WO2006025683A1 - Arylaminomethyl propenyl benzhydroxyamid derivatives with inhibitory activity against histone deacetylase and method for the preparation thereof - Google Patents

Arylaminomethyl propenyl benzhydroxyamid derivatives with inhibitory activity against histone deacetylase and method for the preparation thereof Download PDF

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WO2006025683A1
WO2006025683A1 PCT/KR2005/002864 KR2005002864W WO2006025683A1 WO 2006025683 A1 WO2006025683 A1 WO 2006025683A1 KR 2005002864 W KR2005002864 W KR 2005002864W WO 2006025683 A1 WO2006025683 A1 WO 2006025683A1
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Prior art keywords
propenyl
hydroxy
methyl
arh
benzamide
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PCT/KR2005/002864
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French (fr)
Inventor
Cheol Hae Lee
Hee Jung Jung
Jae Hak Kim
Joong Myung Cho
Seong Gu Ro
Tae Gyu Lee
Young-Lan Hyun
Dong Kyu Shin
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Korea Research Institute Of Chemical Technology
Crystalgenomics, Inc.
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Application filed by Korea Research Institute Of Chemical Technology, Crystalgenomics, Inc. filed Critical Korea Research Institute Of Chemical Technology
Publication of WO2006025683A1 publication Critical patent/WO2006025683A1/en

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    • C07C239/08—Hydroxylamino compounds or their ethers or esters
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Definitions

  • the present invention relates to a novel arylaminomethyl propenyl benzhydroxyamide derivative, a method for preparing same and a pharmaceutical 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 groups of their lysine residues.
  • the reversible acetylation is involved in the formation of chromatin higher order structures, the cell division cycle and ultimately the gene expression, and can be regulated by the dynamic equilibrium established between the opposing activities of histone acetyl transferases (HATs) and histone deacetylases (HDACs): HATs neutralize the positive charges of the lysine residues (e.g., 4 residues in H4) to an facilitate transcriptional activity and HDACs restore the positive charges by deacetylation to inhibit gene transcription.
  • HATs histone acetyl transferases
  • HDACs histone deacetylases
  • HDACs play an important role in cell cancerization or differentiation; 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.
  • HDAC has been a target for the study of anticancer drug as well as gene expression inhibitor to develope HDAC inhibitors to be used 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
  • Friend murine erythroleukemia cells Yoshida M. et al., Cancer research 47: 3688, 1987; Yoshida M. & Beppu T. Exp Cell Res. 177: 122, 1988; Yoshida M. et al., J of Biol Chem. 265: 17174, 1990).
  • HDAC inhibitors Although a variety of HDAC inhibitors have been disclosed, there has been a need for developing more efficient HDAC inhibitors. Accordingly, the present inventors have found that a novel arylaminomethyl propenyl benzhydroxyamide derivative is an efficient inhibitor against cell proliferation which can be advantageously used for treating cancer.
  • It is another object of the present invention to provide a pharmaceutical composition comprising the inventive compound as an active ingredient for preventing or treating cancers or various diseases caused by excessive histone deacetylase activity.
  • an arylaminomethyl propenyl benzhydroxyamide derivative of formula (I) or a pharmaceutically acceptable salt thereof and a method for preparing same:
  • Ri is hydrogen, aryloxy, arylthio, arylimido, C 1 . 5 alkylimido, arylamido, Ci_ 5 alkylamido or arylsulfonamido, in which the aryl is phenyl, naphthyl or carbazole, each being optionally substituted with one or more substituents selected from the group consisting of hydroxy, C 1 . 5 alkyloxy, C1. 5 alkyl, aryl, C 1 . 5 alkylainino, cyano, cyanophenyl, C ⁇ 5 alkylthio and nitro;
  • R 2 is phenyl which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C 1 . 5 alkyloxy, C ⁇ 5 alkyl, Ci_ 5 alkylamino, cyano, cyanophenyl and mercaptoalkyl; or heteroaryl selected from the group consisting of piperazine, triazole, thiazole, benzothiazole, dibenzofurane, pyridine, quinoline and isoquinoline, the heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1 . 5 alkyloxy, amino C 1 . 5 alkyloxy, C1. 5 alkyl, amino C ⁇ 5 alkyl, C ⁇ 5 alkylamino, aryl C 1 . 5 alkylamino and aryloxy Cj -5 alkylamino; and
  • R 3 is hydroxy amino
  • an anti-cancer composition comprising the compound of formula (I) as an active ingredient and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating a disease caused by excessive histone deacetylase activity comprising the compound of formula (I) as an active ingredient and a pharmaceutically acceptable carrier.
  • inventive compound of formula (I) may be used in the form of a pharmaceutically acceptable addition salt formed with an acid or base.
  • the acid examples include an inorganic acid such as hydrochloric, hydrobromic, phosphoric and sulfuric acids; and an organic acid such as acetic, trifluoroacetic, citric, formic, maleic, oxalic, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic, malic acid, methanesulfonic and p- toluenesulfonic acids.
  • an inorganic acid such as hydrochloric, hydrobromic, phosphoric and sulfuric acids
  • an organic acid such as acetic, trifluoroacetic, citric, formic, maleic, oxalic, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic, malic acid, methanesulfonic and p- toluenesulfonic acids.
  • the base examples include an inorganic base such as an alkali metal hydroxide (e.g., sodium hydroxide and potassium hydroxide), an alkali metal bicarbonate (e.g., sodium bicarbonate and potassium bicarbonate), an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate and calcium carbonate) and an organic base such as amines.
  • an inorganic base such as an alkali metal hydroxide (e.g., sodium hydroxide and potassium hydroxide), an alkali metal bicarbonate (e.g., sodium bicarbonate and potassium bicarbonate), an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate and calcium carbonate) and an organic base such as amines.
  • an inorganic base such as an alkali metal hydroxide (e.g., sodium hydroxide and potassium hydroxide), an alkali metal bicarbonate (e.g., sodium bicarbonate and potassium bicarbonate), an alkali metal carbonate (e.g
  • inventive compound of formula (I) may be prepared by any one of the synthetic routs shown in Reaction Schemes 1 to 3.
  • step 1) of Reaction Scheme 1 an alkoxycarbonyl hydroxyl allyl compound is obtained by the Baylis-Hillman reaction carried out between an aldehyde and an alkylacrylate in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO).
  • DABCO l,4-diazabicyclo[2.2.2]octane
  • the ECC treatment in step 4) is carried out using tetrahydrofuran as a solvent over an ice bath.
  • the amine reaction in step 5 is carried out using acetone or acetonitrile as a solvent in the presence of potassium carbonate.
  • the reaction of step 6) is preferably carried out using an aqueous solution of an alcohol, preferably methanol, ethanol or isopropanol, or an aqueous tetrahydrofuran as a solvent, and lithium hydroxide (LiOH-H 2 O) or sodium hydroxide as an inorganic base.
  • an alcohol preferably methanol, ethanol or isopropanol, or an aqueous tetrahydrofuran
  • lithium hydroxide LiOH-H 2 O
  • sodium hydroxide sodium hydroxide
  • reaction step 7 is carried out using N 5 N- dimethylformamide as the solvent together with hydrochloric acid or sulfuric acid as the water-soluble inorganic acid.
  • step 2) is carried out using an arylalcohol or arylthiol as a nucleophilic agent in an organic solvent such as acetone or acetonitrile in the presence of an organic or inorganic base such as triethylamine and potassium carbonate.
  • the ECC treatment in step 3) is carried out using tetrahydrofuran as a solvent over an ice bath.
  • Step 5) of Reaction Scheme 2 is preferably carried out using an aqueous solution of an alcohol, preferably methanol, ethanol or isopropanol, or an aqueous tetrahydrofuran as the solvent, and lithium hydroxide (LiOH-H 2 O) or sodium hydroxide as the inorganic base.
  • an alcohol preferably methanol, ethanol or isopropanol, or an aqueous tetrahydrofuran
  • lithium hydroxide LiOH-H 2 O
  • sodium hydroxide sodium hydroxide
  • step 6 is carried out using N,N- dimethylformamide as the solvent in the presence of N-methansulfonyloxy-6- trifluoro benzotriazole, and hydrochloric acid or sulfuric acid as the water- soluble inorganic acid.
  • a methyl arylaminomethylpropenyl benzoate of formula (XII) may also be obtained by an alternative method, for example, reacting the compound of formula (XI) with tetrabromomethane (CBr 4 ) in the presence of triphenylphosphine (PPh 3 ) to form a methyl bromomethylpropenyl benzoate and refluxing the resulting product together with an arylamine or arylalkylamine using acetone or acetonitrile as a solvent in the presence of potassium carbonate.
  • CBr 4 tetrabromomethane
  • Ph 3 triphenylphosphine
  • R 1 C alkylamido, arylamido, alkyl imido, arylimido or arylsulfoneamido
  • step 1) is carried out using alkylamide, arylamide, alkylimide, arylimide or arylsulfonamide as the nucleophilic agent in the presence of triethylamine or potassium carbonate as an organic or inorganic base.
  • the ECC treatment in step 2) is carried out using tetrahydrofuran as the solvent over an ice bath, and the amine reaction in step 3) is carried out using acetone or acetonitrile as the solvent in the presence of potassium carbonate.
  • Step 4) of Reaction Scheme 3 is carried out using an aqueous solution of an alcohol, preferably methanol, ethanol or isopropanol, or an aqueous tetrahydrofuran as the solvent, and lithium hydroxide or sodium hydroxide as the inorganic base.
  • an alcohol preferably methanol, ethanol or isopropanol, or an aqueous tetrahydrofuran as the solvent, and lithium hydroxide or sodium hydroxide as the inorganic base.
  • Step 5 is carried out using N,N-dimethylformamide as a solvent, and hydrochloric acid or sulfuric acid as the water-soluble inorganic acid, in the presence of N-methansulfonyloxy-6-trifluoro benzotriazole.
  • the inventive arylaminomethyl propenyl benzhydroxyamide derivative of formula (I) efficiently inhibits the activity of histone deacetylase to suppress the differentiation of tumor cells, thereby preventing the cancer-cell proliferation.
  • the present invention also provides an anti-cancer composition
  • an anti-cancer composition comprising the compound of formula (I) as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition for preventing or treating a disease caused by excessive histone deacetylase activity such as osteoporosis and central nervous system disorders (e.g.,
  • Alzheimer's disease comprising the compound of formula (I) as an active ingredient and a pharmaceutically acceptable carrier.
  • the inventive pharmaceutical composition comprises the compound of formula (I) 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 (I) ranges from about 2.5 to 100 mg/kg, preferably 5 to 60 mg/kg for mammals including a human subject, and can be orally or parenterally administered in a single dose or in divided doses.
  • Methyl 4-(l-acetoxy-2-t-butoxycarbonylallyl) benzoate (IV) (350 mg, 1.04 mM) was dissolved in anhydrous tert-butanol (10 ml), to which sodium borohydride (78 nig, 2.08 mM) was slowly added, followed by stirring the mixture at room temperature for 3 hours. After completing the reaction, tert-butanol was distilled under a reduced pressure and ice water was poured thereinto. The resulting mixture was extracted with diethyl ether and the organic layer was washed with brine. The resulting residue was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under a reduced pressure, concentrated and purified by silica gel column chromatography to obtain the title compound as a white solid (230 mg, 73%).
  • Methyl 4-(2-carboxy-propenyl) benzoate (220 ing, 1.00 mM) was dissolved in tetrahydrofuran (10 ml), to which triethylamine (209 ⁇ , 1.05 mM) and ethyl chloroformate (0.124 m£, 1.3 mM) were added at 0°C, followed by stirring for 1 hour.
  • Sodium borohydride (192 ing, 5.00 mM) was added to the reacting solution and distilled water (2 ml) was slowly added dropwise thereto, followed by stirring the mixture at room temperature for 2.5 hours.
  • reaction solution was treated with 1 N hydrochloric acid to adjust pH thereof to 2, extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate. The resulting residue was dried over anhydrous sodium sulfate, filtered and purified by silica gel column chromatography to obtain the title compound as a white solid (89%).
  • Example 1 4-[3-(Quinoline-3-ylamino)-2-methyIpropehyl]-N-hydroxy benzamide Step 1: Methyl 4-[3-(quinoline-3 ⁇ ylamino)-2-methyIpropenyl] benzoate
  • Step 3 4-[3-(Quinoline-3-ylamino)-2-methylpropenyl]-N-hydroxy benzamide 4-[3-(Quinoline-3-ylamino)-2-methylpropenyl] benzoic acid (73 mg,
  • Step 1 Methyl 4-[3-(3-benzyloxyphenylami ⁇ o)-2-methylpropenyl] benzoate The procedure of Step 1 of Example 1 was repeated except for using 3- benzyloxyphenylaminel as the starting material to obtain the title compound (60%).
  • Step 2 4-[3-(3-Benzyloxy-phenylammo)-2-methylpropenyl] benzoic acid
  • the procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(3-benzyloxyphenylamino)-2-methylpro ⁇ enyl] benzoate to obtain the title compound (92%).
  • Step 3 4-[3-(3-Benzyloxy-phenylamino)-2-methylpropenyl]-N-hydroxy benzamide
  • Step 3 of Example 1 was repeated except for using 4-[3-(3-benzyloxy-phenylamino)-2-methyl ⁇ ropenyl] benzoic acid to obtain the title compound (12%).
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 1.2,3.4-tetrahydroisoquinoline as the starting material to obtain the title compound (73%).
  • Step 2 4-[3-(3,4-Dihydro-ll H-isoquinoline-2-yl)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(3,4-dihydro-l lH-isoquinoline-2-yl)-2-methylpropenyl] benzoate to obtain the title compound (49 % ).
  • Step 3 4-[3-(3,4-Dihydro-l lH-isoquinoline-2-yl)-2-methylpropenyl]-N- hydroxy benzamide
  • Step 3 of Example 1 was repeated except for using 4- [3-(3 5 4-dihydro-llH-isoquinoline-2-yl)-2-methylpropenyl] benzoic acid to obtain the title compound (74%).
  • Step 1 Methyl 4-[3-(quinoli ⁇ e-8-yIamino)-2-niethyIpropenyl] benzoate
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 8- aminoquinoline as the starting material to obtain the title compound (62 %).
  • Step 2 4-[3-(Quinoline-8-yIammo)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(quinoline-8-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (84 % ).
  • Step 3 4-[3-(QuinoIme-8-yIamino)-2-methylpropenyl]-N-hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using 4-
  • Step 1 Methyl 4-[3-(4-phenyloxy-phenylamino)-2-methylpropenyl] benzoate
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 4- phenyloxyphenylamine as the starting material to obtain the title compound (54%).
  • Step 2 4-[3-(4-Phenyloxy-phenylamino)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(4-phenyloxy-phenylamino)-2-methyl ⁇ ropenyl] benzoate to obtain the title compound (43 % ).
  • Step 3 4-[3-(4-Phenyloxy-phenylamino)-2-methylpropenyI]-N-hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using 4-
  • Step 1 Methyl 4-[3-(4-dimethylamino-phenylamino)-2-methylpropenyI] benzoate The procedure of Step 1 of Example 1 was repeated except for using 4- dimethylamino-phenylamine as the starting material to obtain the title compound (30%).
  • Step 2 4-[3-(4-Dimethylamino-phenylamino)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(4-Dimethylamino-phenylamino)-2-methylpropenyl] benzoate to obtain the title compound ⁇ 66%).
  • Step 3 4-[3-(4-Dimethylamino-phenylamino)-2-methylpropenyl]-N- hydroxy benzamide
  • Step 3 of Example 1 was repeated except for using 4- [3-(4-dimethylamino-phenylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (82%).
  • Step 1 of Example 1 was repeated except for using 5- aminoquinoline as the starting material to obtain the title compound (60%).
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(quinoline-5-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (88%).
  • Step 3 4-[3-(Quinoline-5-ylamino)-2-methyIpropenyl]-N-hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using 4-
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 3-aminoquinoline as the starting material to obtain the title compound (43 % ).
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(qumoline-3-;ylamino)-2-methylpropenyl] benzoate to obtain the title compound (86%).
  • Step 3 4-[3-(QuinoIine-3-ylamino)-2-methylpropenyl]-N-hydroxy benzamide
  • Step 1 Methyl 4-[3-(5-hydroxy-naphthalene-l-ylamino)-2- methylpropenyl] benzoate
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 5 -hydroxy- 1-naphthaleneamine as the starting material to obtain the title compound (68%).
  • Step 2 4-[3-(5-Hydroxy-naphthalene-l-ylamino)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(5-hydroxy-naphthalene-l -ylamino)-2-methylpropenyl] benzoate to obtain the title compound (83 %).
  • Step 3 4-[3-(5-Hydroxy-naphthalene-l-ylamino)-2-methylpropenyl]-N- hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using
  • Step 1 Methyl 4-[3-(benzo[l,2,5]thiadiazoI-4-ylamino>2- methy ⁇ propenyl] benzoate
  • the procedure of Step 1 of Example 1 was repeated except for using berizo[l,2,5]thiadiazol-4-ylamine as the starting material to obtain the title compound (98%).
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(benzo[ 1 5 2,5]thiadiazol-4-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (75%).
  • Step 3 4-[3-(Benzo[l,2,5]thiadiazol-4-ylamino)-2-iiiethyIpropenyl]-N- hydroxy benzamide
  • Step 2 4-[3-(Anthracene-l-y ⁇ amino)-2-methyIpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(anthracene-l-ylamino)-2-methylpro ⁇ enyl] benzoate to obtain the title compound ( 100 % ) .
  • Step 3 4-[3-(Anthracene-l-ylamino)-2-methylpropeny ⁇ ]-N-hydroxy benzamide
  • Step 3 of Example 1 The procedure of Step 3 of Example 1 was repeated except for using 4-[3 -(anthracene- l-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (52%).
  • Example 12 4-[3-(4,6-Dihydropyrene-l-ylamino)-2-methyIpropenyl]-N- hydroxy benzamide
  • Step 1 Methyl 4-[3-(4,6-dihydropyrene-l-ylamino)-2-methylpropenyl] benzoate The procedure of Step 1 of Example 1 was repeated except for using 4 3 6-dihydropyrene-l-ylamine as the starting material to obtain the title compound (95%).
  • Step 2 4-[3-(4,6-Dihydropyrene-l-ylamino)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(4,6-dihydropyrene-l-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (95 %).
  • Step 3 4-[3-(4,6-Dihydropyrene-l-ylamino)-2-methylpropenyl]-N- hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using
  • Step 1 Methyl 4-[3-(4-methyl-2-2H-chromene-7-ylamino)-2- methylpropenylj benzoate
  • Step 1 of Example 1 was repeated except for using 4-methyl-2-2H-chromene-7-ylamine as the starting material to obtain the title compound (46%).
  • Step 2 4-[3-(4-Methyl-2-2H-chromene-7-ylamino)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(4-methyl-2-2H-chromene-7-ylamino)-2-methylpiOpenyl] benzoate to obtain the title compound (91 %).
  • Step 3 4-[3-(4-Methyl-2-2H-chromene-7-ylamino)-2-methylpropenyl]-N- hydroxy benzamide
  • Step 3 of Example 1 was repeated except for using 4-[3-(4-methyl-2-2H-chromene-7-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (98%).
  • Step 2 4-[3-(3-Benzyloxypyridine-2-y ⁇ amino)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(3-benzyloxypyridine-2-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (90%).
  • Step 3 4-[3-(3-Benzyloxypyridine-2-ylamino)-2-methyIpropenyl]-N- hydroxy benzamide
  • Step 2 4-[3-(9-EthyI-9H-carbazoI-2-ylamino)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(9-ethyl-9H-carbazol-2-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (96%).
  • Step 3 4-[3-(9-Ethyl-9H-carbazol-2-ylamino)-2-methylpropenyI]-N- hydroxy benzamide
  • Step 3 of Example 1 was repeated except for using 4-[3-(9-ethyl-9H-carbazol-2-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (100%).
  • Example 16 4-[3-(5-Methyl-lH-pyrazol-3-ylamino)-2-methyIpropenyI]- N-hydroxy benzamide Step 1: Methyl 4-[3-(5-methyl-lH-pyrazoI-3-yIamino)-2-methy ⁇ propenyl] benzoate
  • Step 2 4-[3-(5-MethyI-lH-pyrazol-3-ylamino)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(5-methyl-lH-pyrazol-3-ylamino)-2-methylpro ⁇ enyl] benzoate to obtain the title compound (92%).
  • Step 3 4-[3-(5-Methyl-lH-pyrazol-3-ylamino)-2-methylpropenyl]-N» hydroxy benzamide
  • Step 3 of Example 1 The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(5-methyl-lH-pyrazol-3-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (91 %).
  • Example 17 4-[3-(5-MethyIsulfenyl-lH-[l,2,4]triazol-3-ylamino)-2- methylpropenyl]-N-hydroxy benzamide
  • Step 1 Methyl 4-[3-(5-methylsulfenyl-lH-[l,2,4]triazoI-3-ylamino)-2- methylpropenyl] benzoate
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 5-methylsulfenyl-lH-[l 5 2.4]triazol-3-ylamine as the starting material to obtain the title compound (43 %).
  • Step 2 4-[3-(5-Methylsulfenyl-lH-[l,2,4]triazol-3-ylamino)-2- methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(5-memylsulfenyl-lH-[l,2 5 4]triazol-3-ylamino)-2- methylpropenyl] benzoate to obtain the title compound (41 %).
  • Step 3 4-[3 ⁇ (5-MethylsulfenyI-lH-[l,2 9 4]triazol-3-ylamino)-2- methyIpropenyl]-N-hydroxy benzamide
  • Step 3 of Example 1 The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(5-methylsulfenyl-lH-[l ,2,4]triazol-3-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (41 %).
  • Step 1 Methyl 4-[3-(3-methoxy phenylamino)-2-methylpropenyl] benzoate
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 3-methoxy phenylamine as the starting material to obtain the title compound (60%).
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(3-methoxy phenylamino)-2-methylpropenyl] benzoate to obtain the title compound (94 % ).
  • Step 3 4-[3-(3-Methoxy phenylamino)-2-methylpropenyl]-N-hydroxy benzamide
  • Step 3 of Example 1 The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(3-methoxy phenylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (96%).
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 1-naphthaleneylamine as the starting material to obtain the title compound (63 %).
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(naphthalene-l-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (100%).
  • Step 3 4-[3-(Naphthalene-l-ylamino)-2-methylpropenyl]-N-hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 2-naphthaleneylamine as the starting material to obtain the title compound (73 %).
  • Step 2 4-[3-(NaphthaIene-2-yIamino)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3 ⁇ (naphmalene-2-ylamino)-2-methyrpropenyl] benzoate to obtain the title compound (100%).
  • Step 3 4-[3-(Naphthalene-2-ylamino)-2-methylpropenyl]-N-hydroxy benzamide
  • Step 3 of Example 1 The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(naphthalene-2-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (97 % ).
  • Step 1 Methyl 4-[3-(biphenyl-4-ylamino)-2-methylpropenyl] benzoate The procedure of Step 1 of Example 1 was repeated except for using
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(biphenyl-4-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (97%).
  • Step 3 of Example 1 The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(biphenyl-4-ylamino)-2-methylpropenyl] benzoic acid to obtain the title ' compound (96 % ).
  • Example 22 4-[3-(6-Nitro-benzothiazol-2-ylammo)-2-methylpropenyl]- N-hydroxy benzamide Step 1: Methyl 4-[3-(6-nitro-benzothiazol-2-ylamino)-2-methylpropenyl] benzoate
  • Step 2 4-[3-(6-Nitro-benzothiazol-2-ylamino)-2-methyIpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4- [3 -(6-nitro-benzothiadiazol-2-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (89 % ) .
  • Step 3 of Example 1 The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(6-nitro-benzothiazol-2-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (91 %).
  • Step 1 of Example 1 was repeated except for using 6-methoxy-benzothiazol-2-ylamine as the starting material to obtain the title compound (35%).
  • Step 2 4-[3-(6-Methoxy-benzothiazol-2-ylamino)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(6-methoxy-benzothiazol-2-ylamino)-2-methylpro ⁇ enyl] benzaote to obtain the title compound (71 %).
  • Step 3 4- [3-(6-Methoxy-benzothiazol-2-ylammo)-2-methylpropenyl]-N- hydroxy benzamide
  • Step 1 Methyl 4-[3-(2-methoxy-dibenzofuran-3-yIamino)-2- methylpropenyl] benzoate
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 2-methoxy-dibenzofuran-3-ylamine as the starting material to obtain the title compound (91 %).
  • Step 2 4-[3-(2-Methoxy-dibenzofuran-3-ylamino)-2-methylpropenyl] benzoic acid
  • the procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(2-methoxy-dibenzofuran-3-ylamino)-2-methylpropenyl] benzaote to obtain the title compound (99%).
  • MS (LC, 70 eV) m/z 389 (M +1 )
  • Step 3 4-[3-(2-Methoxy-dibenzofuran-3-ylamino)-2-methyIpropenyl]-N- hydroxy benzamide
  • the procedure of Step 3 of Example 1 was repeated except for using
  • Example 25 4-[3-(6-Methoxypyridme-3-ylamino)-2-methylpropenyl]-N- hydroxy benzamide Step 1: Methyl 4-[3-(6-methoxypyridine-3-ylamino)-2-m)Bithylpropenyl] benzoate
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 6-methoxypyridine-3-ylamine as the starting material to obtain the title compound (285 ing, 91 %).
  • Step 2 4-[3-(6-Methoxypyridme-3-ylamino)-2-methylpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(6-methoxypyridine-3-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (90 % ).
  • Step 3 4-[3-(6-Methoxypyridine-3-yIamino)-2-methylpropenyl]-N- hydroxy benzamide
  • the procedure of Step 3 of Example 1 was repeated except for using 4-[3-(6-methoxypyridine-3-ylammo)-2-methylpropenyl] benzoic acid to obtain the title compound.
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 2-chloropyridine-3-ylamine as the starting material to obtain , ; £tie title compound (25%).
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(2-chloropyridine-3-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (100%).
  • Step 3 4-[3-(2-Chloropyridine-3-ylammo)-2-methyIpropenyl]-N-hydroxy benzamide
  • Step 3 of Example 1 was repeated except for using 4-[3-(2-chloropyridine-3-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound.
  • Example 27 4-[3-(6-Morpholine-4-ylmethylquinoline ⁇ 3-ylamino)-2- methyl-propenyl]-N-hydroxy benzamide Step 1: Methyl 4-[3-(6-morpholine-4-ylmethylquinoline-3-ylamino)-2- methyl-propenyl] benzoate
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 6-morpholine-4-ylmethylquinoline-3-ylamine as the starting material to obtain the title compound (38%). ..- . • . .. ⁇
  • Step 2 4-[3-(6-Morpholine-4-ylmethylquinoline-3-ylamino)-2-methyl- propenylj-benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(6-morpholine-4-ylmethylquinoline-3-ylamino)-2-methyl- propenyl] benzoate to obtain the title compound (92%).
  • Step 3 4-[3-(6-Morpholine-4-ylmethylquinoline-3-ylamino)-2-methyl- propenyI]-N-hydroxy benzamide
  • Step 3 of Example 1 was repeated except for using 4-[3-(6-moipholine-4-ylmethylqumoline-3-ylammo)-2-metriyl-piOpenyl]- benzoic acid to obtain the title compound (35%).
  • Step 1 Methyl 4-[3-(4'-cyanobiphenyl-4-ylamino)-2-methylpropenyl] benzoate The procedure of Step 1 of Example 1 was repeated except for using
  • Step 2 4-[3-(4'-CyanobiphenyI-4-ylamino)-2-methyIpropenyl] benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(4'-cyanobiphenyl-4-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (87%).
  • Step 3 4-[3-(4'-Cyanobiphenyl-4-ylamino)-2-methylpropenyl]-N- hydroxy benzamide
  • Example 29 4-[3-(4-Pyridine-2-ylpiperazine-l-yl)-2-methyl-propenyI]-N- hydroxy-benzimide Step 1: Methyl 4-[3-(4-pyridine-2-ylpiperazine-l-yl)-2-methyl-propenyl] benzoate
  • Step 2 4-[2-Methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl]-benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[2-methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl] benzoate to obtain the title compound (75 %).
  • Step 3 4-[2-MethyI-3-(4-pyridine-2-ylpiperazine-l-yl) ⁇ propenyl]-N- hydroxy-benzimide
  • Step 3 of Example 1 was repeated except for using 4-[2-methyl-3-(4- ⁇ yridine-2-ylpi ⁇ erazine-l-yl)-propenyl]-benzoic acid to obtain the title compound (25%).
  • Step 1 Methyl 4-[2-methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl] o benzoate
  • Step 2 4-[2-Methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl]-benzoic o acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[2-methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl] benzoate to obtain the title compound (95 %).
  • Step 3 4-[2-Methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl] -N- o hydroxy-benzimide
  • the procedure of Step 3 of Example 1 was repeated except for using 4-[2-methyl-3 -(4-pyridine-2-ylpiperazine- 1 -yl)-propenyl]-benzoic acid to obtain the title compound (25%).
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using benzyl-methyl-amine as the starting material to obtain the title compound (80%).
  • Step 2 4-[3-(Benzyl-methyl-amino)-2-methyl-propenyl]-benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(benzyl-methyl-amino)-2-methyl- ⁇ ro ⁇ enyl] benzoate to obtain the title compound (48%).
  • Step 3 4-[3-(Benzyl-methylamino)-2-methyl-propenyl]-N-hydroxy- benzamide
  • Step 3 of Example 1 was repeated except for using 4-[3-(benzyl-methyl-amino)-2-methyl-propenyl]-benzoic acid to obtain the title compound (33%).
  • Step 2 4-[3-(2-Phenoxy-ethylamino)-2-methyl-propenyI]-benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[2-methyl-3-(2-phenoxy-ethylamino)-propenyl] benzoate to obtain the title compound (97%).
  • Step 3 4-[3-(2-Phenoxy-ethylamino)-2-methyI-propenyl]-N-hydroxy- benzamide The procedure of Step 3 of Example 1 was repeated except for using
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 8-bromoquinoline-3-ylamine as the starting material to obtain the title compound (53 %).
  • Step 2 4-[3-(8-Bromoquinoline-3-ylamino)-2-methyl-propenyl]-benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(8-bromoquinoline-3-ylamino)-2-methyl-propenyl] benzoate to obtain the title compound (90%).
  • Step 3 4-[3-(8-Bromoquinoline-3-ylamino)-2-methyl-propenyl]-N- hydroxy-benzamide The procedure of Step 3 of Example 1 was repeated except for using
  • Step 1 of Example 1 was repeated except for using 6-methoxyquinoline-3-ylamine as the starting material to obtain the title compound.
  • Step 2 4-[3-(6-Methoxyquinoline-3-yIamino)-2-methyl-propenyl]-benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(6-methoxyquinoline-3-ylamino)-2-methyl-propenyl] benzoate to obtain the title compound (99%).
  • Step 3 4-[3-(6-MethoxyquinoIine-3-ylamino)-2-methyl-propenyl]-N- hydroxy-benzamide The procedure of Step 3 of Example 1 was repeated except for using
  • Step 1 Methyl 4-[3-(6-hydroxy-quinoline-3-ylamino)-2-methyI-propenyl) benzoate The procedure of Step 1 of Example 1 was repeated except for using
  • Step 2 4-[3-(6-Hydroxy-quinoIine-3-ylamino)-2-methyl-propenyl]- benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(6-hydroxy-quinoline-3-ylamino)-2-methyl-propenyl] benzoate to obtain the title compound (58%).
  • Step 3 4-[3-(6-Hydroxy-quinoline-3-ylamino)-2 ⁇ m ⁇ thyl-propenyl]-N- hydroxy-benzamide
  • Step 1 Methyl 4-[3-(propyl-quinoline-3-ylamino)-2-methyl-propenyl] benzoate The procedure of Step 1 of Example 1 was repeated except for using propyl-quinoline-3-ylamine as the starting material to obtain the title compound (19%).
  • Step 2 4-[3-(Propyl-quinoline-3-yIamino)-2-methyl-propenyI]-benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[2-methyl-3-(propyl-quinoline-3-ylamino)- ⁇ ro ⁇ enyl] benzoate to obtain the title compound (50%).
  • Step 3 4-[3-(Propyl-quinoline-3-ylamino)-2-methyl-propenyl]-N- hydroxy-benzamide
  • Step 3 of Example 1 was repeated except for using 4-[2-methyl-3-(propyl-quinoline-3-ylamino)-pro ⁇ enyl]-benzoic acid to obtain the title compound (19%).
  • Step 1 Methyl 4-(3- ⁇ [2-(fer ⁇ butyl-dimethyl-silanyIoxy)-ethyI]-quinoline-
  • Step 2 ,4-(3- ⁇ [2-( ⁇ -Butyl-dimethyl-silanyloxy)-ethyl]-quinoline-3- ylamino ⁇ -2-methyl-propenyl)-benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-(3- ⁇ [2-(terr-buryl-dimethyl-silanyloxy)-ethyl]-quinolme-3- ylamino ⁇ -2-methyl-propenyl) benzoate to obtain the title compound (69%).
  • Step 3 4- ⁇ 3-[(2-Hydroxy-ethyl)-quinoline-3-ylamino]-2-methyI- propenyl ⁇ -N-hydroxy-benzamide
  • Step 3 of Example 1 The procedure of Step 3 of Example 1 was repeated except for using 4-(3 - ⁇ [2-(fer/-butyl-dimethyl-silanyloxy)-ethyl]-quinoline-3 -ylamino ⁇ -2- methyl-propenyl)-benzoic acid to obtain the title compound (20 %).
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using fon ⁇ yl-quinoline-3-ylamine as the starting material to obtain the title compound (96%).
  • Step 2 4-[3-(Formyl-quinoline-3-ylamino)-2-methyl-propenyl]-benzoic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(formyl-quinoline-3-ylamino)-2-methyl-propenyl] benzoate to obtain the title compound (85 %).
  • Step 3 4-[3-(Eormyl-quinoline-3-ylamino)-2-methyl-propenyI]-N- hydroxy-benzamide
  • Step 3 of Example 1 The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(formyl-quinoline-3-ylamino)-2-methyl-propenyl]-benzoic acid to obtain the title compound (73 %).
  • Step 1 Methyl 4-[2-ter/-butoxycarbonyl-3-(naphthalene-l-yloxy)- propenyl] benzoate
  • Methyl 4-(3-Bromo-2-t-butoxycarbonyl ⁇ ro ⁇ enyl) benzoate (9) (355 ing 1.00 mM) obtained in Preparation Example 7 was dissolved in acetone (5 mi), to which potassium carbonate (207 mg 1.50 mM) and 1-naphthalenol (144 mg 1.00 mM) were added, followed by refluxing for 3 hours. After completing the reaction, the mixture was cooled to room temperature, filtered to remove solvent. The resulting residue was purified by silica gel column chromatography to obtain the title compound as a white solid (438 mg, 99%).
  • Methyl 4- [2-fer?-butoxycarbonyl-3 -(naphthalene- 1 -yloxy)-propenyl] benzoate (372 mg 0.89 mM) was dissolved in dichloromethane (12 ml), to which trifluoroacetic acid (0.90 mi 1.00 mM) was slowly added dropwise, followed by reacting at room temperature for 6 hours. After completing the reaction, the solvent was removed under a reduced pressure at room temperature. The residue was diluted dichloromethane and concentrated again under a reduced pressure to remove residual trifluoroacetic acid to obtain the title compound as a brown solid (315 mg, 98%).
  • Methyl 4-[2-carboxy-3-(na ⁇ hthalene-l-yloxy)- ⁇ ro ⁇ enyl] benzoate (2 g, 5.52 mM) was dissolved in tetrahydrofuran (30 mi), to which triethylamine (1.15 mi, 8.27 mM) and ethyl chloroformate (0.792 mi, 8.279 niM) were added dropwise at 0 ° C, followed by stirring for lhour.
  • Sodium borohydride 1.62 mg, 38.64 mM was added to the reaction solution, distilled water (10 mi) was slowly added thereto, followed by stirring at temperature for 2.5 hours.
  • reaction solution was treated with 1 N hydrochloric acid to adjust pH thereof to 2 and extracted with ethyl acetate.
  • the resulting organic layer was washed saturated sodium bicarbonate and brine, dried over magnesium sulfate and filtered.
  • the residue was purified by silica gel column chromatography to obtain the title compound as a white solid (1.58 mg, 82%).
  • Step 4A Methyl 4-[2-hydroxymethyl-3-(naphthalene-l-yloxy)-propenyIJ benzoate
  • Methyl 4-[2-hydroxymethyl-3-(naphthalene-l-yloxy)-pro ⁇ enyl] benzoate (1.2 g, 3.44 mM) was dissolved in dichloromethane (11 ml) and manganese dioxide (4.5 g, 51.67 mM) was added thereto, followed by refluxing for 3 hours. The mixture was filtered and the solvent was removed under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound as a white solid (526 mg, 44%).
  • Step 4B Methyl 4-[2-bromomethyl-3-(naphthalene-l-yloxy)-propenyl] benzoate
  • Methyl 4-[2-hydroxymethyl-3-(naphthalene- 1 -yloxy)-propenyl] benzoate (1.57 g, 4.52 mM) was dissolved in dichloromethane (15 mi), and triphenylphosphine (1.78 g, 6.79 mM) was added thereto. The mixture was cooled to 0 ° C to which tetrabromomethane (2.25 g, 6.79 mM) was added, followed by stirring for 6 hours. The solvent was removed under a reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound as a white solid (1.36 g, 73 %).
  • Step 5B Methyl 4-[2-(quinoline-3-yIaminomethyl)-3-(naphthalene-l- yloxy)-propenyl] benzoate
  • Methyl 4- [2-bromomethy 1-3 -(naphthalene- l-yloxy)-propenyl] benzoate (300 mg 0.72 mM) was dissolved in acetone (8 M), to which potassium carbonate (150 mg 1.08 mM) and 3-aminoquinoline (57 mg 0.61 mM) were added thereto, followed by allowing the mixture to reflux for 3 hours. After completing the reaction, the resulting mixture was cooled to room temperature, filtered and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound as a white solid (158 mg, 32%).
  • Step 6 4-[2-(Quinoline-3-ylaminomethyl)-3-(naphthalene-l-yloxy)- p ropenyl] benzoic acid
  • Methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(na ⁇ hthalene- 1 -yloxy)- propenyl] benzoate (156 mg, 0.316 mM) was dissolved in tetrahydrofuran (3 ml), and lithium hydroxide (133 mg, 3.16 mM) was added thereto. After adding distilled water (3 mi) thereto, the mixture was stirred at room temperature for 10 minutes and stirred at 50 °C for 3 hours. ' After completing the reaction, the resulting mixture was cooled to room temperature and ice water was added thereto.
  • Step 7 4-[2-(Quinoline-3-ylammomethyl)-3-(naphthalene-l-yloxy)- propenyl]-N-hydroxy-benzamide 4-[2-(Quinoline-3-ylaminomethyl)-3-(naphthalene- 1 -yloxy)- propenyl]benzoic acid (140 mg, 0.30 mM) was dissolved in dimethylformimide (3 mi), cooled to 0 ° C and triethylamine (64 ⁇ i, 0.456 mM) and N-methansulfonyloxy-6-trifluoro benzotriazole (103 mg, 0.365 mM) were added thereto, followed by stirring for 30 minutes, tert- Butyldimethylsilyloxyamine (67 mg , 0.45 mM) was added to the reaction solution and stirred at room temperature for 3 hours. After completing the reaction, the resulting mixture was cooled and concentrated under a reduced pressure. The resulting residue was purified by
  • Step 1 of Example 39 was repeated except for using 4-cyano-phenol as the starting material to obtain the title compound.
  • Step 2 Methyl 4-[2-carboxy-3-(4-cyano-phenoxy)-propenyl] benzoate The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-fer ⁇ -butoxycarbonyl-3-(4-cyano-phenoxy)-propenyl] benzoate to obtain the title compound.
  • Step 4 Methyl 4-[2-bromo-3-(4-cyano-phenoxy)-propenyl] benzoate The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydromethyl-3-(4-cyano-phenoxy)-propenyl] benzoate to obtain the title compound.
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromo-3-(4-cyano-phenoxy)- ⁇ ropenyl] benzoate to obtain the title compound (34%).
  • Step 6 4- ⁇ 2-(Qui ⁇ io ⁇ ine-3-y ⁇ ammomethyI)-3-(4-cyano-phenoxy)- propenyl]-benzoic acid
  • Step 7 4-[2-(QuinoIine-3-ylaminomethyl)-3-(4-cyano-phenoxy)- propenyl]-N-hydroxy benzamide The procedure of Step 7 of Example 39 was repeated except for using
  • Step 1 of Example 39 was repeated except for using 3,5-dimethoxy-phenol) as the starting material to obtain the title compound.
  • Step 2 of Example 39 The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-ter/-butoxycarbonyl-3-(3,5-dimethoxy-phenoxy)-propenyl] benzoate to obtain the title compound.
  • Step 3 Methyl 4-[2-hydroxymethyl-3-(3,5-dimethoxy-phenoxy)- propenyl] benzoate The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(3,5-dimethoxy-phenoxy)-propenyl] benzoate to obtain the title compound.
  • Step 4B of Example 39 The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(3,5-dimethoxy-phenoxy)-propenyl] benzoate to obtain the title compound.
  • Step 5 Methyl 4-[2-(quinoline-3-yIaminomethyl)-3-(3,5-dimethoxy- phenoxy)-propenyl] benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(3,5-dimethoxy-phenoxy)-propenyl] benzoate to obtain the title compound (34%).
  • Step 6 4-[2-(Quinoline-3-yIaminomethyl)-3-(3,5-dimethoxy-phenoxy)- propenylj-benzoic acid
  • Step 7 4-[2-(Qinnoline-3-ylaminomethyI)-3 ⁇ (3,5-diniethoxy-phenoxy)- propenyl]-N-hydroxybenzamide
  • Example 42 4-[2-(QuinoIine-3-ylaminomethyl)-3-(4-benzyloxy-phenoxy)- propenyl]-N-hydroxybenzamide
  • Step 1 Methyl 4-[2-te/ ⁇ /-b ⁇ itoxycarbonyl-3-(4-benzyloxy-phenoxy)- propenyl] benzoate
  • Step 2 of Example 39 The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-ter/-butoxycarbonyl-3-(4-benzyloxy-phenoxy)-propenyl] benzoate to obtain the title compound.
  • Step 3 Methyl 4-[2-hydroxymethyl-3-(4-benzyloxy-phenoxy)-propenyl] benzoate
  • Step 4B of Example 39 was repeated except for using methyl . 4-[2-hydroxymethyl-3-(4-benzyloxy-phenoxy)-propenyl]- benzoate to obtain the title compound.
  • Step 5 Methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(4-benzyIoxy- phenoxy)-propenyl] benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(4-benzyloxy-phenoxy)-pro ⁇ enyl] benzaote to obtain the title compound (40%).
  • Step 6 4-[2-(Quinoline-3-ylaminomethyl)-3-(4-benzyloxy-phenoxy)- propenyl]-benzoic acid
  • Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(4-benzyloxy-phenoxy)- propenyl] benzoate to obtain the title compound (85 %).
  • Step7 4-[2-(Quinoline-3-ylaminomethyl)-3-(4-benzyloxy-phenoxy)- propenyl]-N-hydroxybenzamide
  • Step 1 of Example 39 was repeated except for using 4-fluoro-phenol as the starting material to obtain the title compound.
  • Step 2 of Example 39 The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-fert-butoxycai"bonyl-3-(4-fluoro-phenoxy)-propenyl] benzoate to obtain the title compound.
  • Step 3 Methyl 4-[2-hydroxymethyl-3-(4-fluoro-phenoxy)-propenyl] benzoate The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(4-fluoro-phenoxy)- ⁇ ropenyl] benzoate to obtain the title compound.
  • Step 4B of Example 39 The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(4-fluoro- ⁇ henoxy)- ⁇ ropenyl] benzoate to obtain the title compound.
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(4-fluoro-phenoxy)-propenyl] benzoate to obtain the title compound (42%).
  • Step 6 4-[2-(Quinoline-3-yIaminomethyI)-3-(4-fluoro-phenoxy)- propenyl]-benzoic acid
  • Step 7 4-[2-(Quinoline-3-yIaminomethyl)-3-(4-fluoro-phenoxy)- propeny ⁇ ]-N-hydroxybenzamide The procedure of Step 7 of Example 39 was repeated except for using
  • Step 1 Methyl 4-[2-fert-butoxycarbonyI-3-(4-acetyIamino-phenoxy)- propenyl] benzoate The procedure of Step 1 of Example 39 was repeated except for using
  • Step 2 of Example 39 The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-/er/-butoxycarbonyl-3-(4-acetylamino-phenoxy)-propenyl] benzoate to obtain the title compound.
  • Step 3 Methyl 4-[2-hydroxymethyl-3-(4-acetylamino-phenoxy)- propenyl] benzoate The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(4-acetylamino-phenoxy)-propenyl] benzoate to obtain the title compound.
  • Step 4 Methyl 4-[2-bromomethyl-3-(4-acetylamino-phenoxy)-propenyl] Methyl
  • the procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(4-acetylamino-phenoxy)-pro ⁇ enyl] benzoate to obtain the title compound.
  • Step 5 Methyl 4-[2-(quinoline-3-yIaminomethyl)-3-(4-acetylamino- phenoxy)-propenyl] benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(4-acetylamino-phenoxy)-propenyl] benzaote to obtain the title compound (10%).
  • Step 6 4-[2-(Quinoline-3-ylaminomethyl)-3-(4-acetylamino-phenoxy)- propenyl]-benzoic acid
  • Step 7 4-[2-(Quinoline-3-ylaminomethyl)-3-(4-acetyIamino-phenoxy)- propenyl]-N-hydroxybenzamide
  • Example 45 4- [2-(Quinoline-3-yIaminomethyl)-3-(4-methylsulfeiiyl- phenoxy)-propenyl]-N-hydroxybenzaniide Step 1: Methyl 4-[2-fert-butoxycarbonyl-3-(4-methylsulfenyl-phenyloxy)- propenyl] benzoate
  • Step 1 of Example 39 was repeated except for using 4-methylsulfenyl-phenol as the starting material to obtain the title compound.
  • Step 2 of Example 39 The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-fert-butoxycarbonyl-3 -(4-methylsulfenyl-phenyloxy)-propenyl] benzoate to obtain the title compound.
  • Step 3 Methyl 4-[2-hydroxymethyl-3-(4-methylsulfenyl-phenyIoxy)- propenyl] benzoate
  • the procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(4-methylsulfenyl-phenyloxy)- ⁇ ropenyl] benzoate to obtain the title compound.
  • Step 4 Methyl 4-[2-bromomethyl-3-(4-methylsulfenyI-phenyloxy)- propenyl] benzoate The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(4-methylsulfenyl- ⁇ henyloxy)-propenyl] benzoate to obtain the title compound.
  • Step 5 Methyl 4-[2-(quinoline-3-ylaminomethyI)-3-(4-methyIsulfenyI- phenoxy)-propenyl] benzoate
  • the procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(4-methylsulfenyl- ⁇ henyloxy)-propenyl] benzoate to obtain the title compound (47%).
  • Step 6 4-[2-(Quinoline-3-yIaminomethyl)-3-(4-methyls ⁇ ilfenyl-phenoxy)- propenyl]-benzoic acid
  • Step 7 4- [2-(Quinoline-3-ylaminomethyl)-3-(4-methylsulf enyl-phenoxy)- propenyl]-N-hydroxybenzamide The procedure of Step 7 of Example 39 was repeated except for using
  • Step 2 Methyl 4 ⁇ (2-carboxy-3-phenoxy propenyl) benzoate
  • Step 3 Methyl 4-(2-hydroxymethyl-3-phenoxy propenyl) benzoate
  • Step 3 of Example 39 The procedure of Step 3 of Example 39 was repeated except for using methyl 4-(2-carboxy-3- ⁇ henoxy propenyl) benzaote to obtain the title compound.
  • Step 4B of Example 39 The procedure of Step 4B of Example 39 was repeated except for using methyl 4-(2-hydroxymethyl-3-phenoxy propenyl) benzoate to obtain the title compound.
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4-(2-bromomethyl-3-phenoxy propenyl) benzoate to obtain the title compound (46%).
  • Step 6 4-[2-(Quinoline-3-ylaminomethyl)-3-phenoxy-propenyl]-benzoic acid
  • Step 7 4-[2-(Quinoline-3-ylaminomethyl)-3-phenoxy-propenyl]-N- hydroxy benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-phenoxy-piOpenyl]-benzoic acid to obtain the title compound (71 %).
  • Step 1 Methyl 4-[2-tertf-butoxycarbonyl-3-(4-ch ⁇ oro-naphthalene-l- yloxy)-propenyl] benzoate
  • Step 1 of Example 39 The procedure of Step 1 of Example 39 was repeated except for using (4 ⁇ ehloro- 1 -naphthalenol) as the starting material to obtain the title compound (2.545 g , 93%).
  • Step 2 of Example 39 The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-/err-butoxycarbonyl-3-(4-chloro-naphthalene-l-yloxy)-propenyl] benzoate to obtain the title compound (1.9 g, 99%).
  • Step 3 Methyl 4-[2-hydroxymethyl-3-(4-chloro ⁇ naphthaIene-l-yIoxy)- propeny ⁇ ] benzoate
  • the procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(4-chloro-naphthalene-l-yloxy)-propenyl] benzoate to obtain the title compound (886 mg, 48%).
  • Step 4 Methyl 4-[2-bromomethyl-3-(4-chloro-naphthaIene-l-yloxy)- propenyl] benzoate
  • Step 4B of Example 39 The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(4-chloro-naphthalene- 1 -yloxy)- propenyl] benzoate to obtain the title compound.
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4- [2-bromomethyl-3 -(4-chloro-naphthalene- 1 -y loxy)-propeny 1] benzoate to obtain the title compound (13 %).
  • Step 6 4-[2-(Quinoline-3-ylaminomethyl)-3-(4-chloro-naphthalene-l- yloxy)-propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(4-chloro-naphthalene-l-yloxy)- propenyl] benzoate to obtain the title compound (50 % ).
