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  • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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  • C07C237/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
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  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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  • 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
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
  • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
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  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
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  • C07C2601/00—Systems containing only non-condensed rings
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  • C07C2601/14—The ring being saturated
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  • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

• the present invention relates to a novel alkylcarbamoyl naphthalenyloxyoctenoyl hydroxyamide derivative, a method for preparing same and an anticancer composition comprising same.
• Histones associate with DNAs in the nuclei of eukaryotic cells as basic proteins and are subject to reversible acetylation at the amino group of the lysine residue.
• the reversible acetylation is involved in the formation of chromatin of a higher order structure, the cell division cycle and ultimately the gene expression, and can be regulated by the dynamic balance established between the opposing activities of histone acetyl transferases (HATs) and histone deacetylases (HDACs): means enzymes neutralize or restore the positive charges of lysine residues (e.g., 4 lysine residues in H4) by acetylation/deacetylation to regulate the gene transcriptional level.
• HATs histone acetyl transferases
• HDACs histone deacetylases
• HDACs play an important role in cell cancerization or differentiation and their expression is enhanced under conditions such as hypoxia, lowered glucose, and cell cancerization, to inhibit the expression of cell proliferation inhibitors. That is, histone deacetylation by HDAC causes cell proliferation, while hyperacetylation of histone facilitates the inhibition of cell proliferation and cell differentiation. Therefore, when HDACs are inhibited, cell proliferation and angiogenesis can be controlled. Abnormal histone deacetylation has been reported to cause acute promyelocytic leukemica (APL) (Lin R. J. et. al. Oncogene 20: 7204, 2001; Zelent A. et. al. Oncogene 20: 7186, 2001).
• APL acute promyelocytic leukemica
• HDAC has been one of the targets for the study of anticancer drugs as well as gene expression inhibitor and there have been attempts to develope ECDAC inhibitors as anticancer drugs.
• HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA) or apicidin inhibit the proliferation of cancer cells and induce cell differentiation (Munster P. N. et al., Cancer research 61 : 8492, 2001 ; Han J. W. et. al. Cancer research 60: 6068, 2000).
• SAHA suberoylanilide hydroxamic acid
• apicidin inhibit the proliferation of cancer cells and induce cell differentiation
• HDAC HDAC
• TSA Trichostatin A
• Ri is hydrogen or Ci -3 alkyl
• R 2 is Ci -6 alkyl optionally having one or more substituents selected from the group consisting of diCi -3 alkylamino, oxopyrrolidinyl, pyrrolidinyl, piperidinyl, morpholinyl, Ci -3 alkylpiperazinyl, cyano, hydroxy, imidazolyl, methoxy, tetrahydrofuran, C 3-8 cycloalkenyl, and thiophenyl; C ]-6 alkyl substituted with hydroxyphenyl, fluorophenyl, diC )-3 alkyl amino phenyl, methoxyphenyl and trifluoromethoxyphenyl; pyrrolidine substituted with C].
• Ri and R 2 may optionally form a morpholinyl, piperidinyl or piperazinyl ring together with the nitrogen atom to which they are bonded.
• an anti-cancer composition and an inhibitor of histone deacetylase activity comprising the compound of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
• alkylcarbamoyl naphthalenyloxyoctenoyl hydroxy amide derivatives of formula (1) include:
• the inventive compound of formula (I) may be used in the form of a pharmaceutically acceptable addition salt formed with an inorganic acid or organic acid.
• the acid include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, glycolic, lactic, pyrubic, malonic, succinic, glutaric, fumaric, malic, mandelic, tartaric, citric, ascorbic, palmitic, maleic, hydroxy maleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, methanesulfonic, benzenesulfonic, and toluenesulfonic acid.
• inventive alkylcarbamoyl naphthalenyloxyoctenoyl hydroxyamide derivatives of formula (1) may be prepared by the method comprising the steps of:
• Ri and R 2 have the same meanings as defined in formula (1) above, and Y is C M alkyl.
• R] and R 2 have the same meanings as defined in formula (1) above, and
• Y is C ]-4 alkyl.
• step 1) of Reaction Scheme 1 ⁇ -caprolactone (formula 2) is dissolved in methanol and treated with concetrated sulfuric acid to form the 1, 6-hydroxy-hexanoic acid methylester of formula 3, which is then added to a pyridinium chlorochromate solution and reacted for 2 hrs to obtain 6-oxo- hexanoic acid methylester (formula 3).
• a solvent such as dichloromethane, tetrahydrofuran, or dichloroethane.
• a hydroxy compound (formula 4) is obtained by the Baylis- Hillman reaction carried out between a 6-oxo-hexanoic acid methylester (formula 3) and a C 1 . 4 alkylacrylate in the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO) at 0-25 ° C for 5-7 days, above ethyl acrylate, isobutyl acrylate, or t-butyl acrylate may be used as the alkyl acrylate.
• DABCO 1,4- diazabicyclo[2.2.2]octane
• the reaction step 3) is carried out using a bromination agent in an organic solvent.
• the organic solvent include ethylether, dichloromethane and hydrofuran
• representative examples of the bromination agent include PBr 3 , CBr 4 and N-bromo succinic acid (NBS).
• the bromo compound (formula 5) is reacted with 1-naphthol to obtain an alcohol compound (formula 6) using acetone or acetonitrile as a solvent in the presence of potassium carbonate, sodium bicarbonate, or sodium carbonate.
