(s,1H), 8.02-7.97(m,2H), 7.93-7.91(m,2H). 7.77(s,1H), 7.63-7.57(m,2H), 7.50-7.46(m,1H), 6.94(dd,1H)
Example 127 : Preparation of N ' -(6- fluoropyridin -3- yl )-2- hydroxydibenzo [b,d]furan-3- carbohydrazide
The title compound (14.1 mg, yield 52%) was obtained in the same manner as in Example 85 except that 2-hydroxydibenzo[b,d]furan-3-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.07(s,1H), 8.10(d,1H), 7.77(s,1H), 7.53(m,3H), 7.46(m,1H), 7.35(t,1H), 6.93(dd,1H)
Example 128 : Preparation of N ' -(6- fluoropyridin -3- yl )-9H- fluorene -2- carbohydrazide
The title compound (13.6 mg, yield 53%) was obtained in the same manner as in Example 85 except that 9H-fluorene-2-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.05(s,1H), 7.90(s,2H), 7.86(d,1H), 7.74(d,1H), 7.57(d,1H), 7.44(m,1H), 7.36(m,2H), 6.91(dd,1H), 3.94(s,2H)
Example 129 : Preparation of N ' -(6- fluoropyridin -3- yl )-9H- fluorene -3- carbohydrazide
The title compound (13.6mg, yield 53%) was obtained in the same manner as in Example 85 except that 9H-fluorene-3-carboxylic acid was used instead of benzoic acid in Example 85.
1H-NMR (500MHz, CD3OD-d4): 8.09(s,1H), 7.93(s,2H), 7.90(d,1H), 7.76(d,1H), 7.60(d,1H), 7.47(m,1H). 7.39(m,2H), 6.94(dd,1H), 3.98(s,2H)
Formulation Example 1: Tablets
50 mg of the compound prepared in Example 1, was granulated, in combination with 20 mg of magnesium stearate, using 35 mg of soluble starch and dried. The granules were then mixed with 65 mg of lactose and 30 mg of corn starch using a mechanical shaker and a mixer for 30 minutes. The resulting mixture was compressed and formulated into tablets.
Test Example 1: In vitro antifungal activity test (MIC)
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. 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℃ for a sufficient period of time, e.g., 24 hours for Candida albicans, and 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. The prepared strain dilutions were diluted in RPMI (Roswell park memorial institute) 1640 medium at a 1:10 ratio, and the resultant was diluted again at a 1:100 ratio to prepare inoculums having a cell density of from 1.0 x 103 to 5.0 x 103 CFU/ml. As for Aspergillus fumigatus, to the cultured Sabouraud dextrose agar was added 1 mL of 0.2% Tween 20 diluted with 0.85% sterile saline solution, and then the plate was shaken to detach conidiums 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 such as medium. The resulting supernatant was transferred into the sterile tube, sufficiently suspended for about 15 seconds, and strain dilutions were prepared with a cell density of from 0.4 x 106 to 5.0 x 106 CFU/ml using a hemocytometer. The thus prepared strain dilutions were diluted in RPMI 1640 medium at a 1:100 ratio to obtain inoculums for Aspergillus fumigatus. Candida albicans was cultured at 35℃ for 24 hours and Aspergillus fumigatus was cultured at 35℃ for 48 hours, and the concentrations, at which growth is inhibited by 80% or 50% compared to a negative control group, were determined using Alamar blue color developing reagent. All experiments were repeated twice for each concentration, and the results of antifungal activities (MIC80 and MIC50 ㎍/ml) are shown in Tables 1 to 3.