  • Step 7 4-[2-(QuinoIine-3-ylaminomethyl)-3-(4-chloro-naphthalene-l- yloxy)-propenyl]-N-hydroxybenzamide
  • the procedure of Step 7 of Example 39 was repeated except for using 4- [2-(quinoline-3 -ylaminomethyl)-3-(4-chloro-naphthalene- 1 -yloxy)- propenyl]-benzoic acid to obtain the title compound (16%).
  • Example 48 4-[2-(3,4-Dimethoxyphenylaminomethyl)-3-(4-chloro- naphthalene-l-yloxy)-propenyl]-N-hydroxybenzamide
  • Step 1 Methyl 4-[2-(3,4-dimethoxyphenylamii.omethyl)-3-(4-chIoro- naphthalene-l-yloxy)-propenyl] benzoate
  • Step 5 of Example 39 The procedure of Step 5 of Example 39 was repeated except for using (4-chloro-l-naphthalenol) as the starting material to obtain the title .compound (36%).
  • Step 2 4-[2-(3,4-Dimethoxyphenylaminomethyl)-3-(4-chloro- naphthalene-l-yloxy)-propenyl]benzoic acid
  • Step 3 4-[2-(3,4-Dimethoxyphenylaminomethy ⁇ )-3-(4-chloro- naphthalene-l-yloxy)-propenyl]-N-hydroxybenzamide
  • Step 7 of Example 39 was repeated except for using 4-[2-(3,4-dimethoxyphenylaminomethyl)-3-(4-chloro-na ⁇ hthalene-l-yloxy)- propenyl]benzoic acid to obtain the title compound (74%).
  • Example 49 4-[2-(Quinoline-3-ylaminomethyl)-3-(3-methoxy- phenylsulfenyl)-propenyl]-N-hydroxybenzamide
  • Step 1 Methyl 4-[2-te/'/-butoxycarbonyl-3-(3-methoxy-phenylsulfenyI)- pr ⁇ penyl] benzoate
  • Step 1 of Example 39 was repeated except for using 3-methoxy-phenylsulfen as the starting material to obtain the title compound.
  • Step 2 of Example 39 The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-/e7'/-butoxycarbonyl-3-(3-methoxy-phenylsulfenyl)-propenyl] benzoate to obtain the title compound.
  • Step 3 of Example 39 The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(3-methoxy- ⁇ henylsulfenyl)-propenyl] benzoate to obtain the title compound.
  • Step 4 Methyl 4-[2-bromomethyl-3-(3-methoxy-phenylsulfenyl)- propenyl] benzoate
  • Step 4B of Example 39 The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(3-methoxy-phenylsulfenyl)-propenyl] benzoate to obtain the title compound (890 ing, 74 %).
  • Step 5 Methyl 4-[2-(quinoline-3-ylaminomethyI)-3-(3-methoxy- phenylsulfenyl)-propenyl] benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(3-methoxy- ⁇ henylsulfenyl)-propenyl] benzoate to obtain the title compound (24 % ).
  • Step 6 4-[2-(Quinoline-3-yIaminomethyl)-3-(3-methoxy-phenyIsulfenyl)- propenyl]benzoic acid
  • Step 7 4- [2-(Quinoline-3-ylaminomethyl)-3-(3-methoxy-phenylsulfenyI)- propenyl) ⁇ N-hydroxybenzamide
  • Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-(3-methoxy-phenylsulfenyl)- propenyl]benzoic acid to obtain the title compound (10%).
  • Example 50 4-[2-(Quinolme-3-ylaminomethyl)-3-(3-methoxy- phenylsulfenyI)-propeny ⁇ ]-N-hydr ⁇ xybenzamide
  • Step 1 Methyl 4-[2-fer/-butoxycarbonyl-3-(3-methoxy-2-phenylsulfenyl)- propenyl] benzoate The procedure of Step 1 of Example 39 was repeated except for using
  • Step 2 Methyl 4-[2-carboxy-3-(3-methoxy-2-phenylsulfenyl)-propenyl] benzoate
  • the procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-fer/-butoxycarbonyl-3-(3-methoxy-2-phenylsulfenyl)-propenyl] benzoate to obtain the title compound (2.573 g, 99%).
  • Step 4B of Example 39 The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(3-methoxy-2-phenylsulfenyl)-propenyl] benzoate to obtain the title compound (76 % ).
  • Step 5 Methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(3-methoxy-2- phenylsulfenyl)-propenyl] benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(3-methoxy-2-phenylsulfenyl)-propenyl] benzoate to obtain the title compound (28%).
  • Step 6 4-[2-(Quinoline-3-ylaminomethyI)-3-(3-methoxy-2- phenylsulfenyl)-propenyl] benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(3-methoxy-2-phenylsulfenyl)- propenyl] benzoate to obtain the title compound (80 % ).
  • Step 7 4- [2-(Quinoline-3-ylaminomethyl)-3-(3-methoxy-phenylsulfenyl)- propenyl]-N-hydroxybenzamide
  • the procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-(3-methoxy-2-phenylsulfenyl)-propenyl] benzoic acid to obtain the title compound (48%).
  • Example 51 4-[2-(Quinoline-3-ylammomethyl)-3-(2-nitro-naphthalene-l- yloxy)-propenyI]-N-hydroxybenzamide
  • Step 1 Methyl 4-[2-te ⁇ -bwtoxycarbonyI-3-(2-nitro»naphthalene-l-y ⁇ oxy)- propenyl] benzoate
  • Step 1 of Example 39 was repeated except for using 2-nitro-l -naphthalenol as the starting material to obtain the title compound.
  • Step 2 of Example 39 The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-ter ⁇ -butoxycarbonyl-3-(2-nitro-naphthalene- 1 -yloxy)-propenyl] benzoate to obtain the title compound.
  • Step 4B of Example 39 The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(2-nitro-naphthalene- 1 -yloxy)-propenyl] benzoate to obtain the title compound (408 mg, 70 %).
  • Step 5 Methyl 4-[2-(quinoIine-3-ylaminomethyl)-3-(2-nitro-naphthalene- l-yloxy)-propenyl] benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(2-nitro-naphthalene- 1 -yloxy)-propenyl] benzoate to obtain the title compound (206 mg, 47 %).
  • Step 6 4-[2-(Quinoline-3-ylaminomethyl)-3-(2-nitro-naphthaIene-l- yloxy)-propenyl]-benzoic acid
  • Step 7 4-[2-(Quinoline-3-yIaminomethyl)-3-(2-nitro-naphthalene-l- yloxy)-propenyl] ⁇ N-hydroxybenzamide The procedure of Step 7 of Example 39 was repeated except for using
  • Step 1 Methyl 4-[2-ter ⁇ butoxycarbonyl-3-(9H-carbazol-l-yloxy)- propenyl] benzoate The procedure of Step 1 of Example 39 was repeated except for using
  • Step 2 of Example 39 The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-/er/-butoxycarbonyl-3-(9H-carbazol-l-yloxy)- ⁇ ropenyl]- benzoate to obtain the title compound (99%).
  • Step 3 Methyl 4-[2-hydroxymethyl-3-(9H-carbazol-l-yloxy)-propenyl] benzoate The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(9H-carbazol-l-yloxy)-propenyl] benzoate to obtain the title compound (28%).
  • Step 4 Methyl 4-[2-bromomethyl-3-(9H-carbazol-l-yloxy)-propenyl] benzoate
  • Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(9H-carbazol-l-yloxy)- ⁇ ro ⁇ enyl] benzoate to obtain the title compound (57%).
  • Step 5 Methyl 4-[2-(3,4-dimethoxyphenyIaminomethyl)-3-(9H-carbazol- l-yloxy) ⁇ propenyl]-benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(9H-carbazol-l -yloxy)-propenyl]-berizoate to obtain the title compound (77%).
  • Step 6 4-[2-(3,4-Dimethoxyphenylaminomethyl)-3-(9H-carbazol-l- yloxy)-propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(3 ,4-dimethoxyphenylaminomethyl)-3-(9H-carbazol- 1 -yloxy)- propenyl]-benzoate to obtain the title compound (96 % ) .
  • Step 7 4-[2-(3,4-Dimethoxyphenylaminomethyl)-3-(9H-carbazol-l- yloxy)-propenyI]-N-hydroxybenzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(3 5 4-dimethoxyphenylaminomethyl)-3-(9H-carbazol- 1 -yloxy)- propenyl]-benzoic acid to obtain the title compound (40 %).
  • Step 4A of Example 39 was repeated except for using 9H-carbazol-l-ylol as the starting material to obtain the title compound (54%).
  • Step 5 A of Example 39 was repeated except for using methyl 4-[2-formyl-3-(9H-carbazol-l-yloxy)-propenyl] benzoate to obtain the title compound (24%).
  • Step 3 4-[2-(Quinoline-3-ylaminomethyl)-3-(9H-carbazo ⁇ -l-yIoxy)- propenylj-benzoic acid
  • Step 4 4-[2-(Quinoh'ne-3-yIaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl] -N-hyd roxybenzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)- ⁇ iOpenyl]- benzoic acid to obtain the title compound (21 %).
  • Example 54 4-[2-Hydroxymethyl-3-(9H-carbazol-l-yloxy)-propenyl]-N- hydroxybenzamide
  • Step 1 4-[2-Hydroxymethyl-3-(9H-carbazol-l-yloxy)-propenyl]-benzoic acid
  • Step 2 4-[2-Hydroxymethyl-3-(9H-carbazol-l-yloxy)-propenyl]-N- hydroxybenzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-hydroxymethyl-3-(9H-carbazol-l-yloxy)-propenyl]-benzoic acid to obtain the title compound (31 %).
  • Step 2 4-[2-(Pyridine-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl] benzoic acid
  • Step 3 4-[2-(Pyridine-3-ylammomethyl)-3-(9H-carbazol-l-yIoxy)- propenyl]-N-hydroxy benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using- 4-[2-(pyridine-3-ylaminomethyl)-3-(9H-carbazol- 1 -yloxy)- ⁇ ropenyl] benzoic acid to obtain the title compound (31 %).
  • Example 56 4-[2-(6-Methoxypyridine-3-yIaminomethyl)-3-(9H-carbazol- l-yloxy)-propenyl]-N-hydroxybenzamide
  • Step 1 Methyl 4-[2-(6-methoxypyridine-3-ylaminomethyI)-3-(9H- carbazol-l-yloxy)-propenyl] benzoate
  • Step 5 A of Example 39 was repeated except for using (6-methoxy-3-aminopyridine) as the starting material to obtain the title compound (52%).
  • Step 2 4-[2-(6-Methoxypyridine-3-ylaminomethyl)-3-(9H-carbazol-l- yloxy)-propenyl]-benzoic acid
  • Step 6 of Example 39 was repeated except for using methyl 4-[2-(6-methoxypyridine-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl]-benzoate to obtain the title compound (93 %).
  • Step 3 4-[2-(6-Methoxypyridine-3-ylaminomethyl)-3-(9H-carbazol-l- yloxy)-propenyl]-N-hydroxybenzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(6-methoxy ⁇ yridine-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl]-benzoic acid to obtain the title compound (31 %).
  • Example 57 4-[2-(4-Methoxyphenylaminomethyl)-3-(9H-carbazol-l- yloxy)-propenyl]-N-hydroxybenzamide
  • Step 1 Methyl 4-[2-(4-methoxyphenylaminomethyl)-3-(9H-carbazol-l- yloxy)-propenyl] benzoate
  • Step 2 4-[2-(4-Methoxyphenylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl]-benzoic acid
  • Step 3 4-[2-(4-Methoxyphenylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyI]-N-hydroxybenzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(4-methoxyphenylaminomethyl)-3-(9H-carbazol-l-yloxy)- ⁇ ropenyl]- benzoic acid to obtain the title compound (20 % ).
  • Step 1 of Example 39 was repeated except for using 4-biphenol as the starting material to obtain the title compound.
  • 1 H NMR 200 MHz 5 CDCl 3 ), ⁇ 1.54 (S 5 9H, CH 3 ), 3.91 (S 5 3H, OCH 3 ), 4.82 (S 5 2H, CH 2 ), 7.05 (m, 2H 5 ArH) 5 7.40-7.57 (m, 9H 5 ArH), 7.94 (S, IH, CH), 8.04 (m, 2H, ArH)
  • Step 2 of Example 39 The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-fer ⁇ -butylcarbonyl-3-(bi ⁇ henyl-4-yloxy)-pro ⁇ enyl]-benzoate to obtain the title compound.
  • Step 3 of Example 39 The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(biphenyl-4-yloxy)-propenyl]-benzoate to obtain the title compound.
  • Step 4B of Example 39 The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydromethyl-3-(bi ⁇ henyl-4-yloxy)-propenyl] benzoate to obtain the title compound.
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(bi ⁇ henyl-4-yloxy)- ⁇ ro ⁇ enyl] benzoate to obtain the title compound (59%).
  • Step 6 4-[2-(Quinoline-3-ylaminomethyI)-3-(biphenyl-4-yIoxy)-propenyI] benzoic acid
  • the procedure of Step 6 of Example 39 was repeated except for using methyl 4- [2-(quinoline-3 -ylaminomethyl)-3 -(biphenyl-4-yloxy)-pro ⁇ enyl] benzoate to obtain the title compound (86%).
  • Step 7 4-[2-(Quinoline-3-ylaminomethyl)-3-(biphenyl-4-yloxy)- propenyI]-N-hydroxybenzamide
  • Step 1 of Example 39 The procedure of Step 1 of Example 39 was repeated except for using 2-benzothiazolol as the starting material to obtain the title compound (89 % ).
  • Step 2 Methyl 4-[2-carboxy-3-(benzothiazol-2-yloxy)-propeny ⁇ ] benzoate The procedure of Step 2 of Example 39 was repeated except for using methyl 4- [2-ter?-butoxycarbonyl-3 -(benzothiazol-2-yloxy)-propenyl] benzoate to obtain the title compound (63 0 Io).
  • Step 4 Methyl 4-[2-bromomethyI-3-(benzothiazol-2-yloxy)-propenyl] benzoate The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(benzothiazol-2-yloxy)-pro ⁇ enyl] benzoate to obtain the title compound (95 %).
  • Step 5 Methyl 4- ⁇ 2-(quinoIine-3-ylaminomethyl)-3-(benzothiazol-2- yloxy)-propenyl ⁇ -benzoate
  • the procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(benzothiazol-2-yloxy)-propenyl]- benzoate to obtain the title compound (79 % ).
  • Step 6 4- ⁇ 2-(Quinoline-3-ylaminomethyl)-3-(benzothiazol-2-yloxy)- propenyl ⁇ -benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-2-(quinoline-3-ylaminomethyl)-3-(benzothiazol-2-yloxy)-propenyl benzoate to obtain the title compound (91 %).
  • Step 7 4-[2-(Quinoline-3-yIaminomethyI)-3-(benzothiazol-2-yloxy)- propenyI]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4- ⁇ 2-(quinoline-3-ylaminomethyl)-3-(benzothiazol-2-yloxy)-propenyl ⁇ - benzoic acid to obtain the title compound (13 %).
  • Step 2 4- ⁇ 2-[(3,4-Dimethoxy-phenylamino)-methyl]-3-(benzothiazoI-2- yloxy)-propenyl ⁇ -benzoic acid
  • Step 2 of Example 39 The procedure of Step 2 of Example 39 was repeated except for using methyl 4- ⁇ 2-[(3,4-dimethoxy- ⁇ henylamino)-methyl]-3-(benzothiazol-2- yloxy)-propenyl ⁇ -benzoate to obtain the title compound.
  • Step 3 4- ⁇ 2-[(3,4-Dimethoxy-phenylamino)-methyl]-3-(benzothiazol-2- yIoxy)-propenyl ⁇ -N-hydroxy-benzamide
  • Step 3 of Example 39 The procedure of Step 3 of Example 39 was repeated except for using 4- ⁇ 2- [(3 ,4-dimethoxy-phenylamino)-methyl]-3 -(benzothiazol-2-yloxy)- propenylj-benzoic acid to obtain the title compound (13 %).
  • Step 1 Methyl 4-[2-ter£-butoxycarbonyl-3-(l,3-dioxo-l,3-dihydro- isoindole-2-yl)-propenyl] benzoate
  • Step 1 of Example 39 The procedure of Step 1 of Example 39 was repeated except for using l,3-dioxo-l,3-dihydro-isoindole as the starting material to obtain the title compound (96 % ) .
  • Step 2 Methyl 4-[2-carboxy-3-(l,3-dioxo-l,3-dihydro-isoindoIe-2-yl)- propenyl] benzoate
  • Step 2 of Example 39 The procedure of Step 2 of Example 39 was repeated except for using methyl 4- [2-ter/-butoxycarbonyl-3 -( 1 ,3 -dioxo- 1 ,3 -dihydro-isoindole-2-yl)- prbpenyl] benzoate to obtain the title compound (99 % ).
  • Step 3 Methyl 4-[2-hydroxymethyl-3-(l,3-dioxo-l,3-dihydro-isoindole-2- yl)-propenyl] -benzoate
  • the procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(l 5 3-dioxo-l 5 3-dihydro-isoindole-2-yl)-propenyl]- benzoate to obtain the title compound (64%).
  • Step 4 Methyl 4-[2-bromomethyI-3-(l,3-dioxo-l,3-dihydro-isoindole-2- yl)-propenyl]-benzoate
  • the procedure of Step 4B of Example 39 was repeated except for using methyl 4- [3 -( 1 ,3 -dioxo- 1 ,3 -dihydro-isoindole-2-yl)-2-hydroxymethyl- propenyl]-benzoate to obtain the title compound (66%).
  • Step 5 Methyl 4-[2-(qumolme-3-ylammomethyl)-3-(l,3-dioxo ⁇ l,3- dihydro-isoindole-2-yl)-propenyl]-benzoate ⁇
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(l ,3-dioxo- 1 ,3-dihydro-isoindole-2-yl)- propenyl]-benzoate to obtain the title compound (46%).
  • Step 6 4-[2-(Quinoline-3-ylaminomethyl)-3-(l,3-dioxo-l,3-dihydro- isoindole-2-yl)-propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4- [2-(quinoline-3 -ylaminomethyl)-3 -( 1 ,3 -dioxo- 1 ,3-dihydro- isoindole-2-yl)-propenyl]-benzoate to obtain the title compound.
  • Step 7 4-[2-(Quinoline-3-ylaminomethyI)-3-(l,3-dioxo-l,3-dihydro- isoindole-2-yl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-(l,3-dioxo-l,3-dihydro-isoindole-2-yl)- propenyl]-benzoic acid to obtain the title compound (16%).
  • Step 1 Methyl 4-[2-phenylaminomethyl-3-(naphthalene-l-yloxymethyl)- propenylj-benzoate
  • Step 5B of Example 39 was repeated except for using 2-phenylamine as the starting material to obtain the title compound (94%).
  • Step 2 4-[2-Phenylaminomethyl-3-(naphthaIene-l-yloxymethyI)- propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4- [2- ⁇ henylaminomethy 1-3 -(naphthalene- 1 -yloxymethyl)-propenyl]- benzoate to obtain the title compound (99%).
  • Step 3 4-[2-Phenylaminomethyl-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide
  • Step 1 Methyl 4-[2-(3,4-dihydro-lH-isoquinoline-2-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenylj-benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using 3 ,4-dihydro- lH-isoquinoline as the starting material to obtain the title compound (92%).
  • Step 2 4-[2-(3,4-Dihydro-lH-isoquinoline-2-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4- [2-(3 ,4-dihydro- 1 H-isoquinoline-2-ylmethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoate to obtain the title compound (99 % ).
  • Step 3 4-[2-(3,4-Dihydro-lH-isoquinoIine-2-yImethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxybenzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(3 ,4-dihydro- 1 H-isoquinoline-2-y lmethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (65 %).
  • Example 64 4-[2-(2-Methoxy-dibenzofuran-3-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(2-methoxy-dibenzofuran-3-yIaminomethyI)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 was repeated except for using 2-methoxy-dibenzofuran-3-ylamine as the starting material to obtain the title compound (58%).
  • Step 2 4-[2-(2-Methoxy-dibenzofuran-3-ylaminomethyl)-3-(naphthalene- l-y ⁇ oxymethyl)-propenylj-benzoic acid
  • the procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(2-methoxy-dibenzofuran-3-ylaminomethyl)-3-(na ⁇ hthalene- 1 - yloxymethyl)-propenyl]-benzoate to obtain the title compound (57%).
  • Step 3 4-[2-(2-Methoxy-dibenzofuran-3-ylaminomethyl)-3-(naphthalene- l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(2-methoxy-dibenzofuran-3-ylaminomethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (91 %).
  • Step 1 Methyl 4-[2-(Naphthalene-l-ylamino)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using 1-naphthaleneamine as the starting material to obtain the title compound (95 %).
  • Step 2 4-[2-(Naphthalene-l-ylaminomethyl)-3-(naphthalene-l- y ⁇ oxymethyl)-propenyl]-benzoie acid
  • Step 3 4-[2-(Naphthalene-l-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using
  • Step 1 Methyl 4-[2-(quinoline-8-yIaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using 8-aminoquinoline as the starting material to obtain the title compound (87%).
  • Step 2 4-[2-(Quinoline-8-ylaminomethyl)-3-(naphthaIene-l ⁇ yloxymethyl)-propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-8-ylaminomethyl)-3-(naphthalene- 1 -yloxymethyl)- propenyl]-benzoate to obtain the title compound (30% ).
  • Step 3 4-[2-(Quinoline-8-y ⁇ aminomethyl)-3-(naphthalene-l- y ⁇ oxymethyl)-propenyI]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-8-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)-propenyl]- benzoic acid to obtain the title compound ⁇ 2,9%).
  • Step 5B of Example 39 was repeated except for using 6-methoxy-3-aminopyridine as the starting material to obtain the title compound (69%).
  • Step 2 4-[2-(6-Methoxy-pyridine-3-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(6-methoxy-pyridine-3-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate to obtain the title compound (94%).
  • Step 3 4-[2-(6-Methoxy-pyridine-3-ylamiiiomethyl)-3-(naphthalene-l- yloxymethyI)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(6-methoxy- ⁇ yridine-3 -ylaminomethyl)-3 -(naphthalene- 1 -yloxymethyl)- propenyl]-benzoic acid to obtain the title compound (95 % ).
  • Step 1 Methyl 4-[2-(l,l-dioxo-lH-116-naphto[l,8-cd]isothiazol-2- ylmethyl)-3-(naphthalene-l-yloxymethyl)-propenyl]-benzoate 10
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using l,l-dioxo-lH-116-naphto[l 5 8-cd]isothiazole as the starting material to obtain the title compound (86%).
  • Step 2 4-[2-(l,l-Dioxo-lH-lI6-naphto[l,8-cd]isothiazol-2-ylmethyl)-3-
  • Step 3 4-[3-(l ? l-Dioxo-lH-lI6-naphto[l,8-cd]isothiazol-2-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(l,l-dioxo-lH-116-naphto[l,8-cd]isothiazol-2-ylmethyl)-3-(na ⁇ hthalene- l-yloxymethyl)-propenyl] -benzoic acid to obtain the title compound (95%).
  • Example 69 4-[2-(4-Methoxy-phenylaminomethyI)-3-(naphthaIene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 1 Methyl 4-[2-(4-methoxy-phenyIaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl] -benzoate
  • Step 5B of Example 39 was repeated except for using 4-methoxy-phenylamine as the starting material to obtain the title compound (99%).
  • Step 2 4-[2-(4-Methoxy-phenylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(4-methoxy-phenylaminomethyl)-3-(naphthalene- 1 - yloxymethyl)-pro ⁇ enyl]-benzoate to obtain the title compound (99%).
  • Step 3 4-[2-(4-Methoxy-phenyIaminomethyl)-3-(naphthalene-l- yIoxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(4-methoxy-phenylaminomethyl)-3 -(naphthalene- 1 -yloxymethyl)- propenyl]-benzoic acid to obtain the title compound (69%).
  • Example 70 4-[2-(Thiazol-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 1 Methyl 4-[2-(thiazol-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using 2-aminothiazole as the starting material to obtain the title compound (64%).
  • Step 2 4-[2-(Thiazol-2-ylaminomethyl)-3-(naphthalene-l-yloxymethyI)- propenylj-benzoic acid
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(thiazol-2-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)-propenyl]- benzoic acid to obtain the title compound (89 % ).
  • Step 1 Methyl 4-[2-(9-ethyl-9H-carbazol-3-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 was repeated except for using 9-ethyl-9H-carbazol-3-ylamine as the starting material to obtain the title compound (99%).
  • Step 2 4-[2-(9-Ethyl-9H-carbazol-3-ylaminomethyI)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(9-ethyl-9H-carbazol-3 -ylaminomethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoate to obtain the title compound (91 %).
  • Step 3 4-[2-(9-Ethy ⁇ -9H-carbazol-3-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(9-ethyl-9H-carbazol-3-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- pro ⁇ enyl]-benzoic acid to obtain the title compound (94 % ).
  • Example 72 4-[2-(6-Methoxy-benzothiazol-2-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(6-methoxy-benzothiazol-2-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using 6-methoxy-benzothiazol-2-ylamine as the starting material to obtain the title compound (73 % ).
  • Step 2 4- [2-(6-Methoxy-benzothiazol-2-ylaminomethy l)-3-(naphthalene- l-yloxymethyl)-propenyl] -benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4- [2-(6-methoxy-benzothiazol-2-ylaminomethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoate to obtain the title compound (99%).
  • Step 3 4-[2-(6-Methoxy-benzothiazol-2-yIaminomethyI)-3-(napfathaIene- l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(6-methoxy-benzothiazol-2-ylaminomethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (85%).
  • Example 73 4-[2-(Naphthalene-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(naphthalene-2-yIaminomethyl)-3-(naphthaIene-l- yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 was repeated except for using 2-naphthaleneamine as the starting material to obtain the title compound (99%).
  • Step 2 4-[2-(Naphthalene-2-yIaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl] -benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(naphthalene-2-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- ⁇ ropenyl]-benzoate to obtain the title compound (99%).
  • Step 3 4-[2-(Naphthalene-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 was repeated except for using 4-[2-(naphthalene-2-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoic acid to obtain the title compound (97%).
  • Step 2 4- [2-(6-Nitro-benzothiazol-2-yIami ⁇ omethyl)-3-(naphthalene-l - yloxymethyl)-propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(6-nitro-benzothiazol-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate to obtain the title compound (93 %).
  • Step 3 4- [2-(6-Nitro-benzothiazol-2-ylaminomethyl)-3-(naphthalene-l - yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(6-nitro-benzothiazol-2-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoic acid to obtain the title compound (98 %).
  • Step 1 Methyl 4-[2-(4-methyl-benzothiazol-2-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 was repeated except for using 4-methyl-benzothiazol-2-ylamine as the starting material to obtain the title compound (99 % ).
  • Step 2 4-[2-(4-Methyl-benzothiazol-2-ylaminomethyl)-3-(naphthaIene-l- yloxymethyl)-propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(4-methyl-benzothiazol-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-pro ⁇ enyl]-benzoate to obtain the title compound (99%).
  • Step 3 4-[2-(4-Methyl-benzothiazol-2-yIaminomethyl)-3-(naphthaIene-l- yIoxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(4-methyl-benzothiazol-2-ylaminomethyl)-3-(naphthalene- 1 - yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (67%).
  • Example 76 4-[2-(5,6-Dimethyl-benzothiazol-2-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(5,6-dimethyl-benzothiazol-2-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using 5,6-dimethyl-benzothiazol-2-ylamine as the starting material to obtain the title compound (81 %).
  • Step 3 4-[2-(5,6-DimethyI-benzothiazol-2-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(5 5 6-dimethyl-benzothiazol-2-ylaminomethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (96%).
  • Example 77 4-[2-Pyrrolidine-l-ylmethyl-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 1 Methyl 4-[2-pyrrolidine-l-ylmethyl-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using 1 -pyrrolidine as the starting material to obtain the title compound (80%).
  • Step 2 4-[2-PyriOlidine-l-ylmethyl-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-pyrrolidine- 1 -ylmethyl-3-(naphthalene- 1 -yloxymethyl)- propenyl]-benzoate to obtain the title compound (54 % ).
  • Step 3 4-[2-Pyrrolidine-l-yImethy I-3-(naphthaIene-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-pyrrolidine- 1 -ylmethyl-3-(naphthalene- 1 -yloxymethyl)- ⁇ ropenyl]- benzoic acid to obtain the title compound (50%).
  • Example 78 4-[2-Cyclopentylaminomethyl-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 1 Methyl 4-[2-cyclopentyIaminomethyl-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using cyclopentylamine as the starting material to obtain the title compound (27%).
  • Step 2 4-[2-Cyclopentylaminomethyl-3-(naphthaIene-l-yloxymethyl)- propenylj-benzoic acid
  • Step 3 4- ⁇ -Cyclopentylaminomethyl-S-t ⁇ aphthalene-l -yloxymethyl)- propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using
  • Step 1 Methyl 4-[2-(l,3-dioxo-l,3-dihydro-isoindole-2-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using l 5 3-dioxo-l,3-dihydro-isoindole as me starting material to obtain the title compound (99%).
  • Step 2 4-[2-(l,3-Dioxo-l,3-dihydro-isoindoIe-2-yImethyI)-3-
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(l,3-dioxo-l,3-dihydro-isoindole-2-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate to obtain the title compound (40%).
  • Step 3 4-[2-(l,3-Dioxo-l,3-dihydro-isoindoIe-2-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(l,3-dioxo-l,3-dihydro-isoindole-2-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (31 %).
  • Step 1 Methyl 4-[2-dimethyIaminomethyl-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate
  • Step 2 4-[2-Dimethylaminomethyl-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoic acid
  • Step 6 of Example 39 was repeated except for using methyl 4-[2-dimethylaminomethyl-3-(naphthalene- 1 -yloxymethyl)- propenyl]-benzoate to obtain the title compound (99%).
  • Step 3 4-[2-Dimethylaminomethyl-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-dimethylaminomethyl-3-(naphthalene-l-yloxymethyl)-propenyl]- benzoic acid to obtain the title compound (24 % ).
  • Step 1 Methyl 4-[2-azidomethyI-3-(naphthalene-l-yIoxymethyl)- propenyl]-benzoate
  • Step 5B of Example 39 was repeated except for using azide as the starting material to obtain the title compound (97%).
  • Step 2 4-[2-Azidoni ⁇ thyl-3-(naphthalene-l-yIoxymethyl)-propenyl]- benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-azidomethyl-3-(naphthalene-l-yloxymethyl)- ⁇ ropenyl] ⁇ benzoate to obtain the title compound (47 % ).
  • Step 3 4-[2-Azidomethyl-3-(naphthalene-l-yloxymethyl)-propenyl]-N- hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using 4-[2-azidomethy 1-3 -(naphthalene- 1 -yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (69%).
  • Example 82 4-[2-(2,5-Dioxo-2,5-dihydro-pyrrole-l-ylmethyl)-3- (naphthalene-l-yloxymethy ⁇ )-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(2,5-dioxo-2,5-dihydro-pyrrole-l-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 was repeated except for using 2 5 5-dioxo-2 5 5-dihydro-pyrrole as the starting material to obtain the title compound (42%).
  • Step 2 4-[2-(2,5-Dioxo-2,5-dihydro-pyrrole-l-yImethyl)-3-(naphthalene- l-yloxymethyl)-propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(2,5-dioxo-2,5-dihydro-pyrrole-l-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate to obtain the title compound (66%).
  • Step 3 4-[2-(2,5-Dioxo-2,5-dihydro-pyrrole-l-ylmethyl)-3-(naphthalene- l-yIoxymethyl)-propenyl]-N-hydroxy-benzamide
  • Step 7 of Example 39 The procedure of Step 7 of Example 39 was repeated except for using
  • Example 83 4-[2-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindoIe-2- ylmethyl)-3-(naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy- benzamide
  • Step 1 Methyl 4-[2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-isoindole-2- ylmethyI)-3-(naphthaIene-l-yIoxymethyl)-propenyl]-benzoate
  • Step 5B of Example 39 The procedure of Step 5B of Example 39 was repeated except for using l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2-isoindole as the starting material to obtain the title compound (84%).
  • Step 2 4-[2-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindoIe-2-yImethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoic acid
  • Step 6 of Example 39 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(l ,3-dioxo-l ,3 5 3a 5 4,7,7a-hexahydro-isoindole-2-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate to obtain the title compound (83 % ).
  • Step 3 4-[2-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindoIe-2-yImethy ⁇ )-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide

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Abstract

This invention discloses a novel arylaminomethyl propenyl benzhydroxyamide derivative of formula (I) useful for preventing or treating various diseases induced by histone deacetylase, a method for preparing same and a pharmaceutical composition comprising same.

Description

ARYLAMINOMETHYL PROPENYL BENZHYDROXYAMIDE
DERIVATIVES WITH INHIBITORY ACTIVITY AGAINST
HISTONE DEACETYLASE AND METHOD FOR THE
PREPARATION THEREOF
FIELD OF THE INVENTION
The present invention relates to a novel arylaminomethyl propenyl benzhydroxyamide derivative, a method for preparing same and a pharmaceutical composition comprising same.
BACKGROUND OF THE INVENTION
Histones associate with DNAs in the nuclei of eukaryotic cells as basic proteins and are subject to reversible acetylation at the amino groups of their lysine residues. The reversible acetylation is involved in the formation of chromatin higher order structures, the cell division cycle and ultimately the gene expression, and can be regulated by the dynamic equilibrium established between the opposing activities of histone acetyl transferases (HATs) and histone deacetylases (HDACs): HATs neutralize the positive charges of the lysine residues (e.g., 4 residues in H4) to an facilitate transcriptional activity and HDACs restore the positive charges by deacetylation to inhibit gene transcription.
HDACs play an important role in cell cancerization or differentiation; 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). Specifically, the abnormal regulation of HDAC activity results in oncoprotein's transcriptional suppression and abnormal chromatin structures, which affect normal cells to induce cancer. Accordingly, HDAC has been a target for the study of anticancer drug as well as gene expression inhibitor to develope HDAC inhibitors to be used as anticancer drugs.
Recent studies of an anticancer drug through chromatin remodeling have shown that 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).
Another HDAC inhibitor reported to be useful for the treatment of large intestine cancer as well as molecular biology test is n-butyrate used at a high concentration in the order of milimolar (mM) to control the function of other enzymes in cells, cytoskeleton, cell membrane, etc. Trichostatin A (TSA) has been reported to inhibit HDAC, which enhances the differentiation and suppresses the proliferation of Friend murine erythroleukemia cells (Yoshida M. et al., Cancer research 47: 3688, 1987; Yoshida M. & Beppu T. Exp Cell Res. 177: 122, 1988; Yoshida M. et al., J of Biol Chem. 265: 17174, 1990). Although a variety of HDAC inhibitors have been disclosed, there has been a need for developing more efficient HDAC inhibitors. Accordingly, the present inventors have found that a novel arylaminomethyl propenyl benzhydroxyamide derivative is an efficient inhibitor against cell proliferation which can be advantageously used for treating cancer.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel compound which efficiently inhibits the activity of histone deacetylases, thereby suppressing the proliferation of tumor cells, and a method for preparing same.
It is another object of the present invention to provide a pharmaceutical composition comprising the inventive compound as an active ingredient for preventing or treating cancers or various diseases caused by excessive histone deacetylase activity.
In accordance with one aspect of the present invention, there is provided an arylaminomethyl propenyl benzhydroxyamide derivative of formula (I) or a pharmaceutically acceptable salt thereof and a method for preparing same:
Figure imgf000004_0001
wherein,
Ri is hydrogen, aryloxy, arylthio, arylimido, C 1.5 alkylimido, arylamido, Ci_5 alkylamido or arylsulfonamido, in which the aryl is phenyl, naphthyl or carbazole, each being optionally substituted with one or more substituents selected from the group consisting of hydroxy, C1.5 alkyloxy, C1.5 alkyl, aryl, C1.5 alkylainino, cyano, cyanophenyl, Cμ5 alkylthio and nitro;
R2 is phenyl which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C 1.5 alkyloxy, Cμ5 alkyl, Ci_5 alkylamino, cyano, cyanophenyl and mercaptoalkyl; or heteroaryl selected from the group consisting of piperazine, triazole, thiazole, benzothiazole, dibenzofurane, pyridine, quinoline and isoquinoline, the heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1.5 alkyloxy, amino C1.5 alkyloxy, C1.5 alkyl, amino Cμ5 alkyl, Cμ5 alkylamino, aryl C 1.5 alkylamino and aryloxy Cj-5 alkylamino; and
R3 is hydroxy amino.
In accordance with another aspect of the present invention, there is provided an anti-cancer composition comprising the compound of formula (I) as an active ingredient and a pharmaceutically acceptable carrier.
In accordance with still another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating a disease caused by excessive histone deacetylase activity, comprising the compound of formula (I) as an active ingredient and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION OF THE INVENTION
The inventive compound of formula (I) may be used in the form of a pharmaceutically acceptable addition salt formed with an acid or base.
Examples of the acid include an inorganic acid such as hydrochloric, hydrobromic, phosphoric and sulfuric acids; and an organic acid such as acetic, trifluoroacetic, citric, formic, maleic, oxalic, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic, malic acid, methanesulfonic and p- toluenesulfonic acids. Examples of the base include an inorganic base such as an alkali metal hydroxide (e.g., sodium hydroxide and potassium hydroxide), an alkali metal bicarbonate (e.g., sodium bicarbonate and potassium bicarbonate), an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate and calcium carbonate) and an organic base such as amines.
The inventive compound of formula (I) may be prepared by any one of the synthetic routs shown in Reaction Schemes 1 to 3.
Reaction Scheme 1
Figure imgf000005_0001
FOBT.
Figure imgf000005_0002
Figure imgf000005_0003
Reaction Scheme 1 shows the synthetic procedure for preparing the compound of formula (I) wherein Ri=H, which comprises the steps of:
1) reacting 4-(methoxycarbonyl) benzaldehyde of formula (II) with tert- buthyl acrylate in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO) (i.e., Baylis-Hillman reaction) to obtain methyl 4-(2-terf-butoxycarbonyl-l- hydroxyallyl)-benzoate of formula (III);
2) reacting the compound of formula (III) with acetylchloride (AcCl) in the presence of pyridine to obtain the acetoxy compound of formula (IV); 3) treating the compound of formula (IV) with sodium borohydride
(NaBELj) in ter/-butanol to convert the compound of formula (IV) into methyl 4-(2-te7-/-butoxycarbonyl propenyl)-benzoate of formula (V);
4) hydrolyzing the compound of formula (V) in triflϋoroacetic acid (TFA) to form methyl carboxypropenylbenzoate, which is then treated with ethyl chloroformate (ECC) and reduced with sodium borohydride (NaBH-O to obtain methyl hydroxymethylpropenyl benzoate of formula (VI);
5) reacting the compound of formula (VI) with tetrabromomethane (CBr4) in the presence of triphenylphosphine (PPh3) to form methyl bromomethylpropenyl benzoate, which is refluxed together with an arylamine (ArNH^) to obtain methyl arylaminomethylpropenyl benzoate of formula (VII);
6) hydrolyzing the compound of formula (VII) with an inorganic base to obtain the compound of formula (VIII); and
7) acylating the compound of formula (VIII) with tert- butyldimethylsilyloxyamine (NH2OTBS) in an organic solvent in the presence of N-hydroxy-6-trifluoro benzotriazole (FOBT) and l-(3- diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl), and removing the tert-butyldimethylsilyl group from the resulting product with a water-soluble inorganic acid to obtain a compound of formula (I). In step 1) of Reaction Scheme 1, an alkoxycarbonyl hydroxyl allyl compound is obtained by the Baylis-Hillman reaction carried out between an aldehyde and an alkylacrylate in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO).
The ECC treatment in step 4) is carried out using tetrahydrofuran as a solvent over an ice bath.
The amine reaction in step 5) is carried out using acetone or acetonitrile as a solvent in the presence of potassium carbonate.
The reaction of step 6) is preferably carried out using an aqueous solution of an alcohol, preferably methanol, ethanol or isopropanol, or an aqueous tetrahydrofuran as a solvent, and lithium hydroxide (LiOH-H2O) or sodium hydroxide as an inorganic base.
Also, it is preferred that the reaction step 7) is carried out using N5N- dimethylformamide as the solvent together with hydrochloric acid or sulfuric acid as the water-soluble inorganic acid.
Reaction Scheme 2
Figure imgf000007_0001
Reaction Scheme 2 shows the synthetic procedure for preparing the compound of formula (I) wherein R]=ArO or ArS, which comprises the steps of: 5 1) reacting methyl 4-(2-tert-butoxycarbonyl-l -hydroxy ally l)-benzoate of formula (III) with tribromophosphine (PBr3) in ethyl ether to obtain methyl 4-(3-bromo-2-ter/-butoxycarbonyl-proρenyl)-benzoate of formula (IX);
2) reacting the compound of formula (IX) with a nucleophilic agent (RiH) to obtain a methyl 4-(3-substitated-2-fer?-butoxycarbonyl-propenyl)- O benzoate of formula (X); 3) hydrolyzing the compound of formula (X) in trifluoroacetic acid (TFA) to form a methyl carboxypropenylbenzoate, which is then treated with ethyl chloroforrnate (ECC) and reduced with sodium borohydride (NaBH4) to obtain a methyl hydroxymethylpropenyl benzoate of formula (XI); 4) refluxing the compound of formula (XI) with manganese dioxide
(MnO2) in dichloromethane to form an aldehyde, which is then reacted with arylamine (ArNH2) or arylalkylamine in the presence of dibutyldichlorotin (Bu2SnCl2) and diphenylsilane (Ph2SiH2) to obtain a methyl arylaminomethylpropenyl benzoate of formula (XII); 5) treating the compound of formula (XII) with an inorganic base to obtain a compound of formula (XIII); and
6) acylating the compound of formula (XIII) with tert- butyldimethylsilyloxy amine (NH2OTBS) and removing the tert- butyldimethylsilyl group from the resulting product with a water-soluble , . inorganic acid to obtain a compound of formula (I).
In Reaction Scheme 2, step 2) is carried out using an arylalcohol or arylthiol as a nucleophilic agent in an organic solvent such as acetone or acetonitrile in the presence of an organic or inorganic base such as triethylamine and potassium carbonate. The ECC treatment in step 3) is carried out using tetrahydrofuran as a solvent over an ice bath.
Step 5) of Reaction Scheme 2 is preferably carried out using an aqueous solution of an alcohol, preferably methanol, ethanol or isopropanol, or an aqueous tetrahydrofuran as the solvent, and lithium hydroxide (LiOH-H2O) or sodium hydroxide as the inorganic base.
Also, it is preferred that step 6) is carried out using N,N- dimethylformamide as the solvent in the presence of N-methansulfonyloxy-6- trifluoro benzotriazole, and hydrochloric acid or sulfuric acid as the water- soluble inorganic acid. In the present invention, a methyl arylaminomethylpropenyl benzoate of formula (XII) may also be obtained by an alternative method, for example, reacting the compound of formula (XI) with tetrabromomethane (CBr4) in the presence of triphenylphosphine (PPh3) to form a methyl bromomethylpropenyl benzoate and refluxing the resulting product together with an arylamine or arylalkylamine using acetone or acetonitrile as a solvent in the presence of potassium carbonate.
Reaction Scheme 3
t-
Figure imgf000009_0001
R1 C alkylamido, arylamido, alkyl imido, arylimido or arylsulfoneamido
Figure imgf000009_0002
Reaction Scheme 3 shows the synthetic procedure for preparing the compound of formula (I) wherein R]= alkylamido, arylamido, alkylimido, arylimido or arylsulfonamido, which comprises the steps of:
1) reacting methyl 4-(l-acetoxy-2-ter?-butoxycarbonyl-allyl)-benzoate of formula (IV) with a micleophilic agent (RiH) to obtain a methyl 4-(3- substituted-2-ter^-butoxycarbonyl-propenyl)-benzoate of formula (X); 2) hydrolyzing the compound of formula (X) in trifluoroacetic acid
(TFA) to form a methyl carboxypropenylbenzoate, which is then treated with ethyl chloroformate (ECC) and reduced with sodium borohydride (NaBH4) to obtain a methyl hydroxymethylpropenyl benzoate of formula (XI);
3) reacting the compound of formula (XI) with tetrabromomethane (CBr4) in the presence of triphenylphosphine (PPh3) to form a methyl bromomethylpropenyl benzoate, which is refluxed together with an arylamine or arylalkylamine to obtain a methyl arylaminomethylpropenyl benzoate of formula (XII);
4) treating the compound of formula (XII) with an inorganic base to obtain a compound of formula (XIII); and
5) acylating the compound of formula (XIII) with tert- butyldimethylsilyloxyamine (NH2OTBS) and removing the tert- butyldimethylsilyl group from the resulting product with a water-soluble inorganic acid, to obtain a compound of formula (I).
In Reaction Scheme 3, step 1) is carried out using alkylamide, arylamide, alkylimide, arylimide or arylsulfonamide as the nucleophilic agent in the presence of triethylamine or potassium carbonate as an organic or inorganic base.
The ECC treatment in step 2) is carried out using tetrahydrofuran as the solvent over an ice bath, and the amine reaction in step 3) is carried out using acetone or acetonitrile as the solvent in the presence of potassium carbonate.
Step 4) of Reaction Scheme 3 is carried out using an aqueous solution of an alcohol, preferably methanol, ethanol or isopropanol, or an aqueous tetrahydrofuran as the solvent, and lithium hydroxide or sodium hydroxide as the inorganic base. , ,
Step 5) is carried out using N,N-dimethylformamide as a solvent, and hydrochloric acid or sulfuric acid as the water-soluble inorganic acid, in the presence of N-methansulfonyloxy-6-trifluoro benzotriazole.
The inventive arylaminomethyl propenyl benzhydroxyamide derivative of formula (I) efficiently inhibits the activity of histone deacetylase to suppress the differentiation of tumor cells, thereby preventing the cancer-cell proliferation.
Accordingly, the present invention also provides an anti-cancer composition comprising the compound of formula (I) as an active ingredient and a pharmaceutically acceptable carrier.
Further, the present invention provides a pharmaceutical composition for preventing or treating a disease caused by excessive histone deacetylase activity such as osteoporosis and central nervous system disorders (e.g.,
Alzheimer's disease), comprising the compound of formula (I) as an active ingredient and a pharmaceutically acceptable carrier.
The inventive pharmaceutical composition comprises the compound of formula (I) 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 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. For parenteral administration, sterile injectable formulations such as istonic solution and suspension may be preferred. The 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 (I) ranges from about 2.5 to 100 mg/kg, preferably 5 to 60 mg/kg for mammals including a human subject, and can be orally or parenterally administered in a single dose or in divided doses.
The present invention is further described and illustrated in Examples provided below, which are, however, not intended to limit the scope of the present invention.
EXAMPLE
Preparation Example 1: tert-Buty\ 3~hydroxy-2-methylene-3-[4- (methoxycarbonyl) phenyl] propanate (III)
4-(Methoxycarbonyl) benzaldehyde (II) (3.3 g, 20 mM), fert-butyl acrylate (3.5 mi, 24 mM) and l,4-diazabicyclo[2,2,2]octane (449 mg, 4 mM) were placed in a sealed vessel and stirred at room temperature for 5 days. The reaction mixture was extracted with diethyl ether, the extract was successively washed with 2 N hydrochloric acid, water and sodium bicarbonate, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound as a white solid (4.2 g, 73 %).
1H NMR (300 MHz, CDCl3) δ 1.40 (s, 9H), 3.28 (m, IH), 3.91 (s, 3H), 5.53 (d, IH, J=5.2 Hz), 5.71 (s, IH), 6.27 (s, IH), 7.45 (d, 2H5 J=8.0 Hz), 7.81 (d, 2H, J=8.0 Hz)
MS (EI, 70 eV) m/z 292(M+), 283, 255, 241, 227, 201, 189, 179, 150, 135; Melting Point: 70 °C
Preparation Example 2: Methyl 4-(l-acetoxy-2--'m'-butoxycarbonylaIIyl) benzoate (IV) ferf-Butyl 3-hydroxy-2-methylene-3-[4-(methoxycarbonyl) phenyl] propanate (III) (305 mg, 1.04 mM) and pyridine (0.20 ml, 2.50 mM) were dissolved in anhydrous methylene chloride (3 m-C), to which acetylchloride (0.149 m-β, 2.08 mM) was slowly added at 0°C, followed by stirring the mixture at room temperature for 10 minutes. After completing the reaction, the resulting mixture was extracted with diethyl ether, the extract was successively washed with 2 N hydrochloric acid, water and sodium bicarbonate, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under a reduced pressure and purified by silica gel column chromatography, to obtain the title compound as a white solid (337 mg, 97%).
1HNMR (300 MHz, CDCl3) δ 1.37 (s, 9H), 2.11 (s, 3H), 3.91 (s, 3H), 5.76 (s,
IH), 6.34 (s, IH), 6.68 (s, IH), 7.44 (d, 2H, J=8.4 Hz), 8.01 (d, 2H, J=8.0 Hz) MS (EI, 70 eV) m/z 334(M+), 325, 297, 283, 255, 241, 202, 179, 162, 135, i n;
Melting Point: 590C Preparation Example 3: Methyl 4-(2-feff-butoxycarbonyIpropenyl) benzoate (V)
Methyl 4-(l-acetoxy-2-t-butoxycarbonylallyl) benzoate (IV) (350 mg, 1.04 mM) was dissolved in anhydrous tert-butanol (10 ml), to which sodium borohydride (78 nig, 2.08 mM) was slowly added, followed by stirring the mixture at room temperature for 3 hours. After completing the reaction, tert-butanol was distilled under a reduced pressure and ice water was poured thereinto. The resulting mixture was extracted with diethyl ether and the organic layer was washed with brine. The resulting residue was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under a reduced pressure, concentrated and purified by silica gel column chromatography to obtain the title compound as a white solid (230 mg, 73%).
1HNMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 2.12 (s, 3H), 3.82 (s, 3H), 7.68 (s, IH), 7.83 (d, 2H, J=8.0 Hz), 7.90 (d, 2H, J=8.0 Hz) MS (EI, 70 eV) m/z 276(M4), 269, 255, 241, 233, 219, 202, 179, 166, 135
Preparation Example 4: Methyl 4-(2-carboxypropenyl) benzoate Methyl 4-(2-ter*-butoxycarbonyl-propeήyl) benzoate (V) (670 mg,
2.43 mM) was dissolved in methylene chloride (30 ml), to which trifluoroacetic acid(3.0 ml) was added dropwise, followed by stirring the mixture at room temperature for 5 hours. After completing the hydrolysis, the solvent was removed under a reduced pressure to obtain the title compound as a light yellow solid for using quantitatively in the next reaction.
Preparation Example 5: Methyl 4-(3-hydroxy-2-methyIpropenyl) benzoate (VI)
Methyl 4-(2-carboxy-propenyl) benzoate (220 ing, 1.00 mM) was dissolved in tetrahydrofuran (10 ml), to which triethylamine (209 ≠, 1.05 mM) and ethyl chloroformate (0.124 m£, 1.3 mM) were added at 0°C, followed by stirring for 1 hour. Sodium borohydride (192 ing, 5.00 mM) was added to the reacting solution and distilled water (2 ml) was slowly added dropwise thereto, followed by stirring the mixture at room temperature for 2.5 hours. The reaction solution was treated with 1 N hydrochloric acid to adjust pH thereof to 2, extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate. The resulting residue was dried over anhydrous sodium sulfate, filtered and purified by silica gel column chromatography to obtain the title compound as a white solid (89%).
1H NMR (200 MHz, CDCl3) δ 1.91 (S, 3H, CH3), 3.91 (S, 3H9 OCH3), 4.21 (m, 2H, CH2), 6.51 (m, IH, CH), 7.33 (d, 2H, J=8.14 Hz5 ArH)5 7.99 (d, 2H5 J=8.45 Hz, ArH)
MS (EI, 7OeV) m/z 206(M+), 191, 189
Preparation Example 6: Methyl 4-(3-bromo-2-methylpropenyI) benzoate
Methyl 4-(3-hydroxy-2~methylproρenyl) benzoate (VI) (734 nig, 3.56 mM) was dissolved in dichloromethane (25 m£), to which triphenylphosphine
(1.4 g, 5.338 mM) was added and the mixture was cooled to 0°C . Then, tetrabromomethane (1.77 mg, 5.338 mM) was added thereto and stirred for 6 hours. The solvent was removed under a reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound as a white solid (99 % ) .
1H NMR (200 MHz, CDCl3) δ 2.03 (S, 3H, CH3), 3.91 (S, 3H, OCH3), 4.13 (S, 3H, CH3), 6.63 (d, IH, J=9.4 Hz, CH), 7.33 (d, 2H, J=8.1 Hz, ArH), 8.00 (d, 2H; J=8.5 Hz, ArH) MS (EI 7OeV) 269(M+), 277, 225, 189, 139
Preparation Example 7: Methyl 4-(3-bromo-2-ter/'- butoxycarbonylpropenyl)- benzoate (IX) ter/-Butyl-3 -hydroxy-2-methylene-3 -(4-methoxycarbony lpheny I)- propanate (III) (994 nig 3.4 mM) was dissolved in ethyl ether (10 ml) and cooled to O0C, to which tribromophosphine (0.35 mi 3.74 mM) was added dropwise, followed by stirring the mixture at room temperature for 1 hour.
After completing the reaction, ice water was poured into the reaction mixture and the mixture was extracted with ethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under a reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound as a yellow green solid (71 %).
1H NMR (300 MHz5 CDCl3) δ 1.40 (S, 9H5 OCH3), 3.88 (S, 3H, OCH3), 3.97 (S, 2H, CH2), 7.41 (d, 2H J=8.4 Hz5 ArH), 7.50 (s, IH), 7.91 (d, 2H, J=8.4 Hz, ArH) MS (EI, 7OeV) 1^ 355 (M+), 338, 296, 278, 259, 219, 187, 143, 115 Melting Point: 78 °C
Example 1 : 4-[3-(Quinoline-3-ylamino)-2-methyIpropehyl]-N-hydroxy benzamide Step 1: Methyl 4-[3-(quinoline-3~ylamino)-2-methyIpropenyl] benzoate
Methyl 4-(3-bromo-2-fer^butoxycarbonylproρenyl)-benzoate (IX) (269 mg, 1 mM) and 3-aminoquinoline (173 mg, 1.2 mM) were dissolved in acetone (8 mi), to which potassium carbonate (207 nig, 1.5 mM) was added, followed by refluxing for 5 hours. After completing the reaction, the resulting mixture was cooled to room temperature, filtered and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (36%).
1H NMR (300 MHz, CDCl3), δ 1.99 (s, 3H), 3.91 (s, 3H), 4.05 (d, 2H, J=5.7 Hz), 4.36 (t, IH, J=5.5 Hz)3 6.61 (s, IH), 7.06 (d, IH, J=2.8 Hz)5 7.31 (d, 2H, J=8.3 Hz), 7.42 (m, 2H), 7.61 (m, IH), 7.93 (m, IH), 7.96(d, 2H, J=9.8 Hz), 8.51(d, lH, J=2.8 Hz) MS (EI5 70eV, m/z) 333(M+1)5 189, 157, 145, 130, 115, 105, 91
Step 2: 4-[3-(Quinoline-3-ylamino)-2-methylpropenyl] benzoic acid
Methyl 4-[3-(quinoline-3-ylamino)-2-methylpropenyl] benzoate (110 mg, 0.331 mM) was dissolved in 30% aqueous ethanol solution (3 mi), to which lithium hydroxide (139 mg, 3.31 mM) was added, followed by stirring at 50 °C for 3 hours. After completing the reaction, the resulting mixture was cooled and ethanol was removed under a reduced pressure. The resulting residue was diluted with water, acidified (pH=3.5) with 2 N hydrochloric acid and the resulting solid was filtered and dried to obtain the title compound as a white solid (86 % ).
1H NMR (300 MHz5 DMSOd6), δ 1.94 (s, 3H), 3.93 (s, 2H), 6.65 (d, IH, J=2.1 Hz), 6.79 (t, IH), 7.08 (s, IH), 7.39 (m, 4H), 7.66 (d, IH, J=7.8 Hz), 7.79 (d, IH, J=8.1 Hz), 7.91 (d, 2H, J=8.1 Hz), 8.57 (d, IH5 J=2.7 Hz), 12.86 (bs, IH)
MS (EI, 7OeV, m/z) 318, 277, 183, 157, 144, 131, 116, 101, 91, 77
Step 3: 4-[3-(Quinoline-3-ylamino)-2-methylpropenyl]-N-hydroxy benzamide 4-[3-(Quinoline-3-ylamino)-2-methylpropenyl] benzoic acid (73 mg,
0.230 mM) was dissolved in dimethylformamide (2 mi) and triethylamine (96 μi, 0.690 mM) was added thereto. The mixture was cooled to 0 °C and N-hydroxy-6-trifluoro benzotriazole (47 mg, 0.230 mM), l-(3- diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (67 mg, 0.345 mM) and te/^butyldimethylsilyloxyamine (51 mg, 0.345 mM) were added thereto, followed by stirring the mixture at room temperature for 4 hours. After completing the reaction, ice water was added to the resulting mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (42%).
1H NMR (300 MHz, DMSO-d6), δ 1.93 (s, 3H), 3.91 (s, 2H), 6.57 (s, IH), 6.74 (t, IH, J=5.7 Hz), 7.06 (d, IH, J=2.4 Hz), 7.35 (m, 4H)5 7.70 (m, 4H), 8.55 (d, IH, J=2.7 Hz)5 8.98 (s, IH), 11.16 (s, IH) MS (EI, 7OeV)5 m/z 333, 318, 289, 172, 144, 131, 116, 91, 77 Example 2: 4-[3-(3-Benzyloxy-phenyIamino)-2-methylpropenyl]-N- hydroxy benzamide
Step 1: Methyl 4-[3-(3-benzyloxyphenylamiπo)-2-methylpropenyl] benzoate The procedure of Step 1 of Example 1 was repeated except for using 3- benzyloxyphenylaminel as the starting material to obtain the title compound (60%).
1H NMR (300 MHz, CDCl3), δ 1.89 (s, 3H)5 3.83 (s, 2H)5 3.91 (s, 3H), 5.03 (S5 2H)5 6.28 (m, 2H)5 6.37 (m, IH), 6.55 (s, IH)5 7.08 (m, IH)5 7.39 (m, 7H)5 7.98 (d, 2H5 J=8.4 Hz) MS (EI, 7OeV)5 m/z 388(M+1), 372, 2965 189, 157, 130, 115, 91
Step 2 : 4-[3-(3-Benzyloxy-phenylammo)-2-methylpropenyl] benzoic acid The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(3-benzyloxyphenylamino)-2-methylproρenyl] benzoate to obtain the title compound (92%).
1H NMR (300 MHz, DMSO-d6), δ 1.88 (s, 3H)5 3.82 (d, 2H5 J=5.3 Hz), 5.08 (s5 2H)5 6.16 (t, IH, J=5.2 Hz), 6.30 (m, 3H)5 6.55 (s, IH)5 7.04 (t, IH5 J=8.1 Hz), 7.29 (d, 2H5 J=8.1 Hz)5 7.43 (m, 5H), 7.94 (d, 2H, J=8.1 Hz) MS (EI, 7OeV)5 m/z 374(M+1), 282, 212, 13I5 91, 77, 65
Step 3: 4-[3-(3-Benzyloxy-phenylamino)-2-methylpropenyl]-N-hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(3-benzyloxy-phenylamino)-2-methylρropenyl] benzoic acid to obtain the title compound (12%).
1H NMR (300 MHz, DMSOd6), δ 1.89 (s, 3H)5 3.77 (d, 2H, J=5.1 Hz)5 5.03 (s, 2H)5 6.09 (m, IH)5 6.24 (m, 3H), 6.49 (s, IH), 6.98 (t, IH, J=7.6 Hz)5 7.35 (m, 9H), 7.75 (d, 2H5 J=8.2 Hz) MS (EI5 7OeV)5 m/z 388, 344, 146, 131, 106, 9I5 77 Example 3: 4-[3-(3,4-Dihydro-llH-isoquinoline-2-yI)-2-methylpropenyl]- N-hydroxy benzamide
Step 1: Methyl 4-[3-(3,4-dihydro-llH-isoquinoIine-2-yl)-2- methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 1.2,3.4-tetrahydroisoquinoline as the starting material to obtain the title compound (73%).
1H NMR (300 MHz5 CDCl3), δ 1.98 (s, 3H)5 2.75 (t, 2H5 J=5.7 Hz)5 2.92 (t, 2H, J=5.7 Hz), 3.21 '(ss 2H), 3.64 (s, 2H)5 3.92 (s, 3H)5 6.54 (s, IH), 7.03 (m, IH), 7.12 (m, 3H), 7.37 (d, 2H5 J=8.4 Hz)5 8.01 (d, 2H, J=8.4 Hz) MS (EI5 7OeV, m/z) 321, 216, 172, 146, 132, 115, 104, 91, 77
Step 2: 4-[3-(3,4-Dihydro-ll H-isoquinoline-2-yl)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(3,4-dihydro-l lH-isoquinoline-2-yl)-2-methylpropenyl] benzoate to obtain the title compound (49 % ).
1H NMR (300 MHz5 DMSOd6), δ 2.08 (s, 3H)5 3.17 (s, 2H)5 3.98 (s, 4H)5 4.35 (s, 2H)5 6.84 (s, IH)5 7.26 (m, 4H), 7.53 (d, 2H, J=8.4 Hz), 7.98 (d, 2H5 J=8.1 Hz)5 10.60 (bs, IH) MS (EI5 7OeV, m/z) 308(M+1), 202, 172, 146, 132, 115, 104, 91, 77
Step 3: 4-[3-(3,4-Dihydro-l lH-isoquinoline-2-yl)-2-methylpropenyl]-N- hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4- [3-(354-dihydro-llH-isoquinoline-2-yl)-2-methylpropenyl] benzoic acid to obtain the title compound (74%).
1H NMR (300 MHz5 MeOH-d4) δ 1.9 (s, 3H)5 2.7-2.8 (q, 2H5 J=12.8, 5.6 Hz), 2.9-3.0 (t, 2H, J=12.4, 6.0 Hz), 3.2 (s, 2H), 3.65-3.68 (d, IH, J=8.2 Hz), 6.5 (s, IH)3 7.1-7.2 (m, 4H), 7.28-7.32 (d, 2H, J=8.2 Hz), 8.0-8.1 (dd, 2H, J=6.4, 2.7 Hz)
MS (LC, 70 eV) m/z 324 (M+1)
Example 4: 4-[3-(QuinoIine-8-yIamino)-2-methyIpropenyI]-N-hydroxy benzamide
Step 1: Methyl 4-[3-(quinoliπe-8-yIamino)-2-niethyIpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 8- aminoquinoline as the starting material to obtain the title compound (62 %).
1H NMR (300 MHz, CDCl3), δ 1.99 (s, 3H), 3.90 (s, 3H)5 4.14 (s, 2H), 6.45 (bs, IH), 6.71 (d, IH, J=7.8 Hz)5 7.08 (d, IH, J=8.1 Hz), 7.39 (m, 5H), 7.98 (d, 2H, J=8.1 Hz), 8.07 (d, IH, J=8.1 Hz)5 8.74 (m, IH) MS (EI, 7OeV), m/z 332, 302, 183, 156, 144, 129, 115, 91,.77
Step 2: 4-[3-(Quinoline-8-yIammo)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(quinoline-8-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (84 % ).
1H NMR (300 MHz, DMSO-d6), δ 1.93 (s, 3H), 4.08 (d, 2H, J=5.7 Hz), 6.55 (s, IH), 6.68 (d, IH5 J=7.8 Hz), 7.00 (t, IH, J=7.8 Hz)5 7.08 (d, IH5 J=8.4 Hz), 7.35 (m5 3H)5 7.50 (m, IH)5 7.89 (d5 2H5 J=8. IHz)5 8.23 (dd5 IH, J=I.2 Hz, 8.1 Hz), 8.77 (dd, IH, J=I .5 Hz, 4.2 Hz), 12.85 (bs, IH) MS (EI, 7OeV, m/z) 318, 288, 183, 156, 144, 129, 115, 91, 77
Step 3: 4-[3-(QuinoIme-8-yIamino)-2-methylpropenyl]-N-hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using 4-
[3-(quinoline-8-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (36%). MS (EI, 7OeV3 m/z) 333, 318, 289, 183, 156, 144, 129, 115, 91, 77
Example 5: 4-[3-(4-Phenyloxy-phenylamino)-2-methylpropenyI]-N- hydroxy benzamide
Step 1 : Methyl 4-[3-(4-phenyloxy-phenylamino)-2-methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 4- phenyloxyphenylamine as the starting material to obtain the title compound (54%).
1H NMR (300 MHz, CDCl3), δ 1.94 (s, 3H), 3.83 (s, 2H), 3.88 (bs, IH), 3.91 (s, 3H), 6.57 (s, IH), 6.64 (d, 2H, J=8.7 Hz), 6.92 (m, 5H)5 7.26 (d, 2H, J=7.2 Hz)5 7.32 (d, 2H, J=8.7 Hz), 7.99 (d, 2H, J=8.1 Hz) MS (EI, 7OeV, m/z) 373, 358, 305, 198, 184, 157, 129, 115, 105, 77
Step 2: 4-[3-(4-Phenyloxy-phenylamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(4-phenyloxy-phenylamino)-2-methylρropenyl] benzoate to obtain the title compound (43 % ).
1H NMR (300 MHz5 DMSO-d6, δ) 1.90 (s, 3H), 3.77 (s, 2H), 4.11 (s, IH)5 6.36 (s, IH), 6.65 (d, IH, J=8.8 Hz)5 6.76 (m, IH), 6.84 (d, 2H5 J=8.5 Hz), 6.91 (d, 2H, J=9.0 Hz)5 7.01 (m, IH), 7.29 (t, 2H, J=7.8 Hz)5 7.38 (d, 2H, J=8.1 Hz), 7.91 (d, 2H, J=8.0 Hz), 8.05 (d, IH5 J=8.3 Hz)
MS (EI, 7OeV, m/z) 360(M+1), 318, 198, 184, 131, 115, 91, 77
Step 3: 4-[3-(4-Phenyloxy-phenylamino)-2-methylpropenyI]-N-hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using 4-
[3-(4-phenyloxy-phenylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (7%). 1H NMR (300 MHz5 DMSO-d6, δ) 1.90 (s, 3H), 3.77 (s, 2H)3 4.11 (s, IH)5 6.36 (s, IH)5 6.65 (d, IH5 J=8.8 Hz)5 6.76 (m, IH)5 6.84 (d, 2H5 J=8.5 Hz)5 6.91 (d5 2H5 J=9.0 Hz)5 7.01 (m, IH)5 7.29 (t, 2H5 J=7.8 Hz)5 7.38 (d, 2H5 J=8.1 Hz)5 7.91 (d5 2H3 J=8.0 Hz)5 8.05 (d, IH5 J=8.3 Hz)
Example 6: 4-[3-(4-Dimethylamino-phenylamino)-2-methylpropenyl]-N- hydroxy benzamide
Step 1: Methyl 4-[3-(4-dimethylamino-phenylamino)-2-methylpropenyI] benzoate The procedure of Step 1 of Example 1 was repeated except for using 4- dimethylamino-phenylamine as the starting material to obtain the title compound (30%).
1H NMR (300 MHz5 CDCl3) δ 1.9 (s, 6H)5 2.8 (s, 3H)5 3.7 (s, 3H)5 3.9 (s, 2H)5 6.4 (s5 IH)5 6.5-6.7 (m, 4H)5 7.2-7.3 (d, 2H, J=8.3 Hz)5 7.96-7.99 (d* 2H5. J=8.3 Hz) MS (LC5 70 eV) m/z 326 (M+1), 325, 324, 323
Step 2: 4-[3-(4-Dimethylamino-phenylamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(4-Dimethylamino-phenylamino)-2-methylpropenyl] benzoate to obtain the title compound {66%).
MS (LC5 70 eV) m/z 312 (M+1), 31 I5 310, 309
Step 3: 4-[3-(4-Dimethylamino-phenylamino)-2-methylpropenyl]-N- hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4- [3-(4-dimethylamino-phenylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (82%).
1H NMR (300 MHz5 MeOH-d4) δ 1.9 (s, 6H), 4.1-4.2 (d, 2H5 J=5.2 Hz)5 6.3- 6.4 (d, IH5 J=5.4 Hz)5 6.5-6.6 (d, IH5 J=8.4 Hz)5 6.8-6.9 (m, 4H)5 7.3-7.4 (d, 2H5 J=8.4 Hz)5 7.9-8.0 (dd, 2H, J=I 0.8, 5.4 Hz) MS (LC5 70 eV) m/z 327 (M+1)
Example 7: 4-[3-(QuinoIine-5-ylamino)-2-methylpropenyl]-N-hydroxy benzamide Step 1: Methyl 4~[3-(quinoline-5-yIamino)-2-methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 5- aminoquinoline as the starting material to obtain the title compound (60%).
1H NMR (300 MHz, CDCl3) δ 1.9 (s, 3H)5 3.9 (s, 3H)5 4.0-4.1 (d, 2H5 J=8.2
Hz), 6.4 (s5 IH)5 7.2-7.3 (m, 4H)5 7.4-7.5 (m, 2H), 7.97-7.99 (d, 2H, J=8.2
Hz), 8.25-8.28 (d, IH5 J=8.4 Hz)5 8.85-8.87 (m, IH)
MS (LC, 70 eV) m/z 334 (M+1)
Step 2: 4-[3-(Quinoline-5-ylamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(quinoline-5-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (88%).
MS (LC, 70 eV) m/z 320 (M+1)
Step 3: 4-[3-(Quinoline-5-ylamino)-2-methyIpropenyl]-N-hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using 4-
[3-(quinoline-5-ylamino)-2-methylpiOpenyl] benzoic acid to obtain the title compound (81 %).
1H NMR (300 MHz, MeOH-d4) δ 1.9 (s, 3H), 4.02-4.12 (d, 2H, J=8.4 Hz)5 6.4 (s, IH), 7.25-7.29 (m, 4H)5 7.4-7.5 (m, 2H)5 7.97-7.99 (d, 2H, J=8.4 Hz)5 8.21-8.25 (d, IH, J=8.4 Hz), 8.84-8.89 (m, IH) MS (LC, 70 eV) m/z 335 (M1"1) Example 8: 4-[3-(Quinoline-3-ylaniino)-2-methyIpropenyl]-N-hydroxy benzamide
Step 1: Methyl 4-[3-(quinolme-3-ylamino)-2-methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 3-aminoquinoline as the starting material to obtain the title compound (43 % ).
1H NMR (300 MHz, CDCl3), δ 1.99 (s, 3H), 3.91 (s, 3H), 4.05 (d, 2H, J=5.7 Hz)5 4.36 (t, IH, J=5.5 Hz), 6.61 (s, IH), 7.06 (d, IH, J=2.8 Hz), 7.31 (d, 2H, J=8.3 Hz)5 7.42 (m, 2H), 7.61 (m, IH), 7.93 (m, IH), 7.96(d5 2H5 J=9.8 Hz), 8.51 (d, IH, J=2.8 Hz)
MS (EI, 7OeV, m/z) 333(M1"1), 189, 157, 145, 130, 115, 105, 91
Step 2: 4-[3-(Quinoline-3-ylamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(qumoline-3-;ylamino)-2-methylpropenyl] benzoate to obtain the title compound (86%).
1H NMR (300 MHz, DMSO-d6), δ 1.94 (s, 3H)5 3.93 (s, 2H), 6.65 (d, IH, J=2.1 Hz)5 6.79 (t, IH), 7.08 (s, IH)5 7.39 (m, 4H), 7.66 (d, IH, J=7.8 Hz)5 7.79 (d, IH5 J=8.1 Hz)5 7.91 (d, 2H, J=8.1 Hz), 8.57 (d, IH5 J=2.7 Hz), 12.86 (bs, IH) MS (EI5 7OeV5 m/z) 318, 277, 183, 157, 144, 131, 116, 101, 91, 77
Step 3: 4-[3-(QuinoIine-3-ylamino)-2-methylpropenyl]-N-hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4- [3-(quinoline-3-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (83%).
1H NMR (300. MHz, DMSO-d6), δ 1.93 (s, 3H), 3.91 (s, 2H), 6.57 (s5 IH)5 6.74 (t, IH5 J=5.7 Hz)5 7.06 (d, IH, J=2.4 Hz), 7.35 (m, 4H), 7.70 (m, 4H)5 8.55 (d5 IH5 J=2.7 Hz), 8.98 (s5 IH), 11.16 (s, IH) MS (EI, 7OeV)5 m/z 333, 318, 289, 172, 144, 131, 116, 91, 77 Example 9: 4-[3-(5~Hydroxy-naphthalene-l-ylamino)-2-methylpropenyl]- N-hydroxy benzamide
Step 1: Methyl 4-[3-(5-hydroxy-naphthalene-l-ylamino)-2- methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 5 -hydroxy- 1-naphthaleneamine as the starting material to obtain the title compound (68%).
1H NMR (300 MHz5 CDCl3) δ 2.0 (s, 3H), 3.9 (s, 3H)5 4.02-4.06 (d, 2H5 J=I 0.6 Hz)5 6.6 (s5 IH)5 6.8-6.9 (m, 2H)5 7.2-7.4 (m, 5H)5 7.86-7.89 (d, 2H5 J=8.4 Hz)5 8.01-8.08 (m, 2H) MS (LC5 70 eV) m/z 349 (M+1)
Step 2: 4-[3-(5-Hydroxy-naphthalene-l-ylamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(5-hydroxy-naphthalene-l -ylamino)-2-methylpropenyl] benzoate to obtain the title compound (83 %).
MS (LC5 70 eV) m/z 335 (M+1)
Step 3: 4-[3-(5-Hydroxy-naphthalene-l-ylamino)-2-methylpropenyl]-N- hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using
4-[3-(5-hydroxy-naphthalene-l-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (99 % ).
1H NMR (300 MHz5 MeOH-d4) δ 2.0 (s, 3H)5 4.02-4.04 (d, 2H5 J=8.2 Hz)5 6.5 (S5 IH)5 6.8-6.9 (m, 2H)5 7.2-7.4 (m, 5H)5 7.84-7.88 (d5 2H5 J=8.2 Hz)5 8.03-8.09 (m, 2H) MS (LC5 70 eV) m/z 350 (M+1) Example 10: 4-[3-(Benzo[l,2,5]thiadiazol-4-ylamino)-2-methyIpropenyI]- N-hydroxy benzamide
Step 1: Methyl 4-[3-(benzo[l,2,5]thiadiazoI-4-ylamino>2- methyϊpropenyl] benzoate The procedure of Step 1 of Example 1 was repeated except for using berizo[l,2,5]thiadiazol-4-ylamine as the starting material to obtain the title compound (98%).
1H NMR (300 MHz5 CDCl3) δ 1.9 (s, 3H), 3.8 (s, 3H)5 3.9-4.0 (d, 2H5 J=6.3 Hz)5 6.32-6.34 (d, IH, J=7.3 Hz)5 6.5 (s, IH), 7.1-7.2 (m, 4H)5 7.90-7.93 (dd5 2H5 J=7.75 3.0 Hz) MS (LC5 70 eV) m/z 341 (M+1)
Step 2: 4-[3-(Benzo[l,2,5]thiadiazol-4-ylamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(benzo[ 152,5]thiadiazol-4-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (75%).
MS (LC, 70 eV) m/z 327 (M+1)
Step 3: 4-[3-(Benzo[l,2,5]thiadiazol-4-ylamino)-2-iiiethyIpropenyl]-N- hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(benzo[l,255]thiadiazol-4-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (84%).
1HNMR (300 MHz5 MeOH-d4) δ 1.9 (s, 3H)5 3.8-4.0 (d, 2H5 J=7.4 Hz)5 6.31- 6.32 (d, IH5 J=7.4 Hz)5 6.5 (s, IH), 7.2-7.3 (m, 4H)5 7.9-8.0 (dd, 2H5 J=7.45 3.8 Hz)
MS (LC5 70 eV) m/z 342 (M+1)
Example 11 : 4-[3-(Anthracene-l-ylamino)-2-methylpropenyl]-N-hydroxy benzamide
Step 1: Methyl 4-[3-(Anthracene-l-ylamino)-2-methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using anthracene- 1-ylamine as the starting material to obtain the title compound (74%).
1H NMR (300 MHz, CDCl3) δ 1.9 (s, 3H), 3.8 (s, 3H), 4.0-4.1 (dd5 2H, J=13.9, 2.7 Hz), 6.5 (s, IH), 7.1-7.2 (m, 4H), 7.3-7.4 (m, 3H), 7.8-7.9 (m, 5H), 8.24-8.28 (d, IH, J=12.9 Hz) MS (LC, 70 eV) m/z 383 (M+1)
Step 2: 4-[3-(Anthracene-l-yϊamino)-2-methyIpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(anthracene-l-ylamino)-2-methylproρenyl] benzoate to obtain the title compound ( 100 % ) .
MS (LC, 70 eV) m/z 369 (M+1)
Step 3: 4-[3-(Anthracene-l-ylamino)-2-methylpropenyϊ]-N-hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3 -(anthracene- l-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (52%).
1H NMR (300 MHz, MeOH-d4) δ 1.9 (s, 3H), 4.0-4.1 (dd, 2H, J=I 2.9, 2.7 Hz), 6.4 (s, IH), 7.1-7.3 (m, 4H), 7.3-7.4 (m, 3H), 7.82-7.88 (m, 5H), 8.24- 8.28 (d, IH, J=12.9 Hz) MS (LC, 70 eV) m/z 384 (M+1)
Example 12: 4-[3-(4,6-Dihydropyrene-l-ylamino)-2-methyIpropenyl]-N- hydroxy benzamide
Step 1: Methyl 4-[3-(4,6-dihydropyrene-l-ylamino)-2-methylpropenyl] benzoate The procedure of Step 1 of Example 1 was repeated except for using 436-dihydropyrene-l-ylamine as the starting material to obtain the title compound (95%).
1H NMR (300 MHz, CDCl3) δ 1.9 (s, 3H)5 3.7 (s5 3H), 3.9-4.0 (dd, 2H, J=12.8, 5.7 Hz), 6.4 (s, IH)3 7.11-7.17 (m, 3H)5 7.61-7.63 (d, IH, J=8.8 Hz), 7.7-7.9 (m5 9H) MS (LC, 70 eV) m/z 407 (M+1)
Step 2: 4-[3-(4,6-Dihydropyrene-l-ylamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(4,6-dihydropyrene-l-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (95 %).
MS (LC, 70 eV) m/z 393 (M+1)
Step 3: 4-[3-(4,6-Dihydropyrene-l-ylamino)-2-methylpropenyl]-N- hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using
4-[3-(456-dihydropyrene-l-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (99%).
1H NMR (300 MHz, MeOH-d4) δ 1.9 (s, 3H), 3.92-3.96 (dd, 2H, J=12.6, 5.7 Hz), 6.4 (s, IH), 7.14-7.18 (m, 3H), 7.61-7.62 (d, IH, J=8.4 Hz), 7.8-7.9 (m, 9H) MS (LC, 70 eV) m/z 408 (M+1)
Example 13: 4-[3-(4-Methyl-2-2H-chromene-7-ylamino)-2- methylpropenyl]-N-hydroxy benzamide
Step 1: Methyl 4-[3-(4-methyl-2-2H-chromene-7-ylamino)-2- methylpropenylj benzoate
The procedure of Step 1 of Example 1 was repeated except for using 4-methyl-2-2H-chromene-7-ylamine as the starting material to obtain the title compound (46%).
1H NMR (300 MHz, CDCl3) δ 1.8 (s, 3H)5 2.2 (s, 3H)5 3.83-3.88 (s, 5H)5 5.9 (S5 IH)5 7.1-7.2 (t, 3H, J=I 3.7, 8.2 Hz)5 7.2-7.3 (d, 2H5 J=8.6 Hz)5 7.90-7.92 (d, 2H5 >=8.2 Hz) MS (LC5 70 eV) m/z 364 (M+1)
Step 2: 4-[3-(4-Methyl-2-2H-chromene-7-ylamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(4-methyl-2-2H-chromene-7-ylamino)-2-methylpiOpenyl] benzoate to obtain the title compound (91 %).
MS (LC5 70 eV) m/z 350 (M+1)
Step 3: 4-[3-(4-Methyl-2-2H-chromene-7-ylamino)-2-methylpropenyl]-N- hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(4-methyl-2-2H-chromene-7-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (98%).
1HNMR (300 MHz5 MeOH-d4) δ 1.8 (s, 3H)5 2.2 (s, 3H)5 3.88 (s, 2H)5 5.9 (s, IH)5 7.14-7.18 (t, 3H5 J=12.6, 8.4 Hz)5 7.25-7.30 (d, 2H5 J=8.4 Hz)5 7.91-7.92 (d, 2H, J=8.2 Hz)
MS (LC5 70 eV) m/z 365 (M+1)
Example 14: 4-[3-(3-Benzyloxypyridine-2-ylamino)-2-methylpropenyl]- N-hydroxy benzamide Step 1: Methyl 4-[3-(3-benzyloxypyridine-2-ylamino)-2-methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 3-benzyloxypyridine-2-ylamine as the starting material to obtain the title compound (14%).
1H NMR (300 MHz5 CDCl3) δ 1.8 (s, 3H)5 3.8 (s, 3H)5 4.1-4.2 (d, 2H5 J=5.8 Hz)3 5.01 (s, 2H)5 6.4 (s, IH)5 6.43-6.47 (q, IH5 1=1.1, 5.2 Hz)5 6.85-6.88 (t, IH5 J=7.7, 6.6 Hz)5 7.1-7.3 (m, 7H)5 7.65-7.67 (dd, IH5 J=5.2, 1.2 Hz)5 7.8- 7.9 (d, 2H5 J=8.3 Hz) MS (LC, 70 eV) m/z 390 (M+1)
Step 2: 4-[3-(3-Benzyloxypyridine-2-yϊamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(3-benzyloxypyridine-2-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (90%).
MS (LC5 70 eV) m/z 376 (M+1)
Step 3: 4-[3-(3-Benzyloxypyridine-2-ylamino)-2-methyIpropenyl]-N- hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(3-benzyloxypyridine-2-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (48%).
1H NMR (300 MHz5 MeOH-d4) δ 1.8 (s, 3H)5 4.1-4.2 (d, 2H5 J=6.2 Hz)5 5.0 (s5 2H)5 6.4 (s, IH)5 6.45-6.47 (q, IH, J=7.754.2 Hz)5 6.8-6.9 (t, IH, J=7.75 5.6 Hz)5 7.2-7.3 (m, 7H)5 7.6-7.7 (dd5 IH5 J=5.65 2.4 Hz)5 7.80-7.85 (d, 2H, J=8.2 Hz) MS (LC5 70 eV) m/z 391 (M+1)
Example 15: 4-[3-(9-Ethyl-9H-carbazol-2-ylamino)-2-methyϊpropenyl]- N-hydroxy benzamide
Step 1: Methyl 4-[3-(9-ethyl-9H-carbazol-2-ylamino)-2-methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 9-ethyl-9H-carbazol-2-ylamine as the starting material to obtain the title compound (69%).
1H NMR (300 MHz5 CDCl3) δ 1.3-1.4 (m, 3H)5 1.96-1.97 (d, 2H3 J=4.3 Hz)5 2.0 (s, 3H)5 3.9 (S5 3H)5 4.2-4.3 (q, 2H5 J=7.2, 7.2 Hz)5 6.5 (s, IH)5 7.2-7.4 (m. 8H)5 7.9-8.0 (m, 3H) MS (LC5 70 eV) m/z 400 (M+1)
Step 2: 4-[3-(9-EthyI-9H-carbazoI-2-ylamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(9-ethyl-9H-carbazol-2-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (96%).
MS (LC5 70 eV) m/z 386 (M+1)
Step 3: 4-[3-(9-Ethyl-9H-carbazol-2-ylamino)-2-methylpropenyI]-N- hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(9-ethyl-9H-carbazol-2-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (100%).
1H NMR (300 MHz5 MeOH-d4) δ 1.3-1.4 (m, 3H)5 1.92-1.94 (d, 2H5 J=5.6 Hz)5 1.98 (s, 3H)5 4.2-4.3 (q, 2H5 J=7.45 7.4 Hz), 6.4 (s, IH)5 7.3-7.4 (m, 8H)5 7.8-7.9 (m5 3H)
MS (LC5 70 eV) m/z 401 (M+1)
Example 16: 4-[3-(5-Methyl-lH-pyrazol-3-ylamino)-2-methyIpropenyI]- N-hydroxy benzamide Step 1: Methyl 4-[3-(5-methyl-lH-pyrazoI-3-yIamino)-2-methyϊpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 5-methyl-lH-pyrazol-3-ylamine as the starting material to obtain the title compound (29%).
1H NMR (300 MHz5 CDCl3) δ 1.4 (s, 3H)5 1.9 (s, 3H)5 3.8 (s, 3H)5 3.9 (s, 2H)5 5.3 (s5 IH)5 6.3 (s, IH)5 7.1-7.2 (m, 2H), 7.8-7.9 (d, 2H5 J=8.2 Hz) MS (LC5 70 eV) m/z 287 (M+1)
Step 2: 4-[3-(5-MethyI-lH-pyrazol-3-ylamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(5-methyl-lH-pyrazol-3-ylamino)-2-methylproρenyl] benzoate to obtain the title compound (92%).
MS (LC5 70 eV) m/z 273 (M+1)
Step 3: 4-[3-(5-Methyl-lH-pyrazol-3-ylamino)-2-methylpropenyl]-N» hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(5-methyl-lH-pyrazol-3-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (91 %).
1H NMR (300 MHz5 MeOH-d4) δ 1.4 (s, 3H)5 1.9 (s, 3H)5 3.8 (s, 3H)5 5.32 (s, IH)5 6.3 (s5 IH)5 7.1-7.2 (m, 2H)5 7.85-7.88 (d, 2H, J=8.4 Hz) MS (LC5 70 eV) m/z 288 (M+1)
Example 17: 4-[3-(5-MethyIsulfenyl-lH-[l,2,4]triazol-3-ylamino)-2- methylpropenyl]-N-hydroxy benzamide
Step 1: Methyl 4-[3-(5-methylsulfenyl-lH-[l,2,4]triazoI-3-ylamino)-2- methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 5-methylsulfenyl-lH-[l52.4]triazol-3-ylamine as the starting material to obtain the title compound (43 %).
1H NMR (300 MHz5 CDCl3) δ 1.1 (s, 3H)5 1.9 (s, 3H)5 3.8 (s, 3H)5 4.1 (s, 2H)5 6.5 (s, IH), 7.23-7.26 (d, 2H5 J=8.4 Hz)5 7.92-7.94 (d, 2H5 J=8.1 Hz) MS (LC5 70 eV) m/z 320 (M+1)
Step 2: 4-[3-(5-Methylsulfenyl-lH-[l,2,4]triazol-3-ylamino)-2- methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(5-memylsulfenyl-lH-[l,254]triazol-3-ylamino)-2- methylpropenyl] benzoate to obtain the title compound (41 %).
MS (LC5 70 eV) m/z 306 (M+1)
Step 3: 4-[3~(5-MethylsulfenyI-lH-[l,294]triazol-3-ylamino)-2- methyIpropenyl]-N-hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(5-methylsulfenyl-lH-[l ,2,4]triazol-3-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (41 %).
1H NMR (300 MHz5 MeOH-d4) δ 1.3 (s, 3H)5 1.9 (s, 3H)5 4.0 (s, 2H), 6.5 (s, IH)5 7.24-7.26 (d, 2H5 J=8.4 Hz), 7.90-7.92 (d, 2H, J=8.4 Hz) MS (LC5 70 eV) m/z 321 (M+1)
Example 18: 4-[3-(3-Methoxy phenylamino)-2-methylpropenyl]-N- hydroxy benzamide
Step 1: Methyl 4-[3-(3-methoxy phenylamino)-2-methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 3-methoxy phenylamine as the starting material to obtain the title compound (60%).
1H NMR (300 MHz5 CDCl3) δ 1.9 (s, 3H)5 3.7 (s, 3H)5 3.80 (s, 2H)5 3.88 (s, 3H)5 6.2 (s5 IH), 6.21-6.29 (m, 2H), 6.5 (s, IH), 7.04-7.09 (t, IH5 J=16.05 8.0 Hz)5 7.26-7.29 (d, 2H5 J=8.2 Hz)5 7.95-7.98 (d, 2H5 J=8.2 Hz) MS (LC5 70 eV) m/z 313 (M+1) Step 2: 4-[3-(3-Methoxy phenylamino)-2-methyIpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(3-methoxy phenylamino)-2-methylpropenyl] benzoate to obtain the title compound (94 % ).
MS (LC, 70 eV) m/z 299 (M+1)
Step 3: 4-[3-(3-Methoxy phenylamino)-2-methylpropenyl]-N-hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(3-methoxy phenylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (96%).
1H NMR (300 MHz, MeOH-d4) δ 1.9 (s, 3H), 3.7 (s, 3H), 3.80 (s, 2H)5 6.2 (s, IH)5 6.25-6.30 (m, 2H), 6.5 (s, IH)5 7.02-7.06 (t, IH, J=I 6.O5 8.2 Hz)5 7.26- 7.28 (d, 2H5 J=8.2 Hz)5 7.94-7.96 (d, 2H, J=8.2 Hz) MS (LC5 70 eV) m/z 314 (M+1)
Example 19: 4-[3-(Naphthalene-l-ylamino)-2-methylpropenyl]-N- hydroxy benzamide
Step 1: Methyl 4-[3-(naphthalene-l-ylamino)-2-methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 1-naphthaleneylamine as the starting material to obtain the title compound (63 %).
1H NMR (300 MHz5 CDCl3) δ 1.9 (s, 3H)5 3.8 (s, 3H)5 3.96-3.98 (d, 2H5 J=4.4 Hz)5 6.5 (s5 IH), 6.60-6.62 (d, IH5 J=7.2 Hz)5 7.1-7.2 (m, 4H)5 7.3-7.4 (q, 2H5 J=6.3, 3.2 Hz)5 7.71-7.73 (d, IH5 J=6.1 Hz)5 7.8-7.9 (dd, 3H5 J=6.6, 1.5 Hz) MS (LC5 70 eV) m/z 333 (M+1) Step 2: 4-[3-(Naphthalene-l-ylamino)-2-methylpropenyI] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(naphthalene-l-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (100%).
MS (LC5 70 eV) m/z 319 (M+1)
Step 3 : 4-[3-(Naphthalene-l-ylamino)-2-methylpropenyl]-N-hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using
4- [3 -(naphthalene- l-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (78%).
1H NMR (300 MHz, MeOH-d4) δ 1.9 (s, 3H), 3.9-4.0 (d, 2H, J=5.4 Hz), 6.5 (s5 IH)5 6.60-6.62 (d, IH5 J=6.6 Hz)5 7.1-7.2 (m, 4H)5 7.3-7.4 (q, 2H5 J=6.6, 3.3 Hz)5 7.72-7.74 (d, IH5 J=6.4 Hz)5 7.80-7.84 (dd5 3H, J=6.6, 3.5 Hz) MS (LC5 70 eV) m/z 334 (M+1)
Example 20: 4-[3-(Naphthalene-2-yIamino)-2-methylpropenyl]-N- hydroxy benzamide
Step 1: Methyl 4-[3-(naphthalene-2-ylamino)-2-methyIpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 2-naphthaleneylamine as the starting material to obtain the title compound (73 %).
1H NMR (300 MHz, CDCl3) δ 2.0 (s, 3H), 3.9 (s, 3H)5 4.0 (s, 2H)5 6.5 (s, IH)5 6.6 (s, IH)5 6.94-6.98 (dd5 IH5 J=8.75 2.3 Hz), 7.2-7.4 (m,' 4H), 7.6-7.7 (q, 4H5 J=18.2, 3.2 Hz)5 8.00-8.03 (d, 2H5 J=8.3 Hz) MS (LC5 70 eV) m/z 333 (M+1)
Step 2: 4-[3-(NaphthaIene-2-yIamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3~(naphmalene-2-ylamino)-2-methyrpropenyl] benzoate to obtain the title compound (100%).
MS (LC, 70 eV) m/z 319 (M+1)
Step 3: 4-[3-(Naphthalene-2-ylamino)-2-methylpropenyl]-N-hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(naphthalene-2-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (97 % ).
1H NMR (300 MHz, MeOH-d4) δ 2.0 (s, 3H)5 4.0 (s, 2H), 6.4 (s, IH), 6.6 (s, IH), 6.9-7.0 (dd, IH, J=8.6, 3.4 Hz), 7.2-7.3 (m, 4H), 7.65-7.69 (q, 4H, J=12.6.2, 6.2 Hz)5 7.8-8.0 (d, 2H, J=8.4 Hz) MS (LC, 70 eV) m/z 334 (M+1)
Example 21 : 4-[3-(Biphenyl-4-ylamino)-2-methylpropenyl]-N-hydroxy benzamide
Step 1: Methyl 4-[3-(biphenyl-4-ylamino)-2-methylpropenyl] benzoate The procedure of Step 1 of Example 1 was repeated except for using
4-biphenylamine as the starting material to obtain the title compound (83 %).
1H NMR (300 MHz, CDCl3) δ 1.9 (s, 3H)5 3.8 (s, 3H)5 4.02-4.04 (d, 2H5 J=7.2 Hz), 6.4 (s, IH), 6.61-6.67 (t, 2H, J=I 7.4, 8.6 Hz), 7.15-7.17 (d, 2H, J=4.8 Hz), 7.2-7.4 (m, 7H), 7.8-7.9 (d, IH, J=6.3 Hz) MS (LC, 70 eV) m/z 359 (M+1)
Step 2: 4-[3-(Biphenyl-4-ylamino)-2-methylpropenyI] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(biphenyl-4-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (97%).
MS (LC, 70 eV) m/z 345 (M+1) Step 3: 4-[3-(Biphenyl-4-ylamino)-2-methylpropenyl]-N-hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(biphenyl-4-ylamino)-2-methylpropenyl] benzoic acid to obtain the title ' compound (96 % ).
1H NMR (300 MHz5 MeOH-d4) δ 1.9 (s, 3H)5 4.02-4.04 (d, 2H5 J=7.2 Hz)5 6.4 (S5 IH)5 6.62-6.66 (t, 2H5 J=16.2, 8.0 Hz)5 7.18-7.22 (d5 2H, J=6.2 Hz)5 7.3-7.5 (m, 7H)3 7.7-7.8 (d, IH5 J=6.4 Hz) MS (LC, 70 eV) m/z 360 (M+1)
Example 22: 4-[3-(6-Nitro-benzothiazol-2-ylammo)-2-methylpropenyl]- N-hydroxy benzamide Step 1: Methyl 4-[3-(6-nitro-benzothiazol-2-ylamino)-2-methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using
6-nitro-benzothiazole-2-ylamine as the starting material to obtain the title compound (97 % ).
1H NMR (300 MHz5 CDCl3) δ 1.9 (s, 3H)5 3.9 (s, 3H); 4.5-4.6 (d, 2H5 J=10.9
Hz)5 6.3 (s, IH)5 7.2-7.3 (dd, 2H5 J=10.8, 2.4 Hz), 7.9-8.0 (dd, IH, J=8.35 2.1
Hz)
MS (LC5 70 eV) m/z 385 (M+1)
Step 2: 4-[3-(6-Nitro-benzothiazol-2-ylamino)-2-methyIpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4- [3 -(6-nitro-benzothiadiazol-2-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (89 % ) .
MS (LC5 70 eV) m/z 371 (M+1) Step 3: 4-[3-(6-Nitro-benzothiazol-2-ylamino)-2-methyIpropenyl]-N- hydroxy benzamide
. The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(6-nitro-benzothiazol-2-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (91 %).
1H NMR (300 MHz, MeOH-d4) δ 1.9 (s, 3H)5 4.52-4.56 (d, 2H5 J=I 0.6 Hz)5 6.3 (s, IH)5 7.22-7.28 (dd, 2H, J=8.45 2.4 Hz)5 7.95-7.98 (dd, IH5 J=8.35 2.4 Hz) MS (LC5 70 eV) m/z 386 (M+1)
Example 23: 4-[3-(6-Methoxy-benzothiazol-2-ylamino)-2- methylpropenyl]-N-hydroxy benzamide
Step 1: Methyl 4-[3-(6-methoxy-benzothiazol-2-ylamino)~2- methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 6-methoxy-benzothiazol-2-ylamine as the starting material to obtain the title compound (35%).
1H NMR (200 MHz5 CDCl3), σ 1.94 (S5 3H5 CH3), 3.82 (S5 3H, OCH3), 3.91
(S5 3H5 OCH3), 4.10 (S, 2H5 CH2), 6.57 (S5 IH5 CH)5 6.89 (m, IH5 ArH)5 7.13
(m, IH5 ArH)5 7.33 (m, 2H5 ArH)5 7.69 (m, IH5 ArH)5 7.99 (d, 2H J=8.5 Hz5
ArH)
MS (LC5 70 eV) m/z 370 (M+1)
Step 2: 4-[3-(6-Methoxy-benzothiazol-2-ylamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(6-methoxy-benzothiazol-2-ylamino)-2-methylproρenyl] benzaote to obtain the title compound (71 %).
1H NMR (200 MHz5 CDCl3), σ 1.95 (S5 3H5 CH3), 3.81 (S5 3H5 OCH3), 4.10 (S5 2H5 CH2), 6.57 (S, IH5 CH)5 6.91 (m, IH5 ArH)9 7.15 (m, IH5 ArH)5 7.33 (m, 2H, ArH)5 7.69 (m, IH5 ArH)5 8.02 (d5 2H J=8.5 Hz, ArH) MS (LC5 70 eV) m/z 356 (M+1)
Step 3 : 4- [3-(6-Methoxy-benzothiazol-2-ylammo)-2-methylpropenyl]-N- hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(6-methoxy-benzothiadiazol-2-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (87%).
1H NMR (200 MHz5 CDCl3), σ 1.97 (S5 3H, CH3), 3.79 (S, 3H, OCH3), 4.11 (S5 2H5 CH2), 6.54 (S, IH, CH)5 6.91 (m5 IH, ArH), 7.15 (m, IH, ArH), 7.31 (m, 2H, ArH), 7.72 (m5 IH5 ArH), 8.04 (d, 2H J=8.5 Hz, ArH) MS (LC, 70 eV) m/z 371 (M+1)
Example 24: 4-[3-(2-Methoxy-dibenzofiiran-3-ylamino)-2- methylpropenyI]-N-hydroxy benzamide
Step 1: Methyl 4-[3-(2-methoxy-dibenzofuran-3-yIamino)-2- methylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 2-methoxy-dibenzofuran-3-ylamine as the starting material to obtain the title compound (91 %).
1HNMR (300 MHz, CDCl3) δ 1.9 (s, 3H)5 3.8 (s, 3H), 3.9 (s, 3H), 4.1-4.2 (d, 2H, J=4.7 Hz), 6.4 (s, IH), 7.1-7.2 (m, 5H), 7.35-7.38 (m, 2H)5 7.9-8.0 (m, 2H)
MS (LC, 70 eV) m/z 403 (M+1)
Step 2: 4-[3-(2-Methoxy-dibenzofuran-3-ylamino)-2-methylpropenyl] benzoic acid The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(2-methoxy-dibenzofuran-3-ylamino)-2-methylpropenyl] benzaote to obtain the title compound (99%). MS (LC, 70 eV) m/z 389 (M+1)
Step 3 : 4-[3-(2-Methoxy-dibenzofuran-3-ylamino)-2-methyIpropenyl]-N- hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using
4-[3-(2-methoxy-dibenzofuran-3-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (98%).