• the ester hydrolysis step 5 is carried out in the presence of an inorganic or organic acid in a solvent such as dichloromethane, tetrahydrofuran or N 5 N ' -dimethylformamide.
• a solvent such as dichloromethane, tetrahydrofuran or N 5 N ' -dimethylformamide.
• Representative examples of the inorganic acid include hydrochloric acid, sulfuric acid and phosphoric acid and representative examples of the organic acid include trifluoroacetic acid (TFA).
• Acylation step 6) is carried out using N-Methanesulfonyloxy-6- trifluoromethylbenzotriazole (FMS), N-hydroxy-6-trifluorobenzotriazole (FOBT) or l-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC • HCl) as an acylation agent in an aprotic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or dichloromethane.
• the reaction in step 7) is preferably carried out using an aqueous alcohol or tetrahydrofuran solvent, and lithium hydroxide (LiOH - H 2 O) or sodium hydroxide as the inorganic base.
• the acylation in step 8) is carried out in an organic solvent in the presence of N-hydroxy-6-trifluorobenzotriazole (FOBT) and l-(3- diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl).
• Representative examples of the organic solvent include N 5 N'- dimethylformamide, dimethylsulfoxide, tetrahydrofuran and dichloromethane.
• Removing the tetrahydropyranyl group from the compound of formula (10) in step 9) is carried out in a solvent such as methanol, ethanol, tetrahydrofuran or dichloromethane.
• the starting material (formula 2) for preparing the alkylcarbamoyl naphthalenyloxyoctenoyl hydroxyamide derivatives of formula (1) is commercially available.
• the inventive alkylcarbamoyl naphthalenyloxyoctenoyl hydroxyamide derivative of formula (1) efficiently inhibits the activity of histone deacetylase, resulting in the efficient suppression of the cancer-cell proliferation.
• the present invention also provides an inhibitor of histone deacetylase activity comprising the compound of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
• the present invention provides an anti-cancer composition
• an anti-cancer composition comprising the compound of formula (1) as an active ingredient and a pharmaceutically acceptable carrier.
• the inventive pharmaceutical composition comprises the compound of formula (1) as an active ingredient in an amount ranging from 0.1 to 75 wt%, preferably 1 to 50 wt%, based on the total weight of the composition.
• the pharmaceutical composition may be formulated for oral or parenteral administration.
• the formulation for oral administration may take various forms such as tablet, pill, powder, sachet, soft and hard capsule, solution, suspension, emulsion, syrup, granule and the like, which may contain conventional additives such as a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), a lubricant (e.g., silica, talc, stearic acid or its zinc, magnesium or calcium salt, and/or polyethylene glycol).
• a diluent e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
• a lubricant e.g., silica, talc, stearic acid or its zinc, magnesium or calcium salt, and/or polyethylene glycol.
• a tablet form may also comprise a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxylmethyl cellulose and/or polyvinylpyrrolidone, and optionally a disintegrant such as starch, agar, alginic acid or its sodium salt, an effervescent mixture, an absorbent, a colorant, a flavor and a sweetener.
• a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxylmethyl cellulose and/or polyvinylpyrrolidone
• a disintegrant such as starch, agar, alginic acid or its sodium salt, an effervescent mixture, an absorbent, a colorant, a flavor and a sweetener.
• sterile injectable formulations such as istonic solution and suspension may be preferred.
• composition may be steriled, additionally include preservatives, stabilizers, wetting agents, emulsifying agents, osmotic pressure-adjusting agents, buffering agents and the like, and may be formulated through a conventional mixing, granulating or coating procedures.
• a typical daily dose of the compound of formula (1) ranges from about
• Preparation Example 2 was dissolved in the mixture of water and dioxane (1 :1) (100 mL), acrylic t-butyl ester (60.96 ml, 461.17 mM) was added thereto, and l,4-diazabicyclo[2.2.2]octane (DABCO) (15.56 g, 138.72 mM) in the mixture of water and dioxane (1 :1) (63 mL) were sequentially added thereto, and the mixture was stirred for 7 days. After the completion of the reaction, ice water was poured thereinto and the mixture was extracted with ethyl ether.
• DABCO l,4-diazabicyclo[2.2.2]octane
• the amine compound (RjR 2 NH or R 2 NH 2 ) for preparing the compound of formula 8 is commercially available, or can be readily synthesized by the conventional method.
• Substituted pyrrolidine and piperidine may be synthesized as described in the Reaction Scheme B.
• R is Ci_ 3 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-3 alkyl, benzyl, or C 3- g cycloalkyl carbonyl.
• l-Benzylpiperidine-4-amine (3g, 15.8mml), the starting material, was dissolved in IM aqueous sodium hydroxide solution (35.8 ml) and t-butanol (32 ml) in the 250 ml reaction vessel, ?-butyl dicarbonate ((?-Boc) 2 O; 3.79 g, 17.38 mmol) was added thereto while stirring, and the mixture was reacted for 12 hrs. After the completion of the reaction, the reaction mixture was extracted with ethyl ether 2 times. The extract was washed with 0.1N hydrochloric acid solution and salt water in order.