Table 1
Result of antifungal activity (㎍/mL)
Example No. Candida albicans MIC80 Aspergillus fumigatus MIC50 Example No. Candida albicans MIC80 Aspergillus fumigatus MIC50
1 0.03 0.4 21 0.07 -
2 0.03 - 22 0.12 -
3 0.03 - 23 0.04 0.3
4 0.03 - 24 0.03 0.6
5 0.03 - 25 0.04 0.3
6 0.03 - 26 0.08 1.3
7 0.03 - 27 <0.01 -
8 0.03 - 28 0.06 1.0
9 0.03 - 29 0.06 -
10 0.03 - 30 0.03 0.5
11 0.03 - 31 0.03 0.5
12 0.03 - 32 0.03 -
13 0.06 - 33 0.04 -
14 0.03 - 34 0.06 -
15 0.06 - 35 0.07 -
16 0.03 - 36 0.03 -
17 0.06 - 37 0.25 -
18 0.06 - 38 0.04 -
19 0.03 - 39 0.03 -
20 0.06 - 40 0.04 -
caspofungin 0.25 0.3 fluconazole 0.25 >32
'-' : No tests performed
Table 2
Result of antifungal activity (㎍/mL)
Example No. Candida albicans MIC80 Aspergillus fumigatus MIC50 Example No. Candida albicans MIC80 Aspergillus fumigatus MIC50
41 0.04 - 61 0.07 -
42 0.12 - 62 0.06 -
43 0.05 0.4 63 0.29 -
44 0.02 - 64 0.01 0.2
45 0.04 - 65 <0.01 0.3
46 0.03 - 66 0.02 0.3
47 0.26 0.5 67 0.04 0.7
48 <0.01 0.6 68 0.04 0.6
49 0.02 - 69 0.53 1.1
50 <0.01 0.3 70 0.02 1.1
51 <0.01 0.3 71 <0.01 -
52 <0.01 0.6 72 0.02 0.3
53 <0.01 - 73 0.03 -
54 0.04 - 74 0.03 0.3
55 <0.01 0.3 75 0.02 0.6
56 <0.01 0.3 76 0.03 0.3
57 <0.01 0.6 77 0.03 0.6
58 0.02 0.3 78 0.06 -
59 0.02 0.3 79 0.06 0.2
60 0.03 - 80 0.06 -
caspofungin 0.25 0.3 fluconazole 0.25 >32
'-' : No tests performed
Table 3
Result of antifungal activity (㎍/mL)
Example No. Candida albicans MIC80 Aspergillus fumigatus MIC50 Example No. Candida albicans MIC80 Aspergillus fumigatus MIC50
81 0.15 - 106 0.14 0.6
82 0.07 - 107 0.04 0.6
83 <0.01 - 108 0.04 0.6
84 <0.01 - 109 0.07 0.6
85 0.05 0.4 110 0.07 0.5
86 0.11 0.9 111 0.06 1.0
87 0.01 0.01 112 0.13 1.0
88 0.12 1.0 113 0.27 1.1
89 0.11 - 114 0.13 0.5
90 0.06 - 115 0.06 -
91 0.09 - 116 0.12 0.5
92 0.09 - 117 0.13 1.1
93 0.09 - 118 0.12 0.5
94 0.18 - 119 0.06 -
95 0.06 0.9 120 0.13 0.5
96 0.06 1.0 121 0.13 0.5
97 0.03 0.3 122 0.06 1.0
98 0.07 - 123 0.07 1.1
99 0.03 0.3 124 0.04 0.6
100 0.07 0.5 125 0.05 -
101 0.12 - 126 0.05 0.9
102 0.13 1.0 127 0.13 -
103 0.06 0.5 128 0.06 -
104 0.01 - 129 0.06 -
105 0.03 0.5
caspofungin 0.25 0.3 fluconazole >32
'-' : No tests performed
As shown in Tables 1 to 3 above, the compounds of the present invention have exhibited significantly excellent antifungal effects compared to the traditional antifungal agents such as caspofungin and fluconazole.
Test Example 2: In vitro fungicidal activity test (Minimum Fungicidal Concentration, MFC )
10 mM stock solutions were diluted 10-fold by adding with RPMI 1640 medium, followed by a 5-fold serial dilution to prepare samples of fungicidal agents. The samples were used at the highest concentration for evaluation of antifungal activity (MIC). The samples with the highest concentration of the fungicidal agents were subjected to 2-fold serial dilutions into 11 different concentrations, and mixed with the strains at a 1:1 ratio to determine the final concentrations. In particular, the concentration of dimethylsulfoxide used as an excipient was made to a final 1 % (V/V). The evaluations of the fungicidal activity of Candida albicans were performed using the test plate already completed of antifungal activity, from the highest concentration of a given sample to the concentration right next to the concentration determined to be MIC. Test solutions at each concentration were pipetted about 5 times, all were collected (about a total of 225 μL), and added into a 12-well Sabouraud dextrose agar plate. The test plate was cultured at 35℃ for 48 hours, and the minimum concentration at which no fungal growth was observed with the naked eye. The result of fungicidal activity (MFC ㎍/mL) is shown in Table 4.