1H NMR (300 MHz, MeOH-d4) δ 1.9 (s, 3H)5 3.8 (s, 3H), 4.12-4.16 (d, 2H, J=4.8 Hz), 6.4 (s, IH), 7.1-7.2 (m, 5H), 7.3-7.4 (m, 2H), 7.8-7.9 (m, 2H) MS (LC, 70 eV) m/z 404 (M+1)
Example 25: 4-[3-(6-Methoxypyridme-3-ylamino)-2-methylpropenyl]-N- hydroxy benzamide Step 1: Methyl 4-[3-(6-methoxypyridine-3-ylamino)-2-m)Bithylpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 6-methoxypyridine-3-ylamine as the starting material to obtain the title compound (285 ing, 91 %).
1H NMR (200 MHz, acetone-d6) δ 1.94 (s, 2H, CH2), 2.91 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 5.21 (brs, IH, NH), 6.57 (d, J=9.0 Hz, IH, ArH)9 6.62 (s, IH, CH), 7.13 (dd, J=9.0, 3.0 Hz, IH, ArH), 7.39 (d, J=8.2 Hz, 2H, ArH), 7.59 (d, J=3.0 Hz, IH, ArH), 7.96 (d, J=8.6 Hz, 2H, ArH)
Step 2: 4-[3-(6-Methoxypyridme-3-ylamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(6-methoxypyridine-3-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (90 % ).
Step 3: 4-[3-(6-Methoxypyridine-3-yIamino)-2-methylpropenyl]-N- hydroxy benzamide The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(6-methoxypyridine-3-ylammo)-2-methylpropenyl] benzoic acid to obtain the title compound.
1H NMR (300 MHz5 acetone-d6) δ 1.94 (s, 2H5 CH2), 2.91 (s, 3H5 CH3), 3.86 (S5 3H5 OCH3), 5.21 (brs, IH5 NH)5 6.57 (d, J=9.0 Hz5 IH5 ArH)5 6.65 (s, IH, CH)5 7.13 (dd, J=9.0, 3.0 Hz, IH5 ArH)5 7.39 (d, J=8.1 Hz5 2H, ArH), 7.59 (d, J=3.0 Hz5 IH5 ArH), 7.96 (d, J=8.6 Hz, 2H5 ArH)
Example 26: 4-[3-(2-Chloropyridine-3-ylamino)-2-methylpropenyI]-N- hydroxy benzamide
Step 1: Methyl 4-[3-(2-chloropyridine-3-ylamino)-2-methyϊpropenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 2-chloropyridine-3-ylamine as the starting material to obtain , ;£tie title compound (25%).
1H NMR (200 MHz, CDCl3) δ 1.94 (s, 3H5 CH3), 3.91 (s, 3H, OCH3), 3.95 (s, 2H, CH2), 4.79 (brs, IH5 NH), 6.52 (s, IH, CH), 6.90 (d, J=8.0 Hz, IH, ArH), 7.07 (m, IH, ArH), 7.30 (d, J=8.8 Hz5 2H5 ArH), 7.74 (d, J=4.8 Hz, IH5 ArH), 8.01 (d, J=8.8 Hz, 2H, ArH) MS (EI, 70 eV) m/z 316 (M+), 189, 157, 145, 1295 115, 105, 91, 77, 59, 43
Step 2: 4-[3-(2-Chloropyridine-3-yIamino)-2-methylpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(2-chloropyridine-3-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (100%).
Step 3: 4-[3-(2-Chloropyridine-3-ylammo)-2-methyIpropenyl]-N-hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(2-chloropyridine-3-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound.
1H NMR (200 MHz, CDCl3) δ 1.94 (s, 3H5 CH3), 3.95 (s, 2H5 CH2), 6.52 (s, IH5 CH), 6.90 (d, J=8.0 Hz, IH5 ArH)5 7.07 (m, IH5 ArH)5 7.30 (d, J=8.8 Hz5 2H5 ArH)5 7.74 (d, J=4.8 Hz5 IH5 ArH), 8.01 (d, J=8.8 Hz5 2H, ArH)5 9.48 (brs5 IH), 10.02 (brs, '1H)
Example 27: 4-[3-(6-Morpholine-4-ylmethylquinoline~3-ylamino)-2- methyl-propenyl]-N-hydroxy benzamide Step 1: Methyl 4-[3-(6-morpholine-4-ylmethylquinoline-3-ylamino)-2- methyl-propenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 6-morpholine-4-ylmethylquinoline-3-ylamine as the starting material to obtain the title compound (38%). ..- .• . .. ■
1H NMR (200 MHz, CDCl3) δ 8.46 (d, J=2.8 Hz5 IH)5 7.98 (d, J=8.0 Hz, 2H), 7.88 (d, J=8.6 Hz5 IH)5 7.51 (s, IH), 7.41 (d, J=8.6 Hz, IH)5 7.30 (d, J=8.6 Hz5 2H)5 7.01 (d, J=2.4 Hz5 IH), 6.59 (s, IH)5 4.47 (brs, IH)5 3.94 (d, J=4.4 Hz, 2H)5 3.89 (s, 3H), 3.71 (t, J=4.8 Hz, 4H)5 3.60 (s, 2H), 2.48 (t, J=4.8 Hz5 4H), 1.97 (s, 3H)
Step 2: 4-[3-(6-Morpholine-4-ylmethylquinoline-3-ylamino)-2-methyl- propenylj-benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(6-morpholine-4-ylmethylquinoline-3-ylamino)-2-methyl- propenyl] benzoate to obtain the title compound (92%).
1H NMR (200 MHz, CDCl3) δ 8.47 (s, IH)5 7.92 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.6 Hz, IH), 7.65 (s, IH)5 7.42 (d, J=8.6 Hz, IH), 7.29 (d, J=7.6 Hz5 2H), 7.13 (s, IH), 6.61 (s, IH), 3.95 (s, 2H), 3.82 (s, 2H), 3.72 (t, J=4.4 Hz, 4H)5 2.68 (t, J=4.4 Hz5 4H), 1.94 (s, 3H)
Step 3: 4-[3-(6-Morpholine-4-ylmethylquinoline-3-ylamino)-2-methyl- propenyI]-N-hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(6-moipholine-4-ylmethylqumoline-3-ylammo)-2-metriyl-piOpenyl]- benzoic acid to obtain the title compound (35%).
1HNMR (200 MHz5 DMSO-d6) δ 11.19 (s, IH)5 10.33 (brs, IH)5 8.98 (s, IH)5 8.50 (d, J=2.4 Hz5 IH)5 7.70 (d, J=8.2 Hz5 IH)5 7.53 (s, IH)5 7.30 (d, J=8.2 Hz5 2H)5 7.01 (d, J=2.4 Hz5 IH)5 6.78 (s, IH)5 6.55 (s, IH)5 4.58 (s, 2H)5 3.88 (s, 2H)5 3.58 (t5 J=4.4 Hz5 4H)5 2.48 (t, J=3.6 Hz5 4H)5 1.91 (s, 3H)
Example 28: 4-[3-(4'-Cyanobiphenyl-4-ylamino)-2-methylpropenyl]-N- hydroxy benzamide
Step 1: Methyl 4-[3-(4'-cyanobiphenyl-4-ylamino)-2-methylpropenyl] benzoate The procedure of Step 1 of Example 1 was repeated except for using
4'-cyanobiphenyl-4-ylamine as the starting material to obtain the title compound (70%).
1H NMR (200 MHz5 acetone-d6) δ 2.92 (s, 3H5 CH3), 3.87 (s, 3H5 OCH3), 3.97 (d, J=6.4 Hz5 2H5 CH2), 5.85 (brs, IH5 NH)5 6.82 (s, J=9.0 Hz5 2H5 ArH)5 7.35 (s, IH5 ArH)5 7.31 (m5 2H5 ArH), 7.55 (d, J=9.0 Hz5 2H5 ArH)5 7.70 (m, 4H, ArH)5 7.96 (d, J=8.2 Hz5 2HS ArH) MS (EI5 70 eV) m/z 382 (M+), 91, 69, 59, 43
Step 2: 4-[3-(4'-CyanobiphenyI-4-ylamino)-2-methyIpropenyl] benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(4'-cyanobiphenyl-4-ylamino)-2-methylpropenyl] benzoate to obtain the title compound (87%).
Step 3: 4-[3-(4'-Cyanobiphenyl-4-ylamino)-2-methylpropenyl]-N- hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(4'-cyanobiphenyl-4-ylamino)-2-methylpropenyl] benzoic acid to obtain the title compound (15 mg).
1H NMR (200 MHz5 acetone-d6) δ 2.90 (s, 3H5 CH3), 3.97 (d, J=6.4 Hz, 2H, CH2), 6.82 (d, J=9.0 Hz, 2H, ArH), 7.35 (s, IH, ArH), 7.31 (m, 2H5 ArH), 7.55 (d, J=9.0 Hz, 2H5 ArH)5 7.70 (m, 4H5 ArH)5 7.96 (d, J=8.2 Hz5 2H5 ArH)
Example 29: 4-[3-(4-Pyridine-2-ylpiperazine-l-yl)-2-methyl-propenyI]-N- hydroxy-benzimide Step 1: Methyl 4-[3-(4-pyridine-2-ylpiperazine-l-yl)-2-methyl-propenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 4-pyridine-2-ylpiperazine as the starting material to obtain the title compound (92%).
1H NMR (200 MHz5 CDCl3), σ 2.18 (m, 2H5 CH2), 2.20 (S5 3H5 CH3), 2.59 (HI, 2H5 CH2), 3.94 (S5 3H5 OCH3), 6.54 (m, 3H5 ArH)5 7.37 (d, 2H J=8.0 Hz5 ArH)5 8.04 (d, 2H J=8.0 Hz5 ArH)5 8.33 (m, 2H, ArH)
Step 2: 4-[2-Methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl]-benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[2-methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl] benzoate to obtain the title compound (75 %).
1H NMR (200 MHz, CDCl3), σ 2.17 (m, 2H5 CH2), 2.24 (S5 3H5 CH3), 2.61 (Hi5 2H, CH2), 6.66 (m5 3H5 ArH)5 7.34 (d, 2H J=8.0 Hz, ArH), 8.02 (d, 2H J=8.0 Hz, ArH)5 8.31 (m, 2H, ArH)
Step 3: 4-[2-MethyI-3-(4-pyridine-2-ylpiperazine-l-yl)~propenyl]-N- hydroxy-benzimide
The procedure of Step 3 of Example 1 was repeated except for using 4-[2-methyl-3-(4-ρyridine-2-ylpiρerazine-l-yl)-propenyl]-benzoic acid to obtain the title compound (25%).
1H NMR (200 MHz5 CDCl3), σ 2.18 (m, 2H5 CH2), 2.22 (S5 3H5 CH3), 2.63 (m, 2H, CH2), 6.59 (m, 3H, ArH)5 7.34 (d, 2H J=8.0 Hz, ArH), 8.01 (d, 2H 5 J=8.0 Hz5 ArH)5 8.32 (m, 2H5 ArH)
Example 30 : 4- [2-Methyl-3-(4-phenyl-piperazine-l -yl)-propenyl] -N- hydroxy-benzimide
Step 1: Methyl 4-[2-methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl] o benzoate
The procedure of Step 1 of Example 1 was repeated except for using 4-pyridine-2-ylpiperazine as the starting material to obtain the title compound (62%).
5 1U NMR (200 MHz5 CDCl3), σl.97 (S5 3H, CH2), 2.63 (m5 2H5 CH2), 3.11 (S5 2H, CH2), 3.25 (m, 2H5 CH2), 3.94 (S, 3H, OCH3), 6.53 (S, IH, CH), 6.91 (m, 3H, ArH), 7.24-7.39 (m, 5H, ArH), 8.02 (d, 2H J=8.5 Hz, ArH)
Step 2: 4-[2-Methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl]-benzoic o acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[2-methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl] benzoate to obtain the title compound (95 %).
5 1H NMR (200 MHz, CDCl3), σl .99 (S, 3H, CH2), 2.64 (m, 2H, CH2), 3.12 (S5 2H5 CH2), 3.24 (m, 2H, CH2), 6.54 (S, IH, CH), 6.93 (m, 3H, ArH), 7.24-7.39 (m, 5H5 ArH)5 8.01 (d, 2H J=8.5 Hz, ArH)
Step 3 : 4-[2-Methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl] -N- o hydroxy-benzimide The procedure of Step 3 of Example 1 was repeated except for using 4-[2-methyl-3 -(4-pyridine-2-ylpiperazine- 1 -yl)-propenyl]-benzoic acid to obtain the title compound (25%).
1H NMR (200 MHz, CDCl3), ), σl .99 (S5 3H5 CH2), 2.67 (m, 2H5 CH2), 3.12 (S, 2H, CH2), 3.21 (m, 2H5 CH2), 6.53 (S5 IH5 CH)5 6.93 (m, 3H5 ArH)5 7.31 (m, 5H5 ArH)5 8.04 (d, 2H J=8.5 Hz5 ArH)
Example 31: 4-[3-(Benzyl-methylamino)-2-methyI-propenyI]-N-hydroxy- benzamide
Step 1: Methyl 4-[3-(benzyl-methyl-amino)-2-methyl-propenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using benzyl-methyl-amine as the starting material to obtain the title compound (80%).
1H NMR (200 MHz5 CDCl3), σ 1.99 (S, 3H, CH3), 2.25 (S, 3H, CH3), 3.10 (S, 2H, CH2), 3.58 (S, 2H, CH2), 3.94 (S, 3H5 OCH3), 6.54 (S5 IH5 CH), 7.38 (m, 7H, ArH), 8.01 (d, 2H J=8.0 Hz, ArH)
Step 2: 4-[3-(Benzyl-methyl-amino)-2-methyl-propenyl]-benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(benzyl-methyl-amino)-2-methyl-ρroρenyl] benzoate to obtain the title compound (48%).
1U NMR (200 MHz, CDCl3), σ 1.97 (S, 3H5 CH3), 2.23 (S, 3H, CH3), 3.11 (S5 2H, CH2), 3.59 (S, 2H, CH2), 6.54 (S5 IH, CH), 7.41 (m, 7H5 ArH)5 8.03 (d, 2H J=8.0 Hz5 ArH)
Step 3: 4-[3-(Benzyl-methylamino)-2-methyl-propenyl]-N-hydroxy- benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(benzyl-methyl-amino)-2-methyl-propenyl]-benzoic acid to obtain the title compound (33%).
1HNMR (200 MHz5 CDCl3), σ 1.99 (S, 3H, CH3), 2.21 (S5 3H, CH3), 3.11 (S, 2H, CH2), 3.57 (S, 2H, CH2), 6.55 (S, IH, CH), 7.41 (m, 7H, ArH), 8.01 (d, 2H J=8.0Hz, ArH)
Example 32: 4-[3-(2-Phenoxy-ethylamino)-2-methyl-propenyI]-N- hydroxy-benzamide
Step 1: Methyl 4-[3-(2-phenoxy-ethylamino)-2-methyl-propenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 2-phenoxy-ethylamine as the starting material to obtain the title compound (42%).
1H NMR (200 MHz, CDCl3), σ 2.05 (S, 3H5 CH3), 3.15 (m, 2H, CH2), 3.46 (S, 2H, CH2), 3.94 (S, 3H, OCH3), 4.20 (m, 2H, CH2), 6.64 (S, IH, CH), 6.84 (m IH, ArH), 6.91 (m, 2H, ArH), 7.32 (m, 4H, ArH), 8.03 (m, 2H, ArH)
Step 2: 4-[3-(2-Phenoxy-ethylamino)-2-methyl-propenyI]-benzoic acid The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[2-methyl-3-(2-phenoxy-ethylamino)-propenyl] benzoate to obtain the title compound (97%).
1H NMR (200 MHz, CDCl3), σ 2.03 (S, 3H5 CH3), 3.17 (m, 2H5 CH2), 3.46 (S, 2H, CH2), 4.21 (m, 2H, CH2), 6.64 (S, IH5 CH)5 6.84 (m IH, ArH), 6.94 (m, 2H5 ArH), 7.32 (m, 4H, ArH), 8.03 (m, 2H5 ArH)
Step 3: 4-[3-(2-Phenoxy-ethylamino)-2-methyI-propenyl]-N-hydroxy- benzamide The procedure of Step 3 of Example 1 was repeated except for using
4-[2-methyl-3-(2-phenoxy-ethylamino)-propenyl]-benzoic acid to obtain the title compound (23%). 1H NMR (200 MHz5 CDCl3), σ 2.03 (S, 3H5 CH3), 3.17 (m, 2H5 CH2), 3.46 (S5 2H5 CH2), 4.21 (m, 2H5 CH2), 6.64 (S5 IH5 CH)5 6.84 (m IH, ArH), 6.92 (m, 2H5 ArH)5 7.31 (m, 4H, ArH), 8.02 (m, 2H5 ArH)
Example 33: 4-[3-(8-Bromoquinoline-3-yIamino)-2-methyl-propenyl]-N- hydroxy-benzamide
Step 1: Methyl 4-[3-(8-bromoquinoline-3-ylamino)-2-methyl-propenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 8-bromoquinoline-3-ylamine as the starting material to obtain the title compound (53 %).
1H NMR (300 MHz5 CDCl3) δ 1.89 (s, 3H), 3.82 (s, 3H)5 3.87 (s, 2H), 6.50 (s, IH)5. 6.96-6.97 (d, IH, J=7.2 Hz), 7.1-7.2 (m, 4H), 7.47-7.49 (d, IH5 J=8.0 Hz), 7.63-7.65 (d, IH, J=8.2 Hz), 7.88-7.91 (d, 2H, J=8.2 Hz)5 7.95-7.98 (d, IH, J=8.0 Hz), 8.59-8.60 (d, IH, J=7.8 Hz)
MS (EI, 70 eV) m/z 411 (M1"), 395, 379, 235, 222, 189, 157, 130, 115, 105, 91, 59
Step 2: 4-[3-(8-Bromoquinoline-3-ylamino)-2-methyl-propenyl]-benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(8-bromoquinoline-3-ylamino)-2-methyl-propenyl] benzoate to obtain the title compound (90%).
MS (EI5 70 eV) m/z 396 (M"1), 222, 149, 131, 115, 91, 66, 58
Step 3: 4-[3-(8-Bromoquinoline-3-ylamino)-2-methyl-propenyl]-N- hydroxy-benzamide The procedure of Step 3 of Example 1 was repeated except for using
4- [3 -(8-bromoquinoline-3 -ylamino)-2-methyl-propenyl]-benzoic acid to obtain the title compound (89%). 1H NMR (300 MHz5 acetone-d6) δ 1.87 (s, 3H), 3.84 (s, 2H)5 6.50 (s, IH), 6.94-6.96 (d, IH, J=7.2 Hz)5 7.1-7.3 (m, 4H)5 7.48-7.50 (d, IH5 J=7.6 Hz), 7.61.-7.63 (d, IH5 J=8.4 Hz), 7.88-7.90 (d, 2H5 J=8.4 Hz)5 7.92-7.94 (d, IH5 J=8.2 Hz)5 8.58-8.60 (d, IH5 J=8.4 Hz) MS (LC, 70 eV) m/z 413 (M+1)
Example 34: 4-[3-(6-Methoxyquinolme-3-ylamino)-2-methyl-propenyl]- N-hydroxy-benzamide
Step 1: Methyl 4-[3-(6-methoxyquinoline-3-ylamino)-2-methyI-propenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using 6-methoxyquinoline-3-ylamine as the starting material to obtain the title compound.
1H NMR (300 MHz, CDCl3) δ 1.89 (s, 3H), 3.56 (s, 3H)5 3.82 (s, 3H), 3.87 (s, 2H)5 6.50 (s, IH), 6.97 (d, IH, J=7.2 Hz), 7.12 (m, 4H)5 7.49 (d, IH5 J=8.0 Hz), 7.65 (d, IH5 J=8.2 Hz), 7.89 (d, 2H, J=8.2 Hz)5 7.98 (d, IH5 J=8.0 Hz)5 8.59 (d, IH5 J=7.8 Hz)
Step 2: 4-[3-(6-Methoxyquinoline-3-yIamino)-2-methyl-propenyl]-benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(6-methoxyquinoline-3-ylamino)-2-methyl-propenyl] benzoate to obtain the title compound (99%).
MS (EI, 70 eV) m/z 348 (M+), 333, 3075 201, 174, 146, 131, 115, 91
Step 3: 4-[3-(6-MethoxyquinoIine-3-ylamino)-2-methyl-propenyl]-N- hydroxy-benzamide The procedure of Step 3 of Example 1 was repeated except for using
4-[3-(6-methoxyquinoline-3-ylamino)-2-methyl-propenyl]-benzoic acid to obtain the title compound (75%). 1H NMR (300 MHz5 acetone-d6) δ 1.88 (s, 3H)5 3.83 (s, 3H)5 3.91 (s, 2H)5 6.54 (s5 IH)5 6.83-6.84 (d, IH5 J=7.4 Hz)5 7.02-7.06 (dd5 2H5 J=7.4 Hz)5 7.19- 7.32 (m, 3H)5 7.92-8.00 (dd, 3H5 J=7.6 Hz)5 8.63-8.64 (d, IH5 J=7.6 Hz) MS (LC5 70 eV) m/z 364 (M+1)
Example 35: 4-[3-(6-Hydroxy-quinoline-3-ylamino)-2-methyl-propenyIJ- N-hydroxy-benzamide
Step 1: Methyl 4-[3-(6-hydroxy-quinoline-3-ylamino)-2-methyI-propenyl) benzoate The procedure of Step 1 of Example 1 was repeated except for using
6-hydroxy-quinoline-3-ylamine as the starting material to obtain the title compound (68%).
1HNMR (200 MHz5 CDCl3), σ 1.84 (S5 3H5 CH3), 3.78 (S5 2H5 CH2), 3.91 (S5 3H5 OCH3), 6.46 (S5 IH5 CH)5 6.78 (S5 2H5 ArH)5 6.86 (m, 2H5 ArH)5 7.18 (d, 2H J=8.0Hz, ArH)5 7.58 (d IH J=9.3Hz5 ArH)5 7.84 (d, 2H J=8.0Hz, ArH)5 8.08 (m, IH5 ArH)
Step 2: 4-[3-(6-Hydroxy-quinoIine-3-ylamino)-2-methyl-propenyl]- benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(6-hydroxy-quinoline-3-ylamino)-2-methyl-propenyl] benzoate to obtain the title compound (58%).
1H NMR (200 MHz, CDCl3), σ 2.45 (S, 3H5 CH3), 4.54 (S5 2H5 CH2), 7.14 (S5 IH5 CH)5 7.68 (m, 2H5 ArH), 7.86 (d, 2H J=8.1Hz5 ArH)5 8.17 (m, IH5 ArH)5 8.39 (d, 2H J=8.5Hz, ArH)5 9.10 (m, IH5 ArH)
Step 3 : 4-[3-(6-Hydroxy-quinoline-3-ylamino)-2~mβthyl-propenyl]-N- hydroxy-benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(6-hydroxy-quinoline-3-ylamino)-2-methyl-piOpenyl]-benzoic acid to obtain the title compound (34%). 1H NMR (200 MHz5 CDCl3), σ 2.47 (S5 3H5 CH3), 4.78 (S, 2H5 CH2), 7.02 (S5 IH, CH)5 7.78 (m, 2H5 ArH)5 7.84 (d, 2H J=8.1Hz, ArH)5 8.25 (m, IH5 ArH)5 8.34 (d, 2H J=8.5Hz5 ArH)5 8.79 (m, IH5 ArH)
Example 36. 4-[3-(Propyl-quinoline-3-ylamino)-2-methyl-propenyl]-N- hydroxy-benzamide
Step 1: Methyl 4-[3-(propyl-quinoline-3-ylamino)-2-methyl-propenyl] benzoate The procedure of Step 1 of Example 1 was repeated except for using propyl-quinoline-3-ylamine as the starting material to obtain the title compound (19%).
1H NMR (200 MHz5 CDCl3), σ 1.01 (t, J=7.4 Hz, 3H, CH3), 1.76 (q, 2H5 J=7.4 Hz, CH2), 1.92 (s, 3H, CH3), 3.47 (t, J=7.4 Hz, 3H5 NCH2), 3.93 Xs5 3H5 OCH3), 4.09 (S, 2H5 NCH2), 6.39 (s, IH, ArCH)5 7.11 (d5 IH5 J=2.8 Hz, ArH)5 7.39 (m, 4H, ArH), 7.61 (t, IH5 J=9.8 Hz5 ArH)5 7.90 (s, IH5 ArH)5 7.94 (d, 2H5 J=8.0 Hz5 ArH)5 8.63 (d, IH J=3.2 Hz5 ArH)
Step 2: 4-[3-(Propyl-quinoline-3-yIamino)-2-methyl-propenyI]-benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[2-methyl-3-(propyl-quinoline-3-ylamino)-ρroρenyl] benzoate to obtain the title compound (50%).
Step 3: 4-[3-(Propyl-quinoline-3-ylamino)-2-methyl-propenyl]-N- hydroxy-benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[2-methyl-3-(propyl-quinoline-3-ylamino)-proρenyl]-benzoic acid to obtain the title compound (19%).
MS (LC5 70 eV) m/z 375 (M+1) Example 37: 4-{3-[(2-Hydroxy-ethyl)-quinoline-3-ylamino]-2-methyI- propenyl}-N-hydroxy-benzamide
Step 1: Methyl 4-(3-{[2-(fer^butyl-dimethyl-silanyIoxy)-ethyI]-quinoline-
3-ylamino}-2-methyl-propenyl) benzoate The procedure of Step 1 of Example 1 was repeated except for using
[2-(ter/-butyl-dimetliyl-silanyloxy)-ethyl]-qumoline-3-ylamine as the starting material to obtain the title compound (51 %).
1H NMR (200 MHz5 CDCl3), σ 0.10 (s, 6H5 SiCH2), 0.88 (s, 9H, CH3X3), 1.84 (s, 3H5 CH3), 3.70 (t, 2H, J=5.8 Hz5 CH2), 3.79 (S, 3H, OCH3), 3.92 (t, 2H5 J=5.8 Hz5 CH2), 4.18 (S, IH5 CH2), 6.36 (S5 IH5 CH)5 7.22 (m, 2H5 ArH)5 7.40 (m, 3HS ArH)5 7.60 (m, IH5 ArH)5 7.91 (s, IH5 ArH), 7.94 (d, 2H, J=8.2 Hz, ArH), 8.66 (d, IH5 J=2.8 Hz, ArH)
Step 2: ,4-(3-{[2-(^^-Butyl-dimethyl-silanyloxy)-ethyl]-quinoline-3- ylamino}-2-methyl-propenyl)-benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-(3-{[2-(terr-buryl-dimethyl-silanyloxy)-ethyl]-quinolme-3- ylamino}-2-methyl-propenyl) benzoate to obtain the title compound (69%).
Step 3: 4-{3-[(2-Hydroxy-ethyl)-quinoline-3-ylamino]-2-methyI- propenyl}-N-hydroxy-benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-(3 - { [2-(fer/-butyl-dimethyl-silanyloxy)-ethyl]-quinoline-3 -ylamino } -2- methyl-propenyl)-benzoic acid to obtain the title compound (20 %).
MS (LC, 70 eV) m/z 377 (M+1)
Example 38: 4-[3-(Formyl-quinoline-3-ylamino)-2-methyl-propenyl]-N- hydroxy-benzamide
Step 1: Methyl 4-[3-(formyl-quinoline-3-ylamino)-2-methyl-propenyl] benzoate
The procedure of Step 1 of Example 1 was repeated except for using fonΗyl-quinoline-3-ylamine as the starting material to obtain the title compound (96%).
1H NMR (200 MHz5 CDCl3), σ 1.90 (s, 3H5 CH3), 3.89 (S5 3H5 OCH3), 4.67 (s5 2H5 CH2), 6.42 (S, IH5 CH)5 7.20 (d, J=8.0 Hz, 2H, ArH), 7.72 (m, 4H, ArH), 7.94 (d, J=8.0 Hz5 2H5 ArH)5 8.12 (d, J=8.6 Hz5 IH, ArH), 8.70 (s, IH, CHO)5 8.88 (d, IH J=2.8 Hz, ArH)
Step 2: 4-[3-(Formyl-quinoline-3-ylamino)-2-methyl-propenyl]-benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(formyl-quinoline-3-ylamino)-2-methyl-propenyl] benzoate to obtain the title compound (85 %).
Step 3: 4-[3-(Eormyl-quinoline-3-ylamino)-2-methyl-propenyI]-N- hydroxy-benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(formyl-quinoline-3-ylamino)-2-methyl-propenyl]-benzoic acid to obtain the title compound (73 %).
1H NMR (200 MHz5 CDCl3), σ 1.90 (s, 3H5 CH3), 4.65 (s, 2H, CH2), 6.42 (S5 IH, CH)5 7.20 (d, J=8.0 Hz, 2H5 ArH)5 7.77 (m, 4H5 ArH), 7.94 (d5 J=8.0 Hz5 2H5 ArH), 8.10 (d, J=8.6 Hz5 IH5 ArH)5 8.70 (s, IH5 CHO), 8.88 (d, IH J=2.8 Hz5 ArH), 10.42 (brs, IH)
Example 39: 4-[2~(Quinoline-3-ylaminomethyI)-3-(naphthalene-l-yloxy)- propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-ter/-butoxycarbonyl-3-(naphthalene-l-yloxy)- propenyl] benzoate Methyl 4-(3-Bromo-2-t-butoxycarbonylρroρenyl) benzoate (9) (355 ing 1.00 mM) obtained in Preparation Example 7 was dissolved in acetone (5 mi), to which potassium carbonate (207 mg 1.50 mM) and 1-naphthalenol (144 mg 1.00 mM) were added, followed by refluxing for 3 hours. After completing the reaction, the mixture was cooled to room temperature, filtered to remove solvent. The resulting residue was purified by silica gel column chromatography to obtain the title compound as a white solid (438 mg, 99%).
1H NMR (200 MHz, CDCl3) δ 1.49 (S, 9H, CH3), 3.89 (S, 3H, OCH3), 4.96 (S, 2H, CH2), 6.84 (d, IH J=7.33 Hz, ArH), 7.53 (m, 5H, ArH), 7.89 (m, IH, ArH), 8.01 (m, 3H, ArH), 8.24 (m, 3H, ArH)
Step 2: Methyl 4-[2-carboxy-3-(naphthalene-l-yloxy)-propenyl] benzoate
Methyl 4- [2-fer?-butoxycarbonyl-3 -(naphthalene- 1 -yloxy)-propenyl] benzoate (372 mg 0.89 mM) was dissolved in dichloromethane (12 ml), to which trifluoroacetic acid (0.90 mi 1.00 mM) was slowly added dropwise, followed by reacting at room temperature for 6 hours. After completing the reaction, the solvent was removed under a reduced pressure at room temperature. The residue was diluted dichloromethane and concentrated again under a reduced pressure to remove residual trifluoroacetic acid to obtain the title compound as a brown solid (315 mg, 98%).
Step 3: Methyl 4-[2-hydroxymethyl-3-(naphthalene-l-yloxy)-propenyl] benzoate
Methyl 4-[2-carboxy-3-(naρhthalene-l-yloxy)-ρroρenyl] benzoate (2 g, 5.52 mM) was dissolved in tetrahydrofuran (30 mi), to which triethylamine (1.15 mi, 8.27 mM) and ethyl chloroformate (0.792 mi, 8.279 niM) were added dropwise at 0°C, followed by stirring for lhour. Sodium borohydride (1.462 mg, 38.64 mM) was added to the reaction solution, distilled water (10 mi) was slowly added thereto, followed by stirring at temperature for 2.5 hours. The reaction solution was treated with 1 N hydrochloric acid to adjust pH thereof to 2 and extracted with ethyl acetate. The resulting organic layer was washed saturated sodium bicarbonate and brine, dried over magnesium sulfate and filtered. The residue was purified by silica gel column chromatography to obtain the title compound as a white solid (1.58 mg, 82%). 1H NMR (200 MHz5 CDCl3) δ 3.89 (S5 3H, OCH3), 4.55 (S5 2H5 CH2), 4.88 (S5 2H , CH2), 6.71 (d, IH J=7.5Hz5 ArH)5 6.96 (S5 IH5 CH)5 7.28-7.54 (m, 6H5 ArH), 7.83 (m, IH, ArH)5 8.03 (d, 2H J=8.1 Hz, ArH)5 8.30 (m, IH, ArH)
Step 4A: Methyl 4-[2-hydroxymethyl-3-(naphthalene-l-yloxy)-propenyIJ benzoate
Methyl 4-[2-hydroxymethyl-3-(naphthalene-l-yloxy)-proρenyl] benzoate (1.2 g, 3.44 mM) was dissolved in dichloromethane (11 ml) and manganese dioxide (4.5 g, 51.67 mM) was added thereto, followed by refluxing for 3 hours. The mixture was filtered and the solvent was removed under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound as a white solid (526 mg, 44%).
1H NMR (200 MHz, CDCl3) δ 3.90 (S, 3H, OCH3), 5.04 (S5 2H , CH2), 6.91 (d, IH J=7.5 Hz, ArH), 7.28 (m, 4H, ArH)5 7.72 (m, 4H, ArH), 8.04 (d, 2H J=8.1 Hz, ArH)5 8.15 (S, IH, CH), 9.78 (s, IH5 COH) MS (EI, 7OeV) m/z 346 (M+), 203, 159, 144, 131, 115, 91, 77, 59, 40
Step 4B: Methyl 4-[2-bromomethyl-3-(naphthalene-l-yloxy)-propenyl] benzoate
Methyl 4-[2-hydroxymethyl-3-(naphthalene- 1 -yloxy)-propenyl] benzoate (1.57 g, 4.52 mM) was dissolved in dichloromethane (15 mi), and triphenylphosphine (1.78 g, 6.79 mM) was added thereto. The mixture was cooled to 0°C to which tetrabromomethane (2.25 g, 6.79 mM) was added, followed by stirring for 6 hours. The solvent was removed under a reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound as a white solid (1.36 g, 73 %).
1H NMR (200 MHz5 CDCl3) δ 3.91 (S, 3H, OCH3), 4.42 (S, 2H, CH2), 4.98 (S, 2H, CH2), 6.71 (d, IH J=7.5 Hz, ArH)5 7.05 (S5 IH, CH), 7.27-7.56 (m, 6H, ArH), 7.83 (m, IH, ArH), 8.03 (d, 2H J=8.1 Hz5 ArH), 8.30 (m, IH, ArH) Step 5A: Methyl 4-[2-(quinoline-3-ylammomethyl)-3-(naphthalene-l- yloxy)-propenyl] benzoate
Methyl 4-[2-bromomethyl-3-(naphthalene- 1 -yloxy)-ρropenyl] benzoate (200 mg 0.58 mM) and 3-aminoquinoline (92 mg 0.64 mM) were dissolved in tetrahydrofuran (2 M), to which dibutyldichlorotin (3.5 ing 0.01 mM) and diphenylsilane (128 mg, 0.70 mM) were added, followed by stirring for 18 hours. After completing the reaction, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound as a white solid (150 mg, 55%).
1H NMR (200 MHz, CDCl3) δ 3.90 (S5 3H, OCH3), 4.19 (d 2H J=LO Hz, CH2), 4.85 (S, 2H, CH2), 6.95 (S, IH, CH), 7.16 (m, IH5 ArH), 7.20 (m, IH, ArH), 7.21-7.60 (m, 1OH, ArH), 7.75-7.95 (m, 5H, ArH), 8.27 (m, IH, ArH)
Step 5B: Methyl 4-[2-(quinoline-3-yIaminomethyl)-3-(naphthalene-l- yloxy)-propenyl] benzoate Methyl 4- [2-bromomethy 1-3 -(naphthalene- l-yloxy)-propenyl] benzoate (300 mg 0.72 mM) was dissolved in acetone (8 M), to which potassium carbonate (150 mg 1.08 mM) and 3-aminoquinoline (57 mg 0.61 mM) were added thereto, followed by allowing the mixture to reflux for 3 hours. After completing the reaction, the resulting mixture was cooled to room temperature, filtered and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound as a white solid (158 mg, 32%).
1H NMR (200 MHz, CDCl3) δ 3.90 (S5 3H, OCH3), 4.19 (d 2H J=LO Hz, CH2), 4.85 (S5 2H5 CH2), 6.95 (S, IH5 CH), 7.16 (m, IH, ArH), 7.20 (m, IH5 ArH)5 7.21-7.60 (m, 1OH, ArH), 7.75-7.95 (m, 5H5 ArH)5 8.27 (m, IH, ArH)
Step 6: 4-[2-(Quinoline-3-ylaminomethyl)-3-(naphthalene-l-yloxy)- p ropenyl] benzoic acid
Methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(naρhthalene- 1 -yloxy)- propenyl] benzoate (156 mg, 0.316 mM) was dissolved in tetrahydrofuran (3 ml), and lithium hydroxide (133 mg, 3.16 mM) was added thereto. After adding distilled water (3 mi) thereto, the mixture was stirred at room temperature for 10 minutes and stirred at 50 °C for 3 hours.' After completing the reaction, the resulting mixture was cooled to room temperature and ice water was added thereto. The solvent was removed under a reduced pressure, and the resulting residue was cooled to 5 °C and acidified (pH 2) with 2 N HCl, followed by filtering and dring in the oven to obtain the title compound as a yellow solid (146 mg, 99%).
Step 7: 4-[2-(Quinoline-3-ylammomethyl)-3-(naphthalene-l-yloxy)- propenyl]-N-hydroxy-benzamide 4-[2-(Quinoline-3-ylaminomethyl)-3-(naphthalene- 1 -yloxy)- propenyl]benzoic acid (140 mg, 0.30 mM) was dissolved in dimethylformimide (3 mi), cooled to 0°C and triethylamine (64 μi, 0.456 mM) and N-methansulfonyloxy-6-trifluoro benzotriazole (103 mg, 0.365 mM) were added thereto, followed by stirring for 30 minutes, tert- Butyldimethylsilyloxyamine (67 mg , 0.45 mM) was added to the reaction solution and stirred at room temperature for 3 hours. After completing the reaction, the resulting mixture was cooled and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (54 mg, 31 %).
1H NMR (200 MHz, CDCl3) δ 4.38 (d 2H J=4.8Hz, CH2), 5.00 (S, 2H , CH2), 6.25 (m, IH, NH), 6.87 (d, IH J=7.4Hz, ArH), 7.10 (S, IH, CH), 7.16 (m, IH, ArH), 7.20 (m, IH5 ArH), 7.21-7.60 (m, 1OH, ArH), 7.75-7.95 (m, 5H, ArH), 8.27 (m, IH, NH), 8.60 (m, IH, OH)
Example 40: 4-[2-(QuinoIine-3-ylaminomethyl)-3-(4-cyano-phenoxy)- propenyl]-N-hydroxy benzamide
Step 1: Methyl 4-[2-tør£-butoxycarbonyl-3-(4-cyano-phenoxy)-propenyl] benzoate
The procedure of Step 1 of Example 39 was repeated except for using 4-cyano-phenol as the starting material to obtain the title compound.
1H NMR (200 MHz5 CDCl3), σ 1.54 (S5 9H5 3CH3), 3.92 (S, 3H, OCH3), 4.83 '• * (S, 2H5 CH2), 7.00 (d, 2H J=8.9Hz5 ArH), 7.49 (d, 2H J=8.7Hz, ArH)5 7.61 (d5 2H J=8.9Hz, ArH)5 8.05 (d, 2H J=8.7Hz, ArH)
Step 2: Methyl 4-[2-carboxy-3-(4-cyano-phenoxy)-propenyl] benzoate The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-fer^-butoxycarbonyl-3-(4-cyano-phenoxy)-propenyl] benzoate to obtain the title compound.
Step 3: Methyl 4-[2-hydromethyl-3-(4-cyano-phenoxy)-propenyl] benzoate
The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(4-cyano-ρhenoxy)-propenyl] benzoate to obtain the title compound.
1H NMR (200 MHz5 CDCl3), σ 3.89 (S5 3H, OCH3), 4.40 (S5 2H, CH2), 4.72 (S5 2H, CH2), 6.89 (S, IH, CH)5 6.91 (d, 2H J=9.0 Hz, ArH), 7.28 (d, 2H J=8.1 Hz, ArH), 7.53 (d, 2H J=9.0Hz5 AiH)5 7.98 (d, 2H J=8.1 Hz5 ArH)
Step 4: Methyl 4-[2-bromo-3-(4-cyano-phenoxy)-propenyl] benzoate The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydromethyl-3-(4-cyano-phenoxy)-propenyl] benzoate to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 3.91 (S5 3H5 OCH3), 4.29 (S5 2H5 CH2), 4.81 (S, 2H5 CH2), 6.89 (d, 2H J=9.0 Hz, ArH), 7.02 (S, IH5 CH)5 7.29 (d, 2H J=8.1 Hz, ArH), 7.56(d, 2H J=9.0 Hz, ArH)5 8.00 (d5 2H J=8.1 Hz5 ArH)
Step 5: Methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(4-cyano-phenoxy)- propenyl] benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromo-3-(4-cyano-phenoxy)-ρropenyl] benzoate to obtain the title compound (34%).
1H NMR (300 MHz, CDCl3) δ 3.91 (s, 3H, OCH3), 4.20 (d~ J=5.0 Hz, 2H5 NCH2), 4.48 (t, J=5.7 Hz, IH, NH), 4.76 (s, 2H, OCH2), 6.90 (d, J=7.2 Hz, 2H, ArH), 7.00 (s, IH, CH), 7.06 (d, J=2.7 Hz, IH, ArH), 7.26 (m, 3H, ArH), 7.43 (m, 2H, ArH), 7.56 (m, 3H, ArH), 7.97 (m, IH, ArH), 8.00 (d, J=7.2 Hz, 2H, ArH)5 8.50 (d, J=2.7 Hz, IH, ArH)
Step 6: 4-{2-(Quiϊioϊine-3-yϊammomethyI)-3-(4-cyano-phenoxy)- propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(4-cyano-phenoxy)-propenyl] benzoate to obtain the title compound (88%).
Step 7: 4-[2-(QuinoIine-3-ylaminomethyl)-3-(4-cyano-phenoxy)- propenyl]-N-hydroxy benzamide The procedure of Step 7 of Example 39 was repeated except for using
4-[2-(quinoline-3-ylaminomethyl)-3-(4-cyano-phenoxy)-propenyl]-benzoic acid to obtain the title compound (70%).
Example 41: 4-[2-(Quinoline-3-ylaminomethyl)-3-(3,5-dimethoxy- phenoxy)-propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-ter/"-butoxycarbonyl-3-(3,5-dimethoxy-phenoxy)- propenyl] benzoate
The procedure of Step 1 of Example 39 was repeated except for using 3,5-dimethoxy-phenol) as the starting material to obtain the title compound.
1H NMR (200 MHz5 CDCl3), σ 1.55 (S5 9H5 3CH3), 3.77 (S, 6H, 2OCH3), 3.92 (S, 3H, OCH3), 4.74 (S5 2H5 CH2), 6.14 (S, 3H, CH), 7.53 (d, 2H J=8.1Hz, ArH), 7.93 (S, IH5 CH), 8.04 (d, 2H J=8.1Hz, ArH) Step 2: Methyl 4-[2-carboxy-3-(3,5-dimethoxy-phenoxy)-propenyl] benzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-ter/-butoxycarbonyl-3-(3,5-dimethoxy-phenoxy)-propenyl] benzoate to obtain the title compound.
Step 3: Methyl 4-[2-hydroxymethyl-3-(3,5-dimethoxy-phenoxy)- propenyl] benzoate The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(3,5-dimethoxy-phenoxy)-propenyl] benzoate to obtain the title compound.
1H NMR (200 MHz5 CDCl3), σ 3.73 (S, 6H, 2OCH3), 3.91 (S, 3H, OCH3), 4.41 (S, 2H, CH2), 4.67 (S, 2H5 CH2), 6.06 (m, 3H, CH)5 6.88 (S, IH5 CH)5 7.32 (d, 2H J=8.1Hz, ArH), 8.00 (d, 2H J=8.1Hz, ArH)
Step 4: Methyl 4-[2-bromomethyI-3-(3,5-dimethoxy-phenoxy)-propenyI] benzoate
The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(3,5-dimethoxy-phenoxy)-propenyl] benzoate to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 3.73 (S, 6H, 2OCH3), 3.91 (S, 3H, OCH3), 4.30 (S, 2H, CH2), 4.74 (S, 2H, CH2), 6.06 (m, 3H, CH)5 6.97 (S, IH, CH), 7.32 (d, 2H J=8.1Hz5 ArH), 8.01 (d, 2H J=8.1Hz, ArH)
Step 5: Methyl 4-[2-(quinoline-3-yIaminomethyl)-3-(3,5-dimethoxy- phenoxy)-propenyl] benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(3,5-dimethoxy-phenoxy)-propenyl] benzoate to obtain the title compound (34%).
1H NMR (300 MHz, CDCl3) δ 3.66 (s5 6H5 OCH3), 3.83 (s5 3H, OCH3), 4.13 (s, 2H5 OCH2), 4.38 (s, IH5 NH)5 4.63 (s, 2H5 NCH2), 5.98 (s, 2H5 ArH), 6.05 (s, IH5 ArH)5 6.86 (s, IH5 CH)5 7.00 (s, IH, ArH)5 7.21 (m, 2H5 ArH), 7.35 (m, 2H, ArH), 7.50 (m5 IH5 ArH)5 7.88 (m, IH, ArH)5 7.97 (d, J=16.2 Hz, 2H, ArH)5 8.43 (d, J=2.7 Hz, IH5 ArH)
Step 6: 4-[2-(Quinoline-3-yIaminomethyl)-3-(3,5-dimethoxy-phenoxy)- propenylj-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinolme-3-ylaminomethyl)-3-(355-dimethoxy-phenoxy)- propenyl] benzoate to obtain the title compound (91 %).
Step 7: 4-[2-(Qinnoline-3-ylaminomethyI)-3~(3,5-diniethoxy-phenoxy)- propenyl]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-(3,5-dimethoxy-phenoxy)-piOpenyl]- benzoic acid to obtain the title compound (39%).
Example 42: 4-[2-(QuinoIine-3-ylaminomethyl)-3-(4-benzyloxy-phenoxy)- propenyl]-N-hydroxybenzamide Step 1: Methyl 4-[2-te/</-bιitoxycarbonyl-3-(4-benzyloxy-phenoxy)- propenyl] benzoate
The procedure of Step 1 of Example 39 was repeated except for using 4-benzyloxy-phenol as the starting material to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 1.54 (S5 9H5 3CH3), 3.93 (S, 3H, OCH3), 4.74 (S5 2H, CH2), 5.04 (S5 2H, CH2), 6.91 (m, 5H5 ArH), 7.36 (m, 4H5 ArH)5 7.56 (d, 2H J=8.5Hz, ArH), 8.02 (S, IH5 CH)5 8.04 (d, 2H J=8.5Hz, ArH)
Step 2: Methyl 4-[2-carboxy-3-(4-benzyloxy-phenoxy)-propenyl] benzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-ter/-butoxycarbonyl-3-(4-benzyloxy-phenoxy)-propenyl] benzoate to obtain the title compound. Step 3: Methyl 4-[2-hydroxymethyl-3-(4-benzyloxy-phenoxy)-propenyl] benzoate
The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(4-benzyloxy-phenoxy)-piOpenyl] benzaote to obtain the title compound. ^
1H NMR (200 MHz, CDCl3), σ 3.91 (S5 3H, OCH3), 4.43 (S, 2H, CH2), 4.65 (S, 2H, CH2), 5.00 (S5 2H, CH2), 6.84 (m, 5H5 ArH)5 7.37 (m, 7H, ArH), 8.00 (d, 2H J=8.5Hz, ArH)
Step 4: Methyl 4-[2-bromomethyϊ-3-(4-benzyloxy-phβnoxy)-propenyl] benzoate
The procedure of Step 4B of Example 39 was repeated except for using methyl. 4-[2-hydroxymethyl-3-(4-benzyloxy-phenoxy)-propenyl]- benzoate to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 3.92 (S5 3H, OCH3), 4.43 (S, 2H, CH2), 4.73 (S5 2H, CH2), 5.01 (S, 2H5 CH2), 6.85 (m, 5H5 ArH), 6.96 (S5 IH, CH), 7.36 (m, 7H5 ArH), 8.02 (d, 2H J=8.5Hz, ArH)
Step 5: Methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(4-benzyIoxy- phenoxy)-propenyl] benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(4-benzyloxy-phenoxy)-proρenyl] benzaote to obtain the title compound (40%).
Step 6: 4-[2-(Quinoline-3-ylaminomethyl)-3-(4-benzyloxy-phenoxy)- propenyl]-benzoic acid The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(4-benzyloxy-phenoxy)- propenyl] benzoate to obtain the title compound (85 %). Step7: 4-[2-(Quinoline-3-ylaminomethyl)-3-(4-benzyloxy-phenoxy)- propenyl]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-(4-beiizyloxy-phenoxy)-propenyl]- benzoic acid to obtain the title compound (39%).
Example 43: 4-[2-(QuinoIine-3-ylaminomethyl)-3-(4-flιioro-phenoxy)- propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-ϊtert-butoxycarbonyl-3-(4-fluoro-phenoxy)-propenyl] benzoate
The procedure of Step 1 of Example 39 was repeated except for using 4-fluoro-phenol as the starting material to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 1.53 (S5 9H, 3CH3), 3.92 (S, 3H, OCH3), 4.72 (S, 2H, CH2), 6.91 (in, 5H, ArH), 7.53 (d, 2H J=8.5Hz, ArH), 7.92 (S, IH, CH), 8.03 (d, 2H J=8.5Hz, ArH)
Step 2: Methyl 4-[2-carboxy-3-(4-fluoro-phenoxy)-propenyl] benzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-fert-butoxycai"bonyl-3-(4-fluoro-phenoxy)-propenyl] benzoate to obtain the title compound.