• Method A ?-butyl piperidin-4-ylcarbamate (3 g, 15 mmol) obtained in Preparation Example II was dissolved in methanol (30ml) in the 100 ml reaction vessel, acetone (7.70 ml, 105 mmol) and acetic acid (0.45 ml, 7.5 mmol) were added thereto while stirring, 4 portions of NaCNBH 3 (1.88 mg, 30 mmol) were added dropwise and reacted for 18 hrs. After the completion of the reaction, ice water was poured thereinto and then the mixture was stirred and extracted with ethyl ether. The extract was washed with sodium bicarbonate and salt water in order.
• Method B /-butyl piperidin-4-ylcarbamate (1.5 g, 7.49 mmol) obtained in Preparation Example II was dissolved in N,N-dimethylformamide (19 ml) in the 25 ml reaction vessel, K 2 CO 3 (2.07 g, 14.98 mmol, 2 eq.) and iodoethane (0.60 ml, 7.49 mmol, 1 eq.) were added thereto while stirring, heated from 0 ° C to room temperature and kept for 4 hrs. After the completion of the reaction, the solvent was distilled under a reduced pressure and the remaining was extracted with ethyl ester.
• the starting material (10 g, 57 mmol) was dissolved in 3M aqueous sodium hydroxide solution (21 ml) and ⁇ -butanol (114 ml) in the 500 ml reaction vessel, r-butyl dicarbonate ((r-Boc) 2 O; 13.07 g, 59.9 mmol) was added thereto while stirring, kept for 12 hrs. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate 2 times. The extract was washed with 0.1N hydrochloric acid solution and salt water in order.
• the starting material (15.75 g, 57.0 mmol) was dissolved in methanol and tetrabutylfuran (4:1) (114 ml) in the 100 ml reaction vessel, catalytic quantities of 10% active palladium/carbon was added thereto, and reacted under the hydrogen for 12 hrs. After the completion of the reaction, the 5 reduction mixture was filtered through a cellite pad to remove palladium/carbon and the solvent was removed therefrom under a reduced pressure. Then, the mixture was subjected to silica gel column chromatography to obtain 9.5 Ig of the title compound (yield: 99%).
• Method B The starting material (1.5 g, 8.05 mmol) was dissolved in N,N-dimethylformamide (20 ml) at 0 ° C in the 100 ml reaction vessel, K 2 CO 3 5 (2.23 g, 16.1 mmol, 2 eq.) and iodoethane (0.64 ml, 8.05 mmol, 1 eq.) were added thereto while stirring, heated from 0 ° C to room temperature, and kept for 12 hrs. After the completion of the reaction, the solvent was distilled under a reduced pressure and the remaining was extracted with ethyl ester. The extract was washed with saturated sodium bicarbonate and salt water in o order.
• Method C The starting material (1 g, 5.4 mmol) was dissolved in dichloromethane (14 ml) at 0 ° C in the 50 ml reaction vessel, triethyl 5 amine(0.83 ml, 5.94 mmol, 1.1 eq.) and cyclohexylcarbonyl chloride (0.79 ml, 5.94 mmol, 1.1 were added thereto while stirring, heated from 0 ° C to room temperature, and kept for 4 hrs. After the completion of the reaction, the solvent was distilled under a reduced pressure and the remaining was extracted with dichloromethane. The extract was washed with sodium o bicarbonate and salt water in order.
• reaction solution was cooled to 5 ° C and 2 N hydrochloric acid was added thereto to adjust its pH to 4.
• the resulting mixture was filtered and dried over anhydrous magnesium sulfate, to obtain 413 mg of the title compound as a white solid (yield: 99%).
• N-t- butyldimethylsilyloxyamine (256 mg, 1.74 mM) was added thereto and stirred at room temperature for 1 hr. After the completion of the reaction, 5 ice water was poured thereinto and the mixture was extracted with ethyl acetate. The extract was successively washed with sodium bicarbonate, dried over anhydrous sodium sulfate, and filtered. The solvent was removed and resulting residue was subjected to silica gel column chromatography, to obtain 280 mg of the title compound as a white solid (yield: 65%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 2- (dimethylamino)ethylamine instead of dimethylaminehydrochloride as the amine to obtain 428 mg of the title compound (yield: 86%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (2-1) as the starting material, to obtain 335 mg of the title compound (yield: 81%).
• Example (1-3) (E)-Nl-(2-(dimethyIamino)ethyl)-N8-hydroxy-2-((naphthalen-l- yloxy)methyl)octenediamide
• Example (2-2) (E)-Nl-(2-(dimethyIamino)ethyl)-N8-hydroxy-2-((naphthalen-l- yloxy)methyl)octenediamide
• Example (1-1) The procedure of Example (1-1) was repeated except for using (2- (dimethylamino)ethyl)(methyl)amine instead of dimethylaminehydrochloride as the amine to obtain 351 mg of the title compound (yield: 77%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (3-1) as the starting material, to obtain 224 mg of the title compound (yield: 92%).
• Example (1-3) The procedure of Example (1-3) was repeated except for using the compound obtained in Example (3-2) as the starting material, to obtain 155 mg of the title compound (yield: 68%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (4-1) as the starting material, to obtain 130 mg of the title compound (yield: 81%).