Table 4
Result of fungicidal activity (MFC ㎍/mL)
Example No. Candida albicans MFC Example No. Candida albicans MFC
1 0.1 61 0.3
6 0.1 62 0.3
13 1.8 64 0.1
14 0.1 69 0.5
16 1.1 70 0.3
17 0.3 71 2.2
23 0.3 72 0.1
24 0.1 75 0.1
25 0.1 76 0.03
26 0.2 77 0.1
27 0.1 81 0.6
28 0.1 87 0.2
29 0.3 91 0.4
30 0.1 95 0.9
31 0.1 97 1.1
42 1.9 102 1.0
47 1.1 111 0.5
48 0.03 113 0.5
50 0.03 116 0.5
51 0.02 117 1.1
52 0.04 118 1.0
53 0.1 120 2.1
55 0.02 121 0.3
56 0.3 123 2.1
57 0.02 124 0.6
58 0.04 126 0.2
59 0.1 127 1.1
60 0.1
caspofungin 4 fluconazole >32
As shown in Table 4 above, the compounds of the present invention have exhibited a significantly excellent fungicidal effect over the traditional fungicides such as caspofungin and fluconazole.

Claims (18)

  1. A compound represented by Chemical Formula 1 below, or a pharmaceutically acceptable salt thereof:
    [Chemical Formula 1]
    Figure PCTKR2014008287-appb-I000013
    wherein, in Chemical Formula 1,
    R1 is H; or halogen,
    R2 is halogen; or C1 -4 alkoxy, and
    R3 is 1,3-benzodioxolyl; 2,3-dihydrobenzo[1,4]dioxinyl; biphenyl; naphthyl; isoquinolinyl; phenyl; pyridinyl; pyrimidinyl; tetrazolo[1,5-a]pyridinyl; pyridazinyl; dibenzofuranyl; or fluorenyl,
    wherein R3 is unsubstituted; or substituted with one to three substituents selected from the group consisting of halogen; C1 -4 alkyl; C1 -4 haloalkyl; cyano; C1 -4 alkoxy; nitro; dimethylamino; thiazolyl; pyrazolyl unsubstituted or substituted with one or two C1 -4 alkyl groups; tetrazolyl; phenyl unsubstituted or substituted with one or two of the same or different groups selected from C1-4 alkyl, halogen, C1-4 haloalkyl andcyano; phenoxy; pyrrolyl; piperidinyl; hydroxy; benzoyl; hydroxy(phenyl)methyl; benzyloxy; hydroxydiphenylmethyl; and
    Figure PCTKR2014008287-appb-I000014
    .
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is H or fluoro.
  3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is fluoro or methoxy.
  4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is fluoro and R2 is methoxy; or R1 is H and R2 is fluoro.
  5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is unsubstituted benzo[1,3]dioxolyl; 2,3-dihydrobenzo[b][1,4]dioxinyl; isoquinolinyl; tetrazolo[1,5-a]pyridinyl; pyridazinyl; or fluorenyl.
  6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is biphenyl, said biphenyl being unsubstituted or substituted with one to three of the same or different groups selected from halogen, hydroxy, methoxy, methyl, and
    Figure PCTKR2014008287-appb-I000015
    .
  7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is naphthyl, said naphthyl being unsubstituted or substituted with one or two of the same or different groups selected from methoxy and dimethylamino.
  8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl, said phenyl being unsubstituted or substituted with one to three of the same or different groups selected from halogen, methyl, trifluoromethyl, cyano, methoxy, nitro, dimethylamino, thiazolyl, pyrazolyl, tetrazolyl, phenoxy, pyrrolyl, benzoyl, hydroxy(phenyl)methyl, benzyloxy, and hydroxydiphenylmethyl.
  9. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R3 is pyridinyl, said pyridinyl being unsubstituted or substituted with one to three of the same or different groups selected from methoxy; fluoro; methyl; and phenyl unsubstituted or substituted with halogen, trifluoromethyl or cyano.
  10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the pyridinyl is substituted with halophenyl; halophenyl and methoxy; (trifluoromethyl)phenyl and methoxy; or cyanophenyl and methoxy.
  11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is pyrimidinyl, said pyrimidinyl being unsubstituted or substituted with one or two of the same or different groups selected from piperidinyl; methyl; phenyl unsubstituted or substituted with halogen; and methoxy.
  12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is dibenzofuranyl, said dibenzofuranyl being unsubstituted or substituted with hydroxy.