Step 3: Methyl 4-[2-hydroxymethyl-3-(4-fluoro-phenoxy)-propenyl] benzoate The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(4-fluoro-phenoxy)-ρropenyl] benzoate to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 3.91 (S, 3H, OCH3), 4.23 (S, 2H, CH2), 4.66 (S, 2H, CH2), 6.93 (m, 4H, ArH), 7.31 (d, 2H J=8.5Hz, ArH)5 7.94 (S5 IH, CH), 8.01 (d, 2H J=8.5Hz5 ArH)
Step 4: Methyl 4-[2-bromomethyl-3-(4-fluoro-phenoxy)-propenyl] benzoate
The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(4-fluoro-ρhenoxy)-ρropenyl] benzoate to obtain the title compound.
1H NMR (200 MHz5 CDCl3), σ 3.91 (S5 3H, OCH3), 4.31 (S5 2H, CH2), 4.73 (S5 2H, CH2), 6.79 (m, 2H5 ArH)5 6.95 (S5 IH, CH)5 6.97 (m, 2H, ArH)5 7.32 (d, 2H J=8.5Hz, ArH), 8.02 (d, 2H J=8.5Hz, ArH)
Step 5: Methyl 4-[2-(quinoline-3-ylaminomethyI)-3-(4-fluoro-phenoxy)- propenyl] benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(4-fluoro-phenoxy)-propenyl] benzoate to obtain the title compound (42%).
1H NMR (300 MHz, CDCl3) δ 3.90 (s, 3H, OCH3), 4.13 (s, 2H, OCH2), 4.47 (s, IH, NH), 4.68 (s, 2H, NCH2), 6.81 (m, 2H, ArH)5 6.97 (m5 3H5 ArH), 7.06 (d, J=2.7 Hz, IH, ArH), 7.29 (d, J=8.4 Hz, 2H, ArH), 7.43 (m, 2H, ArH)5 7.54 (m, IH, ArH), 7.95 (m, IH5 ArH)5 8.00 (d5 J=8.4 Hz5 2H, ArH), 8.50 (d, J=3.0 Hz5 IH5 ArH)
Step 6: 4-[2-(Quinoline-3-yIaminomethyI)-3-(4-fluoro-phenoxy)- propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(4-fluoro-phenoxy)-propenyl] benzoate to obtain the title compound (92%).
Step 7: 4-[2-(Quinoline-3-yIaminomethyl)-3-(4-fluoro-phenoxy)- propenyϊ]-N-hydroxybenzamide The procedure of Step 7 of Example 39 was repeated except for using
4-[2-(quinoline-3-ylaminomethyl)-3-(4-fluoro-phenoxy)-propenyl]-benzoic acid to obtain the title compound (39%). Example 44: 4-[2-(Quinoline-3-ylaminomethyI)-3-(4-acetyIamino- phenoxy)-propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-fert-butoxycarbonyI-3-(4-acetyIamino-phenoxy)- propenyl] benzoate The procedure of Step 1 of Example 39 was repeated except for using
4-acetylamino-phenol as the starting material to obtain the title compound.
1H NMR (200 MHz5 CDCl3), σ 1.53 (S, 9H5 3CH3), 2.30 (S5 3H5 CH3), 3.83 (S5 3H5 OCH3), 4.56 (S, 2H5 CH2), 6.72 (m, 2H, ArH), 6.81 (S, IH5 CH)5 7.27 (m, 4H5 ArH)5 7.91 (d, 2H J=8.5Hz5 ArH)
Step 2: Methyl 4-[2-carboxy-3=(4-acetylamino-phenoxy)-propenyl] benzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-/er/-butoxycarbonyl-3-(4-acetylamino-phenoxy)-propenyl] benzoate to obtain the title compound.
Step 3: Methyl 4-[2-hydroxymethyl-3-(4-acetylamino-phenoxy)- propenyl] benzoate The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(4-acetylamino-phenoxy)-propenyl] benzoate to obtain the title compound.
1H NMR (200 MHz5 CDCl3), σ 2.30 (S5 3H5 CH3), 3.83 (S5 3H, OCH3), 4.29 (S5 2H5 CH2), 4.56 (S, 2H5 CH2), 6.72 (m, 2H, ArH), 6.81 (S5 IH5 CH)5 7.27 (m, 4H5 ArH)5 7.91 (d, 2H J=8.1Hz, ArH)
Step 4: Methyl 4-[2-bromomethyl-3-(4-acetylamino-phenoxy)-propenyl] Methyl The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(4-acetylamino-phenoxy)-proρenyl] benzoate to obtain the title compound. 1H NMR (200 MHz, CDCl3), σ 2.30 (S5 3H5 CH3), 3.83 (S5 3H5 OCH3), 4.56 (S5 2H5 CH2), 6.72 (m, 2H, ArH), 6.81 (S, IH5 CH)5 7.27 (m, 4H, ArH), 7.91 (d, 2H J=8.1Hz, ArH)5 9.73 (S, IH5 CH)
Step 5: Methyl 4-[2-(quinoline-3-yIaminomethyl)-3-(4-acetylamino- phenoxy)-propenyl] benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(4-acetylamino-phenoxy)-propenyl] benzaote to obtain the title compound (10%).
Step 6: 4-[2-(Quinoline-3-ylaminomethyl)-3-(4-acetylamino-phenoxy)- propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(4-acetylamino-phenoxy)- propenyl] benzoate to obtain the title. compound (36%).
Step 7: 4-[2-(Quinoline-3-ylaminomethyl)-3-(4-acetyIamino-phenoxy)- propenyl]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-(4-acetylamino-phenoxy)-propenyl]- benzoic acid to obtain the title compound (38%).
Example 45 : 4- [2-(Quinoline-3-yIaminomethyl)-3-(4-methylsulfeiiyl- phenoxy)-propenyl]-N-hydroxybenzaniide Step 1: Methyl 4-[2-fert-butoxycarbonyl-3-(4-methylsulfenyl-phenyloxy)- propenyl] benzoate
The procedure of Step 1 of Example 39 was repeated except for using 4-methylsulfenyl-phenol as the starting material to obtain the title compound.
1H NMR (200 MHz5 CDCl3), σ 1.54 (S5 9H, 3CH3), 2.43 (S, 3H5 CH3), 3.90 (S, 3H5 OCH3), 4.68 (S5 2H5 CH2), 6.82 (d, 2H J=8.9Hz5 ArH), 7.23 (d, 2H J=9.0Hz, ArH), 7.32 (d, 2H J=8.14Hz5 ArH), 7.89 (S5 IH5CH), 8.01 (d, 2H J=7.7Hz5 ArH) Step 2: Methyl 4-[2-carboxy-3-(4-methylsuϊfenyl-phenyloxy)-propenyl] benzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-fert-butoxycarbonyl-3 -(4-methylsulfenyl-phenyloxy)-propenyl] benzoate to obtain the title compound.
Step 3: Methyl 4-[2-hydroxymethyl-3-(4-methylsulfenyl-phenyIoxy)- propenyl] benzoate The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(4-methylsulfenyl-phenyloxy)-ρropenyl] benzoate to obtain the title compound.
1H NMR (200 MHz5 CDCl3), σ 2.43 (S, 3H5 CH3), 3.90 (S5 3H5 OCH3), 4.68 (S5 2H5 CH2), 6.82 (d, 2H J=8.9Hz, ArH), 6.89 (S5 IH5CH)5 7.23 (d, 2H J=9.0Hz5 ArH)5 7.32 (d, 2H J=8.14Hz5 ArH)5 8.01 (d, 2H J=7.7Hz, ArH)
Step 4: Methyl 4-[2-bromomethyl-3-(4-methylsulfenyI-phenyloxy)- propenyl] benzoate The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(4-methylsulfenyl-ρhenyloxy)-propenyl] benzoate to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 2.45 (S5 3H5 CH3), 3.92 (S5 3H5 OCH3), 4.31 (S, 2H, CH2), 4.75 (S, 2H, CH2), 4.79 (m, 2H, ArH)5 6.98 (S, IH5CH), 7.28 (m, 2H, ArH), 8.03 (dd, 2H J=8.3, 1.5Hz, ArH)
Step 5: Methyl 4-[2-(quinoline-3-ylaminomethyI)-3-(4-methyIsulfenyI- phenoxy)-propenyl] benzoate The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(4-methylsulfenyl-ρhenyloxy)-propenyl] benzoate to obtain the title compound (47%). 1H NMR (300 MHz, CDCl3) δ 3.90 (s, 3H5 OCH3), 4.19 (d, J=5.7 Hz, 2H, NCH2), 4.52 (t, J=6.0 Hz, IH, NH), 4.70 (s, 2H, OCH2), 6.81 (d, J=8.7 Hz, 2H, ArH), 6.93 (s, IH, CH), 7.04 (d, J=2.4 Hz, IH, ArH), 7.26 (m, 5H, ArH), 7.41 (m, 2H, ArH), 7.54 (m, IH, ArH), 7.94 (m, IH, ArH), 7.99 (d, J=8.7 Hz, 2H, ArH), 8.49 (d, J=2.7 Hz, IH, ArH)
Step 6: 4-[2-(Quinoline-3-yIaminomethyl)-3-(4-methylsιilfenyl-phenoxy)- propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(4-methylsulfenyl-phenoxy)- propenyl] benzoate to obtain the title compound (73 %).
Step 7 : 4- [2-(Quinoline-3-ylaminomethyl)-3-(4-methylsulf enyl-phenoxy)- propenyl]-N-hydroxybenzamide The procedure of Step 7 of Example 39 was repeated except for using
4-[2-(quinoline-3-ylaminomethyl)-3-(4-methylsulfenyl-phenoxy)-propenyl]- benzoic acid to obtain the title compound (39%).
Example 46: 4-[2-(Quinolrae-3-yϊaminomethyϊ)-3-phenoxy-propenyl]-N- hydroxybenzamide
Step 1: Methyl 4-(2-fertf-butoxycarbonyl-3-phenoxy propenyl) benzoate
The procedure of Step 1 of Example 39 was repeated except for using (phenol) as the starting material to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 1.55 (S5 9H5 3CH3), 3.92 (S5 3H, OCH3), 4.79 (S5 2H, CH2), 6.99 (m, 3H, ArH), 7.32 (m, 3H, ArH), 7.56 (d, 2H J=8.1Hz, ArH)5 7.95 (S5 IH, CH), 8.04 (d, 2H J=7.7Hz, ArH)
Step 2: Methyl 4~(2-carboxy-3-phenoxy propenyl) benzoate The procedure of Step 2 of Example 39 was repeated except for using methyl 4-(2-ter/-butoxycarbonyl-3-phenoxy propenyl) benzoate to obtain the title compound. Step 3: Methyl 4-(2-hydroxymethyl-3-phenoxy propenyl) benzoate
The procedure of Step 3 of Example 39 was repeated except for using methyl 4-(2-carboxy-3-ρhenoxy propenyl) benzaote to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 3.90 (S, 3H, OCH3), 4.40 (S5 2H, CH2), 4.69 (S5 2H, CH2), 6.88 (m5 3H, ArH)5 7.30 (m, 5H5 ArH), 8.00 (d5 2H J=8.3Hz, ArH)
Step 4: Methyl 4-(2-bromomethyl-3-phenoxy propenyl) benzoate
The procedure of Step 4B of Example 39 was repeated except for using methyl 4-(2-hydroxymethyl-3-phenoxy propenyl) benzoate to obtain the title compound.
-v 1H NMR (200 MHz, CDCl3), σ 3.91 (S5 3H5 OCH3), 4.32 (S, 2H, CH2), 4.78 (S, 2H, CH2), 6.89 (m, 4H5 ArH)5 7.32 (m, 4H, ArH), 8.02 (d, 2H J=8.3Hz, ArH)
Step 5: Methyl 4-[2-(quinoline-3-yIaminomethyl)-3-phenoxy-propenyl] benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-(2-bromomethyl-3-phenoxy propenyl) benzoate to obtain the title compound (46%).
1H NMR (300 MHz5 CDCl3) δ 3.40 (s, 3H5 OCH3), 4.21 (d, J=3.6 Hz, 2H, NCH2), 4.52 (brs, IH, NH), 4.73 (s, 2H, OCH2), 6.88 (d5 J=7.8 Hz, 2H, ArH), 6.90 (s, IH5 CH), 6.97 (t, J=13.2Hz, IH, ArH), 7.06 (d, J=2.7 Hz, IH, ArH), 7.29 (m, 4H, ArH)5 7.41 (m, 2H, ArH), 7.55 (m, IH, ArH), 7.94 (m, IH, ArH), 7.99 (d, J=8.1 Hz, 2H, ArH), 8.50 (d, J=2.7 Hz, IH, ArH)
Step 6: 4-[2-(Quinoline-3-ylaminomethyl)-3-phenoxy-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-phenoxy-propenyl] benzoate to obtain the title compound (90%).
Step 7: 4-[2-(Quinoline-3-ylaminomethyl)-3-phenoxy-propenyl]-N- hydroxy benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-phenoxy-piOpenyl]-benzoic acid to obtain the title compound (71 %).
Example 47: 4-[2-(Quinoline-3-ylaminomethyl)-3-(4-chloro-naphthaIene- l-yIoxy)-propenyI]-N-hydroxybenzamide
Step 1: Methyl 4-[2-tertf-butoxycarbonyl-3-(4-chϊoro-naphthalene-l- yloxy)-propenyl] benzoate
The procedure of Step 1 of Example 39 was repeated except for using (4~ehloro- 1 -naphthalenol) as the starting material to obtain the title compound (2.545 g , 93%).
1H NMR (200 MHz, CDCl3), σ 1.49 (S, 9H, 3CH3), 3.89 (S, 3H, OCH3), 4.95 (S, 2H, CH2), 6.74 (m, IH, CH), 7.39-7.66 (m, 5H, ArH), 7.98 (m, 5H, ArH)5 8.23 (m, 5H, ArH)
Step 2: Methyl 4-[2-carboxy-3-(4-chloro-naphthalene-l-yloxy)-propenyl] benzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-/err-butoxycarbonyl-3-(4-chloro-naphthalene-l-yloxy)-propenyl] benzoate to obtain the title compound (1.9 g, 99%).
Step 3: Methyl 4-[2-hydroxymethyl-3-(4-chloro~naphthaIene-l-yIoxy)- propenyϊ] benzoate The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(4-chloro-naphthalene-l-yloxy)-propenyl] benzoate to obtain the title compound (886 mg, 48%). 1H NMR (200 MHz, CDCl3), σ 3.89 (S, 3H5 OCH3), 4.52 (S, 2H, CH2), 4.84 (S, 2H, CH2), 6.74 (m, IH, CH), 7.39-7.66 (m, 5H, ArH), 7.98 (m, 5H, ArH)3 8.23 (m, 5H, ArH)
Step 4: Methyl 4-[2-bromomethyl-3-(4-chloro-naphthaIene-l-yloxy)- propenyl] benzoate
The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(4-chloro-naphthalene- 1 -yloxy)- propenyl] benzoate to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 3.90 (S, 3H, OCH3), 4.38 (S5 2H, CH2), 4.95 (S, 2H5 CH2), 6.74 (m, IH, CH), 7.39-7.66 (m, 5H5 ArH), 7.98 (m, 5H, ArH), 8.23 (m, 5H5 ArH)
Step » -. 5: _ Methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(4-chloro- naphthalene-l-yloxy)-propenyl] benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4- [2-bromomethyl-3 -(4-chloro-naphthalene- 1 -y loxy)-propeny 1] benzoate to obtain the title compound (13 %).
1H NMR (200 MHz, CDCl3), σ 3.89 (S, 3H, OCH3), 4.30 (d, 2H J=4.68Hz, CH2), 4.89 (S5 2H, CH2), 6.58 (d, IH J=8.4Hz, ArH), 7.04 (d, IH J=8.2Hz, ArH), 7.30-7.66 (m, 8H, ArH), 7.95 (m, 3H, ArH)5 8.28 (dd, 2H J=I 6.7 7.3Hz, ArH), 8.49 (m, IH J=8.1Hz, ArH)
Step 6: 4-[2-(Quinoline-3-ylaminomethyl)-3-(4-chloro-naphthalene-l- yloxy)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(4-chloro-naphthalene-l-yloxy)- propenyl] benzoate to obtain the title compound (50 % ).
Step 7: 4-[2-(QuinoIine-3-ylaminomethyl)-3-(4-chloro-naphthalene-l- yloxy)-propenyl]-N-hydroxybenzamide The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(quinoline-3 -ylaminomethyl)-3-(4-chloro-naphthalene- 1 -yloxy)- propenyl]-benzoic acid to obtain the title compound (16%).
1H NMR (200 MHz5 CDCl3), σ 4.35 (S5 2H5 CH2), 5.00 (S5 2H, CH2), 6.85 (d, IH J=8.5Hz, ArH)5 7; 10 (S5 IH5 CH), 7.20 (m, IH, ArH)5 7.33-7.83 (m5 HH, ArH)5 8.16 (d, IH J=8.5Hz5 ArH), 8.29 (m5 IH J=8.2Hz5 ArH), 8.54 (m, IH5 ArH)
Example 48: 4-[2-(3,4-Dimethoxyphenylaminomethyl)-3-(4-chloro- naphthalene-l-yloxy)-propenyl]-N-hydroxybenzamide Step 1: Methyl 4-[2-(3,4-dimethoxyphenylamii.omethyl)-3-(4-chIoro- naphthalene-l-yloxy)-propenyl] benzoate
The procedure of Step 5 of Example 39 was repeated except for using (4-chloro-l-naphthalenol) as the starting material to obtain the title .compound (36%).
1H NMR (200 MHz5 CDCl3), σ 3.75 (S5 3H, OCH3), 3.80 (S, 3H, OCH3), 3.89 (S, 3H5 OCH3), 4.14 (d, 2H J=I .2Hz5 CH2), 4.84 (S5 2H5 CH2), 6.24 (m, 3H5 ArH), 6.58 (d, IH J=8.1Hz, ArH)5 6.74 (d, IH J=8.5Hz, ArH), 6.98 (S5 IH5 CH)5 7.37 (m, IH5 ArH), 7.54-7.64 (m, 3H5 ArH)5 7.98 (d, 2H J=8.3Hz5 ArH)5 8.20-8.32 (m, 2H, ArH)
Step 2: 4-[2-(3,4-Dimethoxyphenylaminomethyl)-3-(4-chloro- naphthalene-l-yloxy)-propenyl]benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(354-dimethoxyphenylaminomethyl)-3-(4-chloro-naρhthalene-l- yloxy)-ρropenyl] benzoate to obtain the title compound (94%).
Step 3: 4-[2-(3,4-Dimethoxyphenylaminomethyϊ)-3-(4-chloro- naphthalene-l-yloxy)-propenyl]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(3,4-dimethoxyphenylaminomethyl)-3-(4-chloro-naρhthalene-l-yloxy)- propenyl]benzoic acid to obtain the title compound (74%).
1H NMR (200 MHz5 CDCl3), σ 3.66 (S5 3H5 OCH3), 3.67 (S, 3H, OCH3), 4.17 (S, 2H5 CH2), 4.94 (S, 2H5 CH2), 6.24 (m, 3H5 ArH)5 6.58 (d, IH J=8.1Hz5 ArH)5 6.74 (d, IH J=8.5Hz, ArH), 6.98 (S, IH5 CH)5 7.37 (m, IH5 ArH)5 7.54-7.64 (m, 3H5 ArH), 7.98 (d, 2H J=8.3Hz, ArH), 8.20-8.32 (m, 2H5 ArH)
Example 49: 4-[2-(Quinoline-3-ylaminomethyl)-3-(3-methoxy- phenylsulfenyl)-propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-te/'/-butoxycarbonyl-3-(3-methoxy-phenylsulfenyI)- prβpenyl] benzoate
The procedure of Step 1 of Example 39 was repeated except for using 3-methoxy-phenylsulfen as the starting material to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 1.54 (S, 9H, 3CH3), 2.43 (S5 3H, CH3), 3.90 (S5 3H5 OCH3), 4.68 (S, 2H, CH2), 6.82 (d, 2H J=8.9Hz, ArH)5 7.23 (d5 2H J=9.0Hz5 ArH)5 7.32 (d, 2H J=8.14Hz, ArH)5 7.89 (S, IH5CH)5 8.01 (d, 2H J=7.7Hz, ArH)
Step 2: Methyl 4-[2-carboxy-3-(3-methoxy-phenylsulfenyl)-propenyl] benzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-/e7'/-butoxycarbonyl-3-(3-methoxy-phenylsulfenyl)-propenyl] benzoate to obtain the title compound.
Step 3: Methyl 4-[2-hydroxymethyl-3-(3-methoxy-phenylsulfenyl)- propenyl] benzoate
The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(3-methoxy-ρhenylsulfenyl)-propenyl] benzoate to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 3.71 (S, 3H5 CH3), 3.80 (S, 2H, CH2), 3.90 (S, 3H, OCH3), 4.38 (S5 2H3 CH2), 6.82 (d, 2H J=8.9Hz5 ArH)5 6.89 (S5 IH5 CH)5 7.23 (d5 2H J=9.0Hz, ArH), 7.32 (d, 2H J=8.14Hz, ArH)5 8.01 (d, 2H J=7.7Hz, ArH)
Step 4: Methyl 4-[2-bromomethyl-3-(3-methoxy-phenylsulfenyl)- propenyl] benzoate
The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(3-methoxy-phenylsulfenyl)-propenyl] benzoate to obtain the title compound (890 ing, 74 %).
1HNMR (200 MHz5 CDCl3), σ 3.71 (S5 3H, CH3), 3.80 (S, 2H, CH2), 3.90 (S, 3H, OCH3), 4.38 (S, 2H, CH2), 6.82 (d5 2H J=8.9Hz, ArH), 6.89 (S, IH5CH), 7.23 (d, 2H J=9.0Hz, ArH), 7.32 (d, 2H J=8.14Hz, ArH), 8.01 (d, 2H J=7.7Hz, ArH)
Step 5: Methyl 4-[2-(quinoline-3-ylaminomethyI)-3-(3-methoxy- phenylsulfenyl)-propenyl] benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(3-methoxy-ρhenylsulfenyl)-propenyl] benzoate to obtain the title compound (24 % ).
1H NMR (200 MHz, CDCl3), σ 3.70 (S5 3H, CH3), 3.83 (S, 2H, CH2), 3.91 (S, 3H, OCH3), 4.18 (d, 2H J=5.1Hz, CH2), 4.37 (m, IH5 NH), 6.71-6.89 (m, 4H, CH, ArH), 7.07-7.39 (m, 4H, ArH)5 7.44 (m, 2H, ArH), 7.60 (m, IH5 ArH), 7.95 (m, 3H5 ArH), 8.49 (m, IH5 ArH)
Step 6: 4-[2-(Quinoline-3-yIaminomethyl)-3-(3-methoxy-phenyIsulfenyl)- propenyl]benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(3-methoxy-phenylsulfenyl)- propenyl] benzoate to obtain the title compound (94%).
Step 7: 4- [2-(Quinoline-3-ylaminomethyl)-3-(3-methoxy-phenylsulfenyI)- propenyl)~N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-(3-methoxy-phenylsulfenyl)- propenyl]benzoic acid to obtain the title compound (10%).
1H NMR (200 MHz5 CDCl3), σ 3.70 (S, 3H5 CH3), 3.83 (S, 2H5 CH2), 4.18 (d, 2H J=5.1Hz5 CH2), 4.37 (m, IH5 NH)5 6.71-6.89 (m, 4H5 CH5 ArH)5 7.07-7.39 (m, 4H5 ArH)5 7.44 (m, 2H5 ArH)5 7.60 (m5 IH5 ArH)5 7.95 (m, 3H5 ArH)5 8.49 (m5 IH5 ArH)
Example 50: 4-[2-(Quinolme-3-ylaminomethyl)-3-(3-methoxy- phenylsulfenyI)-propenyϊ]-N-hydrβxybenzamide
Step 1: Methyl 4-[2-fer/-butoxycarbonyl-3-(3-methoxy-2-phenylsulfenyl)- propenyl] benzoate The procedure of Step 1 of Example 39 was repeated except for using
3-methoxy-2-phenylsulfen as the starting material to obtain the title compound (2.55 g5 97%).
1HNMR (200 MHz5 CDCl3), σ 1.53 (S5 9H5 3CH3), 3.91 (S5 3H5 OCH3), 4.05 (S5 2H5 CH2), 7.30-7.48 (m, 5H5 ArH)5 7.62-7.76 (m5 5H, ArH), 8.89 (d, 2H J=8. IHz5 ArH)
Step 2: Methyl 4-[2-carboxy-3-(3-methoxy-2-phenylsulfenyl)-propenyl] benzoate The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-fer/-butoxycarbonyl-3-(3-methoxy-2-phenylsulfenyl)-propenyl] benzoate to obtain the title compound (2.573 g, 99%).
Step 3: Methyl 4-[2-hydroxymethyl-3-(3-methoxy-2-phenylsulfenyl)- propenyl] benzoate
The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(3-niethoxy-2-phenylsulfenyl)-propenyl] benzoate to obtain the title compound (1.896 mg, 76 %). 1H NMR (200 MHz, CDCl3), σ 3.91 (S, 3H, OCH3), 3.93 (S, 2H, CH2), 4.43 (S, 2H, CH2), 6.71 (S, IH, CH), 7.14-7.60 (m, 7H, ArH), 7.65-7.96 (m, 5H, ArH)
Step 4: Methyl 4-[2-bromomethyl-3-(3-methoxy-2-phenylsulfenyl)- propenyl] benzoate
The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(3-methoxy-2-phenylsulfenyl)-propenyl] benzoate to obtain the title compound (76 % ).
1H NMR (200 MHz, CDCl3), σ 3.91 (S, 3H, OCH3), 3.93 (S, 2H, CH2), 4.43 (S, 2H, CH2), 6.71 (S, IH, CH), 7.14-7.60 (m, 7H, ArH), 7.65-7.96 (m, 5H, ArH)
Step 5: Methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(3-methoxy-2- phenylsulfenyl)-propenyl] benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(3-methoxy-2-phenylsulfenyl)-propenyl] benzoate to obtain the title compound (28%).
1H NMR (200 MHz, CDCl3), σ 3.91 (S, 3H, OCH3), 3.94 (S, 2H, CH2), 4.21 (d, 2H J=6.5Hz, CH2), 4.37 (m, IH, NH), 6.76 (S, IH, CH), 7.03 (m, IH, ArH), 7.22-7.49 (m, 8H, ArH), 7.58-7.80 (m, 5H, ArH), 7.93 (d, 2H J=8.6Hz. ArH), 8.47 (d, IH J=2.9Hz. ArH)
Step 6: 4-[2-(Quinoline-3-ylaminomethyI)-3-(3-methoxy-2- phenylsulfenyl)-propenyl] benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(3-methoxy-2-phenylsulfenyl)- propenyl] benzoate to obtain the title compound (80 % ).
Step 7: 4- [2-(Quinoline-3-ylaminomethyl)-3-(3-methoxy-phenylsulfenyl)- propenyl]-N-hydroxybenzamide The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-(3-methoxy-2-phenylsulfenyl)-propenyl] benzoic acid to obtain the title compound (48%).
1H NMR (200 MHz5 CDCl3), σ 3.94 (S, 2H, CH2), 4.21 (d, 2H J=6.5Hz, CH2), 4.37 (m, IH5 NH)5 6.76 (S, IH, CH), 7.03 (m, IH, ArH), 7.22-7.49 (m, 8H5 ArH), 7.58-7.80 (m, 5H, ArH), 7.93 (d, 2H J=8.6Hz. ArH), 8.47 (d, IH J=2.9Hz. ArH)
Example 51: 4-[2-(Quinoline-3-ylammomethyl)-3-(2-nitro-naphthalene-l- yloxy)-propenyI]-N-hydroxybenzamide
Step 1: Methyl 4-[2-te^-bwtoxycarbonyI-3-(2-nitro»naphthalene-l-yϊoxy)- propenyl] benzoate
The procedure of Step 1 of Example 39 was repeated except for using 2-nitro-l -naphthalenol as the starting material to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 1.13 (S, 9H5 3CH3), 3.95 (S, 3H, OCH3), 5.07 (S, 2H, CH2), 7.51-7.71 (m5 5H, ArH), 7.89 (t, 3H J=9.2Hz, ArH), 8.00 (S, IH, CH), 8.12 (d, 2H J=8.1Hz, ArH), 8.31 (d, 2H J=8.4Hz, ArH)
Step 2: Methyl 4-[2-carboxy-3-(2-nitro-naphthalene-l-yloxy)-propenyl] benzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-ter^-butoxycarbonyl-3-(2-nitro-naphthalene- 1 -yloxy)-propenyl] benzoate to obtain the title compound.
Step 3: Methyl 4-[2-hydroxymethyl-3-(2-nitro-naphthalene-l-yloxy)- propenyl] benzoate
The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(2-nitro-naρhthalene-l-yloxy)-propenyl] benzoate to obtain the title compound (536 mg, 57%).
1H NMR (200 MHz, CDCl3), σ 3.90 (S, 3H, OCH3), 4.51 (S, 2H, CH2), 5.03 (S, 2H, CH2), 7.03 (S5 IH, CH), 7.27 (d, 2H J=8.1Hz, ArH), 7.59 (m, 3H, ArH), 7.84 (t, 2H, ArH), 7.96 (d, 2H J=8.1Hz, ArH), 8.14 (d, 2H J=8.1Hz, ArH)
Step 4: Methyl 4-[2-bromomethyl-3-(2-nitro-naphthalene-l-yloxy)- propenyl] benzoate
The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(2-nitro-naphthalene- 1 -yloxy)-propenyl] benzoate to obtain the title compound (408 mg, 70 %).
1H NMR (200 MHz, CDCl3), σ 3.90 (S, 3H, OCH3), 4.51 (S, 2H, CH2), 5.03 (S, 2H, CH2), 6.93 (m, 4H, ArH), 7.03 (S, IH, CH), 7.27 (d, 2H J=8.1Hz, ArH), 7.59 (m, 3H, ArH), 784 (m, 2H, ArH), 7.96 (d, 2H J=8.5Hz, ArH), 8.23 (d, 2H J=8.5Hz, ArH) . . .
Step 5: Methyl 4-[2-(quinoIine-3-ylaminomethyl)-3-(2-nitro-naphthalene- l-yloxy)-propenyl] benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(2-nitro-naphthalene- 1 -yloxy)-propenyl] benzoate to obtain the title compound (206 mg, 47 %).
Step 6: 4-[2-(Quinoline-3-ylaminomethyl)-3-(2-nitro-naphthaIene-l- yloxy)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-3-ylaminomethyl)-3-(2-nitro-naphthalene-l-yloxy)- propenyl] benzoate to obtain the title compound (89%).
Step 7: 4-[2-(Quinoline-3-yIaminomethyl)-3-(2-nitro-naphthalene-l- yloxy)-propenyl]~N-hydroxybenzamide The procedure of Step 7 of Example 39 was repeated except for using
4-[2-(quinoline-3-ylaminomethyl)-3-(2-nitro-naphthalene-l-yloxy)- propenyl]-benzoic acid to obtain the title compound (24%). Example 52: 4-[2-(3,4-DimethoxyphenylaminomethyI)-3-(9H-carbazoϊ-l- yloxy)-propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-ter^butoxycarbonyl-3-(9H-carbazol-l-yloxy)- propenyl] benzoate The procedure of Step 1 of Example 39 was repeated except for using
9H-carbazol-l-ylol as the starting material to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 1.53 (S5 9H5 3CH3), 3.90 (S5 3H5 CH2), 4.86 (S5 2H5 CH2), 6.90 (d, IH J=8.5Hz5 ArH)5 6.95 (d, IH J=I LSHz5 ArH), 7.29 (m, 2H, ArH), 7.35 (m, 3H, ArH)5 7.57 (d, IH J=8.3Hz5- ArH), 7.98 (m, IH, ArH)
Step 2: Methyl 4-[2-carboxy-3-(9H-carbazol-l-yloxy)-propenyl] benzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-/er/-butoxycarbonyl-3-(9H-carbazol-l-yloxy)-ρropenyl]- benzoate to obtain the title compound (99%).
Step 3: Methyl 4-[2-hydroxymethyl-3-(9H-carbazol-l-yloxy)-propenyl] benzoate The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(9H-carbazol-l-yloxy)-propenyl] benzoate to obtain the title compound (28%).
1H NMR (200 MHz, CDCl3), σ 3.88 (S5 3H5 OCH3), 4.59 (S5 2H5 CH2), 4.94 (S5 2H5 CH2), 7.97 (m, 2H5 ArH)5 7.17-7.41 (m, 5H5 ArH), 7.97 (m, 2H, ArH), 8.12 (S, IH, CH)
Step 4: Methyl 4-[2-bromomethyl-3-(9H-carbazol-l-yloxy)-propenyl] benzoate The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(9H-carbazol-l-yloxy)-ρroρenyl] benzoate to obtain the title compound (57%). 1H NMR (200 MHz, CDCl3), σ 3.91 (S, 3H5 OCH3), 4.36 (S, 2H, CH2), 4.87 (S, 2H, CH2), 6.83 (m, 3H, ArH), 6.99 (S, IH5 CH), 7.35 (m, 5H, ArH), 8.03 (m, 3H5 ArH)
Step 5: Methyl 4-[2-(3,4-dimethoxyphenyIaminomethyl)-3-(9H-carbazol- l-yloxy)~propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(9H-carbazol-l -yloxy)-propenyl]-berizoate to obtain the title compound (77%).
1H NMR (200 MHz, CDCl3), σ 3.78 (S, 6H, 2OCH3), 3.91 (S, 3H, OCH3), 4.24 (S, 2H, CH2), 4.51 (S5 2H, CH2), 6.16-6.31 (m, 2H5 ArH), 6.55-6.70 (m, 2H, ArH), 6.99 (S, IH, CH), 7.10-7.39 (m, 5H, ArH), 7.99 (d, 2H J=8.1Hz, ArH)
Step 6: 4-[2-(3,4-Dimethoxyphenylaminomethyl)-3-(9H-carbazol-l- yloxy)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(3 ,4-dimethoxyphenylaminomethyl)-3-(9H-carbazol- 1 -yloxy)- propenyl]-benzoate to obtain the title compound (96 % ) .
Step 7: 4-[2-(3,4-Dimethoxyphenylaminomethyl)-3-(9H-carbazol-l- yloxy)-propenyI]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(354-dimethoxyphenylaminomethyl)-3-(9H-carbazol- 1 -yloxy)- propenyl]-benzoic acid to obtain the title compound (40 %).
1H NMR (200 MHz, CDCl3), σ 3.78 (S, 6H5 2OCH3), 4.24 (S5 2H5 CH2), 4.51 (S5 2H5 CH2), 6.16-6.31 (m, 2H, ArH), 6.55-6.70 (m, 2H, ArH)5 6.99 (S, IH, CH), 7.10-7.39 (m, 5H5 ArH), 7.99 (d, 2H J=8.1Hz, ArH)
Example 53: 4-[2-(Quinoline-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl]-N-hydroxybenzamide Step 1: Methyl 4-[2-formyl-3-(9H-carbazol-l-yloxy)-propenyI] benzoate
The procedure of Step 4A of Example 39 was repeated except for using 9H-carbazol-l-ylol as the starting material to obtain the title compound (54%).
1H NMR (200 MHz5 CDCl3) δ 3.89 (s, 3H, OCH3), 4.90 (s, 2H5 OCH2), 6:90 (dd5 J=2.4, 8.2 Hz, IH5 ArH), 6.94 (d, J=2.4 Hz, IH, ArH), 7.22 (m, IH, ArH), 7.35 (m, IH, ArH), 7.60 (s, IH, CH), 7.70 (d, J=8.6 Hz, 2H, ArH), 7.90 (s, IH, ArH), 7.94 (d, J=3.4 Hz, IH5 ArH)5 8.06 (m, 3H, ArH), 9.71 (s, IH5 CHO)
Step 2: Methyl 4-[2-(quinoline=3-ylaminomethyl)-3-(9H-earbazβl-l- yloxy)-propenyl] benzoate
The procedure of Step 5 A of Example 39 was repeated except for using methyl 4-[2-formyl-3-(9H-carbazol-l-yloxy)-propenyl] benzoate to obtain the title compound (24%).
1H NMR (300 MHz, CDCl3) δ 3.88 (s, 3H, OCH3), 4.34 (d, J=5.4 Hz, 2H5 NCH2), 4.57 (t, J=5.4 Hz5 IH, NH), 4.98 (s, 2H, OCH2), 6.53 (d, J=8.4 Hz5 IH5 ArH)5 7.02 (s, IH, CH), 7.08 (m, 2H5 ArH), 7.24 (m, IH5 ArH), 7.41 (m, 7H5 ArH)5 7.90 (m, IH5 ArH)5 7.98 (d, J=8.4 Hz5 2H5 ArH), 8.25 (s, IH5 ArH), 8.36 (d5 J=7.8 Hz5 IH5 ArH)5 8.42 (d, J=3.0 Hz5 IH, ArH)
Step 3: 4-[2-(Quinoline-3-ylaminomethyl)-3-(9H-carbazoϊ-l-yIoxy)- propenylj-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinolme-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)-propenyl] benzoate to obtain the title compound (86%).
Step 4: 4-[2-(Quinoh'ne-3-yIaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl] -N-hyd roxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)-ρiOpenyl]- benzoic acid to obtain the title compound (21 %).
Example 54: 4-[2-Hydroxymethyl-3-(9H-carbazol-l-yloxy)-propenyl]-N- hydroxybenzamide Step 1: 4-[2-Hydroxymethyl-3-(9H-carbazol-l-yloxy)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(9H-carbazol-l-yloxy)-propenyl] benzoate as the starting material to obtain the title compound (95%).
Step 2: 4-[2-Hydroxymethyl-3-(9H-carbazol-l-yloxy)-propenyl]-N- hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-hydroxymethyl-3-(9H-carbazol-l-yloxy)-propenyl]-benzoic acid to obtain the title compound (31 %).
Example 55: 4-[2-(Pyridine-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-(pyridine-3-yIaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl] benzoate
The procedure of Step 5 A of Example 39 was repeated except for using 3-aminopyridine as the starting material to obtain the title compound (92%).
1H NMR (300 MHz5 CDCl3) δ 3.89 (s, 3H5 OCH3), 4.11 (d, J=6.0 Hz, 2H5 NCH2), 4.57 (t, J=6.0 Hz5 IH5 NH)5 4.74 (s, 2H5 OCH2), 6.83 (m, 4H5 ArH + CH)5 7.06 (m5 IH, ArH), 7.26 (m, IH5 ArH)5 7.32 (m, 2H5 ArH)5 7.96 (m, 5H5 ArH)5 8.10 (d, J=3.0 Hz5 IH5 ArH)5 8.27 (s, IH5 ArH)
Step 2: 4-[2-(Pyridine-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl] benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(pyridine-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)-propenyl] benzoate to obtain the title compound (52%).
Step 3: 4-[2-(Pyridine-3-ylammomethyl)-3-(9H-carbazol-l-yIoxy)- propenyl]-N-hydroxy benzamide
The procedure of Step 7 of Example 39 was repeated except for using- 4-[2-(pyridine-3-ylaminomethyl)-3-(9H-carbazol- 1 -yloxy)-ρropenyl] benzoic acid to obtain the title compound (31 %).
Example 56: 4-[2-(6-Methoxypyridine-3-yIaminomethyl)-3-(9H-carbazol- l-yloxy)-propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-(6-methoxypyridine-3-ylaminomethyI)-3-(9H- carbazol-l-yloxy)-propenyl] benzoate
The procedure of Step 5 A of Example 39 was repeated except for using (6-methoxy-3-aminopyridine) as the starting material to obtain the title compound (52%).
1H NMR (300 MHz5 CDCl3) δ 3.86 (s, 3H5 OCH3), 3.92 (s, 3H5 OCH3), 4.07 (s5 2H5 NCH2), 4.14 (brs, IH, NH), 4.74 (s, 2H, OCH2), 6.61 (d, J=8.7 Hz, IH, ArH), 6.78 (m, 2H5 ArH)5 6.87 (s, IH, CH), 7.00 (m, 2H, ArH)5 7.30 (m, 4H, ArH), 7.65 (d, J=3.0 Hz, IH, ArH)5 7.96 (m, 5H5 ArH)
Step 2: 4-[2-(6-Methoxypyridine-3-ylaminomethyl)-3-(9H-carbazol-l- yloxy)-propenyl]-benzoic acid The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(6-methoxypyridine-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl]-benzoate to obtain the title compound (93 %).
Step 3: 4-[2-(6-Methoxypyridine-3-ylaminomethyl)-3-(9H-carbazol-l- yloxy)-propenyl]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(6-methoxyρyridine-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl]-benzoic acid to obtain the title compound (31 %). Example 57: 4-[2-(4-Methoxyphenylaminomethyl)-3-(9H-carbazol-l- yloxy)-propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-(4-methoxyphenylaminomethyl)-3-(9H-carbazol-l- yloxy)-propenyl] benzoate
The procedure of Step 5 A of Example 39 was repeated except for using 4-methoxyphenylamine as the starting material to obtain the title compound (66%).
1H NMR (300 MHz5 CDCl3) δ 3.69 (s, 3H5 OCH3), 3.92 (s, 3H5 OCH3), 4.15 (s, 2H5 NCH2+ NH)5 4.76 (s, 2H, OCH2), 6.29 (m, 3H5 ArH)5 6.80 (m, IH5 ArH)5 6.93 (m, IH5 CH)5 7.08 (m, IH5 ArH)5 7.35 (m, 5H5 ArH)5 7.82 (m, IH5 ArH)5 7.98 (m, 4H5 ArH)
Step 2: 4-[2-(4-Methoxyphenylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(4-methoxyphenylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl]-benzoate to obtain the title compound (99%).
Step 3: 4-[2-(4-Methoxyphenylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyI]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(4-methoxyphenylaminomethyl)-3-(9H-carbazol-l-yloxy)-ρropenyl]- benzoic acid to obtain the title compound (20 % ).
Example 58: 4-[2-(Quinoline-3-ylaminomethyl)-3-(biphenyI-4-yIoxy)- propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-te^butylcarbonyI-3-(biphenyl-4-yloxy)-propenyl] benzoate
The procedure of Step 1 of Example 39 was repeated except for using 4-biphenol as the starting material to obtain the title compound. 1H NMR (200 MHz5 CDCl3), σ 1.54 (S5 9H, CH3), 3.91 (S5 3H, OCH3), 4.82 (S5 2H, CH2), 7.05 (m, 2H5 ArH)5 7.40-7.57 (m, 9H5 ArH), 7.94 (S, IH, CH), 8.04 (m, 2H, ArH)
Step 2: Methyl 4-[2-carboxy-3-(bipheπyl-4-yloxy)-propenyI]-beπzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-fer^-butylcarbonyl-3-(biρhenyl-4-yloxy)-proρenyl]-benzoate to obtain the title compound.
Step 3: Methyl 4-[2-hydromethyI-3-(biphenyI-4-yIoxy)~propenyl] benzoate
The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(biphenyl-4-yloxy)-propenyl]-benzoate to obtain the title compound.
1H NMR (200 MHz5 CDCl3), σ 3.89 (S, 3H5 OCH3), 4.44 (S, 2H, CH2), 4.73 (S5 2H, CH2), 6.94 (m, 3H, ArH)5 7.31-7.99 (m, 9H, ArH)5 8.01 (d, 2H J=8.3Hz, ArH)
Step 4: Methyl 4-[2-bromomethyl-3-(biphenyl-4-yloxy)-propenyI] benzoate
The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydromethyl-3-(biρhenyl-4-yloxy)-propenyl] benzoate to obtain the title compound.
1H NMR (200 MHz, CDCl3), σ 3.93 (S, 3H, OCH3), 4.89 (S, 2H, CH2), 7.03 (d, 2H J=8.7Hz, ArH), 7.27-7.73 (m, 1OH, ArH), 8.10 (d, 2H J=8.7Hz, ArH)5 9.73 (S5 IH5 CH)
Step 5: Methyl 4-[2-(qumoIine-3-ylaminomethyl)-3-(biphenyI-4-yloxy)- propenyl] benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(biρhenyl-4-yloxy)-ρroρenyl] benzoate to obtain the title compound (59%).
Step 6: 4-[2-(Quinoline-3-ylaminomethyI)-3-(biphenyl-4-yIoxy)-propenyI] benzoic acid The procedure of Step 6 of Example 39 was repeated except for using methyl 4- [2-(quinoline-3 -ylaminomethyl)-3 -(biphenyl-4-yloxy)-proρenyl] benzoate to obtain the title compound (86%).
Step 7: 4-[2-(Quinoline-3-ylaminomethyl)-3-(biphenyl-4-yloxy)- propenyI]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-(biphenyl-4-yloxy)-propenyl] benzoic acid to obtain the title compound (49%).
Example 59: 4-[2-(Quinoline-3-ylaminomethyl)-3-(benzothiazol-2-yloxy)- propenyI]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-fe/^-butoxycarbonyI-3-(benzothiazol-2-yloxy)- propenyl] benzoate
The procedure of Step 1 of Example 39 was repeated except for using 2-benzothiazolol as the starting material to obtain the title compound (89 % ).
1H NMR (200 MHz, CDCl3), σ 1.40 (S5 9H, 3CH3), 3.92 (S, 3H, OCH3), 5.00
(S5 2H, CH2), 6.69 (m, IH5 ArH)5 7.01-7.36 (m, 5H, ArH)5 7.83 (S5 IH, CH),
8.02 (d, 2H J=8.1 Hz, ArH)
Step 2: Methyl 4-[2-carboxy-3-(benzothiazol-2-yloxy)-propenyϊ] benzoate The procedure of Step 2 of Example 39 was repeated except for using methyl 4- [2-ter?-butoxycarbonyl-3 -(benzothiazol-2-yloxy)-propenyl] benzoate to obtain the title compound (630Io).
Step 3: Methyl 4-[2-hydroxymethyl-3-(benzothiazol-2-yloxy)-propenyl] benzoate
The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(benzothiazol-2-yloxy)-propenyl] benzoate to obtain the title compound (98%).
1H NMR (200 MHz5 CDCl3), σ 3.94 (S5 3H5 OCH3), 4.07 (S, 2H, CH2), 4.89 (S5 2H, CH2), 6.25 (m, IH, ArH)5 6.88 (S, IH5 CH), 7.03-7.19 (m, 2H5 ArH), 7.37 (m, 4H, ArH)5 8.11 (d, 2H J=8.1 Hz5 ArH)
Step 4: Methyl 4-[2-bromomethyI-3-(benzothiazol-2-yloxy)-propenyl] benzoate The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(benzothiazol-2-yloxy)-proρenyl] benzoate to obtain the title compound (95 %).
1H NMR (200 MHz5 CDCl3), σ 3.94 (S5 3H5 OCH3), 4.01 (S5 2H, CH2), 4.96 (S5 2H5 CH2), 6.60 (m, IH5 ArH)5 7.03 (S5 IH5 CH)5 7.13 (m, 3H5 ArH)5 7.33 (m, 3H5 ArH)5 8.08 (d5 2H J=8.1 Hz5 ArH)
Step 5: Methyl 4-{2-(quinoIine-3-ylaminomethyl)-3-(benzothiazol-2- yloxy)-propenyl}-benzoate The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(benzothiazol-2-yloxy)-propenyl]- benzoate to obtain the title compound (79 % ).
1H NMR (200 MHz5 CDCl3), σ 3.93 (S, 3H5 OCH3), 4.91 (S, 2H5 CH2), 6.41 (m, IH5 ArH)5 6.86 (m, IH, ArH)5 7.00 (S5 IH5 CH)5 7.10 (m, IH5 ArH)5 7.40 (m, 4H J=8.1 Hz5 ArH), 7.89 (m, 2H5 ArH)5 8.07 (m, 3H5 ArH)5 8.44 (d, 2H J=5.7 Hz5 ArH)
Step 6: 4-{2-(Quinoline-3-ylaminomethyl)-3-(benzothiazol-2-yloxy)- propenyl}-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-2-(quinoline-3-ylaminomethyl)-3-(benzothiazol-2-yloxy)-propenyl benzoate to obtain the title compound (91 %). Step 7: 4-[2-(Quinoline-3-yIaminomethyI)-3-(benzothiazol-2-yloxy)- propenyI]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-{2-(quinoline-3-ylaminomethyl)-3-(benzothiazol-2-yloxy)-propenyl}- benzoic acid to obtain the title compound (13 %).
Example 60: 4-{2-[(3,4-Dimethoxy-phenylamino)-methyl]-3-
(benzothiazol-2-yIoxy)-propenyl}-N-hydroxy-benzamide Step 1: Methyl 4-{2-[(3,4-dimethoxy-phenyϊamino)-methyI]-3- (benzothiazol-2-yloxy)-propenyl}-benzoate
The procedure of Step 1 of Example 39 was repeated except for using 2-benzothiazolol as the starting material to obtain the title compound (52%).
1H NMR (200 MHz, CDCl3), σ 3.74 (S, 5H, OCH3), 3.78 (S5 3H, OCH3), 3.94 (S, 3H, OCH3), 4.87 (S, 2H, CH2), 6.11 (m, IH, ArH), 6.22 (m, IH, ArH), 6.40 (m, IH, ArH), 6.69 (d, IH J=8.1 Hz, ArH), 6.94 (S, IH, CH), 7.04-7.14 (m, 2H, ArH), 7.30-7.41 (m, 3H, ArH), 8.09 (d, 2H J=8.1 Hz, ArH)
Step 2: 4-{2-[(3,4-Dimethoxy-phenylamino)-methyl]-3-(benzothiazoI-2- yloxy)-propenyl}-benzoic acid
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-{2-[(3,4-dimethoxy-ρhenylamino)-methyl]-3-(benzothiazol-2- yloxy)-propenyl}-benzoate to obtain the title compound.
Step 3: 4-{2-[(3,4-Dimethoxy-phenylamino)-methyl]-3-(benzothiazol-2- yIoxy)-propenyl}-N-hydroxy-benzamide
The procedure of Step 3 of Example 39 was repeated except for using 4- {2- [(3 ,4-dimethoxy-phenylamino)-methyl]-3 -(benzothiazol-2-yloxy)- propenylj-benzoic acid to obtain the title compound (13 %).