• N-hydroxy-6-trifluoro-6- trifluorobenzotriazole 159 mg, 0.78 mM
• l-(3-diethylaminopropyl)-3- ethylcarbodiimidhydrochloride 177 mg, 0.92 mM
• tetrahydropyranyl oxyamine 125 mg, 1.07 mM
• Example (1-1) The procedure of Example (1-1) was repeated except for using (2- (diethylamino)ethyl)(methyl)amine instead of dimethylaminehydrochloride as the amine to obtain 483 mg of the title compound (yield: 71%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (5-1) as the starting material, to obtain 300 mg of the title compound (yield: 65%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (5-2) as the starting material, to obtain 320 mg of the title compound (yield: 87%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (5-3) as the starting material, to obtain 285 mg of the title compound (yield: 93%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 2- (pyrrolidin-l-yl)ethylamine instead of dimethylaminehydrochloride as the amine to obtain 74 mg of the title compound (yield: 29%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (6-1) as the starting material, to obtain 69 mg 5 of the title compound (yield: 96%).
• Example (6-2) The procedure of Example (6-2) was repeated except for using the compound obtained in Example (4-3) as the starting material, to obtain 87 mg of the title compound (yield: 85%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the o compound obtained in Example (6-3) as the starting material, to obtain 72 mg of the title compound (yield: 84%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 2- (piperidin-l-yl)ethylamine instead of dimethylaminehydrochloride as the amine to obtain 290 mg of the title compound (yield: 94%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (7-1) as the starting material, to obtain 256 mg of the title compound (yield: 94%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (7-2) as the starting material, to obtain 288 mg of the title compound (yield: 91%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (7-3) as the starting material, to obtain 213 mg of the title compound (yield: 94%).
• Example 8 (E)-N8-hydroxy-Nl-(2-morphoIinoethyl)-2-((naphthalen-l- yloxy)methyl)octenediamide (8-l):(E)-8-(2-morphoIinoethylamino)-7-((naphthalen-l-yloxy)methyl)-8- oxo-6-octene acid methylester
• Example (1-1) The procedure of Example (1-1) was repeated except for using 2- morpholinoethylamine instead of dimethylaminehydrochloride as the amine to obtain 266 mg of the title compound (yield: 91%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (8-1) as the starting material, to obtain 250 mg of the title compound (yield: 96%).
• Example (1-3) The procedure of Example (1-3) was repeated except for using the compound obtained in Example (8-2) as the starting material, to obtain 155 mg of the title compound (yield: 90%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using A- methylpiperazin-1-ylamine instead of dimethylaminehydrochloride as the amine to obtain 175 mg of the title compound (yield: 41%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (9-1) as the starting material, to obtain 168 mg of the title compound (yield: 100%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (9-2) as the starting material, to obtain 317 mg of the title compound (yield: 83%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (9-3) as the starting material, to obtain 287 mg of the title compound (yield: 92%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 2-(4- methylpiperazin-l-yl)ethylamine instead of dimethylaminehydrochloride as the amine to obtain 225 mg of the title compound (yield: 48%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the 0 compound obtained in Example (10-1) as the starting material, to obtain 157 mg of the title compound (yield: 76%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (10-2) as the starting material, to obtain 137 mg of the title compound (yield: 54%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (10-3) as the starting material, to obtain 118 mg of the title compound (yield: 76%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using cyanomethylamineas instead of dimethylaminehydrochloride the amine to obtain 299 mg of the title compound (yield: 76%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (11-1) as the starting material, to obtain 250 mg of the title compound (yield: 84%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (11-2) as the starting material, to obtain 222 mg of the title compound (yield: 64%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (11-3) as the starting material, to obtain 170 5 mg of the title compound (yield: 75%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 2- o hydroxyethylamine instead of dimethylaminehydrochloride as the amine to obtain 366 mg of the title compound (yield: 93%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (12-1) as the starting material, to obtain 320 mg of the title compound (yield: 88%).
• Example (1-3) The procedure of Example (1-3) was repeated except for using the compound obtained in Example (12-2) as the starting material, to obtain 262 mg of the title compound (yield: 90%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 1- methylpyrrolidin-3-ylamine instead of dimethylaminehydrochloride as the amine to obtain 355 mg of the title compound (yield: 91%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (13-1) as the starting material, to obtain 320 mg of the title compound (yield: 86%).
• Example (1-3) The procedure of Example (1-3) was repeated except for using the compound obtained in Example (13-2) as the starting material, to obtain 188 o mg of the title compound (y ield : 41 %) .
• Example (1-1) The procedure of Example (1-1) was repeated except for using 3- (dimethylamino)propylamine instead of dimethylaminehydrochloride as the amine to obtain 467 mg of the title compound (yield: 73%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (14-1) as the starting material, to obtain 154 mg of the title compound (yield: 83%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (14-2) as the starting material, to obtain 160 mg of the title compound (yield: 89%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (14-3) as the starting material, to obtain 142 mg of the title compound (yield: 92%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using morpholinoamine instead of dimethylaminehydrochloride as the amine to obtain 416 mg of the title compound (yield: 67%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (15-1) as the starting material, to obtain 85 mg of the title compound (yield: 89%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (15-2) as the starting material, to obtain 92 mg of the title compound (yield: 88%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (15-3) as the starting material, to obtain 64 mg of the title compound (yield: 72%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 6-(4- methylpiperazin-l-yl)pyridin-3-ylamine instead of dimethylaminehydrochloride as the amine to obtain 216 mg of the title compound (yield: 37%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (16-1) as the starting material, to obtain 249 mg of the title compound (yield: 94%).