  13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is one selected from the group consisting of:
    1) N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    2) 3-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    3) 4-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    4) 3-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    5) 4-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    6) 3-bromo-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    7) 4-bromo-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    8) N'-(5-fluoro-6-methoxypyridin-3-yl)-3-methylbenzohydrazide,
    9) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-methylbenzohydrazide,
    10) N'-(5-fluoro-6-methoxypyridin-3-yl)-3-(trifluoromethyl)benzohydrazide,
    11) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-(trifluoromethyl)benzohydrazide,
    12) 3-cyano-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    13) 4-cyano-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    14) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-methoxybenzohydrazide,
    15) 6-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)nicotinohydrazide,
    16) 6-bromo-N'-(5-fluoro-6-methoxypyridin-3-yl)nicotinohydrazide,
    17) N'-(5-fluoro-6-methoxypyridin-3-yl)-6-(trifluoromethyl)nicotinohydrazide,
    18) 6-cyano-N'-(5-fluoro-6-methoxypyridin-3-yl)nicotinohydrazide,
    19) N'-(5-fluoro-6-methoxypyridin-3-yl)-2-methoxynicotinohydrazide,
    20) N'-(5-fluoro-6-methoxypyridin-3-yl)-2-methoxypyrimidine-4-carbohydrazide,
    21) 4-bromo-3-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    22) 4-cyano-3-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    23) 4-bromo-3-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    24) 3-bromo-4-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    25) 3-bromo-4-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    26) 3-bromo-N'-(5-fluoro-6-methoxypyridin-3-yl)-4-(trifluoromethyl)benzohydrazide,
    27) 4-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-3-methylbenzohydrazide,
    28) 4-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)-3-methylbenzohydrazide,
    29) N'-(5-fluoro-6-methoxypyridin-3-yl)-3-methyl-4-nitrobenzohydrazide,
    30) 4-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-3-(trifluoromethyl)benzohydrazide,
    31) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzohydrazide,
    32) N'-(5-fluoro-6-methoxypyridin-3-yl)-2,3-dimethoxybenzohydrazide,
    33) 5-bromo-N'-(5-fluoro-6-methoxypyridin-3-yl)-2-methoxybenzohydrazide,
    34) 4-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-3-nitrobenzohydrazide,
    35) 3-(dimethylamino)-N'-(5-fluoro-6-methoxypyridin-3-yl)-4-methoxybenzohydrazide,
    36) N'-(5-fluoro-6-methoxypyridin-3-yl)benzo[d][1,3]dioxole-5-carbohydrazide,
    37) N'-(5-fluoro-6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide,
    38) 6-bromo-5-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)picolinohydrazide,
    39) 5-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-6-methylnicotinohydrazide,
    40) 5-bromo-6-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)nicotinohydrazide,
    41) 5-bromo-6-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)nicotinohydrazide,
    42) 2-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)-6-methylisonicotinohydrazide,
    43) N'-(5-fluoro-6-methoxypyridin-3-yl)pyrimidine-5-carbohydrazide,
    44) 5-bromo-2,4-dichloro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    45) 5-bromo-2,4-difluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    46) N'-(5-fluoro-6-methoxypyridin-3-yl)-3,5-dimethoxy-4-methylbenzohydrazide,
    47) N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    48) 3'-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    49) 2'-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    50) 4'-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    51) 2'-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    52) 3'-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    53) 4'-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    54) N'-(5-fluoro-6-methoxypyridin-3-yl)-2'-methoxy-[1,1-biphenyl]-3-carbohydrazide,