Example 61: 4-[2-(Quinoline-3-ylaminomethyl)-3-(l,3-dioxo-l,3-dihydro- isoindole-2-yl)-propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-ter£-butoxycarbonyl-3-(l,3-dioxo-l,3-dihydro- isoindole-2-yl)-propenyl] benzoate
The procedure of Step 1 of Example 39 was repeated except for using l,3-dioxo-l,3-dihydro-isoindole as the starting material to obtain the title compound (96 % ) .
1H NMR (200 MHz5 CDCl3), σ 1.53 (S5 9H5 3CH3), 3.92 (S5 3H5 OCH3), 4.72 (S, 2H5 CH2), 6.91 (m, 5H, ArH)5 7.53 (d5 2H J=8.5 Hz5 ArH), 7.92 (S, IH, CH)5 8.03 (d, 2H J=8.5 Hz, ArH)
Step 2: Methyl 4-[2-carboxy-3-(l,3-dioxo-l,3-dihydro-isoindoIe-2-yl)- propenyl] benzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4- [2-ter/-butoxycarbonyl-3 -( 1 ,3 -dioxo- 1 ,3 -dihydro-isoindole-2-yl)- prbpenyl] benzoate to obtain the title compound (99 % ).
Step 3: Methyl 4-[2-hydroxymethyl-3-(l,3-dioxo-l,3-dihydro-isoindole-2- yl)-propenyl] -benzoate The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(l53-dioxo-l53-dihydro-isoindole-2-yl)-propenyl]- benzoate to obtain the title compound (64%).
1H NMR (200 MHz5 CDCl3), σ 3.91 (S, 3H5 OCH3), 4.23 (S, 2H5 CH2), 4.66 (S5 2H, CH2), 6.93 (m, 4H, ArH), 7.31 (d, 2H J=8.5Hz, ArH)5 7.94 (S, IH5 CH), 8.01 (d, 2H J=8.5 Hz, ArH)
Step 4: Methyl 4-[2-bromomethyI-3-(l,3-dioxo-l,3-dihydro-isoindole-2- yl)-propenyl]-benzoate The procedure of Step 4B of Example 39 was repeated except for using methyl 4- [3 -( 1 ,3 -dioxo- 1 ,3 -dihydro-isoindole-2-yl)-2-hydroxymethyl- propenyl]-benzoate to obtain the title compound (66%). 1H NMR (200 MHz, CDCl3), σ 3.93 (S5 3H, OCH3), 4.25 (S, 2H, CH2), 4.67 (S, 2H, CH2), 6.93 (m, 4H, ArH), 7.35 (d, 2H J=8.5 Hz, ArH), 7.95 (S, IH, CH), 8.03 (d, 2H J=8.5 Hz, ArH)
Step 5: Methyl 4-[2-(qumolme-3-ylammomethyl)-3-(l,3-dioxo~l,3- dihydro-isoindole-2-yl)-propenyl]-benzoate <
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(l ,3-dioxo- 1 ,3-dihydro-isoindole-2-yl)- propenyl]-benzoate to obtain the title compound (46%).
1H NMR (200 MHz, CDCl3), σ 3.78 (S, 6H, OCH3X2), 3.91 (S, 3H, OCH3), 4.24 (S, 2H, CH2), 4.51 (S, 2H, CH2), 6.24 (m, 2H, ArH), 6.63 (m, 2H5 ArH)5 6.99 (S, IH, CH), 7.25 (m, 5H, ArH)5 7.99 (d, 2H J=8.1 Hz5 ArH)
Step 6: 4-[2-(Quinoline-3-ylaminomethyl)-3-(l,3-dioxo-l,3-dihydro- isoindole-2-yl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4- [2-(quinoline-3 -ylaminomethyl)-3 -( 1 ,3 -dioxo- 1 ,3-dihydro- isoindole-2-yl)-propenyl]-benzoate to obtain the title compound.
Step 7: 4-[2-(Quinoline-3-ylaminomethyI)-3-(l,3-dioxo-l,3-dihydro- isoindole-2-yl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-3-ylaminomethyl)-3-(l,3-dioxo-l,3-dihydro-isoindole-2-yl)- propenyl]-benzoic acid to obtain the title compound (16%).
Example 62: 4-[2-Phenylaminomethyl-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxy benzamide
Step 1: Methyl 4-[2-phenylaminomethyl-3-(naphthalene-l-yloxymethyl)- propenylj-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 2-phenylamine as the starting material to obtain the title compound (94%). 1H NMR (300 MHz5 CDCl3) δ 3.9 (s, 3H), 4.18 (s, 2H), 4.85 (s, 2H), 6.6-6.9 (Hi5 4H)5 7.17-7.20 (d, 2H5 J=7.4 Hz)5 7.33-7.36 (q, 4H5 J=8.2, 2.1 Hz)5 7.45- 7.53 (m, 3H), 7.82 (s, IH), 7.97-8.00 (d, 2H, J=8.2 Hz), 8.29-8.32 (d, IH, J=8.9 Hz)
MS (EI5 70 eV) m/z 423 (M-1), 330, 315, 280, 27I5 220, 187, 144, 129, 115, 106, 77
Step 2: 4-[2-Phenylaminomethyl-3-(naphthaIene-l-yloxymethyI)- propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4- [2-ρhenylaminomethy 1-3 -(naphthalene- 1 -yloxymethyl)-propenyl]- benzoate to obtain the title compound (99%).
MS (EI, 70 eV) m/z 409 (M-1), 398, 316, 301, 266, 220, 195, 144, 129, 115, 106, 93
Step 3: 4-[2-Phenylaminomethyl-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide The procedure of Step 7 of Example 39 was repeated except for using
4- [2-phenylaminomethyl-3 -(naphthalene- 1 -yloxymethyl)-ρropenyl j-benzoic acid to obtain the title compound (92%).
1H NMR (300 MHz, MeOH-d4) δ 4.18 (s, 2H), 4.84 (s, 2H), 6.61-6.70 (m, 4H)5 7.18-7.19 (d5 2H, J=7.2 Hz), 7.34-7.36 (d, 4H, J=8.2 Hz), 7.42-7.51 (m, 3H), 7.81 (s, IH)5 7.98-8.00 (d, 2H, J=8.2 Hz)5 8.26-8.30 (d, IH, J=8.4 Hz) MS (LC, 70 eV) m/z 426 (M+1), 266, 220, 115, 106
Example 63: 4-[2-(3,4-Dihydro-lH-isoquinoline-2-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyI]-N~hydroxy-benzamide
Step 1: Methyl 4-[2-(3,4-dihydro-lH-isoquinoline-2-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenylj-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 3 ,4-dihydro- lH-isoquinoline as the starting material to obtain the title compound (92%).
1H NMR (300 MHz5 CDCl3) δ 2.77-2.82 (q, 4H5 J=10.9, 4.5 Hz)5 3.4 (s, 2H)5 3.6 (s, 2H)5 3.7 (s, 3H)5 4.7 (s, 2H), 6.62-6.64 (d, IH5 J=7.5 Hz)5 6.64 (s, 2H)5 6.99-7.02 (t, 3H5 J=9.25 5.1 Hz)5 7.19-7.22 (d, IH5 J=7.8 Hz)5 7.30-7.39 (m. 5H)5 7.68-7.70 (d, IH5 J=7.2 Hz)5 7.86-7.89 (d, 2H5 J=8.2 Hz)5 8.17-8.20 (d, IH5 J=7.5 Hz)
MS (EI5 70 eV) m/z 463 (M'1), 320, 187, 157, 146, 132, 115, 104, 91, 59
Step 2: 4-[2-(3,4-Dihydro-lH-isoquinoline-2-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4- [2-(3 ,4-dihydro- 1 H-isoquinoline-2-ylmethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoate to obtain the title compound (99 % ).
MS (EI5 70 eV) m/z 449 (M"1), 409, 398, 354, 318, 302, 251, 229, 214, 186, 172, 157, 144, 131, 115, 98, 83
Step 3: 4-[2-(3,4-Dihydro-lH-isoquinoIine-2-yImethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(3 ,4-dihydro- 1 H-isoquinoline-2-y lmethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (65 %).
1H NMR (300 MHz5 CDCl3) δ 2.78-2.82 (q5 4H5 J=10.6, 4.4 Hz), 3.4 (s, 2H), 3.6 (s, 2H)5 4.7 (s5 2H)5 6.62-6.64 (d5 IH5 J=7.4 Hz), 6.65 (s, 2H)5 6.89-6.99 (t, 3H5 J=9.45 5.2 Hz), 7.20-7.22 (d, IH, J=7.6 Hz), 7.28-7.34 (m, 5H)5 7.68- 7.70 (d, IH, J=7.6 Hz), 7.88-7.90 (d, 2H5 J=8.0 Hz)5 8.18-8.20 (d, IH5 J=7.4 Hz) MS (LC, 70 eV) m/z 465 (M+1), 409, 229, 215, 196, 157, 144, 131, 114, 83
Example 64: 4-[2-(2-Methoxy-dibenzofuran-3-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(2-methoxy-dibenzofuran-3-yIaminomethyI)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 2-methoxy-dibenzofuran-3-ylamine as the starting material to obtain the title compound (58%).
1H NMR (300 MHz5 CDCl3) δ 3.8 (s, 3H)5 3.9 (s, 3H)5 4.00 (s, 2H)5 5.36 (s, 2H)5 6.66 (s, IH)5 6.79-6.82 (d, 2H5 J=7.0 Hz)5 7.15-7.40 (m, 10H)5 7.65-7.80 (m, 2H)5 7.91-7.95 (t5 2H5 J=I 1.6, 8.1 Hz), 8.10-8.19 (d, IH5 J=8.2 Hz) MS (EI5 70 eV) m/z 543 (M-1), 474, 331, 316, 280, 253, 226, 213, 183, 157, 106
Step 2: 4-[2-(2-Methoxy-dibenzofuran-3-ylaminomethyl)-3-(naphthalene- l-yϊoxymethyl)-propenylj-benzoic acid The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(2-methoxy-dibenzofuran-3-ylaminomethyl)-3-(naρhthalene- 1 - yloxymethyl)-propenyl]-benzoate to obtain the title compound (57%).
MS (EI5 70 eV) m/z 529 (M"1), 334, 316, 302, 277, 253, 239, 226, 213, 198, 170, 155, 144, 127, 115, 85
Step 3: 4-[2-(2-Methoxy-dibenzofuran-3-ylaminomethyl)-3-(naphthalene- l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(2-methoxy-dibenzofuran-3-ylaminomethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (91 %).
1H NMR (300 MHz, CDCl3) δ 3.9 (s, 3H)5 4.04 (s, 2H)5 5.30 (s, 2H)5 6.64 (s, IH)5 6.74-6.80 (d, 2H5 J=7.2 Hz)5 7.11-7.35 (m, 10H)5 7.60-7.78 (m, 2H), 7.90-7.92 (t, 2H5 J=12.45 8.2 Hz)5 8.10-8.19 (d, IH, J=8.2 Hz)
MS (LC5 70 eV) m/z 546 (M+1), 335, 277, 253, 24O5 227, 198, 17O5 155, 144, 115, 83 Example 65: 4-[2-(Naphthalene-l-ylaminomethyl)-3-(naphthalene-l- yIoxymethyl)-propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-(Naphthalene-l-ylamino)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate The procedure of Step 5B of Example 39 was repeated except for using 1-naphthaleneamine as the starting material to obtain the title compound (95 %).
1H NMR (300 MHz5 CDCl3) δ 3.9 (s, 3H), 4.41 (s, 2H), 4.94 (s, 2H), 6.75- 6.76 (d, 2H, J=3.5 Hz), 7.07 (s, IH), 7.32-7.58 (m, 10H), 7.82-7.86 (t, 3H, J=12.9, 5.1 Hz), 8.00-8.03 (d, 2H, J=8.2 Hz), 8.40-8.43 (d, IH, J=9.2 Hz) MS (EI, 70 eV) m/z 473 (M'1), 330, 187, 156, 143, 129, 115
Step 2: 4-[2-(Naphthalene-l-ylaminomethyl)-3-(naphthalene-l- yϊoxymethyl)-propenyl]-benzoie acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(naphthalene-l-ylamino)-3-(naphmalene-l-yloxymethyl)- propenyl]-benzoate to obtain the title compound (99%).
MS (EI, 70 eV) m/z 459 (M1), 316, 302, 271, 253, 231, 195, 183, 156, 143, 127, 115
Step 3: 4-[2-(Naphthalene-l-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide The procedure of Step 7 of Example 39 was repeated except for using
4- [2-(naphthalene- 1 -ylaminomethyl)-3 -(naphthalene- 1 -y loxymethyl)- propenylj-benzoic acid to obtain the title compound (69%).
1H NMR (300 MHz, CDCl3) δ 4.40 (s, 2H), 4.94 (s, 2H)5 6.74-6.76 (d, 2H, J=4.6 Hz), 7.04 (s, IH)5 7.28-7.46 (m, 10H); 7.80-7.84 (t, 3H, J=12.8, 5.2 Hz), 8.01-8.03 (d, 2H, J=8.2 Hz), 8.42-8.44 (d, IH, J=8.2 Hz) MS (LC, 70 eV) m/z 475 (M+1), 316, 303, 274, 183, 143, 127, 115 Example 66: 4-[2-(Quinoline-8-ylaminomethyI)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-(quinoline-8-yIaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate The procedure of Step 5B of Example 39 was repeated except for using 8-aminoquinoline as the starting material to obtain the title compound (87%).
1H NMR (300 MHz, CDCl3) δ 3.8 (s, 3H), 4.35 (s, 2H), 4.85 (s, 2H), 6.63- 6.66 (d, IH, J=7.5 Hz)5 7.04-7.06 (d, IH, J=8.0 Hz), 7.17-7.43 (m, 10H), 7.71-7.74 (t, IH, J=8.7, 1.5 Hz), 7.86-7.89 (d, 3H, J=8.2 Hz), 8.25-8.30 (m, IH), 8.63-8.64 (dd, IH, J=4.4, 1.4 Hz) MS (EI5 70 eV) m/z 474 (M"1), 33I5 187, 157, 144, 129, 115
Step 2: 4-[2-(Quinoline-8-ylaminomethyl)-3-(naphthaIene-l~ yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(quinoline-8-ylaminomethyl)-3-(naphthalene- 1 -yloxymethyl)- propenyl]-benzoate to obtain the title compound (30% ).
MS (EI, 70 eV) m/z 460 (M'1), 315, 301, 278, 195, 184, 169, 157, 144, 129, 117, 89, 63
Step 3: 4-[2-(Quinoline-8-yϊaminomethyl)-3-(naphthalene-l- yϊoxymethyl)-propenyI]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(quinoline-8-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)-propenyl]- benzoic acid to obtain the title compound {2,9%).
1H NMR (300 MHz, CDCl3) δ 4.34 (s, 2H)5 4.85 (s, 2H), 6.64-6.66 (d, IH, J=7.4 Hz), 7.04-7.06 (d, IH, J=8.2 Hz), 7.15-7.33 (m, 10H)5 7.72-7.74 (t, IH, J=8.4, 1.8 Hz)5 7.84-7.86 (d, 3H, J=8.4 Hz)5 8.18-8.20 (m, IH), 8.60-8.62 (dd, 1H, J=5.4, 1.7 Hz) MS (LC5 70 eV) m/z 477 (]Vr)"1)5 461, 316, 195, 183, 157, 144, 129, 117
Example 67: 4-[2-(6-Methoxy-pyridine-3-ylaminomethyl)-3-
(naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(6-methoxy-pyridine-3-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 6-methoxy-3-aminopyridine as the starting material to obtain the title compound (69%).
1H NMR (300 MHz, CDCl3) δ 3.8 (s, 3H), 3.9 (s, 3H)5 4.12 (s, 2H), 4.83 (s, 2H), 6.58-6.62 (dd, IH, J=7.4, 2.7 Hz), 6.93 (s, IH), 7.18-7.24 (m, 3H), 7.37- 7.43 (m, 2H), 7.73 (s, 2H), 7.88-7.93 (t, 4H, J=15.1, 6.9 Hz), 8.10-8.15 (m, IH) MS (EI, 70 eV) m/z 494 (M"1), 480, 454, 330, 316, 289, 275, 255, 231, 215, 195, 181, 164, 149, 137, 115, 101
Step 2: 4-[2-(6-Methoxy-pyridine-3-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(6-methoxy-pyridine-3-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate to obtain the title compound (94%).
MS (EI, 70 eV) m/z 480 (M'1), 316, 290, 229, 181, 164, 149, 115
Step 3: 4-[2-(6-Methoxy-pyridine-3-ylamiiiomethyl)-3-(naphthalene-l- yloxymethyI)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(6-methoxy-ρyridine-3 -ylaminomethyl)-3 -(naphthalene- 1 -yloxymethyl)- propenyl]-benzoic acid to obtain the title compound (95 % ).
1H NMR (300 MHz, CDCl3) δ 3.9 (s, 3H), 4.12 (s, 2H), 4.82 (s, 2H), 6.60- 6.62 (d, IH, J=7.4 Hz), 6.92 (s, IH), 7.20-7.23 (m, 3H), 7.36-7.42 (m, 2H), 7.72 (s, 2H), 7.86-7.90 (t, 4H5 J=14.8, 7.4 Hz)5 8.10-8.12 (m, IH)
MS (LC5 7O eV) 111/2497 (M+1), 481, 316, 276, 213, 181, 164, 149, 137, 115,
101
5 Example 68: 4-[2-(l,l-Dioxo-lH-lI6-naphto[l,8-cd]isothiazol-2- ylmethyI)-3-(naphthalene-l-yIoxymethyl)-propenyI]-N-hydroxy- benzamide
Step 1: Methyl 4-[2-(l,l-dioxo-lH-116-naphto[l,8-cd]isothiazol-2- ylmethyl)-3-(naphthalene-l-yloxymethyl)-propenyl]-benzoate 10 The procedure of Step 5B of Example 39 was repeated except for using l,l-dioxo-lH-116-naphto[l58-cd]isothiazole as the starting material to obtain the title compound (86%).
1H NMR (300 MHz, CDCl3) δ 3.8 (s, 3H)5 4.9 (s, 2H), 5.1 (s, 2H), 6.89-6.92 15. (d, IH, J=7.7 Hz), 7.11 (s, IH), 7.31-7.36 (t, 2H, J=16.1, 7.7 Hz), 7.43-7.61
(m, 5H), 7.91-7.94 (d, 3H, J=7.4 Hz)5 7.98-8.00 (d, 3H5 J=8.3 Hz)5 8.12-8.14
(d, 2H, J=7.1 Hz), 8.26-8.29 (d, IH, J=8.3 Hz)
MS (EI, 70 eV) m/z 535 (M+), 504, 392, 330, 317, 299, 271, 253, 231, 218,
202, 187, 154, 143, 127, 115, 86, 59 20
Step 2: 4-[2-(l,l-Dioxo-lH-lI6-naphto[l,8-cd]isothiazol-2-ylmethyl)-3-
(naphthalene-1 -yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-( 1 , 1 -dioxo- IH- 116-naphto[ 1 ,8-cd]isothiazol-2-ylmethyl)-3 -
25 (naphthalene- l-yloxymethyl)-propenyl]-benzoate to obtain the title compound (99%).
MS (EI, 70 eV) m/z 521 (M+), 503, 330, 315, 272, 25I5 187, 154, 143, 128, 115 30
Step 3: 4-[3-(l?l-Dioxo-lH-lI6-naphto[l,8-cd]isothiazol-2-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(l,l-dioxo-lH-116-naphto[l,8-cd]isothiazol-2-ylmethyl)-3-(naρhthalene- l-yloxymethyl)-propenyl] -benzoic acid to obtain the title compound (95%).
1H NMR (300 MHz, acetone-d6) δ 4.8 (s, 2H), 5.0 (s, 2H)5 6.84-6.86 (d, IH, J-7.6 Hz), 7.10 (s5 IH), 7.31-7.34 (t, 2H, J=I 6.1, 7.4 Hz)5 7.43-7.60 (m, 5H), 7.92-7:94 (d5 3H, J=7.6 Hz), 7.96-7.98 (d, 3H5 J=8.2 Hz), 8.10-8.12 (d, 2H5 J=7.4 Hz), 8.24-8.27 (d, IH, J=8.2 Hz) MS (LC5 70 eV) m/z 537 (M+1)
Example 69: 4-[2-(4-Methoxy-phenylaminomethyI)-3-(naphthaIene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-(4-methoxy-phenyIaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl] -benzoate
The procedure of Step 5B of Example 39 was repeated except for using 4-methoxy-phenylamine as the starting material to obtain the title compound (99%).
1H NMR (300 MHz5 CDCl3) δ 3.6 (s, 3H), 3.8 (s, 3H), 4.2 (s, 2H), 4.6 (s, 2H), 6.43-6.46 (d, IH, J=7.5 Hz), 6.63-6.76 (m, 4H)5 7.15-7.20 (q, 2H, J=7.2, 2.4 Hz)5 7.28-7.40 (m, 4H), 7.69-7.72 (d, IH, J=8.0 Hz)5 7.82-7.87 (t, 2H, J=12.7, 4.5 Hz), 8.15-8.18 (d, IH, J=8.3 Hz)
MS (EI, 70 eV) m/z 453 (M+), 372, 351, 33O5 311, 271, 231, 189, 165, 150, 136, 77, 59
Step 2: 4-[2-(4-Methoxy-phenylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(4-methoxy-phenylaminomethyl)-3-(naphthalene- 1 - yloxymethyl)-proρenyl]-benzoate to obtain the title compound (99%).
MS (EI, 70 eV) m/z 439 (M1), 316, 297, 282, 163, 136, 123, 108, 91, 77
Step 3: 4-[2-(4-Methoxy-phenyIaminomethyl)-3-(naphthalene-l- yIoxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(4-methoxy-phenylaminomethyl)-3 -(naphthalene- 1 -yloxymethyl)- propenyl]-benzoic acid to obtain the title compound (69%).
1H NMR (300 MHz, acetone-d6) δ 3.6 (s, 3H), 4.2 (s, 2H), 4.6 (s, 2H)5' 6.44- 6.46 (d, IH, J=7.4 Hz), 6.60-6.72 (m, 4H), 7.16-7.20 (q, 2H, J=7.4, 2.6 Hz)5 7.30-7.42 (m, 4H)5 7.67-7.71 (d, IH5 J=8.2 Hz)5 7.83-7.86 (t, 2H5 J=12.65 4.4 Hz), 8.15-8.18 (d, IH5 J=8.2 Hz)
Example 70: 4-[2-(Thiazol-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-(thiazol-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate The procedure of Step 5B of Example 39 was repeated except for using 2-aminothiazole as the starting material to obtain the title compound (64%).
1H NMR (300 MHz, CDCl3) δ 3.7 (s, 3H)5 4.1 (s, 2H), 4.7 (s, 2H)5 5.96 (s, IH)5 6.54-6.57 (t, IH, J=7.5, 3.0 Hz), 7.24-7.30 (m, 3H)5 7.41-7.48 (m, 4H),
7.80-7.82 (d, IH5 J=7.4 Hz), 7.91-7.96 (dd, 2H, J=8.1, 6.0 Hz)5 8.25-8.27 (d,
IH, J=8.1 Hz)
MS (EI5 70 eV) m/z 430 (M+), 330, 315, 299, 271, 255, 239, 228, 195, 165,
152, 139, 128, 114, 101, 59
Step 2: 4-[2-(Thiazol-2-ylaminomethyl)-3-(naphthalene-l-yloxymethyI)- propenylj-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(thiazol-2-ylaminomethyl)-3-(naphthalene- 1 -yloxymethyl)- propenylj-benzoate to obtain the title compound (92%).
MS (EI, 70 eV) m/z 416 (M+), 316, 301, 27I5 239, 228, 195, 165, 144, 128, 115, 100, 89, 58 Step 3: 4-[2-(Thiazol-2-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxy-benzainide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(thiazol-2-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)-propenyl]- benzoic acid to obtain the title compound (89 % ).
1H NMR (300 MHz, acetone-d6) δ 4.1 (s, 2H), 4.6 (s, 2H)5 5.97 (s, IH), 6.54- 6.58 (t, IH5 J=7.5, 3.0 Hz), 7.22-7.28 (m, 3H), 7.42-7.48 (m, 4H), 7.80-7.82 (d, IH5 J=7.5 Hz), 7.92-7.96 (dd, 2H5 J=8.15 5.2 Hz), 8.25-8.27 (d, IH, J=8.1 Hz) MS (LC5 70 eV) m/z 432 (M+1)
Example 71: 4-[2-(9-Ethyl-9H-carbazol-3-ylaminomethyl)-3- (naphthaIene-l-yloxymethyI)-propenyI]-N-hydroxybenzamide
Step 1: Methyl 4-[2-(9-ethyl-9H-carbazol-3-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 9-ethyl-9H-carbazol-3-ylamine as the starting material to obtain the title compound (99%).
1H NMR (300 MHz, CDCl3) δ 1.32-1.44 (m, 3H), 3.89 (s, 3H), 4.21-4.33 (m, 2H), 4.50 (s, 2H), 4.78 (s, 2H), 6.50-6.52 (d, IH, J=7.6 Hz), 6.93 (s, IH)5 7.19 (s, IH), 7.25-7.54 (m, HH), 7.64-7.70 (t, 2H, J=8.1, 4.5 Hz), 7.91-7.94 (d, 2H, J=8.2 Hz)5 8.34-8.37 (d, IH, J=8.3 Hz)
MS (EI, 70 eV) m/z 540 (M+), 395, 330, 315, 289, 275, 25O5 231, 210, 195, 181, 165, 115, 101
Step 2: 4-[2-(9-Ethyl-9H-carbazol-3-ylaminomethyI)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(9-ethyl-9H-carbazol-3 -ylaminomethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoate to obtain the title compound (91 %).
MS (EI, 70 eV) m/z 526 (M+), 395, 315, 288, 274, 232, 210, 194, 181, 165, 115
Step 3: 4-[2-(9-Ethyϊ-9H-carbazol-3-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(9-ethyl-9H-carbazol-3-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- proρenyl]-benzoic acid to obtain the title compound (94 % ).
1HNMR (300 MHz, acetone-d6) δ 1.32-1.38 (m, 3H), 4.24-4.30 (m, 2H), 4.48 (s, 2H), 4.78 (s, 2H), 6.52-6.54 (d, IH, J=7.4 Hz), 6.92 (s, IH), 7.19 (s, IH), 7.35-7.52 (m, HH)5 7.66-7.75 (t, 2H, J=8.2, 4.2 Hz), 7.92-7.94 (d, 2H, J=8.2 Hz), 8.35-8.37 (d, IH, J=8.2 Hz) MS (LC, 70 eV) m/z 542 (M+1)
Example 72: 4-[2-(6-Methoxy-benzothiazol-2-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(6-methoxy-benzothiazol-2-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 6-methoxy-benzothiazol-2-ylamine as the starting material to obtain the title compound (73 % ).
1H NMR (300 MHz, CDCl3) δ 3.8 (s, 3H), 3.9 (s, 3H), 4.7 (s, 2H), 4.8 (s, 2H), 6.61-6.63 (d, IH, J=7.4 Hz), 6.87-6.92 (d, IH, J=14.4 Hz), 7.26-7.52 (m, 9H), 7.8 (s, IH), 7.98-8.01 (d, 2H, J=8.2 Hz), 8.30-8.33 (d, 2H, J=8.2 Hz) MS (EI, 70 eV) m/z 510 (M+), 473, 367, 330, 315, 271, 231, 187, 161, 144, 129, 115, 59
Step 2 : 4- [2-(6-Methoxy-benzothiazol-2-ylaminomethy l)-3-(naphthalene- l-yloxymethyl)-propenyl] -benzoic acid The procedure of Step 6 of Example 39 was repeated except for using methyl 4- [2-(6-methoxy-benzothiazol-2-ylaminomethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoate to obtain the title compound (99%).
1H NMR (200 MHz5 CDCl3), σ 3.81 (S5 3H5 OCH3), 4.41 (S, 2H, CH2), 4.89 (S5 2H5 CH2), 6.67 (d, IH J=6.8 Hz5 ArH)5 6.87 (m, IH, ArH)5 7.03 (S5 IH5 CH), 7.13 (m, IH, ArH)5 7.28-7.56 (m, 7H, ArH), 7.83 (m, IH5 ArH), 7.97 (d, 2H J=8.5 Hz, ArH)5 8.26 (m, IH, ArH)
MS (EI5 70 eV) m/z 496 (M+), 316, 30I5 271, 253, 231, 220, 194, 180, 166, 129, 115, 91, 71, 57
Step 3 : 4-[2-(6-Methoxy-benzothiazol-2-yIaminomethyI)-3-(napfathaIene- l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(6-methoxy-benzothiazol-2-ylaminomethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (85%).
1H NMR (300 MHz5 acetone-d6) δ 3.8 (s, 3H)5 4.7 (s, 2H), 4.8 (s, 2H)5 6.60- 6.62 (d, IH5 J=7.2 Hz)5 6.88-6.90 (d, IH5 J=8.4 Hz)5 7.24-7.48 (m, 9H)5 7.8 (s, IH)5 7.92-7.98 (d, 2H5 J=8.4 Hz)5 8.30-8.32 (d, 2H, J=8.4 Hz) MS (LC, 70 eV) m/z 511 (M+1)
Example 73: 4-[2-(Naphthalene-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(naphthalene-2-yIaminomethyl)-3-(naphthaIene-l- yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 2-naphthaleneamine as the starting material to obtain the title compound (99%).
1H NMR (300 MHz5 CDCl3) δ 3.8 (s, 3H)5 4.20 (s, 2H), 4.79 (s, 2H), 6.58- 6.60 (d, IH5 J=7.5 Hz), 6.84-6.86 (dd, IH5 J=3.55 1.0 Hz)5 6.92 (s, IH), 7.14 (s, IH), 7.21-7.25 (dd5 4H5 J=8.0, 3.7 Hz)5 7.35-7.45 (m, 6H)5 7.51-7.56 (t, 3H3 J=12.7. 3.3 Hz)5 7.84-7.87 (d, 2H5 J=8.2 Hz)5 8.23-8.26 (d, IH5 J=7.0 Hz) MS (EI5 70 eV) m/z 473 (M+), 330, 315, 271, 255, 231, 195, 182, 156, 143, 127, 115, 77
Step 2: 4-[2-(Naphthalene-2-yIaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl] -benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(naphthalene-2-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- ρropenyl]-benzoate to obtain the title compound (99%).
MS (EI, 70 eV) m/z 459 (M+), 331, 316, 271, 244, 230, 196, 181, 154, 144, 127, 115, 74
Step 3: 4-[2-(Naphthalene-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(naphthalene-2-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoic acid to obtain the title compound (97%).
1H NMR (300 MHz, acetone-d6) δ 4.20 (s, 2H), 4.78 (s, 2H), 6.56-6.58 (d, IH, J=7.4 Hz)5 6.80-6.84 (dd, IH, J=8.5, 3.6 Hz)5 6.90 (s, IH), 7.14 (s, IH), 7.23-7.26 (dd, 4H, J=8.45 3.6 Hz), 7.36-7.46 (m, 6H), 7.52-7.55 (t, 3H5 J=12.75 3.5 Hz), 7.82-7.84 (d, 2H, J=8.4 Hz), 8.20-8.22 (d, IH, J=7.8 Hz) MS (LC, 70 eV) m/z 475 (M+1)
Example 74: 4-[2-(6-Nitro-benzothiazoI-2-yIammomethyl)-3-
(naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-(6-nitro-benzothiazol-2-ylaminomethyI)-3-
(naphthalene-l-yloxymethyl)-propenyl]-benzoate The procedure of Step 5B of Example 39 was repeated except for using 6-nitro-benzothiazol-2-ylamine as the starting material to obtain the title compound (99%). 1H NMR (300 MHz5 CDCl3) δ 3.9 (s, 3H)5 4.79 (s, 2H)5 4.91 (s, 2H)5 6.56- 6.58 (d, IH5 J=7.4 Hz)5 6.84 (s, IH)5 7.21-7.50 (m, 9H)5 7.85-7.86 (d, IH, J=2.6 Hz)5 7.97-8.00 (d, 2H5 J=8.3 Hz)5 8.22-8.25 (d, IH3 J=7.9 Hz) MS (EI5 70 eV) m/z 525 (M+), 381, 33O5 315, 299, 271, 23I5 209, 195, 181, 165, 152, 128, 115
Step 2 : 4- [2-(6-Nitro-benzothiazol-2-yIamiπomethyl)-3-(naphthalene-l - yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(6-nitro-benzothiazol-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate to obtain the title compound (93 %).
MS (EI5 70 eV) m/z 511 (M+), 495, 366, 344, 330, 316, 302, 269, 255, 239, 228, 209, 195, 181, 165, 144, 128, 115, 91, 77, 63
Step 3 : 4- [2-(6-Nitro-benzothiazol-2-ylaminomethyl)-3-(naphthalene-l - yloxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(6-nitro-benzothiazol-2-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoic acid to obtain the title compound (98 %).
1H NMR (300 MHz, acetone-d6) δ 4.75 (s, 2H), 4.90 (s, 2H)5 6.54-6.56 (d, IH, J=7.6 Hz), 6.82 (s, IH), 7.22-7.50 (m, 9H), 7.84-7.86 (d, IH, J=4.6 Hz), 7.94-7.98 (d, 2H, J=8.4 Hz), 8.22-8.24 (d, IH, J=7.6 Hz) MS (LC, 70 eV) m/z 527 (M+1)
Example 75: 4-[2-(4-Methyl-benzothiazoI-2-ylaminomethyI)-3-
(naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-(4-methyl-benzothiazol-2-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 4-methyl-benzothiazol-2-ylamine as the starting material to obtain the title compound (99 % ). 1H NMR (300 MHz5 CDCl3) δ 2.46 (s, 3H)5 3.9 (s, 3H)5 4.77 (s, 2H)5 4.85 (s, 2H)5 6.61-6.63 (d, IH5 J=7.5 Hz)5 6.92 (s, IH)5 7.28-7.53 (m, 9H)5 7.82-7.84 (d, IH5 J=8.1 Hz)5 7.99-8.04 (t, 2H5 J=15.35 7.2 Hz)5 8.31-8.34 (d, IH5 J=8.2 Hz)
MS (EI3 70 eV) m/z 494 (M+), 351, 187, 177, 165, 144, 129, 115
Step 2: 4-[2-(4-Methyl-benzothiazol-2-ylaminomethyl)-3-(naphthaIene-l- yloxymethyl)-propenyl]-benzoic acid The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(4-methyl-benzothiazol-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-proρenyl]-benzoate to obtain the title compound (99%).
MS (EI, 70 eV) m/z 480 (M+), 313, 302, 268, 254, 228, 195, 181, 164, 144, 128, 115, 105, 91, 78, 63
Step 3 : 4-[2-(4-Methyl-benzothiazol-2-yIaminomethyl)-3-(naphthaIene-l- yIoxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(4-methyl-benzothiazol-2-ylaminomethyl)-3-(naphthalene- 1 - yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (67%).
1H NMR (300 MHz5 acetone-d6) δ 2.44 (s, 3H), 4.78 (s, 2H), 4.85 (s, 2H), 6.62-6.64 (d, IH, J=7.4 Hz)5 6.90 (s, IH), 7.36-7.50 (m, 9H), 7.80-7.82 (d, IH, J=8.2 Hz), 7.88-7.92 (t, 2H, J=I 5.2, 7.4 Hz), 8.32-8.34 (d, IH, J=8.2 Hz) MS (LC, 70 eV) m/z 496 (M+1)
Example 76: 4-[2-(5,6-Dimethyl-benzothiazol-2-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(5,6-dimethyl-benzothiazol-2-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 5,6-dimethyl-benzothiazol-2-ylamine as the starting material to obtain the title compound (81 %).
1HNMR (300 MHz5 CDCl3) δ 2.29 (s, 3H), 2.30 (s, 3H)5 3.91 (s, 3H)5 4.72 (s, 2H)5 4.82 (s5 2H)5 6.59-6.62 (d, IH5 J=7.5 Hz), 6.76-6.78 (d, IH, J=8.2 Hz)5 7.24-7.49 (m, 8H), 7.89-7.92 (d, IH, J=8.2 Hz), 7.94-7.98 (dd, 3H, J=8.1, 4.6 ' '• Hz), 8.28-8.31 (d, IH5 J=8.3 Hz)
MS (EI, 70 eV) m/z 508 (M+), 365, 33O5 315, 271, 255, 239, 228, 217, 192, 178, 164, 144, 128, 115
Step 2: 4-[2-(5,6-Dimethyl-benzothiazoI-2-yIaminomethyl)-3-
(naphthalene-l-yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(5,6-dimethyl-benzothiazol-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate to obtain the title compound (97%).
MS (EI5 70 eV) m/z 494 (M+), 334, 316, 301, 271, 255, 231, 218, 202, 192, 181, 164, 144, 128, 115, 91, 69, 57
Step 3: 4-[2-(5,6-DimethyI-benzothiazol-2-ylaminomethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(556-dimethyl-benzothiazol-2-ylaminomethyl)-3 -(naphthalene- 1 - yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (96%).
1H NMR (300 MHz, acetone-d6) δ 2.28 (s, 3H), 2.30 (s, 3H), 4.74 (s, 2H),
4.84 (s, 2H), 6.57-6.60 (d, IH, J=7.4 Hz), 6.74-6.76 (d, IH, J=8.4 Hz), 7.26-
7.40 (m, 8H)5 7.80-7.82 (d, IH, J=8.4 Hz), 7.90-7.96 (dd, 3H, J=8.2, 4.8 Hz),
8.26-8.28 (d, IH, J=8.4 Hz)
MS (LC, 70 eV) m/z 510 (M+1)
Example 77: 4-[2-Pyrrolidine-l-ylmethyl-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-pyrrolidine-l-ylmethyl-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 1 -pyrrolidine as the starting material to obtain the title compound (80%).
1H NMR (300 MHz, CDCl3) δ 1.73 (s, 4H), 2.46 (s, 4H)5 2.9.1 (s, 2H), 3.83 (s, 3H)5 4.75 (s5 2H)5 6.65-6.67 (d, IH, J=7.5 Hz), 6.84 (s, IH)5 7.19-7.42 (m, 5H), 7.87-7.89 (d, 5H, J=8.0 Hz) MS (EI5 70 eV) m/z 401 (M+), 258, 128, 115, 84, 70, 58
Step 2: 4-[2-PyriOlidine-l-ylmethyl-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-pyrrolidine- 1 -ylmethyl-3-(naphthalene- 1 -yloxymethyl)- propenyl]-benzoate to obtain the title compound (54 % ).
MS (EI, 70 eV) m/z 387 (M+), 258, 129, 113, 84, 70, 58
Step 3 : 4-[2-Pyrrolidine-l-yImethy I-3-(naphthaIene-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-pyrrolidine- 1 -ylmethyl-3-(naphthalene- 1 -yloxymethyl)-ρropenyl]- benzoic acid to obtain the title compound (50%).
1H NMR (300 MHz, acetone-d6) δ 1.74 (s, 4H), 2.46 (s, 4H)5 3.01 (s, 2H), 4.64 (s, 2H), 6.64-6.65 (d, IH5 J=7.4 Hz), 6.81 (s, IH), 7.20-7.38 (m, 5H), 7.86-7.88 (d, 5H, J-7.6 Hz) MS (LC, 70 eV) m/z 403 (M+1)
Example 78: 4-[2-Cyclopentylaminomethyl-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-cyclopentyIaminomethyl-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate The procedure of Step 5B of Example 39 was repeated except for using cyclopentylamine as the starting material to obtain the title compound (27%).
1H NMR (300 MHz, CDCl3) δ 1.33-1.47 (m, 4H)5 1.72-1.88 (m, 4H)5 3.01- 3.11 (m, IH), 3.44 (s, 2H), 3.84 (s, 3H), 4.85 (s, IH), 5.07 (S5 IH), 6.51 (s5 IH)5 6.64-6.66 (d, IH, J=7.2 Hz)5 7.19-7.24 (in, 5H), 7.87-7.92 (m, 5H) MS (EI, 70 eV) m/z 415 (M+), 372, 258, 126, 115, 84, 69, 57
Step 2: 4-[2-Cyclopentylaminomethyl-3-(naphthaIene-l-yloxymethyl)- propenylj-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-cyclopentylaminomethyl-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoate to obtain the title compound (58%).
MS (EI, 70 eV) m/z 401 (M+), 370, 258, 127, 115, 84, 69, 57
Step 3 : 4- β-Cyclopentylaminomethyl-S-tøaphthalene-l -yloxymethyl)- propenyl]-N-hydroxy-benzamide The procedure of Step 7 of Example 39 was repeated except for using
4-[2-cycloρentylaminomethyl-3-(naphthalene-l-yloxymethyl)-propenyl]- benzoic acid to obtain the title compound (93 %).
1H NMR (300 MHz, acetone-d6) δ 1.34-1.44 (m, 4H), 1.74-1.86 (m, 4H)5 3.06-3.12 (m, IH), 3.44 (s, 2H), 3.87 (s, 3H), 4.84 (s, IH)5 5.06 (S, IH), 6.52 (s, IH), 6.64-6.66 (d, IH, J=7.4 Hz), 7.20-7.23 (m, 5H)5 7.86-7.94 (m, 5H) MS (LC, 70 eV) m/z 417 (M+1)
Example 79: 4-[2-(l,3-Dioxo-l,3-dihydro-isoindole-2-ylmethyl>3- (naphthaIene-l-yIoxymethyl)-propenyI]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-(l,3-dioxo-l,3-dihydro-isoindole-2-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using l53-dioxo-l,3-dihydro-isoindole as me starting material to obtain the title compound (99%).
1HNMR (300 MHz5 CDCl3) δ 3.82 (s, 3H), 4.14 (s, 2H), 4.30 (s, 2H), 6.38 (s, IH)5 7.17-7.20 (dd5 4H5 J=3.84, 1.74 Hz), 7.60-7.69 (m, 5H), 7.77-7.89 (m, 5H)
MS (EI, 70 eV) m/z 477 (M+), 321, 304, 232, 182, 176, 160, 154, 128, 115, 104, 91, 76
Step 2: 4-[2-(l,3-Dioxo-l,3-dihydro-isoindoIe-2-yImethyI)-3-
(naphthalene-l-yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(l,3-dioxo-l,3-dihydro-isoindole-2-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate to obtain the title compound (40%).
MS (EI, 70 eV) m/z 463 (M+), 321, 303, 275, 231, 186, 174, 160, 148, 129, 115, 104, 91, 77
Step 3: 4-[2-(l,3-Dioxo-l,3-dihydro-isoindoIe-2-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(l,3-dioxo-l,3-dihydro-isoindole-2-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (31 %).
1H NMR (300 MHz, acetone-d6) δ 4.15 (s, 2H), 4.30 (s, 2H), 6.34 (s, IH), 7.12-7.18 (d, 4H5 J=I .72 Hz), 7.62-7.70 (m, 5H), 7.74-7.80 (m, 5H) MS (LC, 70 eV) m/z 479 (M+1)
Example 80: 4-[2-DimethyIaminomethyl-3-(naphthalene-l-yloxymethyl)- propenyI]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-dimethyIaminomethyl-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using dimethylamine as the starting material to obtain the title compound (68%).
1HNMR (300 MHz5 CDCl3) δ 2.11 (s, 3H), 2.23 (s, 3H)5 2.66 (s, IH)5 2.90 (s, IH)5 3.83 (S5 3H)5 6.37 (s, IH)5 7.19-7.33 (m5 6H)5 7.86-7.93 (m, 5H) MS (EI5 70 eV) m/z 375 (M+), 232, 189, 144, 129, 115, 58
Step 2: 4-[2-Dimethylaminomethyl-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoic acid The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-dimethylaminomethyl-3-(naphthalene- 1 -yloxymethyl)- propenyl]-benzoate to obtain the title compound (99%).
MS (EI5 70 eV) m/z 362 (M+1), 219, 204, 144, 115, 9I5 82, 58
Step 3: 4-[2-Dimethylaminomethyl-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-dimethylaminomethyl-3-(naphthalene-l-yloxymethyl)-propenyl]- benzoic acid to obtain the title compound (24 % ).
1H NMR (300 MHz, acetone-d6) δ 2.16 (s, 3H)5 2.22 (s, 3H), 2.72 (s, IH)5
2.82 (s5 IH)5 6.34 (s, IH)5 7.20-7.34 (m5 6H)5 7.86-7.92 (m, 5H)
MS (LC, 70 eV) m/z 377 (M+1)
Example 81: 4-[2-Azidomethyl-3-(naphthaIeiie-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-azidomethyI-3-(naphthalene-l-yIoxymethyl)- propenyl]-benzoate The procedure of Step 5B of Example 39 was repeated except for using azide as the starting material to obtain the title compound (97%).
1HNMR (300 MHz5 CDCl3) δ 2.03 (s, 2H)5 3.88 (s, 3H)5 4.54 (s, 2H)5 6.32 (s, IH)5 7.19-7.30 (m, 6H)5 7.68-7.71 (dd5 2H5 J=8.5, 3.0 Hz)5 7.79-7..82 (dd, 2H5 J=5.45 3.0 Hz)5 7.90-7.96 (q, IH5 J=10.05 8.1 Hz)
MS (EI5 70 eV) m/z 373 (M+), 315, 289, 274, 230, 194, 180, 164, 115, 101, 74
Step 2: 4-[2-Azidoniβthyl-3-(naphthalene-l-yIoxymethyl)-propenyl]- benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-azidomethyl-3-(naphthalene-l-yloxymethyl)-ρropenyl]^benzoate to obtain the title compound (47 % ).
MS (EI, 70 eV) m/z 359 (M+), 314, 289, 220, 195, 180, 164, 115, 101, 74
Step 3: 4-[2-Azidomethyl-3-(naphthalene-l-yloxymethyl)-propenyl]-N- hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-azidomethy 1-3 -(naphthalene- 1 -yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (69%).
1H NMR (300 MHz5 acetone-d6) δ 2.02 (s, 2H)5 3.88 (s, 3H)5 4.54 (s, 2H)5 6.34 (s5 IH)5 7.20-7.30 (m, 6H)5 7.68-7.70 (dd5 2H5 J=8.45 3.0 Hz), 7.80-7.82 (dd, 2H5 J=8.2, 3.0 Hz)5 7.89-7.94 (q, IH5 J=10.25 8.2 Hz) MS (LC5 70 eV) m/z 375 (M+1)
Example 82: 4-[2-(2,5-Dioxo-2,5-dihydro-pyrrole-l-ylmethyl)-3- (naphthalene-l-yloxymethyϊ)-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(2,5-dioxo-2,5-dihydro-pyrrole-l-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 255-dioxo-255-dihydro-pyrrole as the starting material to obtain the title compound (42%).
1HNMR (300 MHz5 CDCl3) δ 3.84 (s, 3H)5 4.14 (s, 2H)5 4.26 (s, 2H)5 6.30 (s, IH)5 6.60 (s, IH), 6.62-6.63 (d, 2H5 J=I .4 Hz)5 6.69 (s, 2H)5 7.16-7.22 (t, 2H5
J=I 7.5, 9.3 Hz)5 7.86-7.95 (q, 2H5 J=I 8.0, 9.8 Hz)
MS (EI5 70 eV) m/z 427 (M+), 366, 315, 270, 187, 161, 154, 119, 114, 57
Step 2: 4-[2-(2,5-Dioxo-2,5-dihydro-pyrrole-l-yImethyl)-3-(naphthalene- l-yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(2,5-dioxo-2,5-dihydro-pyrrole-l-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate to obtain the title compound (66%).
MS (EI, 70 eV) m/z 413 (M+), 315, 271, 184, 154, 119, 115, 59
Step 3: 4-[2-(2,5-Dioxo-2,5-dihydro-pyrrole-l-ylmethyl)-3-(naphthalene- l-yIoxymethyl)-propenyl]-N-hydroxy-benzamide The procedure of Step 7 of Example 39 was repeated except for using
4-[2-(2,5-dioxo-2,5-dihydro-pyrrole-l-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (87%).
1H NMR (300 MHz, acetone-d6) δ 4.14 (s, 2H), 4.24 (s, 2H), 6.31 (s, IH), 6.68 (s, IH), 6.70-6.72 (d, 2H, J=3.4 Hz), 6.70 (s, 2H), 7.20-7.24 (d, 2H, J=8.4 Hz)5 7.84-7.89 (dd52H5 J=16.0, 8.6 Hz) MS (LC, 70 eV) m/z 429 (M+1)
Example 83: 4-[2-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindoIe-2- ylmethyl)-3-(naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy- benzamide
Step 1: Methyl 4-[2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-isoindole-2- ylmethyI)-3-(naphthaIene-l-yIoxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using l,3-dioxo-l,3,3a,4,7,7a-hexahydro-2-isoindole as the starting material to obtain the title compound (84%).
1H NMR (300 MHz, CDCl3) δ 2.13-2.16 (t, 2H, J=7.5, 2.7 Hz)5 2.18-2.21 (t, 2H5 J=7.55 4.8 Hz)5 2.55-2.64 (m5 2H)5 3.82 (s, 3H)54.09 (s, 2H)5 4.42 (s, IH)5 4.67 (s5 IH)5 5.81-5.83 (t, IH5 J=6.35 3.3 Hz)5 5.86-5.88 (t, IH5 J=17.45 8.1 Hz)5 7.86-7.91 (t5 5H5 J=I 5.0, 8.4 Hz)
MS (EI5 70 eV) m/z 481 (M+), 45O5 338, 317, 306, 187, 155, 143, 129, 115, 79
Step 2: 4-[2-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindoIe-2-yImethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(l ,3-dioxo-l ,353a54,7,7a-hexahydro-isoindole-2-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate to obtain the title compound (83 % ).
MS (EI5 70 eV) m/z 467 (M+), 450, 325, 315, 303, 27I5 255, 231, 202, 190, 174, 162, 152, 129, 115, 91, 79
Step 3: 4-[2-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindoIe-2-yImethyϊ)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(l53-dioxo-l,3,3a,457,7a-hexahydro-isoindole-2-ylmethyl)-3-
(naphthalene-l~yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (24%).