• Example (1-3) The procedure of Example (1-3) was repeated except for using the compound obtained in Example (16-2) as the starting material, to obtain 132 mg of the title compound (yield: 72%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 6-(2- morpholinoethylamino)pyridin-3-yl instead of dimethylaminehydrochloride amine as the amine to obtain 350 mg of the title compound (yield: 64%).
• Example (1-2) was repeated except for using the compound obtained in Example (17-1) as the starting material, to obtain 207 mg of the title compound (yield: 87%).
• Example (1-3) The procedure of Example (1-3) was repeated except for using the compound obtained in Example (17-2) as the starting material, to obtain 171 5 mg of the title compound (yield: 48%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using not dimethylaminehydrochloride but 6-(dimethylamino)pyridin-3-ylamine as the o amine to obtain 256 mg of the title compound (yield: 63%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (18-1) as the starting material, to obtain 190 mg of the title compound (yield: 76%).
• Example (1-3) The procedure of Example (1-3) was repeated except for using the compound obtained in Example (18-2) as the starting material, to obtain 90 mg of the title compound (yield: 46%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 6-(2- (dimethylamino)ethylamino)pyridin-3-ylamine instead of dimethylaminehydrochloride as the amine to obtain 307 mg of the title compound (yield: 31%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (19-1) as the starting material, to obtain 226 mg of the title compound (yield: 75%).
• Example (1-3) The procedure of Example (1-3) was repeated except for using the compound obtained in Example (19-2) as the starting material, to obtain 11 mg of the title compound (yield: 5%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using (6- methoxypyridin-3-yl)amine instead of dimethylaminehydrochloride as the amine to obtain 1.67 mg of the title compound (yield: 42%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (20-1) as the starting material, to obtain 670 mg of the title compound (yield: 40%).
• Example (1-3) The procedure of Example (1-3) was repeated except for using the compound obtained in Example (20-2) as the starting material, to obtain 482 mg of the title compound (yield: 69%).
• Example 21 (E)-Nl-(3-(lH-imidazoI-l-yl)propyl)-N8-hydroxy-2- ((naphthalen-l-yl)methyl)octenediamide (21-l):(E)-8-(3-(lH-imidazol-l-yl)propylamino)-7-((naphthalen-l- yl)methyl)-8-oxo-6-octene acid methylester
• Example (1-1) The procedure of Example (1-1) was repeated except for using 3-(1H- imidazol-l-yl)propylamine instead of dimethylaminehydrochloride as the amine to obtain 449 mg of the title compound (yield: 77%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (21-1) as the starting material, to obtain 350 mg of the title compound (yield: 85%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (21-2) as the starting material, to obtain 220 mg of the title compound (yield: 63%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (21-3) as the starting material, to obtain 63 mg of the title compound (yield: 37%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 4- hydroxyphenetylamine instead of dimethylaminehydrochloride as the amine to obtain 461 mg of the title compound (yield: 95%).
• Example (1-2) was repeated except for using the compound obtained in Example (22-1) as the starting material, to obtain 439 mg of the title compound (yield: 92%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (22-2) as the starting material, to obtain 394 mg of the title compound (yield: 75%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (22-3) as the starting material, to obtain 121 mg of the title compound (yield: 78%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 3- (dimethylamino)-2,2-dimethylpropylamine instead of dimethylaminehydrochloride as the amine to obtain 454 mg of the title 5 compound (yield: 75%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (23-1) as the starting material, to obtain 339 mg of the title compound (yield: 93%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (23-2) as the starting material, to obtain 304 mg of the title compound (yield: 52%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (23-3) as the starting material, to obtain 144 mg of the title compound (yield: 74%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 2- (diisopropylamino)ethylamine instead of dimethylaminehydrochloride as the amine to obtain 420 mg of the title compound (yield: 89%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (24-1) as the starting material, to obtain 420 mg of the title compound (yield: 78%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (24-2) as the starting material, to obtain 319 mg of the title compound (yield: 50%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (24-3) as the starting material, to obtain 145 mg of the title compound (yield: 85%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 1- methoxypropan-2-ylamine instead of dimethylaminehydrochloride as the amine to obtain 413 mg of the title compound (yield: 83%).
• the procedure of Example (1-2) was repeated except for using the compound obtained in Example (25-1) as the starting material, to obtain 346 mg of the title compound (yield: 81%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (25-2) as the starting material, to obtain 289 mg of the title compound (yield: 75%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (25-3) as the starting material, to obtain 125 mg of the title compound (yield: 88%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 4- methoxybenzylamine instead of dimethylaminehydrochloride as the amine to obtain 461 mg of the title compound (yield: 98%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (26-1) as the starting material, to obtain 454 mg of the title compound (yield: 86%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (26-2) as the starting material, to obtain 378 mg of the title compound (yield: 85%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (26-3) as the starting material, to obtain 142 mg of the title compound (yield: 80%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 4- fluorophenetylamine instead of dimethylaminehydrochloride as the amine to obtain 463 mg of the title compound (yield: 93%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (27-1) as the starting material, to obtain 434 mg of the title compound (yield: 86%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (27-2) as the starting material, to obtain 362 mg of the title compound (yield: 651%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (27-3) as the starting material, to obtain 83 mg of the title compound (yield: 76%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using tetrahydropyran-2-yl)methylamine instead of dimethylaminehydrochloride as the amine to obtain 426 mg of the title compound (yield: 87%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (28-1) as the starting material, to obtain 370 mg of the title compound (yield: 90%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (28-2) as the starting material, to obtain 323 mg of the title compound (yield: 65%).