    55) N'-(5-fluoro-6-methoxypyridin-3-yl)-3'-methoxy-[1,1-biphenyl]-3-carbohydrazide,
    56) N'-(5-fluoro-6-methoxypyridin-3-yl)-4'-methoxy-[1,1-biphenyl]-3-carbohydrazide,
    57) 6-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    58) 4'-chloro-6-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    59) 6-chloro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    60) N'-(5-fluoro-6-methoxypyridin-3-yl)-3-(thiazole-2-yl)benzohydrazide,
    61) 3-(3,5-dimethyl-1H-pyrazol-1-yl)-N'-(5-fluoro-6-methoxypyridin-3-yl)benzohydrazide,
    62) N'-(5-fluoro-6-methoxypyridin-3-yl)-3-(1H-tetrazol-1-yl)benzohydrazide,
    63) 6-(4-chlorophenyl)-N'-(5-fluoro-6-methoxypyridin-3-yl)picolinohydrazide,
    64) N'-(5-fluoro-6-methoxypyridin-3-yl)-5-(4-fluorophenyl)-6-methoxynicotinohydrazide,
    65) 5-(4-chlorophenyl)-N'-(5-fluoro-6-methoxypyridin-3-yl)nicotinohydrazide,
    66) 5-(4-chlorophenyl)-N'-(5-fluoro-6-methoxypyridin-3-yl)-6-methoxynicotinohydrazide,
    67) N'-(5-fluoro-6-methoxypyridin-3-yl)-6-methoxy-5-(4-(trifluoromethyl)phenyl)nicotinohydrazide,
    68) 5-(4-cyanophenyl)-N'-(5-fluoro-6-methoxypyridin-3-yl)-6-methoxynicotinohydrazide,
    69) N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-4-carbohydrazide,
    70) 2-fluoro-N'-(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-4-carbohydrazide,
    71) N'-(5-fluoro-6-methoxypyridin-3-yl)-2-methyl-[1,1-biphenyl]-4-carbohydrazide,
    72) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-phenoxybenzohydrazide,
    73) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-(1H-pyrrole-1-yl)benzohydrazide,
    74) N'-(5-fluoro-6-methoxypyridin-3-yl)-2-phenylpyrimidine-5-carbohydrazide,
    75) 2-(4-chlorophenyl)-N'-(5-fluoro-6-methoxypyridin-3-yl)pyrimidine-5-carbohydrazide,
    76) N'-(5-fluoro-6-methoxypyridin-3-yl)-2-(piperidin-1-yl)pyrimidine-5-carbohydrazide,
    77) N'-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-2-phenylpyrimidine-5-carbohydrazide,
    78) N'-(5-fluoro-6-methoxypyridin-3-yl)-2-naphthohydrazide,
    79) N'-(5-fluoro-6-methoxypyridin-3-yl)isoquinoline-4-carbohydrazide,
    80) N'-(5-fluoro-6-methoxypyridin-3-yl)tetrazolo[1,5-a]pyridine-6-carbohydrazide,
    81) N'-(5-fluoro-6-methoxypyridin-3-yl)-4,7-dimethoxy-1-naphthohydrazide,
    82) 4-(dimethylamino)-N'-(5-fluoro-6-methoxypyridin-3-yl)-1-naphthohydrazide,
    83) N'3,N'3'-bis(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3,3'-dicarbohydrazide,
    84) N'3,N'4'-bis(5-fluoro-6-methoxypyridin-3-yl)-[1,1-biphenyl]-3,4'-dicarbohydrazide,
    85) N'-(6-fluoropyridin-3-yl)benzohydrazide,
    86) 4-cyano-3-fluoro-N'-(6-fluoropyridin-3-yl)benzohydrazide,
    87) 4-fluoro-N'-(6-fluoropyridin-3-yl)-3-methylbenzohydrazide,
    88) N'-(6-fluoropyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzohydrazide,
    89) 3-cyano-4-fluoro-N'-(6-fluoropyridin-3-yl)benzohydrazide,
    90) 3-(dimethylamino)-N'-(6-fluoropyridin-3-yl)-4-methoxybenzohydrazide,
    91) N'-(6-fluoropyridin-3-yl)pyrimidine-4-carbohydrazide,
    92) N'-(6-fluoropyridin-3-yl)pyrimidine-2-carbohydrazide,
    93) N'-(6-fluoropyridin-3-yl)pyrimidine-5-carbohydrazide,
    94) N'-(6-fluoropyridin-3-yl)pyridazine-4-carbohydrazide,
    95) N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    96) 4'-fluoro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    97) 4'-chloro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    98) 2',4'-difluoro-N'-(6-fluoropyridin-3-yl)-4-hydroxy-[1,1-biphenyl]-3-carbohydrazide
    99) 6-(4-chlorophenyl)-N'-(6-fluoropyridin-3-yl)picolinohydrazide,
    100) 5-(4-chlorophenyl)-N'-(6-fluoropyridin-3-yl)nicotinohydrazide,
    101) N'-(6-fluoropyridin-3-yl)-6-phenylpyrimidine-4-carbohydrazide,
    102) 6-(4-fluorophenyl)-N'-(6-fluoropyridin-3-yl)pyrimidine-4-carbohydrazide,
    103) 6-fluoro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    104) 4'-chloro-6-fluoro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    105) 6-chloro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-3-carbohydrazide,