1HNMR (300 MHz5 acetone-d6) δ 2.14-2.16 (t5 2H5 J=7.45 2.7 Hz), 2.18-2.20 (t, 2H, J=7.45 2.8 Hz)5 2.55-2.65 (m5 2H)5 4.09 (s5 2H)5 4.42 (s, IH)5 4.67 (s5 IH), 5.82-5.85 (t, IH5 J=6.35 3.3 Hz)5 5.88-5.90 (t, IH5 J=17.45 8.1 Hz)5 7.88- 7.91 (t, 5H5 J=I 5.0, 8.4 Hz) MS (LC, 70 eV) m/z 483 (M+1)
Example 84: 4-[2-(2-Oxo-pyrrolidine-l-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-(2-oxo-pyrroIidine-l-ylmethyl)-3-(naphthaIene-l- yloxymethyl)-propenyl]-benzoate The procedure of Step 5B of Example 39 was repeated except for using 2-oxo-pyiτolidine as the starting material to obtain the title compound (10%).
1H NMR (300 MHz, CDCl3) δ 1.80-1.87 (m, 2H)3 2.08-2.09 (t, 2H5 J=3.6, 1.5 Hz)5 2.55 (s, 2H)5 3.83 (s, 3H)5 4.13 (s, 2H)5 4.81 (s, 2H), 6.49 (S5 IH)5 6.63- 6.65 (d, IH5 J=7.5 Hz), 7.19-7.42 (m, 6H), 7.90-7.93 (dd, 4H5 J=8.45 1.8 Hz) MS (EI5 70 eV) m/z 415 (M+), 348, 317, 245, 223, 205, 187, 173, 155, 144, 129, 115, 105, 91, 77, 59
Step 2: 4-[2-(2-Oxo-pyrrolidine-l-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(2-oxo-pyrrolidine-l-ylmethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoate to obtain the title compound (73 % ).
MS (EI, 70 eV) m/z 401 (M+), 317, 244, 205, 186, 174, 155, 144, 115, 105, 92, 77, 59
Step 3: 4-[2-(2-Oxo-pyrrolidine-l-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(2-oxo-pyrrolidine-l-ylmethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoic acid to obtain the title compound (78%).
1HNMR (300 MHz, acetone-d6) δ 1.82-1.86 (m, 2H), 2.06-2.08 (t, 2H, J=7.6, 3.4 Hz), 2.54 (s, 2H), 4.15 (s, 2H), 4.81 (s, 2H)5 6.48 (s, IH)5 6.63-6.65 (d, IH5 J=7.5 Hz), 7.22-7.44 (m, 6H), 7.88-7.90 (dd, 4H, J=8.6, 3.4 Hz) MS (LC5 70 eV) m/z 417 (M+1)
Example 85: 4-[2-(2-Oxo-2,3-dihydro-indole-l-ylmethyl)-3-(naphthalene- l-yloxymethyl)-propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[2-(2-oxo-2,3-dihydro-indole-l-ylraethyl)-3- (naphthalene-l-yloxymethyl)-propenyϊ]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 2-oxo-2,3 -dihydro-indole as the starting material to obtain the title compound (81 %)/
•v 1H NMR (300 MHz5 CDCl3) δ 3.47 (s, 2H), 3.79 (s, 3K), 4.00 (s, 2H)5 4.25 (s, 2H)5 6.51 (s, IH), 6.78-6.81 (d, IH, J=7.8 Hz)5 6.92-6.97 (t5 2H, J=I 4.4, 7.5 Hz), 7.12-7.19 (m, 8H), 7.71-7.90 (m, 4H)
MS (EI5 70 eV) m/z 463 (M+), 360, 320, 288, 260, 189, 158, 145, 130, 115, 91, 59
Step 2: 4-[2-(2-Oxo-2,3-dihydro-indole-l-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(2-oxo-2,3-dihydro-indole-l-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate to obtain the title compound (99%).
MS (EI, 70 eV) m/z 449 (M+), 359, 324, 288, 259, 189, 156, 144, 130, 115, 91
Step 3: 4-[2-(2-Oxo-2,3-dihydro -indole-l-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(2-oxo-2,3-Dihydro-indole-l-ylmethyl)-3-(naphthalene-l-yloxymethyl)- propenylj-benzoic acid to obtain the title compound (86 % ).
1H NMR (300 MHz, acetone-d6) δ 3.48 (s, 2H), 4.04 (s, 2H), 4.45 (s, 2H)5 6.52 (s5 IH)5 6.78-6.80 (d, IH5 J=7.6 Hz), 6.90-6.93 (t, 2H5 J=I 4.O5 7.4 Hz)5 7.15-7.19 (m5 8H)5 7.70-7.88 (m, 4H) MS (LC, 70 eV) m/z 465 (M+1)
Example 86: 4-[2-(2,3-Dioxo-2,3-dihydro-indole-l-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(2,3-dioxo-2,3-dihydro-indole-l-ylmethyl)-3- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 2,3-dioxo-2,3-dihydro-indole as the starting material to obtain the title compound (99%).
1HNMR (300 MHz5 CDCl3) δ 3.44 (s, 2H)5 3.89 (s, 3H), 4.45 (s, 2H)5 6.54 (s, IH), 6.64-6.65 (d, IH, J=4.2 Hz)5 7.19-7.38 (m, 8H), 7.90-7.98 (m, 6H) MS (EI, 70 eV) m/z 477 (M+), 364, 316, 270, 238, 220, 192, 177, 164, 144, 128, 115
Step 2: 4-[2-(2,3-Dioxo-2,3-dihydro-indole-l-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(2,3-dioxo-2,3-dihydro-indole-l-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate to obtain the title compound (80%).
MS (EI, 70 eV) m/z 463 (M+), 310, 271, 236, 220, 176, 164, 144, 127, 115
Step 3: 4-[2-(2,3-Dioxo-2,3-dihydro-indole-l-ylmethyl)-3-(naphthalene-l- yIoxymethyI)-propenyI]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(2,3-dioxo-2,3-dihydro-indole-l-ylmethyl)-3-(naρhthalene-l- yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (93 %). '
1H NMR (300 MHz, acetone-d6) δ 3.44 (s, 2H), 4.44 (s, 2H), 6.52 (s, IH), 6.64-6.66 (d, IH5 J=4.2 Hz), 7.20-7.34 (m, 8H), 7.88-7.94 (m, 6H) MS (LC, 70 eV) m/z 479 (M+1)
Example 87: 4-[2-(Pyridine-3-ylaminomethyl)-3-(naphthalene-l- yIoxymethyl)-propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-(Pyridine-3-ylaminomethyl)-3-(naphthaIene-l- yloxymethyl)-propenyl] benzoate The procedure of Step 5 A of Example 39 was repeated except for using pyridine-3-ylamine as the starting material to obtain the title compound (85%).
1H NMR (200 MHz3 CDCl3) δ 3.89 (s, 3H5 OCH3), 4.22 (s, 3H, NH + OCH2), 4.86 (s, 2H5 NCH2), 6.68 (d, J=7.2 Hz, IH, ArH), 6.95 (m, 2H, ArH), 7.08 (m, IH, ArH), 7.31 (m, 4H, ArH), 7.52 (m, 3H5 ArH)5 7.83 (m, IH5 ArH), 7.98 (d, J=8.2 Hz, 2H, ArH)5 8.10 (s, IH5 CH), 8.26 (m, IH, ArH)
Step 2: 4-[2-(Pyridine-3-ylaminomethyl)-3-(naphthaIene-l-yIoxymethyl)- propenyl] benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(pyridine-3-ylaminomethyl)-3-(naρhthalene-l-yloxymethyl)- propenyl] benzoate to obtain the title compound (86%).
Step 3: 4-[2-(Pyridine-3-ylaminomethyI)-3-(naphthaIene-l-yloxymethyl)- propenyl]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(pyridine-3-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)-propenyl] benzoic acid to obtain the title compound (28 %).
Example 88: 4-[2-(2-Chloropyridine-3-ylaminomethyl)-3-(naphthalene-l- yIoxymethyl)-propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-(2-chloropyridine-3-ylaminomethyI)-3-(naphthaIene- l-yloxymethyl)-propenyl]-benzoate
The procedure of Step 5 A of Example 39 was repeated except for using 2-chloropyridine-3-ylamine as the starting material to obtain the title compound (75%).
1H NMR (200 MHz5 CDCl3) δ 3.90 (s, 3H, OCH3), 4.26 (d, J=7.6 Hz, 2H, NCH2), 4.87 (s5 2H5 OCH2), 6.69 (d, J=7.6 Hz5 IH5 ArH), 6.91 (S5 IH5 CH)5 7.02 (m, 3H, ArH)5 7.34 (d, J=8.4 Hz5 2H5 ArH)5 7.49 (m, 3H5 ArH)5 7.75 (m, IH5 ArH), 7.83 (m, IH, ArH)5 7.80 (d, J=8.4 Hz5 2H, ArH)5 8.28 (m, IH, ArH)
Step 2: 4-[2-(2-Chloropyridine-3-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl] -benzoic acid The procedure of Step 6 of Example 39 was repeated except for using methyl *"' 4-[2-(2-chloropyridine-3-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate to obtain the title compound (99%).
Step 3: 4-[2-(2-ChIoropyridine-3-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(2-chloropyridine-3-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoic acid to obtain the title compound (13%).
Example 89: 4-[2-(3-MethoxyphenylaminomethyI)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-(3-methoxyphenylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl] benzoate
The procedure of Step 5B of Example 39 was repeated except for using 3-methoxyphenylamine as the starting material to obtain the title compound (68%).
1H NMR (200 MHz5 CDCl3) δ 3.72 (s, 3H5 OCH3), 3.88 (s, 3H5 OCH3), 4.19 (s, 3H, NH + OCH2), 4.88 (s, 2H, NCH2), 6.27 (m, 3H, ArH), 6.68 (d5 J=7.6 Hz5 IH3 ArH)5 6.95 (s, IH5 CH)5 7.08 (t, J=8.0 Hz5 IH, ArH)5 7.25 (d, J=4.0 Hz, IH, ArH), 7.33 (d, J=8.4 Hz5 2H5 ArH)5 7.53 (m, 3H5 ArH)5 7.82 (m, IH, ArH), 7.97 (d, J=8.4 Hz, 2H, ArH), 8.29 (m, IH, ArH) MS (EI5 70 eV) m/z 453 (M+), 31O5 136, 115, 108, 93, 77, 59, 41 -
Step 2: 4-[2-(3-Methoxyphenylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl] benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(3-methoxyphenylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]benzoate to obtain the title compound (99%).
Step 3: 4-[2-(3-MethoxyphenyIaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxybenzamide The procedure of Step 7 of Example 39 was repeated except for using
4-[2-(3-methoxyphenylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyljbenzoic acid to obtain the title compound (32%).
1H NMR (300 MHz, acetone-d6) δ 3.67 (s, 3H5 OCH3), 4.21 (s, 2H5 OCH2), 4.94 (s, 2H, NCH2), 5.59 (brs, IH5 NH), 6.19 (d, J=7.5 Hz, IH, ArH), 6.33 (s,
IH, CH), 6.34 (d, J=7.5 Hz5 IH, ArH)5 6.88 (d, J=7.5 Hz, IH5 ArH), 6.99 (m,
2H, ArH)5 7.48 (m, 6H5 ArH), 7.77 (d, J=8.1 Hz, IH5 ArH), 7.85 (d, J=7.5 Hz,
IH, ArH), 7.97 (s, IH, ArH), 8.29 (d, J=7.5 Hz, IH5 ArH), 10.85 (brs, IH5
NH)
Example 90: 4-[2-(Biphenyl-4-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-(biphenyl-4-ylammomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-benzoate The procedure of Step 5 A of Example 39 was repeated except for using biphenyl-4-ylamine as the starting material to obtain the title compound
(82%).
1H NMR (200 MHz5 CDCl3) δ 3.88 (s, 3H, OCH3), 4.23 (s, 3H, NH + OCH2), 4.86 (s, 2H, NCH2), 6.71 (d, J=2.2 Hz, IH, ArH), 6.74 (d, J=8.0 Hz, 2H,
ArH), 6.97 (s, IH, CH), 7.43 (m, 13H5 ArH), 7.82 (m, IH, ArH), 7.97 (d,
J=8.0 Hz5 2H5 ArH), 8.30 (m, IH, ArH)
MS (EI5 70 eV) m/z 499 (M+), 330, 315, 271, 182, 169, 152, 151, 128, 115,
77, 59, 40
Step 2: 4-[2-(Biphenyl-4-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[2-(biphenyl-4-ylaminomethyl)-3-(naphthalene- 1 -yloxymethyl)- propenyl]-benzoate to obtain the title compound (96%).
Step 3: 4-[2-(Biphenyl-4-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyI]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4- [2-(bipheny l-4-ylaminomethyl)-3 -(naphthalene- 1 -yloxymethyl)-propeny 1] - benzoic acid to obtain the title compound (39%).
1H NMR (300 MHz, acetone-d6) δ 4.27 (s, 2H5 OCH2), 5.00 (s, 2H, NCH2), 6.10 (brs, IH, NH), 6.86 (d, J=8.7 Hz3 IH5 ArH), 7.00 (d, J=8.1 Hz, IH, ArH), 7.10 (s, IH, CH), 7.47 (m, 15H, ArH), 7.82 (d, J=8.1 Hz, IH, ArH), 7.92 (m, IH5 ArH)5 8.29 (m, IH, ArH), 11.14 (brs, IH, NH)
Example 91: 4-[2-(Indan-2-ylaminomethyl)-3-(naphthalene-l-yloxy)- propenyI]-N-hydroxy-beπzamide
Step 1: Methyl [2-(indan-2-ylaminomethyl)-3-(naphthaIene-l-yIoxy)- propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 2-aminoindan as the starting material to obtain the title compound
(52%).
1H NMR (200 MHz5 CDCl3), σ 3.00 (d, 4H, J=8.0Hz, 2CH2), 3.55 (S5 2H, CH2), 3.91 (S5 3H, OCH3), 3.97 (m, IH5 CH)3 4.60 (S5 2H5 CH2), 6.25 (d, IH J=7.6Hz, ArH)5 6.90 (S, IH5 CH), 7.09-7.28 (m, 7H, ArH)5 7.44 (m, 3H, ArH), 7.80 (d, IH J=8.0Hz, ArH)5 7.88 (d, 2H J=8.4Hz, ArH), 8.11 (d, IH J=8.0Hz, ArH)
Step 2: 4-[2-(Indan-2-ylammomethyl)-3-(naphthalene-l-yIoxy)- propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl [2-(indan-2-ylaminomethyl)-3-(naphthalene- 1 -yloxy)-proρenyl]- benzoate to obtain the title compound (99%). 1H NMR (200 MHz, CDCl3), σ 2.98 (d, 4H, J=8.0Hz, 2CH2), 3.62 (S, 2H, CH2), 3.96 (m, IH, CH)5 4.57 (S, 2H5 CH2), 6.24 (d, IH J=7.6Hz, ArH), 6.90 (S, IH, CH)5 7.07-7.25 (m, 7H, ArH), 7.44 (m, 3H, ArH), 7.81 (d, IH J=8.0Hz, ArH), 7.86 (d, 2H J=8.4Hz, ArH), 8.09 (d, IH J=8.0Hz, ArH)
Step 3: 4-[2-(Indan-2-ylaminomethyl)-3-(naphthalene-l-yloxy)- propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[2-(indan-2-ylaminomethyl)-3-(naphthalene-l-yloxy)-propenyl]-benzoic acid to obtain the title compound (45 %).
1H NMR (200 MHz, CDCl3), σ 3.00 (d, 4H, J=8.0Hz, 2CH2), 3.64 (S, 2H, CH2), 3.97 (m, IH, CH), 4.58 (S, 2H, CH2), 6.25 (d, IH J=7.6Hz, ArH)5 6.90 (S, IH5 CH), 7.08-7.25 (m, 7H5 ArH), 7.47 (m, 3H, ArH), 7.81 (d, IH J=8.0Hz, ArH), 7.85 (d, 2H J=8.4Hz, ArH), 8.11 (d, IH J=8.0Hz, ArH)
Example 92: 4-[2-(4-Pyridine-2-yl-piperazine-l-ylmethyl)-3-
(naphthalene-l-yloxy)-propenyl]-N-hydroxy-benzamide Step 1: Methyl 4-[2-(4-pyridine-2-yl-piperazine-l-ylmethyl)-3- (naphthalene-l-yloxy)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 4-pyridine-2-yl-piperazine as the starting material to obtain the title compound (71 %).
1H NMR (200 MHz, CDCl3), σ 2.67 (m5 4H, 2CH2), 3.43 (S, 2H, CH2), 3.91 (S, 3H, OCH3), 3.91 (m, 4H, 2CH2), 4.90 (S, 2H, CH2), 6.48 (m, IH, ArH), 6.79 (d, IH J=6.5Hz, ArH)5 6.98 (S5 IH, CH), 7.31-7.56 (m, 7H, ArH), 7.84 (m, IH, ArH), 8.00 (d, 2H J=8.5Hz, ArH), 8.30 (m, 3H, ArH) ■
Step 2: 4-[2-(4-Pyridine-2-yI-piperazine-l-ylmethyl)-3-(naphthalene-l- yloxy)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[3-(naphthalene-l-yloxy)-2-(4-pyridine-2-yl-piperazine-l- ylmethyl)-propenyl]-benzoate to obtain the title compound (99%).
1H NMR (200 MHz5 CDCl3), σ 2.66 (m, 4H5 2CH2), 3.43 (S, 2H5 CH2), 3.91 (m, 4H5 2CH2), 4.88 (S5 2H5 CH2), 6.47 (m, IH5 ArH)5 6.77 (d, IH J=6.5Hz, ArH), 6.99 (S5 IH, CH)5 7.31-7.55 (m, 7H5 ArH)5 7.84 (m, IH5 ArH)5 7.98 (d, 2H J=8.5Hz, ArH)5 8.29 (m, 3H5 ArH)
Step 3: 4-[2-(4-Pyridine-2-yl-piperazine-l-ylmethyl)-3-(naphthalene-l- yIoxy)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[3-(naphthalene- 1 -yloxy)-2-(4-pyridine-2-yl-piperazine- 1 -ylmethyl)- propenyl]-benzoic acid to obtain the title compound (27%).
1H NMR (200 MHz5 CDCl3), σ 2.69 (m, 4H5 2CH2), 3.44 (S5 2H5 CH2), 3.91 (m, 4H5 2CH2), 4.91 (S, 2H, CH2), 6.47 (m, IH5 ArH)5 6.77 (d, IH J=6.5Hz, ArH), 6.99 (S, IH, CH)5 7.31-7.55 (m, 7H5 ArH)5 7.84 (m5 IH, ArH)5 7.98 (d, 2H J=8.5Hz5 ArH)5 8.31 (m, 3H5 ArH)
Example 93: 4-{2-[(2-Phenoxy-ethylamino)-methyl]-3-(naphthalene-l- yloxy)-propenyl}-N-hydroxy-benzamide
Step 1: Methyl 4-{2-[(2-phenoxy-ethylamino)-methyl]-3-(naphthalene-l- yloxy)-propenyl}-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 2-phenoxy-ethy'lamine as the starting material to obtain the title compound (72%).
1H NMR (200 MHz, CDCl3), σ 3.05 (m, 2H5 CH2), 3.74 (S, 2H, CH2), 3.91 (S5 2H5 CH2), 3.95 (S5 3H, OCH3). 4.06 (m, 2H, CH2), 6.80 (d, 2H J=8.1Hz, ArH)5 6.96 (m, 3H, ArH), 7.01-7.51 (m, 8H, ArH), 7.81 (m, IH, ArH)5 8.01 (d, 2H J=8.1Hz5 ArH), 8.34 (d 2H J=9.0Hz, ArH)
Step 2: 4-{2-[(2-Phenoxy-ethylamino)-methyI]-3-(naphthalene-l-yloxy)- propenyl}-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-{2-[(2-phenoxy-ethylamino)-methyl]-3-(naphthalene-l-yloxy)- propenyl}-benzoate to obtain the title compound (99%).
1H NMR (200 MHz5 CDCl3), σ 3.08 (m, 2H5 CH2), 3.82 (S5 2H5 CH2), 3.91 (S5 2H5 CH2), 4.07 (Hi5 2H5 CH2), 6.83 (d, 2H J=8.1Hz5 ArH)5 6.96 (m, 3H5 ArH)5 7.01-7.51 (m, 8H5 AfH)5 7.87 (m, IH5 ArH)5 8.01 (d, 2H J=8.1Hz5 ArH)5 8.37 (d 2H J=9.0Hz5 ArH)
Step 3: 4-{2-[(2-Phenoxy-ethylamino)-methyl]-3-(naphthalene-l-yloxy)- propenyl}-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-{2-[(2-phenoxy-ethylamino)-methyl]-3-(naphthalene-l-yloxy)-propenyl}- benzoic acid to obtain the title compound (43 % ).
1H NMR (200 MHz5 CDCl3), σ 3.09 (m, 2H5 CH2), 3.83 (S5 2H5 CH2), 3.91 (S5 2H5 CH2), 4.11 (m5 2H, CH2), 6.79 (d, 2H J=8.1Hz5 ArH)5 6.96 (m, 3H5 ArH)5 7.01-7.51 (m, 8H5 ArH)5 7.88 (m, IH5 ArH)5 8.03 (d, 2H J=8.1Hz5 ArH)5 8.35 (d 2H J=9.0Hz5 ArH)
Example 94: 4-{2-[(Benzyl-methyl-amino)-methyl]-3-(naphthalene-l- yloxy)-propenyl}-N-hydroxy-benzamide
Step 1: Methyl 4-{2-[(benzyl-methyl-amino)-methyl]-3-(naphthalene-l- yloxy)-propenyl}-benzoate
The procedure of Step 5B of Example 39 was repeated except for using benzylmethylamine as the starting material to obtain the title compound (95%).
1H NMR (200 MHz5 CDCl3), σ 2.27 (S5 3H, CH3), 3.03 (S5 2H5 CH2), 3.62 (S5 2H, CH2), 3.88 (S5 3H5 OCH3), 4.46 (S, 2H5 CH2), 6.54 (S5 2H5 CH)5 6.64 (m, IH5 ArH)5 7.06 (m, 3H5 ArH)5 7.14 (m, 2H5 ArH)5 7.23 (m, 2H5 ArH)5 7.36 (m, 2H5 ArH), 7.41 (d, 2H J=8.1Hz, ArH)5 7.66 (m, IH5 ArH)5 7.92 (d, 2H J=8.1Hz, ArH)5 8.17 (m, IH5 ArH)
Step 2: 4-{2-[(Benzyl-methyI-amino)-methyI]-3-(naphthalene-l-yIoxy)- propenyl}-benzoic acid The procedure of Step 6 of Example 39 was repeated except for using methyl 4-{2-[(benzyl-methyl-amino)-methyl]-3-(naphthalene-l-yloxy)- proρenyl}-benzoate to obtain the title compound (99%).
1H NMR (200 MHz5 CDCl3), σ 2.29 (S5 3H5 CH3), 3.06 (S5 2H5 CH2), 3.64 (S, 2H, CH2), 4.47 (S5 2H5 CH2), 6.54 (S5 2H5 CH)5 6.67 (m, IH5 ArH)5 7.09 (m, 3H5 ArH), 7.14 (m, 2H5 ArH)5 7.23 (m, 2H5 ArH), 7.36 (m, 2H, ArH), 7.41 (d, 2H J=8.1Hz, ArH), 7.66 (m, IH5 ArH)5 7.92 (d, 2H J=8.1Hz, ArH)5 8.14 (m, IH5 ArH)
Step 3: 4-{2-[(Benzyl-methyl-amino)-metliyl]-3-(naphthalene-l-yloxy)- propenyl}-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-2-[(benzyl-methyl-amino)-methyl]-3-(naphthalene-l-yloxy)-propenyl- benzoic acid to obtain the title compound (55%).
1H NMR (200 MHz5 CDCl3), σ 2.31 (S5 3H, CH3), 3.09 (S5 2H5 CH2), 3.67 (S, 2H5 CH2), 4.47 (S5 2H, CH2), 6.54 (S, 2H5 CH)5 6.67 (m, IH, ArH)5 7.09 (m, 3H5 ArH), 7.24 (m, 3H5 ArH)5 7.36 (m, 2H5 ArH)5 7.41 (d, 2H J=8.1Hz5 ArH)5 7.66 (m, IH5 ArH), 7.89 (d, 2H J=8.1Hz5 ArH)5 8.14 (m5 IH5 ArH)
Example 95: 4-[3-(6-Methoxyquinoϊme-3-ylamino)-2-(naphthalene-l- yloxymethyI)-propenyl]-N-hydroxy-benzamide
Step 1: Methyl 4-[3-(6-methoxyquinoϊine-3-ylamino)-2-(naphthalene-l- yloxymethyl)-propenyl]-benzoate The procedure of Step 5 A of Example 39 was repeated except for using (6-methoxy-3-aminoquinoline) as the starting material to obtain the title compound (62%). 1H NMR (200 MHz5 CDCl3), σ 3.83 (s, 3H5 OCH3), 3.94 (s, 3H, OCH3), 4.30 (d, J=5.2 Hz, IH, CH2), 4.50 (t, J=6.0 Hz, IH, NH), 4.91 (s, 2H, CH2), 6.66 (s, IH, CH), 6.07 (m, IH, ArH), 7.03 (m, 2H, ArH), 7.27 (m, IH, ArH), 7.35 (m, 3H, ArH), 7.49 (m, 3H, ArH), 7.81 (m, 2H, ArH), 7.99 (d, J=8.2 Hz, 2H, ArH), 8.34 (d, J=5.6 Hz, 2H, ArH)
MS (EI, 70 eV) m/z 504 (M+1), 361, 214, 188, 174
Step 2: 4-[3-(6-Methoxyquinolme-3-ylammo)-2-(naplithalene-l- yloxymethyl)-propenyl]-benzoic acid The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[3-(6-methoxyquinoline-3-ylamino)-2-(naphthalene-l- yloxymethyl)-ρroρenyl]-benzoate to obtain the title compound (83 %).
MS (EI, 70 eV) m/z 490 (M+1), 439, 315, 302, 278, 213, 188, 175, 159, 144, 130, 115, 101, 88, 77, 64, 44
Step 3: 4-[3-(6-Methoxyquinoline-3-ylamino)-2-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4- [3 ~(6-methoxyquinoline-3 -ylamino)-2-(naphthalene- 1 -yloxymethyl)- propenylj-benzoic acid to obtain the title compound (38%).
MS (LC, 70 eV) m/z 506 (M+1), 491, 363
Example 96: 4-[3-(8-Bromoquinoline-3-ylamino)-2-(naphthalene-l- yloxymethyl)-propenyϊ]-N-hydroxy-benzamide
Step 1: Methyl 4-[3-(8-bromoquinoline-3-ylamino)-2-(naphthalene-l- yloxymethyl)-propenyl]-benzoate
The procedure of Step 5 A of Example 39 was repeated except for using 8-bromo-3-aminoquinoline as the starting material to obtain the title compound (57%).
1H NMR (200 MHz, CDCl3), σ 3.87 (s, 3H, OCH3), 4.37 (brs, 2H, CH2), 4.90 (s, 2H, CH2), 6.67 (d, J=7.0 Hz5 IH5 ArH)5 6.98 (s, IH5 CH)5 7.06 (d, J=2.2 Hz5 IH5 ArH)5 7.40 (m, 8H5 ArH)5 7.70 (dd5 J=I .2, 7.2 Hz5 IH5 ArH)5 7.83 (m, IH5 ArH)5 7.99 (d, J=6.6 Hz5 2H5 ArH)5 8.29 (dd, J=2.65 6.8 Hz5 IH5 ArH)5 8.58 (d, J=2.6 Hz5 IH5 ArH) MS (EI5 70 eV) m/z 554 (M+1), 329, 262, 236, 222
Step 2: 4-[3-(8-Bromoquinoline-3-ylamino)-2-(naphthaϊene-l- yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[3-(8-bromoquinoline-3-ylamino)-2-(naphthalene-l-yloxymethyl)- propenyl]-benzoate to obtain the title compound (87%).
Step 3: 4-[3-(8-Bromoquinoline-3-ylamino)-2-(naphthalene-l- yloxymethyI)-propenyI]-N-hydroxy-benzamide The procedure of Step 7 of Example 39 was repeated except for using
4- [3 -(8-bromoquinoline-3 -ylamino)-2-(naphthalene- 1 -yloxymethyl)- propenyl]-benzoic acid to obtain the title compound (25%).
MS (LC5 70 eV) m/z 556 (M+1), 541, 395
Example 97: 4-[3-(5,6-DimethoxyquinoIine-3-ylainino)-2-(naphthalene-l- yIoxymethyl)-propenyI]-N-hydroxy-benzamide
Step 1: Methyl 4-[3-(5,6-dimethoxyquinoline-3-ylamino)-2-(naphthalene- l-yloxymethyl)-propenyl]-benzoate The procedure of Step 5B of Example 39 was repeated except for using 556-dimethoxy-3-aminoqumoline as the starting material to obtain the title compound (49%).
1H NMR (200 MHz, CDCl3), σ 3.89 (s, 6H, OCH3X2), 3.96 (s, 3H, OCH3), 4.28 (d, J=5.4 Hz, 2H, CH2), 4.36 (d, J=5.4 Hz, IH, NH)5 4.90 (s, 2H, CH2), 6.68 (t, J=3.6 Hz, 2H, ArH), 6.99 (s, IH5 CH), 7.05 (d, J=2.6 Hz5 IH, ArH)5 7.32 (m, 4H5 ArH), 7.48 (m, 3H5 ArH)5 7.83 (m, IH5 ArH), 8.16 (d, J=8.4 Hz, 2H5 ArH), 8.30 (d, J=2.6 Hz, IH5 ArH) Step 2: 4-[3-(5,6-Dimethoxyquinoline-3-ylamino)-2-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[3-(5,6-dimethoxyquinoline-3-ylamino)-2-(naρhthalene-l - yloxymethyl)-propenyl]-benzoate to obtain the title compound (85 % ).
Step 3: 4-[3-(5,6-Dimethoxyquinoline-3-ylamino)-2-(naphthaIene-l- yIoxymethyl)-propenyl]-N-hydroxy-benzamide The procedure of Step 7 of Example 39 was repeated except for using
4-[3-(5,6-dimethoxyquinoline-3-ylamino)-2-(naphthalene-l-yloxymethyl)- propenyl]-benzoic acid to obtain the title compound (60%).
MS (LC5 70 eV) m/z 536 (M+1), 521, 393, 205 . .
Example 98: 4-{2-[(3,4-Dimethoxy~phenyIamino)-methyl]-3-
(naphthalene-l-yloxy)-propenyl}-N-hydroxybenzamide
Step 1: Methyl 4-{2-[(3,4-dimethoxy-phenylamino)-methyl]-3-
(naphthalene-l-yloxy)-propenyl}-benzoate The procedure of Step 5B of Example 39 was repeated except for using 3,4-dimethoxy-phenylamine as the starting material to obtain the title compound (83%).
1H NMR (200 MHz5 CDCl3) δ 3.76 (S, 3H, OCH3), 3.82 (S, 3H, OCH3), 3.91 (S, 3H, OCH3), 4.39 (S, 2H, CH2), 4.87 (S, 2H, CH2), 6.46 (m, 2H, ArH), 6.98 (S, IH, CH)5 7.45-7.54 (m, 6H, ArH), 7.85 (m, IH, ArH), 8.01 (m, 2H, ArH), 8.32 (m, IH5 ArH)
Step 2: 4-{2-[(3,4-Dimethoxy-phenylamino)-methyl]-3-(naphthalene-l- yloxy)-propenyl}-benzoic acid
The procedure of Step 6 Example 39 was repeated except for using methyl 4-{2-[(3,4-dimethoxy-phenylamino)-methyl]-3-(naphthalene-l- yloxy)-propenyl}-benzoate to obtain the title compound (99%). 1H NMR (200 MHz3 CDCl3) δ 3.68 (S5 3H5 OCH3), 3.79 (S, 3H, OCH3), 4.37 (S5 2H, CH2), 5.01 (S5 2H, CH2), 6.46 (m, 2H5 ArH)5 7.52 (m, 6H5 ArH), 7.86 (S, IH5 CH)5 7.98 (m, IH5 ArH)5 8.01 (m, 2H5 ArH), 8.24 (m, IH5 ArH)
Step 3: 4-{2-[(3,4-Dimethoxy-phenylamino)-methyl]-3-(naphthalene-l- yloxy)-propenyI}-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-2-[(3,4-dimethoxy-phenylamino)-methyl]-3-(naphthalene-l-yloxy)- propenyl-benzoic acid to obtain the title compound (67 % ).
1H NMR (200 MHz, CDCl3), σ 3.75 (S5 3H, OCH3), 3.77 (S, 3H5 OCH3), 4.28 (S, 2H5 CH2), 5.22 (S5 ZH, CH2), 6.88 (d, IH J=8.9Hz5 ArH)5 7.00 (m, IH, ArH)5 7.25-7.53 (m, 6H, ArH)5 7.65 (d, 2H J=8.1Hz, ArH), 7.82 (S5 IH, CH), 8.03 (d, 2H J=8. IHz, ArH), 8.20 (m, IH5 ArH), 9.49 (m, IH5 NH)
Example 99: 4-{2-[(7-Morpholme-4-yInaphthalene-2-ylamino)-methyI]-3- (naphthalene-l-yloxy)-propenyl}-N-hydroxybenzamide Step 1: Methyl 4-{2-[(7-morpholine-4-ylnaphthaIene-2-ylamino)-methyl]- 3-(naphthalene-l-yloxy)-propenyl}-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 7-morpholine-4-ylnaphthalene-2-ylamine as the starting material to obtain the title compound (28%).
1H NMR (200 MHz5 CDCl3) δ 8.46 (d, J=2.8 Hz, IH)5 8.34 (d, J=5.8 Hz, IH), 8.01 (d, J=8.0 Hz, 2H)5 8.89 (d, J=8.2 Hz5 IH), 7.83 (d, J=5.4 Hz5 IH)5 7.26- 7.57 (m, 8H)5 7.07 (d, J=2.6 Hz5 IH), 7.00 (s, IH)5 6.69 (d, J=7.4 Hz5 IH)5 4.90 (s, 2H), 4.77 (brs, IH), 3.30 (d, J=5.2 Hz5 2H), 3.89 (s, 3H), 3.72 (t, J=2.4 Hz5 4H), 3.58 (s, 2H)5 2.47 (t, J=2.4 Hz, 4H)
Step 2: 4-{2-[(7-Morpholine-4-ylnaphthalene-2-ylamino)-methyl]-3- (naphthalene-l-yloxy)-propenyl}-benzoic acid
The procedure of Step 6 Example 39 was repeated except for using methyl 4- {2-[(7-morpholine-4-ylnaphthalene-2-ylamino)-methyl]-3 -
(naphthalene- l-yloxy)-propenyl}-benzoate to obtain the title compound (86%).
1H NMR (200 MHz5 CDCl3) δ 8.42 (d, J=2.8 Hz5 IH)5 8.17 (d, J=8.2 Hz5 IH)5 7.93 (d, J=8.0 Hz5 2H)5 7.81 (d, J=8.4 Hz5 IH)5 7.74 (d, J=8.4 Hz5 IH)5 7.23- 7.51 (m, 8H)5 7.08 (d, J=2.4 Hz5 IH)5 7.02 (s, IH)5 6.72 (d, J=7.8 Hz5 IH), 4.93 (s, 2H), 4.28 (s, 2H)5 3.70 (t, J=4.4 Hz5 4H)5 3.67 (s, 2H)5 2.56 (t, J=4.4 Hz5 4H)
Step 3: 4-{2-[(7-Morpholine-4-ylnaphthalene-2-yIamino)-methyl]-3- (naphthalene-l-yloxy)-propenyI}-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-2-[(7-morpholine-4-ylnaphthalene-2-ylamino)-methyl]-3-(naphthalene-l- yloxy)-propenyl-benzoic acid to obtain the title compound (76 % ).
1H NMR (200 MHz5 DMSOd6) δ 11.16 (s, IH)5 9.01 (brs5 IH)5 8.49 (s, IH)5 8.18 (d, J=7.8 Hz5 IH)5 7.88 (d, J=9.0 Hz5 2H)5 7.24-7.57 (m, 9H)5 6.81-7.02 (m, 4H)5 4.91 (s, 2H)5 4.20 (s, 2H)5 3.55 (brs, 4H)5 3.41 (s, 2H)5 2.35 (brs, 4H)
Example 100: 4-{2-[(7-Methoxynaphthalene-2-ylamino)-methyl]-3-
(naphthalene-l-yloxy)-propenyl}-N-hydroxybenzamide
Step 1: Methyl 4-{2-[(7-methoxynaphthalene-2-yIamino)-methyl]-3-
(naphthalene-l-yloxy)-propenyl}-benzoate . The procedure of Step 5 Example 39 was repeated except for using 7- methoxynaphthalene-2-ylamine as the starting material to obtain the title compound.
1H NMR (200 MHz5 CDCl3), σ 3.89 (s, 3H5 OCH3), 3.96 (s, 3H5 OCH3), 4.28 (d, J=5.4 Hz5 2H5 CH2), 4.36 (d, J=5.4 Hz5 IH5 NH)5 4.90 (s, 2H5 CH2), 6.68 (t, J=3.6 Hz, 2H, ArH), 6.99 (s, IH5 CH)5 7.05 (d, J=2.6 Hz5 IH5 ArH), 7.32 (m, 4H5 ArH)5 7.48 (m, 3H5 ArH)5 7.83 (m, IH5 ArH)5 8.16 (d, J=8.4 Hz5 2H5 ArH), 8.30 (d, J=2.6 Hz5 IH5 ArH) Step 2: 4-{2-[(7-Methoxynaphthalene-2-ylamino)-methyl]-3-
(naphthalene-l-yloxy)-propenyl}-benzoic acid
The procedure of Step 6 Example 39 was repeated except for using methyl 4- {2-[(7-methoxynaphthalene-2-ylamino)-methyl]-3-(naphthalene- 1 - yloxy)-propenyl}-benzoate to obtain the title compound.
Step 3: 4-{2-[(7-Methoxynaphthalene-2-ylamino)-methyl]-3-
(naphthaϊene-l-yloxy)-propenyl}-N-hydroxybenzamide The procedure of Step 7 of Example 39 was repeated except for using
4-2-[(7-methoxynaphthalene-2-ylamino)-methyl]-3-(naphthalene-l-yloxy)- propenyl-benzoic acid to obtain the title compound.
Example 101: 4-[2-(Pyridine-3-ylaminoraethyl)-3-(3,5-dimethoxy- phenoxy)-propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[2-(pyridine-3-ylaminomethyl)-3-(3,5-dimethoxy- phenoxy)-propenyl]-benzoate
The procedure of Step 5 A of Example 39 was repeated except for using (3-aminopyridine) as the starting material to obtain the title compound (67%).
■ 1H NMR (200 MHz3 CDCl3), σ 3.72 (S, 6H, 2OCH3), 3.89 (S, 3H, OCH3), 4.09 (S, 2H, CH2), 4.63 (S, 2H, CH2), 4.71 (m, IH, NH), 6.06 (m, 3H, ArH), 6.85 (S, IH5 CH), 6.96 (m, IH, ArH), 7.12 (m, IH, ArH), 7.27 (d, 2H J=8. IHz, ArH), 8.96 (d, 2H J=8. IHz, ArH)5 8.18 (m, IH, ArH)
Step 2: 4-[2-(Pyridine-3-ylaminomethyl)-3~(3,5-dimethoxy-phenoxy)- propenyLj-benzoic acid
The procedure of Step 6 Example 39 was repeated except for using methyl 4-[2-(pyridine-3-ylaminomethyl)-3-(3,5-dimethoxy-ρhenoxy)- propenylj-benzoate to obtain the title compound (99%).
1H NMR (200 MHz, CDCl3), σ 3.69 (S, 6H, 2OCH3), 4.22 (S, 2H, CH2), 4.77 (S, 2H5 CH2), 6.09 (m, 3H5 ArH)5 6.98 (S5 IH5 CH)5 6.96 (m, IH5 ArH)5 7.12 (m, IH, ArH)5 7.27 (d, 2H J=8.1Hz, ArH)5 8.96 (d, 2H J=8.1Hz5 ArH), 8.18 (m, IH5 ArH)
Step 3: 4-[2-(Pyridine-3-yIaminomethyl)-3-(3,5-dimethoxy-plienoxy)- propenyl] -N-hyd roxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using
4-[2-(pyridine-3-ylaminomethyl)-3-(355-dimethoxy-phenoxy)-propenyl]- benzoic acid to obtain the title compound (73 %).
1H NMR (200 MHz5 CDCl3), σ 3.71 (S5 6H5 2OCH3), 4.23 (S, 2H, CH2), 4.75
(S5 2H, CH2), 6.08 (m, 3H, ArH), 7.01 (S, IH5 CH), 6.96 (m, IH5 ArH), 7.14
(m, IH5 ArH), 7.28 (d, 2H J=8.1Hz, ArH), 8.97 (d, 2H J=8.1Hz, ArH)5 8.19
(m, IH5 ArH)
Example 102: 4-[3-(3-Methoxy phenylsulfenyl)-2-(quinoline-3- ylaminomethyl)-propenyl]-N-hydroxy~benzamide
Step 1: Methyl 4-[2-/-?r/-butoxycarbonyl-3-(3-methoxy phenylsulfenyl) propenyl ]-benzoate The procedure of Step 1 of Example 39 was repeated except for using
3-methoxy phenylsulfen as the starting material to obtain the title compound
(95%).
1H NMR (200 MHz, CDCl3), σ 1.54 (S5 9H5 3CH3), 2.43 (S, 3H5 CH3), 3.90 (S5 3H, OCH3), 4.68 (S, 2H5 CH2), 6.82 (d, 2H J=8.9Hz, ArH), 7.23 (d, 2H J=9.0Hz, ArH), 7.32 (d, 2H J=8.14Hz, ArH), 7.89 (S5 IH5CH), 8.01 (d, 2H J=7.7Hz, AiΗ)
Step 2: Methyl 4-[2-carboxy-3-(3-methoxy phenylsulfenyl) propenyl]- benzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-fer£-butoxycarbonyl-3-(3-methoxy phenylsulfenyl) propenyl ]- benzoate to obtain the title compound (99%). 1H NMR (200 MHz5 CDCl3), σ 2.41 (S, 3H, CH3), 3.89 (S, 3H, OCH3), 4.69 (S, 2H, CH2), 6.82 (d, 2H J=8.9Hz, ArH)3 7.23 (d, 2H J=9.0Hz, ArH), 7.32 (d, 2H J=8.14Hz, ArH), 7.89 (S, IH5CH), 8.01 (d, 2H J=7.7Hz, ArH)
Step 3: Methyl 4-[2-hydroxymethyl-3-(3-methoxy phenylsulfenyl) propenylj-benzoate
The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(3-methoxy phenylsulfenyl) propenyl]-benzoate to obtain the title compound (78 % ).
1H NMR (200 MHz, CDCl3), σ 3.71 (S5 3H5 CH3), 3.80 (S5 2H5 CH2), 3.90 (S5 3H5 OCH3), 4.38 (S5 2H5 CH2), 6.82 (d, 2H J=8.9Hz5 ArH), 6.89 (S5 IH5CH)5 7.23 (d, 2H J=9.0Hz, ArH)5 7.32 (d, 2H J=8.14Hz5 ArH)5 8.01 (d, 2H J=7.7Hz, ArH)
Step 4: Methyl 4-[2-bromomethyl-3-(3-methoxy phenylsulfenyl) propenylj-benzoate
The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(3-methoxy phenylsulfenyl) propenyl]- benzoate to obtain the title compound (74%).
1H NMR (200 MHz5 CDCl3), σ 3.71 (S, 3H5 CH3), 3.80 (S5 2H5 CH2), 3.90 (S5 3H, OCH3), 4.38 (S5 2H5 CH2), 6.82 (d, 2H J=8.9Hz, ArH), 6.89 (S, IH5CH)5 7.23 (d, 2H J=9.0Hz5 ArH)5 7.32 (d, 2H J=8.14Hz, ArH)5 8.01 (d, 2H J=7.7Hz5 ArH)
Step 5: Methyl 4-[3-(3-methoxy phenylsulfenyl)-2-(quinoline-3- ylaminomethyl)-propenyl]-benzoate The procedure of Step 5B of Example 39 was repeated except for using 4-[2-bromomethyl-3-(3-methoxy phenylsulfenyl) propenylj-benzoate to obtain the title compound (24%). 1H NMR (200 MHz5 CDCl3), σ 3.70 (S5 3H5 CH3), 3.83 (S5 2H5 CH2), 3.91 (S5 3H5 OCH3), 4.18 (d, 2H J=5.1Hz, CH2), 4.37 (m, IH5 NH), 6.71-6.89 (m, 4H5 CH5 ArH)5 7.07-7.39 (m, 4H5 ArH), 7.44 (m, 2H5 ArH)5 7.60 (m, IH, ArH)5 7.95 (m, 3H, ArH)5 8.49 (m, IH, ArH)
Step 6: 4-[3-(3-Methoxy phenylsulfenyl)-2-(quinoline-3-ylammomethyl)- propenylj-benzoic acid
The procedure of Step 6 Example 39 was repeated except for using methyl 4- [3 -(3 -methoxy phenylsulfenyl)-2-(quinoline-3 -ylaminomethyl)- propenyl]-benzoate to obtain the title compound (94 % ) .
1H NMR (200 MHz, CDCl3), σ 3.70 (S5 3H, CH3), 3.82 (S, 2H5 CH2), 4.18 (d, 2H J=5.1Hz, CH2), 6.71-6.89 (m, 4H, CH, ArH), 7.07-7.39 (m, 4H, ArH), 7.44 (m, 2H, ArH), 7.60 (m, IH, ArH), 7.95 (m, 3H5 ArH), 8.49(m, IH5 ArH)
Step 7: 4-[3-(3-Methoxy phenylsulfenyl)-2-(quinoline-3-ylaminomethyl)- propenylJ-N-hydroxy-benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[3-(3-methoxy phenylsulfenyl)-2-(quinoline-3-ylaminomethyl)-propenyl]- benzoic acid to obtain the title compound (9 %).
1H NMR (200 MHz, CDCl3), σ 3.71 (S, 3H, CH3), 3.84 (S, 2H5 CH2), 4.16 (S5 2H5 CH2), 6.71-6.89 (m, 4H, CH, ArH), 7.07-7.39 (m, 4H5 ArH), 7.44 (m, 2H, ArH)5 7.60 (m, IH, ArH), 7.95 (m, 3H, ArH), 8.49 (m, IH5 ArH)
Example 103: 4-[3-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindoϊe-2-yl)-2-
(quinoline-3-yϊaminomethyl)-propenyl]-N-hydroxy benzamide
Step 1: Methyl 4-[2-før^butoxycarbonyl-3-(l,3-dioxo-l,3,3a,4,7,7a- hexahydro-isoindole-2-yl)-propenyl]-benzoate ■ Methyl 4-(l-acetoxy-2-ter/-butoxycarbonyl-allyl)-benzoate (IV) (1.67 g, 5 mM) was dissolved in N,N-dimethylforrnamide (8 m#), to which 3a,45757a-tetrahydro-isoindole-l53-dion (831 mg, 5.5 mM) and potassium carbonate (829 mg, 6 mM) were added, followed by stirring the mixture at room temperature for 24 hours. After completing the reaction, the reaction mixture was cooled and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (58 %).
1H NMR (200 MHz, CDCl3), σ 1.51 (S, 9H5 3CH3), 2.18 (m, 2H, CH2), 2.52 (m, 2H, CH2), 2.88 (m, 2H, CH2), 3.93 (S, 3H, OCH3), 4.47 (S, 2H, CH2), 5.82 (m, 2H, ArH), 7.46 (d, 2H J=8.9Hz, ArH), 7.77 (S5 IH5CH)5 8.04 (d, 2H J=7.7Hz5 ArH)
Step 2: Methyl 4-[2-carboxy~3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro- isoindole-2-yl)-propenyl]-benzoate
The procedure of Step 2 of Example 39 was repeated except for using methyl 4-[2-ter£-butoxycarbonyl-3-(l ,3-dioxo- 1 ,3,3a,4,7,7a-hexahydro- isoindole-2-yl)-propenyl]-benzoate to obtain the title compound (99 % ).
1H NMR (200 MHz5 CDCl3), σ 2.18 (m, 2H, CH2), 2.51 (m5 2H5 CH2), 2.86 (m, 2H5 CH2), 3.91 (S, 3H, OCH3), 4.45 (S, 2H, CH2), 5.82 (m, 2H, ArH), 7.46 (d, 2H J=8.9Hz, ArH), 7.77 (S5 IH5CH)5 8.04 (d5 2H J=7.7Hz, ArH)
Step 3: Methyl 4-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-isoindole-2-yl)-2- hydroxymethyl-propenyl]-benzoate
The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(l53-dioxo-l53,3a,4,757a-hexahydiO-isoindole-2-yl)- propenyl]-benzoate to obtain the title compound (69 % ).
1H NMR (200 MHz, CDCl3), σ 2.20 (m, 2H5 CH2), 2.56 (m5 2H, CH2), 3.05 (m, 2H5 CH2), 3.92 (S, 3H5 OCH3), 4.03 (S, 2H, CH2), 4.44 (S5 2H, CH2), 5.89 (m, 2H5 ArH), 6.71 (S, IH5CH), 7.46 (d, 2H J=8.9Hz, ArH)5 8.02 (d5 2H J=7.7Hz, ArH)
Step 4: Methyl 4-[2-Bromomethyl-3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro- isoindole-2-yl)-propenyl]-benzoate The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[3-(l,3-dioxo-l53j3a,4,7.7a-hexahydiO-isoindole-2-yl)-2- hydroxymethyl-propenyl]-benzoate to obtain the title compound (97%).