• 1 H NMR (200 MHz, CDCl 3 ) ⁇ 1.42-1.95 (m, 14H), 2.08 (m, 2H), 2.25 (q, J 7.6 Hz, 2H), 3.28 (m, IH), 3.59 (m, 3H), 3.89 (m, 2H), 4.88 (s, 2H), 4.90 (m, IH), 6.77 (m, 2H), 6.85 (d, J - 7.2 Hz, IH), 7.40 (m, 4H), 7.77 (m, IH), 8.14 (m, IH), 8.68 (br, IH).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (28-3) as the starting material, to obtain 85 mg of the title compound (yield: 85%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 2- cyclohexenylethylamine instead of dimethylaminehydrochloride as the amine to obtain 449 mg of the title compound (yield: 89%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (29-1) as the starting material, to obtain 401 mg of the title compound (yield: 95%).
• Example (4-43) The procedure of Example (4-43) was repeated except for using the compound obtained in Example (29-2) as the starting material, to obtain 370 mg of the title compound (yield: 82%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (29-3) as the starting material, to obtain 112 mg of the title compound (yield: 91%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 3-(2- oxopyrrolidin-l-yl)propylamine instead of dimethylaminehydrochloride as the amine to obtain 466 mg of the title compound (yield: 79%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (30-1) as the starting material, to obtain 370 mg of the title compound (yield: 88%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (30-2) as the starting material, to obtain 316 mg of the title compound (yield: 80%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (30-3) as the starting material, to obtain 166 mg of the title compound (yield: 82%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using furan- 2-ylamine instead of dimethylaminehydrochloride as the amine to obtain 421 mg of the title compound (yield: 83%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (31-1) as the starting material, to obtain 353 mg of the title compound (yield: 90%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (31-2) as the starting material, to obtain 306 mg of the title compound (yield: 55%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (31-3) as the starting material, to obtain 156 mg of the title compound (yield: 79%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 4- (dimethylamino)benzylamine instead of dimethylaminehydrochloride as the amine to obtain 547 mg of the title compound (yield: 72%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (32-1) as the starting material, to obtain 397 mg of the title compound (yield: 99%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (32-2) as the starting material, to obtain 380 mg of the title compound (yield: 96%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (32-3) as the starting material, to obtain 305 mg of the title compound (yield: 92%). 5
• Example (1-1) The procedure of Example (1-1) was repeated except for using 2- o methoxyethylamine instead of dimethylaminehydrochloride as the amine to obtain 399 mg of the title compound (yield: 85%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (33-1) as the starting material, to obtain 339 mg of the title compound (yield: 95%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (33-2) as the starting material, to obtain 313 mg of the title compound (yield: 70%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (33-3) as the starting material, to obtain 87 mg of the title compound (yield: 68%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using cyclohexylamine instead of dimethylaminehydrochloride as the amine to obtain 423 mg of the title compound (yield: 94%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (34-1) as the starting material, to obtain 397 mg of the title compound (yield: 67%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (34-2) as the starting material, to obtain 257 mg of the title compound (yield: 95%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (34-3) as the starting material, to obtain 122 mg of the title compound (yield: 83%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using thiophen-2-ylmethylamine instead of dimethylaminehydrochloride as the amine to obtain 438 mg of the title compound (yield: 100%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (35-1) as the starting material, to obtain 438 mg of the title compound (yield: 92%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (35-2) as the starting material, to obtain 390 mg of the title compound (yield: 66%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (35-3) as the starting material, to obtain 168 mg of the title compound (yield: 87%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 4- methoxyphenetylamine instead of dimethylaminehydrochloride as the amine to obtain 476 mg of the title compound (yield: 100%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (36-1) as the starting material, to obtain 476 mg of the title compound (yield: 90%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (36-2) as the starting material, to obtain 121 mg of the title compound (yield: 93%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (36-3) as the starting material, to obtain 155 mg of the title compound (yield: 84%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 4- o (trifluoromethoxy)benzylamine instead of dimethylaminehydrochloride as the amine to obtain 515 mg of the title compound (yield: 57%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (37-1) as the starting material, to obtain 293 mg of the title compound (yield: 95%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (37-2) as the starting material, to obtain 291 mg of the title compound (yield: 60%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (37-3) as the starting material, to obtain 74 mg of the title compound (yield: 52%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 1- (cyclohexylmethyl)pyrrolidin-3-ylamine instead of dimethylaminehydrochloride as the amine to obtain 506 mg of the title compound (yield: 26%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (38-1) as the starting material, to obtain 135 mg of the title compound (yield: 89%).
• Example (4-3) (E)-Nl-(l-(cyclohexylmethyl)pyrrolidin-3-yl)-2-((naphthaIen-l- yIoxy)methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
• Example (4-3) was repeated except for using the compound obtained in Example (38-2) as the starting material, to obtain 117 mg of the title compound (yield: 53%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (38-3) as the starting material, to obtain 58 mg of the title compound (yield: 77%).