    106) 5-(4-fluorophenyl)-N'-(6-fluoropyridin-3-yl)-6-methoxynicotinohydrazide,
    107) 5-(4-chlorophenyl)-N'-(6-fluoropyridin-3-yl)-6-methoxynicotinohydrazide,
    108) N'-(6-fluoropyridin-3-yl)-6-methoxy-5-(4-(trifluoromethyl)phenyl)nicotinohydrazide,
    109) 5-(4-cyanophenyl)-N'-(6-fluoropyridin-3-yl)-6-methoxynicotinohydrazide,
    110) 3-benzoyl-N'-(6-fluoropyridin-3-yl)benzohydrazide,
    111) N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-4-carbohydrazide,
    112) 4'-fluoro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-4-carbohydrazide,
    113) 4'-chloro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-4-carbohydrazide,
    114) 2-fluoro-N'-(6-fluoropyridin-3-yl)-[1,1-biphenyl]-4-carbohydrazide,
    115) N'-(6-fluoropyridin-3-yl)-2-methyl-[1,1-biphenyl]-4-carbohydrazide,
    116) N'-(6-fluoropyridin-3-yl)-2-phenylpyrimidine-5-carbohydrazide,
    117) 2-(4-chlorophenyl)-N'-(6-fluoropyridin-3-yl)pyrimidine-5-carbohydrazide,
    118) N'-(6-fluoropyridin-3-yl)-2-(piperidin-1-yl)pyrimidine-5-carbohydrazide,
    119) N'-(6-fluoropyridin-3-yl)-4-methyl-2-phenylpyrimidine-5-carbohydrazide,
    120) 4-benzoyl-N'-(6-fluoropyridin-3-yl)benzohydrazide,
    121) N'-(6-fluoropyridin-3-yl)-4-(hydroxy(phenyl)methyl)benzohydrazide,
    122) N'-(6-fluoropyridin-3-yl)-4-phenoxybenzohydrazide,
    123) 4-(benzyloxy)-N'-(6-fluoropyridin-3-yl)benzohydrazide,
    124) N'-(6-fluoropyridin-3-yl)-4-(hydroxydiphenylmethyl)benzohydrazide,
    125) N'-(6-fluoropyridin-3-yl)-1-naphthohydrazide,
    126) N'-(6-fluoropyridin-3-yl)-2-naphthohydrazide,
    127) N'-(6-fluoropyridin-3-yl)-2-hydroxydibenzo[b,d]furan-3-carbohydrazide,
    128) N'-(6-fluoropyridin-3-yl)-9H-fluorene-2-carbohydrazide, and
    129) N'-(6-fluoropyridin-3-yl)-9H-fluorene-3-carbohydrazide.
  14. A method for preparing a compound represented by Chemical Formula 1, the method comprising:
    reacting a compound represented by Chemical Formula 2 below with tert-butyl carbamate(=Boc) to obtain a compound represented by Chemical Formula 3 below;
    reacting a compound represented by Chemical Formula 3 below with hydroxylamine in the presence of a base to obtain a compound represented by Chemical Formula 4 below;
    reacting a compound represented by Chemical Formula 4 below with an acid to remove a protecting group, thereby obtaining a compound represented by Chemical Formula 5 below; and
    reacting a compound represented by Chemical Formula 5 below with a compound represented by Chemical Formula 6 below to obtain a compound represented by Chemical Formula 1 below:
    [Chemical Formula 1]
    Figure PCTKR2014008287-appb-I000016
    [Chemical Formula 2]
    Figure PCTKR2014008287-appb-I000017
    [Chemical Formula 3]
    Figure PCTKR2014008287-appb-I000018
    [Chemical Formula 4]
    Figure PCTKR2014008287-appb-I000019
    [Chemical Formula 5]
    Figure PCTKR2014008287-appb-I000020
    [Chemical Formula 6]
    Figure PCTKR2014008287-appb-I000021
    wherein, in above Chemical Formulas, R1, R2, and R3 are the same as defined in claim 1.
  15. A compound represented by Chemical Formula 5 below:
    [Chemical Formula 5]
    Figure PCTKR2014008287-appb-I000022
    wherein, in above Chemical Formula, R1 and R2 are the same as defined in claim 1.
  16. A pharmaceutical composition comprising a compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.
  17. A pharmaceutical composition for treating or preventing fungal infections comprising a compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient.
  18. A method for treating or preventing fungal infections in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.
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CN111533687A (en) * 2020-05-08 2020-08-14 张建蒙 Cinnamide pyridine derivatives and application thereof in antifungal drugs
CN113968852A (en) * 2020-07-23 2022-01-25 同济大学 Thiazole hydrazide derivative and preparation method and application thereof
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