1H NMR (200 MHz, CDCl3), σ 2.15 (m, 2H, CH2), 2.59 (m, 2H, CH2), 3.03 (m, 2H, GH2), 3.91 (S5 3H5 OCH3), 3.99 (S, 2H5 CH2), 4.47 (S, 2H, CH2), 5.89 (m, 2H5 ArH), 6.87 (S, IH5CH)5 7.44 (d, 2H J=8.9Hz, ArH)5 8.02 (d, 2H J=7.7Hz, ArH)
Step 5: Methyl 4-[3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro-isoindoIe-2-yI)-2- (quinoline-3-ylaminomethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro- isoindole-2-yl)-propenyl]-benzoate to obtain the title compound (53 %).
1H NMR (200 MHz, CDCl3), σ 2.17 (m, 2H, CH2), 2.55 (m, 2H, CH2), 2.95 (m, 2H5 CH2), 3.81 (d, 2H J=5.7 Hz5 CH2), 3.89 (S5 3H5 OCH3), 4.37 (S5 2H, CH2), 5.81 (m, 2H5 ArH)5 6.81 (S5 IH5CH)5 7.02 (m, IH, ArH)5 7.42 (m, 5H5 ArH)5 7.58 (m, 2H, ArH)5 7.97 (m, 3H, ArH), 8.49 (m5 IH5 ArH)
Step 6: 4- [3-(l ,3-Dioxo-l ,3,3a,4,7,7a-hexahydro-isoindole-2-yl)-2- (quinoline-3-ylaminomethyl)-propenyI]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[3-(l,3-dioxo-l,3,3a545757a-hexahydro-isoindole-2-yl)-2-(quinoline- 3-ylaminomethyl)-ρropenyl]-benzoate to obtain the title compound (65 %).
1H NMR (200 MHz5 CDCl3), σ 2.17 (m, 2H5 CH2), 2.55 (m, 2H, CH2), 2.95 (m, 2H, CH2), 3.94 (S, 2H, CH2), 4.38 (S5 2H5 CH2), 5.81 (m, 2H5 ArH), 6.81 (S5 IH5CH)5 7.02 (m, IH5 ArH)5 7.42 (m, 5H, ArH)5 7.58 (m, 2H5 ArH), 7.97 (m, 3H, ArH), 8.49 (m, IH, ArH)
Step 7: 4-[3-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindole-2-yl)-2- (quinoline-3-ylaminomethyl)-propenyl]-N-hydroxy benzamide The procedure of Step 7 of Example 39 was repeated except for using 4-[3-(l53-dioxo-l5353a54.757a-hexahydro-isoindole-2-yl)-2-(quinoline-3- ylaminomethyl)-propenyl]-benzoic acid to obtain the title compound (32%).
1H NMR (200 MHz5 CDCl3), σ 2.17 (m, 2H5 CH2), 2.51 (m5 2H5 CH2), 2.95 (m, 2H5 CH2), 3.97 (S5 2H5 CH2), 4.41 (S5 2H, CH2), 5.67 (m, 2H5 ArH)5 6.81 (S3 IH5CH), 7.02 (m, IH5 ArH), 7.45 (m, 5H, ArH), 7.61 (m, 2H5 ArH)5 7.97 (m, 3H, ArH), 8.45 (m, IH5 ArH)
Example 104: 4-[3-(2-Oxo-pyrrolidine-l-yI)-2-(quinoIine-3- ylaminomethyl)-propenyl]-N-hydroxy benzamide
Step 1: Methyl 4-[2-tert-butoxycarbonyl-3-(2-oxo-pyrroIidine-l-yI)- propenylj-benzoate
The procedure of Step 1 of Example 102 was repeated except for using 2-oxo-pyrrolidine as the starting material to obtain the title compound (26%).
1H NMR (200 MHz5 CDCl3), σ 1.94 (S5 9H5 CH3), 2.03 (dd, 2H J=7.5 1.2 Hz, CH2), 2.41 (t, 2H, CH2), 3.15 (t, 2H, CH2), 3.91 (S, 3H, OCH3), 4.09 (S, 2H, CH2), 6.75 (S, IH5CH), 7.26 (d, 2H J=8.1 Hz, AiH), 8.04 (d, 2H J=8.2 Hz5 ArH)
Step 2: Methyl 4-[2-carboxy-3-(2-oxo-pyrrolidine-l-yl)-propenyl]- benzoate The procedure of Step 2 of Example 39 was repeated except for using methyl 4- [2-terf-butoxycarbonyl-3 -(2-oxo-pyrrolidine- 1 -yl)-propenyl]- benzoate to obtain the title compound (99%).
1H NMR (200 MHz5 CDCl3), σ 2.03 (m, 2H, CH2), 2.41 (t, 2H5 CH2), 3.15 (t, 2H, CH2), 3.91 (S, 3H, OCH3), 4.09 (S5 2H5 CH2), 6.75 (S, IH5CH)5 7.26 (d, 2H J=8.1 Hz5 ArH)5 8.04 (d, 2H J=8.2 Hz5 ArH)
Step 3: Methyl 4-[2-hydroxymethyl-3-(2-oxo-pyrrolidine-l-yl)-propenyl]- benzoate
The procedure of Step 3 of Example 39 was repeated except for using methyl 4-[2-carboxy-3-(2-oxo-pyrrolidine-l-yl)-propenyl]-benzoate to obtain the title compound (55%). 1H NMR (200 MHz5 CDCl3), σ 2.01 (dd, 2H J=7.5 1.2 Hz5 CH2), 2.42
(t, 2H5 CH2), 3.17 (V2H, CH2), 3.93 (S5 3H5 OCH3), 4.09 (S5 2H5 CH2), 4.16 (S5 2H5 CH2), 6.75 (S, IH5 CH), 7.26 (d, 2H J=8.1 Hz, ArH)5 8.04 (d, 2H J=8.2 Hz, ArH)
Step 4: Methyl 4-[2-bromomethyl-3-(2-oxo-pyrroIidine-l-yI)-propenyl]- benzoate
The procedure of Step 4B of Example 39 was repeated except for using methyl 4-[2-hydroxymethyl-3-(2-oxo-pyrrolidine-l-yl)-propenyl]- benzoate to obtain the title compound (49%). 1H NMR (2OQ MHz5 CDCl3), σ 1.91 (m, 2H, CH2), 2.29 (t, 2H5 CH2),
3.22 (t, 2H, CH2), 3.92 (S, 3H5 OCH3), 4.09 (S, 2H, CH2), 4.25 (S, 2H, CH2), 6.94 (S, IH, CH)5 7.31 (d, 2H J=8.1 Hz, ArH), 8.02 (d, 2H J=8.2 Hz5 ArH)
Step 5: Methyl 4-[3-(2-oxo-pyrrolidine-l-yl)-2-(quinoline-3- ylaminomethyl)-propenyl] -benzoate
The procedure of Step 5B of Example 39 was repeated except for using methyl 4-[2-bromomethyl-3-(2-oxo-pyrrolidine-l -yl)-propenyl]- benzoate to obtain the title compound (30%).
1H NMR (200 MHz5 CDCl3), σ 1.88 (m, 2H5 CH2), 2.37 (t, 2H5 CH2), 3.11 (t, 2H5 CH2), 3.93 (d, 2H j=4.9 Hz5 CH2), 3.90 (S5 3H5 OCH3), 4.11 (S5 2H5 CH2), 5.19 (m, IH5 NH)5 6.93 (S5 IH5 CH)5 7.07 (m, IH5 ArH)5 7.20 (d, 2H J=8.1 Hz, ArH), 7.40 (m, 2H, ArH), 7.58 (m, IH5 ArH)5 7.96 (m, 3H, ArH), 8.54 (m, IH5 ArH)
Step 6: 4-[3-(2-Oxo-pyrrolidine-l-yl)-2-(quinoline-3-ylaminomethyl)- propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[3-(2-oxo-pyrrolidine- 1 -yl)-2-(quinoline-3-ylaminomethyl)- propenyl]-benzoate to obtain the title compound (90%).
1H NMR (200 MHz5 CDCl3), σ 1.88 (m, 2H, CH2), 2.37 (t, 2H, CH2), 3.11 (t, 2H. CH2), 3.91 (s, 2H, CH2), 4.11 (S5 2H5 CH2), 5.19 (m, IH5 NH)5 6.93 (S5 IH5 CH)5 7.07 (m, IH, ArH)5 7.20 (d, 2H J=8.1 Hz5 ArH)5 7.40 (m, 2H5 ArH)5 7.58 (m, IH5 ArH)5 7.96 (m5 3H5 ArH)5 8.54 (m, IH5 ArH)
Step 7: 4- [3-(2-Oxo-pyrrolidine-l-yl)-2-(quinoline-3-ylaminomethyl)- propenyl]-N-hydroxy benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[3-(2-oxo-pyrrolidine-l-yl)-2-(quinoline-3-ylaminomethyl)-ρropenyl]- benzoic acid to obtain the title compound (45%).
1H NMR (200 MHz5 CDCl3), σ 1.88 (m, 2H5 CH2), 2.37 (t, 2H5 CH2), 3.16 (t. 2H5 CH2), 3.94 (s, 2H, CH2), 4.11 (S5 2H5 CH2), 5.19 (m, IH5 NH)5 6.99 (S5 IH5 CH)5 7.07 (m, IH5 ArH)5 7.20 (d, 2H J=8.1 Hz, ArH)5 7.40 (m, 2H5 ArH)5 7.62 (m, 4H5 ArH)5 8.54 (m, IH5 ArH)
Example 105: 4-[3-(6-DimethyIaminomethyl-quinoIine-3-ylamino)-2- methyl-propenyϊ]-N-hydroxy benzamide
Step 1: Methyl 4-[3-(6-dimethylaminomethyl-quinoline-3-ylamino)-2- methyl-propenyl]-benzoate
The procedure of Step 1 of Example 1 was repeated except for using 6-dimethylaminomethyl-quinoline-3-ylamine as the starting material to obtain the title compound (56%).
1H NMR (200 MHz5 CDCl3) δ 8.49 (d, J=2.8 Hz5 IH)5 7.86-8.07 (m, 3H)5 7.28-7.55 (m, 4H)5 7.04 (d, J=3.0 Hz, IH), 6.62 (s, IH), 4.43 (brs5 IH)5 3.98 (d, J=5.8 Hz5 2H)5 3.92 (s, 3H)5 3.57 (s, 2H)5 2.30 (s, 6H)5 1.99 (s, 3H)
Step 2: 4-[3-(6-Dimethylaminomethyl-quinolme-3-ylamino)-2-methyl- propenyl]-benzoic acid The procedure of Step 2 of Example 1 was repeated except for using methyl 4- [3-(6-dimethylaminomethyl-quinoline-3 -ylamino)-2-methyl- propenyl]-benzoate to obtain the title compound (98%).
1H NMR (200 MHz, CD3OD) δ 8.58 (s, IH)5 7.87-8.08 (m, 4H), 7.22-7.62 (m, 4H)5 6.66 (s, IH)5 4.44 (d, J=2.6 Hz5 2H)5 4.03 (s, 2H)5 2.90 (s, 6H)5 2.00 (s, 3H)
Step 3: 4-[3-(6-Dimethylaminomethyl-quinoIine-3-ylamino)-2-methyl- propenyl]-N-hydroxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[3-(6-dimethylaminomethyl-quinoline-3-ylamino)-2-methyl-propenyl]- benzoic acid to obtain the title compound (48%).
1H NMR (200 MHz5 DMSO-d6) δ 11.22 (s, IH)5 9.02 (brs, IH)5 8.55 (s, IH)5 7.55-81 (m5 3H)5 7.31-7.41 (m, 3H)5 6.57-7.14 (m, 3H)5 3.91 (d, J=5.2 Hz5 2H), 3.76 (s, 2H)5 2.51 (s, 3H)5 2.34 (s, 6H)
Example 106: 4-[3-(6-DimethyIaminomethyl-quinoline-3-ylamino)-2- (naphthalene-1 -yloxymethyl)-propenyl]-N-hydroxy benzamide
Step 1: Methyl 4-[3-(6-dimethylammomethyI-quinoline-3-yIamino)-2- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 6-dimethylaminomethyl-quinoline-3-ylamine as the starting material to obtain the title compound (20 % ).
1H NMR (200 MHz5 CDCl3) δ 7.76-8.45 (m, 6H)5 7.18-7.56 (m, 8H)5 6.68- 7.18 (m, 3H)5 4.91 (s, 2H)5 4.63 (brs, IH)5 4.31 (d, J=4.8 Hz5 2H)5 3.91 (s, 3H), 3.55 (s, 2H)5 2.29 (S3 6H)
Step 2: 4-[3-(6-DimethyIaminomethyl-quinoline-3-yIamino)-2-
(naphthalene-l-yϊoxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[3-(6-dimethylaminomethyl-quinoline-3-ylamino)-2-(naphthalene- l-yloxymethyl)-propenyl]-benzoate to obtain the title compound (86%).
1H NMR (200 MHz5 CD3OD) δ 7.76-8.51 (m. 6H), 7.22-7.53 (m, 8H)5 6.64- 7.14 (m, 3H)5 4.92 (s, 2H)54.27 (d, J=7.4 Hz5 2H)5 4.13 (s, 2H)5 2.67 (s, 6H)
Step 3: 4-[3-(6-DimethyIaminomethyl-quinoline-3-ylamino)-2-
(naphthalene-l-yloxymethyl)-propenyl]-N-hydroxy benzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[3-(6-dimethylaminomethyl-quinoline-3-ylamino)-2-(naphthalene-l- yloxymethyl)-propenyl]-benzoic acid to obtain the title compound (56%).
1H NMR (200 MHz5 DMSO-d6) δ 11.12 (s, IH)5 9.02 (brs5 IH)5 8.18-8.53 (m, 2H)5 7.29-7.89 (m5 HH)5 6.80-7.111 (m, 4H)5 5.02 (s, 2H)5 4.18 (d, J=I 0.6 Hz5 2H)5 3.44 (s, 2H)5 2.52. (s, 6H)
Example 107: 4-[3-(6-PyrroIidine-l-ylmethyl-quinoIine-3-ylamino)-2- methyl-propenyl]-N-hydroxybenzamide
Step 1: Methyl 4-[3-(6-pyrrolidine-l-yImethyI-quinolme-3-ylamino)-2- methyl-propenyl]-benzoate
The procedure of Step 1 of Example 1 was repeated except for using 6-pyrrolidine-l-ylmethyl-quinoline-3-ylamine as the starting material to obtain the title compound (34%).
1H NMR (200 MHz5 CDCl3) δ 8.50 (d, J=3.0 Hz5 IH)5 7.58-8.06 (m, 3H)5 7.66 (s5 IH)5 7.28-7.49 (m, 3H)5 7.04 (d, J=3.0 Hz5 IH)5 6.60 (s, IH)5 4.53 (t, J=6.6 Hz5 IH)5 3.95 (d, J=6.6 Hz, 2H)5 3.91 (s, 3H)5 3.85 (s, 2H)5 2.70 (brs, 4H), 1.98 (s5 3H)5 1.87 (brs5 4H)
Step 2: 4-[2-MethyI-3-(6-pyrrolidine-l-ylmethyl-quinoline-3-ylamino)- propenyl] -benzoic acid
The procedure of Step 2 of Example 1 was repeated except for using methyl 4-[3-(6-pyrrolidine-l-ylmethyl-quinoline-3-ylamino)-2-methyl- propenyl]-benzoate to obtain the title compound (72%).
1H NMR (200 MHz5 CD3OD) δ 8.55 (s, IH), 7.82-8.05 (m, 4H)5 7.16-7.55 (m, 4H)5 6.63 (s, IH)5 4.47 (s, 2H)5 3.99 (s, 2H), 3.33 (brs, 4H)5 2.11 (brs, 4H)5 1.98 (s, 3H)
Step 3: 4-[3-(6-Pyrrolidine-l-yϊmethyl-quinoline-3-ylaraino)-2-methyl- propenyl] -N-hy droxy benzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-[2-methyl-3-(6-pyrrolidine- 1 -ylmethyl-quinoline-3-ylamino)-propenyl]- benzoic acid to obtain the title compound.
1H NMR (200 MHz, DMSO-d6) δ 11.21 (s, IH), 9.02 (s, IH), 8.52 (s, IH), 7.31-7.79 (m, 6H)5 7.03 (s, IH)5 6.78 (s, IH)5 6.57 (s, IH), 3.90 (d, J=4.8 Hz, 2H)5 3.77 (s, 2H), 2.57 (brs, 4H)5 1.93 (s, 3H)5 1.73 (brs, 4H)
Example 108: 4-[3-(6-Pyrrolidine-l-ylmethyI-quinoline-3-yIamino)-2- (naphthalene-l-yloxymethyI)-propenyl]-N-hydroxybenzamide Step 1: Methyl 4-[3-(6-pyrrolidine-l-yImethyl-quinoline-3-yIamino)-2- (naphthalene-l-yloxymethyl)-propenyl]-benzoate
The procedure of Step 5B of Example 39 was repeated except for using 6-pyrrolidine-l-ylmethyl-quinoline-3-ylamine as the starting material to obtain the title compound (25 %).
1H NMR (200 MHz, CDCl3) δ 7.78-8.42 (m, 6H), 7.28-7.57 (m, 8H)5 6.65- 7.07 (m, 3H), 4.88 (s, 2H), 4.24 (d, J=12.4 Hz, 2H), 3.90 (s, 3H), 3.78 (s, 2H), 2.64 (brs, 4H)5 1.83 (brs, 4H)
Step 2: 4-[3-(6-Pyrrolidine-l-ylmethyl-quinoline-3-ylamino)-2- (naphthalene-l-yloxymethyl)-propenyl]-benzoic acid
The procedure of Step 6 of Example 39 was repeated except for using methyl 4-[3-(6-pyrrolidine-l-ylmethyl-quinoline-3-ylamino)-2-(naρhthalene- l-yloxymethyl)-propenyl]-benzoate to obtain the title compound (98%). 1H NMR (200 MHz5 CD3OD) δ 7.81-8.53 (m, 7H)5 6.64-7.61 (m, 10H)5 4.94 (s, 2H), 4.42 (S5 2H)5 4.29 (d, J=7.4 Hz5 2H), 3.30 (brs, 4H)5 1.99 (brs5 4H)
Step 3: 4-[3-(6-PyrroIidine-l-ylmethyl-quinoline-3-ylamino)-2-
(naphthalene-l-yIoxymethyI)-propenyl]-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-[3 -(6-pyrrolidine- 1 -ylmethyl-quinoline-3 -ylamino)-2-(naρhthalene- 1 - yloxymethyl)-piOpenyl]-benzoic acid to obtain the title compound (39%).
1H NMR (200 MHz3 DMSO-d6) δ 11.21 (s, IH), 9.02 (s, IH), 7.33-8.54 (m, 13H), 6.72-7.14 (m5 4H)5 4.94 (s, 2H)5 4.20 (d, J=I 8.6 Hz5 2H)5 3.81 (s, 2H)5 3.35 (brs, 4H)5 1.77 (brs, 4H)
Example 109: 4-{3-[6-(4-Methyl-piperazme-l~yϊmethyl)-q«inoϊine-3- ylamino]-2-methyl-propenyI}-N-hydroxybenzamide Step 1: Methyl 4-{3-[6-(4-methyl-piperazine-l-yImethyl)-quinoϊine-3- ylamino]-2-methyl-propenyl}-benzoate
The procedure of Step 1 of Example 1 was repeated except for using 4-methyl-piperazine as the starting material to obtain the title compound (79%).
1H NMR (200 MHz5 CDCl3) δ 8.48 (d, J=3.0 Hz5 IH)5 7.86-8.08 (m, 3H), 7.28-7.53 (m, 4H), 7.05 (d, J=3.0 Hz, IH)5 6.62 (s, IH)5 4.04 (t, J=5.8 Hz5 IH)5 3.98 (d, J=5.8 Hz5 2H), 3.93 (s, 3H), 3.64 (s, 2H)5 2.54 (brs, 8H), 2.33 (s, 3H)5 2.00 (s, 3H)
Step 2: 4-{3-[6-(4-Methyl-piperazine-l-ylmethyl)-quinoline-3-ylamino]-2- methyl-propenyl}-benzoic acid The procedure of Step 2 of Example 1 was repeated except for using methyl 4-3-[6-(4-methyl-piperazine-l-ylmethyl)-quinoline-3-ylamino]-2- methyl-propenyl-benzoate to obtain the title compound (97%). 1H NMR (200 MHz5 CD3OD) δ 8.49 (d, J=2.6 Hz5 IH), 7.32-8.08 (m, 7H)5 7.15 (d, J=2.2 Hz5 IH)5 6.64 (s5 IH)5 3.99 (s5 2H)5 3.77 (s, 2H)5 3.23 (brs, 4H)5 2.83 (s, 3H)5 2.79 (brs5 4H)5 1.98 (s, 3H)
5 Step 3: 4-{3-[6-(4-MethyI-piperazine-l-ylraethyl)-quinoline-3-ylamino]-2- methyl-propenyl}-N-hydroxybenzamide
The procedure of Step 3 of Example 1 was repeated except for using 4-3-[6-(4-methyl-piperazine-l-yhnethyl)-quinoline-3-ylamino]-2-metriyl- propenyl-benzoic acid to obtain the title compound (67%). 10
1H NMR (200 MHz5 DMSO-d6) δ 11.19 (s, IH)5 9.01 (s, IH)5 8.51 (d, J=3.0 Hz5 IH)5 7.24-7.80 (m, 6H)5 7.03 (d, J=2.6 Hz5 IH), 6.57-6.75 (m, 2H)5 3.90 (d, J=4.4 Hz, IH), 3.53 (s, 2H)52.32 (brs, 3H), 2.15 (brs, 3H)5 1.93 (s, 3H)
-15 Example 110: 4-{3-[6-(4-Methyl-piperazine-l-ylraethyl)-q«moϊine-3- yIamino]-2-(naphthalene-l-yloxymethyl)-propenyl}-N- hydroxybenzamide
Step 1: Methyl 4-{3-[6-(4-methyl-piperazine-l-ylmethyl)-qumoline-3- ylamino]-2-(naphthalene-l-yloxymethyl)-propenyl}-benzoate
20 The procedure of Step 5B of Example 39 was repeated except for using 4-methyl-piperazine as the starting material to obtain the title compound (42%).
1H NMR (200 MHz, CDCl3) δ 7.78-8.45 (m, 6H)5 6.69-7.56 (m, HH), 4.86 25 (s, 2H), 4.43 (brs, IH), 3.95 (s, 2H), 3.91 (s, 3H), 3.60 (s, 2H), 2.59 (brs, 8H), 2.36 (S5 3H)
Step 2: 4-{3-[6-(4-methyl-piperazine-l-ylmethyl)-quinoline-3-ylamino]-2- (naphthalene-l-yloxymethyl)-propenyl}-benzoic acid
30 The procedure of Step 6 of Example 39 was repeated except for using methyl 4-{3-[6-(4-methyl-piperazine-l-ylmethyl)-quinolme-3-ylamino]-2- (naphthalene-l-yloxymethyl)-propenyl}-benzoate to obtain the title compound (95%). 1H NMR (200 MHz, CD3OD) δ 7.71-8.45 (m, 6H)5 6.72-7.56 (m, HH)5 4.95 (s5 2H)5 4.30 (d5 J=4.8 Hz5 2H)5 3.68 (s5 2H)5 3.24 (brs5 4H)5 2.84 (s5 3H)5 2.76 (brs, 4H)
Step 3: 4-{3-[6-(4-methyl-piperazine-l-ylmethyl)-quinoline-3-ylamino]-2- (naphthaIene-l-yIoxymethyI)-propenyl}-N-hydroxybenzamide
The procedure of Step 7 of Example 39 was repeated except for using 4-{3-[6-(4-methyl-piperazine-l-ylmethyl)-quinoline-3-ylamino]-2- (naphthalene- l-yloxymethyl)-propenyl} -benzoic acid to obtain the title compound (72 % ).
1H NMR (200 MHz5 DMSO-d6) δ 11.20 (s, IH)5 9.02 (s, IH)5 8.53 (d5 J=2.6 Hz5 IH)5 8.21 (d5 J=7.6 Hz5 IH)5 7.57-7.94 (m5 4H)5 6.77-7 '.49 (m5 HH)5 4.94 (ss 2H)5 4.23 (d, J=5.8 Hz5 2H), 3.56 (s5 2H), 2.75 (brs,.4H), 2.50 (brs, 4H)5 2.44 (s5 3H)
Test Example 1
HDAC activity was analized using BIOMOL Quantizyme™ Assay system which comprised two steps of 1) enzyme reaction between HDAC and an HDAC inhibitor and 2) determination of the level of HDAC inhibitory activity. In step I)5 42 ≠ of a buffer solution (25 mM Tris-HCl [pH 8.0], 137 mM NaCl5 2.7 mM KCl5 1 mM MgCl2) and 5 ≠ of 250 μM Fluor de Lys™ substrate were added to each well of a 96-well plate, to which 2.5 βi of a test compound was added. 0.5 βi of HeLa nuclear extract( 10 μM) (a source of HDAC enzymes) was then added thereto to a final concentration of 10OnM. The enzyme reaction was carried out for 1 hour. Subsequently, in step 2), 2 μM tricostatin A was added to 50 μi of Flour de Lys™ 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 increased as the enzyme activity became higher. The HDAC inhibitory activity of each of the test compounds was determined and compared with that- of the control.
The HDAC inhibitory concentrations of the compounds according to the present invention are shown in Table 1.
Table 1
Figure imgf000144_0001
As shown in Table 1, each of the inventive arylaminomethyl propenyl benzhydroxyamide derivatives of formula (I) has a markedly higher inhibitory activity against HDAC.
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made and also fall within the scope of the invention as defined by the claims that follow.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000146_0001
wherein,
Ri is hydrogen, aryloxy, arylthio, arylimido, Ci-5 alkylimido, arylamido, Ci-5 alkylamido or arylsulfonamido, in which the aryl is phenyl, naphthyl or carbazole, each being optionally substituted with one or more substituents selected from the group consisting of hydroxy, Ci-5 alkyloxy, Ci-5 alkyl, aryl, Cj-5 alkylamino, cyano, cyanophenyl, Ci-5 alkylthio and nitro;
R2 is phenyl which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C 1.5 alkyloxy, Cj-5 alkyl, Ci-5 alkylamino, cyano, cyanophenyl and mercaptoalkyl; or heteroaryl selected from the group consisting of piperazine, triazole, thiazole, benzothiazole, dibenzofurane, pyridine, quinoline and isoquinoline, the heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-5 alkyloxy, amino Ci-5 alkyloxy, Ci-5 alkyl, amino Ci-5 alkyl, Ci-5 alkylamino, aryl Ci-5 alkylamino and aryloxy Ci-5 alkylamino; and
R3 is hydroxyamino.
2. The compound of claim 1, which is selected from the group consisting of:
4-[3-(quinoline-3-ylammo)-2-methylpropenyl]-N-hydroxy benzamide;
4-[3-(3-benzyloxy-phenylamino)-2-methylpropenyl]-N-hydroxy benzamide; 4-[3 -(3 ,4-dihydro- 11 H-isoquinoline-2-yl)-2-methylpropenyl]-N- hydroxy benzamide;
4-[3-(quinoline-8-ylamino)-2-methylproρenyl]-N-hydroxy benzamide; 4-[3-(4-phenyloxy-phenylamino)-2-methylpropenyl]-N-hydiOxy benzamide;
4-[3-(4-dimethylamino-phenylamino)-2-methylpropenyl]-N-hydroxy benzamide;
4-[3-(quinoline-5-ylamino)-2-methylpropenyl]-N-hydroxy benzamide; 4- [3 -(quinoline-3 -ylammo)-2-methylpropenyl] -N-hydroxy benzamide; 4-[3-(5-hydroxy-naphthalene-l-ylamino)-2-methylρropenyl]-N- hydroxy benzamide;
4-[3-(benzo[1.255]thiadiazol-4-ylamino)-2-methylρropenyl]-N- hydroxy benzamide;
4- [3 -(antracene- 1 -ylamino)-2-methylpropeny 1] -N-hydroxy benzamide;
4-[3-(456-dihydropyrene-l-ylamino)-2-methylpropenyl]-N-hydroxy benzamide;
4-[3-(4-methyl-2-2H-chromene-7-ylamino)-2-methylpropenyl]-N- hydroxy benzamide; 4-[3-(3-benzyloxypyridine-2-ylamino)-2-methylpropenyl]-N-hydiOxy benzamide;
4-[3-(9-ethyl-9H-carbazol-2-ylamino)-2-methylpropenyl]-N-hydroxy benzamide;
4-[3-(5-methyl-lH-pyrazol-3-ylamino)-2-methylproρenyl]-N-hydroxy benzamide;
4-[3-(5-methylsulfenyl- IH-[1 ,254]triazol-3-ylamino)-2- methylpropenyl] -N-hydroxy benzamide;
4-[3-(3-methoxy phenylamino)-2-methylpropenyl]-N-hydroxy benzamide; 4- [3 -(naphthalene- 1 -ylamino)-2-methylpropenyl]-N-hydroxy benzamide;
4-[3-(naphthalene-2-ylamino)-2-methylpropenyl]-N-hydroxy benzamide; 4-[3-(biphenyl-4-ylamino)-2-methylpropenyl]-N-hydroxy benzamide;
4-[3-(6-nitrobenzothiazol-2-ylamino)-2-methylpropenyl]-N-hydiOxy benzamide;
4-[3-(6-methoxybenzothiazol-2-ylamino)-2-methylpropenyl]-N- hydroxy benzamide;
4-[3-(2-meth.oxydibenzofuran-3-ylamino)-2-methylpiOpenyl]-N- hydroxy benzamide;
4-[3-(6-methoxypyridine-3-ylamino)-2-methylpropenyl]-N-hydroxy benzamide; 4-[3-(2-chloropyridine-3-ylamino)-2-methylproρenyl]-N-hydroxy benzamide;
4-[3-(6-morpholine-4-ylmethylquinoline-3-ylamino)-2-methyl- propenyl]-N-hydroxy benzamide;
4-[3-(4'-cyanobiphenyl-4-ylamino)-2-methylpropenyl]-N-hydroxy benzamide;
4-[2-methyl-3-(4-pyridine-2-ylpiperazine-l-yl)-propenyl]-N-hydroxy- benzimide;
4-[2-methyl-3-(4-phenyl-piperazine-l-yl)-propenyl]-N-hydroxy- benzimide; 4-[3-(benzyl-methylamino)-2-methyl-propenyl]-N-hydroxy- benzamide;
4-[2-methyl-3-(2-phenoxy-ethylamino)-proρenyl]-N-hydroxy- benzamide;
4-[3-(8-bromoquinoline-3-ylamino)-2-methyl-propenyl]-N-hydroxy- benzamide;
4-[3-(6-methoxyqumoline-3-ylamino)-2-methyl-proρenyl]-N- hydroxy-benzamide;
4-[3-(6-hydroxy-quinoline-3-ylamino)-2-methyl-propenyl]-N- hydroxy-benzamide; 4-[2-methyl-3-(propyl-quinoline-3-ylamino)-proρenyl]-N-hydroxy- benzamide;
4-{2-methyl-3-[(2-hydroxy-ethyl)-qumoline-3-ylamino]-propenyl}-N- hydroxy-benzamide; 4-[2-methyl-3-(formyl-quinoline-3-ylamino)-propenyl]-N-hydroxy- benzamide;
4-[2-(quinoline-3-ylaminomethyl)-3-(naphthalene- 1 -yloxy)- propenyl]-N-hydroxy-benzamide; 4-[2-(quinoline-3-ylaminomethyl)-3-(4-cyano-phenoxy)-piOpenyl]-N- hydroxy benzamide;
4-[2-(quinoline-3-ylaminomethyl)-3-(3.5-dimethoxy-ρhenoxy)- propenyl]-N-hydroxybenzamide;
4-[2-(quinoline-3-ylaminomethyl)-3-(4-benzyloxy-phenoxy)- propenyl]-N-hydroxybenzamide;
4- [2-(quiπoline-3 -ylaminomethyl)-3 -(4-fluoro-phenoxy)-propenyl]-N- hydroxybenzamide;
4-[2-(quinoline-3-ylaminomethyl)-3-(4-acetylamino-phenoxy)- propenyl]-N-hydroxybenzamide; 4-[2-(quinoline-3-ylaminomethyl)-3-(4-methylsulfenyl-phenoxy)- propenyl]-N-hydroxybenzamide;
4- [2-(quinoline-3 -ylaminomethyl)-3 -phenoxy-propenyl] -N- hydroxybenzamide;
4-[2-(quinoline-3-ylaminomethyl)-3-(4-chloro-naphthalene-l-yloxy)- propenyl]-N-hydroxybenzamide;
4-[2-(3,4-dimethoxyphenylaminomethyl)-3-(4-chloro-naphthalene-l- yloxy)-propenyl]-N-hydroxybenzamide;
4- [2-(quinoline-3 -ylaminomethyl)-3 -(3 -methoxy-phenylsulfenyl)- propenyl]-N-hydroxybenzamide; 4-[2-(quinoline-3-ylaminomethyl)-3-(3-methoxy-phenylsulfenyl)- propenyl]-N-hydroxybenzamide;
4-[2-(quinoline-3-ylaminomethyl)-3-(2-nitro-naphthalene-l-yloxy)- propenyl]-N-hydroxybenzamide;
4-[2-(3,4-dimethoxyphenylaminomethyl)-3-(9H-carbazol- 1 -yloxy)- propenyl]-N-hydroxybenzamide;
4-[2-(quinoline-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)- propenyl]-N-hydroxybenzamide; 4-[2-hydroxymethyl-3-(9H-carbazol- 1 -yloxy)-propeny I]-N- hydroxybenzamide;
4-[2-(pyridine-3-ylaminomethyl)-3-(9H-carbazol-l-yloxy)-propenyl]- N-hydroxybenzamide; 4-[2-(6-methoxypyridine-3-ylaminomethyl)-3-(9H-carbazol- 1 -yloxy)- propenyl]-N-hydroxybenzamide;
4-[2-(4-methoxyphenylaminomethyl)-3-(9H-carbazol- 1 -yloxy)- propenyl]-N-hydroxybenzamide;
4-[2-(quinoline-3-ylaminomethyl)-3-(biphenyl-4-yloxy)-propenyl]-N- hydroxybenzamide;
4-[2-(quinoline-3-ylaminomethyl)-3-(benzothiazol-2-yloxy)- propenyl]-N-hydroxy-benzamide;
4- {2- [(3 ,4-dimethoxy-phenylamino)-methyl]-3 -(benzothiazol-2- yloxy)-propenyl}-N-hydroxy-benzamide; 4-[2-(qυinoline-3-ylaminomethyl)-3-(l ,3-dioxo-l ,3-dihydro- isoindole-2-yl)-propenyl]-N-hydroxy-benzamide;
4-[2-(indan-2-ylaminomethyl)-3-(naphthalene- 1 -yloxy)-propenyl]-N- hydroxy-benzamide;
4- [3 -(naphthalene- 1 -yloxy)-2-(4-pyridine-2-yl-piperazine- 1 - ylmethyl)-propenyl]-N-hydroxy-benzamide;
4-{3-(naphthalene-l-yloxy)-2-[(2-phenoxy-ethylamino)-methyl]- propenyl} -N-hydroxy-benzamide;
4-{2-[(benzyl-methyl-amino)-methyl]-3-(naphthalene- 1 -yloxy)- propeny 1 } -N-hydroxy-benzamide; 4-[3-(6-methoxyquinoline-3-ylamino)-2-(naphthalene- 1 - yloxymethyl)-ρroρenyl]-N-hydroxy-benzamide;
4-[3-(8-bromoquinoline-3-ylamino)-2-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide;
4-[3-(5,6-dimethoxyquinolme-3-ylamino)-2-(naphthalene- 1 - yloxymethyl)-propenyl]-N-hydroxy-benzamide;
4- [2-phenylaminomethyl-3 -(naphthalene- 1 -yloxymethyl)-propenyl]- N-hydroxy-benzamide; 4-[2-(3,4-dihydro-lH-isoquinoline-2-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide;
4-[2-(2-methoxy-dibenzofuran-3-ylaminomethyl)-3-(naphthalene- 1 - yloxymethyl)-propenyl]-N-hydroxy-benzamide; 4- [2-(naphthalene- 1 -ylaminomethy l)-3 -(naphthalene- 1 -yloxymethy I)- propenyl]-N-hydroxy-benzamide;
4-[2-(quinoline-8-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide;
4-[2-(6-methoxy-pyridine-3-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide;
4-[2-(l5l-dioxo-lH-116-naρhto[l58-cd]isothiazol-2-ylmethyl)-3- (naphthalene- 1 -yloxymethyl)-propenyl]-N-hydroxy-benzamide;
4-[2-(4-methoxy-phenylaminomethyl)-3-(naphthalene- 1 - yloxymethyl)-propenyl]-N-hydroxy-benzamide; 4-[2-(thiazol-2-ylaminomethyl)-3-(naphthalene- 1 -yloxymethyl)- propenyl]-N-hydroxy-benzamide;
4-[2-(9-ethyl-9H-carbazol-3-ylaminomethyl)-3-(naρhthalene- 1 - yloxymethyl)-propenyl]-N-hydroxy-benzamide;
4-[2-(6-methoxy-benzothiazol-2-ylaminomethyl)-3-(naphthalene- 1 - yloxymethyl)-proρenyl]-N-hydroxy-benzamide;
4-[2-(naphthalene-2-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide;
4-[2-(6-nitro-benzothiazol-2-ylaminomethyl)-3-(naphthalene- 1 - yloxymethyl)-propenyl]-N-hydroxy-benzamide; 4-[2-(4-methyl-benzothiazol-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-piOpenyl]-N-hydiOxy-benzamide;
4-[2-(5,6-dimethyl-benzothiazol-2-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide;
4-[2-pyτrolidine-l-ylmethyl-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide;
4-[2-cyclopentylaminomethyl-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide; 4-[2-(l ,3-dioxo-l ,3-dihydro-isoindole-2-ylmethyl)-3-(naphthalene-l - yloxymethyl)-propenyl]~N-hydroxy-benzamide;
4-[2-dimethylaminomethyl-3-(naphthalene-l-yloxymethyl)-propenyl]- N-hydroxy-benzamide; 4-[2-azidomethyl-3-(naphthalene- 1 -yloxymethyl)-propenyl]-N- hydroxy-benzamide;
4-[2-(2,5-dioxo-2,5-dihydro-pyrrol-l-ylmethyl)-3-(naphthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide;
4-[2-(l 53-dioxo-l .3,3a,457,7a-hexahydro-isoindole-2-ylmethyl)-3- (naphthalene- 1 -yloxymethyl)-propenyl]-N-hydroxy-benzamide;
4-[2-(2-oxo-ρyrrolidine-l-ylmethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxy-benzamide;
4-[2-(2-oxo-2,3-dihydro-indole-l -ylmethyl)-3-(naρhthalene- 1 - yloxymethyl)-propenyl]-N-hydroxy-benzamide; 4-[2-(2,3-dioxo-253-dihydro-indole-l-ylmethyl)-3-(naρhthalene-l- yloxymethyl)-propenyl]-N-hydroxy-benzamide;
4-[2-(pyridine-3-ylaminomethyl)-3-(naphthalene- 1 -yloxymethyl)- propenyl]-N-hydroxybenzamide;
4-[2-(2-chloropyridine-3-ylaminomethyl)-3-(naphthalene-l- yloxymethyl)-proρenyl]-N-hydroxybenzamide;
4-[2-(3-methoxyρhenylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxybenzamide;
4-[2-(biρhenyl-4-ylaminomethyl)-3-(naphthalene-l-yloxymethyl)- propenyl]-N-hydroxybenzamide; 4-{2-[(3,4-dimethoxy-phenylamino)-methyl]-3-(naphthalene-l- yloxy)-propenyl } -N-hydroxybenzamide;
4-{2-[(7-morpholine-4-ylnaphthalene-2-ylamino)-methyl]-3- (naphthalene- 1 -yloxy)-propenyl} -N-hydroxybenzamide;
4-{2-[(7-methoxynaphthalene-2-ylamino)-methyl]-3-(naphthalene-l- yloxy)-propenyl } -N-hydroxybenzamide;
4-[2-(pyridine-3-ylaminomethyl)-3-(355-dimethoxy-ρhenoxy)- propenyl]-N-hydroxybenzamide; 4- [3 -(3 -methoxy pheny lsulfeny l)-2-(quinoline-3 -ylaminomethy I)- propenyl]-N-hydroxy-benzamide;
4- [3 -(1 ,3 -dioxo- 1.3,3 a54.757a-hexahydro-isoindole-2-yl)-2-(quinoline- 3-ylaminomethyl)-propenyl]-N-hydroxy benzamide; 4-[3-(2-oxo-pyrrolidine-l-yl)-2-(quinoline-3-ylaminomethyl)- propenyl]-N-hydroxy benzamide;
4-[3-(6-dimethylaminomethyl-quinoline-3-ylamino)-2-methyl- propenyl]-N-hydroxy benzamide;
4- [3 -(6-dimethylaminomethyl-quinoline-3 -ylamino)-2-(naphthalene- l-yloxymethyl)-ρropenyl]-N-hydroxy benzamide;
4-[3-(6-pyrrolidine-l-ylmethyl-quinoline-3-ylamino)-2-methyl- propenyl]-N-hydroxybenzamide;
4-[3-(6-pyrrolidine-l-ylmethyl-quinoline-3-ylamino)-2-(naphthalene- l-yloxymethyl)-proρenyl]-N-hydroxybenzamide; 4-{3-[6-(4-methyl-piperazine-l-ylmethyl)-quinoline-3-ylamino]-2- methy 1-propenyl } -N-hydroxybenzamide; and
4- { 3 -[6-(4-methyl-piperazine- 1 -ylmethyl)-quinoline-3 -ylamino]-2- (naphthalene- 1 -yloxymethyl)-propenyl} -N-hydroxybenzamide.
3. A method for preparing the compound of formula (I), which comprises the steps of:
1) reacting the compound of formula (II) with fer/-buthyl acrylate in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO) to obtain the Baylis-
Hillman compound of formula (III); 2) reacting the compound of formula (III) with acetylchloride (AcCl) in the presence of pyridine to obtain the compound of formula (IV);
3) treating the compound of formula (IV) with sodium borohydride (NaBH4) in tert-butanol to obtain the compound of formula (V);
4) hydrolyzing the compound of formula (V) in trifluoroacetic acid (TFA) to form methyl carboxypropenylbenzoate, which is then treated with ethyl chloroformate (ECC) and reduced with sodium borohydride (NaBH4) to obtain the compound of formula (VT);
5) reacting the compound of formula (VI) with tetrabromomethane (CBfy) in the presence of triphenylphosphine (PPh.3) to form methyl bromomethylpropenylbenzoate, which is refluxed together with an arylamine (ArNH2) to obtain the compound of formula (VII);
6) hydrolyzing the compound of formula (VII) of formula with an inorganic base to obtain the compound of formula (VIII); and
7) acylating the compound of formula (VIII) with tert- butyldimethylsilyloxyamine (NH2OTBS) in an organic solvent in the presence of N-hydroxy-6-trifluoro benzotriazole (FOBT) and l-(3- diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl) and removing the ter^butyldimethylsilyl group from the resulting product with a water-soluble inorganic acid to obtain the compound of formula (I):
Figure imgf000154_0001
Figure imgf000155_0001
wherein,
R] is hydrogen; R2 is phenyl which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, Cμ5 alkyloxy, Cj-5 alkyl, Cμ5 alkylamino, cyano, cyanophenyl and mercaptoalkyl; or heteroaryl selected from the group consisting of piperazine, triazole, thiazole, benzothiazole, dibenzofurane, pyridine, quinoline and isoquinoline, the heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, Cμ5 alkyloxy, amino C i_5 alkyloxy, Ci.5 alkyl, amino Ci_5 alkyl, Ci-5 alkylamino, aryl C1-5 alkylamino and aryloxy Cj-5 alkylamino; and
R3 is hydroxyamino.
4. The method of claim 3, wherein the ECC treatment in step 4) is carried out in tetrahydrofuran over an ice bath.
5. The method of claim 3, wherein the reaction with arylamine in step 5) is carried out in acetone or acetonitrile in the presence of potassium carbonate.
6. The method of claim 3, wherein step 6) is carried out in an aqueous alcohol solution in the presence of tetrahydiOfuran, and the inorganic base is lithium hydroxide (LiOH-H2O) or sodium hydroxide.
7. The method of claim 3, wherein step 7) is carried out in N,N- dimethylformamide, and the water-soluble inorganic acid is hydrochloric acid or sulfuric acid.
8. A method for preparing the compound of formula (I), which comprises the steps of: 1) reacting the compound of formula (III) with tribromophosphine
(PBrs) in ethyl ether to obtain the compound of formula (IX);
2) reacting the compound of formula (IX) with a nucleophilic agent (RiH) to obtain a compound of formula (X);
3) hydrolyzing the compound of formula (X) in trifluoroacetic acid (TFA) to form a methyl carboxypropenylbenzoate, which is then treated with ethyl chloroformate (ECC) and is reduced with sodium borohydride (NaBH4) to obtain a compound of formula (XT);
4) refluxing the compound of formula (XI) with manganese dioxide (MnO2) in dichloromethane to form an aldehyde, which is then reacted with an arylamine (ArNH2) or arylalkylamine in the presence of dibutyldichlorotin (Bu2SnCl2) and diphenylsilane (Ph2SiH2) to obtain a compound of formula (XII);
5) treating the compound of formula (XII) with an inorganic base to obtain a compound of formula (XIII); and 6) acylating the compound of formula (XIII) with tert- butyldimethylsilyloxy amine (NH2OTBS) and removing the tert- butyldimethylsilyl group from the resulting product with a water-soluble inorganic acid to obtain the compound of formula (I):
Figure imgf000156_0001
Figure imgf000157_0001
wherein,
Ri is axyloxy or arylmercapto;
R2 is phenyl which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, Ci_5 alkyloxy, Ci_5 alkyl, Ci-5 alkylamino, cyano, cyanophenyl and mercaptoalkyl; or heteroaryl selected from the group consisting of piperazine, triazole, thiazole, benzothiazole, dibenzofurane, pyridine, quinoline and isoquinoline, the heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1.5 alkyloxy, amino C]_5 alkyloxy, Cμ5 alkyl, amino Ci_5 alkyl, Cμ5 alkylamino, aryl Cμ5 alkylamino and aryloxy Ci-5 alkylamino; and
R3 is hydroxyamino.
9. The method of claim 8, wherein step 2) is carried out in acetone solvent in the presence of an organic or inorganic base, and the nucleophilic agent is arylalcohol or arylmercaptan.
10. The method of claim 8, wherein the ECC treatment in step 3) is carried out in tetrahydrofbran over an ice bath.
11. The method of claim 8, wherein step 5) is carried out in an aqueous alcohol solution, and the inorganic base is lithium hydroxide or sodium hydroxide.
12. The method of claim 8, wherein step 6) is carried out in N5N- dimethylformamide solvent in the presence of N-methansulfonyloxy-6- trifluoro benzotriazole, and the water-soluble inorganic acid is hydrochloric acid or sulfuric acid.
13. The method of claim 8, wherein the compound of formula (XII) is obtained in step 4) by reacting the compound of formula (XI) with tetrabromomethane (CBr4) in the presence of triphenylphosphine (PPh3) to form methyl bromomethylpropenylbenzoate and refluxing the resulting product together with an arylamine or arylalkylamine.
14. The method of claim 13, wherein the amine reaction is carried out in acetone or acetonitrile in the presence of potassium carbonate.
15. A method for preparing the compound of formula (I), which comprises the steps of:
1) reacting the compound of formula (IV) with a nucleophilic agent (RiH) to obtain a compound of formula (X);
2) hydrolyzing the compound of formula (X) in trifluoroacetic acid (TFA) to form a methyl carboxypropenylbenzoate, which is then treated with ethyl chloroformate (ECC) and reduced with sodium borohydride (NaBH4) to obtain a compound of formula (XI); 3) reacting the compound of formula (XI) with tetrabromomethane
(CBr4) in the presence of triphenylphosphine (PPh3) to form a methyl bromomethylpropenylbenzoate, which is refluxed together with an arylamine or arylalkylamine to obtain a compound of formula (XII); 4) treating the compound of formula (XII) with an inorganic base to obtain a compound of formula (XIII); and
5) acylating the compound of formula (XIII) with tert- butyldimethylsilyloxyamine (NH2OTBS) and removing the tert- butyldimethylsilyl group from the resulting product with a water-soluble inorganic acid to obtain the compound of formula (I):
Figure imgf000159_0001
wherein,
Ri is arylimido, alkylimido, arylamido, alkylamido or arylsulfonamido; R2 is phenyl which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, Ci „5 alkyloxy, Cμ5 alkyl, C1.5 alkylamino, cyano, cyanophenyl and mercaptoalkyl; or heteroaryl selected from the group consisting of piperazine, triazole, thiazole, benzothiazole, dibenzofurane, pyridine, quinoline and isoquinoline, the heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C i_5 alkyloxy, amino Cj-5 alkyloxy, Cμ5 alkyl, amino C1.5 alkyl, C1.5 alkylamino, aryl C\.5 alkylamino and aryloxy C1.5 alkylamino; and
R3 is hydroxyamino.
16. The method of claim 15, wherein step 1) is carried out using an organic or inorganic base, and the nucleophilic agent is selected from the group consisting of alkylamide, arylamide, alkylimide, arylimide or arylsulfonamide.
17. The method of claim 15, wherein step 2) is carried out in tetrahydrofuran over an ice bath
18. The method of claim 15, wherein the amine reaction in step 3) is carried out in acetone or acetonitrile in the presence of potassium carbonate.
19. The method of claim 15, wherein step 4) is carried out in an aqueous alcohol solution, and the inorganic base is lithium hydroxide or sodium hydroxide.
20. The method of claim 15, wherein step 5) is carried out in N5N- dimethylformamide in the presence of N-methansulfonyloxy-6-trifluoro benzotriazole, and the water-soluble inorganic acid is hydrochloric acid or sulfuric acid.
21. An anti-cancer composition comprising the compound of formula (I) of claim 1 as an active ingredient and a pharmaceutically acceptable carrier.
22. A pharmaceutical composition for preventing or treating a disease caused by excessive histone deacetylase activity, comprising the compound of formula (I) of claim 1 as an active ingredient and a pharmaceutically acceptable carrier.
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