• Example (1-1) (E)-8-(l-cyclopentyIpiperidin-4-ylamino)-7-((naphthalen-l-yloxy) methyl)-8-oxo-6-octene acid methylester
• the procedure of Example (1-1) was repeated except for using 1- cyclopentylpiperidin-4-ylamine instead of dimethylaminehydrochloride as the amine to obtain 492 mg of the title compound (yield: 55%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (39-1) as the starting material, to obtain 274 mg of the title compound (yield: 96%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (39-2) as the starting material, to obtain 257 mg of the title compound (yield: 48%).
• Example (4-4) (E)-Nl-(l-cycIopentylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen- l-yloxy)methyl)-2-octenediamide
• the procedure of Example (4-4) was repeated except for using the compound obtained in Example (39-3) as the starting material, to obtain 122 mg of the title compound (yield: 70%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 1- 0 benzylpyrrolidin-3-ylamine instead of dimethylaminehydrochloride as the amine to obtain 501 mg of the title compound (yield: 70%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (40-1) as the starting material, to obtain 352 mg of the title compound (yield: 55%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (40-2) as the starting material, to obtain 188 mg of the title compound (yield: 67%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (40-3) as the starting material, to obtain 64 mg of the title compound (yield: 68%).
• Example 41 (E)-N8-hydroxy-Nl-(l-isopropylpyrrolidin-3-yl)-2- ((naphthalen-l-yloxy)methyl)-2-octenediamide (41-l):(E)-8-(l-isopropylpyrrolidin-3-ylamino)-7-((naphthalen-l-yloxy) methyl)-8-oxo-6-octene acid methylester
• Example (1-1) The procedure of Example (1-1) was repeated except for using 1- isopropylpyrrolidin-3-ylamine instead of dimethylaminehydrochloride as the amine to obtain 452 mg of the title compound (yield: 41%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (41-1) as the starting material, to obtain 184 mg of the title compound (yield: 83%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (41-2) as the starting material, to obtain 122 mg of the title compound (yield: 69%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (41-3) as the starting material, to obtain 101 mg of the title compound (yield: 82%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 1- (cyclohexanecarbonyl)pyrrolidin-3-ylamine instead of dimethylaminehydrochloride as the amine to obtain 520 mg of the title compound (yield: 66%).
• Example (2-2) (E)-8-(l -(cyclohexanecarbonyl)py rrolidin-3-ylam ino)-7- ((naphthalen-l-y!oxy)methyl)-8-oxo-6-octene acid
• Example (1-2) was repeated except for using the compound obtained in Example (42-1) as the starting material, to obtain 342 mg of the title compound (yield: 78%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (42-2) as the starting material, to obtain 262 mg of the title compound (yield: 40%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (42-3) as the starting material, to obtain 154 mg of the title compound (yield: 80%).
• Example 43 (E)-3-(8-(hydroxyamino)-2-((naphthalen-l-yloxy)methyl)- 8-oxo-2-octeneamido)pyrrolidin-l-carboxylic acid t-butylester (43-l):(E)-3-(8-methoxy-2-((naphthalen-l-yloxy)methyl)-8-oxo-2- octeneamido)pyrrolidin-l-carboxylic acid t-butylester
• Example (1-1) The procedure of Example (1-1) was repeated except for using 3- aminopyrrolidin-1-carboxylic acid t-butylester instead of dimethylaminehydrochloride as the amine to obtain 510 mg of the title compound (yield: 83%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (43-1) as the starting material, to obtain 423 mg of the title compound (yield: 77%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (43-2) as the starting material, to obtain 320 mg of the title compound (yield: 72%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (43-3) as the starting material, to obtain 255 o mg of the title compound (yield: 95%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 3- aminopyrrolidin-1-carboxylic acid t-butylester instead of dimethylaminehydrochloride as the amine to obtain 510 mg of the title compound (yield: 83%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (44-1) as the starting material, to obtain 423 mg of the title compound (yield: 77%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the 5 compound obtained in Example (44-2) as the starting material, to obtain 320 mg of the title compound (yield: 72%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (44-3) as the starting material, to obtain 255 o mg of the title compound (yield: 95%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (44-4) as the starting material, to obtain 172 mg of the title compound (yield: 92%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 1- cyclohexylpyrrolidin-3-ylamine instead of dimethylaminehydrochloride as the amine to obtain 492 mg of the title compound (yield: 54%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (45-1) as the starting material, to obtain 269 mg of the title compound (yield: 100%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (45-2) as the starting material, to obtain 269 5 mg of the title compound (yield: 43%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (45-3) as the starting material, to obtain 140 mg of the title compound (yield: 88%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 1- cyclopropylpyrrolidin-3-ylamine instead of dimethylaminehydrochloride as the amine to obtain 450 mg of the title compound (yield: 78%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (46-1) as the starting material, to obtain 355 mg of the title compound (yield: 98%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (46-2) as the starting material, to obtain 334 mg of the title compound (yield: 61%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (46-3) as the starting material, to obtain 154 mg of the title compound (yield: 89%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 1- cyclopropylpiperidin-4-ylamine instead of dimethylaminehydrochloride as the amine to obtain 464 mg of the title compound (yield: 47%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (47-1) as the starting material, to obtain 221 mg of the title compound (yield: 100%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (47-2) as the starting material, to obtain 221 mg of the title compound (yield: 51%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (47-3) as the starting material, to obtain 150 mg of the title compound (yield: 90%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 1- ethylpiperidin-4-ylamine instead of dimethylaminehydrochloride as the amine to obtain 452 mg of the title compound (yield: 62%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (48-1) as the starting material, to obtain 279 mg of the title compound (yield: 100%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (48-2) as the starting material, to obtain 279 mg of the title compound (yield: 80%).
• Example (4-4) The procedure of Example (4-4) was repeated except for using the compound obtained in Example (48-3) as the starting material, to obtain 146 mg of the title compound (yield: 94%).
• Example (1-1) The procedure of Example (1-1) was repeated except for using 1- ethylpyrrolidin-3-ylamine instead of dimethylaminehydrochloride as the amine to obtain 438 mg of the title compound (yield: 52%).
• Example (1-2) The procedure of Example (1-2) was repeated except for using the compound obtained in Example (49-1) as the starting material, to obtain 224 mg of the title compound (yield: 100%).
• Example (4-3) The procedure of Example (4-3) was repeated except for using the compound obtained in Example (49-2) as the starting material, to obtain 224 mg of the title compound (yield: 69%). 0
• Example (4-4) was repeated except for using the compound obtained in Example (49-3) as the starting material, to obtain 184 mg of the title compound (yield: 91%).
• HDAC activity was analyzed using BIOMOL QuantizymeTM Assay system which comprised two steps of 1) enzyme reaction between HDAC and a substrate and 2) determination of the level of HDAC inhibitory activity.
• step I 5 42 ⁇ JL of a buffer solution (25 mM Tris-HCl [pH 8.0], 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 ) and 5 ⁇ l of 250 ⁇ M Fluor de LysTM substrate were added to each well of a 96-well plate, to which 2.5 ⁇ l of a test compound (compounds of Example 1 to 49) was added.
• HeLa nuclear extract(10 ⁇ M) (a source of HDAC enzymes) was then added thereto to a final concentration of 100 nM.
• the enzyme reaction was carried out for 1 hr.
• 2 ⁇ M tricostatin A was added to 50 ⁇ l of Flour de LysTM developer, followed by allowing the mixture to react at room temperature for 15 minutes.
• the light excited at 355 nm and emitted at 460 nm from the fluorophore was measured with a fluorometric plate reader. The intensity of the fluorescence increases as the enzyme activity is higher.
• the HDAC inhibitory activity of each of the test compounds was determined and compared with that of the control.
• SAHA suberoylanilide hydroxamic acid
• SAHA suberoylanilide hydroxamic acid
• each of the inventive alkylcarbamoyl naphthalenyloxyoctenoyl hydroxyamide derivatives of formula (1) has a markedly higher inhibitory activity against HDAC than SAHA which is known as a HDAC inhibitor.
• Cancer cells were inoculated into a 96-well microplate at a concentration of l x l0 3 ⁇ 3x l0 3 cells/well and incubated under the condition of 37 ° C , 5% CO 2 for 24 hrs. After the incubation was completed, 0.2, 1, 5, 25, or 100 ⁇ M of each of the compounds of Examples was added to the plate, and
• the reactant was incubated again. After the substrate was stained, the anti-cancer activity was determined by comparing the amount of protein in the cells treated with compound of Examples with that of protein in non- treated cells.
• the culture medium 0 was removed from each well, and the cells were washed 3 times with PBS (pH7.4). Then, a solution of 50% trichloroacetic acid (TCA) was added to each well in an amount of 50 ⁇ £/well at 4 ° C for 1 hr to fix them. Then, the microplate was washed 5 times with distilled water and dried at room temperature. 5 50 ⁇ i of a staining solution prepared by dissolving 0.4% SRB in 1% acetic acid was added to the wells, and the microplate was kept at room temperature for 1 hr. The well plate was then washed 5 times with 1% acetic acid to remove unbound SRB and dried at room temperature.
• TCA trichloroacetic acid
• the stained cells were treated with 150 ⁇ C/well of 10 mM Tris-HCl 0 solution (pH 10.5) to elute SRB from the cells, and the absorbance of each well at 520 ran was measured.
• the ED 50 value representing inhibition of the cancer cell growth by the extent of 50% was calculated from the measured absorbance, and the results are shown in Table 2.
• HeIa cells were inoculated into a 6-well microplate at a concentration of 1.5x10 8 cells/well and incubated overnight under the condition of 37 ° C , 5% CO 2 . 10 ⁇ M of each compound of Examples, and suberoylanilide hydroxamic acid (SAHA) as a control was added to the plate and the plate was incubated again for 24 hrs.
• SAHA suberoylanilide hydroxamic acid
• the cells were harvested in the presence of the test compound and were subjected to fractionation to separate the nuclei from the cells.
• the cells were allowed to swell in a hypotonic solution, lysed by several rounds of freezing-thawing cycles, and then centrifuged of 1,300 rpm for 5 min to collect the nuclei.
• the nuclei was lysed in a lysis buffer solution (20 mM HEPES (pH 7.9), 25% glycerol, 420 mM KCl, 1.5 mM MgCl 2 , 0.2 mM EDTA) to obtain a protein extract.
• the resulting protein extract was subjected to SDS-PAGE to separate the proteins by the size and transferred onto the nitrocellulose membrane according to the conventional method.
• the inventive alkylcarbamoyl naphthalenyloxyoctenoyl hydroxyamide derivatives of formula (1) has a markedly enhanced inhibitory activity against HDAC, which leads to effective suppression of the cancer cell proliferation.

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